Referat Kepaniteraan Klinik

Ilmu Anestesiologi dan Terapi Intensif

SEPSIS AND SEPTIC SHOCK

Disusun oleh:
Dimas Arsana Prayoga

Penguji:
dr. Rosalia Andri Dahliasari, Sp.An, KIC

KEPANITERAAN KLINIK DEPARTEMEN ANESTESIOLOGI DAN

TERAPI INTENSIF
RUMAH SAKIT MARINIR CILANDAK
FAKULTAS KEDOKTERAN UNIVERSITAS PELITA HARAPAN
PERIODE JANUARI-FEBRUARI 2019
JAKARTA

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DAFTAR ISI
ABSTRACT .................................................................................................................................... 3
CHAPTER I .................................................................................................................................... 4
INTRODUCTION .......................................................................................................................... 4
CHAPTER II................................................................................................................................... 5
LITERATURE REVIEW ............................................................................................................... 5
2.1 Sepsis 5
2.1.1 Definition .................................................................................................................. 5
2.1.2 Etiology ..................................................................................................................... 6
2.1.3 Epidemiology .......................................................................................................... 10
2.1.4 Risk Factor .............................................................................................................. 11
2.1.5 Sign and Symptoms ................................................................................................ 11
2.1.6 Clinical Criteria to Identify Patients with Sepsis .................................................... 15
2.1.7 Treatment ................................................................................................................ 17
2.1.8 Prevention ............................................................................................................... 22
2.1.9 Prognosis ................................................................................................................. 23
2.2 Septic Shock ................................................................................................................... 25
2.2.1 Definition ................................................................................................................ 25
2.2.2 Pathophysiology...................................................................................................... 25
2.2.3 Treatment ................................................................................................................ 26
CHAPTER III ............................................................................................................................... 33
REFERENCES ............................................................................................................................. 33

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 ABSTRACT

Sepsis and septic shock are syndromes. Sepsis is life-threatening organ dysfunction due
to a dysregulated host response to infection and septic shock is a subset of sepsis in which
underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially
increase mortality. The incidence of sepsis is as high as 35% and with mortality rates in the
intensive care unit from 27% to 54% in sepsis and septic shock, respectively. Many new
treatments have been tested but only few have been implemented in clinical practise. The
treatment of sepsis and septic shock is based on the Surviving Sepsis Campaign guidelines and
Sepsis-3, developed by an international expert panel. Early diagnosis, optimization of
haemodynamics, rapid identification of focus and adequate antibiotic treatment are the most
important strategies.

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 CHAPTER I

INTRODUCTION

Sepsis is life-threatening organ dysfunction caused by a dysregulated host

response to infection.1,2,3 Sepsis and septic shock are major healthcare problems, affect-
ing millions of people around the world each year, and killing as many as one in four
(and often more).4,5,6 Similar to polytrauma, acute myocardial infarction, or stroke, early
identification and appropriate management in the initial hours after sepsis develops
improves outcomes.

Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities

induced by infection, is a major public health concern, accounting for more than $20
billion (5.2%) of total US hospital costs in 2011.1 The reported incidence of sepsis is
increasing,2,3 likely reflecting aging populations with more comorbidities, greater
recognition,4 and, in some countries, reimbursement favorable coding.5 Although the true
incidence is unknown, conservative estimates indicate that sepsis is a leading cause of
mortality and critical illness worldwide.6,7 Furthermore, there is increasing awareness that
patients who survive sepsis often have longterm physical, psychological, and cognitive
disabilities with significant health care and social implications.8

A 1991 consensus conference developed initial definitions that focused on the

then-prevailing view that sepsis resulted from a host’s systemic inflammatory response
syndrome (SIRS) to infection.9 Sepsis complicated by organ dysfunction was termed
severe sepsis, which could progress to septic shock, defined as “sepsis-induced
hypotension persisting despite adequate fluid resuscitation.” A 2001 task force,
recognizing limitations with these definitions, expanded the list of diagnostic criteria but
did not offer alternatives because of the lack of supporting evidence.10 In effect, the
definitions of sepsis, septic shock, and organ dysfunction have remained largely
unchanged for more than 2 decades.

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 CHAPTER II

LITERATURE REVIEW

2.1 Sepsis
2.1.1 Definition

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host

response to infection.7 If not recognized early and managed promptly, it can lead to septic
shock, multiple organ failure and death. Any type of infectious pathogen can potentially
cause sepsis. Antimicrobial resistance is a major factor determining clinical
unresponsiveness to treatment and rapid evolution to sepsis and septic shock. Sepsis
patients with resistant pathogens have been found to have a higher risk of hospital
mortality.

The current use of 2 or more SIRS criteria to identify sepsis was unanimously
considered by the task force to be unhelpful. Changes in white blood cell count,
temperature, and heart rate reflect inflammation, the host response to “danger” in the
form of infection or other insults. The SIRS criteria do not necessarily indicate a
dysregulated, life-threatening response. SIRS criteria are present in many hospitalized
patients, including those who never develop infection and never incur adverse outcomes
(poor discriminant validity).25 In addition, 1 in 8 patients admitted to critical care units in
Australia and New Zealand with infection and new organ failure did not have the
requisite minimum of 2 SIRS criteria to fulfill the definition of sepsis (poor concurrent
validity) yet had protracted courses with significant morbidity and mortality.26
Discriminant validity and convergent validity constitute the 2 domains of construct
validity; the SIRS criteria thus perform poorly on both counts.

Severity of organ dysfunction has been assessed with various scoring systems that
quantify abnormalities according to clinical findings, laboratory data, or therapeutic
interventions. Differences in these scoring systems have also led to inconsistency in
reporting. The predominant score in current use is the Sequential Organ Failure
Assessment (SOFA) (originally the Sepsis-related Organ Failure Assessment).27,28 A

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higher SOFA score is associated with an increased probability of mortality.28 The score
grades abnormality by organ system and accounts for clinical interventions. However,
laboratory variables, namely, PaO2, platelet count, creatinine level, and bilirubin level,
are needed for full computation. Furthermore, selection of variables and cutoff values
were developed by consensus, and SOFA is not well known outside the critical care
community. Other organ failure scoring systems exist, including systems built from
statistical models, but none are in common use.

2.1.2 Etiology
The etiology of sepsis is diverse, and clinical clues to various organ systems aid in
appropriate workup and diagnosis. It is also pertinent to be able to distinguish between
the infectious and noninfectious causes of fever in a septic patient. The following are
organ system specific etiologies of possible sepsis:
 Skin/soft tissue:
Necrotizing fasciitis, cellulitis, myonecrosis, or gas gangrene, among others, with
erythema, edema, lymphangitis and positive skin biopsy result
 Wound infection:
Inflammation, edema, erythema, discharge of pus, with positive Gram stain and
culture results from incision and drainage or deep cultures
 Upper respiratory tract:
Pharyngitis, tonsillitis, or sinusitis, among others, with inflammation, exudate with or
without swelling, and lymphadenopathy or positive throat swab culture or rapid test
result
 Lower respiratory tract:
Pneumonia, empyema, or lung abscess, among others, with productive cough,
pleuritic chest pain, consolidation on auscultation, positive sputum culture result,
positive blood culture result, rapid viral testing, urinary antigen testing (eg,
Pneumococcus, Legionella), quantitative culture of protected brush, or
bronchoalveolar lavage

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 Central nervous system:
Meningitis, brain abscess, or infected hematoma, among others, with signs of
meningeal irritation, elevated CSF cell count and protein level, reduced CSF glucose
level, positive Gram stain and culture results
 Cerebrovascular system:
Myocardial infarction, acute valvular dysfunction, myocarditis, pericardialis, ruptured
aortic aneurysm, aortitis, or septic emboli, among others, with elevated levels of
cardiac enzymes, and imaging (ultrasonography, CT scanning, or MRI) of the chest,
abdomen, and/or pelvis showing vascular involvement
 Vascular catheters (arterial, venous):
Redness or drainage at insertion site, positive blood culture result (from the catheter
and a peripheral site), and catheter tip culture after sterile removal
 Gastrointestinal:
Colitis, infectious diarrhea, ischemic bowel, or appendicitis, among others, with
abdominal pain, distension, diarrhea, and vomiting; positive stool culture result and
testing for toxigenic Escherichia coli, Salmonella, Shigella, Campylobacter, or
Clostridium difficile.
 Intra-abdominal:
Renal abscess, pyelonephritis, pancreatitis, cholecystitis, liver abscess, intra-
abdominal abscesses, or perforation, compromise, or rupture of an intra-abdominal or
pelvic structure, among others, with specific symptoms and signs;4 aerobic and
anaerobic culture of drained abdominal fluid collections; peritoneal dialysis (PD)
catheter infection with cloudy PD fluid, abdominal pain, deranged cell count, and
positive PD fluid culture result
 Urinary tract:
Cystitis, pyelonephritis, urethritis, or renal abscess, among others, with urgency,
dysuria, pelvic, suprapubic, or back pain; urine microscopy showing pyuria or a
positive urine culture result; urosepsis has also been reported after prostatic biopsy10
 Female genital tract:

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 Pelvic inflammatory disease, cervicitis, or salpingitis, among others, with lower
abdominal pain, vaginal discharge, positive results on endocervical and high vaginal
swabs
 Male genital tract:
Orchitis, epididymitis, acute prostatitis, balanitis, or prostatic abscess, among others,
with dysuria, frequency, urgency, urge incontinence, cloudy urine, prostatic
tenderness, and positive urine Gram stain and culture results
 Bone:
Osteomyelitis presenting with pain, warmth, swelling, decreased range of motion,
positive blood and/or bone culture results, and MRI changes
 Joint:
Septic arthritis presenting with pain, warmth, swelling, decreased range of motion,
positive arthrocentesis with cell counts, and positive Gram stain and culture results
 Nonspecific systemic febrile syndromes:
Babesiosis, rickettsial diseases, lyme disease, typhus, or typhoid fever, among others,
with multiorgan involvement, specific travel and epidemiological exposures, and
associated rashes or other symptoms
There are numerous noninfectious causes of fever and organ dysfunction that can
mimic sepsis:11
 Alcohol/drug withdrawal
 Postoperative fever (48 hours postoperatively)
 Transfusion reaction
 Drug fever
 Allergic reaction
 Cerebral infarction/hemorrhage
 Adrenal insufficiency/adrenal hemorrhage
 Myocardial infarction
 Pancreatitis
 Acalculous cholecystitis
 Ischemic bowel
 Aspiration pneumonitis

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 ARDS (both acute and late fibroproliferative phase)
 Subarachnoid hemorrhage
 Fat emboli
 Transplant rejection
 Deep venous thrombosis
 Pulmonary emboli
 Gout/pseudogout
 Hematoma
 Cirrhosis (without primary peritonitis)
 Gastrointestinal hemorrhage
 Phlebitis/thrombophlebitis
 IV contrast reaction
 Neoplastic fevers
 Decubitus ulcers

Table 1. Infectious and Noninfectious Causes of Sepsis12

System Infectious Causes Noninfectious Causes

Posterior fossa syndrome,

central fever, seizures,
Central nervous Meningitis, encephalitis cerebral infraction,
hemorrhage,
cerebrovascular accident

Central line, infected

pacemaker, endocarditis,
Myocardial infarction,
sternal osteomyelitis, viral
Cardiovascular balloon pump syndrome,
pericarditis,
Dressler syndrome
myocardial/perivalvular
abscess

Ventilator-associated Pulmonary emboli, ARDS,

pneumonia, mediastinitis, atelectasis (without
Pulmonary pneumonia), cryptogenic
tracheobronchitis,
empyema organizing pneumonia,
bronchogenic carcinoma

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 without postobstructive
pneumonia, systemic lupus
erythematosus,
pneumonitis, vasculitis

Intra-abdominal abscess, Pancreatitis, acalculous

cholangitis, cholecystitis, cholecystitis, ischemia of
Gastrointestinal viral hepatitis, peritonitis, the bowel/colon, bleeding,
diarrhea (Clostridium cirrhosis, irritable bowel
difficile) syndrome

Catheter-associated
Allergic interstitial
Urinary tract bacteremia, urosepsis,
nephritis
pyelonephritis, cystitis

Decubitus ulcers,
Skin/soft tissue Vascular ulcers
cellulitis, wound infection

Chronic osteomyelitis,
Bone/joint Acute gout
septic arthritis

Adrenal insufficiency,
phlebitis/thrombophlebitis,
neoplastic fever,
alcohol/drug withdrawal,
Transient bacteremia,
Other delirium tremens, drug
sinusitis
fever, fat emboli, deep
venous thrombosis,
postoperative fever (48 h),
fever after transfusion

2.1.3 Epidemiology

The incidence of sepsis and the number of sepsis-related deaths are increasing
because of an increased use of immunosuppressive medications. The incidence varies by
race and sex. The highest incidence is among black males. The incidence also shows
seasonal variation, with the highest number of cases in winter, probably because of the
increased prevalence of respiratory infections during this season. Older patients (≥65

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years) account for most (60%-85%) sepsis cases, attributable to multiple comorbidities
and frequent hospitalizations.17
The predominant infectious organisms (pathogen) that cause sepsis have changed
over the years. Gram-positive bacteria are the most common etiologic pathogens,
although the incidence of gram-negative sepsis remains substantial. The incidence of
fungal sepsis has been rising with more patients on immunosuppressive therapies and
more cases of HIV infection. In approximately half of sepsis cases, the organism is not
identified (culture-negative sepsis).

2.1.4 Risk Factor

Anyone affected by an infection can progress to sepsis conditions but some

vulnerable populations such as elderly people, pregnant women, neonates, hospitalized
patients, and people with cancer, kidney disease, are at higher risk.8 Other risk factors for
sepsis include the following:
 Bacteremia
 Advanced age (≥65 years)
 Immunosuppression : Conditions that impair host defenses such as seen with
neoplasms, renal failure, hepatic failure, AIDS, asplenism, diabetes,
autoimmune diseases, organ transplant, alcoholism, and the use of
immunosuppressant medications and immunomodulators
 Previous hospitalization and antibiotic therapy in the preceding 90 days
 Genetic factors : Defects of cellular and humoral immunity (low or absent
antibody production, T cells, phagocytes, natural killer cells, complement)
 Urosepsis due to benign prostatic hypertrophy (BPH) in older males or
complicated UTI

2.1.5 Sign and Symptoms

Sepsis is a medical emergency. However, because of the characteristics of sepsis

as a disease condition with multiple causative organisms and its evolving nature over
time, people with sepsis can present various signs and symptoms at different times.

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Warning signs and symptoms include fever or low temperature and shivering, altered
mental status, difficulty breathing/rapid breathing, increased heart rate, weak pulse/low
blood pressure, low urine output, cyanotic or mottled skin, cold extremities, and extreme
body pain or discomfort.9,10,11
Suspecting sepsis is a first major step towards early recognition and diagnosis.
There are many types of sign and symptoms such as:
 Nonspecific signs and symptoms
The history and physical examination findings are nonspecific but may
suggest the likely source of the septic process and thereby help determine the
appropriate antimicrobial therapy and other interventions. General signs and
symptoms of sepsis may include the following:
 Fever, with or without shaking chills (temperature >38.3ºC or < 36ºC)
 Impaired mental status (in the setting of fever or hypoperfusion)
 Increased breathing rate (>20 breaths/min) resulting in respiratory
alkalosis
 Warm or cold skin, depending on the adequacy of organ perfusion and
dilation of the superficial skin vessels
 Hypotension requiring pressor agents to maintain systolic blood
pressure above 65 mm Hg.

 Systemic signs and symptoms

The clinical features depicted below may provide important diagnostic
clues.
 Respiratory infection
Cough, chest pain, and dyspnea may suggest pneumonia or
empyema but may also be observed in patients with pulmonary
embolism or pleural effusion.
 Gastrointestinal (GI) or genitourinary (GU) infection
The patient may have a history of antecedent conditions
predisposing to perforation or abscess. In many cases, the history is

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 critical for diagnosis. Abdominal findings on physical examination
may be absent or unimpressive.
o Patients with an intra-abdominal or pelvic source of infection
usually have a history of antecedent conditions that predispose to
perforation or abscess (eg, chronic or retrocecal subacute
appendicitis, diverticulitis, Crohn disease, previous abdominal
surgery, or cholecystitis).
o Diffuse abdominal pain may suggest pancreatitis or generalized
peritonitis, whereas right upper abdominal quadrant (RUQ)
tenderness may suggest a biliary tract etiology (eg, cholecystitis,
cholangitis), and tenderness in the right lower abdominal quadrant
(RLQ) suggests appendicitis or Crohn disease. Discrete tenderness
over the left lower abdominal quadrant suggests diverticulitis,
particularly in elderly patients.
o A rectal examination may reveal exquisite tenderness caused by a
prostatic abscess or, more commonly, an enlarged noninflamed
prostate suggestive of prostatitis.
o A urinary tract source is suggested by an antecedent history of
pyelonephritis, stone disease, congenital abnormal collecting
system, prostatic hypertrophy, or previous operations or procedures
involving the prostate or kidneys.32,33 Costovertebral angle
tenderness with a fever suggests acute pyelonephritis. Subacute or
chronic pyelonephritis may manifest as only mild tenderness.
 Intravenous line infection
Evidence of infection at a central IV line site suggests the
probable etiology.34 However, it is important to note that many patients
with central IV line infections do not have superficial evidence of
infection at the insertion site. Always suspect IV line infections,
especially when other sources of sepsis are eliminated.35,36 Central IV
lines are the lines most commonly associated with bacteremia or
sepsis. Peripheral venous lines and arterial lines are rarely associated

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 with bacteremia. Thrombophlebitis may be noted at the peripheral IV
line site.
 Surgical wound infection
Pain, purulent exudate, or crepitus in a surgical wound may
suggest wound infection, cellulitis, or abscess.

 Signs of end-organ hypoperfusion

These signs include the following:
 Warm, flushed skin may be present in the early phases of sepsis. The
skin may become cool and clammy with progression to shock due to
redirection of blood flow to core organs. Decreased capillary refill,
purpura cyanosis, or mottling may be seen.
 Altered mental status, obtundation, restlessness
 Oliguria or anuria due to hypoperfusion
 Ileus or absent bowel sounds
 Special considerations
 Elderly patients may present with peritonitis and may not experience
rebound tenderness of the abdomen.37
 Elderly individuals, persons with diabetes and patients on beta-
blockers may not exhibit an appropriate tachycardia as blood pressure
falls.
 Younger patients develop a severe and prolonged tachycardia without
hypotension until acute decompensation occurs.
 Patients with chronic hypertension may develop critical hypoperfusion
at a blood pressure that is higher than in healthy patients (ie, relative
hypotension).
 An acute surgical abdomen in a pregnant patient may be difficult to
diagnose. The most common cause of sepsis in pregnancy is
urosepsis.38

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2.1.6 Clinical Criteria to Identify Patients with Sepsis

The task force recognized that no current clinical measures reflect the concept of
a dysregulated host response. However, as noted by the 2001 task force, many bedside
examination findings and routine laboratory test results are indicative of inflammation or
organ dysfunction.10 The task force therefore evaluated which clinical criteria best
identified infected patients most likely to have sepsis.
This objective was achieved by interrogating large data sets of hospitalized
patients with presumed infection, assessing agreement among existing scores of
inflammation (SIRS)9 or organ dysfunction (eg, SOFA,27,28 Logistic Organ Dysfunction
System30) (construct validity), and delineating their correlation with subsequent outcomes
(predictive validity). In addition, multivariable regression was used to explore the
performance of 21 bedside and laboratory criteria proposed by the 2001 task force.10 Full
details are found in the accompanying article by Seymour et al.12
In brief, electronic health record data of 1.3 million encounters at 12 community
and academic hospitals within the University of Pittsburgh Medical Center health system
in southwestern Pennsylvania were studied. There were 148 907 patients with suspected
infection, identified as those who had body fluids sampled for culture and received
antibiotics. Two outcomes hospital mortality and mortality, ICU stay of 3 days or longer,
or both were used to assess predictive validity both overall and across deciles of baseline
risk as determined by age, sex, and comorbidity. For infected patients both inside and
outside of the mortality risk of approximately 10% in a general hospital population with
presumed infection.12 This is greater than the overall mortality rate of 8.1% for ST-
segment elevation myocardial infarction,31 a condition widely held to be life threatening
by the community and by clinicians.
Depending on a patient’s baseline level of risk, a SOFA score of 2 or greater
identified a 2 to 25 old increased risk of dying compared with patients with a SOFA score
less than 2.12 As discussed later, the SOFA score is not intended to be used as a tool for
patient management but as a means to clinically characterize a septic patient.
Components of SOFA (such as creatinine or bilirubin level) require laboratory testing and
thus may not promptly capture dysfunction in individual organ systems. Other elements,
such as the cardiovascular score, can be affected by iatrogenic interventions. However,

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 SOFA has widespread familiarity within the critical care community and a well validated
relationship to mortality risk. It can be scored retrospectively, either manually or by
automated systems, from clinical and laboratory measures often performed routinely as
part of acute patient management. The task force noted that there are a number of novel
biomarkers that can identify renal and hepatic dysfunction or coagulopathy earlier than
the elements used in SOFA, but these require broader validation before they can be
incorporated into the clinical criteria describing sepsis. Future iterations of the sepsis
definitions should include an updated SOFA score with more optimal variable selection,
cutoff values, andweighting, or a superior scoring system.

Tabel 2. qSOFA Criteria

Quick SOFA (qSOFA) Criteria :

 Respiratory rate?
22/min
 Altered mentation
 Systolic blood pressure?
100mmHg

Tabel 3. Sequential [Sepsis-Related] Organ Failure Assessment Scorea

Score
System
0 1 2 3 4
Respiration
<200 (26.7) with
PaO2/FIO2,mmHg <100 (13.3) with
≥400 (53.3) <400 (53.3) <300 (40) respiratory
(kPa) respiratory support
support
Coagulation
Platelets, ×103/μL ≥150 <150 <100 <50 <20
Liver
Bilirubin, mg/dL <1.2 (20) 1.2-1.9 2.0-5.9 (33- 6.0-11.9 (102-
>12.0 (204)
(μmol/L) (20-32) 101) 204)
Dopamine 5.1-
Dopamine
15 or Dopamine >15 or
<5 or
MAP MAP epinephrine ≤0.1 epinephrine >0.1 or
Cardiovascular dobutamine
≥70mmHg <70mmHg or norepinephrine
(any dose)b
norepinephrine >0.1b
≤0.1b
Central nervous system
Glasgow Coma
15 13-14 10-12 6-9 <6
Scale scorec

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Renal
Creatinine, mg/dL 1.2-1.9 2.0-3.4 (171- 3.5-4.9 (300-
<1.2 (110) >5.0 (440)
(μmol/L) (110-170) 299) 440)
Urine output,mL/d <500 <200
Abbreviations: FIO2, fraction of inspired oxygen; b
Catecholamine doses are given as μg/kg/min for at
MAP, mean arterial pressure; PaO2, partial least 1 hour.
c
pressure of oxygen. Glasgow Coma Scale scores range from 3-15; higher
a
Adapted from Vincent et al.27 score indicates better neurological function.

Figure 1. Operationalization of Clinical Criteria Identifying Patients with Sepsis and Septic Shock18

2.1.7 Treatment

Early fluid resuscitation to improve volume status is also important in the initial
phase of sepsis management. In addition, vasopressors may be required to improve and
maintain tissue perfusion. Repeated exams and diagnostics, including monitoring vital
signs, will guide the appropriate management of sepsis over time.
Appropriate antimicrobial therapy depends on adequate coverage of the bacteria
associated with the specific organ or organ system associated with the infection.46, 29, 47, 28,
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30
Agents suitable for empiric monotherapy regimens (depending on the source and
underlying microbiology of the sepsis because the agent must be able to cover all of the
likely pathogens) may include the following:

 Imipenem

 Meropenem

 Tigecycline

 Piperacillin-tazobactam

 Ampicillin-sulbactam

 Moxifloxacin

Combination therapeutic regimens include metronidazole plus either levofloxacin,

aztreonam, a third or fourth generation cephalosporin, or an aminoglycoside. Many
advocate also using antistaphylococcal coverage (eg, vancomycin) empirically.

Although no drug regimen may be superior to another, time to first dose

administration is very important. Mortality data suggest that early administration of
appropriate antibiotics is correlated with better survival. Alternative agents may be used
alone or in combination, with a good adverse effect profile.46, 29, 47, 28

Antibiotics are normally continued until the septic process and surgical
interventions have controlled the source of infection. Ordinarily, patients are treated for
approximately 2 weeks, although duration may vary according to the source, site, and
severity of the infection. As soon as patients are able to tolerate medications orally, they
may be switched to an equivalent oral antibiotic regimen in an IV to oral conversion
program.

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 Empiric therapy for IV line infections

A detailed discussion of catheter associated infections is available in the IDSA

catheter associated line related infections (CRBSI) guidelines.57 IV line infections are
most often due to Staphylococcus aureus (methicillin-sensitive S aureus [MSSA] or
methicillin-resistant S aureus [MRSA]), but gram-negative bacilli can be involved. The
preferred empiric therapy for these infections is meropenem or cefepime (for
Pseudomonas) plus additional coverage for staphylococci.35,36 If MRSA is prevalent in
the institution, add linezolid, vancomycin, or daptomycin. Otherwise, nafcillin, oxacillin,
or cefazolin provides adequate coverage for MSSA.

Unless coagulase negative, methicillin sensitive staphylococci are recovered from

the blood, with high level bacteremia (3 or 4 positive blood cultures out of 4), avoid
vancomycin for empiric therapy if possible; these are low virulence organisms and may
represent contaminants. If treatment is advised, the duration of therapy depends on the
severity and site of infection.57

Treatment of staphylococcal central line infection and fungal or gram-negative

organisms typically requires removal of the line.

Minimize the use of vancomycin in order to prevent the emergence of

vancomycin-resistant enterococci (VRE).35

 Empiric therapy for biliary tract infections

IDSA guidelines for complicated intra-abdominal infections such as biliary tract

infections are available.58 The main biliary tract pathogens include Escherichia coli,
Klebsiella species, and Enterococcus faecalis. Coverage for staphylococci is not needed
in the biliary tract. Anaerobes can also be important, especially in patients with diabetes
or immunosuppression.

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 Preferred monotherapy regimens for biliary tract infections include imipenem,
meropenem, ampicillin-sulbactam, or piperacillin-tazobactam. Cephalosporins or
quinolones in combination with metronidazole are alternate first-line agents for the
treatment of biliary tract infections.

 Empiric therapy for intra abdominal and pelvic infections

The main pathogens in the lower abdomen and pelvis include aerobic coliform
gram-negative bacilli and B fragilis. Enterococci do not require special coverage unless
the patient has recurrent infection or enterococci have been specifically and repeatedly
isolated. Potent anti B fragilis and aerobic gram-negative bacillary coverage are essential,
in addition to surgical intervention when drainage or repair of intra-abdominal viscera is
required.

Preferred monotherapy regimens for intra-abdominal and pelvic infections include

imipenem, meropenem, piperacillin tazobactam, ampicillin sulbactam, or tigecycline.
Alternate combination therapy for intra-abdominal and pelvic infections consists of
clindamycin or metronidazole plus a third or fourth generation cephalosporin, aztreonam,
levofloxacin, or an aminoglycoside. Some authors raise concerns about the use of
tigecycline.

 Empiric therapy for urosepsis

The primary uropathogens include gram-negative aerobic bacilli, such as

coliforms or enterococci. Pseudomonas aeruginosa, Enterobacter species, and Serratia
species are rare uropathogens and are associated with urologic instrumentation.

Monotherapy for urosepsis due to aerobic gram-negative bacilli may include

aztreonam, levofloxacin, a third or fourth generation cephalosporin, or an
aminoglycoside. However, preferred monotherapy for enterococcal urosepsis involves
ampicillin or vancomycin. For VRE urosepsis, linezolid or daptomycin may be used.

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 Empiric therapy for community-acquired urosepsis consists of levofloxacin,
aztreonam, or an aminoglycoside plus ampicillin. For nosocomial urosepsis, a fourth-
generation cephalosporin, piperacillin-tazobactam, imipenem, or meropenem, with or
without an aminoglycoside, is preferred.

 Empiric therapy for staphylococcal, pneumococcal, and meningococcal sepsis

S aureus sepsis is usually associated with infection caused by devices or bacterial

endocarditis. Empiric therapy may be with an anti-staphylococcal penicillin (nafcillin or
oxacillin), vancomycin, a cephalosporin, daptomycin, or linezolid, depending on the
concern for MRSA.

Pneumococcal or meningococcal sepsis may be treated with penicillin G or a

beta-lactam. In patients with associated meningococcal meningitis, the antibiotic selected
should penetrate the cerebrospinal fluid (CSF) and should be given in meningeal doses.
Consider the regional prevalence of drug-resistant pneumococci when selecting an
antibiotic.

 Empiric therapy for sepsis of unknown origin

The usual sources of sepsis are the distal gastrointestinal (GI) tract, the pelvis, and
the genitourinary (GU) tract. Organisms that should be covered from these areas include
aerobic gram-negative bacilli (coliforms) and B fragilis. Enterococci are important
pathogens in biliary tract sepsis and urosepsis.

Preferred empiric monotherapy includes meropenem, imipenem, piperacillin-

tazobactam, or tigecycline.

Empiric combination therapy includes metronidazole plus levofloxacin,

aztreonam, or a third- or fourth-generation cephalosporin.

 Outpatient management

21
 If orally administered antibiotics are continued at home, advise the patient about
possible adverse effects. If additional antimicrobial therapy is needed outside the hospital
setting, it should be given orally, not intravenously. Do not allow the total course of
antibiotics to exceed 3 weeks, except for specific clinical scenarios, which may require
prolonged courses of oral antibiotics for cure or complete clinical resolution.

2.1.8 Prevention

There are two main steps to preventing sepsis:

1. prevention of microbial transmission and infection
2. prevention of the evolution of an infection to sepsis conditions.
Prevention of infection in the community involves using effective hygiene
practices, such as hand washing, and safe preparation of food, improving sanitation and
water quality and availability, providing access to vaccines, particularly for those at high
risk, as well as appropriate nutrition, including breastfeeding for newborns.
Prevention of infection in health care facilities mainly relies on having
functioning infection prevention and control (IPC) programmes and teams, effective
hygiene practices and precautions, including hand hygiene, along with a clean, well-
functioning environment and equipment.
Prevention of the evolution to sepsis in both community and health care facilities
requires the appropriate antibiotic treatment of infection, including reassessment for
optimization, prompt seeking of medical care, and early detection of sepsis signs and
symptoms.
Scientific evidence has clearly demonstrated the effectiveness of infection
prevention. For instance, improved hand hygiene practice in health care can reduce
infection by as much as 50%,12 while, in community settings, it can cut the risk of
diarrhoea by at least 40%.13 Water, sanitation and hygiene (WASH) improvements could
result in a 10% reduction of the total burden of disease worldwide.14 Vaccinations
prevent 2–3 million infection-associated deaths every year.15

22
2.1.9 Prognosis
Sepsis is a common cause of mortality and morbidity worldwide. The prognosis
depends on underlying health status and host defenses, prompt and adequate surgical
drainage of abscesses, relief of any obstruction of the intestinal or urinary tract, and
appropriate and early empiric antimicrobial therapy.17
The prognosis of sepsis treated in a timely manner and with appropriate therapy is
usually good, except in those with intra-abdominal or pelvic abscesses due to organ
perforation. When timely and appropriate therapy has been delivered, the underlying
physiologic condition of the patient determines outcome.
A systematic review by Winters et al suggested that beyond the standard 28 day in
hospital mortality endpoint, ongoing mortality in patients with sepsis remains elevated up
to 2 years and beyond.18 In addition, survivors consistently demonstrate impaired quality
of life.19
Clinical characteristics that affect the severity of sepsis and, therefore, the
outcome include the host's response to infection, the site and type of infection, and the
timing and type of antimicrobial therapy.

Host-related
Abnormal host immune responses may increase susceptibility to severe disease
and mortality. For example, extremes of temperature and the presence of leukopenia
and/or thrombocytopenia, advanced age, presence of co-morbid conditions,
hyperglycemia, bleeding diatheses, and failure of procalcitonin levels to fall have all been
associated with worsened outcome.20
Important risk factors for mortality include the patient's comorbidities, functional
health status, newly onset atrial fibrillation, hypercoagulability state, hyperglycemia on
admission, AIDS, liver disease, cancer, alcohol dependence, and immune suppression.
Age older than 40 years is associated with comorbid illnesses, impaired
immunologic responses, malnutrition, increased exposure to potentially resistant
pathogens in nursing homes, and increased use of medical devices, such as indwelling
catheters and central venous lines.21,22,23,24

23
Infection site
Sepsis due to urinary tract infection has the lowest mortality rate, while mortality
rates are higher with unknown sources of infection, gastrointestinal sources (highest in
ischemic bowel), and pulmonary sources.25,26,27

Infection type
Sepsis due to nosocomial pathogens has a higher mortality rate than sepsis due to
community-acquired pathogens. Increased mortality is associated with bloodstream
infections due to Staphylococcus aureus, fungi, and Pseudomonas, as well as
polymicrobial infections. When bloodstream infections become severe (ie, septic shock),
the outcome may be similar regardless of whether the pathogenic bacteria are gram-
negative or gram-positive.

Antimicrobial therapy
Studies have shown that the early administration of appropriate antibiotic therapy
(ie, antibiotics to which the pathogen is sensitive) is beneficial in septic patients
demonstrating bacteremia. Previous antibiotic therapy (ie, antibiotics within the prior 90
days) may be associated with increased mortality risk, at least among patients with gram-
negative sepsis. Patients who have received prior antibiotic therapy are more likely to
have higher rates of antibiotic resistance, reducing the likelihood that appropriate
antibiotic therapy will be chosen empirically.28,29,30,31

Restoration of perfusion
Failure to attempt aggressive restoration of perfusion early may also be associated
with an increased mortality risk. A severely elevated lactate level (>4 mmol/L) is
associated with a poor prognosis in patients with sepsis.

24
2.2 Septic Shock
2.2.1 Definition

Septic shock is defined as a subsetof sepsis in which underlying cir-culatory and

cellular metabolism abnormalities are profound enough to substantially increase
mortality. The 2001 task force definitions described septic shock as “a state of acute
circulatory failure”.10 The task force favored abroader view to differentiate septic shock
from cardiovascular dysfunction alone and to recognize the importance of cellular
abnormalities.There was unanimous agreement that septic shock should reflect a more
severe illness with a much higher likelihood of death than sepsis alone.

2.2.2 Pathophysiology

Figure 2. Pathophysiology of Septic Shock

Diagram depicting the pathogenesis of sepsis and multiorgan failure.

DIC = disseminated intravascular coagulation; IL = interleukin.

25
2.2.3 Treatment

General Treatment Guidelines in Septic Shock

The major focus of resuscitation is on supporting cardiac and respiratory
functions. The other organ systems may also require attention and support during
this critical period. Patients generally require intubation and assisted ventilation
because respiratory failure either is present at the onset of illness or may develop
during its course. Correction of the shock state and abnormal tissue perfusion is
the next step in the treatment of patients with septic shock.
In 2004, the first set of formal treatment guidelines for septic shock were
published.54 These guidelines, known as the Surviving Sepsis Campaign, were
formulated by an international consensus group that was composed of experts
from 11 organizations, including the Society of Critical Care Medicine (SCCM),
the American College of Chest Physicians (ACCP), the European Society of
Intensive Care Medicine (ESICM), and the American College of Emergency
Physicians (ACEP). These guidelines are reviewed and updated periodically.
The Surviving Sepsis Campaign guidelines were last updated in 2012, and
the current versions reflect the opinion of a reasonable approach to the treatment
of septic shock.11 Specifically, with the recently large clinical trials in the
management of septic shock completed, specific recommendations may be
degraded. Those are highlighted below.
The first 6 hours of resuscitation of a critically ill patient with sepsis or
septic shock are critical.11 The following should be completed within 3 hours:
 Obtain the lactate level (Although recommended, the three recent trials
showed that lactate-guided therapy had no impact on survival. Still, lactate
levels parallel septic shock severity and have prognostic implication.)
 Obtain blood cultures before administering antibiotics
 Administer broad-spectrum antibiotics
 Administer 30 mL/kg of crystalloid solution for hypotension or for lactate
levels of 4 mmol/L or higher (Again, although most patients presenting with
severe sepsis are in a functional hypovolemic state, requiring fluid
resuscitation, careful monitoring of right ventricular volume overload is

26
 essential if large quantiles of fluid are to be given quickly, to avoid inducing
acute cor pulmonale). Important to note, the figure 30 mL/kg was chosen as
an approximation of the average initial fluid resuscitation given on most
clinical trials of septic shock resuscitation. Regrettably, this volume level has
since been set as a quality measure of adequacy of sepsis resuscitation, which,
by definition, is not accurate. The process trial demonstrated that similar
survival occurred when the bedside clinician gave the initial amount of fluids
he or she thought the patient needed based on clinical signs of peripheral
perfusion, compared with the group given a fixed initial fluid resuscitation.
Thus, the most accurate method for fluid resuscitation is to monitor the
response to fluid infusions given rapidly and stop once adequacy of
resuscitation has occurred or when the patient no longer is volume responsive.
The following should be completed within 6 hours:
 Administer vasopressors for hypotension that does not respond to initial fluid
resuscitation to maintain a mean arterial pressure (MAP) of 65 mm Hg or
higher (Recent studies showed the validity of the 70-75 mm Hg lower mean
arterial pressure target or 80-85 mm Hg in those patients with preexisting
hypertension.)
 If hypotension persists despite volume resuscitation or the initial lactate level
is 4 mmol/L or higher, then measure central venous pressure (CVP) (aiming
for ≥8 mm Hg), measure central venous oxygen saturation (ScvO2) (aiming
for ≥70%), and normalize lactate levels (These recommendations will
probably be modified in lieu of the findings that CVP does not represent an
effective target. See below about the venoarterial PCO2 gradient analysis as
being a more specific measure of tissue hypoperfusion.)

Respiratory support
An initial assessment of airway and breathing is vital in a patient with
septic shock. Supplemental oxygen should be administered to all patients with
suspected sepsis. Early intubation and mechanical ventilation should be strongly
considered for patients with any of the following:

27
 Oxygen requirement
 Dyspnea or tachypnea
 Persistent hypotension
 Evidence of poor peripheral perfusion

Circulatory support
Patients with suspected septic shock require an initial crystalloid fluid
challenge of 30 mL/kg (1-2 L) over 30-60 minutes, with additional fluid
challenges. (A fluid challenge consists of rapid administration of volume over a
particular period, followed by assessment of the response).
Administration of crystalloid solution is titrated to a goal of adequate
tissue perfusion. CVP should not be used to target resuscitation; it should be used
as a stopping rule. If, during fluid resuscitation, CVP rapidly increases by more
than 2 mm Hg, absolute CVP greater than 8-12 mm Hg, or signs of volume
overload (dyspnea, pulmonary rales, or pulmonary edema on the chest
radiograph) occur, fluid infusion as primary therapy needs to be stopped. Patients
with septic shock often require a total of 4-6 L or more of crystalloid solution.
However, CVP measurement should not be entirely relied upon, because it does
not correlate with intravascular volume status or cardiac volume responsiveness.48
Some studies have used noninvasive means of estimating CVP for
example, ultrasonography to measure inferior vena cava diameter as a surrogate
for volume status. Nagdev et al used the difference between inspiratory and
expiratory caval diameter (the caval index) to predict CVP and found that a 50%
difference predicted a CVP lower than 8 mm Hg with both a sensitivity and a
specificity greater than 90%.49 Similarly, variations in this diameter change with
respiration correlated with volume responsiveness.
UO should also be monitored as a measure of dehydration. UO lower than
30-50 mL/h should prompt further fluid resuscitation or other measures to
increase cardiac output in a non–fluid-responsive patient. Important to note,
during fluid resuscitation for severe sepsis, increased intra-abdominal fluid
accumulation and ileus often occur and can induce increases in intra-abdominal

28
pressure. If intra-abdominal pressure is greater than 12 mm Hg, intra-abdominal
hypertension exists. Since renal perfusion pressure can be approximated as mean
arterial pressure minus CVP or intra-abdominal pressure (whichever is higher),
low UO may reflect low renal perfusion pressure. In general, targeting a renal
perfusion pressure of 70-75 mm Hg sustains adequate renal blood flow in severe
sepsis unless preexisting hypertension is present, in which case targeting a higher
renal perfusion pressure of 80-85 mm Hg is indicated.30
Given that third-spacing of intravascular fluid is a hallmark of septic
shock, it makes sense that administration of colloid solution might be beneficial.
However, although colloid resuscitation with albumin has not been shown in
many meta-analyses to have any advantage over isotonic crystalloid resuscitation
(isotonic sodium chloride solution or lactated Ringer solution) in this
setting,31 Delaney et al found adjunctive albumin resuscitation to provide a
statistically significant mortality benefit in relation to other regimens.32
In the Saline versus Albumin Fluid Evaluation (SAFE) trial, in which
about 1200 of 7000 ICU patients who required fluid resuscitation had severe
sepsis, no overall difference between the 2 treatment groups was seen.38 However,
the investigators noted a trend toward improved outcome in patients with severe
sepsis who received 4% albumin rather than normal saline. The data are
inconclusive, especially with regard to the initial resuscitation phase for septic
shock in the ED; therefore, crystalloid fluid resuscitation is recommended.
The current Surviving Sepsis guidelines recommend rapid administration
of an initial fluid challenge with 30 mL/kg of crystalloid solution.11 Albumin
should be used only when substantial amounts of crystalloid solution are required.
Hydroxyethyl starch solutions are not recommended.11 Several recent
retrospective and smaller prospective clinical trials have underscored the risk that
0.9 N NaCl has as a primary resuscitation fluid. It causes hyperchloremic
metabolic acidosis and is associated with an increased mortality relative to
balanced salt solutions (eg, plasmalyte).44

29
Correction of anemia and coagulopathy
Hemoglobin levels as low as 7 g/dL are well tolerated by patients, and
transfusion is not required unless the patient has poor cardiac reserve or
demonstrates evidence of myocardial ischemia. Thrombocytopenia and
coagulopathy are common in patients with sepsis; these patients do not require
replacement with platelets or fresh frozen plasma (FFP) unless they develop
active clinical bleeding.
If hemoglobin levels fall below 7 g/dL, red blood cell (RBC) transfusion is
recommended to a target hemoglobin range of 7-9 g/dL.11 Even in the absence of
apparent bleeding, patients with severe sepsis should receive platelet transfusion
if platelet counts fall below 10 × 109/L (10,000/µL). Platelet transfusion may also
be considered when bleeding risk is increased and platelet counts are below 20 ×
109/L (20,000/µL).11 Patients who are to undergo surgery or other invasive
procedures may require higher platelet counts (eg, ≥50 × 109/L [50,000/µL]).
Other points to consider with respect to the administration of blood
products include the following 11,60 :
 Erythropoietin is not recommended for specific treatment of anemia
associated with severe sepsis; rather, it should be given to such patients for
other acceptable indications (eg, anemia associated with renal failure)
 FFP is not recommended for the correction of laboratory clotting
abnormalities unless bleeding is present or invasive procedures are planned
 Antithrombin agents are not recommended for treatment of severe sepsis and
septic shock
 Recombinant activated protein C (rhAPC) is no longer available for treating
patients with severe sepsis or septic shock

Antimicrobial therapy
therapy should be initiated within the first hour after the recognition of
septic shock or severe sepsis; delays in administration are associated with
increased mortality. 5,11,30 Selection of antibiotic agents is empiric, based on an

30
assessment of the patient’s underlying host defenses, the potential source of
infection, and the most likely responsible organisms.
When the source is unknown, the antibiotic chosen must be a broad-
spectrum agent that covers gram-positive, gram-negative, and anaerobic bacteria.
In addition, consideration must be given to pathogens with antibiotic resistance,
such as methicillin resistant Staphylococcus aureus (MRSA),
Pseudomonasspecies, and gram-negative organisms with extended spectrum beta-
lactamase (ESBL) activity.
Patients who are at risk for these types of infection are those with recent,
prolonged, or multiple hospitalizations. The 2012 Surviving Sepsis Campaign
guidelines recommend combination empiric therapy for neutropenic patients as
well as for those with difficult-to-treat, multidrug-resistant microorganisms, such
as Acinetobacter and Pseudomonas.11

Temperature control
Fever generally requires no treatment, except in patients who have limited
cardiovascular reserve as a consequence of increased metabolic requirements.
Antipyretic drugs and physical cooling methods, such as sponging or cooling
blankets, may be used to lower the patient’s temperature.
External cooling is another method of fever control that has been reported
to be safe and to decrease vasopressor requirements and early mortality in patients
with septic shock. In a multicenter, randomized, controlled study comprising
febrile patients with septic shock who required vasopressors, mechanical
ventilation, and sedation, the group that received external cooling, as compared
with the group that did not, exhibited the following 25:
 Significantly lower body temperature after 2 hours
 Significantly more common occurrences of shock reversal in the ICU
 Significantly lower day 14 mortality
Although a 50% decrease in the vasopressor dose was significantly more
common after 12 hours of external cooling treatment, the same result was not
found after 48 hours of this therapy.25

31
Metabolic and nutritional support
Patients with septic shock develop electrolyte abnormalities. Potassium,
magnesium, and phosphate levels should be measured and corrected if deficient.
Patients with septic shock generally have high protein and energy
requirements. Although a brief period (several days) without nutrition does not
cause deleterious effects, prolonged starvation must be avoided.
Early nutritional support is of critical importance in patients with septic
shock. The oral or enteral route is preferred, unless the patient has an ileus or
other intestinal abnormality. Gastroparesis is commonly observed and can be
treated by administering motility agents or placing a small-bowel feeding tube.
Diminished bowel sounds are not a contraindication to a trial of enteral
nutrition, though motility agents or a small-bowel feeding tube may be necessary.
The benefits of enteral nutrition are as follows:
 Protection of gut mucosa
 Prevention of translocation of organisms from the gastrointestinal (GI) tract
 Reduction of the complication rate
 Lower cost
The 2012 Surviving Sepsis Campaign guidelines recommend using
nutritional support without specific immunomodulating supplementation.11

32
 CHAPTER III

REFERENCES

1. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and

Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit
Care Med 2016; 193(3): 259-72.
2. Laxminarayan R, Matsoso P, Pant S, et al. Access to effective antimicrobials: a
worldwide challenge. Lancet 2016; 387(10014): 168-75.
3. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic
analysis. The Lancet Global health 2014; 2(6): e323-33.
4. International Bank for Reconstruction and Development / The World Bank.; 2016.
5. World Health Organization. WHO Report on the burden of endemic health care-
associated infection worldwide. 2017-11-21 15:11:22 2011.
6. http://apps.who.int/iris/bitstream/handle/10665/80135/9789241501507_eng.pdf?sequence
=1 (accessed February 11, 2019).
7. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus
Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315(8): 801-10.
8. Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. British
Medical Journal 2016.
9. United States Centers for Disease Control and Prevention. Healthcare Professional (HCP)
Resources : Sepsis. 2018-02-01T06:23:15Z.
10. https://www.cdc.gov/sepsis/get-ahead-of-sepsis/hcp-resources.html (accessed February
11, 2019).
11. Global Sepsis Alliance. Toolkits. https://www.world-sepsis-day.org/toolkits/ (accessed
April 10 2018).
12. UK SepsisTrust. Education. 2018. https://sepsistrust.org/education/ (accessed February
11, 2019).
13. Luangasanatip N, Hongsuwan M, Limmathurotsakul D, et al. Comparative efficacy of
interventions to promote hand hygiene in hospital: systematic review and network meta-
analysis. British Medical Journal. 2015;351:h3728.
14. UNICEF. UNICEF Data : Monitoring the Situation of Children and Women - Diarrhoeal
Disease. https://data.unicef.org/topic/child-health/diarrhoeal-disease/ (accessed February
11, 2019).
15. Pruss-Ustun A, Bartram J, Clasen T, et al. Burden of disease from inadequate water,
sanitation and hygiene in low- and middle-income settings: a retrospective analysis of
data from 145 countries. Tropical medicine & international health : TM & IH 2014;
19(8): 894-905.
16. World Health Organization. Fact sheet: Immunization coverage. 2018-04-10 14:55:37.
17. http://www.who.int/mediacentre/factsheets/fs378/en/ (accessed February 11, 2019).
18. Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al.
Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For
the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
JAMA. 2016 Feb 23. 315 (8):775-87.

33
19. Torio CM, Andrews RM. National inpatient hospital costs: the most expensive conditions
by payer, 2011. Statistical Brief #160. Healthcare Cost and Utilization Project (HCUP)
Statistical Briefs. August 2013. http://www.ncbi.nlm.nih.gov/books /NBK169005/.
Accessed October 31, 2015.
20. Iwashyna TJ, Cooke CR,Wunsch H, Kahn JM. Population burden of long-term
survivorship after severe sepsis in older Americans. J AmGeriatr Soc. 2012;60(6):1070-
1077.
21. Gaieski DF, Edwards JM, KallanMJ, Carr BG. Benchmarking the incidence and
mortality of severe sepsis in the United States. Crit Care Med. 2013;41(5):1167-1174.
22. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines
Committee Including the Pediatric Subgroup. Surviving Sepsis Campaign: international
guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med.
2013;41(2):580-637.
23. Rhee C, Gohil S, Klompas M. Regulatory mandates for sepsis care—reasons for caution.
N Engl J Med. 2014;370(18):1673-1676.
24. Vincent J-L, Marshall JC, Namendys-Silva SA, et al; ICONInvestigators. Assessment of
the worldwide burden of critical illness: the Intensive CareOver Nations (ICON) audit.
Lancet Respir Med. 2014;2(5):380-386.
25. Fleischmann C, Scherag A, Adhikari NK, et al; International Forum of Acute Care
Trialists. Assessment of global incidence and mortality of
26. hospital-treated sepsis: current estimates and limitations.AmJ Respir Crit Care Med.2015.
27. Iwashyna TJ, ElyEW, Smith DM, Langa KM. Long-term cognitive impairment and
functional disability among survivors of severe sepsis. JAMA. 2010;304(16):1787-1794.
28. Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of
Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure
and guidelines for the use of innovative therapies in sepsis. Crit Care Med.
1992;20(6):864-874.
29. Levy MM, FinkMP, Marshall JC, et al; International Sepsis Definitions Conference. 2001
SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive
Care Med. 2003; 29(4):530-538.
30. Vincent J-L, Opal SM, Marshall JC, Tracey KJ. Sepsis definitions: time for change.
Lancet.2013; 381(9868):774-775.
31. SeymourCW, Liu V, Iwashyna TJ, et al Assessment of clinical criteria for sepsis. JAMA.
doi: 10.1001/jama.2016.0288.
32. Shankar-HariM, Phillips G, LevyML, et al Assessment of definition and clinical criteria
for septic shock. JAMA.doi:10.1001/jama.2016.0289
33. Angus DC, van der Poll T. Severe sepsis and septic shock.N Engl J Med.
2013;369(9):840-851.
34. WiersingaWJ, Leopold SJ, Cranendonk DR, van der Poll T. Host innate immune
responses to sepsis. Virulence. 2014;5(1):36-44.
35. Hotchkiss RS, Monneret G, PayenD. Sepsis-induced immunosuppression: from cellular
dysfunctions to immunotherapy. Nat Rev Immunol. 2013;13(12):862-874.
36. Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity.
2014;40 (4):463-475.

34
37. Singer M, De Santis V, VitaleD, JeffcoateW. Multiorgan failure is an adaptive,
endocrine- mediated,metabolic response to overwhelming systemic inflammation.
Lancet. 2004;364(9433): 545-548.
38. Hotchkiss RS, Swanson PE, Freeman BD, et al. Apoptotic cell death in patientswith
sepsis, shock, and multiple organ dysfunction. Crit Care Med. 1999;27(7):1230-1251.
39. Kwan A, Hubank M, Rashid A, Klein N, Peters MJ. Transcriptional instability during
evolving sepsismay limit biomarker based risk stratification. PLoS One.
2013;8(3):e60501.
40. Iskander KN,OsuchowskiMF, Stearns-KurosawaDJ, et al. Sepsis: multiple abnormalities,
heterogeneous responses, and evolving understanding. Physiol Rev. 2013;93(3): 1247-
1288.
41. WongHR, Cvijanovich NZ, Anas N, et al. Developing a clinically feasible personalized
medicine approach to pediatric septic shock.AmJ Respir Crit Care Med.
2015;191(3):309-315.
42. Langley RJ, Tsalik EL, van Velkinburgh JC, et al. An integrated clinico-metabolomic
model improves prediction of death in sepsis. Sci Transl Med.2013;5 (195):195ra95.
43. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin
Invest. 2012;122(8):2711-2719.
44. Churpek MM, Zadravecz FJ,WinslowC, Howell MD, Edelson DP. Incidence and
prognostic value of the systemic inflammatory response syndrome and organ
dysfunctions inward patients.AmJ Respir Crit Care Med. 2015;192(8):958-964.
45. Kaukonen K-M, BaileyM, PilcherD, CooperDJ, Bellomo R. Systemic inflammatory
response syndrome criteria in defining severe sepsis.N Engl J Med. 2015;372(17):1629-
1638.
46. Vincent JL, Moreno R, Takala J, et al;Working Group on Sepsis-Related Problems of the
European Society of Intensive Care Medicine. The SOFA (Sepsis-relatedOrgan Failure
Assessment) score to describe organ dysfunction/failure. Intensive Care Med.
1996;22(7):707-710.
47. Vincent JL, de Mendonça A, Cantraine F, et al; Working Group on “Sepsis-Related
Problems” of the European Society of Intensive Care Medicine. Use of the SOFA score
to assess the incidence of organ dysfunction/failure in intensive care units: results of a
multicenter, prospective study. Crit Care Med. 1998;26(11):1793-1800.
48. Rubulotta FM, Ramsay G, Parker MM, Dellinger RP, Levy MM, PoezeM; Surviving
Sepsis Campaign Steering Committee; European Society of Intensive Care Medicine;
Society of Critical Care Medicine. An international survey: public awareness and
perception of sepsis. Crit Care Med. 2009;37(1): 167-170.
49. LeGallJ-R,KlarJ,LemeshowS,etal; ICU Scoring Group. The Logistic OrganDysfunction
system: a newway to assess organ dysfunction in the intensive care unit. JAMA.
1996;276(10):802-810.
50. Shah RU, Henry TD, Rutten-Ramos S, Garberich RF, TighiouartM, Bairey Merz CN.
Increasing percutaneous coronary interventions for ST-segment elevationmyocardial
infarction in the United States: progress and opportunity. JACC Cardiovasc Interv.
2015;8(1 pt B):139-146.
51. Kraut JA, Madias NE. Lactic acidosis.N Engl J Med. 2014;371(24):2309-2319.

35
52. Casserly B, Phillips GS, Schorr C, et al. Lactate measurements in sepsis-induced tissue
hypoperfusion: results from the Surviving Sepsis Campaign database. Crit Care Med.
2015;43(3):567- 573.
53. Cecconi M, De BackerD, Antonelli M, et al. Consensus on circulatory shock and
hemodynamic monitoring. Task Force of the European Society of Intensive Care
Medicine. Intensive Care Med.2014; 40(12):1795-1815.
54. Czura CJ. “Merinoff symposium 2010: sepsis”—speaking with one voice. Mol Med.
2011;17 (1-2):2-3.
55. Ait-Oufella H, Bige N, Boelle PY, et al. Capillary refill time exploration during septic
shock. Intensive Care Med. 2014;40(7):958-964.

36