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OMICS Group eBooks

Bedside Critical Care Guide

Edited by
Ramzy H Rimawi


Bedside Critical Care Guide

Edited by: Ramzy H. Rimawi
Published by OMICS Group eBooks
731 Gull Ave, Foster City. CA 94404, USA

Copyright 2014 OMICS Group

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First published January, 2014
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Critical care medicine is an intriguing, rapidly evolving medical field aimed
to support and restore productive lives in seriously ill patients. Critical care
specialists often seek up-to-date, evidence-based literature applicable at the
patient bedside for common and uncommon disorders encountered in the
intensive care unit (ICU). In this review of adult critical care medicine, we provide
a comprehensive guide of bedside ICU principles and best practice standards.
East Carolina University has a 24-bed medical ICU (MICU), a 24-bed
cardiac ICU (CICU), and a 24-bed surgical ICU (SICU). The MICU commonly
admits critically ill patients with infectious disease, central nervous system,
respiratory, metabolic and endocrine, hematologic, oncologic, gastrointestinal,
environmental, obstetric, pharmacologic disorders and renal disorders. Our
CICU typically admits patients suffering from myocardial infarctions, congestive
heart failure, arrhythmias, cardiogenic shock and post-cardiovascular surgical
complications. The SICU cares for patients with surgical and trauma related
Currently, critical care is a multidisciplinary specialty that includes many
subspecialties of medicine, surgery and anesthesiology. I have personally
asked the contributing authors of multidisciplinary departments at East Carolina
University, including critical care medicine, pulmonology, infectious diseases,
nephrology, cardiology, and trauma. The contributing authors and I thank OMICS
for their assistance is publishing this text.

Thank you,
Ramzy H Rimawi

About Editor

Dr. Ramzy Rimawi earned his BA in English and Biology at the State
University at Stony Brook. He then earned his medical doctorate degree
from Ross University School of Medicine. After completing his Internal
Medicine residency training, he pursued a fellowship in Infectious Diseases
followed by Critical Care Medicine at East Carolina University for the Brody
School of Medicine. His passion for critical care lies in its rapid physiologic
and complex reasoning often in the face of uncertainty. His clinical interests
are nosocomial infections in the ICU, antibiotic stewardship, infection
control and HIV.

Dr. Ramzy Rimawi has established himself as not only a competent clinician,
but also quickly becoming a leader in the field of infectious disease and critical
care medicine. At a young age he has been very successful in publishing several
articles in his field of practice and continues to contribute to the progression of
science and medicine. He has presented and been recognized for his work
at a national and local level. He has board certifications in Internal Medicine,
Infectious disease medicine and currently completing his training in critical care
Bowling Mark
I had the pleasure to work with Dr. Ramzy over the past 3 years. He is a great
example of ambition, dedication, hard working and a great team player. His
shinning mind has brought our department to a whole new level. I have no doubt
that he will be an exceptional physician. Bringing the critical care to bedside and
presenting it in such simplified way to assist other medical providers is a true
example of his thrives to provide a better care for patients.
Saadah Khalid
This is my first year working with Dr. Rimawi. During my time with him, I
have found him to be very smart and hardworking. He is an ardent supporter
of antibiotic stewardship, has worked a great deal in the use of procalcitonin
assay, and his work in the field of Penicillin allergy skin testing to help choose
appropriate antibiotics is remarkable.
Dr. Rimawi has taken a lot of initiatives to help improve the healthcare at our
hospital. He is very active academically and has worked on multiple research
projects and publications. The initiative he took to get this eBook published is a
testament to his academic inclinations.
The idea of a bedside ICU eBook was excellent, especially with the limited
availability of content at the graduate medical education level for residents. The
book had to be something that was evidence based, concise and practical, and
easy to understand. I am sure this book meets the above requirements and will
be of great benefit to all.
Nazia Sultana

Ramzy Rimawi and I both did our training in Infectious Diseases together at
East Carolina University for the Brody School of Medicine. While there, Ramzy
has been great mentor that helped oversee my fellowship training as a chief
fellow and research career. We presented several oral and poster presentations
at national and international conferences together. We have successfully
published several articles in well-recognized, peer-reviewed journals on topics
such as MRSA screening in an ICU setting, tularemia, and infectious disease/
critical care practitioner collaboration. But other than being great academic
partner, Ramzy and I have been great friends. It was an honor to be able to work
with him on this e-Book and I look forward to future joint collaborations with him
and OMICS.
Kaushal B Shah
I am pleased to write about Dr Ramzy Rimawi. I have known Dr. Rimawi since
July 2013 as a colleague at ECU Brody School of Medicine (BSOM). He has
extensive fund of knowledge and practices evidence based medicine. He is
very well respected as a finest clinician, avid clinical researcher and mentor for
fellows/house staff at Vidant Medical Centre.
Dr Rimawi has done a great effort in compiling Bedside Critical Care Guide
as excellent evidence based guide for house staff and busy clinicians.
Manjit Singh Dhillon
Dr Rimawi is an outstanding clinician with excellent bedside manners. He has
demonstrated an ongoing commitment to research as well as teaching, and this
book will go a long way in furthering the understanding of critical illness and its
Abid Butt
It was a great experience for me to write the chapter on scoring systems in
critically ill patients. I thank Dr Ramzy Rimawi for the opportunity of writing the
chapter. He is a great physician and person.
Ogugua N Obi

I am pleased to say that the contributors have provided information
that was accurate, up-to-date, evidence-based and unbiased. I would like
to express my sincere appreciation to them for their generous, voluntary
Ramzy H Rimawi

The chapters in this eBook include topics from cardiology, nephrology,
pulmonary, infectious disease (including sepsis), neuro-critical care,
burns, and gastroenterology. Highly specialized topics have been left to
qualified authors of other specialty texts. Each chapter is meant to provide
pertinent clinical, diagnostic, and management strategies when caring for
critically ill patients. The chapters are relatively brief, clinically relevant
and evidence-based according to currently accepted literature. References
are provided for readers wanting to explore subjects in greater detail. I
have edited and revised the content and style of each chapter so as to
unify the voice of the entire text.

Chapter 1: Principles of Mechanical Ventilation
Chapter 2: Management of Common Respiratory Disorders in the ICU: Asthma,
Chapter 3: Bedside approach to Gastrointestinal Bleeding in the Intensive Care Unit

Page #

Chapter 4: Renal Disorders in the ICU


Chapter 5: Nutritional Support in an ICU Setting


Chapter 6: An ICU Bedside Review of Burns


Chapter 7: Management of Common Neurocritical Care Disorders


Chapter 8: ICU Delirium - Attention to Inattention


Chapter 9: Approach to Fever In the Intensive Care Unit


Chapter 10: Bedside Fundamentals of Pneumonia in the ICU


Chapter 11: Antibiotic Therapy in Sepsis


Chapter 12: ICU Infection Control and Preventive Measures


Chapter 13: Bedside Management of Shock


Chapter 14: Acute Myocardial Infarction in an ICU


Chapter 15: Heart failure in an ICU


Chapter 16: Critical Care Scoring Systems and Checklists


Principles of Mechanical Ventilation

Robert A Shaw*
Critical Care & Sleep Medicine, Section of Pulmonary, Department of
Internal Medicine, Brody School of Medicine, East Carolina University,
*Corresponding author: Robert A. Shaw, Critical Care & Sleep
Medicine, Section of Pulmonary, Department of Internal Medicine,
Brody School of Medicine, East Carolina University, Brody 3E-149,
Greenville, NC 27834, USA, Tel: 252-744-4650

In this chapter, you will learn basic pulmonary physiology necessary to understand the modes of mechanical ventilation. You will
then learn how these ventilator modes can be applied in the different types of respiratory failure. Using ventilator monitoring to trouble
shoot patient/ventilator asynchrony problems will be discussed. Finally clinical cases to illustrate teaching points will be presented.

Basic Respiratory System Mechanics and Pathophysiology

In the spontaneously breathing patient, downward movement of the diaphragm during inspiration generates negative pressure
in the chest relative to atmospheric pressure, and air moves from the atmosphere into the lungs. In spontaneously breathing patients
on mechanical ventilators, positive pressure from the ventilator assists this effort by the patient and reduces the work the patient
must do to inhale a given tidal volume. In patients who have respiratory failure, the ventilator reduces the work of breathing and
aids in inflating the lungs. The work of breathing is related to a pressure-time product, which is the pressure needed to inflate the lungs
multiplied by the time of inspiration. For our purpose, we will assume that expiration does not involve significant work by the patient. The
pressure which is needed to drive air into the lungs is related to the resistance and compliance of the system. Resistance is increased by
narrowing of the airways or narrowing of the endotracheal tube, which can occur if a patient bites on the tube or secretions collect on
the inside. Calculation of resistance, which modern ventilators can estimate, is related to pressure/ flow (R= P/Flow). Compliance
is simplistically understood as the work needed to inflate a balloon. Stiff balloons like stiff alveoli require more pressure to inflate.
Compliance = volume/pressure [1]. Compliance is the opposite of elastance, thus alveoli with high elastance have low compliance.
There are 2 components of compliance: compliance related to the alveoli and compliance related to the chest wall. Diseases which cause
low compliance of the lungs include fibrosis, interstitial edema, and pneumonia. Conditions in which there is low chest wall compliance
include abdominal distention, pleural effusion, or obesity. The following image demonstrates how at low lung volumes compliance is
low, but as the lungs are inflated compliance increases.

It is also important to know that diseased lungs are heterogeneous, and there are areas with low compliance (severely injured
areas) and high compliance (emphysema), and also areas with high resistance (bronchospasm) and less resistance. If the physician
orders a high tidal volume to be delivered by the ventilator, that volume may go mostly to the more compliant (normal) part of the
lung and cause over distention and injury to that part of the lung. This is called volutrauma and is why lower tidal volumes (6-8 mL/
kg/IBW) are recommended in patients with ARDS. Lower tidal volumes (i.e. 4 mL/kg/IBW) have also been described). Positive end
expiratory pressure (PEEP) is used to inflate the lungs and usually improves the compliance by putting the lung in a more favorable
place on the pressure volume curve seen in Figure 1 [2]. A sudden drop in compliance would be manifested by the ventilator graphics
showing a higher pressure at the end of both inspiration and expiration and sudden drop in tidal volumes. This could be seen with a

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Figure 1: Compliance in Relation to Pressure and Volume.


Mechanical Ventilation Principles

As mentioned above, a mechanical ventilator assists breathing and inflates lungs by delivering oxygen enriched air into the lungs.
The ventilator will target either pressure or volume in doing this. In spontaneously breathing patients, each breath will be triggered by
a change in pressure or flow in the circuit. Each inspiration will be cycled off by either a time limit or decrease in flow. Let us make this
terminology understandable so that you will know what different modes of ventilation mean.
A. Volume targeted ventilation: When patients are intubated, usually a volume targeted mode is initiated. This is because you
would like to assure that the patient is receiving an adequate tidal volume with each breath. In volume targeted ventilation, the therapist
tells the ventilator to deliver a given volume, say 500 ml. The therapist sets a flow rate and the machine delivers the gas at that flow rate
until the desired volume is given. The machine times how long it takes to give that volume. This is commonly called assist control mode
(AC). In more modern ventilators, a microprocessor looks at previous breaths, and if they have been below the target, it will increase the
pressure and inspiratory time to reach the targeted tidal volume. An example of this mode is: pressure regulated volume control (PRVC)
or sometimes called APV-CMV. With this mode of ventilation, the patient can trigger the breath or if the patient has no drive to breath
a back- up rate is set to insure that a minimum number of breaths occur each minute.
B. Pressure targeted ventilation: In this mode, the therapist tells the ventilator to deliver the gas at a given inspiratory pressure
above the PEEP. Breaths are generated by the patient or the machine and the machine then delivers the gas with a high flow rate until
the targeted pressure is achieved. Note that there is no guarantee of a set tidal volume. If compliance drops or resistance increases,
the patient will receive a lower tidal volume. Examples of pressure targeted modes are: pressure support ventilation (PSV), pressure
control (PC), and airway pressure release ventilation (APRV). In reality, when a therapist is doing PSV, the inspiratory pressure is set so
the patient receives tidal volumes that are comfortable for the patient. The work of breathing is reduced and the patient breaths with a
lower respiratory rate. For example, if a patient is tachypneic with low tidal volumes on PSV, the therapist would usually increase the
pressure support so the patient receives higher tidal volumes and becomes less tachypneic. It is important to realize that with PSV, the
patient must trigger each breath, and this mode is not appropriate for patients who have no drive to breath or cannot generate a breath
due to paralysis. Pressure control mode is a mode in which the therapist sets the time for inspiration and expiration. Patients are heavily
sedated or paralyzed.
C. Airway pressure release ventilation: Another pressure targeted mode, which is often used in patients with ARDS, is airway
pressure release ventilation (APRV). This mode is similar to having a patient on continuous airway pressure (CPAP) with intermittent
drops in the pressure. APRV holds the alveoli inflated (during P HIGH), except for the brief releases (P LOW) and recruits (opens)
alveoli similar to higher PEEP, as illustrated in Figure 2 [3]. It is used to reduce shunt and improve oxygenation in patients with ARDS.
The following graphic illustrates the physiology of APRV:

Figure 2: Airway pressure release ventilation vs Conventional Volume-Targeted Ventilation.

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D. Combined pressure and volume targeted ventilation: Some ventilators can target either pressure or volume with delivered
breaths. An example of this is synchronized intermittent mandatory ventilation (SIMV). In this mode, some breaths are triggered by
the patient initiating a breath and some are time cycled by the ventilator. The therapist tells the ventilator to give a minimum number
of breaths/minute. These are the intermittent mandatory breaths, and they are volume targeted. The ventilator also allows the patient to
trigger breaths spontaneously and these breaths are pressure supported. Graphically this is shown in Figure 3:

Figure 3: Synchronized Intermittent Mandatory Ventilation.


If the ventilator is set on SIMV mode and the therapist tells the machine to do 6 intermittent mandatory breaths/minute with tidal
volume 400 cc and pressure support of 15 cm H2O, then the patient will receive a 400 cc tidal volume every 10 seconds synchronized with
the patients effort. Other patient initiated breaths will be pressure support breaths with 15 cm pressure.

Positive End Expiratory Pressure (PEEP)

PEEP is the pressure that the ventilator maintains at the end of exhalation. When you see a patient with COPD doing pursed lip
breathing, he/she is exhaling against pursed lips, which is creating a small amount of PEEP. PEEP helps to prevent atelectasis and
also opens previously closed alveoli. It recruits alveoli and can improve oxygen entering into the capillaries supplying those alveoli.
Increasing PEEP will usually improve compliance (unless the lung is over distended) and improve oxygenation. It also helps to reduce
atelectrauma, which is lung injury caused by repeated closure and opening of alveoli. There are tables which help in setting the amount
of PEEP to use but in reality, most physicians gradually increase PEEP so that the inspired FiO2 is <0.6 with a pO2 >60. In patients with
very low compliance, such as severe obesity, higher PEEP is really effective in opening the lungs and improving oxygenation. In ARDS
patients PEEP is often as high as 20 cm H2O and in obese patients PEEP is sometimes as high as 30-35 cm H2O. Some centers insert an
esophageal balloon in patients in order to measure transpulmonary pressure (TPP) and set the PEEP high enough so that TPP is positive.

Weaning from Mechanical Ventilation or Liberation from Mechanical

Assuming that the underlying cause of the respiratory failure has been improved, one then considers transition to having the patient
assume more of the work of breathing and ultimately being liberated from mechanical ventilation. Spontaneous breathing trials (SBT)
are conducted to evaluate the readiness of the patient to be extubated. Before starting an SBT, the patient should be alert and able to follow
simple commands. The patient should be adequately oxygenated with FiO2 of 0.4 or less and PEEP should be <10. The exception to this
is in obese patients, who often are on higher PEEP amounts to maintain inflation of the lungs. Usually patients are on pressure support
mode and respiratory rate is <24 before considering an SBT. Most physicians and therapists will calculate the rapid shallow breathing
index (respiratory rate/tidal volume) and if <105 it is reasonable to do an SBT. An SBT means the patient is on minimal PS (5 cm H2O)
or just on T Bar (oxygen but no positive pressure). A successful SBT means the patient breaths spontaneously for >30 minutes with
respiratory rate <35 breaths/minute, O2 sat> 90%, heart rate increase of <20%, no significant change in blood pressure, and no severe
anxiety. Before removing the tube, the patient should be able to protect the airway and clear secretions effectively. If the patient fails the
SBT, then he/she is placed back on mechanical ventilation (usually PS mode) for 24 hours and the underlying problems are addressed
further. This often requires diuresis and/or antibiotics to treat an infection. Patients with COPD sometimes fail the SBT because of
weakness of the respiratory muscles, and they should be rested on adequate PS so that they are not tachypneic.

Noninvasive Positive Pressure Ventilation NIPPV

This refers to positive pressure ventilation via a mask rather than insertion of an endotracheal tube. Endotracheal intubation can have
the following complications: trauma to airway, infection due to bypassing the airway defenses, discomfort, need for sedation and pain
control. While NIPPV can be uncomfortable, it reduces the risks of intubation. NIPPV, sometimes simply called noninvasive ventilation
(NIV), can deliver a fixed pressure CPAP or a higher pressure during inspiration than during expiration (BIPAP bilevel pressure). CPAP
is used to treat diseases where the problem is simply oxygenation, such as pulmonary edema. BIPAP is used when there is a problem of
both ventilation and oxygenation, such as COPD, neuromuscular disease like amyotrophic lateral sclerosis, or obesity hypoventilation
NIPPV has improved outcomes in patients with obstructive disease such as COPD. It has also been beneficial in restrictive chronic
diseases such as kyphoscoliosis, obesity hypoventilation syndrome, and neuromuscular disease (amyotrophic lateral sclerosis). It
also has helped in patients with extubation failure. There are many contraindications to NIPPV including hemodynamic instability,
respiratory arrest, excessive secretions, agitated, unable to fit mask, or recent airway surgery. It can be time consuming for respiratory
care practitioners to work with the patient to help him/her get used to the device and find the right mask. Frequent assessment of the
patient is important, and if the patient is not breathing with a slower rate and improved oxygenation and ventilation after 2 hours, then
intubation will probably be necessary.
An Ideal patient, who would benefit from short term CPAP, would be one who comes to the emergency department with acute
pulmonary edema and needs help with oxygenation until diuresis occurs. Typically a pressure of 10-12 cm H2O is used. An ideal patient,
who would benefit from BIPAP would be one with COPD exacerbation and labored breathing that is hypercapnic. BIPAP at 14/8 cm
H2O would help reduce the work of breathing while bronchodilators and steroids start working. A COPD patient who is extubated and
is working hard to breath might also benefit by avoiding re-intubation. There are complications from NIPPV including: mask discomfort,
air leaking, aspiration, failure to ventilate, and pneumothorax. Patients should always have head of bed elevated and be monitored with
oximitry and EKG.

Case 1: A patient with COPD has been converted from a volume targeted mode to a pressure targeted mode, pressure support. The
therapist places the patient on PS 12/5 cm pressure with FiO2 of 0.4. The patient has a RR of 35 breaths/minute, O2 sat is 93%, and tidal
volumes are 200 cc-260 cc. Arterial Blood Gas: pCO2 45, pO2 75, pH 7.38. What would you recommend?
Case 2: A patient with diffuse infiltrates caused by sepsis and fluid resuscitation is on a volume targeted mode, PRVC. The ventilator
has the following settings: target tidal volume 400 cc (6 cc/kg IBW), FiO2 0.8, set rate 8/minute, PEEP 20cm H2O. ABG: pCO2 38, pO2
50, sat 82%, pH 7.36. What options do you have?
Case 3: A patient with COPD is on a volume targeted mode, PRVC. Target tidal volume is 500cc, FiO2 0.4, PEEP 5. He has become
very tachypneic and is fighting the ventilator. You notice that he is trying to breathe with his abdomen protruding 40 times per minute but
the ventilator is only delivering 20 breaths/minute. The following graphic is noted (the patient in blue, normal in red). Why is the patient
not getting a breath with every effort? What is the problem?

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Cases to Illustrate Common Ventilator Related Problems


Figure 4: Graphic for Case 3.

Case 4: A patient was on volume mode, PRVC, and was improving so you decide to put him on pressure support mode (PSV) to see
if he could do a spontaneous breathing trial and be weaned. On the PRVC mode, the set rate was 14/breaths/minute and the patient was
breathing 14 breaths/minute. ABG: pCO2 34 pO2 70 pH 7.48. After being placed on PSV, the nurse calls and reports the patient has long
apnea periods. What is the problem and what would you do?
Case 5: A patient is on PRVC mode and suddenly becomes tachypneic and airway pressures increase. The ventilator graphic
shows that the difference between the peak airway pressure and the plateau pressure (pressure when expiratory hold is prolonged) has
decreased significantly. This is shown below:

Figure 5: Graphic for Case 5.

Discussion of Cases 1-5

Case 1: This COPD patient is very tachypneic with low tidal volumes on PSV 12/5. Many events could cause tachypnea, including
pulmonary embolism, sepsis, pneumothorax, or metabolic acidosis. The most often cause of this, however, would be that the patient is
not getting enough help from the ventilator. Patient needs more pressure support. After examining the patient, it would be appropriate
to increase the PS to 16 and see if that corrected the tachypnea and labored breathing. Remember that with mechanical ventilation, we
are trying to partially unload the breathing muscles but do not want to excessively work them. It is not known exactly how much work
to impose on the patient, but tachypnea (RR>30) often is a sign of fatigue of respiratory muscles. Exhausting the muscles will prolong
weaning in a COPD patient.

Case 3: You should note on the graphic that even at the end of exhalation, the patient has flow continuing. In a normal patient, all
of the air is exhaled and flow goes to 0 at end exhalation. When there is continuing flow at the end of exhalation, which means there is
air trapping and auto-PEEP. Auto Peep means there is pressure in the alveoli at the end of expiration because not all of the inspired gas
was exhaled. Remember that in order to trigger the ventilator the patient must generate about 2 cm of negative pressure below the set
PEEP. If, for example, there is 6 cm of auto-PEEP the patient will have to generate negative 8cm pressure to trigger the next breath. In a
hyper-inflated COPD patient that may be impossible. This patient is not triggering the ventilator due to auto-peep. The solution to this
includes bronchodilators, reducing the tidal volume, sedation of patient to slow the respiratory rate and allow more time for exhalation,
or increasing the inspiratory flow rate so as to give longer exhalation time [4]. When auto-peep is severe, it is best to disconnect the
patient from the ventilator to let trapped air to escape and bag the patient for a few minutes.
Case 4: On the PRVC mode this patient is on a rate of 14. This is really a back-up rate meaning the patient will receive a minimum
of 14 breaths/minute, even if the patient is apneic. This patient is riding the rate and is not breathing over the rate. The ABG indicates
respiratory alkalosis, which will reduce the drive to breath. When the patient is changed to PSV, there is no back up rate, and since the
drive to breath has been reduced by the respiratory alkalosis, the patient has apneas. You could just let the apneas continue and the
patients pCO2 will rise, and then the patient will have increased ventilatory drive. Another option would be to put the patient back on
the PRVC mode but decrease the rate to a more appropriate rate, say 6. The patient will eventually start breathing over the rate and then

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Case 2: This patient has severe ARDS with a pO2/FiO2 ratio of 62. Patient has hypoxemia with low oxygen saturation, and that will
reduce oxygen delivery to the tissues. You would like to increase saturation to >90%. Option 1 would be to increase the FiO2, but that
is not the best option because of potential oxygen toxicity. You would like to recruit lung in order to better oxygenate the patient and
reduce FiO2. Since the patient is already on 20cm PEEP, which is about as high as is generally done (except in patients with obesity or
low chest wall compliance), raising the PEEP further is not a good option. This is a situation where changing the mode to airway pressure
release ventilation (APRV) would be appropriate. On this mode, the mean airway pressure would increase and areas of collapsed alveoli
would open up. Changing to this mode will often reduce the shunt fraction and oxygenation of blood will improve. This often takes 6-12
hours to work, so do not expect immediate improvement in ABG. You may want to also increase the FiO2 temporarily to insure adequate
oxygenation of the patient. The respiratory care practitioner will help in deciding the best P high and P low.


can be put back on PSV. In patients like this narcotics/sedatives should be reduced because that can cause apneas. In a few patients,
too much oxygen can reduce drive to breath, and FiO2 should be reduced. This is often the case in obesity hypoventilation syndrome
Case 5: It is important to know that airway resistance is related to the difference between the peak airway pressure and the plateau
pressure. In this graphic that difference is higher in the graphic on the left (patient in trouble) than the graphic on the right (patient doing
well). Thus the patient in trouble on the left has higher airway resistance than the patient on the right, possibly due to bronchospasm or
mucous in the endotracheal tube. In this case, you would be sure the tube is clear and it is easy to pass suction catheter. Bronchodilators
would help if there is wheezing and bronchospasm. If both the peak pressure and plateau pressure suddenly increase by the same
amount, then there has been a drop in compliance (pneumothorax could cause that).

Respiratory failure usually occurs because there is high airway resistance or low compliance. Less common is decreased drive to
breath, such as with benzodiazepine or narcotic ingestion. The high work of breathing can be relieved by either non-invasive positive
pressure ventilation, NIPPV (COPD exacerbation or pulmonary edema), intubation with volume targeted mode (assist control or
PRVC), or intubation with pressure targeted mode (pressure support or airway pressure release ventilation). Positive end expiratory
pressure (PEEP) is used to recruit alveoli and improve oxygenation. When the underlying problem has been corrected, the patient should
be evaluated for liberation from mechanical ventilation with a spontaneous breathing trial.

1. MacIntyre NR, Branson RD (2009) In: Mechanical Ventilation. (2ndedn), Saunders Elsevier, St. Louis, USA.
2. Berne RM, Levy MN (1999) In: Berne & Levy Principles of Physiology. (3rdedn), Mosby, USA.
3. Habashi NM (2005) Other approaches to open-lung ventilation: airway pressure release ventilation. Crit Care Med 33: S228-240.

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4. Dhand R (2005) Ventilator graphics and respiratory mechanics in the patient with obstructive lung disease. Respir Care 50: 246-261.


Management of Common
Respiratory Disorders in the ICU:
Asthma, COPD, and ARDS
Mark A Bowling1* and Hunter A Coore2
Assistant Professor of Medicine, Brody School of Medicine, East
Carolina University, Greenville, USA

Chief Resident/Clinical Instructor, Brody School of Medicine, East

Carolina University, Greenville, USA

*Corresponding author: Mark R Bowling, Assistant Professor

of Medicine, Brody School of Medicine - East Carolina University,
Department of Internal Medicine, Division of Pulmonary, Critical Care
and Sleep Medicine, 3 E-149 Brody Medical Sciences Building, 600
Moye Blvd., Mail Stop 328, Greenville, NC, USA, Tel: 278834-4354;
Off: 252-744-4650; Fax: 252-744-1115; E-mail:

Source of Funding/Conflicts of Interest: Author Mark A Bowling has a potential conflict of interest

with Covidien Surgical Solutions (consultant). Covidien Surgical Solutions was not involved in the production of this manuscript.
Dr. Hunter Coore does not have financial disclosures to report. None of the authors have received any source(s) of funding for this
manuscript. The corresponding author, Mark A. Bowling, had full access to all the data in the study and had final responsibility for the
decision to submit for publication.

Pulmonary disorders are frequently encountered in the intensive care unit (ICU). Complications of asthma, chronic obstructive
pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS) are three of the most common respiratory disorders faced
by the ICU physician. This chapter will focus on the basic ICU management for these pulmonary disorders.

Keywords: ARDS; Asthmaticus; COPD exacerbation; Hypercapnia; Status respiratory failure

Respiratory disorders are a common problem faced in the intensive care unit. In this section we will discuss three of the most
common pulmonary disorders seen in critical care medicine; this includes chronic obstructive pulmonary disease (COPD) exacerbation,
acute asthma, and acute respiratory distress syndrome (ARDS).

Chronic Obstructive Pulmonary Disease Exacerbation

Chronic obstructive pulmonary disease (COPD) is characterized by persistent non-reversible airflow obstruction due to destruction
of the distal airways from local inflammation as a result of exposure to noxious particles and gases (mostly from tobacco abuse). This
permanent change in lung structure coupled with chronic inflammation leads to a progressive decline in lung function, abnormal
gas exchange, pulmonary hypertension, air trapping (inability to deflate the lung), increased sputum production, skeletal muscle
wasting and cachexia [1]. The Global Initiative for Chronic Obstructive Lung Disease (GOLD guidelines)defines COPD as a ratio of
forced expiratory volume in 1second (FEV1) over forced vital capacity<0.70 (FEV1/FVC<0.70) [1]. The severity of airflow obstruction
measured by spirometry is based on the measurement of the FEV1:

The Center for Disease Control and Prevention (CDC) in 2011 reported that COPD was the third leading cause of death in the
United Statesand approximately fifteen million people have been diagnosed with the disease [2]. It is has been predicted that in 2020
it will be the 3rd leading cause of mortality worldwide and the 5th leading cause of burden of disease [3,4]. Many of the patients that
are diagnosed with COPD will have acute symptoms of the disease termed exacerbations. In the United States, acute exacerbations of
COPD (AECOPD) are responsible for about 500,000 admissions to the hospital yearly, with half of these admissions requiring ICU
level care [4]. The mainstays of therapy for AECOPD include the maintenance of adequate oxygenation and ventilation, bronchodilator
therapy, corticosteroids and antibiotics [5]. Below we will describe the definition, risk factors and therapy in the care of patients with
these exacerbations.

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Stage 1 = mild (FEV1>70 ml)

Stage 2 = moderate (FEV1 50-70 ml)
Stage 3 = severe (FEV1 30-50 ml)
Stage 4 = very severe (FEV1 <30)


Definition and risk factorst

COPD exacerbations are defined by the GOLD criteria as an increase in the frequency or severity of a cough, worsening dyspnea and
a change in character or volume of sputum production [1]. There are several identifiable predictors for patients at risk for COPD, which
include: the duration of COPD diagnosis, number of hospitalizations, sputum production, steroid use, antibiotic use, and co-morbidities
(cardiovascular disease) [6]. Additionally, those with GOLD Stage 3-4 are at an increased risk for exacerbations [1].

Clinical presentation and initial evaluation

Patients experiencing an AECOPD may present with several complaints and symptoms, including increased dyspnea and cough,
worsened hypoxemia, hypercapnia (resulting in an acute metabolic acidosis), mental status changes, and symptoms related to a primary
issue such as pneumonia, cardiovascular events, arrthymias, and organ failure [7]. Many of these patients will require ICU admission
[7]. The initial approach in the care of these patients starts with a history and physical examination focusing on potential causes of the
exacerbation (infections, cardiac events) and evidence of impending respiratory failure. It is important to remember that many of these
patients will have significant co-morbidities, which may add to the complexity of the situation. For example, it is rare that a patient with
COPD and heart failure will present with just heart failure or COPD symptoms alone, it is usually a combination of both. Therefore, both
problems need to be addressed. A quick evaluation of the patients ability to maintain adequate oxygenation and ventilation is necessary
and pertinent. The following may help in this assessment:

Oxygen saturation <88% on room air

Use of accessory muscles
Increase respiratory rate
Inability to talk clearly due to difficulty breathing
Mental status changes and evidence of inability to adequately protect the airway (i.e. decrease gag reflex).
Arterial blood gas demonstrating hypoxia and hypercapnia with an acute respiratory acidosis

If there is concern that the patient cannot adequately protect the airway or experiencing significant hypercapnic respiratory failure,
either endotracheal intubation or non-invasive mechanical ventilation should be considered immediately. If airway protection is of a
concern, non-invasive mechanical ventilation should not be utilized. Other studies to consider include a chest roentogram (to evaluate
for lung parenchymal abnormalities such as pneumonia, pneumothorax, or pulmonary edema, etc.), measurement of arterial blood gas,
and appropriate studies focusing on the underlying cause of the exacerbation.

Mechanical ventilation and Oxygen therapy

Non-invasive mechanical ventilation: Most patients with acute respiratory failure from a COPD exacerbation can be managed with
non-invasive positive pressure ventilation (NIPPV). NIPPV is considered first-line therapy for patients with COPD exacerbations that
have acute hypercapnic respiratory failure and no contraindications to NIPPV [1]. Several studies have reported improvement in clinical
outcomes such as a decrease in mortality, need for intubation, treatment failure, improvement in respiratory failure, and decreased
respiratory rate [8]. It is unclear as to what initial settings one should consider when treating these patients. An approach can be to place
these patients on a bi-levelventilator mode, triggered by spontaneous breathing. The inspiratory pressure is initially started at 10-12 cm
H2O and expiratory pressures at 5 cm H2O. The inspiratory pressure is adjusted to ensure comfort and ventilator synchrony. The goal of
therapy is to relieve the work of breathing and increase ventilation. Attempt to correct the hypercapnia by following the change in pH to
near normal levels and not to a normal pCO2, since a majority of these patients have a baseline chronic hypercapnia.
Invasive mechanical ventilation: Some AECOPD patients, based on clinical judgment, require endotracheal intubation and
mechanical ventilation to maintain adequate oxygenation and ventilation. There are several different strategies for managing patients on
a mechanical ventilator with COPD and it is unclear if which particular strategy is best. However, it has beenwell describedthat liberation
from the ventilatorshould begin early to prevent muscle atrophy.
Oxygen therapy: Oxygen therapy and smoking cessation remainsa corner stone of COPD treatment. Best practices with oxygen
therapy are to observer the arterial hemoglobin saturation with pulse oximetry and maintain the level of approximately 90%, commonly
between 88-92%, but not higher [4].

Pharmacologic therapy

Ipratropium bromide

1) MDI: 18 mcg 2 puffs with spacer every 4 hours

2) Nebulizer: 500 mcg every 4 hours


1) MDI: 90mcg four puffs every 4 hours with a spacer

2) Nebulizer: 2.5 mg (dilute to 3 ml) every 4 hours

Ipratropium bromide & albuterol combination

1) MDI: (90 mcg albuterol/18 mcg Ipratropium) 2 puffs with a spacer every 4 hours
2) Nebulizer: (2.5 mg albuterol/0.5 mg ipratropium) in 3 ml vial every 4 hours
Table 1: Common dosing regimens in AECOPD

Glucocorticoids: Systemic corticosteroids have been shown to improve symptoms, lung function, and decrease hospital length of
stay [1,12]. The optimal dose and duration of glucocorticoids is unknown and may depend on the patients response to therapy. While
the consensus in the literature favors a moderate dose of steroids (30 to 40 mg daily), this may not pertain to critically ill patients [1].
Evidence suggests oral administration is just as efficacious as an intravenous route [13]. A commonly prescribed agent is 125 mg of
methylprednisolone every 6 hours for 72 hours followed by a 2-week oral taper starting at 60 mg [8]. Prolonged treatment leads to
increased adverse reactions from corticosteroids without improving efficacy, morbidity or mortality [12-15]. Hence, shorter tapering
regimens have been suggested starting witha standard 3-day intravenous regimen noted above followed by a 30 mg dose for 5-10 days.

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Bronchodilators: Short acting inhaled anticholinergic agents (i.e. ipratropium) and beta-agonist (i.e. albuterol) are the main
stay of therapy for AECOPD. Although they can be given separately or in combination solutions, several studies have demonstrated
thesignificant bronchodilatation when these agents are givenconcomitantlyversuseither agent being given alone [9-11]. These agents have
a rapid onset and can be administered in a nebulizer fashion or a metered dose inhaler (MDI) (Table 1). Evidence suggests that there is
no difference in the efficacy between nebulizer versus MDI with a spacer in the delivery of inhaled medication [1]. In the acute setting,
the nebulizer method may be easier for the patient to administer [1].


Antibiotics: There is a large and consistent beneficial effect of antibiotics in AECOPD patients admitted to an ICU [16]. Typical
bacteria isolates recovered in AECOPD patients include Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis
[17]. While mild-moderate AECOPD is usually treated with a conventional broad-spectrum agent (i.e. doxycycline, trimethoprimsulfamethoxazole and amoxicillin-clavulonate potassium), severe AECOPD usually includes a 3rd generation cephalosporin (i.e.
ceftriaxone) in combination with a macrolide (i.e. azithromycin) or a fluoroquinolone (i.e. moxifloxacin). Agents may be changed based
on community or institutional antibiogram and resistance patterns. While it may not provide efficacy in the ICU setting, influenza and
pneumococcal vaccines should be considered prior to hospital discharge.

Asthma is a chronic inflammatory disease of the airways similar to COPD in that patients typically have recurrent respiratory
symptoms such as cough, chest tightness, dyspnea and wheezing. The pathophysiology of asthma includes airway inflammation,
hyper-responsiveness, and remodeling resultingin completely reversible airflow obstruction either spontaneously or with therapy.The
severe airflow obstruction can result from bronchial constriction, edema, and/or secretions from inflammation. In turn, this can lead
to air trapping (increasing intrathoracic pressure), hypercapnia, hypoxemia, and an increase in the work of breathing. If not treated
appropriately, the airflow obstruction can be permanent as a result of this alteration of the bronchial mucosa.
The CDC reports that 1 in every 12 adults have asthma in the US [18]. In the 2009, there were 1.9 million adult and child emergency
department (ED) visits as a result of asthma, of which 479,000 required hospital admission and 3,388 died (an age-adjusted death rate
of 1.1 per 100,000 population) [19]. Like COPD, asthma can have acute worsening of symptoms (exacerbations) and require ICU
admission. The major risk factors for a patient suffering from severe asthma include a slow onset of symptoms [20] and prior history of
poorly controlled or near fatal asthma [21-23].

Clinical presentation and initial evaluation

On physical exam you may find the patient in significant respiratory distress with inability to talk in full sentences or lie flat. An
increase in the respiratory rate is often observed with use of accessory muscles. Pulsus paradoxicus (a significant decrease in systolic
blood pressure upon inspiration) is often present in severe cases as a result of an increase in the intrathoracic pressure from air trapping.
A chest roentogram may demonstrate hyperinflation and peak flow measurements may be significantly decreased from the patients
baseline values.

Pharmacologic therapy
The goal of therapy is to quickly reverse the significant airflow obstruction and inflammation with bronchodilators and glucocorticoids,
Inhaled beta-agonist: Short-acting -receptor agonists (i.e. albuterol) are the drugs of choice in acute asthma exacerbations and
quickly cause bronchial smooth muscle relaxation [24]. Long-acting beta-agonist is not typically used in these acute cases. Inhaled
MDI or aerosol delivery is preferred over oral or intravenousroute due to improved efficacy [25-27]. There does not appear to be any
difference in efficacy between the nebulized versus MDI with a spacer administration [28]. When giving these therapies one needs to be
mindful of the side effects of the -receptor agonists in high doses, these include tachycardia, tremor, and hyperglycemia and decreased
serum potassium. Dosing can either be recurring/cyclic or continuous: repetitive nebulizer treatments (2.5-5 mg dose) or in the case of
ventilated patients repetitive use of MDI (4-8 puffs of 90 g of albuterol per puff); continuously given as 1-hour nebulizer treatments
using 10-15 mg of albuterol.
Anticholinergic therapy: Inhaled anticholinergic agents (i.e., ipratropium) are recommended for acute asthma inED, but not
hospitalized, patients [29]. However, many studies have suggested that the combination of inhaled anticholinergics and beta-agonists be
utilized in ED patients with severe airflow obstruction since this combination results in a greater bronchodilation than either drug alone
[10,30,31]. When using ipratropium in combination with albuterol, the dosing is 0.5 mg every 20 minutes x 3 doses then every 2 to 4
hours as needed (nebulized). If using an MDI, the dose is 4-8 puffs (18 g per puff) in the same regimen.
Systemic steroids: The goal of using corticosteroids is to help reduce inflammation. It may take a few hours before it is effective and
therefore, the quick relief of bronchoconstriction by a short-acting beta-agonist and anticholinergic is important. Systemic steroids may
help improve long-term recovery by decreasing airways inflammation. Steroids are recommended in patients with severe acute asthma
and should be administered intravenously [29]. Based on expert opinion [32], the dosing should include intravenous methylprednisolone
(60-80 mg every 12 hours) followed by a transition to10-14 day course of oral steroids when the patient can tolerate oral medications.
Magnesium sulfate: Magnesium sulfate (2 grams administered IV over 20 minutes) may be helpful in acute asthma due to its ability
to relax bronchial smooth muscle [33]. Its use is recommended to patients with severe symptoms that have not resolved after one hour
of aggressive conventional therapy [29].

Approximately 4% of hospitalized asthmatics develop significant respiratory failure that requires endotracheal intubation and
mechanical ventilation [34]. This can be a very challenging problem to manage as they can develop various complications from securing
the airway to barotrauma from the mechanical ventilation. In this section, we will highlight some of the basic ICU principals in the airway
management and ventilation strategies for the patient with respiratory failure due to acute asthma.
Airway management: The decision to intubate is based on clinical judgment based on the patients ability to protect their airway
and maintain adequate oxygenation with supplemental oxygen and NIPPV. It is important to remember that the patients respiratory
issues can continue post-intubated and adding a mechanical ventilator may further complicate the problem. It is highly recommended
that experienced physicians and respiratory therapists treat patients with acute asthma. Additionally, it is also recommended that the
healthcare provider performing the intubation be experienced and trained in the management of patients with potentially difficult

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Respiratory failure


Non-invasive mechanical ventilation: NIPPV is an excellent option for patients that do not require immediate endotracheal
intubation or have a contraindication to NIPPV therapy [35-39]. Typically, a bi-level mode with inspiratory pressure starting at 10-12
cm H2O and expiratory pressures of 5-8 cm H2O is used and adjustments are made to increase ventilation and work of breathing. Of
importance is that if NIPPV is utilized, frequent monitoring is necessary for response to therapy and a declining respiratory status.
NIPPV should not be a substitute for the patient that requires endotracheal intubation and mechanical ventilation.
Invasive mechanical ventilation: Due to the physiologic consequences of significant airway constriction (airflow obstruction,
hypoxia, hypercapnia, air trapping) in asthmatic patients, the ventilator management can be very challenging and may result in
complications. General principles to consider in the ventilator management of these patients include dynamic hyperinflation as a result
of a prolonged expiration from constricted airways. This can be made worse by mechanical ventilation if the respiratory rate is not
spaced far enough apart allowing the inhaled gas time to escape before a second breathe is administered. This can cause a tremendous
amount of pressure in the chest, resulting in hypotension from a decrease in blood return to the right heart, worsening hypercapnia, and
barotrauma (pneumothorax, pneumomediastinium, etc.).
Strategies to decrease hyperdynamic inflation include [40]:
Increase the ventilator flow rate in order to decrease the inspiratory time and increase the expiratory time.
Decrease the respiratory rate, allowing the inhaled gas time to be exhaled.
Decrease the tidal volume, allowing less inhaled gas to be exhaled.
Adjunctive therapies: In some severe cases when oxygenation and ventilation cannot be achieved by conventional methods, other
therapies have been utilized in the management of acute asthma. Listed below is a brief description of these therapies. We recommend
that only those physicians that are familiar with the utility of these agents should administer these treatments
i. Heliox Therapy
Heliox is the blend of helium and oxygen that can be helpful by enhancing the delivery of oxygen and inhaled medication to the
distal airway in acute asthmatics [41]. It has a density less than air and can overcome the significant airway resistance in these patients
ii. General Anesthesia
Several different agents such as ketamine and isoflurane have been used in the management of these patients mostly due to their
bronchodilatation properties [45-47].

Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a common condition encountered in the ICU with an estimated 190,000 cases per
year in the United States [48]. Respiratory failure results from an acute inflammation resulting in diffuse alveolar damage, non-cardiac
pulmonary edema, poor lung compliance and significant hypoxemia. In general, there is an indirect (transfusion reactions, sepsis,
pancreatitis,) or direct (trauma, aspiration, pneumonia) insult to the lungs that results in diffuse alveolar damage from disruption
of the alveolar lining and capillary endothelium. In turn, this leads to alveolar edema and protein exudation coupled with a marked
inflammatory response consequentially resulting in fibrosis. The physiological effect of this damage manifests as abnormal gas exchange
due to ventilation perfusion disparities [49] and poor lung compliance [50] and pulmonary hypertension [51].

Clinical presentation and initial evaluation

The initial signs of ARDS are tachypnea and progressive hypoxemia. Physical exam may reveal manifestations of the initial insult
such as pneumonia, sepsis or trauma. Typically, the patient will have an increased respiratory rate, use of accessory muscles and diffuse
crackles upon auscultation of the lungs. There may be signs of peripheral cyanosis and poor perfusion if shock is present. The chest
roentogram is often unrevealing in the first few hours, but will eventually show dense bilateral infiltrates. As the disease progresses, the
patients hypoxemia often progresses to require mechanical ventilation.
Appropriate laboratory and radiologic studies should be directed to the underlying disease. For example, if pneumonia is suspected,
blood and sputum cultures may be appropriate. If the patient had significant trauma, radiologic studies should be directed to evaluate
the extent of the injury. It is imperative to evaluate the arterial oxygen and carbon dioxide tension with arterial blood gas monitoring
in all these patients.


Respiratory symptoms must occur or become worse within one week of the initial insult
Bilateral pulmonary opacities consistent with pulmonary edema on radiographic imaging (not be due to pleural effusions, lobar
or lung collapse, or pulmonary nodules)
The respiratory failure must not be due to cardiac failure or volume overload. This must be verified by an objective measure
such as (echocardiogram, pulmonary occlusion pressure, etc.) to exclude hydrostatic pulmonary edema if there is no risk factors
explain the ARDS.
Impaired oxygen exchange must be present as defined by the ratio of arterial oxygen tension to fraction of inspired oxygen
The severity of hypoxemia defines the severity of ARDS and associated mortality risk:

Mild (27% mortality risk): PaO2/FiO2>200mmHgbut 300 mmHg, [positive end-expiratory pressure (PEEP) 5 cm H2O]

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In 2011, an expert panel from an initiative of the European Society of Intensive Care Medicine endorsed by the American Thoracic
Society and the Society of Critical Care Medicine developed the Berlin definition of ARDS [52]. According to the Berlin ARDS definition,
all of the following criteria must be met:


Moderate (32% mortality risk): PaO2/FiO2 >100 mmHg but < 200 mmHg. [PEEP 5 cm H2O]
Severe (45% mortality risk): PaO2/FiO2 <100 mmHg [PEEP 5 cm H2O]

Initial therapy should focus on treating the underlying cause of ARDS (i.e. antibiotics for infections, reversing antidote for overdoses,
etc) and maintaining adequate gas exchange while minimizing complications that are common in patients with ARDS.
The following treatment modalities may be used:
Mechanical ventilation lung protective strategy:
Low tidal volume ventilation: In patients with ARDS, positive pressure ventilation may generate extreme pressure in the distal
airways due to the decrease in lung compliance from pulmonary edema, proteinaceous material, and fibrosis. This can lead to
further lung damage, resulting in worsened hypoxemia, pneumothorax, and pneumomediastinium (coined ventilator induced
lung injury and barotrauma). Therefore, the lung protective strategy approach to mechanical ventilation in ARDS patients is to
minimize the elevated distal airway pressure (displayed by the mechanical ventilator as the plateau pressure) by utilizing low
tidal volumes defined as 6-8 mL/kg of ideal body weight [53]. Mortality is also reduced with low distal airway pressures (plateau
pressure <30cm H2O) [54,55]. Our experience has been to utilize lung protective strategies by targeting tidal volumes to 6-8 mL/
kg of ideal body weight.
PEEP: One of the factors that may contribute to ventilator induced lung injury is inflammation from cyclic atelectasis (termed
alectotrauma). PEEP improves oxygenation and prevents alectotrauma, although it is unclear at what level of PEEP prevents
this complication [55-57]. Several studies have evaluated various approaches to utilizing PEEP with conflicting results [58-62].
While some studies report no difference in mortality between higher versus lower levels of PEEP [58], other studies illustrate an
improved mortality with higher levels of peep in patients with severe hypoxemia (PaO2/FiO2<200mmHg) [61,62]. Furthermore,
studies have shown a decrease in hypoxemia, ventilator free days, and days free of organ failure when combined with a low tidal
volume strategy [59,60]. While nearly all patients should have a minimum PEEP of 5 cm H2O, PEEP is increased to a plateau
pressure of 30-32 cm H2O in patients with severe hypoxemia (PaO2/FiO2<200mmHg).
Fluid management strategies: Patients with ARDS have non-cardiogenic pulmonary edema due to vascular permeability from
inflammation and changes in oncotic forces due to damage to the alveolar-capillary interface. Conservative fluid management
approaches have shown to have a significant clinical benefit by decreasing ventilator free days, ICU days, improved oxygenation
and lung injury scores [63]. A conservative fluid management strategy should therefore be pursued as long as the patient is not
in shock or experiencing hypo perfusion. Effective fluid strategies can be achieved with daily diuretics, avoiding unnecessary
intravenous fluids, and meticulously monitoring fluid intake/output and electrolytes if diuretics are utilized.
Novel therapies: Several other therapies and management strategies have been utilized in the management of ARDS such as
systemic steroids [64], antioxidants [65] and prone positioning [66] to improve oxygenation. The benefits of these treatment
modalities remain controversial and should be approached with caution under the direction of a physician that is an expert in
the management of patients with ARDS.
Supportive care: Appropriate supportive measures should be given to all patients in the ICU. Maintaining adequate nutrition,
sedation and pain control is paramount but often overseen. The prevention of secondary infections by maintaining aggressive
hand hygiene, ventilator-associated infection preventative measures, and diligent central venous and urinary catheter care is vital.
Gastric ulcers and deep venous thrombosis prophylaxis should be addressed on a case-by-case basis.

COPD, asthma and ARDS are common pulmonary disorders encountered in the ICU. COPD and asthma are initially managed
initially with rapid bronchodilators, anti-inflammatory steroids, and oxygenation via invasive and non-invasive ventilation. In patients
with ARDS, management focuses primarily on treating the underlying cause, lung protective strategies for those receiving mechanical
ventilation, and adequate supportive care. Management of all these conditions can be challenging and a consultation by experts in critical
care medicine is often warranted. Providers caring for critically ill patients should be familiar with the identification and management of
patients with COPD, asthma and ARDS.

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6. Niewoehner DE, Lokhnygina Y, Rice K, Kuschner WG, Sharafkhaneh A, et al. (2007) Risk indexes for exacerbations and hospitalizations due to
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tract in fatal asthma. Clin Exp Allergy 35: 602-611.
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38. Meduri GU, Cook TR, Turner RE, Cohen M, Leeper KV (1996) Noninvasive positive pressure ventilation in status asthmaticus. Chest 110: 767-774.
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41. Gluck EH, Onorato DJ, Castriotta R (1990) Helium-oxygen mixtures in intubated patients with status asthmaticus and respiratory acidosis. Chest 98:
42. Manthous CA, Hall JB, Caputo MA, Walter J, Klocksieben JM, et al. (1995) Heliox improves pulsus paradoxus and peak expiratory flow in nonintubated
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45. Saulnier FF, Durocher AV, Deturck RA, Lefbvre MC, Wattel FE (1990) Respiratory and hemodynamic effects of halothane in status asthmaticus.
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46. Johnston RG, Noseworthy TW, Friesen EG, Yule HA, Shustack A (1990) Isoflurane therapy for status asthmaticus in children and adults. Chest 97:
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48. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, et al. (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685-1693.
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44. Schaeffer EM, Pohlman A, Morgan S, Hall JB (1999) Oxygenation in status asthmaticus improves during ventilation with helium-oxygen. Crit Care
Med 27: 2666-2670.


50. Roupie E, Dambrosio M, Servillo G, Mentec H, el Atrous S, et al. (1995) Titration of tidal volume and induced hypercapnia in acute respiratory distress
syndrome. Am J Respir Crit Care Med 152: 121-128.
51. Villar J, Blazquez MA, Lubillo S, Quintana J, Manzano JL (1989) Pulmonary hypertension in acute respiratory failure. Crit Care Med 17: 523-526.
52. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, et al. (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307: 25262533.
53. Sud S, Sud M, Friedrich JO, Wunsch H, Meade MO, et al. (2013) High-frequency ventilation versus conventional ventilation for treatment of acute lung
injury and acute respiratory distress syndrome. Cochrane Database Syst Rev 2:CD004085.
54. [No authors listed] (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory
distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 342: 1301-1308.
55. Needham DM, Colantuoni E, Mendez-Tellez PA, Dinglas VD, Sevransky JE, et al. (2012) Lung protective mechanical ventilation and two year survival
in patients with acute lung injury: prospective cohort study. BMJ 344: e2124.
56. Webb HH, Tierney DF (1974) Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection
by positive end-expiratory pressure. Am Rev Respir Dis 110: 556-565.
57. Muscedere JG, Mullen JB, Gan K, Slutsky AS (1994) Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med
149: 1327-1334.
58. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, et al. (2004) Higher versus lower positive end-expiratory pressures in patients with the
acute respiratory distress syndrome. N Engl J Med 351: 327-336.
59. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, et al. (2008) Ventilation strategy using low tidal volumes, recruitment maneuvers, and high
positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299: 637-645.
60. Mercat A, Richard JC, Vielle B, Jaber S, Osman D, et al. (2008) Positive end-expiratory pressure setting in adults with acute lung injury and acute
respiratory distress syndrome: a randomized controlled trial. JAMA 299: 646-655.
61. Briel M, Meade M, Mercat A, Brower RG, Talmor D, et al. (2010) Higher vs lower positive end-expiratory pressure in patients with acute lung injury and
acute respiratory distress syndrome: systematic review and meta-analysis. JAMA 303: 865-873.
62. Gattinoni L, Caironi P (2008) Refining ventilatory treatment for acute lung injury and acute respiratory distress syndrome. JAMA 299: 691-693.
63. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al.
(2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354: 2564-2575.
64. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, et al. (2006) Efficacy and safety of corticosteroids for persistent acute respiratory
distress syndrome. N Engl J Med 354: 1671-1684.
65. Gadek JE, DeMichele SJ, Karlstad MD, Pacht ER, Donahoe M, et al. (1999) Effect of enteral feeding with eicosapentaenoic acid, gamma-linolenic
acid, and antioxidants in patients with acute respiratory distress syndrome. Enteral Nutrition in ARDS Study Group. Crit Care Med 27: 1409-1420.

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66. Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NK, et al. (2010) Prone ventilation reduces mortality in patients with acute respiratory failure and
severe hypoxemia: systematic review and meta-analysis. Intensive Care Med 36: 585-599.


Bedside approach to Gastrointestinal

Bleeding in the Intensive Care Unit
Diana A Gliga, Ramzy H Rimawi, Zahid Vahora and Mark
A Mazer
Brody School of Medicine at East Carolina University, Jacksonville, NC
28546, USA
*Corresponding author: Diana A. Gliga, MS, Brody School of
Medicine at East Carolina University, 134 Empire BLVD, Jacksonville,
NC 28546, USA, E-mail:

Disclosure/Funding: Dr. Ramzy Rimawi is on the speakers bureau for ALK-Abello. None of the other authors have
conflicts of interest. None of the authors have received funding for this manuscript.

Keywords: Bleeding; Critical care; Gastrointestinal system; Intensive care; Resuscitation

Acute gastrointestinal bleeding is a common problem in the intensive care unit (ICU). Depending on comorbidities and other critical
factors, it can be potentially life threatening and thus, requires prompt assessment and often multidisciplinary medical management
[1]. Admission to ICU takes into account various high-risk profiles, which are often associated with a poor outcome and prolonged
ICU stay [2,3]. These features include hemodynamic instability, incessant bleeding, coagulopathy, aspirin use, comorbid conditions and
age above 65 years, anemia, elevated blood urea nitrogen and leukocytosis [3]. This chapter will integrate current research findings and
recommendations for managing ICU adult patients with GI bleeding.
Although the BLEED classification tool developed in 1997 suggested a great percentage of low-risk patients were hospitalized in
the ICU, it helped to identify high-risk patients that required immediate intervention, developed bleed recurrence, required surgery for
source control, and had increased mortality [4]. High-risk patients had additional multi-organ failure, required more transfusions of
blood products, and were hospitalized for longer periods of time. The BLEED criteria should be used as a triage prediction tool for of
ICU admission, as well as probable length of stay in the hospital. Other prognostic indicators include the Rockall bleeding score and
the Glasgow Blachford prognostic scales.

Upper vs. Lower GIB

Gastrointestinal (GI) bleeding can be overt (i.e., hematemesis, coffee-ground emesis, hematochezia, melena) or occult. Occult blood
can be detected by guaiac examination of the stool. Acute upper GI bleed (AUGIB) has a yearly incidence of 40-150 per 100,000 persons,
with a 6-10% mortality rate [5]. Acute lower GI bleed (ALGIB) is defined as bleeding distal to the ligament of Treitz and has incidence
estimated at 20-30 per 100,000 adults. ALGIB is primarily caused by non-life threatening anal pathology, with hemorrhoids or fissures
being the most common cause of rectal bleeding in individuals up to 30 years of age. In older individuals, the main source is colonic
diverticula (80%).
Overall, 80% of GI bleeds cease without intervention. However, the overall risk of recurrence is about 25%. Moreover, the mortality
rate increases in patients with advanced age and comorbid conditions, specifically renal and/or hepatic dysfunction, heart disease, and
malignancy. Intermittent or spontaneous cessation of bleeding, along with anatomical barriers such as the intra-peritoneal location of
the intestines, the robust intestinal contractility, and the superimposed bowel loops lead to an overall difficulty of diagnosing a precise
source for ALGIB in 10% of the cases [6] (Table 1). The Rockall Scoring System is a parameter used for stratifying the risks of rebleeding
and death after admission to the hospital for an acute GI bleed.
Causes of AUGIB

Causes of ALGIB

Ulcers (esophageal, gastric, duodenal)


Dieulafoys lesions

Ischemic colitis

Arterial-venous malformations

Vascular ectasias

Varices (esophageal, gastric)


Aortoesophageal fistula

Rectal varices
NSAID induced
Inflammatory Bowel Disease

Risk Factors
There are various reversible and irreversible pharmacologic agents associated with GI bleeding. For example, numerous studies have
illustrated the risk of GI bleed and GI perforation with non-steroidal anti-inflammatory drugs (NSAID) use [7]. As the incidence of GI
bleeding in elderly patients using NSAIDS is up to 1 in 7 persons, NSAID use is responsible for about 30% of GI bleed hospitalizations
and mortality [8]. Multiple locations, including gastric, duodenal and pre-pyloric areas may be affected by NSAID use. Aspirin is

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Table 1: Causes of AUGIB and ALGIB.


associated with about a 4-time increase risk of GI bleed. Coating the ASA enterically does not reduce its risk. There is also a positive
correlation between higher doses of ASA and GI bleed. The concomitant use of clopidogrel and warfarin versus monotherapy is related
to higher incidence of bleeding.

Age over 65 years is the strongest risk factor GI bleeding and is associated with increased morbidity and mortality compared with the
general population [7,9]. Male gender, extensive comorbidities, prior history of complicated peptic ulcer disease or alcoholic cirrhosis,
and presence of neoplasm are other common risk factors associated with poor prognosis. Rebleeding is primarily encountered in
hemodynamically unstable patients or those with elevated blood urea nitrogen, creatinine, or liver enzymes (particularly aminotransferases).
Other risks for rebleeding include GI hemorrhage (>20 g/L reduction in hemoglobin), septic shock, prior abdominal aortic aneurysm
repair, and malnutrition [10]. As expected, length of stay in the ICU is prolonged in these patients. The incidence of stress associated GI
bleed is about 0.17% due to the use of routine prophylaxis in the ICU.

Helicobacter pylori
Bacterial infection with Helicobacter pylori is a well-described risk factor in the development of ICU upper GI bleed. A multicenter
cohort study conducted in medical and surgical ICUs suggested that an increase in anti-H. pylori immunoglobulin A concentration was
predictive of an active infection and risk of developing GI bleeding [11]. Additionally, the mortality rate was substantially increased by
34% in those who developed this infection.

Portal hypertension
Esophageal or gastric variceal bleeding is associated with portal hypertension, the most common cause of morbidity and mortality
in liver cirrhosis [12]. When the hepatic venous pressure exceeds 12 mmHg, acute esophageal variceal bleeding can occur. With an
associated mortality rate of 20-25%, clinical scoring predicting the risk of bleeding in this patient population is of tremendous importance.
Cholinesterase level <2.25 kU/L, INR >1.2, variceal presence and viral or alcoholic etiology were four parameters effective in identifying
high-risk patients [13]. These factors were used to supplement EGD diagnostic power. Treating the underlying cause is an essential part
of variceal bleeding prevention. This includes hepatitis C antiviral therapy, alcohol abstinence, and iron chelation. Other modalities that
may prevent rebleeding secondary to portal hypertension include nitrates, non-selective beta-blockers, and diuretics [12]. The efficacy of
the somatostatin analogue, octreotide, in stopping variceal bleeding is controversial [14].

Dysenteric diarrhea
Infectious diarrhea involving dysentery can be caused by enteric pathogens such as Salmonella, Shigella, enterohemorrhagic E. coli
(O157:H7), enteroinvasive E. coli, Yersinia, Entamoeba histolytica, and Clostridium difficile. Campylobacter jejuni is the most common
identified organism, associated with grossly blood diarrhea in up to 91% of patients [15]. Stool cultures are usually requested but their yield
is low (0.9% in Salmonella, 0.6% in Shigella, 1.4% in Campylobacter, and 0.3% in E. coli O157 infections). Presence of stool leukocytes and
fecal lactoferrin are also used in guiding infectious etiology of bloody stools. The three day rule is enforced to diminish extraneous stool
cultures in patients with non-Clostridium difficile diarrhea related to hospitalization >3 days. Exceptions to this include HIV, neutropenia,
age over 65 years, or those with questionable C. difficile infection.

Diverticular disease
Diverticular bleeding accounts for approximately 40% of ALGIB [16]. As diverticulosis incidence increases with age, diverticular
bleeding is an important consideration in the differential diagnosis of GI bleeding. They can often present without pain, potentially
making the presentation of such a patient misleading. Such bleeds can be arterial in origin, frequently from the neck or dome of the
diverticulum [17]. While diverticular bleeds often cease without intervention, they have high rates of rebleeding, often prompting further
radiologic studies as there is a wide range in diagnostic yield of colonoscopy in all ALGIB, ranging from 48-90% [18].

Aggressive hemodynamic resuscitation is imperative in patients with rapid bleeding, defined as a hemorrhage >100 mL/hr with
signs of hypovolemic shock (i.e., tachycardia, hypotension, tachypnea). The estimated blood volume depletion in such cases is 15%.
Hemodynamic stability is a providers top priority and should supersede diagnostic interventions [19].

Setup and consult requisitions

Aggressive and early resuscitation in the ICU care is warranted in patients who meet high-risk criteria with hemodynamic instability,
active hemorrhage, and/or comorbid risk factors. Immediate intravenous access should be obtained with large bore peripheral catheters
or a central venous line. Large bore venous access, ideally through peripheral catheters, is essential for volume resuscitation, serial blood
count monitoring, medication infusion(s), and transfusion of blood products when appropriate. Consultation with gastroenterology,
general surgery, and/or interventional radiology should be requested early to avoid delays in diagnostic and therapeutic interventions.

Most AUGIB secondary to peptic ulcers and other non-variceal bleeds cease spontaneously [15]. However, the majority of patients
with bleeding, and rebleeding complications require hemostasis with the use of endoscopic therapy to obtain source control. Despite rapid
endoscopic repair, subsequent rebleeding occurs in 20% of patients. Histamine-2-receptor antagonists are efficient in preventing these
rebleeding episodes; however, their use is limited in reducing the need for transfusions or surgical interventions. While intravenous proton
pump inhibitors (PPI) are effective in reducing bleeding recurrences, they have little-to-no impact on mortality or need for surgery [20-22].

Transfusion of red-blood-cell products may be warranted in patients with active bleeding, hypovolemia, and hemodynamic instability
regardless of laboratory values. Due to the paucity of coagulation factors in packed red cells, one unit of fresh frozen plasma should
be administered for every four units of packed red blood cells transfused [3]. At concentration hemoglobin levels lower than 5-6 g/dL,

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Hemostasis control


cognitive impairment may become clinically apparent. In cases of acute GI bleeding at hemoglobin levels below 7-8 g/dL, the risk of
postoperative death increases. Based on randomized trials, hemoglobin goals in the ICU are a concentration of 7 g/dL in hemodynamically
stable young patients without comorbidities and 8 g/dL for other medical or surgical patients who are hemodynamically stable [23]. A
liberal transfusion trigger of hemoglobin level of 10 g/dL was associated with higher mortality than a restrictive trigger of 7 g/dl, except
in older patients and those with active coronary artery disease [24]. If the patient is hemodynamic stable, esophagogastroduodenoscopy
(EGD) can be performed during the blood product transfusion [25]. If coagulopathy is present, fresh frozen plasma (FFP), prothrombin
complex concentrate, or cryoprecipitate should be transfused depending on the circumstances. As FFP (typically dosed 10-15 mL/kg)
contains about 70% of the original coagulant factor VIII, normal stable clotting factor levels, albumin and immunoglobulins, is not
recommended when INR is below <1.5 [26]. Platelet infusions are recommended when platelet counts fall below 50,000/microL [3].

The incidence of acute GI bleeding from oral anticoagulants (OA) is higher than the incidence related to acetaminophen, NSAIDs, and
aspirin (ASA) [4]. Dabigatran is particularly problematic in patients with superimposed renal failure [27]. Concomitant anticoagulants
and/or antiplatelet therapies yield a greater risk of GI bleeding: 8.0 incidence ratio (IR) versus OA use with Tylenol (4.4 IR) and OA use
with ASA (3.8 IR) [4]. If the risks of anticoagulants and platelet inhibitor agents outweigh their benefits, these agents, including aspirin,
should be held in patients with GI bleeding [4]. While there are no set criteria for these scenarios, consulting the prescribing provider in
a timely fashion is highly recommended [3]. Reversal of these agents is often necessary to help achieve timely source control. In patients
with INR is >3, EGD may need to be postponed until the anticoagulation is reversed. If the INR is still >1.5 prior to the procedure, fresh
frozen plasma can also be administered during the endoscopy.
Additional pharmacologic modalities for GI hemorrhage management are under investigation. In animal models, nitric oxide-based
therapy (i.e., nitroglycerin) helps reduce the NSAID induced damage to the gastric mucosa. However, this effect may be limited by an
inhibitory effect on platelet aggregation [8]. Statistical analysis of agents that predispose to a bleeding event showed an odds-ratio (OR) of
7.4 with NSAIDS, 2.4 with aspirin, and 0.6 with nitro-vasodilators and anti-secretory therapies [28].

The diagnostic tool of choice in patients who have been resuscitated is colonoscopy and esophagogastroduodenoscopy (EGD) for
ALGIB and AUGIB, respectively.

AUGIB pre-endoscopic management

An appropriate history and physical can help direct ones clinical suspicion as to the cause of a patients bleeding. The suspicion of
peptic ulcer disease will prompt a clinician to infuse a PPI (80mg bolus, followed by 8mg/hr) versus a history of liver cirrhosis, which
would prompt octreotide infusion [14,29]. Unfortunately in the ICU setting, appropriate history acquisition can be difficult and clinical
judgment must often be used.
Active bleeding, a visible vessel at the ulcer base with an adherent clot, and an ulcer larger than 2 cm are factors associated with a
greater risk of re-bleeding [9]. In these patients, endoscopic interventions such as cautery, injection, or hemoclipping therapies are effective
in achieving hemostasis during acute bleeding and may help decrease the risk of future bleeding. Early EGD can improve outcome while
reducing ICU length of stay and rate of re-bleed [30]. Conversely, inaccurate diagnosis due to delayed endoscopy increases risks of
re-bleed, surgery, hospitalization, ICU stay, and ICU re-admission. In patients without frank signs of AUGIB, a lavage via nasogastric
tube may be done to help identify whether the bleeding is distal to ligament of Treitz. EGD should follow a bloody lavage [5]. However,
nasogastric lavage remains controversial as approximately 15% of gastric aspirates in patients with AUGIB will not yield blood return
[31]. Radionuclide imaging and computed tomographic (CT) angiography are two other useful diagnostic interventions. However, their
sensitivity depends on the presence of active bleeding during the examination. Post-procedure high-dose PPI infusion is recommended
for 72 hours to reduce the risk of rebleeding in patients with ulcers and high risk stigmata [14].

ALGIB pre-endoscopic management

Colonoscopy can diagnose the source of up to 89% of ALGIB, as compared to angiography, which has a diagnostic sensitivity of about
41% [5]. Colonoscopy can provide for direct visualization of the entire colon, biopsy, and therapy (laser, pharmaceutical, or physical
ligation). Colonoscopy is associated with low mortality and morbidity risks (0.1% and 0.3% respectively) and shortened length of stay
[14]. Urgent colonoscopy can result in successful permanent hemostasis in 67% of the cases [32].

Push enteroscopy or endoscopy is a procedure reserved for identifying small bowel bleeding past the ligament of Treitz (2-10% of all
GI bleeding cases) [5]. This procedure is essentially an upper endoscopy with an additional 15-160 cm of small intestine visualization. The
evaluator can take biopsy samples and apply treatment, but the diagnostic yield reaches a mere 54%. While capsule endoscopy is painless,
non-invasive and has a diagnostic yield of 66-69%, biopsies cannot be taken. As a last resort, exploratory laparotomy may be employed,
with a sensitivity of 70% in locating GI bleeding sources [5].
While sclerotherapy and variceal band ligation with rubber rings via endoscopy can help control or prevent rebleeding in patients
who cannot tolerate beta blockade, it does not reduce the portal pressure. In cirrhotic patients, variceal bleeding related to portal
hypertension can be managed via transjugular intrahepatic portosystemic shunting (TIPS). If placed within three days, TIPS improved
two-year survival, reduced rebleeding rates, and reduced the risk of hepatic encephalopathy. Given the risk of esophageal rupture, balloon
tamponade is only reserved for 24-hour hemostasis in patients with massive bleeding. In cirrhotic patients, the only definitive therapy for
variceal rebleeding is liver transplantation [12].

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Specialized procedures are employed in cases where the source of bleeding is more enigmatic. These include Meckels scan, barium
contrast upper GI series with small bowel follow-through, technetium-99mtagged red blood cell scan, and push enteroscopy [5]. Nuclear
studies (i.e., technetium-99mtagged red blood cell scan) are indicated in cases with a low rate of bleeding (0.1 to 0.4 mL per minute).
The accuracy is increased when used concomitantly with arteriography. Angiography is the desired diagnostic tool if the rate of bleeding
is approximately 0.5 mL/min, and if the patient experiences active bleeding. However, this intervention is invasive and nephrotoxic.
Sensitivity is also poorer than that of colonoscopies, with an estimated upper range of 65% [19]. The advantages include embolization and
infusion of vasoactive treatment.


Stress Ulcers Prophylaxis

Ulceration and stress-related mucosal disease (SRMD) are some of the more common GI complications in patients hospitalized in
the ICU, with an associated increase mortality rate [33]. The majority of critically ill patients who develop SRMD are affected within 24
hours of admission to ICU, likely related to acid production and ischemia. Suppressing hydrogen ion production with antacids, sucralfate,
histamine2-receptor antagonists or PPI is critical in SRMD prophylaxis [13]. Ranitidine and enteral feeding were shown to be superior
to sucralfate in ensuring lower bleeding rates in mechanically ventilated patients [34]. While a gastric pH >4 is adequate to prevent stress
ulcers, a pH >6 is necessary to prevent rebleeding from a peptic ulcer. Also, while both IV histamine-2-receptor antagonists and PPIs
increase the gastric pH, maintenance at pH >6 are primarily achieved with PPIs [22]. As critically ill patients rarely develop clinically
significant GI bleeding, stress ulcer prophylaxis should be withheld unless they have a coagulopathy or require mechanical ventilation [34].

Laboratory Markers
Early hemodynamic resuscitation, correction of coagulopathy and judicious blood transfusions are imperative for patients with an
acute GIB in the ICU [35]. Complete blood counts should be frequently and serially monitored every 4-6 hours. Critically ill patients with
GI bleeding can progress to disseminated intravascular coagulation as a result of the hypovolemic shock. Activated partial thromboplastin,
prothrombin time, and D-dimer should be monitored to assess for this complication. D-dimer elevation at the time of ICU admission
suggests a 5.6 times increased risk of developing a venous thromboembolic event and a 3.94 greater relative mortality risk [36]. GI
bleeding may be associated with inflammatory bowel disease exacerbations. In such instances, mean platelet volume, mean platelet count,
white blood cell count, and inflammatory markers (i.e., C-reactive protein, erythrocyte sedimentation rate) should be monitored [37].

Other Considerations
Restarting aspirin for primary cardiovascular prophylaxis is not recommended, except in secondary prophylaxis for patients with a
history of CAD where it is recommended to restart soon (1-7 days) in addition to a PPI. In terms of restarting NSAIDs in patients with
bleeding ulcers, it is recommended not to resume NSAIDs and, if necessary, cyclo-oxygenase (Cox)-2 selective NSAIDS be started with
PPI [38].

The ICU provider plays an important role in coordinating and managing the care of high-risk patients with acute GI bleeding. These
patients require intensive clinical and hemodynamic monitoring, correction of coagulopathy, appropriate pharmacologic intervention,
and rapid diagnostic and therapeutic intervention. As GI bleeds are frequently encountered in the ICU setting, ICU providers should
obtain adequate education and training in the timely and effective management of acute GI bleeds.

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Am 29: 309-336.
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important gastrointestinal bleeding in critically ill patients. Crit Care 5: 368-375.
3. Strate L (2013) Approach to resuscitation and diagnosis of acute lower gastrointestinal bleeding in the adult patient. UpToDate.
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gastrointestinal hemorrhage. Crit Care Med 25: 1125-1132.
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9. Pitchumoni CS, Brun A (2012) Geriatric Gastroenterology. Springer, New York.
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11. Ellison RT, Perez-Perez G, Welsh CH, Blaser MJ, Riester KA, et al. (1996) Risk factors for upper gastrointestinal bleeding in intensive care unit
patients: role of helicobacter pylori. Federal Hyperimmune Immunoglobulin Therapy Study Group. Crit Care Med 24: 1974-1981.
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13. Tacke F, Fiedler K, Trautwein C (2007) A simple clinical score predicts high risk for upper gastrointestinal hemorrhages from varices in patients with
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15. Guerrant RL, Van Gilder T, Steiner TS, Thielman NM, Slutsker L, et al. (2001) Practice guidelines for the management of infectious diarrhea. Clin
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18. Zuckerman GR, Prakash C (1998) Acute lower intestinal bleeding: part I: clinical presentation and diagnosis. Gastrointest Endosc 48: 606-617.
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20. Conrad SA (2002) Acute upper gastrointestinal bleeding in critically ill patients: causes and treatment modalities. Crit Care Med 30: S365-368.

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14. Hwang JH, Fisher DA, Ben-Menachem T, Chandrasekhara V, Chathadi K, et al. (2012) The role of endoscopy in the management of acute nonvariceal upper GI bleeding. Gastrointest Endosc 75: 1132-1138.


21. Cochran EB, Phelps SJ, Tolley EA, Stidham GL (1992) Prevalence of, and risk factors for, upper gastrointestinal tract bleeding in critically ill pediatric
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critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340: 409-417.
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25. Wychowski MK, Kouides PA (2012) Dabigatran-induced gastrointestinal bleeding in an elderly patient with moderate renal impairment. Ann
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(2009) Recommendations for the transfusion of plasma and platelets. Blood Transfus 7: 132-150.
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coagulation or venous thromboembolic disease. Intensive Care Med 25: 207-210.
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38. Laine L, Jensen DM (2012) Management of patients with ulcer bleeding. Am J Gastroenterol 107: 345-360.


Renal Disorders in the ICU

NRuba Sarsour1* and Tejas Desai2
East Carolina University Brody School of Medicine, Department of Internal
Medicine, Greenville, NC 27834, USA
Assistant Professor of Medicine, East Carolina University Brody School of
Medicine, Department of Internal Medicine, Greenville, NC 27834, USA

*Corresponding author: Ruba Sarsour, DO, East Carolina University

Brody School of Medicine, Department of Internal Medicine, Greenville,
NC 27834, USA, E-mail:

Acute Kidney Injury (AKI) is a sudden decrease in kidney function due to a reduction in glomerular filtration rate (GFR),
increase in creatinine or a decrease in urine output. AKI consists of different etiologies including pre-renal, acute tubular necrosis,
interstitial nephritis, glomerular and vasculitic renal diseases, and post-renal obstructive nephropathy [1]. AKI is commonly seen in
critically ill patients with important consequences including increased risk of death even in mild and/or reversible AKI [1].

Acute Kidney Injury

Whether the disorder is pre-renal, intrinsic or post-renal, identifying the underlying etiology is imperative in an intensive care
unit (ICU) setting. The investigation includes a detailed history, medication reconciliation, assessment for recent exposure to toxins
or trauma, and a detailed review of symptoms.
A detailed physical exam should include a careful assessment of patients volume status. Hypotensive patients are at risk for
over-resuscitation after they achieve hemodynamic stability due to a lack of serial fluid status reassessments. Fluid overload may
present as peripheral edema, jugular venous distention, and/or crackles on lung auscultation. Evidence of systemic syndromes or
vasculitis may be suggested by a rash, arthritis and signs of embolic events. Abdominal distention can direct towards bladder outlet
obstruction, ascites, or abdominal compartment syndrome [2].
Laboratory and radiologic tests are key diagnostic modalities in renal disease, regardless of the hospital setting. Providers should
inquire prior records for baseline renal functions. A basic metabolic profile is crucial as the rate of rise of serum creatinine can be
suggestive of the underlying etiology; a slow rise is mostly seen with pre-renal etiology whereas in ATN serum creatinine tends to
rise at a rate of 0.3-0.5 mg/dL per day. A sudden oliguria (urine output <500 mL/day) can also be suggestive of an acute process.
Urinalysis and microscopy for urine sediment, quantification of urine protein or albumin and fractional excretion of sodium can
be important diagnostic tests that aid in the diagnosis of the underlying origin. A renal ultrasound with Doppler can demonstrate
obstructive pathologies or anomalies in renal size or structure. A renal biopsy is often last resort if the non-invasive evaluation is not
sufficient for diagnosis [3].
It is essential to identify patients that are at higher risk of developing AKI as this will allow for certain protective and/or preventative
measures to be undertaken [4]. High risk individuals and/or susceptibility factors include: dehydration, hypoalbuminemia, advanced
age, exposure to nephrotoxic agents, female gender, history of chronic kidney disease (CKD), history of Diabetes Mellitus, history of
Heart disease, patients undergoing cardiac surgery, patients with liver disease or malignancy and patients on mechanical ventilation [4,5].

Etiologies of Acute Kidney Injury

Pre-renal acute kidney injury
Pre-renal disorders are responsible for 30-40% of acute renal injury the ICU [6]. Pre-renal diseases result from a decreased
arterial blood volume or from any process that reduces renal blood/oxygen delivery [3]. In pre-renal diseases, the decrease in GFR is
a physiological response to hypoperfusion rather than tissue damage [2].
In the ICU, certain measurements such as a low central venous pressure (CVP) of 1-2 mm Hg or 10-12 mm Hg in ventilator
dependent patients may suggest hypovolemia. In ventilator dependent patients, a decrease in blood pressure shortly after lung
inflation can be used as evidence of inadequate cardiac filling. Central venous oxyhemoglobin saturation (ScvO2) below 50% suggests
a low cardiac output. If anemia is not the cause of reduced tissue perfusion, a ScvO2 below 25-30% is highly indicative of low cardiac
output [6]. Pre-renal disease is seen in multiple scenarios:
-Hypovolemic states (i.e. acute hemorrhage, diarrhea, or insensible losses) [3].
- Hypervolemic states with low arterial blood volume (i.e. acutely decompensated heart failure)[3].
- Acutely decompensated liver disease with portal hypertension [6].
- Rise in intraabdominal pressure >20 mm Hg leading to abdominal compartment syndrome [2].
In the setting of renal hypoperfusion, sodium reabsorption increases and urinary sodium excretion decreases. A urine sodium
<20 mEq/L usually indicates a prerenal condition [2]. However urine sodium >40 mEq/L does not rule out pre-renal disease [6].
Fractional excretion of sodium (FENa) is the most sensitive index for pre-renal disease for patients not exposed to loop diuretics.
For patients taking diuretics, the fractional excretion of urea (FEUrea) is superior, with a specificity and sensitivity above 95%.
FEUrea<35% suggests renal hypoperfusion. Rapid reversal of renal hypoperfusion is critical, as prolonged ischemia can lead to renal
tubular necrosis [2].

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- Alteration in renal vasculature auto-regulation due to non-steroidal anti-inflammatory drugs (NSAIDS) or iodinated contrast [3].


Cardiorenal syndrome
Cardiorenal syndrome occurs when one organ dysfunction (heart or kidney) causes another organ dysfunction [7]. Although there
are 5 types of cardiorenal syndromes, types 1 and 5 are the most related to acute kidney injury in the ICU. Type 1 (acute) is when AKI is
a consequence of acute heart failure. Type 5 is AKI and/or acute heart failure that occurs secondary to a systemic disorder like sepsis [8].
In decompensated heart failure, renal injury can be secondary to decreased cardiac output, increased renal venous pressure or activation
of Renin-angiotensin-aldosterone system which leads to systemic vasoconstriction to ensure brain and heart perfusion while decreasing
renal perfusion [9].

Hepatorenal syndrome
Hepatorenal syndrome is a diagnosis of exclusion that can be seen with end stage liver disease and fulminant hepatic failures. In
this syndrome, effective hypovolemia leads to severe intrarenal vasoconstriction. It can occur spontaneously in advanced liver disease,
or develop after a precipitating event such as infection, gastrointestinal bleeding, or large-volume paracentesis without albumin [10]. It
carries a poor prognosis [2]. There are 2 main types of hepatorenal syndrome; in type 1 there is a 2 fold increase in serum creatinine to a
level >2.5 mg/dL in <2 weeks; while type 2 has a slower increase in serum creatinine and presents with refractory ascites [10].

Acute tubular necrosis

Acute Tubular Necrosis (ATN) is the cause of 50% of cases of acute kidney injury in intensive care unit. Unlike pre-renal disease, in
ATN, there is parenchymal damage with sloughing of damaged cells into the renal tubules. These cells create an obstruction that lead to
an increased pressure in the proximal tubules and a decrease in the glomerular filtration rate. With urine microscopy, tubular epithelial
cells with epithelial cell casts are pathognomonic of ATN. Renal recovery can be expected in >90% of patients who previously had normal
baseline function [6] if managed appropriately. There are several phases of ATN:
1. Initiation Phase: oxidative injury secondary to prolonged ischemia [5].
2. Extension phase: inflammatory state secondary to initiation phase leading to medullary congestion and hypoxic injury [5].
3. Maintenance phase: restoration of tubule cells [5]. It can be either oliguric or nonoliguric. Nonoliguric ATN has a better
outcome; however, attempts to change from oliguric to non-oliguric have not shown improved outcomes [5].
4. Repair phase: restoration of polarity and function [5].
There are several etiologies that predispose patients to ATN. Common causes include:
Ischemia from prolonged pre-renal state [11]
Aminoglycosides can cause ATN in 25% of hospitalized patients receiving therapeutic drug levels. It is more common in
patients with higher risks for AKI. It causes a reversible non-oliguric renal injury 5-10 days into treatment. Aminoglycosides
can remain in renal tissue for up to a month, thus renal function is not restored immediately after discontinuing the drug.
Streptomycin is the least nephrotoxic of the aminoglycosides. Prior to starting an aminoglycoside, experts advocate inquiring
into any family history of drug-induced vestibular disorders as well as informed consent that they are aware of the potential
nephrotoxicity [11].
Amphotericin B can have a cumulative nephrotoxic effect. Toxicity leads to a type-I renal tubular acidosis. Liposomal
preparations have lower propensity for nephrotoxicity [2].
Cyclosporine toxicity is dose dependent and can lead to a type-4 renal tubular acidosis from severe vasoconstriction. Blood
level monitoring is crucial. In some cases, a renal biopsy is needed to distinguish transplant rejection from cyclosporine toxicity.
Renal function usually improves after reducing the dose or stopping the drug [11].
Acyclovir can potentiate renal disease. Discontinuation of acyclovir usually reverses renal injury [11].
Cisplatin toxicity is dose-depending and cumulative but can be avoided by hydration prior to the initiation of therapy [11].
Ethylene Glycol/Methanol poisoning can elevate the osmolar gap and cause an anion gap metabolic acidosis. Urine sediment is
usually positive for envelope shaped oxalate crystals [2]. Toxicity may be managed with fomepizole antidote but hemodialysis
is indicated for refractory metabolic acidosis/AKI [2].
Rhabdomyolysis can have several etiologies: trauma (crush injury), infection, immobility, drugs (especially statins), electrolyte
abnormalities (hypophosphatemia, hypokalemia), snake venom, and status epilepticus [6]. Dehydration and acidosis
can predispose to the development of myoglobin, which can cause direct tubular damage [11]. Rhabdomyolysis of clinical
importance commonly occurs with serum creatinine kinase above 20,000-50,000 international units/L [2].
Hemoglobinuria results from substantial intravascular hemolytic processes due to transfusion reactions or hemolytic anemia
[11]. Patients would present with elevated lactate dehydrogenase, decreased haptoglobin, and elevated unconjugated bilirubin [2].
Tumor Lysis Syndrome can be seen 48-72 hours after chemotherapy or from rapid cell turnover in the setting of lymphomas.
Renal injury takes place through uric acid precipitation in the acidic environment of the tubules. Serum uric acid levels are often
> 15-20 mg/dL and urine uric acid levels >600 mg/24h [11]. Also, hyperphosphatemia can lead to calcium-phosphate crystal
formation and renal deposition [2]. A urine uric acid to urine creatinine ratio >1.0 indicates a high risk of acute kidney injury [11].

Iodinated contrastinduced nephropathy

This is the third leading cause of acute renal failure in hospitalized patients and is caused by both renal vasoconstriction and tubular
injury [5]. Renal injury becomes apparent as rising serum creatinine within 72 hours after contrast administration [6]. Risk factors include
preexisting renal dysfunction, heart failure, diabetes, volume depletion, multiple myeloma, large volume and high osmolarity contrast

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Cast nephropathy is composed of light chains (myeloma) that can lead to direct tubular injury and intratubular obstruction [2].


administration. Preventative measures include premedication with isotonic saline volume infusion and/or N-acetylcysteine. However,
the KDIGO guidelines discourage using N-acetylcysteine to prevent AKI in critically ill or postsurgical patients with hypotension.

Acute interstitial nephritis

Acute interstitial nephritis (AIN) is an interstitial inflammatory process that occurs mostly through cell-mediated immune reactions
[11]. It is often caused by medications (70% of cases) or infections (usually viral or atypical pathogens) [6].It usually presents without
oliguria and the classic triad of rash, eosinophilia and fever is rarely seen. Urinary sediment is routinely positive for white blood cells,
white blood cell casts and eosinophils (detected with Hansels stain) [6]. Renal biopsy may be needed for a definite diagnosis [2].
Drugs responsible for interstitial nephritis include antibiotics (aminoglycosides, amphotericin B, beta-lactams, fluoroquinolones,
sulfonamides, vancomycin), anti-epileptics (carbamazapine, phenobarbital, phenytoin), NSAIDs (aspirin, ibuprofen, ketorolac,
naproxen), diuretics (acetazolamide, furosemide, thiazides), acetaminophen, ACE-inhibitors, iodinated dyes, and ranitidine [6].

Obstructive nephropathy
Obstructive nephropathy accounts for 10% of the cases of acute kidney injury [6]. Although obstruction can occur anywhere in the
urinary tract, bilateral obstruction (or unilateral obstruction in a single functioning kidney) is necessary for a reduction in glomerular
filtration rate to take place [3]. If left untreated, obstructive nephropathy can lead to irreversible tubulointerstitial fibrosis [3].

Staging of AKI
The RIFLE criteria, which is used to define the severity of AKI:
-Risk: 1.5 fold rise in the serum creatinine, a 25% reduction in glomerular filtration rate (GFR), or a urine output below 0.5 ml/kg/
hr for six hours.
-Injury: Two fold rise in the serum creatinine, a 50% reduction in GFR, or a urine output <0.5 ml/kg/hr for 12 hours.
-Failure: Threefold rise in serum creatinine, a 75% reduction in GFR, or a urine output <0.3 ml/kg/hr for 24 hours, or anuria for 12
-Loss: Complete loss of kidney function (e.g., need for renal replacement therapy) for > 4 weeks.
-End stage renal disease (ESRD): Complete loss of kidney function (e.g., need for renal replacement therapy) for >3 months [12].
The Kidney Disease Improving Global Outcomes (KDIGO) foundation does not use GFR for staging:
-Stage 1: serum creatinine of 1.5-1.9 from baseline, 0.3 mg/dL ( 26.5 micromole/L) rise in serum creatinine, or urine output <0.5
mL/kg per hour for 6 to 12 hours.
-Stage 2: serum creatinine of 2.0-2.9 or urine output <0.5 mL/kg per hour for 12 hours.
-Stage 3: serum creatinine >3.0, urine output <0.3 mL/kg per hour for 24 hours, anuria for 12 hours, renal replacement therapy
necessitation, age below 18 years, or a reduction decrease in estimated GFR to <35 mL/min per 1.73m2 [12]
Patients should be classified according to the criteria that result in the highest (most severe) stage of injury [12]. Nevertheless, there
are limitations to these criteria; for example in the early stages of AKI; the serum creatinine level does not correlate with the degree of
renal injury [4]. Another example would be patients with sepsis have decreased creatinine production; hence the serum creatinine level
will not accurately reflect the degree of renal injury [4]. Also, in patients with rhabdomyolysis, creatinine release from skeletal muscle
adds to serum creatinine and therefore will not accurately reflect the degree of renal injury [2].

Management of AKI

Patients with all cases of AKI can develop hyperkalemia, metabolic acidosis, hypocalcemia and hyperphosphatemia. In general,
patients with AKI should avoid receiving medications containing potassium. Hyperkalemia should be treated as medically indicated.
Patients with refractory hyperkalemic metabolic acidosis in the setting of volume overload or severe acidosis (PH<7.1) often necessitate
renal replacement therapy. Bicarbonate infusion in patients with metabolic acidosis and oliguria/anuria should be avoided as it can
reduce ionized calcium and increase the partial pressure of carbon dioxide and intracranial pressure in patients with diabetic ketoacidosis.
Hypocalcemia and hyperphosphatemia are also commonly seen in AKI, and hypocalcemia should only be treated in symptomatic patients
unless the serum phosphate level is >8 mg/dL, in which case the patient should be dialyzed due to the risk of calcium-phosphate binding
and deposition in organs and vessels [13].
In the setting of cardiorenal syndrome, optimizing cardiac function is goal. In critically ill patients, treatment is directed at establishing
volume hemostasis through the use of intravenous (IV) loop diuretics, even if it leads toa temporary worsening of renal function. Thiazide
diuretics can be added in patients who are refractory to loop diuretics. Ultrafiltration is only indicated in cases refractory to IV diuretics,
not as first line, as studies have shown better outcomes with the use of diuretics [8].
In the case of hepatorenal syndrome in the ICU, it is usually managed with a combination of norepinephrine and albumin [2].
Norepinephrine is given as a continuous infusion (0.5 to 3 mg/hr) with the goal of raising the mean arterial pressure by 10 mmHg,

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In all cases of AKI, treating the underlying cause and discontinuation of all offending agents is the first step in management. However,
this may not always be possible in the ICU setting. Secondly, initiation of volume resuscitation is important for volume expansion using
isotonic crystalloid fluids, or in the case of hemorrhagic shock, colloid fluids [1]. The early initiation of fluid therapy can also identify
patients with pre-renal kidney injury if renal function responds quickly [1]. Fluid resuscitation should be directed towards an objective
physiologic endpoint, such as mean arterial pressure or urine output [13]. The KDIGO guidelines recommend using vasopressors in
conjunction with fluids in patients with shock irresolute with fluid resuscitation [1]. Norepinephrine is currently the vasopressor of
choice, as it raises mean arterial pressure without increasing mortality and without the accompanying arrhythmic events associated with
dopamine [1].


and albumin is given as 1 g/kg per day for 2 days (maximum of 100 g per day) [10]. In patients with spontaneous bacterial peritonitis,
albumin infusion may prevent development of hepatorenal syndrome [2].
Patients with rhabdomyolysis induced renal failure should be treated with vigorous hydration (may require up to 10 L of normal
saline during 24 hr), however, 30% of the patients will require dialysis [6]. Patients with Tumor Lysis syndrome will also require
vigorous hydration as well as allopurinol and rasburicase [2].
In the setting of ATN, there are experimental studies that suggest that the administration of growth factors insulin like growth
factor-I (IGF-I), epidermal growth factor (EGF), and hepatocyte growth factor may expedite the recovery of renal function [5].
AIN is managed with the removal of the offending agent and/or treating the underlying infection [11]. The use of steroids is
controversial, but a treatment dose of methylprednisolone 0.5 to 1 g/d for one to four days or prednisone 60 mg/d orally for 1-2 weeks,
followed by a prednisone taper can be used in severe cases [11]. Complete resolution can take months [6].
However, in glomerular disease (which is less commonly seen in the ICU setting), treatment includes immediate intravenous
corticosteroids (methylprednisolone at 7 mg/kg/day for 3 days followed by oral prednisone at 1 mg/kg/day up to 60 mg) and with
cytotoxic immunosuppressants (cyclophosphamide at 2 to 3 mg/kg/day). Goodpastures disease often requires plasma exchange for
therapy. In TTP, plasma volume exchange is the lifesaving therapy, whereas antibiotics and platelets transfusion are contraindicated [2].

Renal Replacement Therapy

Renal replacement therapy (RRT) is indicated in the setting of refractory fluid overload, electrolyte abnormalities (especially
hyperkalemia and hypocalcemia), metabolic acidosis, and uremic encephalopathy, as well as certain drug intoxications [14]. In the
ICU setting there are different forms of RRT; intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT)
but CRRT is becoming more favorable due to it being more physiologic-like and is better tolerated in critically ill patients [6]. There
have been studies to suggest that CRRT can also have an advantage in septic patients due to better removal of inflammatory mediators
and an advantage in the cases of fulminant hepatic failure and acute brain injury due to hypothesized better cerebral perfusion [14].
Nevertheless, there is no evidence to support that one method is associated with better outcomes compared to the other [15]. The
timing for initiation of RRT continues to be controversial; there are no definitive criteria at which RRT should be initiated, however, it
is recommended to initiate RRT prior to the development of life threatening symptoms or complications [14]. Once there is evidence
of renal function improvement; continuous decrease in creatinine, an increase in urine output, electrolyte stabilization, symptomatic
improvement and an improvement in creatinine clearance, then RRT can be discontinued [15].

We present the common causes of acute kidney injury in an ICU setting, from pre-renal to renal and post-renal anomalies. Regardless
of the type of renal disease, identifying the underlying disorder is imperative in order to adequately manage the critically ill patient and
prevent further complication. Renal disease is an exceptionally common problem in an ICU setting and providers should be familiar
with the clinical features and management strategies.

1. Kellum JA, Lameire N; for the KDIGO AKI Guideline Work Group (2013) Diagnosis, evaluation, and management of acute kidney injury:
a KDIGO summary (Part 1). Crit Care 17: 204.
2. Li Tingting and Anitha Vijayan (2012) Acute Kidney Injury The Washington Manual of Critical Care. In: Wolters Kluwer Health/
Lippincott Williams & Wilkins, (2nd ed) 351-65, Philadelphia.
3. Hsu Chi-yuan (2013) Diagnostic Approach to the Patient with Acute Kidney Injury (acute Renal Failure) or Chronic Kidney Disease,
Pedram Fatehi and Waltham, UpToDate.
4. Palevsky PM, Liu KD, Brophy PD, Chawla LS, Parikh CR, et al. (2013) KDOQI US commentary on the 2012 KDIGO clinical practice
guideline for acute kidney injury. Am J Kidney Dis 61: 649-672.
5. Okusa Mark D (2013) Possible Prevention and Therapy of Postischemic (ischemic) Acute Tubular Necrosis, Scott Sanoff and
Waltham, UpToDate.
6. Marino Paul L and Kenneth M. Sutin (2007) Oliguria and Acute Renal Failure. In: The ICU Book- Lippincott, Williams & Wilkins, 58092, Philadelphia.
7. Acute Kidney Injury (2012) MKSAP In: Medical Knowledge Self-assessment Program- American College of Physicians, 72,
8. Kiernan Michael S, James E Udelson, Mark Sarnak and Marvin Konstam (2013) Cardiorenal Syndrome: Prognosis and Treatment,
Waltham. UpToDate.
9. Kiernan Michael S, James E Udelson, Mark Sarnak, and Marvin Konstam (2013) Cardiorenal Syndrome: Definition, prevalence,
diagnosis, and pathophysiology, Waltham. UpToDate.
10. Runyon Bruce A (2013) Hepatorenal Syndrome, Waltham, UpToDate.

12. Palevsky Paul M (2013) Definition of Acute Kidney Injury, Waltham, UpToDate.
13. Rosner, Mitchell H, (2013) Overview of the Management of Acute Kidney Injury (acute Renal Failure) Mark D. Okusa and Waltham,
14. Palevsky Paul M (2013) Renal replacement therapy (dialysis) in acute kidney injury (acute renal failure) in adults: Indications, timing,
and dialysis dose, Waltham, UpToDate.
15. Tolwani A (2012) Continuous renal-replacement therapy for acute kidney injury. N Engl J Med 367: 2505-2514.

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11. McPhee, Stephen J, Maxine A. Papadakis, and Michael W. Rabow (2012) Kidney Disease. In: Current Medical Diagnosis & Treatment.
(51st ed), McGraw-Hill Medical 880-84, New York.


Nutritional Support in an ICU Setting

Christina Lipay1*, Paul J McCarthy2 and Laura E Matarese3

RD, LDN, Vidant Medical Center, USA

MD, East Carolina University Brody School of Medicine, Department of Internal

Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, USA

PhD, RD, LDN, CNSC, FADA, FASPEN, Associate Professor, East Carolina
University Brody School of Medicine, Department of Internal Medicine, Section
of Gastroenterology, Hepatology and Nutrition, USA

*Corresponding author: Vidant Medical Center, USA, Tel: (252)845-5114;

Pager: (252) 847-4999; Ext.1090; E-mail:

Key Points:
1. ICU admission is a risk for malnutrition.
2. Malnutrition is a risk factor for poor outcomes, increased length of stay and increased healthcare costs.
3. A nutritional assessment should be made daily on all ICU patents.
4. Enteral feeding within 24-48 hours of ICU admission should be the goal for the majority of ICU patients.
5. Parenteral nutrition and specialized formulas may be indicated in select patient groups.
6. Nutritional therapies should be monitored closely for complications such as re-feeding syndrome.
7.When managing critically ill patients, a multi-faceted team approach to nutrition should include a member trained in
nutritional support.

The importance of nutritional support in the intensive care unit (ICU) is supported by current and emerging evidence [1]. All
patients admitted to the ICU should have a nutritional assessment and, if at all possible, receive enteral nutrition within the first 24
to 48 hours of admission as most ICU patients are at risk of malnutrition and muscle loss [2]. In addition, early enteral nutrition
provides protection against infection and maintains the integrity of the gastrointestinal system [1].
There are some indications for parenteral nutrition and specialized formulas; however, the routine use of either of these therapies
is not recommended. All patients receiving nutritional support should be monitored for tolerance and complications associated with
the therapy. Nutritional assessment and delivery is optimal when done by a multi-disciplinary team that includes a specialist in
nutrition [1].

Nutritional Assessment
Loss of body and muscle mass during a critical illness is associated with decreased survival and delays in recovery and
rehabilitation after ICU discharge [1]. The Joint Commission on Accreditation of Healthcare Organization (JCAHO) mandates a
nutritional screening within 24 hours of hospital admission. Nutritional screening can determine if the patient is malnourished, or
at risk of malnourishment, with screening risk factors [2].
Nutritional evaluation is a global assessment of both nutritional status and severity of illness because of the fundamental
relationship between the two. Hospital admission is a risk factor for detritions in nutritional status resulting in loss muscle mass in
about a third of all hospitalized patients. A major factor associated with malnutrition in the ICU is a nil per os (NPO) order typically
placed for diagnostic tests or surgery. Interruptions in nutrition are common in the intensive care unit and consequently promote
insulin resistance in addition to weight loss [1]. The preservation of lean body mass when patients leave the ICU plays a key role in
recovery and regaining long-term function.
A complete nutritional history is the first step in nutritional risk assessment. During an acute illness, it is often difficult to obtain
a detailed history. However, every attempt should still be made to obtain patient information, even if obtained indirectly from family
members. Any patient staying in the ICU over 2 days without normal oral intake is at a risk of malnutrition. The nutritional history
has three key indicators:
Actual weight and height (to determine body mass index, or BMI)
Recent decrease in nutrient intake
During a critical illness, lean body mass can be affected by illness severity, degree of inflammatory response, balance between
protein breakdown and synthesis, and the response to nutrition. Nutritional support is the standard of care in the ICU and although
advances have been made in this area, many knowledge gaps remain.
The Nutritional Risk Screening (NRS)-2002 is often used for hospitalized patients; however, it does not provide usable information
in the assessment of nutritional risk in the ICU. When assessing nutritional risk, one should include consideration of shock, motility
disorders, and intra-abdominal hypertension. The ultimate goal should be to feed patients within 24 to 48 hours of ICU admission

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Recent unintentional weight loss (3 6 months)


with enough calories and nutrients to meet the needs of the patient without causing complications such as re-feeding syndrome (to be
discussed later).

Nutritional Support
In a critical illness, hyper-metabolism in conjunction with nutritional deprivation can quickly lead to malnourishment. Malnutrition,
as a result of a preexisting condition or acute illness, significantly increases the risk of a poor outcome. Malnourishment is associated
with increased risk of infections, prolonged mechanical ventilation, and ICU and hospital length of stay [3]. Early initiation of enteral
nutrition is associated with improvement in intestinal absorption and clinical outcomes. Barriers to nutritional support include disease
state, NPO status for procedures and tests, and physician bias. The too sick to feed philosophy is an all too common practice.
Despite the many positive clinical impacts associated with optimal nutritional support, its importance is often underappreciated and
many clinical questions remain unanswered. For example, the optimal goal for caloric deliver is unclear and there is mixed data on the
benefits of many specialized formula and supplements [3].

Enteral Nutrition
Enteral nutrition is an ideal feeding solution to maintain gut integrity if a patient has a functioning gastrointestinal tract but is unable
to safely swallow and orally consume nutrients. Enteral nutrition should be initiated within 24-48 hours of an ICU admission [4], and
may be started despite the absence of bowel sounds in hemodynamically stable patients. It may also be initiated or continued with the
presence of a mild to moderate ileus [4,5]. The greatest benefit of early enteral nutrition is achieved with 50-65% of the target goal volume
being met within the first week of hospitalization [6]. When feeding a critically ill patient, early initiation of enteral nutrition has various
benefits that include sustaining gut barrier function, preventing microbial invasion, resuming normal digestion and absorption and
reducing metabolic response to stress. Early nutritional support therapy may reduce disease severity with reduction in complications and
decreased lengths of ICU stay [4].
Predictive equations determine a critically ill patients calorie and protein requirements in the absence of indirect calorimetry. It is
essential to obtain an accurate height and weight to calculate body mass index (BMI) and estimate nutritional needs. Adults with normal
or overweight BMI of 18.5-29.9 kg/m2 require 20-30 kcal/kg actual body weight per day. Protein requirements for this population should
range between 1.2-2.0 g/kg actual body weight daily. Providing additional protein may delay or prevent further lean body mass breakdown
in the setting of critical care inactivity and prolonged hospitalization days. Multiple factors contribute to protein loss, including trauma,
infection, burns, surgery, wounds, bed rest and medications [7]. Catabolic and severely stressed patients with multiple trauma sites and
burns require additional protein up to 2.5 g/kg daily.
Providing a hypocaloric, protein sparing feeding regimen is recommended for critically ill obese patients. Contrary to popular belief,
obesity does not ward off malnutrition due to additional fat stores and body habitus. Poor fuel utilization, futile cycling issues and insulin
resistance may predispose patients to protein degradation and greater loss of lean body mass, leading to sarcopenic obesity [8-10].
Hypocaloric and protein-rich diets decrease risks of infection and hospital length of stay compared to eucaloric feeds [7]. Furthermore,
underfeeding an obese patient boosts fat mass loss, while improving insulin sensitivity [5,8]. The goal for a critically ill obese patient
should be to avoid exceeding 60-70% of the estimated nutritional needs by providing 22-25 kcal/kg ideal body weight or 11-14 kcal/
kg actual body weight daily. Ideal body weight for females is calculated as 100 pounds for the first five feet in height, with the addition
of five pounds for each exceeding inch. Ideal body weight for males is calculated as 106 pounds for the first five feet in height and six
pounds for each additional inch. General nutritional goals are to provide 2.0 g/kg ideal body weight daily of protein for patients with a
BMI of 30-40 kg/m2 (class I and II) and 2.5g/kg for BMI 40 kg/m2 (class III). In addition, patients that are receiving hemodialysis or
continuous renal replacement therapy have increased protein requirements of up to 2.5 g/kg daily. Avoid restricting protein in patients
with liver failure [6].
Once estimated calorie and protein needs are determined, the appropriate formula should be determined. For example, a polymeric
1.5 kcal/ml solution is the formula chosen to feed a newly intubated patient. The estimated goal energy needs of this patient are 1,800
calories. Determine the total volume needed daily: 1800 divided by 1.5, as this is the calorie density of Isosource 1.5 (1.5 kcal/mL). Next,
divide the quotient by 24 hours to determine the continuous feeding goal rate. The ultimate goal volume is 50mL/hr.
Continuous infusion of enteral nutrition is often the suggested frequency for feeding critically ill patients [7]. Bolus feedings
are generally not recommended for critically ill patients due to the risk of intolerance and aspiration [7]. However, a patient may be
transitioned to an intermittent, nocturnal or bolus-feeding regimen as they clinically improve.

Caution should be practiced when initiating enteral nutrition in a hemodynamically unstable patient requiring vasopressors. A
marginally perfused gut can be further exacerbated with the initiation of enteral nutrition and the metabolic efforts of absorption [7].
Occasionally, trophic enteral nutrition will be initiated and monitored closely in patients at increased risk of aspiration. As arterial
blood pressure and hemodynamic stability improves and requires less vasoactive agents, the rate and volume of enteral nutrition can be
increased towards a goal rate as tolerated.
Additional sources of calories (i.e. dextrose intravenous fluids, propofol, dialysate solutions) should not be overlooked. Dextrose
infusions provide 3.4 calories per gram. Thus, D5W @ 100mL/hr continuously provides 120g dextrose x 3.4 kcal/g totaling 408 kcals
daily. Propofol contains a 10% lipid emulsion, which provides 1.1 kcal/mL. Propfol infusion should be monitored for extended use and
included in the overall nutrition equation. Clevidipine (cleviprex) is formulated as a 20% lipid emulsion providing 2 kcal/mL. Lipid
restrictions may be warranted for patients with significant lipid metabolism disorders. In addition, 60-70% of dextrose absorption can be
calculated from the total volume of dialysate solution received.

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Starting enteral nutrition at a minimal rate is recommended to monitor tolerance closely. A low rate of 10-30 mL/hr can be initiated
as tolerated by the patients medical condition [4]. In an intubated and/or sedated patient in the intensive care unit setting, 10mL/hr is
often ordered once the decision is made to enterally feed [4]. Trophic feedings, or the practice of feeding a small hourly volume, do not
provide a significant source of calories and nutrients. Nevertheless, this is likely a safe method to maintain gut integrity and monitor the
ability to advance towards the goal rate. The feeding can be advanced 10mL every 4-6 hours to the goal rate. Slower advancement may
be warranted with certain conditions and circumstances such as gastrointestinal intolerances, risk of refeeding syndrome and medical


Fluid requirements must be addressed in the ICU, as patients may receive unrecognized fluid(s) from multiple sources, including
intravenous resuscitation, medication co-formulations, enteral nutrition free water formulas, and free water flushes. Hydration and fluid
volume should be closely monitored, as organ failure, diuresis and increased fluid losses are especially common in the ICU. Free water
flushes with a minimum of 30-50mL every 4-6 hours are ideal to assist in meeting a patients fluid requirement and to prevent blockage
of a gastric feeding tube.
Short term feeding tubes can be inserted nasally or orally and terminate in the stomach, duodenum or jejunum. An oral tube
terminating in the stomach is appropriate for a critically ill, intubated patient. Post-pyloric termination and placement distal to the
ligament of Treitz may be warranted in certain scenarios such as pancreatitis, gastric dysmotility and recurrent emesis. This can be
achieved with a small bore, flexible tube with a weighted tip that can terminate in the appropriate location. Feeding tubes may be placed
incorrectly, increasing the risk for aspiration and perforation. Short term feeding tubes can be placed at the bedside and placement should
be confirmed by x-ray. Should enteral nutrition be expected for over four weeks of time, placement of a gastrostomy, jejunostomy or
gastrojejunostomy tube may be indicated.

Specialized Formulas
Enteral nutrition formulas vary with calorie and protein density, fiber content, and source of macro and micronutrients. Standard
formulas should be used in the ICU. Specialized formulas are designed for specific disease states and conditions; however they have
little impact in the majority of patients [7]. Standard, polymeric formulas are nutritionally complete for patients that are able to tolerate
unaltered molecules of macronutrients and can absorb nutrients without difficulty. Standard formulas have a caloric density of 1.0-2.0
calories/mL and may contain fiber to help support normal bowel function.
Elemental-type or predigested formulas may be better tolerated with minimal digestion requirements for patients with impaired
gastrointestinal function. Such conditions include pancreatitis, chronic diarrhea, malabsorption, Crohns disease, irritable bowel disease,
short-bowel syndrome, and those transitioned from parenteral nutrition. Elemental formulas contain a balanced amino acid and peptide
profile from hydrolyzed, predigested protein. In addition, the majority of the fat content is from medium chain triglycerides, decreasing
the potential for fat malabsorption. A variety of elemental formulas designed and marketed for specific clinical situation exist.
Specialized formulas such as those designed for renal disease, diabetes, pulmonary disease, hepatic disease and immunocompromised
individuals can address and often prevent exacerbations of certain conditions. For examples, renal formulas with low in electrolytes and
high protein formulations are ideal for patients on dialysis, while calorically dense renal formulas with restricted protein are ideal for
those that are not on renal replacement therapy but require fluid restriction. A change from a standard formula to a specialty formula
is warranted if electrolyte abnormalities exit or develop [3]. Modular protein can be added to a tube feeding regimen to better meet a
patients nutritional needs.

Parenteral Nutrition
Parenteral nutrition can supply calories to malnourished patients and has been associated with improved outcomes in specific patient
populations that will be discussed later in this section. Parenteral nutrition is not without risks and in many ICU patients can even be
harmful. The purpose of this section is to include an introduction to parenteral nutrition and not an exhaustive review, as the topic
can be relatively complex. One should understand that parenteral nutrition is not a benign therapy and a trained specialist should be
participating in the specific indications and prescription of parenteral nutrition.
In a previously healthy, well-nourished subject in whom enteral nutrition cannot be used, parenteral nutrition should be held for a
minimum of 7 days [7]. However, in patients with evidence of protein-calorie malnutrition upon admission, it may be appropriate to
initiate parenteral nutrition once resuscitated if enteral administration is not feasible. In patients undergoing gastrointestinal surgery and
enteral nutrition is contraindicated, parenteral nutrition should be started 5 to 7 days prior to surgery and continued post-operatively [7].
In post-operative patients not already on parenteral nutrition, parenteral therapy should be delayed in well-nourished patients for 5 to 7
days if enteral nutrition is not practicable. There is little-to-no benefit of giving parenteral nutrition for less than 7 days and thus, persons
expected to tolerate enteral nutrition by the 7th post-operative day should not receive parenteral nutrition [7].
In ICU patients receiving parenteral nutrition, permissive underfeeding to a goal of 80% of nutritional requirements should be
considered [1]. Once the patient is clinically stable and tolerating parenteral nutrition, a slow titration of parenteral nutrition to the
nutritional goal should then be done. During the first week of parenteral nutrition in the ICU setting, it is recommended to use parenteral
glutamine formulations without soy-based lipids [7]. Periodic efforts should be made to initiate enteral feedings in patients on parenteral
nutrition. As enteral nutrition is increased, parenteral nutrition should also be reduced [7].

Monitoring of Nutritional Therapy

Avoid holding enteral nutrition for <500mL of gastric residuals in the absence of other signs of intolerance [6]. In the presence
of elevated gastric residuals, consider prokinetic agents or a more concentrated tube feeding formula to be infused at a lower rate. In
the event of continuous high gastric residual volumes, placing a feeding tube below the ligament of Treitz may be considered. Gastric
residuals do not need to be assessed when enteral nutrition is infused through a small bore feeding tube.
It is important to avoid aspiration by elevating the head of the patients bed to 30-45 degrees. For patients that are at risk of aspirating,
continuous feedings, prokinetic drugs and post-pyloric feedings should be considered [6]. As oropharyngeal secretions can be aspirated,
research to support feeding directly into the small bowel as a method to decrease the risk of aspiration is inconclusive [4]. During emesis
episodes, providers should hold enteral nutrition and restart and monitor tolerance closely at a lower rate when possible. In the event of
severe intractable vomiting, the need for parental nutrition should be carefully evaluated.

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Continuous monitoring is warranted for a patient receiving nutritional support in order to evaluate whether the estimated nutritional
needs are being met. Should impediments be determined, a restructured plan needs to be implemented to meet the overall nutrition
goal. Avoidance and cessation of unnecessary tube feeding is vital in critically ill patients. Gastric dysmotility with delayed emptying
is common in the ICU, with multifactorial etiologies including hyperglycemia, medication effects, electrolyte abnormalities, elevated
intracranial pressures, hyperosmolar formulas and sepsis [7,11].


Diarrhea is defined as greater than 500 mL of stool output per day or >1,000 mL of output from an ileostomy [4,8]. Avoid inappropriate
cessation of enteral nutrition in the occurrence of diarrhea and rule out infectious and medicinal causes. Antibiotic-associated diarrhea,
including Clostridium difficile colitis, should not be mistaken for osmotic diarrhea. Collect stool specimens for Clostridium difficile
sampling prior to initiating any antimotility agents. In addition to sorbitol preparations used as elixirs, histamine H2-receptor antagonists,
and proton pump inhibitors, additional factors that may cause diarrhea include reduced absorptive surfaces, bacterial overgrowth and
gastric or colonic hypersecretion [4,7]. The actual formula and/or formulary delivery system may be bacterially contaminated and cause
diarrhea. An enteral nutrition formula may be hyperosmolar and/or have inadequate fiber to form bulk, excessive fiber, or high fat
content in the presence of fat malabsorption syndromes [12,13]. Diarrhea can also result from the rapid advancement in enteral nutrition
rate, in which case the rate should be reduced and recalibrated as tolerated. Modifying a standard or specialized formula to an elemental
formula or alternating between fiber-free and fiber containing formulas can be considered when diarrhea is due to enteral nutrition
Diarrhea output sometimes may be managed and reduced without medication. Increasing soluble fiber may be helpful in stable ICU
patients with diarrhea receiving enteral nutrition [6]. Soluble fiber formulations and bulk forming fibers (i.e. psyllium) can thicken stool
consistency and decrease colonic transit time. While the use of probiotics in replacing gastrointestinal microbiota has been described,
data remains limited and controversial [6].
An enterally fed critically ill patient should also be monitored for metabolic complications, including hyperglycemia and fluid or
electrolyte imbalances. Effective monitoring and control of blood glucose is vital. Moderate glucose control should be kept below 180
mg/dL [5].
Refeeding syndrome is a metabolic and clinical syndrome that may result when a carbohydrate infusion is aggressively initiated
with a malnourished patient. An intracellular shift of glucose and electrolytes as a result of insulin secretion can lead to dangerously low
levels of serum potassium, phosphorous and magnesium, potentially resulting in respiratory, cardiac, skeletal, neurologic, endocrine,
hematologic, metabolic, and/or gastrointestinal complications. Severe consequences also include seizures, paralysis, cardiac dysfunction,
and respiratory failure with ventilator dependency or death [14].
Refeeding syndrome is preventable but requires keen awareness and identification of patients at risk. It is crucial to understand a
patients nutrition history, including dietary patterns, weight changes and barriers from receiving adequate nutrition prior to admission.
High risk patients often have one or more of the following: BMI <16, unintentional weight loss >15% over the previous 3-6 months,
poor nutritional intake for >10 days, and/or low levels of potassium, phosphate or magnesium prior to the initiation of feeding [15].
A patient is considered high risk when 2 of the following are present: BMI <18.5, unintentional weight loss > 10% within 3-6 months
prior to admission, suboptimal nutritional intake for >5 days, or a history of alcohol abuse or use of insulin, chemotherapy, antacids or
diuretics medications [16-20]. Therefore, the nutritional re-introduction in patients at high risk for refeeding syndrome should be done
carefully. It is imperative to replete slowly, initiating enteral nutrition at 10mL/hr, and provide 1,000 kcal/day or 15-20 kcal/kg/day for
adults within the first 1-3 days. Enteral nutrition may continue to advance, reaching the goal rate within 5-7 days of initiation Monitor
phosphorous, magnesium and potassium daily and replete as warranted [20].
Malnourished patients are also at risk for vitamin deficiencies. Deficiency in thiamine, an essential coenzyme in carbohydrate
metabolism, can occur in less than 28 days in patients with inadequate nutritional intake and should be supplemented to prevent
Korsakoffs syndrome and Wernickes encephalopathy [15,18,19].

In general, enteral feeding within 24 to 48 hours of ICU admission should be a goal for critically ill patients. Patients admitted to the
ICU are frequently at risk of malnutrition and therefore should have routine nutritional assessments. Once a nutritional plan is in place,
the patients should be followed for enteral feeding tolerance and complications. There are limited, but important, roles for parenteral
nutrition and specialized formulas in the ICU. Nutritional therapies are best delivered with the input of a specialist trained in nutrition.

1. Chapman MJ, Nguyen NQ, Deane AM (2011) Gastrointestinal dysmotility: clinical consequences and management of the critically ill patient. Gastroenterol
Clin North Am 40: 725-739.
2. Hiesmayr M (2012) Nutrition risk assessment in the ICU. Curr Opin Clin Nutr Metab Care 15: 174-180.
3. Mueller C, Compher C, Ellen DM; American Society for Parenteral and Enteral Nutrition (AS.P.E.N.) Board of Directors. (2011) A.S.P.E.N. clinical guidelines:
Nutrition screening, assessment, and intervention in adults. JPEN J Parenter Enteral Nutr 35: 16-24.
4. The A.S.P.E.N (2012) Adult Nutrition Support Core Curriculum, (2ndedn): 171-183.
5. Ukleja A, Freeman KL, Gilbert K, Kochevar M, Kraft MD, et al. (2010) Standards for nutrition support: adult hospitalized patients. Nutr Clin Pract 25: 403-414.
6. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, et al. (2009) Guidelines for the Provision and Assessment of Nutrition Support Therapy
in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J
Parenter Enteral Nutr 33: 277-316.
7. Martindale RG, McClave SA, Vanek VW (2009) Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient:
Society of Critical Care Medicine and American Society for Parenteral and Enteral Nutrition: Executive Summary*. Crit Care Med. 37: 1757-1761.

9. McClave SA, Kushner R, Van Way CW 3rd, Cave M, DeLegge M, et al. (2011) Nutrition therapy of the severely obese, critically ill patient: summation of
conclusions and recommendations. JPEN J Parenter Enteral Nutr 35: 88S-96S.
10. Honiden S, McArdle JR (2009) Obesity in the intensive care unit. Clin Chest Med 30: 581-599, x.
11. Port AM, Apovian C (2010) Metabolic support of the obese intensive care unit patient: a current perspective. Curr Opin Clin Nutr Metab Care 13: 184-191.
12. Gottschlich MM (2007) The A.S.P.E.N Nutrition Support Core Curriculum: A Case-Based Approach- The Adult Patient. American Society for Parenteral and
Enteral Nutrition. Silver Spring, MD.
13. Kulick D, Deen D (2011) Specialized nutrition support. Am Fam Physician 83: 173-183.
14. Eisenberg P (2002) An overview of diarrhea in the patient receiving enteral nutrition. Gastroenterol Nurs 25: 95-104.

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8. Miller KR, Kiraly LN, Lowen CC, Martindale RG, McClave SA (2011) CAN WE FEED? A mnemonic to merge nutrition and intensive care assessment of
the critically ill patient. JPEN J Parenter Enteral Nutr 35: 643-659.


15. Mehanna HM, Moledina J, Travis J (2008) Refeeding syndrome: what it is, and how to prevent and treat it. BMJ 336: 1495-1498.
16. McCray S, Walker S, Parrish CR (2005) Much ado about refeeding. Pract Gastroenterol 29: 26, 3137
17. Mehanna H, Nankivell PC, Moledina J, Travis J (2009) Refeeding syndrome--awareness, prevention and management. Head Neck Oncol 1: 4.
18. National Institute for Health and Clinical Excellence Nutrition support in adults (2006) Clinical guideline CG32.
19. Romanski SA, McMahon MM (1999) Metabolic acidosis and thiamine deficiency. Mayo Clin Proc 74: 259-263.

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20. Yantis MA, Velander R (2008) How to recognize and respond to refeeding syndrome. Nursing 38: 34-39.


An ICU Bedside Review of Burns

Nazia Sultana* and Abid Butt
East Carolina University Brody School of Medicine, Department of Internal
Medicine, Section of Pulmonary, Critical Care & Sleep Medicine, Greenville, NC
27834, USA

*Corresponding author: Nazia Sultana, East Carolina University

Brody School of Medicine, Department of Internal Medicine, Section
of Pulmonary, Critical Care & Sleep Medicine, Greenville, NC 27834,
USA, E-mail:

The therapy of burn injuries has been described since the time of the ancients [1]. The evolution in our understanding of burn
management has progressed rapidly over the past century, with standards of care in burn management now well established. This
chapter will summarize the current management recommendations of burn injuries.

Emergency Triage
The initial evaluation of a seriously burned patient consists of a primary and secondary survey approach advocated by the
American College of Surgeons Committee on Traumas Advanced Trauma Life Support. The primary survey is focused on initial
stabilization (airway, breathing, circulation, disability assessment and adequate exposure) while the secondary survey provides a
more detailed attention to the burn injury location, extent and depth. Superficial or first-degree burns should not be included when
calculating the percent of total body surface area (TBSA), and thorough cleaning of soot and debris is mandatory to avoid confusing
areas of soiling with burns. Table 1 presents a potential approach to evaluating a seriously burned patient.
Step 1



Primary Survey

Vascular access and volume resuscitation

Step 2

Inhalation Injury

Pulse oximetry, oxygenation

Step 3

Secondary Survey

History and head-to-toe physical


Step 4

Estimate Burn Size

Lund-Browder diagram or Rule of Nines

(Figure 1)

Step 5

Estimate Burn Depth

Serial wound examinations

Step 6

Evaluate for other burns

Electrical, chemical, drug burns. Treat


Step 7

Evaluate need for antibiotics

Treat according to susceptibility patterns

Step 8

Evaluate for abuse

Notify proper authorities

As this chapter involves care for critically ill adult patients, we have not included the diagram adjusting TBSA for children.
Figure 1: Rule of nines to determine total body surface area that has been burned [3].

With direct thermal injury to the upper airway or smoke inhalation, rapid and severe airway edema is a potential life-threatening
complication. Anticipating the need for intubation and establishing an early airway is critical. Perioral burns and singed nasal hairs are
signs that the oral cavity and pharynx should be further evaluated for mucosal injury. However, these physical findings do not indicate

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Table 1: Management Summary of Burns [2].


an upper airway injury in itself. Signs of impending respiratory compromise may include a hoarse voice, wheezing, or stridor; subjective
dyspnea is a particularly concerning symptom, and should trigger prompt elective endotracheal intubation. In patients with concomitant
multiple traumatic injuries, especially oral trauma, nasotracheal intubation may be useful but should be avoided if oral intubation is

Classification of Burn Injury Based on Depth

Burn wounds are commonly classified as superficial (first degree), partial thickness (second degree), full thickness (third degree), and
fourth-degree burns (in which the underlying soft tissue affected) [4]. Partial-thickness burns are then sub-classified by depth of involved
dermis to either superficial or deep partial thickness burns. First-degree burns are painful but do not blister, while second-degree burns
have dermal involvement and are extremely painful with weeping and blistering. Third-degree burns are generally hard, painless, nonblanching lesions.Jackson described three zones of tissue injury following burn injury [4]. The zone of coagulation is the most severely
burned portion and is typically in the center of the wound. As the name implies, the affected tissue is coagulated and sometimes necrotic,
often requiring excision and grafting. Peripheral to coagulation zone is the zone of stasis, which has a local response of vasoconstriction
and resultant ischemia. Appropriate resuscitation and wound care may help prevent conversion to a deeper wound, but infection or
suboptimal perfusion may result in an increased burn depth. This is clinically relevant, as many superficial partial-thickness burns will
heal with expectant management, while the majority of deep partial-thickness burns require excision and skin grafting. The last area of a
burn is called the zone of hyperemia, which will heal with minimal or no scarring.

Fluid Resuscitation
As accurate estimation of a burn injury is crucial in guiding appropriate therapy, the size and depth are used as the prime determinants
of burn severity. The well-known rule of nines provides a quick estimate of burn extent, while the Lund-Browder chart [3], though more
laborious, is more accurate at quantifying the burnt TBSA. The Parkland or Consensus formula is the most widely used tool to estimate
the fluid resuscitation requirement in the first twenty-four hours after burn. It suggests administering volume resuscitation at 4 ml/kg/
TBSA, half of which is given in the first 8 hours post-injury and the remaining half in following16 hours. Traditionally, lactated ringers
have been the resuscitating fluid of choice as colloids may result in increased mortality [5]. Current guidelines do not recommend the use
of either hypertonic solutions or fresh frozen plasma, unless specifically indicated.

Infectious Complications
The burn wound provides a rich environment for pathogen colonization; transmission and infection. Burn victims who develop
infection have a substantially increased morbidity and mortality [6]. Early excision and grafting of the burn wound and early institution
of enteral feeding can help reduce the risk of infection. Topical antibiotics should be applied as needed on wounds. Although a metaanalysis [7] suggested potential benefit of prophylactic systemic antibiotics in burn patients, expert consensus advocates against it and
this remains an area of ongoing research [8]. The American Burn Association has published guidelines that advise not to use the term
systemic inflammatory response syndrome (SIRS) in burns patients as they are in a state of chronic inflammation. Instead, they
advocate using the modified criteria to define sepsis in these patients [9]. When an infection is suspected, local pathogen resistance
patterns should be taken into consideration when administering empiric antibiotics.
Invasive device infections secondary to Staphylococcus aureus, enterococci, gram-negative bacteria, and candida are often the cause
of infection in patients with burns less than 30% of TBSA [6]. Patients exposed to contaminated supplies or dusts during construction
are at risk for Aspergillus infections. Hydrotherapy equipment is discouraged due to its risk of gram-negative organism infections (i.e.
Pseudomonas, Acinetobacter). Instead, excision of burn wounds in an operating room setting is recommended. At this time, there is no
consensus on the most effective infection control practices and routine barrier precautions (i.e. contact, droplet, standard precautions).
As with any infection control measure, hand washing is imperative. A status of tetanus immunization should be sought and a tetanus
booster should be administered in the emergency room if needed.

Pain Management
Burns can produce excruciating pain, and thus aggressive analgesia with intravenous long and short-acting acting analgesics are
recommended [10]. It is also important to administer anxiolytic agents (i.e. benzodiazepines) with the analgesics to help reduce longterm anxiety.

Another important contributor to early mortality resulting from smoke inhalation is carbon monoxide (CO) poisoning [11]. The
affinity of CO for hemoglobin is approximately 200250 times greater than oxygen. Once bound to hemoglobin, it prevents the offloading of oxygen in the peripheral circulation, which can quickly lead to anoxia and death. Diagnosis requires an astute index of
suspicion as the pulse oximtery and standard arterial blood gases (ABG) may not be diagnostic. Arterial blood gas with co-oximetry will
reveal an elevated CO-Hb level if present. Treatment is by administering 100% oxygen, which effectively reduces the CO half-life from
about 250 minutes to 60 minutes. Hyperbaric oxygen may be appropriate for patients with serious exposure to CO (CO levels >25% with
depressed mental status suspected secondary to carbon monoxide exposure) who are hemodynamically stable and not requiring ongoing
Hydrogen cyanide toxicity may also be a cause of smoke inhalation injury. Patients may have a persistent lactic acidosis or STsegment elevation on electrocardiogram. Cyanide inhibits cytochrome oxidase, which in turn inhibits cellular oxygenation. Treatment
consists of sodium thiosulfate, hydoxocobalamin, and 100% oxygen. Sodium thiosulfate works by transforming cyanide into a nontoxic
thiocyanate derivative; however, it works slowly and is not effective for acute therapy. Hydroxocobalamin is recommended for immediate
therapy as it quickly complexes with cyanide and is excreted by the kidney. In the majority of patients, the lactic acidosis will resolve with
oxygenation and sodium thiosulfate treatment becomes unnecessary.

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When to Transfer Burn Patients

Specific criteria guide transfer of patients with more complex injuries or other medical needs to a burn center [5]:
Partial thickness burns greater than 10% of TBSA
Burns involving face, hands, feet, genitalia, perineum
Third degree burns in any age group
Electrical or chemical burns
Inhalational injury
Burns in children at a facility without pediatric support
Patients with complicated preexisting co-morbidities
Victims who require special social/emotional/rehabilitative interventions

Burn injuries remain a critical condition that should be managed by experienced personnel. Patients should be managed rapidly and
effectively to prevent morbidity and mortality. Healthcare providers should be familiar with recognizing burns, estimating body surface
area percentage, resuscitating victims, and transferring to specialized facilities if necessary.

1. Bryan CP (1930) The papyrus ebers.
2. Du Bois D, Du Bois EF (1989) A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 5: 303-311.
3. Lund C, Browder N (1944) The estimation of areas of burns. Surg Gynecol Obstet 79: 352-358.
4. JACKSON DM (1953) [The diagnosis of the depth of burning]. Br J Surg 40: 588-596.
5. Saffle J (2001) Practice Guidelines for Burn Care. J Burn Care Rehabil 22: 31.
6. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Health Care Infection Control Practices Advisory Committee (2007) 2007 Guideline for Isolation Precautions:
Preventing Transmission of Infectious Agents in Health Care Settings. Am J Infect Control 35: S65-164.
7. Avni T, Levcovich A, Ad-El DD, Leibovici L, Paul M (2010) Prophylactic antibiotics for burns patients: systematic review and meta-analysis. BMJ 340: 341.
8. Endorf FW, Gibran NS (2010) Chapter 8. Burns. In Schwartzs Principles of Surgery, Brunicardi FC, Andersen DK, Billiar TR, Dunn DL, Hunter JG, Matthews
JB, Pollock RE (Eds).
9. Greenhalgh DG, Saffle JR, Holmes JH 4th, Gamelli RL, Palmieri TL, et al. (2007) American Burn Association consensus conference to define sepsis and
infection in burns. J Burn Care Res 28: 776-790.
10. Faucher L, Furukawa K (2006) Practice guidelines for the management of pain. J Burn Care Res 27: 659-668.

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11. Hampson NB, Mathieu D, Piantadosi CA, Thom SR, Weaver LK (2001) Carbon monoxide poisoning: interpretation of randomized clinical trials and
unresolved treatment issues. Undersea Hyperb Med 28: 157-164.


Management of Common
Neurocritical Care Disorders
Paul J McCarthy1* and Arash Afshinnik2
East Carolina University- Brody School of Medicine, Department of Internal
Medicine, Section of Critical Care Medicine

Oschner Health Systems, New Orleans, LA

*Corresponding author: Paul J McCarthy, MD, East Carolina

University- Brody School of Medicine, Department of Internal Medicine,
Section of Critical Care Medicine, Greenville, NC 27834, Tel: +1 (318)
751-5462; E mail:

Neurocritical care specialists strive to improve health and clinical outcomes in patients with life-threatening neurological
illnesses that require urgent medical and/or surgical intervention(s). In the United States, neurocritical care is typically undertaken
by a collaboration of trained specialties, including neurologists, neurosurgeons, neuro-intensivists, and anesthesiologists. Common
conditions treated in a neurointensive unit include cerebrovascular accidents, traumatic brain/spinal cord injuries, epilepsy,
ruptured aneurysms, and neurologic infections. In this chapter, we will review major critical illnesses commonly managed in a
neurointensive unit.

Status Epilepticus
Brief overview
The traditional definition of Status Epilepticus (SE) is 30 minutes of sustained seizure or a period of 30 minutes in which a patient
has more than one seizure without recovery from the post-ictal state. Clinicians should understand that most seizures will terminate
spontaneously within a few minutes and seizures that persist over five to seven minutes should almost always be treated; and for
practical purposes are status epilepticus.
The estimated incidence of Generalized Convulsive SE (GCSE) in the United States ranges from 50,000 to 250,000 cases/year
[1]. Most seizures in the ICU are non-convulsive and cannot be diagnosed by physical exam. In dedicated Neurologic ICUs (NICU),
non-convulsive seizures have been reported in 18% to 34% of those that undergo EEG monitoring and 10% are in Non-Convulsive
Status Epilepticus (NCSE).The most common cause of SE is a prior history of epilepsy (usually associated with noncompliance).
However, a significant proportion of SE occurs in patients without a history of seizures. Other causes of seizures include cerebral
hemorrhage, encephalitis, Cerebrovascular Accident (CVA), alcohol, drugs, and metabolic derangements. Up to 10% of patients
admitted to medical wards for non-neurologic diagnoses will have a seizure and this is most often NCSE (7). Although there is
limited data, reports of up to a third of patients with altered consciousness are found to have non-convulsive seizures on EEG.
Multiple risks factors for seizure can occur in the ICU, with patient pathology and medications covering most of the risk factors.
Anoxic encephalopathy, renal failure, autoimmune disorders, hyper or hypoglycemia, infections, sepsis, liver failure and stroke
are a short list of pathologic processes that can be associated with seizures. Some of the medications that can contribute to the
development of seizures include antibiotics (especially beta-lactams), cyclosporine, theophylline, antipsychotics, diphenhydramine,
and tramadol. The likely cause of status epilepticus in a newly admitted general ICU patient may be noncompliance of antiepileptics,
infection, and alcohol withdrawal or drug toxicity.

Clinical features
Status epilepticus may be difficult to identify, especially in the ICU when factors such as an unknown neurologic baseline,
sedation or delirium can blunt the neurologic examination. Status epilepticus may present as frank tonic-clonic seizures or
obtundation, or anything in between. Moreover, non-convulsive status epilepticus is far more common in an ICU. Patients that
present with a tonic-clonic seizure and are treated with antiepileptic can appear to be asleep while instead they are in NCSE.About
20% of patients that have had clinical seizures terminated are in NCSE when the EEG is applied.Both convulsive status epilepticus
and NCSE as prolonged seizures correlate with poor outcomes due to direct neuronal injury. Systemic complications of convulsive
status epilepticus include rhabdomyolysis, acidosis, renal failure, hyperthermia, arrhythmias, trauma, and aspiration.

Status epilepticus is a medical emergency. The diagnostic workup and management should be done simultaneously. The initial
approach includes airway management, assessment of volume status, and concomitant antiepileptics. Most patients should have
the following tests and studies: Head computed tomography (CT), monitoring of vital signs, EEG (continuous if a suspicion of
SE), metabolic panel, and magnesium. Additional tests to consider based on clinical situation include magnetic resonance imaging
(MRI), lumbar puncture, toxicology, coagulation, liver enzymes, and antiepileptic levels. The importance of continuous EEG should
be stress as routine EEG only gives a brief snapshot of neurologic activity.

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Diagnostic workup


The basic principles include (1) control of all seizure activity as soon as possible and (2) ensuring appropriate dosing of antiepileptics
to prevent recurrence of seizures. Earlierinitiation of antiepileptic treatment allows for increased likelihoodof terminating the seizures.
Lorazepam has the most data supporting its use; followed by diazepam. While these medications are often under-dosed in fear of
associated respiratory depression, there is a higher risk of respiratory failure due to continued status epilepticus.
Initial therapy should include lorazepam at a minimum 4 mg initial dose (occasionally 0.05 0.1 mg/kg) with repeat does every five
minutes. Diazepam 0.15 mg/kg and midazolam 0.2 mg/kg are acceptable alternatives. Consider adding either valproic acid at 20 - 40
mg/kg IV with a target serum level of 15 microgram/mL or phenytoin/fosphenytoin at 20 mg /kg phenytoin equivalents with a target
serum level of 15 20 microgram/mL. Additional dosing of 5 mg/kg of phenytoin may be given if a patient remains in status epilepticus.
Although fosphenytoin is associated with less phlebitis than phenytoin, it provides no other benefits. Phenobarbital and levetiracetam are
acceptable alternatives with levetiracetam being used with increased frequency. Status epilepticus that continues despite treatment with
two medications is considered refractory. For patients continuing to be in SE after an infusion of midazolam or propofol, phenobarbital
infusion should be considered. Other potential therapies include lacosamide, ketamine, topirate, inhaled anesthetics and therapeutic
hypothermia. Patients in status epilepticus should be monitored with continuous EEG. Generally once complete termination is achieved
on EEG for several hours infusions can be slowly decreased. If seizure activity is noted on EEG, infusions are increased and antiepileptics
are increased and/or additional agents are added.

Neurointensive management of acute ischemic stroke (AIS) is a dynamic process and should be approached as a multi-organ, critical
care disease. Up to one third of patients with AIS will be admitted to a critical care setting [1]. However, with the concurrent growth
of tele-stroke networks, even higher rates of complicated AIS get referred to tertiary centers for critical care admission. AIS patients are
admitted to the ICU for many reasons including blood pressure control after tPA administration, hourly management of hyperglycemia,
frequent neurologic examinations and altered mental status due to cerebral edema that can lead to respiratory insufficiency. Our
discussion will focus on practical considerations that health care provides should be aware of surrounding the admission of an AIS
patient to the critical care setting.

Post-tPA care
Generally, there are two groups of AIS patients admitted to the critical care unit. The first group is obligated to spend at least 24 hours
in the ICU setting after acute intervention with tPA, mechanical thrombectomy or a combination of therapies. The second group of AIS
patients is critically ill as a result of their stroke, regardless of having or not having received an acute intervention. In this section, our
discussion will focus on practical hemodynamic, cardiac and hyperosmolar therapy principles related to admitting an AIS patient to the
critical care unit.

First published in 1955 and then approved for use within three hours in 1996, intravenous (IV)-tPA is the only AIS therapy with
randomized controlled trial data demonstrating improve outcomes [2]. In 2008, Hacke et al [3] demonstrated that certain patients can
receive IV-tPA within an extended window of time up to 4.5 hours. As a result of growing adoption of AHA guidelines and improved
education of both patients and health care providers, more patients with AIS are being treated with IV-tPA. The most feared side effect of
IV-tPA is intracranial bleeding. Per the AHA guidelines [1], patients that receive IV-tPA should have a systolic blood less than 180/105
mmHg for up to 24 hours after receiving IV-tPA. Otherwise, AIS patients who were not exposed to an acute intervention should be
allowed permissive hypertension up to a systolic blood pressure of 220mmg or diastolic blood pressure of 120mmHg.Depending on the
clinical context, the recommendation is to use labetalol as needed (PRN) and/or nicardipine infusion to keep the patients systolic blood
pressure below the desired limit. Correct use of these agents depends on understanding the patients baseline level of hypertension and
volume status on admission.

The use of isotonic fluids that include dextrose should be avoided due to negative impact hyperglycemia (blood glucose > 200) has
on stroke outcomes. First, even if a patient has been cleared for oral intake, the likelihood of patients consuming enough fluids to remain
euvolemic is low and supporting perfusion of the cerebral penumbra is a key aspect of managing AIS patients in the ICU. Secondly,
time and further study is required to completely understand the patients cerebrovascular injury. If evidence suggests contribution from
collateral flow is preventing further ischemia or a critical arterial stenosis is related to stroke etiology, poor intravascular volume could
lead to further ischemia. There are cases where induced hypertension may be beneficial; therefore euvolemia is essential for proper
vasopressor administration.

Cardiac Complications
The current AHA/ASA guidelines recommend a baseline electrocardiogram and troponin assessment on initial evaluation of patients
with AIS. These studies should not delay reperfusion strategies, but are very important on admission for both diagnosing the potential
stroke etiology as well as management of the patient. Cardiac ischemia and arrhythmias after AIS are a very real complication of AIS and

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AIS can acutely elevate blood pressure and patients who do not demonstrate this acute elevation may suffer from Chronic Heart
Failure (CHF) or sympathetic stunned myocardium. Actively lowering systolic blood pressure after acute stroke intervention can reduce
the risk of intracerebral hemorrhage. However, it may also place the remaining organ systems at risk for ischemia due to the patients
chronic adaptation towards higher perfusion pressures. In addition to blood pressure management, the patients volume status on
admission is also an important clinical parameter to determine. The goal for AIS patients is euvolemia [1], but realistically most patients
are hypovolemicupon admission. Therefore, AIS patients should receive IV isotonic fluids (i.e. normal saline) unless the patient has risk
factors that would lead to volume overload and pulmonary edema. Anticipating volume overload is important because pulmonary edema
can increase work of breathing, which could influence an AIS patient to evolve from respiratory insufficiency to acute respiratory failure.
If an AIS patient can tolerate IV fluids, they should remain on maintenance fluids for a few days.


most likely attributed to the increase in sympathetic tone, especially in patients with a history of coronary artery disease [4]. To allow
for proper detection of evolving myocardial infarction, AIS patients should be admitted with continuous telemetry and serial cardiac
troponins. Very mild elevation of serum troponin can be seen in about 10% of AIS patients and is associated in patients with renal
insufficiency and heart failure [5]. In addition to myocardial ischemia, arrhythmias such as atrial fibrillation alone or atrial fibrillation
with rapid ventricular response are also encountered in AIS patients on admission. AIS patients may not report chest pain or common
anginal equivalents due to a many reasons such as altered mental status or hemianesthesia. Therefore if EKG changes and serum troponin
levels raise the concern for ongoing myocardial ischemia, a cardiology consultation may be warranted. If myocardial ischemia is suspect,
management strategies to lower myocardial oxygen demand should be balanced with the possibility of further cerebral ischemia. Another
challenging decision is the use of IV anticoagulation in the acute stroke setting. The risk of hemorrhagic conversion can supersede the
benefits of its use, and this is often a discussion of risks and balances with your cardiology colleagues of what the best medical practice
should be for your individual patient. Factors to consider include the size of ischemic burden, presence of a prosthetic metallic valve,
trend and magnitude of serum troponin elevation, presence of atrial fibrillation and history of clotting disorder. Finally, the anatomical
location cerebral of ischemia can also play a role in the discussion of anticoagulation in the setting of acute stroke.

Hyperosmolar therapy
The result of ischemia to neurons is the loss of mitochondrial ATP production. This inhibits proper maintenance of the energy
dependent sodium potassium pump located at the cell membrane. As a result of AIS, concentrations of intracellular sodium increase
above normal and thereby promote the movement of water from the extracellular to intracellular compartment [6]. The macroscopic
result of increasing cellular swelling is cytotoxic edema. As cytotoxic edema involves larger areas of brain parenchyma, the tissue affected
will exert mass effect upon surrounding tissues. This growing intracranial mass effect can have serious life threatening consequences
and can lead to an increase in intracranial pressure. The medical management of cytotoxic edema in AIS patients includes the use of
hyperosmolar agents like mannitol and hypertonic saline solution. The ultimate goal of hyperosmolar therapy is to mitigate ongoing mass
effect and its sequelae by drawing water back into the intravascular space.
Mannitol is one of the most frequently used osmotic agents. It is a very large sugar alcohol that acts as an osmotic agent that is excreted
unchanged by the kidneys. When choosing mannitol to limit cerebral edema, concurrent administration of isotonic fluids is suggested
because of the diuretic effects of mannitol could create a hypovolemic state. The loss of intravascular volume in AIS patients could expand
the ischemic stroke burden by worsening oliguria within the penumbra surrounding the ischemic core. Therefore patients being treated
with mannitol should have their volume status closely monitored and urine output replaced with isotonic fluids. Mannitol typically has a
half-life of about 2.5 hours and under normal conditions is not able to cross an intact blood brain barrier. Thus, in AIS patients with renal
insufficiency and ESRD, mannitol should be used with caution because it may leak from the intravascular space into the extracellular
compartment. Another strategy employed to treat cerebral edema in the setting of ischemic stroke is hypertonic saline solutions [6-8].
Hypertonic saline solutions share the same proposed clinical benefits to mannitol, which include increasing cerebral blood volume and
oxygen delivery. This triggers the reflex autoregulatory vasoconstriction of cerebral arteries and thereby reducing cerebral blood volume
which inturn reduces intracranial pressure. Further benefits include improved blood flow due to decreased viscosity and improved red
blood cell rheology [9].
The benefits of hyperosmolar therapy should be balanced by the possible side effects of their use. Once ischemic changes begin to
compromise the BBB integrity, agents used to counteract cerebral swelling can leak out of the intravascular space and begin to occupy the
extracellular space. The result is hyperosmolar agents moving into ischemic tissue and thereby diminishing the gained osmotic gradient
that previously acted to move water out of the cell [6]. These exogenous solutes add to the existing extracellular oncotic pressure. This
imposes a further impediment to water moving back into the intravascular space; therefore, acting to keep the brain water content high.
As a result, regions of non-infarcted brain can lose more water content when compared to regions of infarction.
Another important consequence to continued administration of osmotic agents such as mannitol and hypertonic saline solutions is
brain adaptation. Brain adaptation is the generation of organic osmolesin response to decreasing brain water content [10]. Although
both mannitol and hypertonic saline can be used to reduce brain water content, hypertonic saline can be considered a better tool to
mitigate brain swelling because it causes less diuresis and can be given to patients with a wide range of renal function. Mannitol continues
to play an important role in the emergency setting where herniation and death may be imminent.

One specific area with very limited evidence is the nutritional support of acute stroke patients. The 2009 SCCM/ASPEN guidelines
find no correlation between gastric residual volume and the incidence of pneumonia [11]. They suggest feeding should not be held for
volumes less than 500ml. The 2002 North American consensus statement on aspiration in the critically ill patient state gastric residual
volume is not representative of gastric emptying, therefore, the practice of holding tube feeds due to assumption that this will lead to
aspiration is not supported by literature [12].Nutritional support of AIS patients should begin with documentation of a bedside dysphagia
screen prior to any oral intake of medication or nutrition. If any question remains about a patients ability to safely swallow after their
initial dysphagia screen, they should remain Nil per os (NPO) until consultation by a speech therapist is available. If a patient is deemed
NPO on admission, nasogastric feeding should be started within 24 hours of admission in patients except those that have received tPA,
wherein a placement of a feeding tube should be delayed.

Neurologic dysfunction of the central or peripheral nervous system can lead to respiratory insufficiency and often results in acute
respiratory failure. One area of neurologic dysfunction that results in acute respiratory failure is neuromuscular weakness. This is a broad
category of disorders arising from a wide range of anatomical locations. To begin your evaluation, start with a comprehensive review of
the current history and physical with special attention to what the patients baseline level of function and medical comorbidities prior
to admission. Combining neuroradiology and the physical exam, begin from the CNS (brain and spinal cord), the provider should
attempt to localize the etiology of weakness. Once a spinal cord etiology has been ruled out, the focus should turn to an evaluation of the
peripheral nerve, neuromuscular junction and muscle. Common etiologies include myasthenia gravis (MG), myopathies, amyotrophic

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Neuromuscular Disorders


lateral sclerosis (ALS), and Guillain-Barre Syndrome (GBS). This section will provide a focused review of MG exacerbation, GBS and
critical illness polyneuropathy/myopathy (CIP/CIM) and a practical approach to these clinical scenarios.

Myasthenia Gravis
Myasthenia Gravis is an autoimmune disease of the neuromuscular junction commonly caused by an antibody targeted against postsynaptic skeletal muscle acetylcholine receptors (AChR). Antibodies against AChR are detected in 80-85% if patients with generalized
weakness and 50% of patients with ocular myasthenia. However, when a patient with suspected MG is sero-negative for AChR antibodies,
5-8% of patients will be positive for another post-synaptic antibody called muscle-specific tyrosine kinase receptor (MuSK) [13].Clinically,
generalized fatigable weakness is a common clinical presentation, but patients can also presents with symptoms centered on the ocular or
bulbar muscle groups. Another key feature of patients who present with MG is tendon reflexes and the sensory exam should be normal.
If there is a question of the presence of facial weakness, looking at previous pictures or speaking with family members can help
establish a baseline. Opthalmoparesis and ptosis are common presentations of MG exacerbation. Double vision experienced by MG
patients is caused by cranial nerve III, IV or VI weakness in isolation or combination. Ptosis can accompany the complaint of double
vision. Dysphagia or dysarthria due to bulbar weakness can be noted with drooping of the mouth and complaints of difficulty handling
oral secretions. Furthermore, patients may note a change in the tone of their voice noted on examination as having a nasal/hypophonic
quality. To test a patient for generalized weakness of the limbs, have the patient repeat limb movements 10-20 times over a few minutes
and comparing their motor exam before and after. Finally, one very important functional test is neck flexor strength. Simply place your
hand on the patients forehead and ask the patient to resist your attempt to extend the neck. Weakness with neck flexion can act as a
bedside tool for anticipating respiratory insufficiency.
About 10-15% of patients can present in myasthenic crisis with a likelihood of acute respiratory failure [13]. Infections of the
respiratory system, stressors such as surgery, medications such as antibiotics and even with initiation of steroids for primary treatment
can precipitate and exacerbation or crisis. On presentation, a good history will help delineate symptoms due to excess cholinergic toxicity
verses a crisis. Patients may attempt to mitigate worsening symptoms by taking extra doses of anti-cholinesterase inhibitors. In practice,
patients can present with a mixed picture of MG symptoms and symptoms of cholinergic crisis which include miosis, excess secretions,
abdominal cramping, sweating, and diarrhea.
Initial evaluation and management of a MG exacerbation or crisis should include a baseline assessment of weakness, respiratory
status and medical evaluation. The assessment of weakness includes examination, understanding the patients baseline level of function.
Evaluation of the patients admission respiratory status should include the ability to count from 1 to 20 with one breath, assessment of
cough strength, gag reflex, chest x-ray and baseline ABG. Another very important tool to measure respiratory function is bedside incentive
spirometry. This tool provides clinical metrics such as vital capacity (VC), Negative Inspiratory Force (NIF), maximal inspiratory pressure
(MIP). VC, NIF, and MIP should be tested two to four times each day.
Patients with respiratory insufficiency can benefit from BiPAP. This mode of non-invasive positive pressure ventilation can provide
ventilatory support and improve oxygenation; however, these benefits should be weighed against the risk of aspiration in a patient too
weak to unmask themselves. Bulbar weakness, excess secretions, inability to handle secretions, poor gag, cough, and generalized weakness
are relative contraindications to non-invasive positive pressure ventilation. If a patient demonstrates respiratory insufficiency and the
risks associated with BIPAP outweigh the benefit, intubation should be performed. Intubation of a patient with neurologic dysfunction
requires unique planning that is tailored to the patients deficits. Specific suggestions when intubating a patient with neuromuscular
weakness includes selection of a non-depolarizing agent (i.e. rocuronium at 0.5mg/kg instead of 1mg /kg) are suggested to prevent
prolonged blockade. Additionally, because atelectasis is a sequel of neuromuscular weakness, hypoxia can rapidly develop once rapid
sequence intubation is initiated.
Oral pyridostigmine is a very important medication to continue during exacerbations and crisis. It can be held temporarily if
cholinergic side effects such as excess secretions have factored into initial management, such as the decision to intubate; however, once the
patient is stable on a ventilator, pyridostigmine should be reinstated. The decision to treat the patient with Intravenous Immunoglobulin
(IVIG) or Plasma Exchange (PLEX) is a decision that should be tailored to the individual patient.Both are equal in efficacy, but have
different risks and benefits. Generally, IVIG can be considered for patients who remain ambulatory on admission, whereas PLEX can
be used during crisis. The side effects of IVIG include flue like symptoms, headache, and symptoms resembling aseptic meningitis. The
potential serious adverse reactions to IVIG include myocardial infarction, stroke, acute kidney injury and anaphylaxis due to previously
undiagnosed IgA deficiency. After receiving either IVIG or PLEX, the next decision to start the patient on an immune modulating
therapy followed by steroids use.

Guillain-Barre Syndrome

The classic GBS symptoms that help make the diagnosis include numbness, paraesthesias, dysesthesias and limb weakness. The
pattern of limb weakness in patients with GBS is progressive, bilateral symmetric weakness that progresses over hours to days and
peaks in a few weeks. Initially the patients reflexes are normal or hyperreflexic, but the disease should ultimately lead to hyporeflexia
or areflexia. The clinical diagnosis of GBS is supported by the CSF finding of elevated protein without pleocytosis; although it should be
noted that albuminocytologic dissociation is seen with only 50% of patients during their first week of illness and up to 75% by the third
week. Additionally, lumbar puncture is necessary to rule out infectious diseases and malignancies.
The common medical complications of GBS include aspiration pneumonia, sepsis, arrhythmias, cardiac arrest, and dysautonomia.
Screening for dysphagia and frequent bedside spirometry is imperative to preventing aspiration and additional respiratory compromise.
GBS patients often require narcotics, gabapentin or carbamazepine to manage their acute pain and a small portion of patients will
continue to experience radicular, arthralgia or meningitic pain up to one year later. A dual approach of psychosocial support and SSRI
therapy is recommended. This approach can help patients accept and adapt to their disease and help improve their quality of life.

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GBS is an Acute Inflammatory Demyelinating Polyneuropathy (AIDP) characterized by diffuse weakness, areflexia and
albuminocytologic dissociation. GBS is also the most frequent cause of acute flaccid paralysis worldwide. Two thirds of patients
diagnosed with GBS experience a preceding illness of either upper respiratory infection or diarrhea with 30% of these cases attributed to
Campylobacter jejuni [14].


Overall, both PLEX and IVIG are effective therapies for patients with GBS. Patients admitted within two weeks of symptom onset,
bed bound on admission, and those that have minimal comorbidities can be considered for PLEX first. IVIG is widely available and may
be easier to administer, especially when placement of a central line is not readily available. A Cochrane systematic review published in
2012 concluded that PLEX is more effective than supportive care, IVIG may be slightly safer, and combination therapy was not more
effective than monotherapy [15].

In summary, there are many neurologic emergencies not discussed in this chapter that managed routinely in a neurointensive unit.
Many institutions do not have a dedicated neurointensive care unit, and intensivists, internists and other medical providers are left to
manage these patients. That said, people working in a critical care setting should be familiar with the diagnosis and management of
neurologic emergencies.

1. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, et al. (2013) Guidelines for the early management of patients with acute ischemic stroke: a
guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44: 870-947.
2. [No authors listed] (1995) Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke
Study Group. N Engl J Med 333: 1581-1587.
3. Hacke W, Kaste M, Bluhmki E, Brozman M, Dvalos A, et al. (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med
359: 1317-1329.
4. Christensen H, Boysen G, Christensen AF, Johannesen HH (2005) Insular lesions, ECG abnormalities, and outcome in acute stroke. J Neurol Neurosurg
Psychiatry 76: 269-271.
5. Jensen JK, Kristensen SR, Bak S, Atar D, Hilund-Carlsen PF, et al. (2007) Frequency and significance of troponin T elevation in acute ischemic stroke.
Am J Cardiol 99: 108-112.
6. Bardutzky J, Schwab S (2007) Antiedema therapy in ischemic stroke. Stroke 38: 3084-3094.
7. Bhardwaj A, Ulatowski JA (2004) Hypertonic saline solutions in brain injury. Curr Opin Crit Care 10: 126-131.
8. Qureshi AI, Suarez JI (2000) Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 28: 3301-3313.
9. Ziai WC, Toung TJ, Bhardwaj A (2007) Hypertonic saline: first-line therapy for cerebral edema? J Neurol Sci 261: 157-166.
10. Lien YH, Shapiro JI, Chan L (1990) Effects of hypernatremia on organic brain osmoles. J Clin Invest 85: 1427-1435.
11. McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, et al. (2009) Guidelines for the Provision and Assessment of Nutrition Support Therapy in
the Adult Critically Ill Patient:: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). J Parenter
Enteral Nutr 33(3):277316.
12. McClave SA, DeMeo MT, DeLegge MH, DiSario JA, Heyland DK, et al. (2002) North American Summit on Aspiration in the Critically Ill Patient: consensus
statement. JPEN J Parenter Enteral Nutr 26: S80-85.
13. Cabrera Serrano M, Rabinstein AA (2010) Causes and outcomes of acute neuromuscular respiratory failure. Arch Neurol 67: 1089-1094.
14. Jacob S, Viegas S, Lashley D, Hilton-Jones D (2009) Myasthenia gravis and other neuromuscular junction disorders. Pract Neurol 9: 364-371.

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15. Hughes RA, Swan AV, van Doorn PA (2012) Intravenous immunoglobulin for Guillain-Barr syndrome. Cochrane Database Syst Rev. Wiley Online Library 7.


ICU Delirium Attention to

Alison L Mortensen1*, Mark A Mazer2, Paul J McCarthy2 and
Ramzy H Rimawi3

Brody School of Medicine, East Carolina University, USA

Critical Care & Sleep Medicine, Section of Pulmonary, Department of

Internal Medicine, Brody School of Medicine, East Carolina University,

Section of Infectious Diseases & Travel Medicine, Section of Critical

Care Medicine, Department of Internal Medicine, Brody School of
Medicine, East Carolina University, USA

*Corresponding author: Alison L. Mortensen, Brody School of

Medicine, East Carolina University, Greenville, NC 27834, USA; Tel:
(252) 744-1020; E-mail:

Delirium is a common occurrence amongst patients in the intensive care unit (ICU).There are both patient and environmental
factors in the ICU that contribute to a high rate of delirium. Prevention, early detection and effective management of delirium are
important elements that can improve patient outcome and reduce length of stay and healthcare costs [1]. Additionally, the mortality
rate increases by approximately 10% each additional day a mechanically ventilated patient experiences ICU delirium [2]. Here we
will discuss methods of detection, risk factors, and management of delirium in the ICU.

The American Psychiatric Associations Diagnostic and Statistical Manual (DSM) and International Classification of Diseases
(ICD) characterize delirium as a disturbance of consciousness resulting inaninability to sustainor shift attention. This disturbance of
consciousness develops over a relatively short period of time, tends to fluctuate over the course of the day, and may not be associated
with pre-existing dementia. Delirium can be classified as hypoactive (i.e. agitated), hypoactive (i.e. quiet) or a combination of both. It is
often related to an underlying medical condition, substance intoxication, and/or medication adverse effect. Unlike dementia, delirium
can be often reversed once the underlying etiology is properly managed. The prevalence of delirium is especially high in the ICU, where
incidence rates areapproximately30%to 80% in elderly or intubated patients [3]. Delirium has been shown to be a strong independent
determinant of ICU and hospital length of stay, days of mechanical ventilation, healthcare cost, patient morbidity and mortality [1,4-6].
Additionally, a prolonged delirium state appears to be associated with long-term cognitive impairment [5]. Therefore, early detection
and appropriate management of delirium is imperative when dealing with critically ill patients.

Early detection of ICU delirium is necessary to avoid the potential adversities described above. Delirium is a psychiatric diagnosis
with specific criteria described in DSM and ICD. Although psychiatrists are well trained in diagnosing delirium, interventions and
checklists have been made so that non-psychiatric clinicians (i.e. ICU providers) can detect and prevent delirium. Extensive mental
status examinations are not always possible in the ICU setting, where patients are critically ill and often unable to communicate. As a
result, a number of bedside assessment tools have been developed to help quickly and accurately detect delirium by non-psychiatric
clinicians, including intensive care physicians and nurses. Amongst these include the Confusion Assessment Method (CAM) and the
intensive care delirium-screening checklist.

Confusion Assessment Method (CAM)

1. Acute onset and fluctuating course determined by observation (usually bya family member or nurse).This may also be measured
as fluctuation of scores such as sedation scales, or Glasgow Coma Scale (GCS) within 24 hours. Presence requires positive response to
the following questions: Is there evidence of an acute change in the patients mental status from their baseline? Does this abnormal
behavior fluctuate during the day?
2. Inattention a positive response to the following question: Did the patient have difficulty focusing attention? Examples included
is tractibility and/or difficulty in keeping track of what was being said.
3. Disorganized thought a positive response to the following question: was the patients thinking disorganized or incoherent (i.e.
rambling or irrelevant conversation), unclear or illogical flow of ideas, or unpredictable moving from subject to subject?
4. Altered level of consciousness a level of consciousness other than alert (i.e. vigilant, lethargic, stupor or coma).

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Inouye et al. developed the CAMas a way for non-psychiatric clinicians to detect delirium acutely in high-risk settings [7]. The
5-minute checklist has a high sensitivity and specificity in the diagnosis of delirium when compared with an official diagnosis made
by a psychiatrist. It is based on the presence of 4 clinical features, including observation, patient interview and collateral information
obtained by family members or healthcare providers. The reported sensitivity and specificity of this test are 76% and 96%, respectively
[1]. The diagnosis of delirium by CAM requires the presence of features 1, 2 and either features 3 or 4 of the following:


Modified Confusion Assessment Method for the ICU (CAM-ICU)

A major limitation of the CAM tool in the ICU is that patients are often unable to verbally communicate during the patient interview,
which makes detection of Inattention and Disorganized thought difficult to assess. In response to this challenge, Ely et al. established a
modified Confusion Assessment Method for use in the intensive care unit (CAM-ICU), which uses attention-screening examinations
(ASE) to assess Inattention by methods other than verbal communication [3]. The picture recognition test involves remembering 5 simple
pictures for a period of 3 seconds. The patient is shown 10 pictures (5 of which they have already seen and 5 of which are new) and asked
to indicate if each picture is one they have just seen (nod for yes) or if this picture is new (shake head for no). In patients with known
visual impairment, the picture recognition ASE is substituted with the vigilance random letter test, in which the patient is instructed to
squeeze the hand of the test administrator every time the letter A is read from a long series of random letters (i.e. SAVEAHAART). To
test for the presence of disorganized thought, the test administrator asks the patient simple yes/no questions such as will a stone float in
water? or does one pound weigh more than two pounds?

Intensive Care Delirium Screening Checklist (ICDSC)

Another modality commonly used to detect ICU delirium is the Intensive Care Delirium Screening Checklist (ICDSC) [8]. Like the
CAM-ICU, this is an 8-item checklist that also does not necessitate verbal communication. A point is given for every category the patient
demonstrates during the evaluation. If an item is not assessable, the patient does not receive a point (scored as negative). A patient is
delirious if 4 points of the following are present:


a) Drowsy and requires mild to moderate stimulation for response; OR
b) Hyper-vigilant. (No points are given for a sleeping state or stupor)


Altered level of consciousness






Hallucination, delusion or psychosis


a) hyperactivity that requires use of sedative drugs or restraints to control potential danger to the patient;
Psychomotor agitation or retardation OR
b) hypoactivity or clinically noticeable psychomotor slowing.

Patient displays a level of Inattention, including distractibility by external stimuli, difficulty keeping up with
conversations, or difficulty shifting focus
Obvious mistake in time, person or place.
Any indication of hallucinations (grabbing for an unseen object), delusion, or gross impairment in reality


Inappropriate speech or mood

Patient displays inappropriate speech or mood


Sleep/wake cycle disturbance

Patient sleeps < 4 hours during the night, has frequent awakenings (not related to medical staff initiated
awakenings), or sleeps throughout most of the day.


Symptom fluctuation

Fluctuation of any of the manifestations of any item or symptom within a 24 hour period (i.e. between
Table 1: Intensive Care Delirium Screening Checklist.

Comparison of CAM-ICU with ICDSC and limitations of these tools

Studies have demonstrated that the ICDSC has a high sensitivity (99%) but low specificity (64%) for the diagnosis of delirium when
compared to formalized psychiatric assessment [6]. The CAM-ICU has a lower sensitivity (93%) and higher specificity (96%) and may
correlate more strongly with patient outcome than ICDSC [9]. The use of sedation and analgesia in the ICU can lead to the over diagnosis
of hypoactive delirium using the above scoring systems. Ideally, patients should be assessed for delirium using CAM-ICU or ICDSC
exclusively during sedation vacations with a Richmond Agitation Sedation Scale (RASS) of -2 [10].





Overtly combative, violent, immediate danger to staff


Very Agitated

Aggressive and pulls tubes/catheters



Fights ventilator, frequent non-purposeful movements



Anxious by movements are not aggressive





Not fully alert but has sustained awakening (eye opens to voice 10 seconds)


Light Sedation

Briefly awakens with eye contact (eye opens to voice <10 seconds)


Moderate Sedation

Eye opens to voice but does not make eye contact


Deep Sedation

No response to verbal stimulation, but responds to physical stimulation


Not Arousable

No response to verbal or physical stimulation

Table 2: Richmond Agitation Sedation Scale.

Many modifiable and non-modifiable risk factors for the development of delirium have been established. A great deal of attention has
been given to the modifiable environmental risk factors, which may be relatively easy and inexpensive to change. Residence in the ICU,
in itself, is associated with ICU delirium, likely related to the environment setting, immobility and disease state [11]. In addition to the
critical medical state that may precipitate delirium, ICU patients often receive medications that can potentiate or worsen their delirium.
Non-modifiable risk factors for delirium include increased age and baseline cognitive or functional impairment. While delirium and
dementia are different diagnoses, demented patients can have concurrent delirium that can be missed. An abrupt onset change in mental
status in a demented patient should still raise the concern for delirium, as this maybe the first sign of an underlying illness (i.e., sepsis).
Modifiable risk factors for the development of delirium include: environmental factors (i.e. lack of windows or a clock in the room),
immobility, disrupted sleep-wake cycles, sensory impairment, choice of sedation and analgesics, and tethers (i.e. physical restraints,
cardiac telemetry wires,urinary catheters) [11]. These risk factors can be modified to reduce the incidence and duration of delirium.

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Risk Factors for the Development of Delirium


Management of ICU Delirium

The management of delirium is focused on identification of the underlying cause, avoiding known triggers and aggravating factors of
delirium, and supportive care to prevent further physical and cognitive decline. Examples include treatment of the underlying infection,
contact lenses/glasses, hearing aids, antipsychotics, mobility, and/or removal of unnecessary catheters.
A. Determining the underlying cause
Essentially, the optimal way to effectively treat delirium is to address the underlying cause. Delirium occurs as a result of a medical
condition, substance intoxication or adverse medication effect. The most common medical etiologies of delirium are fluid and electrolyte
disturbances, infections, and metabolic disturbances. Intoxication with any number of illegal substances, including cocaine and
hallucinogens, as well as therapeutically prescribed medications, can cause a transient state of delirium. Additionally, withdrawal from
alcohol or sedatives can be the underlying etiology or a confounding factor. Medications associated with delirium include benzodiazepines,
narcotics and anticholinergic medications. The majority of delirium cases have up to 3 separate underlying etiologies per case [12].
B. Avoiding factors known to trigger or aggravate delirium
There are many known triggers and aggravating factors that may cause or worsen delirium (see modifiable risk factors). Here, we
will discuss how to optimize the environment of the ICU in order to reduce the duration and severity of delirium. Topics of focus include
the use of tethers, disruption of sleep-wake cycles, sensory impairments, and immobility.
Tethers include physical restraints, bladder catheters, cardiac telemetry wires, and intravenous catheters. Efforts should be made to
limit the use of physical restraints in ICU patients, as they have been shown to increase the severity and duration of delirium [11]. Bladder
catheterization and rectal tubes are also considered physical restraints as they limit the patients ability to move freely in order to void.
Although often necessary, the need for continued catheterization should be assessed on a daily basis.
Disruption of the normal sleep-wake cycle is a common occurrence in the ICU and a recognized risk factor for delirium. Simple
measures such as providing low light and limited sensory stimulation at night may promote a natural sleep/wake cycle [13]. To take this
concept one step further, some programs have begun incorporating bright light therapy to consolidate circadian activity rhythms and
improve sleep, which has shown to improve sleep and functional status of primarily hyperactive delirious patients [14]. Other factors
to consider in optimizing sleep-wake cycles include opening window blinds during the day, avoiding continuous televisions watching,
limiting visitors, and/or avoiding frequent awakenings at night. The use of pharmacological sleep remedies are generally ill advised in the
delirious patient as many work via GABA-receptor modification and have strong anti-cholinergic side-effect profiles. Natural sleep, while
difficult to accomplish, should be encouraged in all patients while being tended for in the ICU.
Sensory impairments such as vision and hearing deficiencies are common comorbidities amongst elderly patients. Providing these
patients with their regular vision glasses and/or hearing aids can greatly improve their ability to stay oriented to their environment. This
may reduce the incidence of delirium while building patient rapport.
Immobility is another risk factor for the development and unnecessary prolongation of ICU delirium. Incorporating early
mobilization is a challenge in the ICU setting, often simply due to the physical limitations and multiple tethers such as ventilators,
catheters, monitors and intravenous access. While these may complicate ambulation and physical activity in the ICU, it is by no means
impossible. Immobility is largely a result of culture that has been continued due to its associated ease of patient management in the ICU.
Immobility has been associated with numerous complications, including ICU delirium, bedsores, and physical deconditioning [15]. Early
physical and occupational therapy in critically ill patients is relatively easy and reduces the incidence and duration of delirium, reduces
healthcare costs, and increases ventilator-free days.
C. Pharmacologic therapy
Pharmacologic agents, including sedatives, can potentiate delirium, further complicating and/or prolonging the patients ICU course.
While certain sedatives (i.e. lorazepam) have been associated with the development of delirium, propofol and opiates have not [16].
Lorazepam may be indicated in patients with alcohol withdrawal syndrome, but should not be discontinued abruptly in benzodiazepine
dependent patients. A meta-analysis of critically-ill patients after high-risk surgery receiving dexmedetomidine led to a modest reduction
in ICU length of stay without effects on delirium or mortality [17]. However, there was a reduction in delirium in mechanically ventilated
patients with dexmedetomidine compared to lorazepam [18]. Dexmedetomidine-induced bradycardia should be monitored closely in
elderly patients underlying heart disease.
In 2002, the clinical practice guidelines and American Psychiatric Association endorsed the use of haloperidol (usually in the
intravenous injection form) for the treatment and prevention of ICU delirium, especially when agitation is present [14]. However,
its effectiveness is limited by the paucity of placebo-controlled trials. The advent of second-generation (atypical) antipsychotics (i.e.
olanzapine, ziprasidone, quetiapine) with their reduced adverse profiles has sparked interest in the efficacy and safety in ICU-delirium.
Although prospective clinical trials and data are limited, olanzapine and resperidone have demonstrated a similar decrease in the incidence
of delirium with less adversities and non-inferior efficacy when compared to haloperidol [19]. The use of scheduled, titrated quetiapine
has also been reported in the treatment of ICU-delirium, with faster resolution, less agitation, and reduced ICU length of stay [20].

Healthcare providers should be proactive in the prevention, diagnosis and treatment of ICU-delirium. Efforts should be made
to prevent ICU-delirium with attention to modifiable and non-modifiable risk factors, and screening using CAM-ICU or ICDSC
methodology implemented. As patient safety is a top-priority for healthcare providers, prevention and appropriate management of ICUdelirium must be a standard of ICU care.

1. Brummel NE, Vasilevskis EE, Han JH, Boehm L, Pun BT, et al. (2013) Implementing Delirium Screening in the ICU: Secrets to Success. Crit Care
Med 41: 2196-2208.
2. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, et al. (2004) Delirium as a predictor of mortality in mechanically ventilated patients in the
intensive care unit. JAMA 291: 1753-1762.

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3. Ely EW, Margolin R, Francis J, May L, Truman B, et al. (2001) Evaluation of delirium in critically ill patients: validation of the Confusion Assessment
Method for the Intensive Care Unit (CAM-ICU). Crit Care Med 29: 1370-1379.
4. Thomason JW, Shintani A, Peterson JF, Pun BT, Jackson JC, et al. (2005) Intensive care unit delirium is an independent predictor of longer hospital
stay: a prospective analysis of 261 non-ventilated patients. Crit Care 9: R375-381.
5. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, et al. (2010) Delirium as a predictor of long-term cognitive impairment in survivors
of critical illness. Crit Care Med 38: 1513-1520.
6. Ouimet S, Kavanagh BP, Gottfried SB, Skrobik Y (2007) Incidence, risk factors and consequences of ICU delirium. Intensive Care Med 33: 66-73.
7. Inouye SK, van Dyck CH, Alessi CA, Balkin S, Siegal AP, et al. (1990) Clarifying confusion: the confusion assessment method. A new method for
detection of delirium. Ann Intern Med 113: 941-948.
8. Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y (2001) Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive
Care Med 27: 859-864.
9. Tomasi CD, Grandi C, Salluh J, Soares M, Giombelli VR, et al. (2012) Comparison of CAM-ICU and ICDSC for the detection of delirium in critically ill
patients focusing on relevant clinical outcomes. J Crit Care 27: 212-217.
10. Haenggi M, Blum S, Brechbuehl R, Brunello A, Jakob SM, et al. (2013) Effect of sedation level on the prevalence of delirium when assessed with
CAM-ICU and ICDSC. Intensive Care Med .
11. McCusker J, Cole M, Abrahamowicz M, Han L, Podoba JE, et al. (2001) Environmental risk factors for delirium in hospitalized older people. J Am
Geriatr Soc 49: 1327-1334.
12. Francis J, Martin D, Kapoor WN (1990) A prospective study of delirium in hospitalized elderly. JAMA 263: 1097-1101.
13. Hessler CS, Josephson (2011) A Diagnosis, Prevention, and Management of Delirium in the ICU. ICU Director 2: 122-127.
14. Chong MS, Tan KT, Tay L, Wong Y, Ancoli-Israel S (2013) Bright light therapy as part of a multicomponent managment program improves sleep and
functional outcomes in delirious older hospitalized adults. Clin Interventions Aging 8: 565-572.
15. Schweickert WD, Pohlman MC, Pohlman AS, Nigos C, Pawlik AJ, et al. (2009) Early physical and occupational therapy in mechanically ventilated,
critically ill patients: a randomised controlled trial. Lancet 373: 1874-1882.
16. Devlin JW, Skrobik Y (2011) Antipsychotics for the prevention and treatment of delirium in the intensive care unit: what is their role? Harv Rev
Psychiatry 19: 59-67.
17. Cavallazzi R, Saad M, Marik PE (2012) Delirium in the ICU: an overview. Ann Intensive Care 2: 49.
18. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, et al. (2007) Effect of sedation with dexmedetomidine vs lorazepam on acute brain
dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 298: 2644-2653.
19. Gilchrist NA, Asoh I, Greenberg B (2012) Atypical antipsychotics for the treatment of ICU delirium. J Intensive Care Med 27: 354-361.

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20. Devlin JW, Roberts RJ, Fong JJ, Skrobik Y, Riker RR, et al. (2010) Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective,
multicenter, randomized, double-blind, placebo-controlled pilot study. Crit Care Med 38: 419-427.


Approach to Fever in the Intensive

Care Unit
Kaushal B Shah1*, Urvi D Gandhi2, Porus S Shah3 and
Thomson Pancoast4
Department of Internal Medicine, Section of Infectious Diseases and Travel
Medicine, East Carolina University- Brody School of Medicine, USA
Vidant Internal Medicine, Vidant Beaufort Hospital, Washington, NC, USA
Keck Graduate Institute, Claremont, California, USA
Department of Internal Medicine, Section of Pulmonary, Critical Care & Sleep
Medicine, East Carolina University- Brody School of Medicine, USA

*Corresponding author: Kaushal B. Shah, Department of Internal

Medicine, Section of Infectious Diseases and Travel Medicine, East
Carolina University- Brody School of Medicine, USA, Tel: 252-7445725; (Fax) 252-744-3472; E-mail:

Fever is a very common manifestation in the intensive care unit (ICU), occurring in about 50% of critically ill patients as a
response to a pathophysiological stressful stimulus [1-3]. Fever has also been linked to an increased mortality in patients admitted
to the ICU [4]. In spite of this, the approach to management of fever remains a challenging controversy. In this chapter, we
will define hyperthermia and present the pathophysiology, epidemiology, etiologies, and management of fever in ICU patients.

Definition & Measurements

While fever and hyperpyrexia may be pathophysiologically similar, hyperthermia is a different condition. Fever is a rise in
the hypothalamic set point in conjunction with a rise in body temperature that exceeds normal daily variations. Hyperpyrexia is
a hypothalamic conjunctive response to an extremely elevated temperature, usually >40.0-41.5C or 104-106.7F. On the other
hand, hyperthermia is an elevation in the core body temperature (usually >37.5-38.3C or 99.5-100.9F) without a change in the
hypothalamic set point due to a failure in dissipating heat in relation to its rate of production. In critically ill patients, it can
be caused by various infectious and non-infectious etiologies, including environmental toxins, pontine hemorrhage, malignant
hyperthermia (due to anesthetic agents), neuroleptic malignant syndrome (due to neuroleptic drugs), and heat stroke [5].
A temperature of 37C (98.6F) is considered normal (normothermic) with a circadian variation of about 0.5-1.0C. The body
temperature can vary depending on site (i.e. rectal versus oral), humidity, menstrual cycle, room temperature, clothing, and the time
of day in which it was recorded, with evenings often being highest. The Infectious Diseases Society of America (IDSA) and Society
of Critical Care Medicine (SCCM) have made a consensus agreement to define fever as a temperature >38.3C (>101F) for ICU
patients [3-6].
Accurate and consistent body temperature measurements are imperative when managing critically ill patients. There are various
methods, sites, instruments and techniques used to measure body temperature. While a mixed venous sample from a pulmonary
artery catheter or internal jugular/subclavian vein central venous catheter is an optimal site for measuring core body temperature,this
may not always be feasible [7-9]. Infrared ear thermometry, urinary bladder catheter thermistor, and esophageal probes provide
slightly lower temperatures, whereas rectal temperatures measured via mercury thermometers or electronic probes provide
temperature recordings slightly higher than the core temperature. Although oral and axillary sites are considered suboptimal sites
for temperature gauging, rectal and ear lobe recordings are acceptable alternatives [7,10,11].


Pyrogenic cytokines, produced by white blood cells, are induced by exogenous stimuli, such as endotoxins. The cytokines
mainly involved in the development of fever include interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor alpha
(TNF-) [14-17]. The primary site of action of these cytokines is at the organum vasculosum of the laminae terminalis (OVLT)
of the central nervous system. The OVLT is bordered by the preoptic nucleus and anterior hypothalamus, where the cytokines
bind to specific toll-like receptors [18,19]. Once bound to their receptors, these cytokines trigger the release of prostaglandin E2
and phospholipase A2. Phospholipase A2 causes the release of arachidonic acid, which then leads to the cyclooxygenase pathway
activation [15]. Prostaglandin E2 diffuses across the blood brain barrier and decreases the degree of preoptic warm sensitive neurons
firing, consequently resetting the hypothalamic thermostat to produce elevated, or hyperthermic, temperatures [15,20,21].
A heat shock response is a protective mechanism mediated by heat shock proteins (HSP) in response to various stressful stimuli
that denature proteins such as increased temperature, hypoxia, and chemical toxins. HSPs, especially HSP-60 and HSP-70, play a
pivotal cytoprotective role by interacting with denatured proteins and activating their preservation and promoting their cellular
elimination [22-24]. HSPs are the potential link between basic science and clinical relevance in the management of fever in critically
ill patients. For example, Nguyen et al described in vivo reduction in HSP-70 following experimental peritonitis in sheep, suggesting
antipyretics do not improve body function [25].

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A febrile response is a coordinated autonomic and neuroendocrine reaction, defined by Plaisance and Mackowiak as a complex
physiologic reaction to disease involving a cytokine-mediated rise in core temperature, generation of acute phase reactants,
and activation of numerous physiologic, endocrinologic, and immunologic systems [12,13]. Fever is ultimately regulated by the
hypothalamus via neural input from peripheral thermoreceptors.


There is limited data describing the epidemiology of fever in critically ill patients (Table1) [1,4,26,27]. Any condition, including
infectious and non-infectious conditions, that leads to a release of proinflammatory cytokines (i.e. IL-1, IL-6, TNF-) can give rise to
fever (Table 2). While 10% of patients with sepsis are hypothermic and approximately 35% are normothermic at presentation, 90%
of patients with severe sepsis are hyperthermic [28-30]. The reason for normothermia in some patients with evidence of infections
while others develop elevated or reduced body temperatures is not well established [31]. In a 2002 public report by Klevens et al. of US
hospitals, approximately 417,946 ICU patients with fever had a healthcare-associated infection, including pneumonia and bloodstream
infections [32].

Number Of Patients

Fever (C) Definition

Fever incidence (%)


Infectious Etiology (%)

Laupland et al. [1]


> 38.3


Odds ratio: 1.91 for

medical patients
acquiring fever in ICU


Barie et al. [4]


> 38.2


Increased mortality
among febrile patients
(26.5 vs 6.5%; p <0.01)


Peres et al. [27]


> 38.3


Increased mortality
among febrile patients
(35.3 vs 10.3%; p <0.01)


Ciciumaru et al.


> 38.4


Increased mortality
among febrile patients
(62.5 vs 29.6%; p <0.01)


Table 1: Review of studies describing epidemiology of fever in an ICU setting [33]

Non-Infectious Causes

Infectious Causes

Alcohol/drug withdrawal


Environmental toxin

Catheter-related infections

Cerebrovascular accident

Infective endocarditis


Primary bacteremia

Aspiration pneumonitis

Clostridium difficile associated disease

Post-transfusion reaction


Drug fever

Urinary tract infections


Intra-abdominal infections (i.e. peritonitis, cholecystitis)

Embolic phenomenon

Fungal infections (i.e. candidemia)



Gastrointestinal bleeding

Skin & soft-tissue infection



Intestinal or myocardial ischemia

Acute respiratory distress syndrome
Transplant rejection
Table 2: Common infectious and non-infectious causes of fever in the ICU.

There are many non-infectious causes of fever >38C (100.4F), including drug reaction, post-transfusion reaction, thromboembolism,
and intracranial bleeding [34-37]. Antibiotics can be the cause of fever and obscure the management of infectious conditions. Common
antibiotics associated with hyperthermia include beta-lactam agents. Drug-fevers, defined by a temperature greater than 38C without
other plausible causes, is more common in patients with cystic fibrosis, likely due to the hyperimmune state, and often resolves 72 hours
after discontinuing the offending antimicrobial agent [38].

The approach to fever in the ICU is difficult to standardize, as the causes of fever in an ICU setting are vast (Figure 1). A comprehensive
history and physical examination should be the first step in evaluating hyperthermia. If a focal source can be ascertained, then sourcedirected diagnostic testing should be performed. If the patient is clinically stable (lacking hemodynamic instability, altered mental status,
decreasing urine output, or coagulopathy) and the temperature is <102 F, it may be reasonable to withhold empirical antibiotics until
diagnostic and microbiologic workup is done. On the other hand, if the patient is clinically worsening, rapid administration of empirical
antibiotics is warranted as there is a significant increase in mortality with each hour that passes without therapy [39].

All medications should be reviewed and reconciled to assess for drug-fever. Doppler studies should be done in patients at
risk for venous or arterial thromboembolic disease. Computed tomography (CT) may be necessary to assess for malignancy
or bleeding, including intracranial and gastrointestinal bleeds, as the cause of fever. Other laboratory diagnostic tests
should be done to assess for rhabdomyolysis, myocardial or intestinal ischemia, and vasculitic or rheumatologic disorders.

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While acquisition of blood cultures and/or other microbiologic sampling should be collected prior to antibiotic administration to
increase the diagnostic yield, this may not always be feasible. Coburn et al. illustrated the relatively low probability of detecting bacteremia
with isolated fever and therefore advocate against blood culture sampling in patients with isolated fever [40]. Serum biomarkers, including
procalcitonin, can help assess for bacterial infectious causes of fever [41].


Figure 1: Approach to fever in an ICU patient

Whether to suppress a fever in patients with sepsis remains a controversy at this time. Hyperthermia can have a favorable improvement
in immune function, including enhancement of neutrophil and macrophage function, antibody production, pathogen inhibition, and
T-cell activation [42]. Therefore, suppressing the fever in septic patients may suppress the host bacteriostatic properties and potentially
prolong the illness. Brain damage from fever is unlikely to occur as long as the temperature is below 107.6F, or 42C [43]. Although an
increased body temperature can raise oxygen consumption (roughly ten percent per degree Celsius), cardiac output, and carbon dioxide
production [23], numerous studies have advocated against suppressing fevers with antipyretics or cooling blankets in septic patients
without intracranial pathologies, including ischemic stroke, subarachnoid and intracerebral hemorrhage, traumatic brain injury [44-48].
Initiating early antipyretics has not been shown to reduce mortality or vasopressor requirement in patients with severe gram-negative
sepsis [49]. Furthermore, while it is plausible that respiratory failure can result from a lack of suppressing tachypnea and high minute
ventilation requirements associated with fever, this has never been proven.
Two randomized trials have evaluated the effects of fever suppression in sepsis. Therefore, while randomized data of antipyretics
in fever in critically ill patients remains limited, the indications for antipyretics are becoming more recognized. Except in patients
with intracranial anomalies and myocardial infarction, antipyretics in septic patients with fever and hyperthermia are discouraged.
Suppression of hyperthermia in septic patients not only increases morbidityassociated with the common antipyretics (renal, hepatic
toxicities from NSAIDs, acetaminophen), but increases mortality as well [26,28,30,50]. Boyle et al demonstrated a significant reduction
in systolic and mean arterial blood pressure by 36% and 34%, respectively, in febrile patients receiving antipyretics versus placebo [39].
Another potential problem associated with antipyretics includes masking the infectious manifestation(s), thus potentially preventing the
diagnosis of infectious foci [39].
In patients with neurologic injury, antipyretics are encouraged as sustained fever >40C may be associated with worsening cerebral
edema and subsequent multi-organ failure [51]. Antipyretics reduce the metabolic rate and thus oxygen demand, which could be crucial
in refractory shock or myocardial infarction patients. In turn, some may argue that avoiding antipyretics in these patients may increase
length of stay and healthcare costs [31]. However, Bernard et al and Gozzolli et al found no significant difference in mortality or length
of stay when they randomized 455 and 38 patients, respectively, to either antipyretics or placebo [30,52]. When Schulman et al compared
aggressive versus permissive management in 82 patients, the study was stopped early due to the increased mortality (7 versus 1) in
aggressive treatment group [53].


1. Laupland KB, Shahpori R, Kirkpatrick AW, Ross T, Gregson DB, et al. (2008) Occurrence and outcome of fever in critically ill adults. Crit Care Med 36:
2. Ryan M, Levy MM (2003) Clinical review: fever in intensive care unit patients. Crit Care 7: 221-225.
3. OGrady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, et al. (2008) Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the
American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med 36: 1330-1349.

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In summary, fever remains a common problem in the ICU. While an infectious etiology is the common assumption, critical care
providers should be aware of the non-infectious causes that may provoke fever in critically ill patients. In turn, recognizing non-infectious
etiologies can help prevent unnecessary antimicrobial adversities and resistance. Fever is a normal host response to an inflammatory
insult and thus, suppression of the normal host response with antipyretics are generally discouraged in patients without intracranial
abnormalities or myocardial infarction. Future studies targeting on biological response to temperature control methods, and constructing
protocols for managing fever in ICU to improve patient outcome are warranted.


4. Barie PS, Hydo LJ, Eachempati SR (2004) Causes and consequences of fever complicating critical surgical illness. Surg Infect (Larchmt) 5: 145-159.
5. Kothari VM, Karnad DR (2005) New onset fever in the intensive care unit. J Assoc Physicians India 53: 949-953.
6. OGrady NP, Barie PS, Bartlett J, Bleck T, Garvey G, et al., (1998) Practice parameters for evaluating new fever in critically ill adult patients. Task Force of
the American College of Critical Care Medicine of the Society of Critical Care Medicine in collaboration with the Infectious Disease Society of America. Crit
Care Med 26: 392408.
7. Schmitz T, Bair N, Falk M, Levine C (1995) A comparison of five methods of temperature measurement in febrile intensive care patients. Am J Crit Care 4:
8. Milewski A, Ferguson KL, Terndrup TE (1991) Comparison of pulmonary artery, rectal, and tympanic membrane temperatures in adult intensive care unit
patients. Clin Pediatr (Phila) 30: 13-16.
9. Nierman DM (1991) Core temperature measurement in the intensive care unit. Crit Care Med 19: 818-823.
10. Erickson RS, Kirklin SK (1993) Comparison of ear-based, bladder, oral, and axillary methods for core temperature measurement. Crit Care Med 21: 15281534.
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Physiol 61: 98-102.
12. Plaisance KI, Mackowiak PA (2000) Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Arch Intern Med 160:
13. Saper CB, Breder CD (1994) The neurologic basis of fever. N Engl J Med 330: 1880-1886.
14. Dinarello CA, Cannon JG, Mancilla J, Bishai I, Lees J, et al. (1991) Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not
in peripheral blood mononuclear cells. Brain Res 562: 199-206.
15. Gourine AV, Rudolph K, Tesfaigzi J, Kluger MJ (1998) Role of hypothalamic interleukin-1beta in fever induced by cecal ligation and puncture in rats. Am J
Physiol 275: 754-761.
16. Leon LR, White AA, Kluger MJ (1998) Role of IL-6 and TNF in thermoregulation and survival during sepsis in mice. Am J Physiol 275: 269-277.
17. Kluger MJ, Kozak W, Leon LR, Conn CA (1998) The use of knockout mice to understand the role of cytokines in fever. Clin Exp Pharmacol Physiol 25:
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20. Cohen (2013) Infectious Disease 2nd.
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27. Peres Bota D, Lopes Ferreira F, Mlot C, Vincent JL (2004) Body temperature alterations in the critically ill. Intensive Care Med 30: 811-816.
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Severe Sepsis Study Group. Crit Care Med 20: 1395-1401.
29. Carlstedt F, Lind L, Lindahl B (1997) Proinflammatory cytokines, measured in a mixed population on arrival in the emergency department, are related to
mortality and severity of disease. J Intern Med 242: 361-365.
30. Arons MM, Wheeler AP, Bernard GR, Christman BW, Russell JA, et al. (1999) Effects of ibuprofen on the physiology and survival of hypothermic sepsis.
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31. Marik PE, Zaloga GP (2000) Hypothermia and cytokines in septic shock. Norasept II Study Investigators. North American study of the safety and efficacy of
murine monoclonal antibody to tumor necrosis factor for the treatment of septic shock. Intensive Care Med 26: 716-721.
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2002. Public Health Rep 122: 160-166.
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39. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, et al. (2006) Duration of hypotension before initiation of effective antimicrobial therapy is the critical
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From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention
Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American
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47. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological Surgeons, Joint Section on Neurotrauma and Critical
Care, AANS/CNS, Bratton SL, Chestnut RM, et al, (2007) Guidelines for the management of severe traumatic brain injury. VI. Indications for intracranial
pressure monitoring. J Neurotrauma 1: 3744.
48. Manthous CA, Hall JB, Olson D, Singh M, Chatila W, et al. (1995) Effect of cooling on oxygen consumption in febrile critically ill patients. Am J Respir Crit
Care Med 151: 10-14.
49. Mohr N, Skrupky L, Fuller B, Moy H, Alunday R, et al. (2012) Early antipyretic exposure does not increase mortality in patients with gram-negative severe
sepsis: a retrospective cohort study. Intern Emerg Med 7: 463-470.
50. Boyle M, Hundy S, Torda TA (1997) Paracetamol administration is associated with hypotension in the critically ill. Aust Crit Care 10: 120-122.
51. Cremer OL, Kalkman CJ (2007) Cerebral pathophysiology and clinical neurology of hyperthermia in humans. Prog Brain Res 162: 153-169.
52. Gozzoli V, Schttker P, Suter PM, Ricou B (2001) Is it worth treating fever in intensive care unit patients? Preliminary results from a randomized trial of the
effect of external cooling. Arch Intern Med 161: 121-123.

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53. Schulman CI, Namias N, Doherty J, Manning RJ, Li P, et al. (2005) The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized,
prospective study. Surg Infect (Larchmt) 6: 369-375.


Bedside Fundamentals of
Pneumonia in the ICU
Ramzy H. Rimawi1* and Hao Nguyen2
East Carolina University Brody School of Medicine, Department
of Internal Medicine, Section of Infectious Diseases & Critical Care
Medicine, Greenville, NC 27834, USA

East Carolina University Brody School of Medicine, Department

of Internal Medicine, Section of Infectious Diseases, Greenville, NC
27834, USA

*Corresponding author: Ramzy H. Rimawi MD, East Carolina

University Brody School of Medicine, Department of Internal
Medicine, Section of Infectious Diseases & Critical Care Medicine,
Greenville, NC 27834, USA, E-mail:

Pneumonia in the intensive care unit (ICU) has been a major concern for critical care practitioners because of its associated
morbidity and mortality. Despite advances in treatment options, pneumonia remains a leading cause of death in the ICU [1]. While,
there are numerous strategies aimed to optimize the outcome of patients with severe pulmonary infections in the ICU, there remains
considerable room for improvement in diagnosis and management. For example, in an effort to better define and predict illness severity,
one of the major strategies is to set clinical criteria for diagnosing pneumonic processes.
The Infectious Diseases Society of America (IDSA) and American Thoracic Society (ATS) established major and minor criteria
to diagnose and manage pneumonia in an ICU setting. The management may differ depending on the exposure in which the patient
presented, whether from the community (community-acquired pneumonia, or CAP) or within a healthcare setting (healthcareassociated pneumonia, or HCAP). A subset of HCAP patients may have developed their infection as a result of mechanical ventilation,
in which case an infection that arises as a result of intubation>48 hours is termed ventilator-associated, or VAP. In this chapter, we will
discuss the definitions and management of pneumonia and its subgroups within an ICU setting.

Causes of pneumonia may vary widely depending in epidemiological and clinical factors (Table 1). Up to 10% of hospitalized
patients with CA Prequire respiratory support, including mechanical ventilation, and hemodynamic support [2]. The frequency of
microbiologic culture isolation in patients with confirmed CAP is about 25% to 50%, depending on the culture techniques. Streptococcus
pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosaare the main pathogens isolated in patients with CAP in the ICU [3].
Streptococcus pneumonia can harbor virulence factors that induce a systemic inflammatory response syndrome responsible for severe
disease [4].
Staphylococcus aureus is a rising cause of CAP, especially in the ICU setting [3]. While methicillin-resistant Staphylococcus aureus
(MRSA) is still a rare source, the associated mortality risk is enough for most critical care physicians to empirically treat nearly all
patients presenting to the ICU with a CAP [4]. The incidence is increasingly common in patients with preceding influenza, prior
antibiotic therapy, injection drug abuse, end-stage renal disease, or nursing home exposure [3]. Pseudomonas-induced CAP may also
have an extremely high mortality rate due to its capacity to produce virulence factors and protective biofilms [1]. Interestingly, Legionella
pneumophila is also described cause of severe CAP with immune-mediated extrapulmonary involvement. Legionella pneumophila as a
cause of HAP is variable, but is increased in immunocompromised patients, such as organ transplant recipients or patients with HIV
disease, as well as those with diabetes mellitus, underlying lung disease, or end-stage renal disease [3].

In cases of HCAP, there is a similar challenge in microbiologic acquisition and organism isolation. Furthermore, the acquisition of
an organism can be a colonizer and not an actual pathogen responsible for the pneumonic process. Rates of HCAP due to multi-drug
resistant organisms (MDRO) have increased dramatically in hospitalized, especially critically ill and transplant patients. The most
common MDROs are MRSA, P. aeruginosa, S. pneumoniae and methicillin sensitive Staphylococcus aureus (MSSA) [2]. There is a high
frequency of drug resistance reported in six leading bacterial species termed ESKAPE, including Escherichia coli, S. aureus, Klebsiella,
Acinetobacter baumannii, P. aeriginosa and Enterobacter (Table 1).

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Viruses and fungi can also contribute as common causative agents for CAP. Amongst the viruses, adenovirus, respiratory syncytial
virus, seasonal influenza and parainfluenzae are often detected in samples of ICU patients with CAP co-infected with bacterial infections.
In 2009, swine associated influenza-A (H1N1) pandemic killed approximately 200,000 people in 214 countries [5]. Pregnancy and
morbid obesity are factors associated with acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and higher mortality.
Though rare, other pathogens associated with CAP in immunocompromised patients include Aspergillus, Pneumocystis jiroveci and
Cryptococcus neoformans.




Streptococcus pneumoniae

Pseudomonas aeruginosa (34%)

Haemophilus influenzae

Escherichia coli (11%)

Staphylococcus aureus

Acinetobacter (5%)

Legionella spp.

Klebsiella (5%)

Gram-negative bacilli

Staphyloccocus aureus
Table 1: Common bacterial organism in ICU pneumonia.

HCAP due to S. aureus is more common in patients with diabetes mellitus, head trauma, and those being care for within the
ICU [6]. Significant growth of oropharyngeal commensals (Viridians Streptococci, coagulase-negative Staphylococci, Neisseriaspp and
Corynebacterium spp) from distal bronchial specimens is difficult to interpret, but these organisms can produce infection in both
immunocompromised and immunocompetent hosts. Rates of polymicrobial infection vary widely, but appear to be increasing, and are
especially high in patients with ARDS [6]. There is limited data differentiating pathogens causing VAP from those that cause HAP in
non-mechanically ventilated patients [7] (Table 2).
Non-ventilator associated HCAP


MRSA (20%)

MRSA (18%)

MSSA (13%)

MSSA (9%)

Pseudomona saeruginosa (9%)

Pseudomonas aeruginosa (18%)

Stenotrophomonas maltophilia (1%)

Stenotrophomonas maltophilia (7%)

Acinetobacter (3%)

Acinetobacter (8%)

Other organisms (18%)

Other organisms (9%)

Table 2: Distribution of common organisms responsible for HCAP and VAP.

Data on mechanisms of antibiotic resistance for specific bacterial pathogens have provided new insight into the adaptability of these
pathogens [8]. Risk factors for colonization and infection with MDROs include:
Antimicrobial therapy in the preceding 90 days
High community frequency of antibiotic resistance
Current hospitalization >5 days or prior hospitalization > 2 days in the preceding 90 days
Residence in a nursing home or long term care facility
Home infusion therapy
Chronic dialysis within the preceding 30 days
Family member with MDRO
Pseudomonas aeruginosa is perhaps the most common MDR gram-negative bacterial pathogen causing HAP/VAP, with increasing
resistance to extended-spectrum penicillins, 3rd/4th generation cephalosporins, carbapenems, aminoglycosides, and/or fluoroquinolones
[8]. While Klebsiella species are intrinsically resistant to aminopenicillins and can acquire resistance to cephalosporins and aztreonam
by the production of extended-spectrum beta-lactamases (ESBL), ESBL-producing strains remain susceptible to carbapenems [8,9]. S.
maltophilia and B. cepaciaare uniformly resistant to carbapenems and share a tendency to colonize the respiratory tract rather than
cause invasive disease. Nosocomial HCAP due to fungi (Candida, Aspergillus) may occur also in immunocompromised hosts, including
transplant recipients or neutropenic patients.

Community-Acquired Pneumonia
CAP is defined as an acute, potentially life-threatening, infection of the pulmonary parenchyma acquired from the community
[10,11]. Although approximately 20% of cases require hospitalization, the majority of cases of CAP are managed in the outpatient
setting. Of this hospitalized subset, about 36% necessitate ICU care and approximately 50% succumb to their illness [3]. Guidelines for
the management of CAP have been produced by several organizations including British Thoracic Society (BTS), ATS and IDSA. The
BTS guidelines illustrated the importance of pre-existing co-morbidities, including chronic obstructive pulmonary diseases (COPD;
32%), asthma (13%), and cardiac disease (15%). Other significant conditions include diabetes, chronic liver diseases, chronic renal
failure, immunosuppression, and alcoholism. The incidence of severe CAP and adverse events increases with age. For example, 90% of
pneumonia death occurred in patients over the age of 70 [11].
Assessment of Severity: Severe CAP often results in multi-organ failure, requiring aggressive oxygen and vasopressor support [10].
Progressive loss of tissue oxygenation needs to be anticipated, recognized, and managed rapidly to prevent further complicationsor
death. In the presence of at least one of the ATS criteria (Table 3), the sensitivity and specificity of necessitating ICU admission was
98% and 32%, respectively. However, the presence of two major criteria and multilobar involvement raised the specificity to 94% [11].
Major Criteria

Minor Criteria

Respiratory rate >30 breaths/minute

Need for mechanical ventilation

Severe respiratory failure (PaO2/FiO2< 250)

Radiographic increase in size of infiltrates >50% in the presence or absence

of a clinical response or deterioration
Need for vasopressor support >4 hours

Diastolic blood pressure <60 mmHg

Worsening renal function

Table 3: ATS CAP guidelines minor and major criteria for severity assessmenton admission.

The BTS guidelines define CAP as a presence of two or more of the following features on hospital admission:
Respiratory rate 30 breaths/minute
Diastolic blood pressure <60 mmHg
Blood Urea Nitrogen >7 mmol/L

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Bilateral or multi-lobar involvement

Systolic blood pressure <90 mmHg


The guidelines also include three additional factors that may increase the risk of death by 50%:
Altered mental status
Hypoxemia PO2<80 or oxygen saturation <90%, with or without a rise in FiO2
Bilateral or multi-lobar shadowing on the chest radiograph
Management: Numerous studies have described the overlap in clinical presentation amongst the different pathogens [12].
Unfortunately, there is no single or combination of symptom(s) or radiograph finding that will reliably differentiate different pathogens
(i.e. pneumococcal vs. staphylococcal infections) and are therefore often treated similarly. The BTS recommends the following routine
investigations in hospitalized patients with severe CAP:
Blood cultures
Sputum or lower respiratory tract sample for gram-stain and culture
Pleural fluid analysis, if present
Pneumococcal antigen test (from sputum, blood, or urine)
Investigation for Legionella pneumoniae including (a) urine for Legionella antigen, (b) sputum or lower respiratory tract samples
for Legionella culture and direct immunofluoresence and/or (c) initial and follow-up Legionella serology
Respiratory samples for direct immunofluorescence to respiratory viruses, Chlamydia species, and possibly Pneumocystis
In all except those with a history of COPD, FiO2 can be rapidly titrated with routine blood gas analysis. Subsequent hypercapnia
may result in respiratory failure requiring continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP) or
mechanical ventilator support. Increasing metabolic acidosis may be indicative of underlying shock requiring fluid resuscitation and/
or inotropic support. A randomized trial of conventional therapy with or without non-invasive ventilation in severe CAP showed a
significant reduction in both intubation rate (58% vs. 21%) and ICU length of stay (6 days 1.8days) with non-invasive ventilator therapy
(13). However, there was an increased rate of mortality in the non-invasively ventilated group without COPD. About 88% of patients with
severe CAP may ultimately require intubation and mechanical ventilation, complicated by ALI and ARDS [14].
Antimicrobial therapy: If the specific pathogen has been isolated, the choice of antimicrobial treatment is relatively straightforward.
However, in most cases the pathogens are not isolated and broad-spectrum empiric treatment is often continued for the entire treatment
course [4]. Antibiotic resistance organisms, including penicillin-resistant S. pneumonia are becoming an increasing problem [7]. Risk
factors for drug resistant S. pneumoniae include:
Age > 65 years
Beta-lactam, macrolide, or fluoroquinolone therapy within the last 3-6 months
Medical co-morbidities
Immunosuppressive illness or therapy
Exposure to a child in a day care center
Critically ill patients requiring ICU with CAP often necessitate broad-spectrum antibiotic coverage, including:
An anti-pneumococcal beta-lactam (cefotaxime, ceftriaxone or ampicillin-sulbactam) PLUS azithromycin
Anti-pneumococcal beta-lactam PLUS a fluoroquinolone
For penicillin-allergic patients, a fluoroquinolone PLUS aztreonam
If there is concern for Pseudomonas:
Consider an anti-pseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, doripenem or meropenem) PLUS a
fluoroquinolone or aminoglycoside
For penicillin-allergic patient, substitute aztreonam for above beta-lactam.
Most patients with CAP show some clinical improvement within 72 hours of initial antibiotic treatment (13). However, about
6-15% of hospitalized patients with CAP do not respond within 72 hours, and treatment failure may be as high as 40% in patients with
severe CAP requiring ICU admission. Two general patterns of unresponsiveness have been described:(A) progressive pneumonia or
clinical deterioration with ventilatory support requirement and/or hemodynamic instability during the first 72 hours; (B) unresponsive
pneumonia due to absence or delay in achieving clinical stability after 72 hours of antibiotic therapy.

HCAP and VAP: Hospital acquired pneumonia (HAP), ventilator associated pneumonias and healthcare associated pneumonias
are important causes of morbidity and mortality despite innovations in antimicrobial therapy, supportive care and prevention [15]. In
2005, the ATS and IDSA collaborated to establish a consensus guideline that helped to define and manage different types of pneumonias:
HAP is a pneumonic process that develops >48 hours after admission and does not appear to have been incubating at the time
of admission. Hospital-acquired pneumonia is the leading cause of hospital-associated infections [10]. While most cases of HAP
occur outside the ICU, the strongest risk factor for HAP is among mechanically ventilated patients, ranging from 4-7 episodes/1000
hospitalizations and accounting for 13-18% of all nosocomial infections.

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The common causes of treatment failure include adelay or lack of appropriate therapy, advanced age, and/or other concomitant,
complicating illnesses (i.e. myocardial infarction, cardiac failure, pulmonary embolism). Pulmonary and extra-pulmonary infection
should also be investigated, including lung abscess, empyema, meningitis, endocarditis, and superimposed nosocomial pneumonia.
Further evaluation with high resolution computed tomography (CT) scan of the chest and bronchoscopy can often be useful in these


VAP is a type of HAP that develops >48-72 hours after endotracheal intubation.VAP occurs in 9-27% of intubated patients and
increases with duration of ventilation [6,10]. The risk of VAP is highest within the first 4 days of mechanical ventilation, estimated at
3%/day during the first 5 days of ventilation, 2% per day during the proceeding 5-10 days, and 1% afterwards.
HCAP was added in 2005 by ATS/IDSA guidelines in order to identify patients with increased risk for multidrug resistant
pathogens coming from the community settings [14]. HCAP is defined as pneumonic process that occurs in a patient with associated
healthcare contact, such as:
- Intravenous antibiotic/chemotherapy or wound care within 30 days.
- Residence in a nursing home or long term care facility.
- Admission to a hospital or hemodialysis clinic within the preceding 30 days.
Pathogenesis: HCAP results from a host response to a number of virulent microorganisms entering the lower respiratory tract
via micro-aspiration. While approximately 45% of healthy subjects aspirate during their sleep, an even higher proportion of severely
ill patients aspirate nocturnally [15]. The presence of an endotracheal tube further permits the aspiration of oropharyngeal material
or gastrointestinal bacteria, resulting in a pneumonia depending on the number and virulence of the organisms aspirated. As many as
75% of severely ill, hospitalized patients are colonized with microorganisms acquired nosocomially within 48 hours [14]. In VAP, the
primary route of bacterial entry is via aspiration of oropharyngeal pathogens or leakage of secretions containing bacteria on or around
the endotracheal tube cuff.
Management: Appropriate therapy significantly improves survival for patients with HCAP [15-17]. However, establishing the
diagnosis of pneumonia in such patients can be difficult, especially in those mechanically ventilation, because of the numerous nonpneumonic processes that can cause similar clinical, radiologic and microbiologic findings. As a result, this often leads to overtreatment
resulting in super-infection and antibiotic toxicity. When therapy is given, antimicrobial selection should also be based on risk factors
for MDROs. The 2005 ATS/ IDSA HCAP guidelines propose the following empiric coverage:
For patient with no known MDRO risk factors:
Levofloxacin or Moxifloxacin (oral, if possible)
For patient with known MDRO risk factors:
Anti-pseudomonal cephalosporin + anti-MRSA therapy (linezolid, vancomycin)
Anti-pseudomonal carbapenem + anti-MRSA therapy (linezolid, vancomycin)
Extended-spectrum penicillin (piperacillin-tazobactam) + anti-MRSA therapy (linezolid, vancomycin)
For patients with penicillin-allergy, aztreonam can be used with an anti-MRSA therapy (linezolid, vancomycin). Please note
that if patient has a history of an IgE-mediated reaction to penicillin, penicillin skin testing with major (benzylpenicilloyl) and minor
(penicillin G potassium) determinants may be done in patients without a history of severe exfoliative disorders prior to using alternative
Combination therapy may be used until in-vitro susceptibility pattern is finalized and therapy is de-escalated to one agent, if
possible. If the patient is clinically improving and able to take oral, antibiotic therapy can be switched to oral route if possible. Antibiotic
therapy should be evaluated daily within the ICU and hospital ward setting. If the patient has improved, antimicrobial therapy should be
changed to a pathogen-directed regimen for a total duration of5-7 days, excluding patients with non-lactose fermenting gram-negative
bacilli (Pseudomonas in whom therapy should be extended to 14 days).

As a result of the associated risk factors, CAP and HCAP are likely to continue being common illnesses encountered in an ICU
setting. While ICU practitioners gain familiarity with managing these infections, by no means are they simple. Practitioners expecting
to manage critically ill patients should be familiar with the presentation and management of both straightforward and complicated cases
of pneumonia.

1. De Pascale G, Bello G, Tumbarello M, Antonelli M (2012) Severe pneumonia in intensive care: cause, diagnosis, treatment and management: a
review of the literature. Curr Opin Pulm Med 18: 213-221.
2. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, et al. (2007) Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44 Suppl 2: S27-72.

6. Confalonieri M, Potena A, Carbone G, Porta RD, Tolley EA, et al. (1999) Acute respiratory failure in patients with severe community-acquired
pneumonia. A prospective randomized evaluation of noninvasive ventilation. Am J Respir Crit Care Med 160: 1585-1591.

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3. Restrepo MI, Mortensen EM, Velez JA, Frei C, Anzueto A (2008) A comparative study of community-acquired pneumonia patients admitted to the
ward and the ICU. Chest 133: 610-617.

7. McEachern R, Campbell GD Jr (1998) Hospital-acquired pneumonia: epidemiology, etiology, and treatment. Infect Dis Clin North Am 12: 761-779, x.


4. Rimawi RH, Mazer MA, Siraj DS, Gooch M, Cook PP (2013) Impact of regular collaboration between infectious diseases and critical care practitioners
on antimicrobial utilization and patient outcome. Crit Care Med 41: 2099-2107.
5. Dawood FS, Iuliano AD, Reed C, Meltzer MI, Shay DK, et al. (2012) Estimated global mortality associated with the first 12 months of 2009 pandemic
influenza A H1N1 virus circulation: a modelling study. Lancet Infect Dis 12: 687-695.

8. Neiderman SM, Craven ED, et al., (2005) American Thoracic Society Documents: Guidelines for the Management of Adults with Hospital-acquired

Pneumonia, Ventilator-associated Pneumonia, and Healthcare-associated Pneumonia. Am J Respir Crit Care Med.. 171: 388-416.
9. Fagon JY, Chastre J, Wolff M, Gervais C, Parer-Aubas S, et al. (2000) Invasive and noninvasive strategies for management of suspected ventilatorassociated pneumonia. A randomized trial. Ann Intern Med 132: 621-630.
10. Osler W. The principles and practice of Medicine. 4th ed. New York: Appleton. 1901.
11. Baudouin SV (2002) The pulmonary physician in critical care . 3: critical care management of community acquired pneumonia. Thorax 57: 267-271.
12. Thomas M File, Jr, Bartlett GJ, Thorner RA (2010) Treatment of community-acquired pneumonia in adults who required pneumonia. Clin Infect Dis
50: 202-220.
13. Epp SF, Khler T, Plsiat P, Micha-Hamzehpour M, Frey J, et al. (2001) C-terminal region of Pseudomonas aeruginosa outer membrane porin OprD
modulates susceptibility to meropenem. Antimicrob Agents Chemother 45: 1780-1787.
14. Bradford PA (2001) Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance
threat. Clin Microbiol Rev 14: 933-951, table of contents.
15. Brochard L, Mancebo J, Wysocki M, Lofaso F, Conti G, et al. (1995) Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary
disease. N Engl J Med 333: 817-822.
16. Ibrahim EH, Ward S, Sherman G, Schaiff R, Fraser VJ, et al. (2001) Experience with a clinical guideline for the treatment of ventilator-associated
pneumonia. Crit Care Med 29: 1109-1115.

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17. Trouillet JL, Chastre J, Vuagnat A, Joly-Guillou ML, Combaux D, et al. (1998) Ventilator-associated pneumonia caused by potentially drug-resistant
bacteria. Am J Respir Crit Care Med 157: 531-539.


Antibiotic Therapy in Sepsis

Ramzy H Rimawi1* and Mark A Mazer2
Travel Medicine and Critical Care Medicine, Section of Infectious
Diseases, Department of Internal Medicine, Brody School of Medicine,
East Carolina University, USA

Critical Care and Sleep Medicine, Section of Pulmonary, Department of

Internal Medicine, Brody School of Medicine, East Carolina University,

*Corresponding author: Ramzy H Rimawi, Travel Medicine and

Critical Care Medicine, Section of Infectious Diseases, Department of
Internal Medicine, Brody School of Medicine, East Carolina University,
Doctors Park 6A, Mail Stop 715, Greenville, NC 27834, USA; Tel: (252)
744-4500; E-mail:

Sepsis is a major cause of morbidity and mortality in the intensive care unit (ICU). While source control is the number priority
in the management of the septic patient, antibiotic therapy is a cornerstone in the management of patients with sepsis. Empiric
broad spectrum antibiotics are recommended within 1 hour of suspected sepsis, as every hour delay is associated with a 6% rise
in mortality. In addition, many septic patients require intravenous fluid resuscitation, vasopressors, mechanical ventilation and
hemodialysis to support organ function. While recommendations for appropriate antibiotic expenditure are often being updated,
we will discuss the empiric antibiotics that should be initiated for major infections treated in the ICU.

Keywords: Sepsis; Septic shock; Antibiotics; Critical care; Infections

The evaluation and management of sepsis is an everyday concern in the intensive care unit (ICU) setting. The sepsis syndrome is,
in part, caused by an amalgamation of host response to pathogens. Broad spectrum antibiotics are recommended within 1 hour of
suspected sepsis, as every hour delay is associated with a 6% rise in mortality [1,2]. Regardless of the infection site, daily measures
to tailor antibiotic therapy should be done in order to avoid potential adverse effects, resistance and increased healthcare costs. In
this chapter, we will discuss the major infections encountered in the ICU and recommended empiric antibiotic therapies. In the
US, common infections in the medical ICU include pneumonia (30%), urinary tract infection (30%), bloodstream infections (16%),
cardiovascular infections (5%), gastrointestinal infections (5%), ear/nose/throat infections (4%), and skin/soft-tissue infections (3%) [3].

Sepsis Criteria
Sepsis is the presence the systemic inflammation with a suspected or documented infection. Signs of systemic inflammation include
Hyperthermia or hypothermia
Altered mentation
Leukocytosis or leucopenia
Plasma C-reactive protein more than two SD above the normal value
Elevated Plasma procalcitonin

Antibiotic Therapy
Immediate initiation of empiric antibiotic therapy is strongly recommended when the likelihood of infection is high in the setting of
progressive organ dysfunction. Several studies have demonstrated a reduction in morbidity and mortality when appropriate initial
antibiotics are chosen [5-8]. However, antibiotics should not be used in patients with noninfectious causes of severe inflammatory
response syndromes. The use of appropriate cultures and biomarkers (e.g., procalcitonin) may be used to help discontinue empiric
antibiotics within 3-5 days in patients who have systemic inflammation, but eventually determined not secondary to an infectious
cause. Furthermore, similar attention should be given to timely cessation of antibiotic therapy after an appropriate course,. The
Surviving Sepsis Campaign recommends duration of therapy of 7 to 10 days when clinically indicated in patients without slow clinical

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Severe Sepsis is organ dysfunction as a result of an underlying infection, including hypoxemia, oliguria, azotemia, coagulopathy,
thrombocytopenia, hyper bilirubinemia, and abnormal tissue perfusion markers (e.g., hyperlactatemia and decreased capillary refill)
[4]. Septic shock suggests concomitant hemodynamic instability (systolic blood pressure <90 mmHg, mean arterial pressure <70
mmHg or a decrease in systolic blood pressure by >40 mmHg or less than two SD below normal for age) despite aggressive fluid


response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections, or immunologic deficiencies,
including neutropenia [1].
Selection of appropriate antibiotic therapy in the ICU is based on several factors. Institutional or regional antibiograms should
be taken into consideration whenever selecting an appropriate antibiotic therapy. Bioavailability and tissue penetration of variable
antibiotics in particular sites, including lungs, central nervous system, bone, must also be taken into consideration. Drug clearance is
another matter, as many antibiotics are cleared renally (exceptions include macrolides, clindamycin, tetracyclines, linezolid, ceftriaxone,
anti-staphylococcal penicillins, voriconazole, amphotericin B and caspofungin) or hepatically. Toxicity profile, including hematologic
or hepatic effects,must be considered. Many intravenous antibiotics require co-administration with intravenous fluids; this may become
important in patients on fluid restriction. Although cost represents a lesser concern during decision making in infectious disease
management, it is, nonetheless, of great importance and relevant financial issues should be considered.

Pneumonias in the ICU

Pneumonia is the second most common cause of hospital-acquired infection in the ICU, mostly occurring in mechanically ventilated
patients [9,10]. Although the discussion of pneumonia in the ICU is further discussed in another chapter, we will briefly discuss the
recommended empiric antibiotic therapy in community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP).
Community-acquired pneumonia is defined as a constellation of suggestive clinical features and a demonstrable infiltrate by chest
radiograph in a patient outside of hospital or extended living facilities. Recommended empiric therapy for patients admitted to the ICU
with CAP includes [11]:
Beta-lactam (ceftriaxone, or ampicillin-sulbactam) plus azithromycin
If penicillin-allergic, a uoroquinolone and aztreonam are recommended
If Pseudomonas infection is suspected, an antipneumococcal, antipseudomonal b-lactam (piperacillin-tazobactam, cefepime,
imipenem, or meropenem) plus a fluoroqinolone (ciprooxacin or levooxacin 750-mg dose) or an aminoglycoside and azithromycin
If community-acquired methicillin-resistant Staphylococcus aureus is suspected, add vancomycin or linezolid.
If influenza is suspected, antiviral therapy (i.e., oseltamivir) should be added.
Healthcare-associated pneumonia is defined as an evident radiographic infiltrate with suggestive clinical features in a patient with the
following risk factors: antimicrobial therapy or hospitalization 2 days in the preceding 90 days, current hospitalization of 5 days, high
frequency of antibiotic resistance in the community or hospital unit, residence in a nursing home or extended care facility, home infusion
therapy (including antibiotics), chronic dialysis within 30 days, home wound care, family member with multidrug-resistant pathogen,
immunosuppressive disease and/or therapy [12]. HCAP is included in the spectrum of hospital-associated and ventilator-associated
pneumonias. For uncomplicated HCAP in patients with good clinical response, 7-8 days is the recommended duration if the infection
does not involve Pseudomonas aeruginosa or Acinetobacter. Combination empiric therapy for a specic pathogen should be aimed at
multi-drug resistant pathogens (Table 1). Often, double-gram negative coverage is given in case a multi-drug resistant Pseudomonas may
be resistant to one of the agents given. If possible, therapy should be de-escalated to just one agent when in-vitro susceptibility data is
Potential Pathogen

Recommended Antibiotics

Haemophilus influenza
Escherichia coli
Proteus spp.
Enterobacter spp.
Serratia spp.
Klebsiella (non-carbapenemase producing)


Methicillin-sensitive S. aureus

Penicillinase-penicillin (e.g., Nafcillin)


Methicilllin-resistnat S. aureus


Pseudomonas aeruginosa
Extended-spectrum beta-lactamase (ESBL) Klebsiellapneumoniae
Acinetobacter spp.

Cefepime, ceftazidime, imipenem, meropenem, doripenem, piperacillintazobactam + ciprofloxacin/levofloxacin or aminoglycoside (gentamicin,

tobramycin, amikacin)

Table 1: Empiric antibiotic therapy for healthcare-associated pneumonias.

The National Nosocomial Infections Surveillance System in ICU patients reports that urinary tract infections (UTI) are the most
common infections in critically ill patients and result in excess deaths, increased length of stay, and higher healthcare costs [3,13].
Complicated UTI arise when there is interference with normal voiding, which results in impaired flushing of bacteria from the genitourinary
tract. Anomalies include pyelonephritis, indwelling catheter infections, nephrolithiasis, prostatic hypertrophy or obstruction, and spinal
cord injuries or other neurologic deficits affecting the genitourinary tract. Admission to the intensive care unit alone is not an inclusion
criteria for complicated UTI. The incidence of bacteruria in patients with indwelling catheters is 3-10%, with a substantial proportion of
them (estimated 10-25%) developing UTI [14]. Although UTIs warrant antibiotic therapy, healthcare providers often treat urine culture
results in the absence of genitourinary symptoms and in the presence of infections in other sites [15]. However, practitioners should be
more circumspect before prescribing antibiotics in this circumstance.
A true catheter-associated UTI is defined as the presence of bacteruria with clinical symptoms including new onset or worsening of
fever, rigors, altered mental status, malaise, or lethargy with no other identied cause; ank pain; costovertebral angle tenderness; acute

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Urinary Tract Infections in the ICU


hematuria; pelvic discomfort; and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain
ortenderness [16]. The recommended duration of therapy is 7 days in patients who have prompt resolution of symptoms and 10-14 days
in patients who have a delayed response. After the indwelling catheter is removed, a 3-day course may be considered in women 65 years
old without evidence of pyelonephritis.
The most effective way to reduce the incidence of bacteruria is to reduce the use of urinary catheterization. This is done viacatheter
restriction only to patients who have clear indications andremoval as soon as it is no longer needed. Several prospective, randomized
trials of asymptomatic bacteriuria therapy consistently conclude that antimicrobial therapy for asymptomatic bacteriuria is not
beneficial in most populations. In symptomatic patients, data on local antibiograms and antimicrobial resistance should be used to help
guide empirical treatment. Although clinical trials of complicated UTI therapy have reported high efficacy rates for a wide variety of
antimicrobial agents (including fluoroquinolones, piperacillin-tazobactam, carbapenems, aminoglycosides, and cephalosporins), there
are limited comparative studies.

Unknown Source of Infection

Many times, when patients are initially admitted to the ICU, the causative etiology is unknown. Nevertheless, appropriate empiric
antimicrobial selection should be rapidly initiated [17]. Most studies recommend starting with broad-spectrum combination therapy and
de-escalating as per culture results. Biomarkers such as procalcitonin, can be used to further assist in decision whether to discontinue
antimicrobial therapy [18]. Attempts should be made to obtain microbial cultures prior to initiation of antimicrobial therapy, as the
argument can be made that the cultures are negative due to the antimicrobial suppression.

ICU Catheter-Related Bloodstream Infections

Admission into the ICU does not affect the management of catheter-related bloodstream infections (CRBSI). Central venous, arterial
and dialysis catheters are commonly placed in the ICU, sometimes during urgent critical situations when sterility may be jeopardized.
Therefore, intensive care units are a common setting for CRBSI, accounting for about 80,000 CRBSIs each year [19]. For patients who are
hospitalized in the ICU with a new onset of fever but without severe sepsis or evidence of bloodstream infection, it is recommended to
obtain simultaneous blood cultures from the non-tunneled central venous catheter, the arterial catheter (if present), and percutaneously,
instead of performing routine catheter removal [20].
Vancomycin is recommended for empiric therapy in areas with elevated prevalence of methicillin-resistant Staphylococcus aureus
(MRSA). Daptomycin is a suitable alternative for suspected MRSA-CRBSI. Empiric therapy with an anti-Pseudomonas agent should be
based on local antimicrobial susceptibility data, disease severity, existence of a femoral catheter in critically ill patients, and presence
of neutropenia or known colonization with multi-drug resistant organisms. Empiric therapy for candidemia should be considered in
patients with history of bowel surgery, prolonged broad-spectrum antibiotic use, solid-organ or bone marrow transplantation, femoral
catherization, total parenteral nutrition, colonization with Candida at multiple sites, or hematologic malignancy.
Antibiotic therapy duration depends on the organism, whether the catheter was retained or removed, concomitant infections (e.g.,
infective endocarditis, osteomyelitis, abscess) and duration of bacteremia. For patients with persistent bacteremia/fungemia at least 72
hours after the catheter was removed, 4-6 weeks of therapy is recommended [20]. For coagulase-negative S. aureus, systemic antibiotic
therapy should be given for 5-7 days if the catheter is removed, and 10-14 days with antibiotic lock therapy if the catheter is retained.
For Enterococcus and gram-negative bacilli (e.g., Pseudomonas), 7-14 days of therapy is recommended after catheter removal. Catheter
removal is strongly recommended in patients with candidemia, followed by 14 days of therapy after the first negative blood culture.

Gastrointestinal Infections in the ICU

While antibiotic therapy plays an important role in the management of intra-abdominal infections, fluid resuscitation, physiologic
organ system support and surgical intervention are also key factors that dramatically affect morbidity and mortality. Bladder pressure
monitoring may be done to detect abdominal compartment syndrome as a complication of extensive intraperitoneal/retroperitoneal
inflammation and aggressive fluid resuscitation [22]. Antibiotic therapy should be directed towards the culture results, if known.
Otherwise, broad-spectrum therapy against gram-negative organisms and anaerobes (e.g., carbapenems, piperacillin-tazobactam,
fluoroquinolones + metronidazole, tigecycline, 3rd/4th generation cephalosporin + clindamycin or metronidazole) should be given
for 4-7 days, assuming there is adequate source control [23]. Source control is attained by adequate drainage, monitored by clinical
improvement, and radiographic improvement of the fluid collection.
With increasing antibiotic and antacid use in the ICU, Clostridium difficile infection (CDI) is commonly seen in critically ill patients.
For patients with severe, complicated CDI, oral vancomycin (per rectum if ileus is present) with or without intravenously administered
metronidazole is the treatment of choice [24]. The reason for considering combination therapy is to increase the likelihood of tissue
penetration and allow for clinical response. If a patient is already clinically improving on oral or per-rectal vancomycin, the addition of
metronidazole is not necessary. In patients with rising hyperlactatemia and leukocytosis 50,000 cells/L, subtotal colectomy with rectal
preservation should be considered.

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Intra-abdominal infections are a major cause of morbidity, mortality and antibiotic expenditure in the ICU [21]. Accurate and
timely diagnosis can have a major impact on clinical outcome, antimicrobial selection, healthcare cost and need for surgical intervention.
Spontaneous bacterial peritonitis in the ICU is commonly seen in decompensated cirrhotic patients, likely due to the translocation of
overgrowing enteric bacteria (usually gram negative organisms, although MRSA has been commonly described in ICU patients) across
an anatomically intact gastrointestinal tract. Gastrointestinal wall perforation or ulceration can result in polymicrobial seeding into
neighboring areas, resulting in signs of acute abdomen. Localized pain suggests the infection is walled-off in the area directly associated
with the area of seeding, whereas diffuse pain suggests generalized peritonitis. Intra-abdominal abscesses, bowel perforation, cholecystitis,
and ascending cholangitis are common ICU gastrointestinal infections.


ICU Skin & Soft-Tissue Infections

While the majority of skin and soft-tissue infections do not often require intensive care (e.g., impetigo, cutaneous abscess, cellulitis,
erysipelas), many still do, including necrotizing associated soft-tissue infections (NASTI), toxic-shock syndrome, Stevens-Johnson
syndrome, toxic-epidermal necrolysis and burns. Clinical or radiographic features may help to guide clinicians into suspecting NASTI,
including failure to respond to initial antibiotic therapy, clinical signs such as systemic toxicity (e.g., renal failure, altered mentation), a
wooden feel of the subcutaneous tissue extending beyond the apparent skin involvement, bullae, skin necrosis, ecchymosis, crepitus, and/
or CT/MRI evidence of fascial plane edema. In addition to rapid assessment for surgical intervention, aerobic and anaerobic antimicrobial
therapy is recommended until the patient has demonstrated clinical improvement (defervesce 72 hours) and no further operative
procedures are needed [25]. Clindamycin is often given due to the in-vitro studies demonstrating toxin suppression and cytokine
production modulation and observational studies showing superiority to beta-lactam antibiotics in children with invasive Streptococcus
pyogenes infections [26].

Antimicrobial selection in the ICU continues to have a fundamental impact on patient outcome, hospital cost, antimicrobial
resistance, and potential adverse reactions. Frequent communication with microbiology, pathology and surgery are key components in
optimizing patient care. Daily collaboration with Infectious Disease specialists can help curtail unnecessary antibiotic expenditure [27].
Many infections are treated similarly, whether the patient is critically ill in the medical intensive care unit, or stable on the medical wards,
including empiric therapy for meningitis, encephalitis, bacterial endocarditis, and prosthesis infections [28-30]. Clinicians are strongly
advised to be familiar with the Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from the American
College of Critical Care Medicine and the Infectious Diseases Society of America, as culture acquisition and diagnostic testing will affect
antimicrobial selection, which ultimately effect clinical outcome [9]. While in most cases empiric antibiotic therapy should be initiated
before or during culture acquisition of unstable or critically ill patients, antimicrobial selection should frequently be reconciled in order
to avoid potential adverse events, reduce incidence of antimicrobial resistance, reduce healthcare costs and improve patient outcome.

1. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, et al. (2013) Surviving sepsis campaign: international guidelines for management of severe
sepsis and septic shock: 2012. Crit Care Med 41: 580-637.
2. Soong J, Soni N (2012) Sepsis: recognition and treatment. Clin Med 12: 276-280.
3. Richards MJ, Edwards JR, Culver DH, Gaynes RP, The National Nosocomial Infections Surveillance System (2000) Nosocomial infections in combined
medical-surgical intensive care units in the United States. Infect Control Hosp Epidemiol 21: 510-515.
4. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
Crit Care Med 31: 1250-1256.
5. Kollef MH, Ward S (1998) The influence of mini-BAL cultures on patient outcomes: implications for the antibiotic management of ventilator-associated
pneumonia. Chest 113: 412-420.
6. Ibrahim EH, Sherman G, Ward S, Fraser VJ, Kollef MH (2000) The influence of inadequate antimicrobial treatment of bloodstream infections on patient
outcomes in the ICU setting. Chest 118: 146-155.
7. Luna CM, Vujacich P, Niederman MS, Vay C, Gherardi C, et al. (1997) Impact of BAL data on the therapy and outcome of ventilator-associated
pneumonia. Chest 111: 676-685.
8. Rello J, Gallego M, Mariscal D, Soora R, Valles J (1997) The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir
Crit Care Med 156: 196-200.
9. OGrady NP, Barie PS, Bartlett JG, Bleck T, Carroll K, et al. (2008) Guidelines for evaluation of new fever in critically ill adult patients: 2008 update from
the American College of Critical Care Medicine and the Infectious Diseases Society of America. Crit Care Med 36: 1330-1349.
10. Rello J, Ollendorf DA, Oster G, Vera-Llonch M, Bellm L, et al. (2002) Epidemiology and outcomes of ventilator-associated pneumonia in a large US
database. Chest 122: 2115-2121.
11. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, et al. (2007) Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 44 Suppl 2: 27-72.
12. American Thoracic Society; Infectious Diseases Society of America (2005) Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 171: 388-416.
13. Centers for Disease Control (CDC) (1992) Public health focus: surveillance, prevention, and control of nosocomial infections. MMWR Morb Mortal
Wkly Rep 41: 783-787.
14. Haley RW, Hooton TM, Culver DH, Stanley RC, Emori TG, et al. (1981) Nosocomial infections in U.S. hospitals, 1975-1976: estimated frequency by
selected characteristics of patients. Am J Med 70: 947-959.
15. Al Raiy Basel, Jahamy Houssein, Fakih Mohamad G, Khatib Riad (2007) Clinicians approach to positive urine culture in the intensive care units. Infect
Dis Clin Pract 15: 382-384.
16. Hooton TM, Bradley SF, Cardenas DD, Colgan R, Geerlings SE, et al. (2010) Diagnosis, Prevention, and Treatment of Catheter-Associated Urinary
Tract Infection in Adults: 2009 International Clinical Practice Guidelines from the Infection Diseases Society of America. Clin Infec Dis 50: 625-663.

18. Heyland DK, Johnson AP, Reynolds SC, Muscedere J (2011) Procalcitonin for reduced antibiotic exposure in the critical care setting: a systematic
review and an economic evaluation. Crit Care Med 39: 1792-1799.
19. Mermel LA (2000) Prevention of intravascular catheter-related infections. Ann Intern Med 132: 391-402.
20. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, et al. (2009) Clinical practice guidelines for the diagnosis and management of intravascular
catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 49: 1-45.
21. Marshall JC, Innes M (2003) Intensive care unit management of intra-abdominal infection. Crit Care Med 31: 2228-2237.
22. Schein M, Wittmann DH, Aprahamian CC, Condon RE (1995) The abdominal compartment syndrome: the physiological and clinical consequences of
elevated intra-abdominal pressure. J Am Coll Surg 180: 745-753.

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17. Kollef M (2005) Why appropriate antimicrobial selection is important: Focus on outcomes. In: Owens RC Jr, Ambrose PG, Nightingale CH (eds.).
Antimicrobial Optimization: Concepts and Strategies in Clinical Practice. Taylor & Francis, United Kingdom.


23. Solomkim JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJC, et al. (2010) Guidelines for the Selection of Anti-infective Agents for Complicated
Intra-Abdominal Infections. Clin Infec Dis 501: 133-164.
24. Cohen SJ, Gerdin DN, Johnson S, Kelly CP, Loo VG et al. (2010) Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update
by the Society of Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol
31: 431-455.
25. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, et al. (2005) Practice guidelines for the diagnosis and management of skin and softtissue infections. Clin Infect Dis 41: 1373-1406.
26. Zimbelman J, Palmer A, Todd J (1999) Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus
pyogenes infection. Pediatr Infect Dis J 18: 1096-1100.
27. Rimawi RH, Mazer MA, Siraj DS, Gooch M, Cook PP (2013) Impact of regular collaboration between infectious diseases and critical care practitioners
on antimicrobial utilization and patient outcome*. Crit Care Med 41: 2099-2107.
28. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, et al. (2004) Practice guidelines for the management of bacterial meningitis. Clin Infect
Dis 39: 1267-1284.
29. Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, et al. (2008) The management of encephalitis: clinical practice guidelines by the Infectious
Diseases Society of America. Clin Infect Dis 47: 303-327.

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30. Baddour LM, Wilson WR, Bayer AS, et al. (2005) Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a
statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular
Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association:
endorsed by the Infectious Diseases Society of America. Circulation 111: 394-434.


ICU Infection Control and Preventive

Manjit S Dhillon1*, Kaushal B Shah1 and Ramzy H Rimawi2
East Carolina University- Brody School of Medicine, Department of Internal
Medicine, Section of Infectious Diseases and Travel Medicine, USA
East Carolina University- Brody School of Medicine, Department of Internal
Medicine, Section of Infectious Diseases and Critical Care Medicine, USA

*Corresponding author: Manjit Singh Dhillon, East Carolina UniversityBrody School of Medicine, Department of Internal Medicine, Section of Infectious
Diseases and Travel Medicine, USA, Tel: 252-744-5725; Fax: 252-744-3472;

Intensive care units (ICU) carry a high risk for nosocomial infections, contributing to an increase in morbidity, mortality, and
healthcare costs. In order to limit the incidence of ICU nosocomial infections, healthcare providers should adopt aggressive infection
control measures. In this chapter, we will discuss the epidemiology and predisposing factors for nosocomial infections. We will also
discuss infection control parameters aimed to reduce infections in the ICU setting.

Keywords: Critical care; Health-care associated infections; Infections; Nosocomial infections; Preventive measures
In 2008, the center for disease control and prevention (CDC) and the National Healthcare Safety Network (NHSN) collaborated
to healthcare-associated infections (HAI) as a localized or systemic condition resulting from an infectious agent or its toxin
[1]. HAIs are either endogenous or exogenous and must not be evident or incubating at the time of admission to the acute care
setting. Endogenous sources are body sites, such as the skin, nose, mouth, gastrointestinal (GI) tract, or vagina that have natural
microorganisms. Exogenous sources are those outside body such as patient care personnel, visitors, medical devices or equipment.


UTI Urinary tract infection; HCAP Healthcare-associated pneumonia; CABSI Catheter-associated bloodstream infection.
Figure 1: Culture results from ICU-acquired infections at Vidant Medical Center [8].

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In 2002, the CDC reported on 417,946 HAIs and 99,000 fatalities in the US among critically ill adults and children in an ICU.
The major HAIs include catheter-associated urinary tract infections (CAUTI; 40%) ventilator-associated and healthcare-associated
pneumonia (25%), catheter-associated bloodstream infections (CABSI; 10%), and surgical site infections (SSI) [2-6]. HAIs, including
those secondary to multidrug resistant gram-negative bacteria (i.e. Acinetobacter, Pseudomonas) and Clostridium difficile account,
for $29 billion dollars in the US annually [3-7]. With evidence-based strategies, Umscheid et al. described how 65-70% of CABSI or
CAUTI and 55% of VAP or SSI are preventable [4]. HAIs are most common in burn units and surgical ICUs, less common in medical
ICUs, and least common in coronary care units [5]. Figure 1 demonstrates the incidence of healthcare-associated infections at our
institution, Vidant Medical Center, a 24-bed ICU at 900-bed tertiary care, teaching hospital for East Carolina University [8]. Figure
2 demonstrates the epidemiology of HAI transmission [9].


Figure 2: Epidemiology of HAI transmission [9].

Catheter-related blood stream infections are recognized when a non-commensal organism (i.e. coagulase-negative Staphylococcus, Bacillus
(not B.anthracis), viridans group Streptococcus) is found in one or more blood cultures and the organism is not related to an infection
from another site. If the organism is commensal, it should be cultured on separate occasions with concomitant signs of infection,
including fever, chills, hypotension, and leukocytosis. Pneumonia is defined as the presence of fever, leukocytosis/leukopenia, respiratory
symptoms (cough, dyspnea, hypoxia, rales) and a demonstrable radiologic infiltrate, consolidation or cavitation. Urinary tract infection is
the presence of symptoms (fever, suprapubic tenderness, costovertebral angle (CVA) tenderness) and positive urine culture. As patients
in the ICU are often unable to articulate symptoms, CAUTI is defined as the presence of a urinary catheter >48hrs in the presence of fever
or CVA/suprapubic tenderness and positive urine culture.

Predisposing factors
Critically ill patients in the ICU are more likely to have invasive catheters, devices, or undergo surgical treatments that disrupt the
skin barrier [2]. Burn victims also develop HAIs as a result of the physical barrier disruption. The ability to clear infections may further be
reduced by an underlying chronic diseases (i.e. diabetes, congestive heart failure, renal failure, liver failure, malnourishment, alcoholism,
chronic obstructive pulmonary disease), thus increasing the risk of HAI [10]. Other significant risk factors include urinary catheter >10
days, ICU confinement >3 days, presence of intracranial pressure monitor/arterial line/central venous catheter, and shock [5]. Adequate
staffing is necessary to allow patient care to be performed in a manner that means high level of compliance. If an ICU is understaffed, this
may not only diminish basic hygienic practices, but also allow for the development of resistant organisms to spread. Intensive care units
should be architecturally constructed in a low traffic flow design that allows for appropriate space to perform daily operations. Materials
and surfaces should be easy to clean with nearby sinks to prevent bacterial colonization.

Modes of transmission
Hospital-acquired infections can be transmitted by direct contact, inhalations of aerosolized droplets or air-borne pathogens, and/or
vehicle-based inoculation. The commonest mode of transmission remains the contact-based acquisition, commonly related to organisms
like methicillin-resistant staphylococcus aureus (MRSA), vancomycin resistant enterococcus (VRE), and Clostridium difficile. Common
infections transmitted by droplet-based route are influenza, adenovirus, rhinovirus, group A Streptococcus, Neisseria meningiditis,
Corynebacterium diphtheria, Bordetella pertussis. In air-borne transmission, as opposed to droplet transmission, the droplet particles
(usually less than 5 microns) remain suspended in the air for a prolonged period resulting. Examples include Mycobacterium tuberculosis
and Rubeola virus (measles). An example of vector-based transmission is the outbreak of fungal meningitis caused by epidural steroids
injections contaminated with environmental molds [11].

Infection control is an application of scientific and epidemiological principles for infection prevention and reduction. Hand washing,
aseptic techniques and environment cleaning are perhaps the most important infection control measures. Infection control programs
have become a requirement for hospital accreditation by the Joint Commission on Accreditation of Healthcare Organizations [12]. The
first formal US infection control hospital surveillance project initiated in as a result of the 1950s Staphylococcus aureus pandemic. The
Institute for Healthcare Initiatives (IHI) is a not-for-profit organization reports how greater than 100,000 annual deaths can be avoided
by quality initiative infection control measures. Infection control consists of standard precautions with or without transmission-based
isolation precautions depending upon site/type of infection. The infection control committee typically includes an infection control
practitioner (physician or nurse), trained ICU epidemiologist, and infectious disease or microbiology specialist. The committee aims to
develop infection control policies, educate hospital personnel, provide wound-infection feedback to surgeons, and investigate suspected

Standard precautions
Standard (universal) precautions are recommended for all hospitalized patients and consist of hand hygiene and respiratory hygiene
with cough etiquettes. This also includes safe disposal of instruments and soiled linens. Hand hygiene, perhaps the most effective method
for infection control, can be done with 60-95% alcohol-based hand rub or soap. Hand hygiene is recommended before clean/ aseptic
procedures, before and after touching a patient or patient surroundings, and after body fluid exposure [13].

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Infection control


Transmission-based isolation
Isolation precautions such as contact, droplet, and airborne precautions are based on the mode of transmission [14-16]. Contact
isolation usually warrants single-bed room with gown and gloves for all patient interactions. Droplet isolation mandates a facemask
for close contact with the patient. Patients on droplet precautions transported outside of the room should wear a mask if tolerated [14].
Airborne isolation requires a class A negative pressure, roofline exhaust isolation room and healthcare workers are expected to wear an
N95-mask or high-level respirator prior to entering patient room. Table 1 enlists both common and uncommon infections and their
required isolation. ICUs should have a centralized, filtered air-handling system capable of providing exchange for at least six rooms per hour.

Type of Precaution






C. difficile






Neisseria meningitis










* - Only if immunocompromised or 2dermatomes; VRE Vancomycin-resistant Enterococcus; MRSA Methicillin-resistant Staphylococcus aureus; RSV
Respiratory syncytial virus
Table 1: Transmission-based isolation precautions.

Patient Bathing and Environmental Precautions

Chlorhexidine gluconate is an antimicrobial skin disinfection used for daily bathing that reduces the incidence of MRSA and VRE
by 23% [13,14]. A multicentered-randomized trial illustrated the higher effectiveness in reducing rates of MRSA clinical isolates and
bloodstream infection using universal decolonization versus targeted decolonization or screening and isolation [17]. Environmental
cleaning, disinfection, and sterilization are also critical infection control measures. Disinfection is a process that eliminates non-spore
forming pathogenic microorganisms from inanimate objects. Sterilization, a complete microbial elimination, can be accomplished with
physical or chemical processes. Ultraviolet markers can be used to assess the adequacy of environmental cleaning [5].

Infection Control Bundles

A multifaceted team approach is necessary to develop and implement strategies to prevent infection in a critically ill patient [1821]. Intervention bundles along with daily reassessments help achieve such goals (Table 2-5). Bundles have also been adopted to avoid
Clostridium difficile infections (CDI). CDI bundles include avoiding judicious use of antibiotics, contact precautions for patients with
suspected or known CDI, mechanical barriers consisting of gowns and gloves for all patient contacts, and use soap and water (not
alcohol-based gels) to wash hands.
Hospitals can reduce their HAI rates by 32% if their infection control program included 4 components: (1) stress on surveillance
and infection control programs; (2) a full-time infection control provider for every 250 beds; (3) an epidemiologist trained in hospital
infections; (4) of surgical wound infection surveillance with wound infection feedback to surgeons [22].
Oral intubation (unless contraindicated)
Head of patients bed raised between 30-45 degree (unless contraindicated)
Scheduled drainage from ventilator circuits
Continuous subglottic suctioning
Avoid gastric distention
Oral care with an antiseptic solution (i.e. chlorhexidine)
Daily assessment for readiness to wean and use of weaning protocols
Meticulous hand hygiene
Proton pump inhibitors/ H2 blockers in intubated patients
Table 2: Ventilator-Associated Pneumonia Bundle.

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Maintain adequate pressure cuff at least 20 cm of water


Daily surveillance regarding further need of catheter

Catheterization only when necessary
Maintenance of free urine flow
Use of aseptic techniques
Proper securing of catheter on body
Maintenance of closed sterile drainage tubes
Aseptic techniques for obtaining urine samples
Meticulous Hand hygiene
Avoidance of prophylactic antibiotics and regular urine culture
Table 3: Catheter-Associated Urinary Tract Infection Bundle.
Facility policies

Central line insertion

Care and use

Infection control and surveillance to determine

infection rates and failures.

Site, catheter, and insertion technique with

lowest complication.

Cleansing of port with chlorhexidine is superior

to iodophor (10% povidine-iodine).

Aseptic technique during catheter placement

and care.

Replacement of wet soiled or dislodged central

line dressing.

Provide checklists to ensure infection

preventive practices.

Catheter site disinfection with 0.5%


Daily assessment and prompt removal of

unnecessary catheter.

Designated, trained personnel for insertion and


Maximal barrier precautions (gloves, gowns

and facemask).

Meticulous hand hygiene for all healthcare


Use of sterile, semi permeable transparent


Education and assessment of adherence to

guidelines for quality assurance/improvement.

Antiseptic/antibiotic impregnated CVCs and

Chlorhexidine-impregnated sponge dressings
can be considered if the rate of infection is not

Table 4: Catheter-Associated Bloodstream Infection Bundle.

Pre-operative Core Measures

Perioperative Core Measures

Administer appropriate antimicrobial prophylaxis within 1 hour prior to

incision (2 hour for vancomycin and fluoroquinolones)

Maintain normothermia early postoperative

Screen and treat remote infections before surgery

Keep operating room doors closed during surgery

If needed, remove hair by clipping or depilatory agents instead of sharp


Perioperative Supplemental Measures

Skin preparation with appropriate antiseptic agents

Repeat antibiotic dose at the 3 hr interval in procedures with duration


Nasal screen and decolonize Staphylococcus aureus carriers undergoing

elective procedures

Dose Adjustment of antimicrobial prophylaxis for obese patients (BMI


Screen preoperative blood glucose levels and maintain glucose control in

first 2 days patients undergoing select elective procedures

Use FiO2 at least 50% in during surgery and immediately post op period
in select procedure

Table 5: Surgical-Site Infection Bundle.

Although the ICU environment cannot be made microbe free, aggressive measures should be made to reduce HAIs and their
associated increased morbidity, mortality, length of stay and financial burden. The majority of these infections are preventable with
adequate preventative measures. Healthcare workers are mandated to implement infection control measures in their daily practice. As
patients in the ICU are critically ill, infection control measures to avoid complications is a priority and integral part of care. ICU providers
must be familiar with their institutions infection control guidelines for the prevention and management of invasive devices/catheters,
endotracheal tubes and tracheostomies.

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7. Fry DE (2008) Surgical site infections and the surgical care improvement project (SCIP): evolution of national quality measures. Surg Infect (Larchmt) 9:


13. Boyce JM, Pittet D, et al., (2002 ) Guideline for Hand Hygiene in Health-Care Settings: recommendations of the Healthcare Infection Control Practices
Advisory Committee and the HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Infect Control Hosp Epidemiol 23:3-40.
14. Sehulster L, Chinn RY; CDC; HICPAC (2003) Guidelines for environmental infection control in health-care facilities. Recommendations of CDC and the
Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep 52: 1-42.
15. Chen W, Li S, Li L, Wu X, Zhang W (2013) Effects of daily bathing with chlorhexidine and acquired infection of methicillin-resistant Staphylococcus aureus
and vancomycin-resistant Enterococcus: a meta-analysis. J Thorac Dis 5: 518-524.
16. Huang SS, Septimus E, Kleinman K, Moody J, Hickok J, et al. (2013) Targeted versus universal decolonization to prevent ICU infection. N Engl J Med 368:
17. Climo MW, Sepkowitz KA, Zuccotti G, Fraser VJ, Warren DK, et al. (2009) The effect of daily bathing with chlorhexidine on the acquisition of methicillinresistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and healthcare-associated bloodstream infections: results of a quasi-experimental
multicenter trial. Crit Care Med 37: 1858-1865.
18. Saint S, Meddings JA, Calfee D, Kowalski CP, Krein SL (2009) Catheter-associated urinary tract infection and the Medicare rule changes. Ann Intern Med
150: 877-884.
19. Tablan OC, Anderson LJ, Besser R, Bridges C, Hajjeh R; CDC; Healthcare Infection Control Practices Advisory Committee (2004) Guidelines for preventing
health-care--associated pneumonia, 2003: recommendations of CDC and the Healthcare Infection Control Practices Advisory Committee. MMWR Recomm
Rep 53: 1-36.
20. Anderson DJ, Kaye KS, Classen D, Arias KM, Podgorny K, et al. (2008) Strategies to prevent surgical site infections in acute care hospitals. Infect Control
Hosp Epidemiol 29 Suppl 1: S51-61.
21. Meyhoff CS, Wetterslev J, Jorgensen LN, Henneberg SW, Hgdall C, et al. (2009) Effect of high perioperative oxygen fraction on surgical site infection and
pulmonary complications after abdominal surgery: the PROXI randomized clinical trial. JAMA 302: 1543-1550.

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22. Haley RW, Culver DH, White JW, Morgan WM, Emori TG, et al. (1985) The efficacy of infection surveillance and control programs in preventing nosocomial
infections in US hospitals. Am J Epidemiol 121: 182-205.


Bedside Management of Shock

Khalid Saadah*
East Carolina University Brody School of Medicine, Department of Internal
Medicine, Section of Pulmonary, Critical Care & Sleep Medicine

*Corresponding author: Khalid Saadah, East Carolina University

Brody School of Medicine, Department of Internal Medicine, Section of
Pulmonary, Critical Care & Sleep Medicine, Greenville, NC 27834, Tel:
252.744.1600; E-mail:

Shock is a life-threatening condition characterized by multi-organ dysfunction and tissue hypoxemia caused by a decrease
in oxygen delivery or impaired oxygen utilization. Several indicators can be used to assess volume status, including mean blood
pressure, heart rate, respiratory rate, peripheral perfusion and urine output. While most patients in shock are hypotensive, a minority
may have a normal blood pressure, likely due to a compensatory peripheral vascular constriction. Alternatively, shock can also be
classified into high cardiac output (i.e. septic shock) and low cardiac output (i.e. heart failure). Treatment generally includes fluid
resuscitation, correction of underlying etiology, and often vasopressors. In this chapter, we will review the major classifications and
bedside management of shock.

Shock is classified into 4 major categories, of which most patients may present with more than one type:
1. Hypovolemic (hemorrhagic and non-hemorrhagic intravascular volume depletion)
2. Distributive (septic, anaphylactic, adrenal crisis, and neurogenic)
3. Cardiogenic (myocardial infarction, cardiomyopathy, valvular heart disease)
4. Obstructive (pulmonary embolism, tension pneumothorax, cardiac tamponade).

Clinical evaluation
The initial assessment of a patient with shock should be rapid yet thorough, as early resuscitation of patients in shock improve
mortality [1,2].Although often limited due to mechanical (endo tracheal tube) or physical status (altered mentation), the initial
bedside evaluation should focus on history taking for symptoms including vomiting, diarrhea, hematemesis, melena, lower extremity
edema, and fever. Clinical findings may include altered level of consciousness, cool or mottled extremities, capillary re-fill, S3 or S4
gallop, extremity edema, and/or jugular venous distention. In addition, a thorough review of the vital signs can assist the provider in
determining the shock etiology, though further hemodynamic monitoring is frequently required for such stratification. For example,
a decreased cardiac output can be evident by calculating the pulse pressure (which is the difference between the systolic and diastolic
blood pressure). A narrow pulse pressure, in addition to delayed capillary refill and cold extremities might be indicative of low
cardiac output, where as widened pulse pressure can be seen in high cardiac output conditions.

Resuscitation and hemodynamic monitoring

The initial resuscitation should focus on restoring tissue hypoxemia and treating the underlying etiology. For example, septic
patients should receive aggressive fluid resuscitation where as cardiogenic shock patients should receive inotropic agents [3].Patients
with conditions that result in compressing the cardiac chambers (i.e. pericardial tamponade, tension pneumothorax) require
drainage and relief.
Passive leg rising is simple bedside maneuver that has also been used to assess fluid responsiveness. By elevating the legs to
45-degreesfor ten minutes, blood is translocation from the lower extremities to the intra thoracic compartment. An increase in blood
pressure, stroke volume, or inferior vena cava diameter by about 12-15% is suggestive of fluid responsiveness [4].Central venous
pressure has been used for many years as a surrogate for intra-vascular status and fluid responsiveness in patients with shock, but
more recent meta-analyses show poor relationships between CVP and blood volume [5].In addition, the CVP is a poor predictor of
hemodynamic response to a fluid challenges. Measuring the inferior vena cava collapsibility or dispensability indices is better tool
for assessing the intravascular volume status. However, a non-spontaneously breathing patient is a requirement, since respiratory
variation has always been an issue.
The more invasive pulmonary artery catheter has been falling out of favor due to the associated complications and risk of
misinterpreting the data. In turn, this has allowed for less invasive intravascular volume assessments to take precedence.

A life-threatening reduction in intravascular volume canreduce venous return (preload), ventricular filling, and stroke volume.
Consequentially, this results in a reduced cardiac output unless compensated for by tachycardia. Although not always evident in an
ICU setting, bleeding is a common cause of hypovolemic shock. Typically, this hemorrhagic shock is due to surgical interventions,
peptic ulcer, esophageal varices, trauma, and/or ruptured aortic aneurysm.

Distributive shock
A distributive shock may results from an arterial or venous vasodilatory intravascular depletion in the face of a normal or low

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Hypovolemic shock


circulating fluid status. In most cases, cardiac output is elevated, systemic vascular resistance is reduced, and there is a reduction in tissue
oxygen consumption. As mentioned earlier, distributive shock can have several etiologies, including sepsis, anaphylaxis, neurogenetic
(due to intracranial injury resulting in the loss of sympathetic regulation), or drug-induced (typically nitrates, opiates, or beta-blockade).
Sepsis is a major cause of death in the medical ICUs in the United States, and likely globally. It has been estimated that around 750,000
patients are affected by sepsis annually [6]. The underlying pathophysiology is thought to be due unopposed inflammatory response
particularly by interluekin (IL)-6 and tumor necrosis factor, resulting in micro-vascular hypoperfusion and thrombosis. Consequentially,
this results in multiorgan dysfunction that is universally observed in these patients [7].
Sepsis is defined as a multisystem inflammatory response in the presence of suspected or confirmed infection [8]. Septic shock refers
to a state of circulatory failure due to infection in the absence of other cause of hypotension, as evident by systolic arterial pressure below
90 mmHg, mean arterial pressure lower than 60 or a reduction in systolic blood pressure of more than 40 mmHg from baseline, despite
adequate volume resuscitation [8].
In 2012, the surviving sepsis campaign defined severe sepsis as the presence of suspected or confirmed infection with related tissue
hypoperfusion or organ dysfunction, including [3]:
Hypotension (SBP <90 mm Hg or reduction by > 40 mm Hg, MAP < 70 mm Hg)
Elevated serum lactate (above the upper limit of normal)
Decreased urine output (<0.5 ml/kg/hr for more than 2 hours, despite fluid resuscitation)
Acute lung injury/Acute respiratory distress syndrome (if pneumonia is not present: PaO2/FiO2 <250; if pneumonia is present:
PaO2/FiO2 <200)
Serum creatinine>2 mg/dL
Serum total bilirubin >2 mg/dL
Thrombocytopenia (platelet count < 100,000)
Coagulopathy (INR > 1.5)
Early goal directed therapy in the treatment of septic shock is detrimental in improving patient outcome [9] (Table 1).
Bundles to be done within 3 hours
Measure serum lactate level
Obtain blood cultures (prior to administration of antibiotics if feasible)
Appropriate antibiotics within one hour
30 mL/kg crystalloid for hypotension or lactate 4mmol/L

Bundles to be done within 6 hours

Administer vasopressors to maintain a MAP 65 mm Hg in the event of persistent
arterial hypotension despite volume resuscitation or initial lactate 4 mmol/L
Measure central venous pressure
Measure central venous oxygen saturation (ScvO2)
Re-measure lactate if initial lactate was elevated

Table 1: The surviving sepsis guideline bundles.

Although the type of fluid to administer has been a debate, the surviving sepsis guidelines recommend crystalloid. The addition
of albumin is to be considered if patients require substantial amounts of crystalloid. In addition, the guidelines suggest avoiding
hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock. This recommendation is based on the results of the VISEP,
CRYSTMAS, 6S, and CHEST trials [10-13].
According to these guidelines, vasopressors should be initiated in patients with persistent septic shock despite fluid resuscitation. In
severely hypotensive patients, concomitant use of vasopressors may be ideal until adequate volume resuscitation is achieved. The goal
of a mean arterial pressure (MAP) of 65 mm Hg for patients receiving vasopressors for septic shock is based on very limited evidence,
according to these guidelines, and should be individualized. Norepinephrine, a beta-1a-receptoragonist, should is the recommended
first-line vasopressor agent. When norepinephrine is insufficient to maintain a MAP of 65 mm Hg, epinephrine should be added next.
Dopamine is discouraged as an alternative to norepinephrine in septic shock, except in highly selective patients such as those with low
cardiac output and absolute or relative bradycardia with a low risk for tachyarrhythmias [14]. Vasopressin should not be used as a
monotherapy. In addition, phenylephrine has limitations as well [3].
Initiating appropriate antibiotics is imperative, as timing may directly affect mortality in patients with septic shock [15,16]. When
possible, antibiotics should be tailored towards in-vitro culture susceptibility results and the patients clinical response in order to avoid
the emergence of resistance and/or unnecessary antibiotic-induced complications.

Cardiogenic shock
Cardiogenic shock is defined as an inappropriately low cardiac output in the setting of adequate intravascular volume status, resulting
in tissue hypoperfusion and hypoxemia. While left ventricular heart failure is the most common, other causes include right ventricular
heart failure, valvular heart disease or pericardial disease (i.e. acute tamponade). Myocardial ischemia is a major cause for cardiogenic
shock [17].
Pericardial tamponade impairs the diastolic filling, which results in right atrial and ventricular collapse during diastole. Pulmonary
artery catheterscan show equalization of the diastolic pressures between the atria and ventricles. In addition, a decrease in the right
atrial pressure is noted during inspiration, which is the opposite of what would happen in constrictive pericarditis. With innovations

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Transfusion of packed red blood cells to a hematocrit of 30% and/or do but amine infusion (to maximum 20 g/kg/min) can be
considered for patients with low central/mixed venous oxygen saturations, despite adequate volume resuscitation and vasopressor
administration. The use of corticosteroids is recommended only if adequate fluid resuscitation along with vasopressor therapy fails to
achieve hemodynamic stability. Steroids should be tapered off once vasopressors are no longer needed.


in echocardiographic technology and interpretation, echosonographyhas widely replaced pulmonary artery catheters for diagnosis of
cardiogenic shock. Treatment generally involves relieving the tamponadevia peri-cardiocentesis or surgical pericardial window. Tension
pneumothorax can result in cardiogenic shock by externally compressing the heart and decreasing venous return. Treating the tension
pneumothorax via drainageoften results in rapid hemodynamic stability.
Valvular heart disease can also result in cardiogenic shock, including severe aortic stenosis, aortic insufficiency, and rupture of the
papillary muscle for the mitral valve. Valvular disease therapy can include minimally invasive, robotic or open-heart procedures. Myocardial
ischemia can result from coronary thrombosis, which is typically treated via percutaneous angioplasty, stenting, thrombolytics, or bypass
grafting. Arrhythmia-induced cardiogenic shock may be effectively controlled with electrical or chemical cardioversion, transcutaneous/
transvenous pacemaker, atropine, or isoproterenol.

Vasoactive Agents
Dopamine: Dopamine has inotropic and chronotropic effectsvia activity on alpha-adrengeric (vasoconstriction), beta-adrenergic
(inotropic effects, chronotropic effects, and vasodilation), and non-adrenergic effects (renal and splanchnic vasodilation). Regardless
to the type of shock, the use of dopamine has been falling out of favor. The latest surviving sepsis campaign guidelines advocate
against the use of dopamine except in the certain situations mentioned above [3]. When comparing dopamine to norepinephrine in
critically ill patients with shock, there was a greater number of adverse events and no difference in mortality [18].
Norepinephrine: Norepinephrine has become the agent of choice for treatment of shock. It works via stimulation of beta1(inotropic and chronotropic effects) and alpha-receptors (vasoconstriction). Many studies has shown favorable use compared to
other pressers as previously mentioned.
Dobutamine: Dobutamine works on both beta-1 and beta-2 receptors, causing a resultant increase in cardiac output. It is
recommended to use in the setting of cardiogenic shock, especially if a concomitant septic shock is present.
Vasopressin: Vasopressin is generally reserved for patients with septic shock refractory to norepinephrine and should not be used
as monotherapy [3].

In summary, shock is a life-threatening condition that results in tissue hypo-perfusion and multi-organ failure. Rapid recognition,
diagnosis and intervention are imperative to reduce morbidity, mortality, and healthcare costs. Providers caring for patients with shock
should be up-to-date with resuscitative strategies.

1. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, et al. (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl
J Med 345: 1368-1377.
2. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, et al. (1999) Early revascularization in acute myocardial infarction complicated by cardiogenic
shock. SHOCK Investigators. Should we Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med 341: 625634.
3. Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlack H et al., (2013) Surviving Sepsis campaign: international guidelines for management of severe
sepsis and septic shock:2012. Crit Care Med 41: 580-637.
4. Marik PE, Cavallazzi R, Vasu T, Hirani A (2009) Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically
ventilated patients: a systematic review of the literature. Crit Care Med 37: 2642-2647.
5. Marik PE, Baram M, Vahid B (2008) Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven
mares. Chest 134: 172-178.
6. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, et al. (2001) Epidemiology of severe sepsis in the United States: analysis of incidence,
outcome, and associated costs of care. Crit Care Med 29: 1303-1310.
7. Kidokoro A, Iba T, Fukunaga M, Yagi Y (1996) Alterations in coagulation and fibrinolysis during sepsis. Shock 5: 223-228.
8. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, et al. (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit
Care Med 31: 1250-1256.
9. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, et al. (2001) Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl
J Med 345: 1368-1377.
10. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, et al. (2008) Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N
Engl J Med 358: 125-139.
11. Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, et al. (2012) Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4
vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care 16: R94.
12. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, et al (2012) Hydroxyethyl starch 130/0.42 versus Ringers acetate in severe sepsis. N
Engl J Med 367:124134.
13. Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, et al. (2012) Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 367:

15. Gaieski DF, Mikkelsen ME, Band RA, Pines JM, Massone R, et al. (2010) Impact of time to antibiotics on survival in patients with severe sepsis or septic
shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 38: 1045-1053.
16. Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, et al. (2010) Early combination antibiotic therapy yields improved survival compared with monotherapy
in septic shock: a propensity-matched analysis. Crit Care Med 38: 1773-1785.
17. Goldberg RJ, Gore JM, Alpert JS, Osganian V, de Groot J, et al. (1991) Cardiogenic shock after acute myocardial infarction. Incidence and mortality from
a community-wide perspective, 1975 to 1988. N Engl J Med 325: 1117-1122.
18. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, et al. (2010) Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J
Med 362: 779-789.

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14. De Backer D, Aldecoa C, Njimi H, Vincent JL (2012) Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis*. Crit Care Med
40: 725-730.


Acute Myocardial Infarction in an

Ramzy H Rimawi*, Matthew R Gay, Joshua R Howell, Endya
L Frye, Nyria L Muhirwa and Jered K Cope Meyers
East Carolina University Brody School of Medicine, Department
of Internal Medicine, Section of Pulmonary, Critical Care and Sleep
Medicine, USA
*Corresponding author: Ramzy H. Rimawi, East Carolina University
Brody School of Medicine, Department of Internal Medicine, Section
of Pulmonary, Critical Care and Sleep Medicine, USA, Fax: 252-7443472; E-mail: RIMAWIR@ECU.EDU

Approximately 15 million Americans over 20 years of age have coronary heart disease (CHD), in which the prevalence for myocardial
infarction (MI) is 2.9% [1]. The prevalence of an MI is higher for men (4.2%, average age 65 years) than for women (1.7%, average age
72 years) and increases with age [1-3]. Moreover, age above 75 years is the strongest predictor of 90-day mortality in patients with STsegment elevation MI (STEMI) undergoing PCI [3]. The incidence of a MI is 525,000 first occurrences per year and 190,000 recurrent
attacks annually, of which approximately 15% die from the acute infarction. The American Heart Association estimates an MI to occur
in the US every 44 seconds [1]. CHD remains the number one cause of death in the United States; accounting for 1 of every 6 deaths in
the US. Although these mortality rates are concerning, there has been a decline in cardiovascular deaths within the past four decades
due to progress made in earlier diagnosis and management [2]. Percutaneous coronary intervention (PCI), antithrombotic therapy and
antihypertensive and lipid-lowering preventive measures have contributed to a significant reduction in hospital mortality related to MI.
In the ICU, the identification and management of MI remains a challenge. Epidemiologic data of MI in an ICU setting is often
underreported as MI can often be missed due to masked symptoms secondary to sedatives, analgesic medications or concomitant
critical conditions (sepsis, traumatic injuries, and cerebrovascular accidents), inability to communicate ischemic symptoms because of
endotracheal intubation or coma, and/or misinterpretation of non-coronary causes of elevated cardiac enzymes. In an ICU, patients
with acute coronary syndromes (STEMI, non-STEM (NSTEMI), stable angina, and unstable angina) exhibit exceedingly higher
morbidity, mortality, length of stay and healthcare costs [4,5]. Ischemic changes can occur in up to 21% of ICU patients with CAD (or
risk factors for CAD) and 37% of ICU patients with troponin elevation.

Acute MI occurs when there is an abnormal ischemic alteration of the myocardium due to an inability of the coronary perfusion to
meet the myocardial contractile demand [5]. In 2012, the Joint Task Force of the European Society of Cardiology, American College of
Cardiology Foundation, the American Heart Association, and the World Health Federation (ESC/ACCF/AHA/WHF) redefined MI as
a rise and/or fall of cardiac biomarkers with at least 1 value above the 99th percentile of the upper reference limit together with evidence
of myocardial ischemia with at least 1 of the following [4]:
Symptoms of myocardial ischemia
Development of pathologic Q waves on electrocardiogram (ECG)
New ST-T changes or new left bundle branch block (LBBB)
Acute loss of viable myocardium or a new regional wall motion abnormality
Identification of an intracoronary thrombus by angiography or autopsy
Sudden, unexpected cardiac death with symptoms suggestive of myocardial ischemia and presumed new ST-segment elevation,
LBBB, and/or evidence of fresh thrombus by coronary angiography and/or autopsy.

The preliminary evaluation of a patient suspected of an acute MI begins with a thorough clinical history and physical examination.
The diagnosis of a myocardial infarction relies heavily on clinical signs, symptoms, electrocardiogram changes, cardiac enzymes, and
radiologic tests [2]. While algorithms may not always be standardized, a possible algorithmic approach to the diagnosis of MI in an
ICU setting may be used (Figure 1).

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Figure 1 Legend: USA= unstable angina; STEMI: ST-segment elevation MI; NSTEMI: non-ST-segment elevation MI; ECG: electrocardiogram;
cTN: cardiac troponin; DX: diagnosis
Figure 1: Diagnostic Algorithm of Acute Coronary Syndromes.

A. Clinical exam: On presentation the patient is likely to present with chest pain or discomfort posterior to the sternum that is not
relieved with rest or exacerbated by movement of the thoracic cage (i.e. when breathing deeply or coughing) [6-8]. Other symptoms
include fatigue, shortness of breath, dizziness, diaphoresis, dyspnea, nausea, vomiting and syncope (Table 1) [2,6-8]. Unfortunately,
patients in an ICU setting may not be able to communicate these symptoms. Furthermore, providers often relate these symptoms to
other non-cardiac causes, including iatrogenic causes (mechanical ventilation, endotracheal tube), sepsis, shock, etc. That said, a clinical
history and physical examination may not always be the best diagnostic modality for acute MI in an ICU setting.
Chest Pain:
Posterior to the sternum
Descriptors: Crushing/Burning/Squeezing
+ Absence of relief on exertion or rest
Often lasting >20 minutes
Radiating to left arm, jaw, neck, shoulder, epigastrum
Table 1: Classic Signs and Symptoms of Acute Myocardial Infarction

B.Daily ECG Recording: Previous studies using once daily 12-lead ECGs show dissociations between ischemia and troponin
elevation in the ICU, more especially in patients with septic shock [9-11]. The sensitivity and specificity of diagnosing acute MI (AMI)
in an ICU setting is very low and thus, using this method alone is not advised.
C. Continuous 12-lead ECG Recording: This should be initiated within 10 min of presentation in order help to detect episodes of
ST-segment deviations or other signs of ischemia. The precise sensitivity and specificity for detecting acute MI using continuous 12-lead
ECH monitoring is unknown.
D. Serum Biomarkers: Initial measurement should be done at presentation followed by second reading 6-9 hours after AMI.
Cardiac troponin, or cTN, is the preferred test. As prolonged myocardial ischemia preceded troponin elevation, myocardial ischemia
with elevated troponin is directly related to short-term and long-term mortality, Acute Physiology and Chronic Health Evaluation
(APACHE)-II score, mechanical ventilation, length of stay, and vasopressor support [12]. Myocardial ischemia can be detected in up
to 37% of patients with elevated troponins, likely related to prolonged ventricular wall stress as a result of the critical illness. Sepsis
without myocardial ischemia can elevate cTNs, likely related to increased myocardial oxygen supply and/or demand, coronary blood
flow, myocardial lactate consumption, biventricular dilatation, coronary plaque rupture, and myocardial injury [13,14].
E. Echocardiography: Early echosonography of the heart can help assess the prevalence of cardiac abnormalities, including wall
motion defects and vegetations [15]. In turn, this can fasten therapeutic decision.
F. Angiography: Myocardial infarction cab be confirmed via angiographic loss of patency of a major or side branch coronary artery
+/- persistently slowed, or no, flow due to embolization. Angiography can also allow for detection of stent thrombosis associated with

Treatment for a myocardial infarction (MI) in ICU patients should be initiated early and individualized and geared towards the
underlying cause, if identified. While the recommended treatment algorithms for critically ill patients with STEMI, NSTEMI and
unstable angina in the ICU are similar in non-critically ill patients, there may be exceptions depending on the clinical situation (i.e.
renal failure, active bleeding, and hemodynamic instability). The goals for management of an ICU patient with AMI include analgesia,
hemodynamic stability, electrolyte control, fluid balance, anticoagulation and/or anti-thrombotic therapy. Acute coronary syndrome
therapies, including beta-blockades and antiplatelets should be given cautiously in critically ill patients with AMI, depending on
hemodynamic stability, renal function, and hepatic function. As thrombocytopenia is often found in patients with sepsis, antiplatelet
agents may not always be feasible.
A. Oxygen: often aimed at a goal of O2 saturation >90% [16-18].
B. Fibrinolysis: A potential therapeutic agent used in STEMI patients. Pretreatment with antiplatelet agents (i.e. clopidogrel) is often
recommended [7].

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Medical Management


C. Nitrates: Assuming the blood pressure can tolerate, nitroglycerin can be used for analgesia. Intravenous nitroglycerin is used for
pain that is not controlled by sublingual administration. Medications should be reviewed for phosphodiesterase inhibitors taken within
the preceding 24 hours [16-18].
D. Morphine: Morphine can be also used from chest pain or anxiety if nitrates have not given a satisfactory affect [16-18].
E. Beta-blockade: As patients with AMI or unstable angina often have tachycardia and elevated blood pressures, beta-blocking agents
can reduce heart rate, blood pressure and the workload of the heart. In turn, this can reduce myocardial oxygen consumption. Betablockers also reduce the risk of MI recurrence [19].
F. Statins: A lipid panel should be taken and, if possible, statin therapy started while tended for in the ICU. Follow-up lipid panels
should be postponed for 2 months following discharge, as MI alone can reduce LDL levels [16-18].
G. Antiplatelet: Aspirin in combination with glycoprotein IIb/IIIa inhibitors is recommended. In patients mechanically ventilated,
aspirin can be crushed and administered via gastric tube [20].
H. Anticoagulant: Unfractionated heparin with reperfusion therapy can reduce mortality [16-18] Anticoagulation therapy with
prasugrel and ticagrelor are currently preferred over clopidogrel [21].
I. Anti-arrhythmic Agents: Lidocaine is discouraged in acute MI. Rapid correction of electrolytes, particularly potassium and
magnesium, may help in acute MI with arrhythmia [16-18].
J. Hypothermia: There is promising evidence supporting induced hypothermia to reduce the extent of cardiomyocytes damage and
improve patient outcome while the cause of a ST-segment elevated myocardial infarction (STEMI) is determined [20, 22].

Percutaneous Coronary Intervention

Although early detection and rapid intervention of myocardial infarction can lead to fewer adverse cardiac effects and reduced
mortality, the identification of acute coronary syndrome in an ICU setting may be challenging. Not only are the patients critically ill from
concomitant conditions (i.e. sepsis, respiratory failure), but also 34% of patients in an ICU setting have elevated cardiac enzymes [23].
Regardless of whether a patient is critically ill in an ICU or clinically stable on a hospital ward when acute coronary syndrome is identified,
early invasive strategies continues to have more favorable outcomes compared to conservative methods in patients with ST-segment
elevation myocardial infarction (STEMI), non-ST-segment myocardial infarction (NSTEMI), and unstable angina [21-25]. Furthermore,
coronary angiography is favored to fibrinolytic therapy in other instances that may cause ST-segment elevations (i.e. pericarditis) [26].
An average of 500,000 percutaneous coronary interventions (PCI) are performed annually in the US averages [27]. However, critically
ill patients are often at high risk for adverse outcomes related to coronary angiography. High risk patients include those with ongoing
chest pain >20 minutes, ST depression 1mm in 2 leads, recent PCI in the past 6 months or prior coronary artery bypass grafting
(CABG), heart failure, sustained ventricular tachycardia, hemodynamic instability, elevated cardiac enzymes, LVEF <40%, and/or diabetes
mellitus [28]. Low risk patients are those with negative troponins, non-diagnostic EKGs, and lack ongoing chest pain. While STEMI
often necessitates immediate PCI, low-risk patients with unstable angina or NSTEMI may be treated medically with aspirin, heparin,
antiplatelet agents (i.e. clopidogrel), beta-blockers, statins and nitrates. Some of these agents may need to be avoided in patients with
contraindications, including hemodynamic compromise, bleeding disorders, and coagulopathy. If acute coronary symptoms continue in
these low risk patients, coronary angiography is then warranted within 12-14 hours. Depending on the angiographic findings, the patient
can then be treated with medical therapy, PCI (followed by glycoprotein IIb/IIIa inhibitors), or CABG.

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, et al. (2013) Executive summary: heart disease and stroke statistics--2013 update: a report
from the American Heart Association. Circulation 127: 143-152.
2. Boateng S, Sanborn T (2013) Acute myocardial infarction. Dis Mon 59: 83-96.
3. Gharacholou SM, Lopes RD, Alexander KP, Mehta RH, Stebbins AL, et al. (2011) Age and outcomes in ST-segment elevation myocardial infarction
treated with primary percutaneous coronary intervention: findings from the APEX-AMI trial. Arch Intern Med 171: 559-567.
4. Ammann P, Maggiorini M, Bertel O, Haenseler E, Joller-Jemelka HI, et al. (2003) Troponin as a risk factor for mortality in critically ill patients without
acute coronary syndromes. J Am Coll Cardiol 41: 2004-2009.
5. Lim W, Qushmaq I, Cook DJ, Crowther MA, Heels-Ansdell D, et al. (2005) Elevated troponin and myocardial infarction in the intensive care unit: a
prospective study. Crit Care 9: R636-644.
6. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, et al. (2012) Third universal definition of myocardial infarction. Circulation 126: 20202035.
7. The Joint European Society of Cardiology/American College of Cardiology Committee (2000) Myocardial infarction redefined- A consensus document
of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. European Heart
Journal 21: 1502-1513.
8. Sabatine MS (2011) Pocket medicine. The Massachusetts General Hospital Handbook of Internal Medicine (4thedn).

10. Spies C, Haude V, Fitzner R, Schrder K, Overbeck M, et al. (1998) Serum cardiac troponin T as a prognostic marker in early sepsis. Chest 113:
11. Turner A, Tsamitros M, Bellomo R (1999) Myocardial cell injury in septic shock. Crit Care Med 27: 1775-1780.
12. Landesberg G, Vesselov Y, Einav S, Goodman S, Sprung CL, et al. (2005) Myocardial ischemia, cardiac troponin, and long-term survival of highcardiac risk critically ill intensive care unit patients. Crit Care Med 33: 1281-1287.
13. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, et al. (1984) Profound but reversible myocardial depression in patients with septic
shock. Ann Intern Med 100: 483-490.
14. Turner A, Tsamitros M, Bellomo R (1999) Myocardial cell injury in septic shock. Crit Care Med 27: 1775-1780.

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9. Guest TM, Ramanathan AV, Tuteur PG, Schechtman KB, Ladenson JH, et al. (1995) Myocardial injury in critically ill patients. A frequently unrecognized
complication. JAMA 273: 1945-1949.


15. Blanc P, Boussuges A, Souk-aloun J, Gazere BA, Sainty JM (1997) Echocardiography on HIV patients admitted to the ICU. Intensive Care Med
23: 1279-1281.
16. Braell JA, Aroesty JA, Simons M (2013) Overview of the acute management of unstable angina and non-ST elevation myocardial infarction. In:
UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA.
17. Hochman JS (2013) Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction. In: UpToDate, Basow, DS (Ed),
UpToDate, Waltham, MA.
18. Reeder GS, Kennedy HL, Rosenson RS (2013) Overview of the acute management of ST elevation myocardial infarction. In: UpToDate, Basow, DS
(Ed), UpToDate, Waltham, MA.
19. Yang EH (2008) ST-segment elevation myocardial infarction. In: Fuster V et al., eds., Hursts The Heart, (12thedn), 1375-14040. New York: McGrawHill Medical.
20. Roe MT, Messenger JC, Weintraub WS, Cannon CP, Fonarow GC, et al. (2010) Treatments, trends, and outcomes of acute myocardial infarction
and percutaneous coronary intervention. J Am Coll Cardiol 56: 254-263.
21. Birkmeier S, Thiele H, Drr R (2013) Management of acute myocardial infarction with ST-segment elevation : Update 2013. Herz .
22. Schwartz BG, Kloner RA, Thomas JL, Bui Q, Mayeda GS, et al. (2012) Therapeutic hypothermia for acute myocardial infarction and cardiac arrest.
Am J Cardiol 110: 461-466.
23. Webb I, Coutts J (2008) Myocardial infarction on the ICU: can we do better? Crit Care 12: 129.
24. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, et al. (2012) ACCF/AHA focused update of the guideline for the management of patients
with unstable angina/Non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the
American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. Aug 14: 126(7): 875-910.
25. Zijlstra F, Patel A, Jones M, Grines CL, Ellis S, et al. (2002) Clinical characteristics and outcome of patients with early (<2 h), intermediate (2-4 h)
and late (>4 h) presentation treated by primary coronary angioplasty or thrombolytic therapy for acute myocardial infarction. Eur Heart J 23: 550-557.
26. Acute Coronary Syndromes and Acute Myocardial Infarction. Chapter 31: 589-646 In: Critical Care Medicine: Principles of diagnosis and management
in the adult, Third Edition. Ed: Parillo JE, Dellinger RP. Mosby Inc.
27. Marso SP, Teirstein PS, Kereiakes DJ, Moses J, Lasala J, et al. (2012) Percutaneous coronary intervention use in the United States: defining
measures of appropriateness. JACC Cardiovasc Interv 5: 229-235.

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28. Albert RK, Slutksy AS, Ranieri VM, Takala J, Torres A (2006) Acute Coronary Syndrome. Chapter 30, 301-318. In: Clinical Critical Care Medicine,
First Edition.


Heart Failure in an ICU

Ramzy H Rimawi*, Beth Cherveny, Joshua Davis, Holly
Dieu, Amber Heckart and Kendall Liner
East Carolina University Brody School of Medicine, Department
of Internal Medicine, Section of Pulmonary, Critical Care & Sleep
Medicine, Greenville, NC 27834, USA
*Corresponding author: Ramzy H. Rimawi, MD, East Carolina
University Brody School of Medicine, Department of Internal Medicine,
Section of Pulmonary, Critical Care & Sleep Medicine, Greenville, NC
27834, USA; E-mail:

Heart failure is an acute or chronic syndrome that results from amplified left ventricular filling pressure, salt and fluid retention, and/
or reduced cardiac output. In an ICU setting, acute heart failure can arise from several bases, including ischemia, valvular ineptitude,
chronic heart failure decompensation, and/or cardiomyopathy. Clinical features typically include dyspnea and hypoxia, which arises
from venous congestion related to hypoperfusion and elevated end-diastolic ventricular pressure. In addition to a detailed history
and physical exam, common diagnostic modalities include electrolyte monitoring, brain natriuretic peptide and echosonography.
Management of heart failure in an ICU setting often includes aggressive afterload reduction, diuresis, and invasive or non-invasive
mechanical ventilation. In this chapter, we will summarize the epidemiology, risk factors, diagnosis and management of critically ill
patients with acute heart failure.

An estimated 5.7 million Americans have heart failure (HF), of whom and two million are admitted annually as a result of acute HF
(AHF), making AHF one of the leading causes of hospitalizations in the US [1]. The prevalence of HF increases with age, partly due to
coronary artery disease (CAD) [2]. As a result, 20% of hospitalizations in patients over the age of 65 are due to AHF, of which 24% are
rehospitalized within 90 days. Although women have a greater number of hospitalizations with severe manifestations related to HF, the
over survival in women without CAD is better. A precise incidence of AHF in the ICU setting is unknown, likely due to the concomitant
extracardiac pathologies that result in AHF, including pericardial disease, sepsis, and renal or hepatic failure.Although mortality has
reducedin the past decade, HF still accounts for over 55,000 deaths annually. Mortality associated with diastolic heart failure (DHF) is
slightly lower than those with systolic heart failure (SHF).
Decompensation in HF due to a respiratory process, ischemia, or renal dysfunction is associated with a longer ICU length of stay
and higher in-hospital mortality [1]. On the contrary, decompensation due to uncontrolled hypertension or medication non-adherence
is associated with a shorter length of stay and lower in-hospital mortality [3].

Heart failure is divided into systolic (SHF) and diastolic heart failure (DHF), both of which result from damaged or impaired cardiac
myocytes. A preserved ejection fraction indicates DHF, while an impaired ejection fraction suggests SHF. SHF is produced by reduced
cardiac contractility or impaired pump function or ejection fraction. In turn, this causes left ventricular dilatation and elevations in left
ventricular systolic and diastolic volumes. DHF results when there is impaired filling of the ventricle during diastole or impaired cardiac
relaxation. Increased systemic pressure or stiffening of the left ventricle elevates the left ventricular pressures, therefore reducing blood
flow from the left atrium during diastole.
Systolic HF, most often secondary to CAD, accounts for 60% of AHF cases [4-6]. SHF often arises from reduced cardiac contractility
and fluid retention when the myocardium is under-perfused and cardiac myocytes are injured. Other causes of SHF include dilated
cardiomyopathy, myocarditis heart valve disorders, hypertensive heart disease, congenital heart disease, sepsis, and toxin induced
cardiomyopathy [4]. On the other hand, common causes of DHF include chronic hypertension (due to progressive increase in arteriolar
resistance), ischemic heart disease, restrictive cardiomyopathy, and hypertrophic cardiomyopathy.
Morphologic and functional changes manifest differently between SHF and DHF. In DHF, left ventricular mass, wall thickness, and
end-diastolic pressure are all increased while left ventricular cavity size is normal or decreased. However, in SHF the wall thickness and
ejection fraction are reduced while end systolic pressure/volume, end diastolic pressure/volume, and left ventricular cavity size are all
increased. Additionally the left ventricle takes on a spherical shape in SHF but often remains unchanged in DHF [6].

There are many modifiable and non-modifiable risk factors for the development of HF. In general, risk factors for AHF in the
ICU are similar to those of chronic HF. For example, non-modifiable risksfor HF may include age, gender, and race. HF is greatest in
African Americans, followed by Hispanics, Caucasians, and Chinese Americans [1]. This can be explained, in part, by hypertensive and
atherosclerotic risk factors, prevalence of diabetes mellitus, and socioeconomic status.CAD accounts for more than 60% of HF cases in

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the US [7]. Other medical conditions associated with the development of HF include hypertension, diabetes mellitus, and valvular heart
disease. Modifiable risk factors for HF include cigarette smoking, physical inactivity, obesity, hypertensive medication non-compliance,
and poor glycemic control. These risk factors are often difficult to modify in critically ill patients during the ICU course. However
possible strategies implementable during the ICU course may include smoking cessation, increased physical activity, weight loss, and
blood pressure and glycemic control.

As with patients in any ward of the hospital, diagnosis of AHF in ICU patients includes an extensive history, physical examination,
and diagnostic testing.
A. Clinical History: History acquisition may be stunted by inability to communicate, such as those with intracranial injury, septic
shock or mechanically ventilation. Patients with AHF typically complain of dyspnea and generalized weakness that progresses with
B. Physical examination: Patients with AHF may havehypertension or cardiogenic shock, peripheral edema, hepatic congestion,
dyspnea, hypoxia, anorexia, ascites, hepatosplenomegaly, pulmonic rales, and anura. These physical exam findings are dependent on
the severity, etiology, and onset of HF. Cardiovascular examination may demonstrate narrow pulse pressure, pulsusalternans, displaced
apical impulse (indicating left ventricular enlargement), S3 gallop (indicating left ventricular pressures >20mmhg), and jugular venous
distention (JVD). Hepatojugular reflux is induced by applying pressure to the right upper quadrant for 10 to 15 seconds with a resulting
JVD > 3cm.
C. Blood Tests: Abnormalities in complete blood count may indicate anemia or infection that may have potentiated AHF. Serum
electrolytes, blood urea nitrogen, and creatinine may be abnormally low due to volume overload and renal hypoperfusion or dysfunction.
Fasting blood glucose levels may be elevated in diabetics and non-diabetics with AHF. Liver function tests may be abnormal due to
hepatic failure. Brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide levels (NT-proBNP) elevation is directly
related with heart failure progression and cardiac dysfunction in the ICU. BNP and NT-proBNP can also be used to distinguish HF
from other causes of dyspnea with greater diagnostic value than initial blood tests, x-ray, and ECG [8,9]. While BNP levels greater than
400 pg/mL suggests AHF and levels below 100 pg/mL argues against AHF, values between 100 and 400 pg/mL have low sensitivity and
specificity for differentiating HF. However, AHF can be reliable excuded when NT-proBNP levelis below 300 with a 98% predictive value.
In AHF, patients <50 years of age typically have NT-proBNPof>450 pg/mL, 50-75 years have NT-proBNPof >900 pg/mL, and patients
>75 years old typically have NT-proBNPof>1800 pg/mL [10]. Some limitations in BNP and NT-proBNP may include obesity, renal
failure and sepsis, which may complicate its use in a critical care setting.
D. Electrocardiogram: The electrocardiogram (ECG) can identify significant abnormalities in patients with HF due to arrhythmias,
acute or remotemyocardial ischemia/infarction, bundle branch blocks, or coronary artery disease.
E. Chest Radiography: Chest x-ray mayillustrate pulmonary congestion, cardiomegaly, pulmonic vessel cephalization, Kerley B-lines
and pleural effusions.
F. Echocardiography: Echocardiographic findings can help determine cause and chronicity of HF by assessing atrial and ventricular
sizes, systolic and diastolic ventricular functions, pulmonary capillary wedge pressure, right ventricle and pulmonary artery pressure, and
cardiac output. Ultrasonographic studies may also identify ventricular dysfunction, segmental abnormalities in dilated cardiomyopathy,
pericardial disease, and valvular heart disease. Although chest roentgenogram and electrocardiogram findings cannot distinguish
between SHF and DHF, echocardiography can be used to determine whether HF is of systolic or diastolic origin. That said, providers
caring for critically ill patients should recognize the importance of appropriately distinguishing SHF from DHF clinically, as this will
consequently guide in treatment.
G. Coronary Arteriography: While this may reveal coronary artery disease as the source of AHF, coronary arteriography may not
always be feasible in critically ill patients. Patients may be restricted from angiogram studies due to hemodynamic instability, renal
failure, coagulopathy, and/or electrolyte imbalances.
Management: While there are general goals for the management of ADHF in critical care settings, optimal therapy requires
identification of the underlying causes of the cardiac decompensation in the context of the declining ability of the patients heart to meet
end organ metabolic demands for oxygen [11]. The Heart Failure Society of America (HFSA) recommends the following treatment goals
for patients with ADHF [12]:
Improve symptoms, especially congestion and low-output symptoms
Restore hemodynamic stability, normal oxygenation and volume status
Identify and etiology and precipitating factors
Minimize adverse effects
Identify patients who might benefit from revascularization, anticoagulant therapy or device therapy
Optimize chronic oral therapy
A. Medical Therapy: In general, the medical management strategies involve reducing the afterload and myocardial oxygen
consumption, increasing perfusion with vasodilators, reducing pulmonary edema with diuretics, and increasing myocardial contractility
with positive inotropic agents.Arterial vasodilators are the first line therapy in patients with pulmonary congestion and adequate blood
pressure. Arterial vasodilators reduce left ventricularpreload and afterloadto help deliver oxygen to cardiac myocytes and relieve
pulmonary congestion. Nitrates (i.e. nitroglycerin and isosorbidedinitrate) are frequently used to liberate nitric oxide molecules to reduce
left-ventricular filling pressure and increase stroke volume. Nitrates and furosemide given concomitantly is superior to furosemide alone
in in acute pulmonary edema [13]. Patients should be monitored closely as excessive vasodilation may potentially result in abrupt
reduction in blood pressure, ischemia, shock and renal failure.

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Advocate medication compliance, weight loss and exercise


Intravenous loop diuretics (i.e. furosemide, bumetanide) can be given to reduce edema stemming from pulmonary congestion.
Reducing the plasma volume with diuretics can decrease the hydrostatic pressure within the pulmonary vessels and thus, decrease the
propensity for fluid to travel out of the vessels and into the interstitial space. For patients already on a loop diuretic regimen, non-loop
diuretics are sometimes used to supplement this natriuresis and diuresis, reduce systemic edema, and reduce pulmonary edema due to
SHF. Additionally, excess volume can be removed mechanically via a simplified peripheral ultrafiltration system. Ultrafiltration systems
have been shown to be effective in decreasing orthopnea, JVD, rales, S3 gallop, and peripheral edema. Because supraventricular and
ventricular arrhythmias can be associated with pulmonary edema, this presents another motive to remove the fluid to alleviate or prevent
worsening of cardiac arrhythmias.
While morphine can reduce heart rate and cause arterial and venous dilatation, its efficacy in treating pulmonary edema remains
unknown. Anticoagulants have only been proven beneficial in critically ill patients with AHF withmyocardial ischemia or atrial flutter,
and atrial fibrillation. Beta-blocking agents and calcium antagonists are contraindicated in patients with significant left ventricular systolic
dysfunction. ACE-inhibitors and angiotensin-receptor blockers may not be applicable in patients with low cardiac output and impaired
renal function and are also not recommended in the initial management of AHF. Low doses of intravenous dopamine in ICU patients does
not significantly protect against renal dysfunction [14].
Patients with end organ hypoperfusion and edema can develop cariogenic shock. While there is mixed data about the use of positive
inotropic agents in managing decompensated heart failure, positive inotropes used (i.e. milrinone, dobutamine, and dopamine)can
reduce heart rate and strengthen contractility of the heart muscle if a patient is in cardiogenic shock. A distinction may exist between the
effectiveness of drugs and therapies in patients with stable congestive heart failure versus critically ill patients with decompensated heart
failure in the ICU. While patients with stable congestive HF and reduced left ventricular ejection fraction benefit from ACE-inhibitors,
beta-blockers, aldosterone antagonists, implantable cardioverter defibrillators, and cardiac resynchronization therapy, the same reduction
in morbidity and mortality is not proven in patients with decompensated heart failure [2].
B. Mechanical Ventilation: Positive pressure ventilation canprovide therapeutic benefits in AHF patients with pulmonary edema,
acidosis related to hypercapnia, andhypoperfusion. This allows for improved oxygen diffusion across the alveolar membrane and reduces
vasoconstriction of pulmonary vessels.Several trials have illustrated the benefical effect of continuous positive airway pressure (CPAP)
ventilation in patients with AHF [15]. Other than reducing the need for endotracheal intubation, CPAP may also reduce hospital mortality
when implanted in AHF patients.
C. Intraaortic Balloon Pump (IABP): Based on a counterpulsation principle, an IABP has clinical efficacy in AHF patients with
a correctable underlying condition and severe myocardial ischemia refractory to medical therapy, severe mitral insufficiency, and
intraventricular septum rupture. In patients with aortic regurgitation or aortic dissection, IABP should not be used.
D. Ventricular Assist Devices (VAD): VADs are indicated in patients with severe myocardial ischemia/infarction refractory to medical
management and IABP. There are several types of ventricular assist devices, none of which are appropriate for all patients with AHF.
Various types include pulative versus non-pulsative flow, right versus left, and internal versus external VADs.

In summary, acute heart failure is a frequentailment encountered in an ICU setting. Rapid interventions can have a profound impact
on morbidity, mortality, length of stay and healthcare costs. Early detection and optimal therapy by those with expertise in the management
of AHFcan improve the outcome for this exceedingly common condition.

1. Alan S. Go, Dariush M., Vronique L. Roger (2013) Heart Disease and Stroke Statistics2013 Update: A Report From the American Heart
Association. Circulation 127: 6-245, published online before print December 12 2012, doi:10.1161/CIR.0b013e31828124ad. Centers for disease
control and prevention heart failure fact sheet. Accessed October1, 2013 from:
2. Jessup M, Brozena S (2003) Heart failure. N Engl J Med 348: 2007-2018.
3. Fonarow GC, Abraham WT, Albert NM, Stough WG, Gheorghiade M, et al. (2008) Factors identified as precipitating hospital admissions for heart
failure and clinical outcomes: findings from OPTIMIZE-HF. Arch Intern Med 168: 847-854.
4. Allen LA, OConnor CM (2007) Management of acute decompensated heart failure. CMAJ 176: 797-805.
5. Arnold M (2008) Merck Manual: Heart Failure. Retrieved October 12, 2013, from Merck Manual Home Health Handbook:
6. Chatterjee Kanu MB, Otto Catherine (2012) Examination of the jugular venous pulse. UpToDate.
7. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, et al. (2001) Risk factors for congestive heart failure in US men and women: NHANES I
epidemiologic follow-up study. Arch Intern Med 161: 996-1002.
8. Maisel A (2002) B-type natriuretic peptide levels: diagnostic and prognostic in congestive heart failure: whats next? Circulation 105: 2328-2331.
9. Mant J, Doust J, Roalfe A, Barton P, Cowie MR, et al. (2009) Systematic review and individual patient data meta-analysis of diagnosis of heart failure,
with modelling of implications of different diagnostic strategies in primary care. Health Technol Assess 13: 1-207, iii.
10. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, et al. (2006) NT-proBNP testing for diagnosis and short-term
prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study.
Eur Heart J 27: 330-337.

12. Heart Failure Society of America, Lindenfeld J, Albert NM, Boehmer JP, Collins SP, et al. (2010) HFSA 2010 Comprehensive Heart Failure Practice
Guideline. J Card Fail 16: e1-194.
13. Cotter G, Metzkor E, Kaluski E, Faigenberg Z, Miller R, et al. (1998) Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide
versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema. Lancet 351: 389-393.
14. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J (2000) Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled
randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356: 2139-2143.
15. Pang D, Keenan SP, Cook DJ, Sibbald WJ (1998) The effect of positive pressure airway support on mortality and the need for intubation in cardiogenic
pulmonary edema: a systematic review. Chest 114: 1185-1192.

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11. Ramrez A, Abelmann WH (1974) Cardiac decompensation. N Engl J Med 290: 499-501.


Critical Care Scoring Systems and

Ogugua N Obi*
MD, MPH, Department of Pulmonary and Critical Care Medicine, Brody School of
Medicine, East Carolina University, Greenville, NC

*Corresponding author: Ogugua N Obi, Department of Pulmonary and

Critical Care Medicine, Brody School of Medicine, East Carolina University,
Greenville, NC, 27834, Tel: 1.800.722.3281; E-mail:

Scoring systems are widely used in the ICU to predict outcome, characterize disease severity and degree of organ dysfunction,
assess resource use, evaluate new therapies, compare ICU care across various settings, and demonstrate equivalence of study and
control patients in clinical research. In this article, we will review the most commonly used scoring systems in the ICU, briefly
examine the history of their development and address when and how to use these systems. We also note the fact, that the different
scoring systems should be seen as complementary and not as mutually exclusive and emphasize the fact, that scoring systems should
not replace individualized care and/or decision making in the ICU.

Scoring systems are necessary in the ICU for several reasons to predict outcome and prognosis, guide the clinical decision
making process, monitor and assess new therapies, compare care between different centers, standardize medical research and
perform cost-benefit analysis with regard to resource utilization. While not specifically designed for individual patient care, scoring
systems may guide (but will NOT replace) clinical decision making regarding withdrawal of treatment and/or futility of continued
aggressive care. This latter reason will become progressively more important as families become more involved in medical decision
making in the ICU.
A good scoring system should meet some basic requirements (Table 1). First, it should assess an important, relevant and easily
determined outcome. Most ICU scoring systems assess mortality while others predict long-term morbidity and functional status.
Next, it should be simple, reliable, easy to use, and in-put data should be readily obtainable. A good scoring system should also have
wide patient applicability, high sensitivity and specificity, and be able to perform well across a wide range of predicted mortalities.
Discrimination and calibration are two characteristics used to judge a scoring system. Discrimination refers to the accuracy of
a given prediction e.g., if a scoring system predicts a mortality of 90%, discrimination is perfect if the observed mortality is 90%.
Calibration describes how an instrument performs over a wide range of predicted mortalities. An instrument would be highly
calibrated if it were accurate at mortalities of 90%, 50% and 20%. Unfortunately however, there is no ideal score. Several scores used
in conjunction would be complementary although potentially more time consuming and labor intensive.
It should be noted, that scoring systems are meant as a guide to clinical care and should not replace good clinical judgment, limit
treatment of individual patients or result in nihilistic, depersonalized care.
1. Based on easily/routinely recordable variables
2. Well calibrated
3. A high level of discrimination
4. Applicable to all patient populations
5. Can be used in different countries
6. The ability to predict functional status or quality of life after ICU discharge
No scoring system currently incorporates all these features
Table 1: The ideal scoring system [40].

Classification of Scoring Systems

Anatomical scoring these depend on the anatomical area involved and are mainly used for trauma patients [e.g. Abbreviated
Injury Score (AIS) and Injury Severity Score (ISS)
Disease specific based on the ongoing disease process ,[e.g. Ransons criteria for acute pancreatitis, subarachnoid hemorrhage
assessment using the World Federation of Neurosurgeons score, and liver failure assessment using Child-Pugh or Model for EndStage Liver Disease (MELD) scoring]
Physiological assessment - based on the degree of derangement of routinely measured physiological variables [e.g. Acute
Physiology and Chronic Health Evaluation (APACHE) and Simplified Acute Physiology Score (SAPS)].

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There is no agreed method of classification of scoring systems used in critically ill patients. Several methods of classification have
been suggested as shown below [1]:


Organ-specific scoring - The underlying premise here is that the sicker a patient is, the more organ systems will be involved (ranging from
organ dysfunction to failure) and the poorer the expected outcome will be [e.g. Sepsis-Related Organ Failure Assessment (SOFA)] Therapeutic
weighted scores - These are based on the assumption that very ill patients require a greater number of interventions and procedures that
are more complex than patients who are less ill. Examples include the Therapeutic Intervention Scoring System (TISS).
Simple scales - based on clinical judgment (e.g., survive or succumb)
For the purpose of simplicity and ease of understanding, we will simplify the scoring systems into 3 broad functional categories:
Disease-specific scores - specic for an organ or disease (for example, the Glasgow Coma Scale (GCS), the Ransonss Criteria for
acute pancreatitis, the Intra Cranial Hemorrhage (ICH) score or the Maddreys discriminant function for alcoholic hepatitis etc.)
Generic ICU score these are generic and applicable to a very wide range of ICU patients independent of their disease specifics.
This category will include the physiologic assessment scores, the organ dysfunction scores and the therapeutic weighted scores.
Scores and check lists used to assess everyday care in the ICU including adequacy of pain control, depth of sedation/degree of
agitation and presence or absence of delirium and adherence to infection prevention.
In this chapter, we focus on the latter 2 broad groups. The objective of this review chapter is to give the ICU provider without any
particular knowledge or expertise in this area an overview of the current status of these instruments and their possible applications.

Generic ICU scores

Generic ICU scores maybe further sub-categorized into:
Outcome prediction scores - based on disease severity on admission (e.g. Acute Physiology and Chronic Health Evaluation
(APACHE), Simplied Acute Physiology Score (SAPS), Mortality Probability Model (MPM))
Organ dysfunction scores - assess the presence and severity of organ dysfunction (e.g. Multiple Organ Dysfunction Score (MODS),
Sequential Organ Failure Assessment (SOFA)).
Scores that assess nursing workload use (e.g. Therapeutic Intervention Scoring System (TISS), Nine Equivalents of Nursing
Manpower Use Score (NEMS)).

Outcome prediction scores

The original outcome prediction scores were developed over 25 years ago to provide an indication of the risk of death in groups of
ICU patients. They were not designed for individual prognostication. They have all undergone recent updates to account for the changing
patient demographics, disease severity and intensive care practices to ensure continued accuracy in todays ICU.
We will limit our discussion to the three most common outcome prediction scores:
Acute Physiology and Chronic health Evaluation Score (APACHE, APACHE II, APACHE III, APACHE IV)
Simplified Acute Physiology Score (SAPS, SAPS II, SAPS III)
Mortality Prediction Model (MPM, MPM II, MPM III)

Acute Physiology and Chronic Health Evaluation (APACHE) score

In 1985, the original model was revised and simplified to create APACHE II by using 12 physiological variables instead of 34 and
incorporating age and chronic health status directly into the model to give a single point score with a maximum score of 71 [3]. The
worst value recorded during the first 24 hours of a patients admission to the ICU is used for each physiological variable. The principal
diagnosis leading to ICU admission was added as a category weight so that the predicted mortality is computed based on the patients
APACHE II score and their principal diagnosis at admission [1,3].Although the original APACHE system was not primarily developed
to be used for individual patient treatment decisions, APACHE II can provide the clinician with a systematic evaluation and an improved
understanding of how an individual patients severity of disease influences his outcome [3]. The APACHE II scoring system is now the
worlds most widely used severity of illness score (1,3). APACHE II score calculators are widely available online.
The APACHE III prognostic system was developed in 1991 and was validated and further updated in 1998 [1,4,5]. It consists of two
options: (i) an APACHE III score, which can provide initial risk stratification for severely ill hospitalized patients within homogenous
independently defined patient groups; and (ii) an APACHE III predictive equation, which uses APACHE III score and reference data
on major disease categories and treatment location immediately prior to ICU admission to provide risk estimates for hospital mortality
for individual ICU patients [4]. APACHE III uses 17 physiological variables with a different weighting system assigned to the original
12 from the APACHE II scoring system. It provides a composite score with a range of 0 to 299 and accounts for any selection bias

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The original APACHE score was developed in 1981 to classify groups of patients according to severity of illness so as to compare
outcomes, evaluate new therapies and study the utilization of ICUs [2]. It was not designed to assist in making individual treatment
decisions. It was divided into two sections: a physiology score to assess the degree of acute illness; and a preadmission evaluation to
determine the chronic health status of the patient before acute illness. A composite numerical physiological score was obtained by using
the worst value from 34 possible physiological measurements obtained in the first 32-hours of ICU admission, reflecting the degree
of derangement of one or more of the bodys 7 major physiological systems [2]. The pre-admission health status was assigned a letter
score of A (excellent health) through D (severe chronic organ system dysfunction) for details concerning functional status, productivity
and medical attention approximately 6 months before admission. The patients complete APACHE classification was indicated by the
numerical sum of the weights for physiological measurements and a letter reflecting chronic health evaluation. Thus designations such
as 13-A or 33-D reflect patients with different levels of acute illness and preadmission health status, while designations 13-A and 13-D
would reflect patients with same level of acute illness but differing levels of preadmission health status.


that may result from the location of a patient prior to ICUcare.ICU readmissions, transfers from other ICUs and admissions from the
hospital wards have marginally increased risk of death relative to patients admitted directly to the ICU from the emergency room. Like
its predecessors, the APACHE III uses the worst physiological variable in the first 24-hours of ICU admissions to obtain a 1st day score.
It can be updated daily to provide a daily risk estimate, which may be used to calculate individual risk estimates over time. Commercially
available APACHE III calculators are available for purchase.
APACHE IV was developed in 2006 using a database of over 110,000 patients admitted to 104 ICUs in 45 hospitals in the USA in
2002/2003, and remodeling APACHE III with the same physiological variables and weights but different predictor variables and refined
statistical methods [6]. A recent study out of 3 medical-surgical Brazilian Intensive Care Units showed that the APACHE IV and the
SAPS III had good discrimination but poor calibration.

Simplified Acute Physiology Score (SAPS)

The Simplified Acute Physiology Score was developed and validated in 679 consecutive patients admitted to 8 multi-disciplinary
referral ICUs in France in 1984 using 13 weighted physiological variable and age to predict the risk of death in ICU patients [7] (Table
2). Like the APCHE scores, SAPS used the worst values obtained during the first 24 hours of ICU admission. The Simplified Acute
Physiology Score performed comparably to the APACHE score and is lauded as being simpler and less time-consuming to compute. Like
the APACHE score, it is used to predict mortality for patient subgroups and should not be used for individual prognosis or treatment
Variable SAPS Scale

Age (yr)







Heart rate (beats/min)


Systolic BP


Temperature (C)















Respiratory rate



Urine output (L/24h)

Blood urea (mMol/L)



















Hematocrit (%)







White blood cell cout







Serum glucose (mMol/L)





Serum potassium (mEq/L




Serum sodium (mEq/L)










Serum HCO3 (mEq/L)



Glasgow coma scale











Table 2: Scoring Values for the 14 Variables of SAPS.

SAPS II was developed in 1993 to provide a method of converting the obtained score to a probability of hospital mortality [8]. It is the
most widely used version and like its predecessor, calculates a severity score using the worst values measured during the initial 24 hours
of ICU admission for 17 variables (12 physiologic variable, age, type of admission (scheduled surgical, unscheduled surgical, or medical)
and 3 underlying dichotomous disease variables (AIDS, metastatic cancer and hematologic malignancy). The physiological variables
are continuous variables that have been made categorical by assigning points to a range of values. SAPS II was developed and validated
using data from 13,125 patients admitted to 137 adult ICUs in 12 countries. It excluded patients younger than 18 years, burns patients,
coronary care unit patients and cardiac surgery [8]. It did however perform well for patients with cardiovascular disease as the primary
reason for admission and may be applied to these patients [9]. SAPS II can be entered into a mathematical formula, which predicts
hospital mortality. It has excellent discrimination and calibration and may be suitable for use in the intermediate care unit settings
[10,11]. Like the APCHE II calculators, SAPS II calculators are freely available online and an example is shown below.
The most updated model the SAPS III was created in 2005 using complex statistical methods to select and weight variables using
a database of 16,784 patients from 303 ICUs in 35 countries [12]. It includes 20 variables divided into 3 sub-scores related to patient
characteristics prior to ICU admission (age, co-morbidities, use of vasoactive drugs before ICU admission, intra-hospital location and
length of hospital stay before ICU admission), circumstances related to ICU admission (reason(s) for ICU admission, planned/unplanned
ICU admission, surgical status at ICU admission, anatomic site of surgery and presence of infection at ICU admission) and the degree
of physiologic derangement within 1 hour before or after of ICU admission. This is in contrast to all prior models that utilized a 24-hour
time window [12]. The total score can range from 0 to 217. Unlike other scores, SAPS 3 includes customized equations for the prediction
of hospital mortality in 7 geographical regions but the sample size in some of the regions was relatively small thus compromising
prognostic accuracy. A subsequent study of over 28, 000 patients in 147 ICUS in Italy found that the SAPS III has good discrimination
but poor calibration [13,14].

In 1985, Lemeshow et al created the first MPM based on multiple logistic regressions modelling of data from 755 patients in 1 ICU
over a period of 7 months (Feb 1 to August 15th, 1983) [15]. The goal was to create a predictive model that would be useful for making
triage decisions as well as determining aggressiveness of care so as to determine patients who would benefit the most in a world with
limited resources. Unlike the APACHE and SAPS scores the weights for the various variables were obtained using Multiple Logistic
Regression (MLR) models instead of based off decisions made by a team of experts and the results are therefore expressed as a probability
rather than as a score. There were two MLR models the first based only on admission data and one used at 24 hours when more
information is available and response to initial therapy can be incorporated. Each of the models used 7-variables. There were sevenadmission treatment independent and seven 24-hour variables reflecting treatments and patients condition in the ICU. Coronary care,
cardiac surgery and burn patients were excluded from the study, as were patients under 14 years of age.

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Mortality Prediction Model (MPM)


The MPM II was developed in 1993 based off a much larger dataset of 19, 124 ICU patients in 12 different countries (Table 3). Like
its predecessor, it used logistic regression techniques and consists of 2 scores: MPM0, the admission model, which was expanded to 15
variables; and MPM24 the 24-hour model, which contains 5 of the admission variables and 8 additional variables and is designed for
patients who stay in the ICU for more than 24 hours. It is to be noted, that in MPM II each variable (except age, which is entered as the
actual age in years), is designated as present or absent and given a score of 1 or 0 accordingly. MPM II is the most common version of
the MPM. An advantage of the MPMII24 is that it can be compared to the SAPS and the APACHE, since all three are determined after
the first 24-hours of admission. The MPM II has excellent calibration and discrimination [10,16,17]. More recently, MPM III has been
developed using a database of 124,885 patients from 135 ICUs in 98 hospitals (all in North America except for one in Brazil) collected
from 2001 to 2004 [18]. MPM0-III uses 16 variables, including 3 physiological parameters obtained within 1 hour of ICU admission to
estimate mortality probability at hospital discharge. The MPM24 III is unchanged from the MPM24II.







(Does not include patients whose coma is due to overdose or who received neuromuscular blocking



Heart rate 150 bpm?























Patient age*
Medical or unscheduled surgical admission?
Cardiopulmonary resuscitation prior to admission?
Coma (Glasgow coma scale 3-5)?

Systolic blood pressure 90 mmHg?

Mechanical ventilation?
Acute renal failure?
(Does not include pre-renal azotemia)
Cardiac dysrhythmias?
Cerebrovascular accident?
Intracranial mass effect?
Gastrointestinal bleeding?
Metastatic carcinoma?
(Distant metastases only; does not include local lymph node involvement)
Chronic renal insufficiency?
(Creatinine >2 mg/dL chronically)

*Patient age does not receive points when calculating the severity score; however, it is used in the formula to calculate predicted mortality.
Table 3: Mortality Prediction Model II (MPM II).

Comparison of ICU general prediction models

A table summarizing the 3 outcome prediction models is shown below:













































Variable selection &


Expert panel

Expert Panel

Expert Panel








Number of Variables











Mortality Prediction











There have been a number of studies examining the difference in accuracy between various second-generation ICU mortality
prediction models (Table 4). A summary of four prospective, large, multicenter studies is shown in table 5 below. Discrimination refers
to the ability of the model to separate those patients predicted to live from those patients predicted to die and is measured using the area
under the receiving operating characteristic curve. Tossing a coin to classify patients as dead or alive would produce an area under the
receiver operating characteristic curve (AUC ROC) of 0.50. As a general rule, the greater the AUC ROC, the better the discriminatory
capability of the model. A model is considered to discriminate well when this area is >0.8.The AUC ROC also measures the specificity and
sensitivity of a prediction method, with an AUC of 1.0 being perfectly sensitive and specific. Calibration refers to the ability of a model
to describe the mortality pattern in the data is evaluated based on goodness-of-fit by the Hosmer-Lemeshow chi-square statistic. Lower

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Table 4: Summary of the 3 general outcome prediction models [1].


chi-square values and higher p-values indicate better fit. When the mortality predicted by a model differs significantly from the observed
pattern, this model does not calibrate well and the goodness-of-fit statistics are high.

Study Type


# of Patient # of ICUs Country




Castella 1995 Prospective

Sept 1991 to



12 European & North 0.861**

American countries



Moreno 1997


Dec 1994
Mar 1995








1995 - 1996







Beck 2003


Apr 1993-Dec 16,646








*14, 745 were enrolled, in the study, however for comparison across all 3 models, the sample size was 4,099.**APACHE III was used. The AUROC comparing
APACHE II to III in the same data set was 0.848
Table 5: Comparing the sensitivity and specificity of the general prediction models.

The studies above show that the models had similar discrimination abilities, but calibration was not always ideal. The newer generation
models in each family generally had better calibration than the older models a principle that is understandable given the changing ICU
population and the fact that newer models account more for this change [10]. The deterioration in calibration over time emphasizes
the need for continuous model updates. The study by Livingston et al demonstrated superior calibration of the APACHE II over other

When using the general prediction models, a few important limitations should be noted: First, all general outcome prediction models
can only at their best predict the behavior of a group of patients that exactly matches the patients in the development population. For
example, the APACHE and MPM scores were largely based on North American populations and the SAPS score on European patients,
while SAPS 3 developers used a database that included a geographically more heterogeneous group of patients [1,12]. In addition, the
scores should not be used in specific patients populations that were excluded from the original databases (e.g., patients with burns,
patients aged less than16 or 18 years, patients with a very short length of ICU stay, cardiac surgery patients, etc.).
Second, the accuracy of any scoring system is highly dependent on the quality of the input. To be used correctly, the definitions, time
of data collection and rules for missing data must exactly match those applied at the time of model building [1]. Third, as the ICU patient
population changes and new treatments and intervention become available, the models will need to be updated. It has been shown,
that despite the fact that predictive models have been developed in large populations, in almost all cases when they are applied to new
populations calibration deteriorates, although discrimination hardly changes. Two recent examples of this effect were given in validation
studies of SAPS 3 in Austria and in Italy [13-25].

Organ dysfunction scores

Organ failure scores are primarily designed to describe the degree of organ dysfunction rather than to predict survival. The severity
of organ dysfunction varies widely among individuals and within an individual over time. Organ failure scores must therefore be able to
take both time and severity into account [1]. Many organ dysfunction scores have been developed over the past few decades, but we will
limit our discussion to three of the scores most commonly used in general ICU patients:
1. Logistic Organ Dysfunction System (LODS) [26]
2. Multiple Organ Dysfunction Score (MODS) [27]
3. Sequential Organ Failure Assessment (SOFA) [28]

Multiple Organ Dysfunction Score (MODS): The development of the MODS in 1995 was based on a literature review of 30
publications that had characterized organ dysfunction [27,31]. Seven organ systems were then selected for further consideration
(respiratory, cardiovascular, renal, hepatic, hematological, central nervous system, gastrointestinal), and variables for each organ
system were chosen according to a set of ideal descriptor criteria (Table 4). No accurate descriptor of gastrointestinal function could
be identified, so this system was not included in the final model. For the cardiovascular system, Marshall and colleagues [27] created a
composite variable, the pressure-adjusted heart rate (heart rate central venous pressure/mean arterial pressure); in patients without
a central line, this variable is assumed to be normal. For each of the six organs, the first parameters of the day are used to calculate the
score and a score of 0 (normal) to 4 (most dysfunction) is awarded, giving a total maximum score of 24. The score was developed in 336
patients admitted to one surgical ICU and validated in 356 patients admitted to the same ICU [27]. Although not designed to predict
ICU mortality, increasing MODS values do correlate with ICU outcome. ICU mortality also increases with increasing numbers of failing
organ systems [27,32]. The delta MODS, defined as the difference between the MODS at admission and the maximum score, may be more
predictive of outcome than individual scores [27]. Tables 6 show the variables for the MODS score.

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Logistic Organ Dysfunction Score (LODS): The LODS was developed in 1996, using a database of 13,152 admissions to 137
ICUs in 12 countries [26]. Using multiple logistic regressions, 12 variables were selected to represent the function of six organ systems
(neurologic, cardiovascular, renal, pulmonary, hematologic, and hepatic). The worst value for each variable in the first 24 hours of
admission is recorded, and for each system, a score of 0 (no dysfunction) to 5 (maximum dysfunction) is awarded. Unlike the MODS and
SOFA scores, LODS is a weighted system: for the respiratory and coagulation systems, the maximum score allowed is 3, and for the liver
the maximum score is 1. LODS values, therefore, can range from 0 to 22. The LODS lies somewhere between a mortality prediction score
and an organ failure score as it combines a global score summarizing the total degree of organ dysfunction across the organ systems, and
a logistic regression equation that can be used to convert the score into a probability of mortality. Within organ systems, greater severity
of organ dysfunction was consistently associated with higher mortality [1,29], and a LODS of 22 was associated with a mortality of 99.7%
[26]. The LODS was not initially validated for repeated use during the ICU stay, but in a study of 1,685 patients in French ICUs, the LODS
was accurate in characterizing the progression of organ dysfunction during the first week of ICU stay [30].


Organ System


Respiratory (PO2/FIO2 ratio)






Renal (creatinine)






Hepatic (bilirubin)






Cardiovascular (PAR)






Hematologic (platelet)






Neurologic (Glasgow)





Table 6: The Multiple Organ Dysfunction Score (MODS) score.

Sequential Organ Failure Assessment (SOFA): The SOFA system (Table 7) was developed in a consensus meeting of the European
Society of Intensive Care Medicine in 1994 [33] and further revised in 1999. The SOFA is a six-organ dysfunction/failure score measuring
multiple organ failure daily. The Six organ systems (respiratory, coagulation, cardiovascular, renal, hepatic, CNS) were selected based on
a review of the literature. The function of each organ system is scored from 0 (normal function) to 4 (most abnormal), giving a possible
score of 0 to 24. The objective in the development of the SOFA was to create a simple, reliable and continuous easily obtainable score that
would be used to describe a sequence of complications in the critically ill and NOT primarily to predict outcome.
SOFA Score
Respiration (PaO2/FiO2)
Coagulation (platelets)
Liver (bilirubin)
Cardiovascular (hypotension)













MAP <70

Dopamine 5

Dopamine 5

Dopamine 15

CNS (Glasgow coma scale)





Renal (creatinine)





Table 7: The Sequential Organ Failure Assessment (SOFA) Score.

Unlike the MODS score in which the first value of each day is used, the SOFA uses the worst value on each day. In addition, for the
cardiovascular component, the SOFA uses a treatment-related variable (dose of vasopressor agents) instead of a calculated composite
variable. This is not ideal, as treatment protocols vary among institutions and among patients and over time, but it is difficult to avoid,
especially for the cardiovascular system [1].The Mean total maximum SOFA score presented a very good correlation to ICU outcome, with
mortality rates ranging from 3.2 % in patients without organ failure to 91.3 % in patients with failure of all the six organs analyzed [34].
The total maximum SOFA score (AUROC=0.847) and the delta SOFA score (AUROC = 0.742) can be used to quantify the cumulative
insult suffered by the patient by comparing the degree of dysfunction/organ failure present on ICU admission to that developing while
in the ICU [35,36]. In a prospective analysis of 1,449 patients, a maximum total SOFA score greater than 15 correlated with a mortality
rate of 90% [34]. In a prospective study of 352 ICU patients, an increase in SOFA score by about 30% during the first 48 hours in the ICU,
predicted a mortality rate of at least 50%, while a decrease was associated with an ICU mortality rate of just 27% [35] The SOFA scores
are calculated 24 hours after admission to the ICU and every 48 hours thereafter. The mean and highest scores are most predictive of
mortality [36]. Several online SOFA calculators are available.

Comparison of the three organ dysfunction scores

A table (Table 8) comparing the characteristics of the 3-major organ dysfunction scores are shown below.

LODS [26]

MODS [27]

SOFA [28, 34, 36]

Year of Publication




Selection of variables and their weights

Multiple Logistic Regression

Literature review & Multiple

Logistic Regression

Panel of Experts

No of patients

13, 152


1, 449

No of ICUs


1 (surgical ICU)


No of countries



Valid for repeated use

No (but can be done) [30]




Glasgow Coma Score

Glasgow Coma Score

Glasgow Coma Score


Heart Rate, SBP

Pressure-adjusted heart rate MAP, Vasopressor use


Serum urea, or urea Nitrogen, creatinine, Serum creatinine

urine output

Serum creatinine, urine output


PaO2/FiO2 ratio, mechanical ventilation

PaO2/FiO2 ratio

PaO2/FiO2 ratio, mechanical



WBCC, Platelet count

Platelet count

Platelet count


Serum bilirubin, prothrombin time

Serum bilirubin

Serum bilirubin

Timing of variable

Worst recording in first 24 hours

1st value of each day

Worst daily value

Variables used to assess organ dysfunction

HR = Heart rate; SBP = Systolic Blood pressure; MAP = Mean Arterial Pressure
WBCC = White blood Cell count

Table 8: Comparing the characteristics of the major Organ Dysfunction Scores.

Several studies have directly compared the performance the various organ dysfunction scoring systems. Pettil and colleagues [37] reported
comparable discriminative power of LODS, SOFA, and MODS to predict hospital mortality in a single centre study. Peres Bota and colleagues [38]
reported no significant differences between MODS and SOFA for mortality prediction in 949 general ICU patients. In a multicenter study, Timsit and
colleagues [30] reported good accuracy and internal consistency for both the SOFA and LODS. However, in a more recent Canadian study of 1,436
ICU patients [39,40], SOFA and MODS had only a modest ability to predict hospital and ICU mortality. Table 9 outlining these studies is shown below.

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LODS, Logistic Organ Dysfunction Score; MODS, Multiple Organ Dysfunction Score; SOFA, Sequential Organ Dysfunction Score



Type of Study Enrollment Period/

# of
time period

Pettila2002 [37] Prospective

Peres 2002 [38] Prospective



Apr-Jul 1999


# of




10-bed medical-surgery ICU in

tertiary care hospital

AUC ROC (Hospital Mortality













Belgium 31-bed University hospital ICU

Oct-Nov 1999
July-Sept 2000
Timsit 2002 [30] Prospective




MedicalSurgical ICUs



Zygun2005 [39] Prospective

May 2000 to April



Calgary, 3-multi-system ICUs






** maximum
+ ICU Day 7
Please note that Pettila et al calculated the MOD score for each day using the worst single value of the day, contrary to the original MOD score as described
by Marshall et al [27]
Table 9: Comparison of the hospital mortality prediction Performance of the organ dysfunction scores.

Severity assessment based on nursing workload use

Scoring systems based on nursing workload are used mainly to assess nurse staffing and changing nursing needs in the ICU. Although higher scores
are associated with worse outcomes, they are neither prognostic nor mortality scores. All the scores are limited by the items included and can be prone to
subjective interpretation and influenced by patient case-mix, local admission and discharge policies, and local management protocols. A recent position
statement by the European Federation of Critical Care Nursing Associations recommends that all units use such a system on a regular basis to monitor
the efficiency of the use of nursing manpower and they have been included in this chapter for this reason.

Therapeutic Intervention Scoring System (TISS)

TISS was originally developed in 1974 to assess severity of illness and compare patient care based on the measurement of nursing
workload [1,41-49]. The original score included 57 therapeutic activities with points assigned for each activity conducted during a 24hour period. Higher values were given for more specialized or time-consuming activities. In 1983, the score was updated and expanded
to include 76 items (TISS-76) but this was criticized for being too time-consuming and cumbersome [42]. TISS-28 was devised in 1996
using advanced statistical analysis and only 28 items, divided into 7 groups: basic activities, ventilatory support, cardiovascular support,
renal support, neurological support, metabolic support, and specific interventions [43]. The scoring is weighted to give a total score of
78. TISS-28 was validated in 22 Dutch ICUs and in 19 ICUs in Portugal [42,43]. According to this system, each nurse can provide care
for 46.35TISS-28 points per shift, with each TISS-28 point requiring 10.6 minutes of each nurses shift. This information can be useful for
planning the allocation of nursing manpower, to evaluate the efficacy in the use of nursing workload use and to objectively classify ICUs
based on the amount (and not the complexity) of care provided [44].

Nine Equivalents of Nursing Manpower Use Score (NEMS)

B coefficients


1. Basic monitoring: hourly vital signs, regular record and calculation of fluid balance



2. Intravenous medication: bolus or continuously, not including vasoactive drugs


3. Mechanical ventilatory support: any form of mechanical/assisted ventilation, with or without PEEP (e.g., continuous
positive airway pressure), with or without muscle relaxants



4. Supplementary ventilatory care: breathingspontaneously through endotracheal tube; supplementary oxygen any
method, except if (3)applies


5. Single vasoactive medication: any vasoactive drug


6. Multiple vasoactive medication: more than one vasoactive drug, regardless of type and dose



7. Dialysis techniques: all


8. Specific interventions in the ICU: such as endotracheal intubation, introduction of pacemaker, cardioversion,
endoscopy, emergency operation in the past 24 h, gastric lavage; routine interventions such as X-rays,
echocardiography, electrocardiography, dressings, introduction of venous or arterial lines, are not included


9. Specific interventions outside the ICU: such as surgical intervention or diagnostic procedure; the intervention/
procedure is related to the severity of illness of the patient and makes an extra demand upon manpower efforts in
the ICU


Coefficients are rounded off to the nearest integer

Table 10: Nine Equivalents of Nursing Manpower use Score.

Nursing Activities Score (NAS)

In 2003, the Nursing Activities Score (NAS) was created from the TISS-28 to reflect nursing work-load in an intensive care unit as a
function of average time consumption instead of severity of illness [47]. It includes a total of five new items and 14 sub items describing

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In 1997, NEMS was created from the TISS-28 with the aim of creating a simpler system that would be more widely used [1,45]. Nursing activities
are separated into nine categories: basic monitoring, intravenous medication, mechanical ventilatory support, supplementary ventilatory care, single
vasoactive medication, multiple vasoactive medication, dialysis techniques, specific interventions in the ICU and specific interventions outside the
ICU (Table 10). Each of these is awarded weighted points, giving a maximum score of 56. NEMS has been validated in large cohorts of ICU patients
and is easy to use with almost no inter-rater variability [46]. Again, this system can be used to evaluate the efficacy of nursing workload use at the ICU
level so as to objectively classify ICUs based on the amount (and not only on the complexity) of care provided [1,44]. The use of NEMS is indicated for:
(a) multicenter ICU studies; (b) management purposes in the general (macro) evaluation and comparison of workload at the ICU level; and (c) the
prediction of workload and planning of nursing staff allocation at the individual patient level [44].


nursing activities in the ICU (e.g. monitoring, care of relatives, administrative tasks) [47]. The list of items was developed by consensus
and the average time consumption of the activities was determined from a 1-week observational cross-sectional study in a cohort of 99
ICUs in 15 countries. The new activities accounted for 60% of the average nursing time; and in the development study, NAS activities
accounted for 81% of the nursing time (versus 43% in TISS-28) [47].

Pain, Agitation/Sedation Delirium (PAD) care bundle scores and ICU checklists
Everyday care in ICU can be daunting, challenging and labor intensive. Majority of the patients are intubated, sedated and otherwise
unable to communicate their needs. Scoring systems and checklists are therefore needed to be sure that our patients are comfortable,
adequately sedated, pain free and meeting treatment goals. The PAD Care bundle refers to the Pain, Agitation and Delirium care bundle
that was created to facilitate proper implementation of the PAD care Guidelines [50]. The central tenet of the bundle is to emphasize the
importance of the prompt and proper management of pain, agitation/sedation and delirium in the ICU in an integrated and interdisplinary
fashion. The PAD bundle links appropriate detection, management and prevention of pain, agitation/sedation and delirium to the
success of other evidence-based ICU practices such as Spontaneous Awakening Trials (SAT), Spontaneous Breathing Trials (SBTs), Early
Mobility Protocols ad ICU sleep hygiene programs. The guideline provides strong recommendations for the following:
1. Use valid and reliable tools for detecting pain, depth of sedation/agitation and presence or absence of delirium in critically ill patients.
2. Screen all ICU patients routinely (at least four times per shift or every 2 to 3 hours minimum) for Pain, agitation/sedation and for
3. Adopt a stepwise approach, beginning with assessment, treatment and then prevention.
4. Assess and treat pain first before giving sedatives.
5. Maintain a light level of sedation that allows the ICU patient to interact in a meaningful way with the environment without agitation.
6.Prevent and treat delirium using both non-pharmacologic and pharmacologic strategies.

Most ICU patients experience significant pain at some point in their ICU stay and it can be a great source of stress and distress. Pain
in the ICU can trigger a significant stress response leading to hemodynamic instability, impaired wound healing, poor glycemic control
and increased risk of infection. Pain also has significant short and long term psychological consequences in the ICU including sleep
deprivation, higher likelihood of developing chronic pain, Post Traumatic Stress Disease syndromes and lower health-related Quality
of Life post ICU discharge. ICU procedures can be a significant source of pain and patients should receive routine pre-procedural
analgesia. Patient self-reporting of pain using a Numerical Rating Scale (NRS such as a Likert scale as shown) is the goal standard for pain
assessment (Table 11). The majority of ICU patients are however unable to self-report and need to be actively accessed for pain using
behavioral pain scales (BPSs). It is to be noted, that although often used, reliance on vital signs is not sufficient to detect the presence of or
the absence of pain [50,51]. A rigorous psychometric analysis of six BPSs included in the PAD guidelines found that the BPS (Table 11)
and the Critical-Care Pain Observation Tool (CPOT) (Table 12) are the most valid and reliable for use in ICU patients who are unable
to self-report [51]. A recently updated psychometric analysis of eight BPSs, including studies published since 2010, came to a similar
conclusion [52]. The BPS uses three domains (facial expression, posture of the upper limbs and compliance with ventilation) to assess
pain in critically ill intubated patients who are unable to self-report [53]. The CPOT uses four domains with a potential score of 0 to 2 in
each domain (Table 12).
Facial Expression

Upper Limbs

Compliance with ventilation




Partially tightened (e.g. brow lowering)

Fully tightened (e.g. eyelid closing)


No movement

Partially bent

Fully Bent with finger flexion

Permanently retracted

Tolerating movement

Coughing but tolerating ventilation for most of the time

Fighting ventilator

Unable to control ventilation

Scores from each of the three domains are summed, with a total score of 3 to 12
Table 11: Behavioral Pain Scale (BPS).

Body Movements

No muscular tension observed

Relaxed, neutral

Presence of frowning, brow lowering, orbit tightening, and Tense

levator contraction

All of the above facial movements plus eyelid tightly


Does not move at all (does not necessarily mean absence of pain) Absence of movements

Slow, cautious movements, touching or rubbing the pain site, Protection

seeking attention through movements

Pulling tube, attempting to sit up, moving limbs/ thrashing,

not following commands, striking at staff, trying to climb out of bed


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Facial Expression


No resistance to passive movements


Resistance to passive movements

Tense, rigid
Muscle tension Evaluation by passive
Strong resistance to passive movements, inability to complete Very tense or rigid
exion and extension of upper
Resistance to passive movements


Strong resistance to passive movements, inability to complete them Relaxed

Compliance with the ventilator

Alarms not activated, easy ventilation

Tolerating ventilator or movement

(intubated patients)

Alarms stop spontaneously

Coughing but tolerating

Asynchrony: blocking ventilation, alarms frequently activated

Fighting ventilator

Talking in normal tone or no sound

Talking in normal tone or no sound

Sighing, moaning

Sighing, moaning

Crying out, sobbing

Crying out, sobbing

Vocalization (extubated patients)

Asynchrony: blocking ventilation, alarms frequently

Fighting ventilator

Total, range

Table 12: The Critical-Care Pain Observation Tool (CPOT).

Agitation and anxiety occur frequently in critically ill patients and can lead to adverse outcomes [51,55-57]. Common causes of
agitation and anxiety include pain, delirium, hypoxia, hypoglycemia, hypotension and withdrawal from alcohol and drugs [50,51,55-57].
Prompt identification and treatment of cause is of utmost importance although not often done. The PAD guidelines strongly recommend
the use of a valid and reliable sedation scoring system to routinely assess depth of sedation and agitation in ICU patients, and the results of
these sedation/agitation assessments should provide the basis for the use of sedatives in critically ill patients [50,51]. The PAD guidelines
define pain as being present and needing to be addressed if:
1. Patients self report pain of four or more on the Numerical Rating Scale (NRS 0 to 10).
2. Six or more on the Behavioral Pain Scale (BPS 3-12 scale).
3. Three or more on the Critical Care Pain Observation Tool (CPOT 0-8 scale).
The PAD guidelines included a rigorous psychometric analysis of 10 sedation scales and concluded that the Richmond AgitationSedation Scale (RASS) and Sedation-Agitation Scale (SAS) are the most valid and reliable sedation assessment tools for measuring quality
and depth of sedation in adult ICU patients. The Depth of sedation in patients using either of these Scales is defined in tables 13 and 14.
The RASS scale uses 10 discrete levels to define depth of sedation and agitation, ranging from 5 (unarousable) to +4 (combative) [58].
The Sedation-Agitation Scale (SAS) has seven discrete levels ranging from 1 (unarousable) to 7 (dangerously agitated) [59]. Agitation is
termed if the RASS is +1 to +4 or SAS = 5 to 7; awake and calm if RASS = 0 or SAS = 4; lightly sedated if RASS = 1 to 2 or SAS = 3; and
deeply sedated if RASS = -3 or SAS = 1 to 2. The guidelines recommend that critically ill patients, who need sedation, be maintained in a
state of light sedation where they can have meaningful interaction with the environment without any agitation.






Very agitated

Pulls on or removes tubes or catheters; exhibits

aggressive behavior to staff



Frequent non-purposeful movement or patientventilator dys-synchrony



Anxious or apprehensive, but movements are not

aggressive or vigorous

Overtly combative or violent, immediate danger to


Alert, calm



Not fully alert, but has sustained awakening with eye

contact to voice


Light sedation

Briefly (<10 seconds) awakens with eye contact to



Moderate sedation


Deep sedation



Any movement (no eye contact) to voice

No response to voice, but any movement on
physical examination
No response to voice or physical stimulation

Table 13: The Richmond Agitation Sedation Scale.



Dangerously agitated

Pulls at tubes/catheters, restless, danger to staff, trashing in bed

Very agitated

Requiring restraints and frequent verbal reminding of limits, biting ETT


Anxious or physically agitated, calm to verbal instructions

Calm, cooperative

Calm, easily arousable and follows commands


Difficult to arouse but awakens to verbal stimuli or gentle shaking

Very sedated

Arouses to physical stimuli, does not communicate/follow commands


Minimal/no response to noxious stimuli, non-communicative

Table 14: The Riker Sedation-Agitation Scale.

Delirium is characterized by the acute onset of cerebral dysfunction, with a change or fluctuation in baseline mental status, inattention,

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and either disorganized thinking or an altered level of consciousness [59-64]. Patients with delirium may either be agitated (i.e., hyperactive
delirium), calm or lethargic (i.e., hypoactive delirium), or may fluctuate between the two subtypes. Hyperactive delirium is more often
associated with hallucinations and delusions, whereas hypoactive delirium is more often characterized by confusion and sedation and is
often undetected [50]. Delirium occurs commonly in critically ill patients. It is estimated that up to 80% of critically ill patients develop
delirium during their ICU stay [63,65,66]. The presence of delirium in ICU patients is associated with significant negative outcomes,
including prolonged duration of mechanical ventilation [67], prolonged hospital LOS [63,66,68], post discharge institutionalization [69],
long-term cognitive dysfunction [70,71], an increased risk of death [66], and higher costs of care [72]. Hypoactive delirium occurs much
more commonly than hyperactive delirium in ICU patients and is associated with a longer duration of mechanical ventilation and ICU
LOS and a higher mortality risk than hyperactive delirium [73-77]. Reliable detection and diagnosis of delirium is essential for delirium
treatment and for improving delirium-related ICU outcomes. The PAD guidelines included a rigorous psychometric analysis of five
delirium monitoring tools and concluded that the CAM-ICU [63] and the Intensive Care Delirium Screening Checklist (ICDSC) [64] are
the most valid and reliable delirium monitoring tools for use in adult ICU patients (Figure 2). A patient is considered delirious if they are
either CAM-ICU positive or their ICDSC score is greater than or equal to 4 (ICDSC Scale range = 0 to 8).

Figure 2: Intensive Care Delirium Screening Checklist (ICDSC).

Ventilator-associated pneumonia (VAP) continues to be a common and potentially fatal complication of mechanically ventilated
patients in the ICU [78]. Intubation impedes the bodys natural defense against respiratory infections. The placement of an Endotracheal
Tube (ETT) negates effective cough reflexes that protect the airway from invasive pathogens. An ETT also prevents mucociliary clearance
of secretions and depresses epiglottic reflexes thus allowing the leakage of virulent bacteria (either from excess secretions or from aspirated
esophageal or gastric contents) that pool around the inflated ETT cuff to infiltrate the lungs and cause pneumonia [79]. VAP is responsible
for 90% of nosocomial infections in the ICU and is the leading cause of death amongst hospital-acquired infections, exceeding the rate
of death from central line infections, severe sepsis and respiratory tract infections in non-intubated patients. VAP is a major health care
burden in terms of mortality, escalating health care costs and increased length of ventilator, ICU and hospital days [78,79]. Hospital
mortality of ventilated patients who develop VAP is 46% compared to 32% for ventilated patients who do not develop VAP [80,81].
VAP can occur early or late during a patients course of intubation and mechanical ventilation. Early onset VAP occurs within 48 to 96
hours of intubation [78,80] and the most common pathogens include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella
catarrhalis. Late-onset VAP occurs 5 or more days after intubation and the common causative pathogens include Staphylococcus aureus,
Acinetobacterbaumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter [80].
The Key components of the Instituite for Healthcare Improvement (IHI) Ventilator Bundle are [82]:
1. Elevation of the head of the bed to 30 to 45 degrees

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VAP and Ventilator Bundle Compliance Checklists


2. Daily sedation vacations and assessment of readiness to extubate

3. Peptic Ulcer disease prophylaxis
4. Deep Venous thrombosis prophylaxis
5. Daily oral Care with chlorhexidine
Implementation of these strategies has been shown in several studies to decrease the incidence of VAP. Other CDC recommended
strategies for prevention of VAP that may be built into checklists for ease of bedside implementation include [83]:
Orotracheal route of intubation instead of nasotracheal route
New ventilator circuits for each patient, with changes recommended only if the circuits become soiled or damaged. There is no
indication for routine circuit changes.
Use a closed endotracheal suctioning system (in-line suctioning system)
Use of continuous sub-glottic suctioning in patients expected to be mechanically ventilated > 72 hours
Washing of hands before and after contact with each patient.

General illness severity scores are widely used in the ICU to predict outcome, characterize disease severity, assess degree of organ
dysfunction and evaluate resource use. They are also being increasingly used in clinical trials for case-mix comparisons and to ensure
equivalence of control and intervention groups. An ideal scoring system should first measure an important outcome and in addition,
should have excellent calibration and discrimination. Discrimination describes the accuracy of a given prediction and Calibration
describes how an instrument performs over a wide range of predicted mortalities.
All the scoring systems were developed in mixed groups of adult ICU patients with exclusion of certain groups of patients including
burns patients and post-cardiac surgery patients. Care should be taken not to apply these scores to patient groups not included in the
development or validation cohorts. As ICU populations change and new diagnostic, therapeutic and prognostic techniques become
available; the scoring systems do not perform as well and need to be updated. Different scoring systems have different purposes and
measure different parameters and should be seen as complementing each other, rather than competing with one another. For example,
outcome prediction models cannot be used to assess the severity of individual organ dysfunctions or to monitor patient progress over
time. Although organ dysfunction scores correlate with outcomes, this is not what they were developed for and outcome prediction
should be left to scores such as the APACHE and SAPS systems [1]. The workload scores complete the picture by offering information on
how the patients disease will impact on staffing requirement and resource use.
It is to be emphasized that scoring systems were developed in groups of patients and should not replace individualized patient care
and decision making in the ICU. Critical care checklists targeting pain control, depth of sedation and presence or absence of delirium is
crucial to overall care and improved outcomes in critically ill patients.

1. Vincent JL, Moreno R (2010) Clinical review: scoring systems in the critically ill. Crit Care 14: 207.
2. Knaus WA, Zimmerman JE, Wagner DP, Draper EA, Lawrence DE (1981) APACHE-acute physiology and chronic health evaluation: a physiologically
based classification system. Crit Care Med 9: 591-597.
3. Knaus WA, Draper EA, Wagner DP, Zimmerman JE (1985) APACHE II: a severity of disease classification system. Crit Care Med 13: 818-829.
4. Knaus WA, Wagner DP, Draper EA, Zimmerman JE, Bergner M, et al. (1991) The APACHE III prognostic system. Risk prediction of hospital mortality for
critically ill hospitalized adults. Chest 100: 1619-1636.
5. Zimmerman JE, Wagner DP, Draper EA, Wright L, Alzola C, et al. (1998) Evaluation of acute physiology and chronic health evaluation III predictions of
hospital mortality in an independent database. Crit Care Med 26: 1317-1326.
6. Zimmerman JE, Kramer AA, McNair DS, Malila FM (2006) Acute Physiology and Chronic Health Evaluation (APACHE) IV: hospital mortality assessment
for todays critically ill patients. Crit Care Med 34: 1297-1310.
7. Le Gall JR, Loirat P, Alperovitch A, Glaser P, Granthil C, et al. (1984) A simplified acute physiology score for ICU patients. Crit Care Med 12: 975-977.
8. Le Gall JR, Lemeshow S, Saulnier F (1993) A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study.
JAMA 270: 2957-2963.
9. Metnitz PG, Valentin A, Vesely H, Alberti C, Lang T, et al. (1999) Prognostic performance and customization of the SAPS II: results of a multicenter Austrian
study. Simplified Acute Physiology Score. Intensive Care Med 25: 192-197.
10. Castella X, Artigas A, Bion J, Kari A (1995) A comparison of severity of illness scoring systems for intensive care unit patients: results of a multicenter,
multinational study. The European/North American Severity Study Group. Crit Care Med 23: 1327-1335.

12. Moreno RP, Metnitz PG, Almeida E, Jordan B, Bauer P, et al. (2005) SAPS 3--From evaluation of the patient to evaluation of the intensive care unit. Part
2: Development of a prognostic model for hospital mortality at ICU admission. Intensive Care Med 31: 1345-1355.
13. Poole D, Rossi C, Anghileri A, Giardino M, Latronico N, et al. (2009) External validation of the Simplified Acute Physiology Score (SAPS) 3 in a cohort of
28,357 patients from 147 Italian intensive care units. Intensive Care Med 35: 1916-1924.
14. Nassar AP Jr, Mocelin AO, Nunes AL, Giannini FP, Brauer L, et al. (2012) Caution when using prognostic models: a prospective comparison of 3 recent
prognostic models. J Crit Care 27: 423.
15. Lemeshow S, Teres D, Pastides H, Avrunin JS, Steingrub JS (1985) A method for predicting survival and mortality of ICU patients using objectively derived
weights. Crit Care Med 13: 519-525.

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11. Auriant I, Vinatier I, Thaler F, Tourneur M, Loirat P (1998) Simplified acute physiology score II for measuring severity of illness in intermediate care units.
Crit Care Med 26: 1368-1371.


16. Lemeshow S, Teres D, Klar J, Avrunin JS, Gehlbach SH, et al. (1993) Mortality Probability Models (MPM II) based on an international cohort of intensive
care unit patients. JAMA 270: 2478-2486.
17. Lemeshow S, Le Gall JR (1994) Modeling the severity of illness of ICU patients. A systems update. JAMA 272: 1049-1055.
18. Higgins TL, Teres D, Copes WS, Nathanson BH, Stark M, et al. (2007) Assessing contemporary intensive care unit outcome: an updated Mortality
Probability Admission Model (MPM0-III). Crit Care Med 35: 827-835.
19. Pearson PE (2013) Predictive scoring systems in the intensive care unit, USA.
20. Metnitz B, Schaden E, Moreno R, Le Gall JR, Bauer P, et al. (2009) Austrian validation and customization of the SAPS 3 Admission Score. Intensive Care
Med 35: 616-622.
21. Moreno R, Morais P (1997) Outcome prediction in intensive care: results of a prospective, multicentre, Portuguese study. Intensive Care Med 23: 177-186.
22. Livingston BM, MacKirdy FN, Howie JC, Jones R, Norrie JD (2000) Assessment of the performance of five intensive care scoring models within a large
Scottish database. Crit Care Med 28: 1820-1827.
23. Beck DH, Smith GB, Pappachan JV, Millar B (2003) External validation of the SAPS II, APACHE II and APACHE III prognostic models in South England:
a multicentre study. Intensive Care Med 29: 249-256.
24. Hanley JA, McNeil BJ (1982) The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143: 29-36.
25. Lemeshow S, Hosmer DW Jr (1982) A review of goodness of fit statistics for use in the development of logistic regression models. Am J Epidemiol 115:
26. Le Gall JR, Klar J, Lemeshow S, Saulnier F, Alberti C, et al. (1996) The Logistic Organ Dysfunction system. A new way to assess organ dysfunction in the
intensive care unit. ICU Scoring Group. JAMA 276: 802-810.
27. Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL, et al. (1995) Multiple organ dysfunction score: a reliable descriptor of a complex clinical
outcome. Crit Care Med 23: 1638-1652.
28. Vincent JL, Moreno R, Takala J, Willatts S, De Mendona A, et al. (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ
dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med
22: 707-710.
29. Metnitz PG, Lang T, Valentin A, Steltzer H, Krenn CG, et al. (2001) Evaluation of the logistic organ dysfunction system for the assessment of organ
dysfunction and mortality in critically ill patients. Intensive Care Med 27: 992-998.
30. Timsit JF, Fosse JP, Troche G, De Lassence A, Alberti C et al., (2002) Calibration and discrimination by daily Logistic Organ Dysfunction scoring
comparatively with daily Sequential Organ Failure Assessment scoring for predicting hospital mortality in critically ill patients. Crit Care Med 30:2003-2013.
31. Marshall JC (1995) Multiple organ dysfunction syndrome. In Clincial Trials for the Treatment of Sepsis. Edited by Sibbald WJ, Vincent JL. Heidelberg:
Springer-Verlag 122-138.
32. Cook R, Cook D, Tilley J, Lee K, Marshall J, et al. (2001) Multiple organ dysfunction: baseline and serial component scores. Crit Care Med 29: 2046-2050.
33. Vincent JL, Moreno R, Takala J, Willatts S, De Mendona A, et al. (1996) The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ
dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med
22: 707-710.
34. Vincent JL, de Mendona A, Cantraine F, Moreno R, Takala J, et al. (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure
in intensive care units: results of a multicenter, prospective study. Working group on sepsis-related problems of the European Society of Intensive Care
Medicine. Crit Care Med 26: 1793-1800.
35. Ferreira FL, Bota DP, Bross A, Mlot C, Vincent JL (2001) Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA 286: 17541758.
36. Moreno R, Vincent JL, Matos R, Mendona A, Cantraine F, et al. (1999) The use of maximum SOFA score to quantify organ dysfunction/failure in intensive
care. Results of a prospective, multicentre study. Working Group on Sepsis related Problems of the ESICM. Intensive Care Med 25: 686-696.
37. Pettil V, Pettil M, Sarna S, Voutilainen P, Takkunen O (2002) Comparison of multiple organ dysfunction scores in the prediction of hospital mortality in
the critically ill. Crit Care Med 30: 1705-1711.
38. Peres Bota D, Melot C, Lopes Ferreira F, Nguyen Ba V, Vincent JL (2002) The Multiple Organ Dysfunction Score (MODS) versus the Sequential Organ
Failure Assessment (SOFA) score in outcome prediction. Intensive Care Med 28: 1619-1624.
39. Zygun DA, Laupland KB, Fick GH, Sandham JD, Doig CJ (2005) Limited ability of SOFA and MOD scores to discriminate outcome: a prospective evaluation
in 1,436 patients. Can J Anaesth 52: 302-308.
40. Bouch, DC, Thompson JP (2008) Severity scoring systems in the critically ill; Critical care & Pain 8: 181-185.
41. Cullen DJ, Civetta JM, Briggs BA, Ferrara LC (1974) Therapeutic intervention scoring system: a method for quantitative comparison of patient care. Crit
Care Med 2:57-60.
42. Miranda DR, de Rijk A, Schaufeli W (1996) Simplified Therapeutic Intervention Scoring System: the TISS-28 items--results from a multicenter study. Crit
Care Med 24: 64-73.
43. Moreno R, Morais P (1997) Validation of the simplified therapeutic intervention scoring system on an independent database. Intensive Care Med 23: 640644.
44. Moreno R, Reis Miranda D (1998) Nursing staff in intensive care in Europe: the mismatch between planning and practice. Chest 113: 752-758.

46. Rothen HU, Kng V, Ryser DH, Zrcher R, Regli B (1999) Validation of nine equivalents of nursing manpower use score on an independent data sample.
Intensive Care Med 25: 606-611.
47. Miranda DR, Nap R, de Rijk A, Schaufeli W, Iapichino G, et al. (2003) Nursing activities score. Crit Care Med 31: 374-382.
48. Padilha KG, de Sousa RM, Queijo AF, Mendes AM, Reis Miranda D (2008) Nursing Activities Score in the intensive care unit: analysis of the related factors.
Intensive Crit Care Nurs 24: 197-204.
49. European Federation of Critical Care Nursing Associations (2007) Position Statement on Workforce Requirements Within European Critical Care Nursing.
Webcite, Netherlands.
50. Barr J, Pandharipande PP (2013) The pain, agitation, and delirium care bundle: synergistic benefits of implementing the 2013 pain, agitation, and delirium
guidelines in an integrated and interdisciplinary fashion. Crit Care Med 41: 99-115.

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45. Reis Miranda D, Moreno R, Iapichino G (1997) Nine equivalents of nursing manpower use score (NEMS). Intensive Care Med 23: 760-765.


51. Barr J, Fraser GL, Puntillo K, et al (2013) American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation,
and delirium in adult patients in the intensive care unit. Crit Care Med 41:263306.
52. Glinas C, Puntillo KA, Joffe AM, Barr J (2013) A validated approach to evaluating psychometric properties of pain assessment tools for use in nonverbal
critically ill adults. Semin Respir Crit Care Med 34: 153-168.
53. Ahlers SJ, van Gulik L, van der Veen AM, van Dongen HP, Bruins P, et al. (2008) Comparison of different pain scoring systems in critically ill patients in a
general ICU. Crit Care 12: 15.
54. Glinas C, Fillion L, Puntillo KA, Viens C, Fortier M (2006) Validation of the critical-care pain observation tool in adult patients. Am J Crit Care 15: 420-427.
55. Fraser GL, Prato BS, Riker RR, Berthiaume D, Wilkins ML (2000) Frequency, severity, and treatment of agitation in young versus elderly patients in the
ICU. Pharmacotherapy 20: 75-82.
56. Atkins PM, Mion LC, Mendelson W, Palmer RM, Slomka J, et al. (1997) Characteristics and outcomes of patients who self-extubate from ventilatory
support: a case-control study. Chest 112: 1317-1323.
57. Vassal T, Anh NG, Gabillet JM, Guidet B, Staikowsky F, et al. (1993) Prospective evaluation of self-extubations in a medical intensive care unit. Intensive
Care Med 19: 340-342.
58. Sessler CN, Gosnell MS, Grap MJ, Brophy GM, ONeal PV, et al. (2002) The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive
care unit patients. Am J Respir Crit Care Med 166: 1338-1344.
59. Riker RR, Picard JT, Fraser GL (1999) Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med 27: 1325-1329.
60. Gupta N, de Jonghe J, Schieveld J, Leonard M, Meagher D (2008) Delirium phenomenology: what can we learn from the symptoms of delirium? J
Psychosom Res 65: 215-222.
61. American Psychiatric Association (1994) Delirium, dementia and amnestic and other cognitive disorders. In: Diagnostic and Statistical Manual of Mental
Disorders. Washington, DC, American Psychiatric Association.
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assessment method for the intensive care unit (CAM-ICU). JAMA 286: 2703-2710.
64. Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y (2001) Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive
Care Med 27: 859-864.
65. McNicoll L, Pisani MA, Zhang Y, Ely EW, Siegel MD, et al. (2003) Delirium in the intensive care unit: occurrence and clinical course in older patients. J Am
Geriatr Soc 51: 591-598.
66. Ely EW, Shintani A, Truman B, Speroff T, Gordon SM, et al. (2004) Delirium as a predictor of mortality in mechanically ventilated patients in the intensive
care unit. JAMA 291: 1753-1762.
67. Lat I, McMillian W, Taylor S, Janzen JM, Papadopoulos S, et al. (2009) The impact of delirium on clinical outcomes in mechanically ventilated surgical and
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68. Ely EW, Gautam S, Margolin R, Francis J, May L, et al. (2001) The impact of delirium in the intensive care unit on hospital length of stay. Intensive Care
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70. Girard TD, Jackson JC, Pandharipande PP, Pun BT, Thompson JL, et al. (2010) Delirium as a predictor of long-term cognitive impairment in survivors of
critical illness. Crit Care Med 38: 1513-1520.
71. Jackson JC, Gordon SM, Hart RP, Hopkins RO, Ely EW (2004) The association between delirium and cognitive decline: a review of the empirical literature.
Neuropsychol Rev 14: 87-98.
72. Milbrandt EB, Deppen S, Harrison PL, Shintani AK, Speroff T, et al. (2004) Costs associated with delirium in mechanically ventilated patients. Crit Care
Med 32: 955-962.
73. Guenther U, Popp J, Koecher L, Muders T, Wrigge H, et al. (2010) Validity and reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU
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75. Stransky M, Schmidt C, Ganslmeier P, Grossmann E, Haneya A, et al. (2011) Hypoactive delirium after cardiac surgery as an independent risk factor for
prolonged mechanical ventilation. J Cardiothorac Vasc Anesth 25: 968-974.
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Hosp Psychiatry 34: 639-646.
77. van den Boogaard M, Schoonhoven L, van der Hoeven JG, van Achterberg T, Pickkers P (2012) Incidence and short-term consequences of delirium in
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78. Chulay M (2005) VAP prevention. The latest guidelines. RN 68: 52-56.
79. OKeefe-McCarthy S, Santiago C, Lau G (2008) Ventilator-associated pneumonia bundled strategies: an evidence-based practice. Worldviews Evid Based
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81. Ibrahim EH, Tracy L, Hill C, Fraser VJ, Kollef MH (2001) The occurrence of ventilator-associated pneumonia in a community hospital: risk factors and
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82. Implement the IHI Ventilator Bundle (2011) Institute for Healthcare Improvement, USA.
83. Wip C, Napolitano L (2009) Bundles to prevent ventilator-associated pneumonia: how valuable are they? Curr Opin Infect Dis 22: 159-166.

OMICS Group eBooks

80. Pruitt B, Jacobs M (2006) Best-practice interventions: How can you prevent ventilator-associated pneumonia? Nursing 36: 36-41.


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