Newsletter The Intensivist

Newsletter of

Intensive Care Chapter Indian Academy of Pediatrics

MY EM YO DE O AD C CA

My best wishes and greetings for the year 2011. I am indeed grateful to all the members of the Chapter for electing me chairperson for this year. I am very happy to acknowledge that due to continuous and unstinted efforts of my predecessors, senior colleagues and members, our Chapter has grown from strength to strength during the last 15 years and achieved membership strength of more than 900. We have already successfully established academic activities like Basic Certificate Course and Fellowship in Pediatric Intensive Care and our Academic Council has decided to start a 2 Year Diploma Course in Pediatric Intensive Care. The Basic Pediatric Intensive Care Course (BPICC) has already been conducted in many cities. The XII National Conference of our Chapter was organized at Surat (Gujarat) in October 2010 with resounding success. We hope to continue to organize various academic activities at state and zonal levels with greater vigor. Building further upon this solid foundation, I with the help of my Executive Team and support of members wish to carry out the following activities in the year 2011: 1) 2) 3) 4) 5) Redrafting the Constitution of the Chapter Start more state branches of the Chapter and increase membership. Publish membership Directory Prepare equipment manuals for guidance to our members Prepare guidelines to bring down cost of establishment and maintenance of PICU. 6) Work on measures to reduce patient care costs. 7) Explore the possibility of Public-Private partnership to help members to establish PICUs at district levels. 8) Start a residential course of 8-12 weeks duration for Nurses in Pediatric Intensive Care. I earnestly solicit along with Executive Committee your valuable suggestions to further strengthen our Chapter. With best wishes and greetings.

Intensive Care Chapter

The Intensivist
January, 2011 Editor Anil Sachdev Chairperson Nirmal Choraria Chairperson Elect Rajiv Uttam Secretary Anil Sachdev Treasurer Dhiren Gupta Executive Members Rashmi Kapoor Prabhat Maheshwari Prakritish Bora Preetha Joshi Ebor Jacob G John Jacob Immediate Past Chairperson Bala Ramchandran

Office Bearers

Contents

Message from Chairperson.............................. 01 Message from Secretary................................... 02

Review Article

Nirmal G. Choraria Chairperson Pediatric Intensive Care Chapter

Acute Respiratory Distress Syndrome Etiopathogenesis (Part 1) .................................. 3 Preload Assessment Static and Dynamic Indices ....................................................................... 7
Journal Scan

Journal Scan ......................................................... 14

Case Report

Anil Sachdev Dept. of Pediatrics, Centre for Child Health Sir Ganga Ram Hospital, Rajindra Nagar, New Delhi-60 Email: anilcriticare@hotmail.com Website: www.piccindia.org

Address for Correspondence

Hemophagocytic Lymphohistiocytosis: A Case Report ...................................................... 16 Pheochromocytoma: A Case Report and Review of Literature .............................................. 23
Technology Update

Jugular Venous Bulb Oxygen Saturation Monitoring ............................................................ 28

S C CS

T TH H

Dear Colleague,

DIAN IN A E

Message from Chairman Desk

DIATR PE I F

Message from the Desk of Secretary

Dear Colleagues, This is the first issue of The Intensivist of 2011 and as a tradition it is my pleasant duty to wish you all a Happy and Prosperous New Year from all the members of the newly constituted executive. The last year was full of academic activities. Some of which include workshops on mechanical ventilation at Chennai, hemodynamic monitoring at Delhi and Basic Pediatric Intensive Care Course at various places. The highlight of the past year was National Critical Care Conference in October at Surat. This was a well organized conference with excellent scientific content. So, my heartiest congratulation goes to Dr. Nirmal Choraria and team. Another achievement of our chapter in the last year was the formation of state branches in Delhi and Mumbai. In Delhi, two meetings were held since November and were very well attended and there was a lot of enthusiasm in the participants especially in the youngsters. It is a sincere request from the executive to all the members to form state branches and keep reporting to me about your activities. Our next national chapter meet is at the beautiful and Hi-Tec twin city of Hyderabad in November this year. All the members will receive participation invitation by email. You all must make an effort and block your dates to attend this annual academic feast. I have requested the organizing committee to keep subsidised conference registration fee for the chapter members. It has also been conveyed to the scientific committee to formulate two level programmes. One for the physicians (paediatricians, cardiologist, anaesthesiologist) who are interested or intended to start emergency and critical care services (Basic intensive care) and other part of the scientific program should include advanced critical care for those who are already practising this speciality. So this meet will provide learning material to all the critical care providers. We are expecting good number of international speakers and stalwarts to deliver lectures and share their experiences in this meet. So, I appeal to all the members of the chapters to attend this national meet. On my personal request, the last date for early bird registration has been extended to 31 March 2011. Hurry Up, Take Advantage and Get Registered Anil Sachdev Secretary IAP- Intensive Care Chapter

Intensive Care Chapter Indian Academy of Pediatrics 2011

Office Bearers

Nirmal Choraria
Chairman

Chairman Elect

Rajiv Uttam

Anil Sachdev Bala Ramachandran Dhiren Gupta

Secretary Past Chairman Treasurer

Prabhat Maheswari
Delhi

Preetha Joshi
Mumbai

Gauwhati Executive Members

Prakritish Bora

Rashmi Kapoor Ebor Jacob G James

Kanpur Vellore

Review Article

Acute Respiratory Distress Syndrome Etiopathogenesis (Part 1)

Veena Ragunathan Fellow, Pediatric Critical Care, Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi

Introduction
A distinct type of hypoxemic respiratory failure characterized by acute abnormality of both lungs was first recognized during the 1960s. Military clinicians working in surgical hospitals in Vietnam called it shock lung, while civilian clinicians referred to it as adult respiratory distress syndrome(1). Subsequent recognition that individuals of any age could be afflicted led to the current term, acute respiratory distress syndrome (ARDS).

Table I: Etiologies of Acute lung injury/Acute respiratory distress syndrome

Pulmonary causes Pneumonia Pulmonary aspiration Pulmonary contusion Fat embolism Submersion injury Inhalational injury Extra- pulmonary causes Sepsis Shock Burns Cardiopulmonary bypass Transfusion-related lung injury Severe trauma Leukoagglutin reactions Pancreatitis Crush injury, polytrauma Following upper airway obstruction Following bone marrow transplantation

Definitions
In 1994, the American-European Consensus Conference on ARDS defined both acute lung injury (ALI) and ARDS which is now universally accepted all over the world(2,3). ALI requires all four of the following features in patients who have a risk factor for ARDS and no history of chronic lung disease: Acute onset Bilateral infiltrates (radiographically similar to pulmonary edema) No evidence of elevated left atrial pressure (the pulmonary capillary wedge pressure is 18 mmHg if measured) A ratio of arterial oxygen tension to fraction of inspired oxygen (PaO 2/FiO2) of 201 to 300 mmHg (PaO 2 is measured in mmHg and the FiO2 is expressed as a decimal between 0.21 and 1.00) For ARDS PaO2/FiO2 is 200 mmHg. The amount of positive end-expiratory pressure (PEEP) is not considered when calculating the PaO 2/FiO 2. Usage of oxyhemoglobin saturation measured by pulse oximetry (SpO 2) is a reasonable substitute for PaO2 (measured by arterial blood gas), where ALI may be defined as ratio of SpO2/ FiO2 < 315 and ARDS as < 235 (sensitivity 91%, specificity 56%) (4).

The commonest causes include pneumonia (33-65%) and sepsis (13-40%). Numerous studies have found more severe reductions in lung compliance and less responsiveness to positive end-expiratory pressure (PEEP) when the ALI/ARDS was due to a pulmonary process than when it was due to an extrapulmonary precipitant, such as sepsis (5-8).

Pathogenesis of ALI/ARDS
Healthy lungs regulate the movement of fluid to maintain a small amount of interstitial fluid and dry alveoli. This is interrupted by lung injury, causing excess fluid in both the interstitium and alveoli. Consequences include impaired gas exchange, decreased compliance, and increased pulmonary arterial pressure. Normal lung function requires that dry, patent alveoli be closely situated to appropriately perfused capillaries. The normal pulmonary capillary endothelium is selectively permeable;fluid crosses the membranes under the control of hydrostatic and oncotic forces, while serum proteins remain intravascular. The balance between oncotic and hydrostatic forces normally allows small quantities of fluid into the interstitium but following three mechanisms prevent alveolar edema (9): Retained intravascular protein maintains an oncotic gradient favoring reabsorption The interstitial lymphatics can return large quantities of fluid to the circulation Tight junctions between alveolar epithelial cells prevent leakage into the air spaces 3

Initiating Factors
ALI/ARDS has traditionally been conceptualized as a pattern of lung injury and clinical manifestations that can be caused by a variety of insults. More than 60 possible causes of ALI/ARDS have been identified and other potential causes continue to emerge as adverse pulmonary reactions to new therapies are observed as shown in Table I.

Acute lung injury and ARDS are consequences of an alveolar injury producing diffuse alveolar damage (10). The injury causes release of pro-inflammatory cytokines such as tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8 (11-13). These cytokines recruit neutrophils to the lungs, where they become activated and release toxic mediators (eg, reactive oxygen species and proteases) that damage the capillary endothelium and alveolar epithelium (14,15). Damage to the capillary endothelium and alveolar epithelium allows protein to escape from the vascular space. The oncotic gradient that favors resorption of fluid is lost and fluid pours into the interstitium, overwhelming the lymphatics (16). The ability to upregulate alveolar fluid clearance may also be lost (17). The result is that the air spaces fill with bloody, proteinaceous edema fluid and debris from degenerating cells. In addition, functional surfactant is lost, resulting in alveolar collapse. Lung injury has numerous consequences including impairment of gas exchange, decreased lung compliance, and increased pulmonary arterial pressure. Impaired gas exchange in ALI/ARDS is primarily due to ventilation-perfusion mismatching. The physiologic shunting causes hypoxemia, while increased physiologic dead space impairs carbon dioxide elimination. Decreased pulmonary compliance is one of the hallmarks of ALI/ARDS. It is a consequence of the stiffness of poorly or non-aerated lung, rather than the pressure-volume characteristics of residual functioning lung units. Even small tidal volumes can exceed the lungs inspiratory capacity and cause a dramatic rise in airway pressures. (Figure 1 A is a normal lung and Figure 1B is ARDS showing altered hysteresis). Following lung injury surfactant production declines and surface activity of surfactant is also impaired. Loss of surfactant dramatically alters the mechanical properties of the lung. Higher transalveolar pressures are required to maintain lung patency. Hysteresis is the normal property of the lung which allows for the maintainence of lung volume at lower transpulmonary pressure during expiration than inspiration. This is as a result of the interaction of the elastic properties of the lung and surfactant (17).

Pulmonary hypertension (PH) occurs in up to 25 percent of patients with ALI/ARDS who undergo mechanical ventilation. Causes include hypoxic vasoconstriction, vascular compression by positive airway pressure, parenchymal destruction, airway collapse, hypercarbia, and pulmonary vasoconstrictors. The clinical importance of PH in most patients with ALI/ARDS is uncertain. Pwmonary hypertension severe enough to result cor pulmonale is rare, but it is associated with an increased risk of death.

Phases of the disease

ARDS is an evolving condition and its pathological features are typically described as passing through three overlapping phases which are as follows (Figure 2) (18): 1. Inflammatory or exudative phase, 2. Proliferative phase 3. Fibrotic phase Exudative phase: This initial phase lasts usually for a week after the onset of symptoms. It is characterized by diffuse alveolar damage leading to decreased pulmonary compliance and hypoxemia. This leads to development of tachypnea. Arterial blood gas analysis reveals hypocarbia at this stage. The chest x-ray usually reveals diffuse alveolar infiltrates from pulmonary edema. Histopathological changes include haemorrhagic interstitial and alveolar oedema with hyaline membranes. Microvascular and alveolar barriers have focal areas of damage and necrosis. Neutrophils are found increasingly during initial phase in the capillaries, interstitial tissue, and progressively within the airspaces. (Table 2) Proliferative phase: This phase occurs in the next 2 weeks after the onset of respiratory failure. The proliferative phase is characterised by organisation of the exudates and by fibrosis. There is increased alveolar dead space and refractory pulmonary hypertension may develop as a result of chronic inflammation and scarring of the alveolar-capillary unit. The lung architecture is distorted and capillary network is damaged. Later on, intimal proliferation begins along

Table 2: Summary of histopathological changes in ARDS

Exudative Macroscopic Heavy, rigid, dark Microscopic Hyaline membranes Edema Neutrophils Epithelial > endothelial damage Local thrombus Proliferative Heavy, grey Barrier disruption Edema Neutrophils Myofibroblast infiltration Fibroproliferation Loss of capillaries Pulmonary hypertension Fibrotic Cobblestoned Fibrosis Macrophages Lymphocytes Matrix organisation Deranged acinar architecture Patchy emphysematous change Myointimal thickening Tortous vessels

Vasculature

Figure 2: Schematic representation of the time course of the acute respiratory distress syndrome

lungs could then carry harmful substances from the lungs to other organs, damaging them leading to MODS.

Conclusion
Acute lung injury and ARDS are both defined by the acute onset of bilateral infiltrates consistent with pulmonary edema, but without evidence of elevated left atrial pressure. The severity of the hypoxemia distinguishes ARDS from ALI. Healthy lungs regulate the movement of fluid to maintain a small amount of interstitial fluid and dry alveoli. In patients with ALI or ARDS, this regulation is interrupted by lung injury, causing excess fluid in both the interstitium and alveoli. Consequences include impaired gas exchange, decreased compliance, and increased pulmonary arterial pressure.Patients with ARDS tend to progress through three relatively discrete pathologic stages: the exudative stage, proliferative stage, and fibrotic stage. More than 60 possible causes of ALI and ARDS have been identified and other potential causes continue to emerge as adverse pulmonary reactions to new therapies are observed. However, only a few common causes account for most cases of ALI or ARDS.

with Type 2 cell proliferation to cover denuded areas of epithelial basement membrane. Collagen fibrils appear and fibrosis occurs; mainly in intra-alveolar space, but it also occurs within the interstitium. Fibrotic stage: This is characterized by scarred lung tissue (cobblestone appearance) and is seen after 10 days of injury. Neutrophils are replaced by lymphocytes and macrophages. Established fibrosis reduces lung compliance thereby increasing the work of breathing, decreasing the tidal volume, and resulting in CO2 retention. Also, because of the alveolar obliteration and interstitial thickening, gas exchange is reduced which contributes to hypoxia and ventilator dependence. The progression can gradually give way to a recovery phase, with restoration of the alveolar epithelial barrier, gradual improvement in pulmonary compliance and resolution of arterial hypoxemia, and eventual return to premorbid pulmonary function in many patients with resolution of radiographic abnormalities (19). Multiorgan dysfunction: Although ARDS primarily affects the lungs, multiple organ dysfunction syndrome (MODS) is one of the most common immediate causes of ARDSrelated mortality. The systemic inflammatory response (SIRS) that accompanies ARDS and its underlying etiology may progress to MODS. The significant contributory factor is VILI. This causes the lungs to release toxic mediators, cytokines, and interleukin 8. Bloods passage through the 5

References
1. Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967; 2: 319-323 2. Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994; 149: 818-824. 3. Artigas A, Bernard GR, Carlet J, et al. The AmericanEuropean Consensus Conference on ARDS, part 2: Ventilatory, pharmacologic, supportive therapy, study design strategies, and issues related to recovery and remodeling. Acute respiratory distress syndrome. Am J Respir Crit Care Med. 1998; 157: 1332-1347. 4. Rice TW, Wheeler AP, Bernard GR, et al. for the National Institutes of Health, National Heart, Lung, and Blood Institute ARDS Network. Comparison of the SpO2/FiO2 ratio and the PaO2/FiO2 ratio in patients with acute lung

injury or ARDS.Chest. 2007; 132: 410-417. 5. Gattinoni L, Pelosi P, Suter PM, et al. Acute respiratory distress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med. 1998; 158: 3-11. 6. Lim CM, Jung H, Koh Y, et al Effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of the patient. Crit Care Med. 2003;31: 411-418. 7. Tugrul S, Akinci O, Ozcan PE, et al. Effects of sustained inflation and postinflation positive end-expiratory pressure in acute respiratory distress syndrome: focusing on pulmonary and extrapulmonary forms. Crit Care Med. 2003; 31: 738-744. 8. Rocco PR, Zin WA. Pulmonary and extrapulmonary acute respiratory distress syndrome: are they different? Curr Opin Crit Care. 2005; 11: 10-17. 9. Matthay, MA. Acute hypoxemic respiratory failure: Pulmonary edema and ARDS. In: George, RB, Light, RW, Matthay, MA, et al (Eds), 3rd ed, Chest Medicine. Essentials of Pulmonary and Critical Care Medicine, Williams & Wilkins, Baltimore, 1995, p. 593 10. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med. 2004; 141: 460-470. 11. Parsons PE, Eisner MD, Thompson BT, et al. NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med. 2005; 33: 1-6.

12. Chollet-Martin S, Gatecel C, Kermarrec N, et al. Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med. 1996; 153: 985-990. 13. Miller EJ, Cohen AB, Matthay MA. Increased interleukin-8 concentrations in the pulmonary edema fluid of patients with acute respiratory distress syndrome from sepsis. Crit Care Med. 1996; 24:1448-1454. 14. Piantadosi CA, Schwartz DA. The acute respiratory distress syndrome. Ann Intern Med. 2004; 141: 460-470. 15. Donnelly SC, MacGregor I, Zamani A, et al. Plasma elastase levels and the development of the adult respiratory distress syndrome.Am J Respir Crit Care Med. 1995;151: 1428-1433. 16. Calandrino FS Jr, Anderson DJ, Mintun MA, et al. Pulmonary vascular permeability during the adult respiratory distress syndrome: a positron emission tomographic study. Am Rev Respir Dis. 1988; 138: 421-428. 17. Ware LB, Matthay MA. Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am J Respir Crit Care Med. 2001; 163: 1376-1383. 18. Katzenstein AA, Askin FB. Surgical Pathology of Nonneoplastic Lung Disease. Saunders, Philadelphia, 1982. 19. G J Bellingan. The pulmonary physician in critical care 6: The pathogenesis of ALI/ARDS. Thorax 2002; 57: 540546

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Review Article

Preload Assessment Static and Dynamic Indices

Manjeet Singh Fellow, Pediatric Critical Care, Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi

Introduction
The identification of relative intravascular volume insufficiency in the hemodynamically unstable patient and the restoration of optimal intravascular volume remain among the core challenges in the ICU. In practice, the clinician is faced with the challenge of not only identifying intravascular volume deficiency but also restoring the volume of the intravascular space while avoiding over resuscitation. It becomes a very vital issue in the management of critically ill child especially with unstable hemodynamic status. The objective of this review article is to understand the physiology of the methods available for the assessment of preload and their clinical implications. Relationship between preload and stroke volume By the Frank-Starling mechanism, the normal heart automatically adjusts stroke volume (SV) for changes in ventricular end-diastolic volume load via the relationship between initial sarcomere length (preload) and force of contraction. Hence, myocardial preload clinically may be considered the end-diastolic volume of the right or left ventricle and, in turn, is a reflection of the relative intravascular volume of the patient. Unlike skeletal muscle however, the heart normally functions not at the maximal, or plateau portion of the cardiac function curve but rather on a roughly linear or ascending portion of the curve. Volume resuscitation will increase SV in the hypovolemic patient only while on the ascending portion of the cardiac function curve; fluid administered once the plateau is reached will contribute to tissue and pulmonary edema, right ventricular dysfunction, and increased intraabdominal pressure.

Table 1: Methods of preload assessment Static methods Central venous pressure (CVP) Pulmonary artery occlusion pressure (Ppao) Right ventricular end-diastolic volume (RVEDV)* Dynamic methods Systolic pressure variation (SPV) Pulse pressure variation (PPV)

Stroke volume variation SVV)

Global end-diastolic Left ventricle end-diastolic area volume (GEDV)* (LVEDA)* *By echocardiogrphically or thermodilution method

Central venous pressure and pulmonary artery occlusion pressure CVP is the simplest and most common invasive method of assessing ventricular preload. For the CVP measurement the right atrial pressure (RAP) is a surrogate for right ventricular end-diastolic pressure (RVEDP) and hence right ventricular preload (RVEDV). The CVP is determined by the interaction between venous return function and cardiac function. The return function is subsequently determined by the blood volume, viscosity, and venous tone. The cardiac function represents the classic Frank-Sterling curve which is dependent on the preload. So the left sided success depends on the right sided success (4). CVP is universally measured in ICUs for preload assessments in critically ill patients and is even incorporated into the formal resuscitative algorithms and guidelines such as the Surviving Sepsis Campaign (5). Although convenient and accessible given the wide use of central venous catheters, the measurement of CVP for assessing preload is complicated by several factors. These are - external reference landmark, effects of the respiratory cycle, effects of cardiac cycle, physiologic and anatomic properties of the heart. External reference landmark (Leveling) The stopcock of the transducer is leveled with a zero point which lies in the centre of right atrium. The zero point is the position in the circulatory system where the CVP varies a little if at all with the change in patient position (6). The classic position used is that of the phlebostatic axis, taken as the line where a coronal plane midway between the back and sternum (in practice, the 7

Assessment of cardiac preload

Techniques for the assessment of cardiac preload attempt to measure either directly or, more commonly, indirectlythe end-diastolic volume of the right or left ventricle or both in combination (Table 1) (1-3). Static Methods Static methods for determining preload, specifically pressure and volumetric indices are measured at the bedside.

midaxillary line) intersects a cross-sectional plane through the fourth intercostal space (7). In reality, changes in the angle of the patients position do have a small effect on CVP measurements because of changes in the position of the heart in the chest (and hence the CVP zero point) relative to the anatomic landmark used to set the transducers external reference point (8,9). It is highly important to check the zero point and levelling by the nursing stall at least once per shift or whenever patients position is changed. Effect of respiratory cycle The effects of the respiratory cycle must be considered when determining CVP (and Ppao). During spontaneous inspiration, the CVP falls as the pleural pressure declines relative to the external atmosphere white during positive pressure ventilation, CVP rises as pleural pressure increases with inspiration. Hence, a respiratory variation is seen in CVP and Ppao measurements (7). All measurements should be taken at the end expiration when pleural pressure relative to atmosphere is closest to zero. However, positive end-expiratory pressure (PEEP) (both intrinsic and extrinsic), active expiration, pericardial fluid or mediastinal edema, and increased intra-abdominal pressure (IAP) will alter pleural pressure in ways that are difficult to quantify so lead to erroneous CVP and Ppao readings (10). Effect of PEEP In practice, when considering PEEP, some comfort may be taken from the fact that approximately half of the airway pressure in normal lungs is transmitted to the pleural space; in diseased lungs (stiffer, less compliant lungs) less than half is transmitted. Thus, in diseased lungs, especially when ventilating with low lung volumes and low levels of PEEP, the increase in end expiratory CVP (and in the approximation of transmural pressure) is likely to be small, less than 4 to 5 cm water at a total PEEP of 10 cm H2O (6,11). Higher PEEP levels will have a greater effect but, even then, the magnitude will depend on the percentage of pressure transmission. A similar effect is seen with IAP, in which investigators have demonstrated the transmission of IAP to the chest and quantified its effects on end-expiratory measurements of CVP and even intracranial pressure (12). Effects of cardiac cycle The CVP should be measured just at the onset of the c-wave (the base of the c- wave) which represents the final atrial pressure (and the ventricular end-diastolic pressure) before the closure of the tricuspid valve and the beginning of ventricular systole. As the c-wave is not always visible, the base of the a-wave may be used instead. Alternatively, the R-wave of the EKG on the monitor may be used to find the end of diastole or beginning of systole on the CVP tracing (13). 8

Physiologic and anatomic properties of heart Physiologic and anatomic properties of the heart affect the CVP. Changes in right ventricular compliance (such as from heart failure) and venous tone (eg, hyperadrenergic states), or conditions such as pulmonary hypertension, may have profound effects on CVP independent of the patients intravascular volume status. Additionally, valvular disorders, such as tricuspid insufficiency, ventricularize the CVP waveform, resulting in an elevated mean CVP. Similarly, tricuspid stenosis elevates the mean CVP, resulting in a gradient between the RAP and the RVEDP (13). Loss of y and x descents indicate cardiac temponade while presence of y descent more than 4 mm suggest fluid responsiveness (14).

Clinical Usefulness of CVP and Ppao

In a prospective observational study in post operative cardiac patients, Magder and Bafaqeeh (15) investigated fluid responsiveness over a range of CVP values in an attempt to identify a threshold CVP above which volume expansion was unlikely to increase (CO). Using fluid challenges that increased CVP by at least 2 mm Hg a response was defined as an increase in (CO) of 300 mL/ min/m2 or more. Of the 66 patients in whom CVP increased by at least 2 mm Hg with fluid challenges, there were 40 responders and 26 non responders. They concluded that no patient responded when the CVP was greater than 13 mm Hg and only 3 of the 12 patients with an initial CVP greater than 10 mm Hg responded to fluids on their first trial. Non responders, however, were identified at all initial CVP levels. Hence, CVP is best viewed as a negative predictor of fluid responsiveness. Similarly, Jellinek et al (16) showed that, in response to increasing PEEP challenges, a CVP less than 10 mm Hg predicted a decrease in CO. However, the response in patients with a CVP greater than 10 mm Hg was unpredictable: increases, decreases, and no changes in CO were observed. Thus, CVP as a predictor of CO change in response to PEEP challenge functioned as a one-way test (17).

Volumetric measurements
Multiple investigators have assessed RVEDV and its index RVEDVI as measures of preload and predictors of fluid responsiveness. GEDV and GEDV index (GEDVI), and the closely related intrathoracic blood volume and index (ITBV and ITBVI), are another set of volumetric estimates of cardiac preload. Overall, the use of transpulmonary thermodilution-derived indices such as GEDVI and ITBVI appear to correlate better with preload and changes in CO or SVI than traditional pressure measurements. Even so, the correlations are generally moderate. Whether this imperfect correlation is due to rapid changes in cardiovascular physiology during illness or is due to flaws in the assumptions underlying thermodilution derived volumetric measurements requires further study (2).

Dynamic Methods
In many patients, a rapid fluid bolus is a reasonable diagnostic and potentially therapeutic option, but in others (eg, acute respiratory distress syndrome [ARDS]), it has the potential to cause harm, and may delay institution of appropriate therapy. In contrast to static measures, dynamic indices rely on the changing physiology of heart lung interactions to determine whether a patient will benefit from increased preload. Physiologic Rationale Preload of the heart is defined as the wall stress at the end of diastole (18). Since direct measurement of wall stress is not possible, end diastolic volumes or pressures have been used but with significant limitations. An understanding of the Frank-Starling curve is fundamental to understanding the concept of preload responsiveness. The slope of the relationship between ventricular preload and SV depends on ventricular contractility. As contractility increases, the Starling curve shifts upwards and to the left and increases its slope. Decreasing contractility has the opposite effect. The increase in preload serves to augment ventricular output predominantly on the steep portion of the curve while on the flat portion of the curve it produces minimal increases in SV. As a ventricle fails, its contractility and therefore the slope of its FrankStarling curve decreases, and a preload that would indicate volume responsiveness in the normal heart may not apply to a failing heart. Additionally, the relationship between preload and SV is curvilinear rather than linear. Dynamic indices apply a controlled and reversible preload variation and measure the hemodynamic response. This can be done by observing the cardiovascular response to positive pressure ventilation, or to reversible preload-increasing maneuvers, such as passive leg raising. Cavallaro et al (19) have proposed a useful classification of dynamic indices. . Group A consists of indices based on cyclic variation in SV or SV-related hemodynamic parameters determined by mechanical ventilation induced cyclic variation in intrathoracic pressure, and includes Stroke volume varialion (SVV) pulse pressure variation (PPV) Systolic Pressure Variation (SPV), and aortic blood flow. Group B is made up of indices based on cyclic variations of non-stroke volume-related hemodynamic parameters determined by mechanical ventilation, and includes vena cava diameter or ventricular pre-ejection period. Group C consists of indices based on preload redistribution maneuvers; mechanical ventilation is not required, and it includes passive leg raising and Valsalva maneuvers (19). Group A and B techniques are based on the physiologic interaction of the heart and lungs within a closed thoracic cavity, and rely on the phasic changes in SV created by changing intrathoracic pressure due to positive pressure mechanical ventilation. During positive pressure inspiration, preload to the right heart is decreased 9

because of increased intrathoracic pressure, both from compression of the vena cava (decreased venous return) and increased (RAP). This decrease in right ventricular (RV) preload leads to a decrease in RV output, which subsequently leads to a decrease in pulmonary artery blood flow, Left Ventaicte filling, and LV output in the next few beats. However the transient and immediate effect of positive pressure ventilation on LV is increase in preload due to squeezing effect on pulmonary veins and increase in blood volume return to left atrium. This leads to increase in the size of left atrium and ventricle and LV SV. Other suggested mechanism for increase in LV SV in reduction in LV afterload due to decrease in transmural aortic pressure. The end result of these pressure changes is that LV SV increases, while RV SV decreases during positive pressure inspiration (20, 21). These phasic changes RV and LV SV are exaggerated in the setting of hypovolemia (20). In summary the mechanical breath induces the cyclic changes in the output of right and left ventricles which include early increase in the LV SV and decrease in the RV SV. In the expiratory phase, LV output decreases and RV output increases. Stroke Volume Variation SVV examines the difference between SV during the inspiratory and expiratory phases of ventilation, and requires a means to directly or indirectly assess SV. This eliminates arterial compliance as a variable, but until recently, has required invasive monitoring such as aortic flow probes. Now, the PiCCO (Pulsion Medical Systems, Munich, Germany), LiDCO (LiDCO Group PLC, London, England) and FloTrac sensor (Edwards Lifesciences, Irvine, CA, USA) monitors uses pulse contour analysis through a proprietary formula to measure CO and SVV. This has Figure 1: Frank-Starling curves demonstrating relationship between change in preload to change in SV in a normal and failing ventricles. A given change in preload may cause variable changes in SV, depending on the slope of the curve

not been consistently reproducible, however, and other studies find poor predictive value (22, 23). Systolic Pressure Variation SPV is the difference between the maximum and the minimum systolic pressure over a single respiratory cycle and can be expressed in mmHg (SPmax SPmin) or as a percent (SPV (%)= 100 (SPmax SPmin)/ [(SPmax + SPmin)/2]). Increased SPV was the first of these indices to be recognized to correlate with hypovolemia and was later shown to have a sensitivity of 82%, specificity of 86%, and area under the receiver operator characteristic curve of 0.92, using a threshold of 8.5 mm Hg (24,25). SPV can be broken down into delta up (dUp) and delta down (dDown). dUp = SPmax SPref dDown = SPref SPmin Where SPmax is the maximum systolic pressure in a single respiratory cycle; SPref is the reference systolic pressure at prolonged endexpiration pause or short apnoea (5 seconds), and SPmin is the minimum systolic pressure measured in a single respiratory cycle. Increased dUp is not a reliable indicator of fluid responsiveness. Indeed, in animal models, dUp is increased in congestive heart failure and with increasing volume resuscitation in the presence of cardiac ischemic dysfunction (26,27). dDown reflects the expiratory decrease in LV SV related to the inspiratory decrease in RV SV (20). Pulse pressure variation Arterial pulse pressure is the difference between arterial systolic and diastolic pressure. This difference is influenced by SV and the arterial compliance. Comparison of the pulse pressure during inspiration with pulse pressure during expiration demonstrates the degree to which the pulse pressure is preload-limited. Analysis of the PPV thus can be used to predict volume responsiveness, and is expressed as a percentage. PPV (%) =100 (PPmax PPmin)/ [(PPmax + PPmin)/2]. Several studies have demonstrated the utility of increased PPV as a predictor of fluid responsiveness. Michard et al (28) found that in mechanically ventilated patients with septic shock, a PPV of 13% identified patients who had a greater than or equal to 15% increase in CO in response to Figure 2: The normal arterial waveform changes during mechanical ventilation depicting delta Up and delta Down.

volume expansion with 500 mL of 6% hydroxyethylstarch, with a sensitivity of 94% and specificity of 96%. Plethmysography Examining amplitude variation between inspiration and expiration phases has been extended to the plethysmographic waveform. Although this technique has several similarities to arterial pulse pressure variation, there are several important differences. Variation in the plethysmographic waveform has been referred to by many names: change in pulse oximetry plethysmography (dPOP), ventilation-induced plethysmographic variation (VPV), and DPPLET. Cannesson et al (29) did not demonstrate volume responsiveness, but only that VPV of greater than or equal to 15% was predictive of having PPV greater than or equal to 13%, the threshold value for volume responsiveness sited in many studies. Although the obvious and tantalizing advantage to the use of the pulse oximeter to determine fluid responsiveness is the complete noninvasiveness of the technique, at this time, evidence does not support reliance on this method. Respiratory variability of the superior and inferior vena cava Using different indices as reference standards, three groups tested the hypothesis that changes in the diameter of the IVC and the SVC with PPV are predictive of fluid responsiveness, and independently concluded that respiratory variations in IVC and SVC diameter during mechanical ventilation could be used to determine preload responsiveness in sedated, mechanically ventilated patients (30-33). Barbier and colleagues determined that the distensibility index of the IVC (dIVC), defined as (Dmax Dmin)/Dmin and expressed as a percentage, was predictive of fluid responsiveness with a sensitivity of 90% and a specificity of 90% (30). Phasic variation of SVC diameter may be more accurate, as it is not influenced by intra-abdominal pressure. However, it necessitates a transesophageal, rather than transthoracic, approach. Further validation of these concepts in large, multicenter trials is warranted. Passive Leg Raising Passive leg raising (PLR) is a form of reversible volume challenge that can be used to evaluate which patients will benefit from intravenous fluid and increased preload. Elevating a patients legs allows a passive transfer of blood from the lower part of the body toward the central circulation. The amount of blood transferred from the legs is variable and has been estimated to be between 150 to 750 mL depending on technique and study (34-37). If the heart is preload-responsive, the shift of fluid from the lower part of the body to the thorax should result in increased CO. This requires that both the right and left 10

ventricles be preload-dependent. Several studies have determined that PLR is effective in determining which patients are preload-responsive (34,38,42). Importantly, PLR can be used in spontaneously breathing patients and in patients not in sinus rhythm. The increase in preload from the maneuver is reversed completely when the legs are returned to horizontal, meaning it is safe even in cases in which increasing blood volume may be harmful, such as ARDS (34,41,42). International consensus guidelines now recommend PLR to evaluate fluid responsiveness in patients with shock (43). In the largest study to date, Thiel and colleagues measured SV changes with PLR in 89 medical ICU patients determined to need volume expansion by their attending clinician. Using a transthoracic Doppler device (USCOM Limited, Sydney, Australia), they determined that a greater than or equal to 15% increase in SV with PLR predicted volume responsiveness with sensitivity and specificity of 81% and 93%, respectively (39). Limitations of Dynamic Indices There are several important caveats to keep in mind when using these dynamic indices to predict fluid responsiveness. Positive pressure, controlled ventilation is required to obtain meaningful values for any of the Cavallaro group A or B indices. Spontaneous respiratory efforts, even when supported by the ventilator, alter the mechanics such that these numbers lose their reliability. Sinus rhythm is required. Many of these techniques require invasive arterial blood pressure monitoring. A single value should never replace clinical judgment. Further investigation of these techniques in the setting of vasoactive medications is needed. How extremes of ventilation settings (ie, low tidal volume, high respiratory rate, high positive end-expiratory pressure ) affect group A and B indices is not yet clear. Further investigation of these indicators in the setting of the open abdomen or open thorax is needed before their use should be relied upon in these populations. Respiratory Systolic Variation Test The respiratory systolic pressure variation (RSVT) is a technique whereby three or four consecutive pressurecontrolled breaths of increasing peak inspiratory pressures are administered over a brief period of time to intubated, sedated patients. The minimum systolic blood pressure (SBP) value following each of these breaths is recorded, and the results plotted against their respective airway pressures. A steeper slope (ie, larger decrease in SBP with increasing tidal volume) implies that the patient will be fluid-responsive, whereas less of a slope implies the patients ventricles are on the flat part of the FrankStarling curve, and the patient will not increase cardiac output with fluid loading (44). A complex respiratory maneuver is required, combined with complicated off-line 11

measurements and calculations, making it unsuitable for routine clinical practice. EndExpiratory Occlusion Pressure Monnet et al (45) hypothesized that an endexpiratory occlusion may abolish the inspiratory increase in intrathoracic pressure, prevent the cyclic drop in cardiac preload, and allow an increase in venous return, thus acting like a fluid challenge. They used this physiological concept in 34 patients of shock and found promising results.This appears to be a new and novel test for volume responsiveness with several advantages. It is simple to perform, and can be used in patients with arrhythmias and those with some spontaneous respiratory effort. As yet, it only has been demonstrated in one small study, and needs further validation, but it does offer promise as a useful clinical tool. To summarize, the dynamic indices repeatedly have been shown to be superior to static measures for determining preload responsiveness in critically ill patients. The number of options for assessing fluid responsiveness available to the clinician are increasing; however, few have been evaluated in large, multicenter trials. Currently there are no data on whether managing patients using dynamic indices affects outcomes. It is important to remember that preload responsiveness does not equate to needing more preload. Healthy individuals are preload-responsive, and will increase their cardiac output in response to a fluid challenge, but they do not require increased blood volume. Therefore even with accurate measures of preload responsiveness, clinical judgment remains essential.

References
1. Scheuren K, Wente MN, Hainer C, et al. Left ventricular end-diastolic area is a measure of cardiac preload in patients with early septic shock. Eur J Anaesthesiol 2009; 26(9):759765. 2. Benington S, Ferris P, Nirmalan M. Emerging trends in minimally invasive haemodynamic monitoring and optimization of fluid therapy. Eur J Anaesthesiol 2009; 26(11):893905. 3. Magder S. Clinical usefulness of respiratory variations in arterial pressure. Am J Respir Crit Care Med 2004; 169:151155. 4. Magder S. More respect for the CVP. Intensive Care Med 1998; 24:651653. 5. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008 [published correction appears in Crit Care Med 2008; 36:139496]. Crit Care Med 2008; 36: 296327. 6. Magder S. Central venous pressure monitoring. Curr Opin Crit Care 2006; 12: 219227. 7. Marino PL. The ICU book. 3rd edition. Philadelphia: Lippincott Williams & Wilkins; 007. p. 181, 183.

8. McGee SR. Physical examination of venous pressure: a critical review. Am Heart 1998; 136(1):1018. 9. Haywood GA, Joy MD, Camm AJ. Influence of posture and reference point on entral venous pressure measurement. BMJ 1991; 303:626627. 10. Magder S. How to use central venous pressure measurements. Curr Opin Crit are 2005; 11:264270. 11. Magder S. Central venous pressure: a useful but not so simple measurement. Crit Care Med 2006; 34(8):22242227. 12. Malbrain ML, Wilmer A. The polycompartment syndrome: towards an understanding of he interactions between different compartments. Intensive Care ed 2007; 33:18691872. 13. Mark JB. Getting the most from a CVP catheter. In: 52nd Annual Refresher Course Lectures, Clinical updates and basic science reviews of the American Society of Anesthesiologists 2001; 231:17. 14. Magder S, Erice F, Lagonidis D. Determinants of the y descent and its usefulness as a predictor of ventricular filling. J Intensive Care Med 2000; 15:262269. 15. Magder S, Bafaqeeh F. The clinical role of central venous pressure measurements. J Intensive Care Med 2007; 22(1):4451. 16. Jellinek H, Krafft P, Fitzgerald RD, et al. Right atrial pressure predicts hemodynamic response to apneic positive airway pressure. Crit Care Med 2000; 28(3): 672678. 17. Pinsky MR. Hemodynamic monitoring in the intensive care unit. Clin Chest Med 2003; 24:549560. 18. Libby P, Bonow RO, Mann DL, et al. Braunwalds heart disease: a textbook of cardiovascular medicine. 8th edition. Philadelphia (PA): Saunders, Elsevier; 2008. 19. Cavallaro F, Sandroni C, Antonelli M. Functional hemodynamic monitoring and dynamic indices of fluid responsiveness. Minerva Anestesiol 2008; 74:123135. 20. Michard F. Changes in arterial pressure during mechanical ventilation. Anesthesiology 2005;103: 419428. 21. Bendjelid K, Romand JA. Fluid responsiveness in mechanically ventilated patients: a review of indices used in intensive care. Intensive Care Med 2003; 29:352360. 22. Wiesenak C, Prasser C, Rodig G, et al. Stroke volume variation as an indicator of fluid responsiveness using pulse contour analysis in mechanically ventilated patients. Anesth Analg 2003;96: 12541257. 23. Pinsky MR. Probing the limits of arterial pulse contour analysis to predict preload responsiveness. Anesth Analg 2003; 96:12451247. 24. Rick JJ, Burke SS. Respiratory paradox. South Med J 1978; 71:13761378. 25. Preisman S, Kogan S, Berkenstadt H, et al. Predicting fluid responsiveness in patients undergoing cardiac surgery: functional hemodynamic parameters including the Respiratory Systolic Variation Test and static preload indicators. Br J Anaesth 2005; 95:746 12

755. 26. Pizov R, Yaari Y, Perel A. The arterial pressure waveform during acute ventricular failure and synchronized external chest compression. Anesth Analg 1989; 68: 150156. 27. Preisman S, DiSegni E, Vered Z, et al. Left ventricular preload and function during graded hemorrhage and retransfusion in pigs: analysis of arterial pressure waveform and correlation with echocardiography. Br J Anaesth 2002;88:716718. 28. Michard F, Boussat S, Chemla D, et al. Relation between respiratory changes in arterial pulse pressure and fluid responsiveness in septic patients with acute circulatory failure. Am J Respir Crit Care Med 2000;162:134138. 29. Cannesson M, Besnard C, Durand PG, et al. Relation between respiratory variation in pulse oximetry plethysmographic waveform amplitude and arterial pulse pressure in ventilated patients. Crit Care 2005;9:R56268. 30. Barbier C, Loubieres Y, Schmit C, et al. Respiratory changes in inferior vena cave diameter are helpful in predicting fluid responsiveness in ventilated septic patients. Intensive Care Med 2004;30:17401746. 31. Feissel M, Michard F, Faller JP, et al. The respiratory variation in inferior vena cava diameter as a guide to fluid therapy. Intensive Care Med 2004; 30:18341837. 32. Feihl F, Broccard AF. Interactions between respiration and systemic hemodynamics. Part I: basic concepts. Intensive Care Med 2009; 35(1):4554. 33. Barbier C, Loubieres Y, Jardin F, et al. Authors reply to the comment by Dr. Bendjelid. Intensive Care Med 2004; 30:1848. 34. Monnet X, Rienzo M, Osman D, et al. Passive leg raising predicts fluid response in the critically ill. Crit Care Med 2006; 34(5):14021407. 35. Rutlen DL, Wackers F, Zaret B. Radionuclide assessment of peripheral intravascular capacity: a technique to measure intravascular volume changes in the capacitance circulation in man. Circulation 1991;64(1):146- 152. 36. Gaffney F, Bastian B, Thai E, et al. Passive leg raising does not produce a significant or sustained autotransfusion effect. J Trauma 1982; 22: 190-193. 37. Jabot J, Teboul JL, Richard C, et al. Passive leg raising for predicting fluid responsiveness: importance of the postural change. Intensive Care Med 2009; 35:8590. 38. Lafanechere A, Pene F, Goulenok C, et al. Changes in aortic blood flow induced by passive leg raising predict fluid responsiveness in critically ill patients. Crit Care 2006; 10:R132. 39. Thiel S, Kollef M, Isakow W. Noninvasive stroke volume measurement and passive leg raising predict volume responsiveness in medical ICU patients: an observational cohort study. Crit Care 2009; 13:R111. 40. Maizel J, Airapetian N, Lorne E, et al. Diagnosis of central hypovolemia by using passive leg raising. Intensive Care Med 2007; 33:11331138.

41. Monnet X, Teboul JL. Passive leg raising. Intensive Care Med 2008; 34:659663. 42. Boulain T, Achard J, Teboul J, et al. Changes in BP induced by passive leg raising predict response to fluid loading in critically ill patients. Chest 2002;121:1245 1252. 43. Antonelli M, Azoulay E, Bonten M, et al. Year in Review in Intensive Care Medicine, 2007. III. Ethics and legislation, health services, research, pharmacology and toxicology, nutrition and paediatrics. Intensive

Care Med 2008; 34: 598609. 44. Perel A, Minkovich L, Preisman S, et al. Assessing fluid responsiveness by a standardized ventilatory maneuver: the respiratory systolic variation test. Anesth Analg 2005;100:942945. 45. Monnet X, Osman D, Ridel C, et al. Predicting volume responsiveness by using the end-expiratory occlusion in mechanically ventilated intensive care unit patients. Crit Care Med 2009;37:951956.

13

Journal Scan

Journal Scan

Nitin Gupta Fellow Critical Care, Department of Pediatrics, Centre for Child Health, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi

Relationship between hypoglycaemia and mortality in critically ill children

Faustino EVS, Bogue CW. Pediatr Crit Care Med 2010; 11: 690-698. Objectives: To determine the prevalence of hypoglycemia in critically ill nondiabetic children and the association of hypoglycaemia with mortality and worsening organ function in critically ill children. Design: Retrospective cohort study with matched-cohort analysis. Setting: Academic pediatric intensive care unit (PICU). Patients: A total of 899 nondiabetic patients <18 yrs old admitted to the PICU for >1 day with at least one blood glucose measurement. Forty-two patients with a blood glucose level of <50 mg/dL (<2.8 mmol/L) were matched with 126 nonhypoglycemic patients. Interventions: None. Measurements and Main Results: Hypoglycemia, based on point-of-care blood glucose measurements, occurred in 2.2% (<40 mg/dL [<2.2 mmol/L]) to 7.5% (<60 mg/dL [<3.3 mmol/L]) of the patients. Hypoglycemia was more common in patients on mechanical ventilation and/or vasopressor support. Severity of hypoglycaemia correlated with an increased mortality rate. The highest odds ratio of mortality was 4.49 (95% confidence interval [CI], 1.69 11.96; p < .01) at a blood glucose level of <40 mg/dL (<2.2 mmol/L). In the matched analysis, hypoglycemia was an independent risk factor for mortality. The unadjusted, covariate-adjusted, and propensity score adjusted odds ratios of mortality were 3.69 (95% CI, 1.78 7.68; p < .01), 4.16 (95% CI, 1.5311.32; p < .01), and 8.45 (95% CI, 1.75 40.86; p < .01), respectively. Hypoglycemia was associated with worsening organ function in the covariate-adjusted model (odds ratio, 2.37; 95% CI, 1.125.01; p = .02) but not in the unadjusted and propensity-score adjusted models. Conclusions: Hypoglycemia is common in critically ill children. It is associated with increased mortality rates in critically ill nondiabetic children. Our data suggest that hypoglycemia is also associated with worsening organ function. Hypoglycemia may merely be a marker of severity of illness. Further investigations are needed to establish the mortality risk with hypoglycemia due to insulin compared to spontaneous hypoglycemia. 14

Predictive factors for the outcome of noninvasive ventilation in pediatric acute respiratory failure
Munoz-Bonet JI, Flor-Macian EM, Brines J, et al. Pediatr Crit Care Med; 2011: 11: 675- 680. Objectives: To identify success and failure prognostic signs of noninvasive ventilation in pediatric acute respiratory failure. Noninvasive ventilation constitutes an alternative treatment for pediatric acute respiratory failure. However, tracheal intubation should not be delayed when considered necessary. Design: Prospective, noncontrolled, clinical study. Setting: Pediatric intensive care unit in a university hospital. Patients: Children (age range, 1 month--16 yrs) with moderate-to-severe acute respiratory failure who received noninvasive ventilation during a 4-year period. Failure was defined as the need for tracheal intubation. Interventions: None. Measurements and Main Results: Nine (19.1%) of 47 patients needed tracheal intubation between the third and 87th hour after the start of treatment (33.6 _ 29.6 hrs). Failure was associated with the younger age group (4 3.3 yrs vs. 7.7 5 yrs, p < .04), acute respiratory distress syndrome (failure/acute respiratory distress syndrome: 5 of 10 vs. failure/non acute respiratory distress syndrome: 4 of 37, p=.013), and worsening radiographic images taken at 24 hrs and/or 4872 hrs (p =.001 and p < .001, respectively). A significant reduction in heart rate was observed between the second and fourth hour after starting noninvasive ventilation (130 25.8 bpm vs. 116 27.7 bpm, p < .001) and PCO2 (54.119.5 torr vs. 48.614.3 torr; 7.212.6 vs. 6.481.91 kPa, p < .007) in the success group. The failure group had a higher rate of breathing assistance, both initial and maximal. In the multivariant analysis, only maximum mean airway pressure and FIO2 formed part of the success/ failure discriminant function with a cutoff point of 11.5 and 0.57, respectively. Conclusions: Modifications in a patients respiratory assistance were made depending on the clinical, blood gas, and radiologic evolution of the patient. Mean airway pressure and FIO2 values of >11.5 and 0.6, respectively, predict failure and possibly set the limit above the patients risk of delayed intubation increases.

Outcomes of etomidate in severe sepsis and septic shock

Dayton Dmello D, Taylor S, OBrien J, et al. Chest 2010; 138; 1327-1332. Objective. The use of single-dose etomidate to facilitate intubation in critically ill patients has recently been debated given its suppression of steroidogenesis with possible resultant adverse outcomes. The objective of the study was to assess the effects of single-dose etomidate used during rapid-sequence intubation (RSI) on various measures of outcome, such as mortality, vasopressor use, corticosteroid use, ICU length of stay (ICU-LOS), and number of ventilator days. Design: Retrospective study Setting: Multidisciplinary ICU of an academic tertiary care institution Methods: This 18-months cohort study included consecutive patients with severe sepsis or septic shock who were intubated and mechanically ventilated were identified and grouped as having received single-dose etomidate during intubation or not. Hospital mortality, ICU length of stay, number of ventilator days, corticosteroid use, vasopressor use, and demographic and clinical variables were recorded. Main Results Two hundred twenty-four patients were identified; 113 had received etomidate. The mean Acute Physiology and Chronic Health Evaluation II scores in the etomidate and nonetomidate groups were 21.3 8.1 and 21.9 8.3, respectively (P = .62). The relative risks for mortality and vasopressor use were 0.92 (CI, 0.74-1.14; P = 0.51) and 1.16 (CI, 0.9-1.51; P = .31), respectively, in the etomidate group. There were no significant differences in ICU-LOS (mean, 14 vs 12 days; P = .31) or number of ventilator days (mean, 11 vs 8 days; P = .13) between the etomidate and nonetomidate groups, respectively. The relative risk for corticosteroid use in the etomidate group was 1.34 (CI, 1.11-1.61; P = .003). Multivariate analysis using logistic regression demonstrated no significant association of etomidate with mortality (OR, 0.9; CI, 0.45-1.83; P = .78). Conclusion Single-dose etomidate used during RSI in critically ill patients with severe sepsis and septic shock was not associated with increased mortality, vasopressor use, ICU-LOS, or number of ventilator days. Patients intubated with etomidate had an increased incidence of subsequent corticosteroid use, with no difference in outcomes.

Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS

Sheu CC, Gong MN, Zhai R, et al. Chest 2010; 138: 559-567 Backgound: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsisrelated and non-sepsis-related ARDS. Design: Prospective study Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. Main Results Compared with patients with non-sepsis-related ARDS (n = 62), patients with sepsis-related ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P < .0001). There were no differences in lung injury score, blood pH, PaO2/FIO2 ratio, and PaCO2 on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower PaO2/FIO2 ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P = .018), day 7 (P = .004), and day 14 (P = .004) (repeatedmeasures analysis, P = .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P = .016), a lower successful extubation rate (53.6% vs 72.6%; P = .005), and fewer ICU-free days (P = .0001) and ventilator-free days (P = .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than nonsepsis-related ARDS. Worse clinical outcomes in sepsisrelated ARDS appear to be driven by disease severity and comorbidities.

15

Case Report

Hemophagocytic Lymphohistiocytosis: A Case Report

Sanjeev Arora Fellow Critical Care, Pediatric Critical Care, Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi 110060

Case report
8 months old, apparently healthy female child, resident of Gwalior (Madhya Pradesh) was admitted in PICU with history of maculopapular rash initially on trunk which spread all over the body including palms and soles in the next. On third day of rash, child developed high grade fever without chills and rigors, decreased appetite and progressive irritability over next 3 days. Initially she received treatment in the form of antibiotics and antipyretics as out-patient. In view of persistence of symptoms, she was admitted where on the investigations revealed hyperbilirubinemia, and leucocytosis. Child was started with intravenous fluid and ceftrixone. In view of worsening clinical condition and laboratory reports she was referred to our institution. On admission, child was irritable with GCS of 14/15, heart rate of 160/min, respiratory rate of 42/min, blood pressure 75/55 mmHg, capillary fill time > 5 sec with bounding pulsations, core and periphery temperature difference >5 C, oxygen saturation of 94% in room air. She had pallor, icterus, pedal edema, and diffuse maculopapular rashes on extremities, face, including palms and soles. She had hepatomegaly of 5 cm below right costal margin but no splenomegaly and lymphadenopathy. At the time of admission, investigations showed leukoc ytosis with lymphoc ytic predominance, coagulopathy with raised transaminases. (Table 1) Renal functions were normal. Chest x-ray showed right sided pleural effusion while echocardiography was normal. . Patient was given oxygen by head box, intravenous fluid boluses and vasopressors support with norepinephrine and parentral broad spectrum antibiotics. Her peripheral blood smear was negative for malaria and serology tests for malaria, Dengue fever, and widal test were negative. Blood and urine cultures sent prior to starting antibiotics were sterile and cerebrospinal fluid examination was not suggestive of intracranial infection. Ferritin and LDH levels were very high, MP smear was negative, ECHO was normal. Over next 2 days, childs condition deteriorated further. Her sensorium worsened (Bispectral index score 30-40) and respiratory distress had increased. So patient was started with pressure regulated volume controlled ventilation with moderate settings. She had blood stained gastric aspirates for which she required blood component therapy. In view of the rising ammonia and deteriorating 16

liver functions, intravenous N-acetylcysteine and oral lactulose were started. Packed cell transfusion given to maintain hematocrits. Bone marrow aspiration and biopsy was done to find out cause of pancytopenia. Pe d i a t r i c h e m a t o n c o l o g i s t , r h e u m a t o l o g i s t , gastroenterologist and neurologist opinions were also sought. Viral markers (EBV PCR, Parvo PCR, CMV PCR, HIV Elisa, Coxsackie IgM, Hepatitis A, B, C, and E), TORCH profile and IgM for Leptospirosis were sent. Coxsackie IgM was reported positive. While the anti-nuclear antigen, Anti Ds DNA, p-ANCA and c-ANCA were negative. Bone marrow aspiration was suggestive of hemophagocytosis. Intravenous immunoglobulins (2 gms/kg over 3 days) and methylprednisolone (2 mg/kg/day ) were started. Gene studies for perforin gene mutation (PRF1) sent to sweden to rule out primary HLH was reported negative. Patient was started with dexamethasone, etoposide and cyclosporine as per HLH protocol 2004 at 60 hours of admission following which she showed improvement in blood counts, liver functions and coagulopathy. Patient has been extubated on day 7 and was on full feeds, initially nasogastric and later oral on day 9 of admission. She was shifted out of PICU on day 10 and discharged home on day 17 on oral steroids and cyclosporine. In the following 6 months, she had normal growth and development.

Review of literature
Introduction Haemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease. It is a disorder of macrophage-related cell proliferation, leading to a hyperstimulated yet ineffective immune response that causes erythrophagocytosis and tissue damage. (1, 2) Pediatric age group is most commonly affected but it can occur at any age. The onset of HLH and bouts of disease may be triggered by infections. The male to female ratio is 1:1.3. (3, 4) Incidence of FHL has been estimated to 1.2/ 1,000,000 children/year. (5) The clinical hallmarks of HLH are prolonged fever, massive hepatosplenomegaly and cytopaenia, but the presentation can be highly variable. Patients may also present with neurological symptoms, jaundice, lymphadenopathy and skin rashes. Hypertriglyceridemia, hypofibrinogenaemia, liver dysfunction, and elevated ferritin are common laboratory

Table1: Relevant investigations of present case

D1 Hb TLC Platelets APTT INR Triglycerides Ferritin T/D Bil SGOT SGPT CRP Procal T. Protein Albumin BUN Creatinine Ammonia 7.9 24,400 2.00 >120 3.75 159 5254 5.3/3.3 3224 2219 53 4.15 4 2 7 O.33 61 3.6 1.9 9 0.33 133 3361 7.4/4.7 2523 2424 9.3/6.2 401 1343 6 3.68 4.2 2.6 8 0.22 205 1.1 4.7 2.3 12 0.46 198 5.3 2.2 14 0.35 136 4.5 1.6 21 0.24 84 D2 10 13,000 99000 54 4.99 D3 8.4 6800 24000 50 4.61 2.53 1.3 146 1200 8.9/5.8 365 932 264 8.7/5.5 266 814 137 4.1/2.5 94 500 5.2/3.4 70 379 Negative 0.47 5.5 3.0 16 0.19 51 5.1 2.7 11 0.18 90 5.5 3.0 14 0.23 57 D4 7.0 11100 80000 D5 9.2 10700 1.56 53 3.59 D6 7.9 10700 1.83 46 3.12 D7 6.2 9400 1.51 40 2.37 D8 9.3 9300 1.54 37 1.97 1.5 336 320 4.4/2.8 70 287 220 2.8/1.6 41 72 D17 9.5 7200 2.03 26.7 1.01

Fibrinogen. Bi 2

findings. Neurological symptoms may complicate, and sometimes dominate the clinical course. A bone marrow examination may demonstrate the presence of hemophagocytosis but an unfortunately, the hallmark (hemophagocytosis) is commonly not found in an initial bone marrow examination. Diagnosing HLH may be difficult and is often delayed because the clinical presentation mimics other conditions like severe sepsis, hepatic failure and malignancies. Diagnostic guidelines devised by the Histiocyte Society are available. Untreated Table 2: Classification and underlying conditions of Haemophagocytic lymphohistiocytosis (6)
Genetic/Primary HLH Familial HLH Known gene defects (perforin, munc 13-4, syntaxin 11) Unknown gene defects Immune deficiency syndromes Chdiak-Higashi syndrome (CHS) Griscelli syndrome (GS) X-linked lymphoproliferative syndrome (XLP) Acquired/Secondary HLH (sHLH) Exogenous agents (infectious organisms, toxins) Infection-associated hemophagocytic syndrome (VAHS, or IAHS) Endogenous products (tissue damage, metabolic products) Rheumatic diseases Malignancy-associated hemophagocytic syndrome (MAHS)

HLH has a high mortality rate but effective treatment with etoposide (VP-16), dexamethasone, and cyclosporine has been shown to improve survival significantly. The aim of this case report was to share our local experience with the disease to heighten physicians awareness of this diagnostic entity. Early recognition and prompt initiation of treatment will improve the prognosis. Classification Haemophagocytic lymphohistiocytosis is divided into two types, primary and secondary, that may be very difficult to distinguish from each other (6) (Table 2). Primary HLH (FHLH) includes familial HLH and immune deficiency syndromes. The former is estimated to occur in a frequency of 1 in 50,000 births and has autosomal recessive inheritance, typically seen during infancy and early childhood, and family history is often negative (7). The diagnosis of FHLH is made based on the presence of clinical criteria and is confirmed by molecular genetic testing (Table 3) (8-13). Secondary HLH occurs after strong immunologic activation such as that occur with a variety of viral, bacterial, fungal, and parasitic infections, as well as collagen-vascular diseases and malignancies, particularly T-cell lymphomas. The term Viral Associated Hemophagocytic Syndrome (VAHS) was redesigned as Infection Associated Hemophagocytic Syndrome (IAHS). Ebstein Barr Virus (EBV) was the triggering virus in 74% of the children (9, 30). Other viral infections, including those caused by cytomegaloviruses, adenoviruses, B19 parvoviruses, herpesviruses, and Coxsackie viruses 17

Table 3: Genetic defects in Haemophagocytic lymphohistiocytosis (8-13)

Disease FHLH-1 FHLH-2 FHLH-3 FHLH-4 GS-2 CHS-1 XLP Chromosome location 9q21.3-22 10q21-22 17q25 6q24 15q21 1q42.1-q42.2 Xq25 Associated gene Not known PRF1 UNC13D STX11 RAB27A LYST SH2D1A Gene function Not known Induction of apoptosis Vesicle priming Vesicle transport; t-SNARE Vesicle transport; small GTPase Vesicle transport; not further defined Signal transduction and activation of lymphocytes

Abbreviations: FHLH, familial hemophagocytic lymphohistiocytosis; GS, Griscelli syndrome; CHS, Chdiak-Higashi syndrome; XLP, X-linked lymphoproliferative syndrome have reportedly triggered secondary HLH. Bacterial and protozoal infections have also been associated with secondary HLH. Patients with macrophage activation syndrome (MAS), an aggressive, fatal condition seen in patients with connective tissue diseases share the same clinical and investigative features, as patients with HLH. The MAS is most commonly seen in association with systemic onset juvenile arthritis (SOJIA), but also occur rarely with systemic lupus erythematosus or other entities (14-15). Pathogenesis The pathogenesis of HLH involves an increased inflammatory response and defective cytotoxic function. Excessive stimulation of T-lymphocytes and histiocytes leads to secretion of high levels of cytokines such as interferon-, tumor necrosis factor, soluble interleukin-2 receptor, interleukin-1 and 6, and granulocyte macrophage colony stimulating factor (GMCSF) (Fig.1). The hypersecretion of these pro-inflammatory cytokines accounts for the clinical manifestation of high fever, cytopaenia, coagulopathy, tissue damage, high triglycerides and organ failure. Despite the excessive activation of cytotoxic cells, the cytotoxic functioning of NK cells and cytotoxic T-lymphocytes is impaired in HLH. NK cells and cytotoxic T-lymphocytes execute their Figure 1: Pathogenesis of Haemophagocytic lymphohistiocytosis
lymphoma cell derived cytokines microbial products (e.g. LPS)

killing function through the release of cytolytic granules containing perforin. Perforin is a protein that inserts into the plasma membrane of the target cells, forms pores and induces apoptosis. The currently identified genetic defects associated with HLH are related to either perforin function or the cell signaling processes involved in the priming, docking, or releasing of cytolytic granules. Factors leading to cytolytic defects in acquired HLH are less clear. Viruses may interfere with T cell activity by specific proteins or cytokines. Patients of JRA were found to have low NK cell function and perforin expression compared to other form of rheumatoid arthritis (8, 19,20). Clinical features Symptoms of HLH can be highly variable and nonspecific. The most common early findings are fever, hepatomegaly and splenomegaly (Table 4) (6,18,19). Other early symptoms include a skin rash, lymph node enlargement and neurological abnormalities. The fever is frequently undulant and protracted but may decline spontaneously. The splenomegaly and hepatomegaly are usually pronounced and progressive. The rash is uncharacteristic, transient and often associated with high fever. Lymph node enlargement develops in only half of the patients but may occasionally be marked. The neurological features include irritability, bulging fontanel, neck stiffness, hypotonia, hypertonia and convulsions. Cranial nerve (sixth or seventh) palsy, ataxia, hemiplegia/ tetraplegia, blindness, and unconsciousness and features Table 4: Clinical signs associated with Haemophagocytic lymphohistiocytosis
Clinical feature Fever Splenomegaly Hepatomegaly Lymphadenopathy Rash Neurological signs % of patients affected 60-100 35-100 39-97 17-52 3-65 7-47

hemophagocytosis

antigen (foreign or self) IFNg TNFa andgen programing cell e g dendrc cell

ILILIL- 12 18

ferritin (s) CD163

inflammatory cytokines/Chemokines & FasL

organ damage
activating pathways inhibting pathways infected target cells antigen reservoir

hy

sis
lysis

(p er

fo rin

FHL GS CHS XLP adult MAS?

antigen eimination

10

18

of increased intracranial pressure may also develop. The non-specific nature of the symptoms leads to delayed diagnosis especially in critically ill child. The treating team should have high index of suspicion (7).

Investigations
Any of the three blood cell lines may be affected to variable degree. Serum bilirubin and transaminases are usually elevated sometimes markedly(Table 5). Elevated serum ferritin, hyponatremia and low protein/albumin are other common findings, which are associated with the general inflammatory condition. Coagulation abnormalities are common during active disease, in particular hypofibrinogenaemia. In the spinal fluid, a moderate pleocytosis with mainly lymphocytes (5-50x106/L) as well as elevated protein levels may be found. MRI or CT may reveal areas of past or ongoing inflammatory activity, or demyelinization areas. Intracranial bleeding, edema, and atrophy may also be found. In revised 2004 HLH diagnostic guidelines, three additional diagnostic criteriaserum ferritin level > 500 g/L, low or absent NK-cell activity and soluble CD25 of above 2400 U/mLwere included. Infections may cause ferritin levels to rise, but the level rarely exceeds 200 g/L. A ferritin level > 500 g/L is 84% sensitive for HLH. As for NK-cell activity and soluble CD25 levels, these investigations are not readily available in India. Absence of haemophagocytosis in the bone marrow aspirate does not rule out HLH and repeat aspirate from different site may be required (17-18, 21). Table 5: Laboratory abnormality associated with Haemophagocytic lymphohistiocytosis (6, 15,16)
Laboratory abnormality Anemia Thrombocytopenia Neutropenia Hypertriglyceridemia Hypofibrinogenaemia Hyperbilirubinemia % of patients affected 89-100 82-100 58-87 59-100 19-85 74

Diagnosis
Diagnostic guidelines for HLH based on clinical features, laboratory and histopathological investigations were devised by the Histiocyte Society in 1991 and were updated in 2004 (3). The diagnosis of HLH can be established if one of either A or B is fulfilled: A. A molecular diagnosis consistent with HLH B. Diagnostic criteria for HLH (5 out of 8 criteria below): Clinical criteria Fever as high as 38.5C for 7 days or more. Splenomegaly 3 cm below left costal margin Laboratory criteria Cytopaenias-Affecting 2 of 3 lineages in the peripheral blood: haemoglobin (<90 g/L), platelets (<100 x109 /L), neutrophils (<1.0 x109 /L); in infants <4 weeks: haemoglobin <100 g/L Hypertriglyceridemia (fasting triglycerides 3.0 mmol/L [ie 265 mg/dL]) and/or hypofibrinogenaemia (fibrinogen 1.5 g/L) Low or absent NK-cell activity Ferritin 500 g/L Soluble CD25 (ie soluble IL-2 receptor) 2400 U/mL Histopathological criteria Hemophagocytosis in bone marrow or spleen or lymph nodes (no evidence of malignancy)

Figure 2: Flow chart of children with HLH in HLH 2004 protocol

Patient with HLH*

Genetic verified or Familial disease

Register and start# Initial 8 weeks therapy

Persistent non-familial, Non-genetically verified Resolved non-familial, Non-genetically verified

Stop therapy

Continuation therapy until Stem cell therapy

Reactivation

# Start therapy if patient has genetically verified disease, familial form of HLH, or if disease is severe, recurrent or persistent *If there is treatable infection it should be treated but be aware this may not be sufficient and patient may need HLH-treatment in addition. All severe form should start HLH-treatment; if HLH is persistent or recurring consider that the patient may have an undiagnosed inherited disease. HLH may also develop secondary to a number of other diseases as malignancies, rheumatic diseases and metabolic disorders, requiring a different treatment.

19

Figure 3: Treatment Haemophagocytic lymphohistiocytosis 2004 protocol

INITIAL THERAPY Dexa (mg/m 2) 10 VP-16 CSA
start 6 mg/kg daily if kidney function are normal, Cyclosporine level (200 microgram/ lt)

SCT/CONTINUATION THERAPY 2.5 1.25

IT therapy Weeks 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 1617181920212223 24

25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Dexa -Dexamethasone-10mg/m2 for 2 weeks, 5 weeks,1.25 mg/m for 1 weeks. - Indicates pulses every second week with 10mg/m2 for 3 days during continuation therapy
- Indicates Etoposide 150 mg/m
2

mg/m2 for 2 weeks,

2.5mg/m2 for 2

IV, twice weekly for the first two weeks during the initial

therapy followed every second week du ring continuous therapy. Only in certain conditions, such as if ANC < 500/cc and the bone marrow is hypocellular, can be the first two doses be omitted. - Indicates Methotrexate dose < 1year 6 mg, 1-2 years 8mg, 2-3 years 10 mg, more than 3 year s 12 mg each dose

Treatment In 1994, the HLH Study Group of the Histiocyte Society designed a treatment protocol using VP-16, dexamethasone, and cyclosporin. Initial treatment aims to suppress the hyperinflammatory response and the cytokines released by activated lymphocytes and histiocytes, which cause the life-threatening symptoms. The secondary aim is to eradicate the stimulus for ongoing but ineffective NK cell and T-suppressor cell activity. Etoposide is a cytotoxic drug highly effective in monocytic and histiocytic diseases. It is an excellent initiator of apoptosis. Corticosteroids are cytotoxic for lymphocytes, inhibit dendritic cell differentiation, and suppress the expression of cytokines. Dexamethasone is the drug of choice due to its high penetration into the central nervous system. Cyclosporin is an immunosuppressive drug shown to be effective in HLH. In view of the high mortality during the first 2 months with the use of HLH-94 protocol, it was revised in 2004 with escalated treatment protocol without increasing the myelotoxicity. Since it is difficult to differentiate between primary and secondary HLH, 2004 protocol is recommended for both. As for primary or persistent HLH, the ultimate curative treatment is a stem cell transplant. (23-24, 29) (Figure 2). Initial therapy: The present treatment protocop HLH2004 has been designed for primary inherited disease, and any severe from of HLH, in patients aged <18 years. The initial therapy covers the first 8 weeks of treatment (Figure 3). Maximal initial supportive care is suggested, and appropriate broad-spectrum antibiotics (until culture results) are made available. The supportive therapy includes prophylactic cotrimoxazole, an oral antimycotic during the initial therapy, consideration of antiviral therapy in patients with ongoing viral infections, and IVIG 20

(0.5 g/kg IV) once every 4 weeks (during the initial and continuation therapy). Gastroprotection with ranitidine is also suggested. If there is clinical evidence after 2 weeks of progressive neurological symptoms or if an abnormal CSF, 4 weekly intrathecal injections are recommended. Continuation therapy: Patients without a family history of HLH and without genetic evidence of the disease are recommended to start continuation therapy if the disease is active after the initial therapy. Increasing disease activity may make it necessary to intensify the treatment in some children. Reactivation therapy: HLH is characterized by frequent reactivations, particularly towards the end of initial therapy. Accordingly, a reactivation will commonly respond to an intensification of the initial therapy. Hematopoietic Cell Transplantation HSCT should be performed as early as possible, when an acceptable donor is available. If an HLA-identical relative is not available, a matched unrelated donor is recommended. If a genetic marker is not available, NK-cell activity can be considered as a surrogate marker of immune dysfunction, although healthy siblings may also have persistently decreased NK-cell activity (25-28). Discontinuation of therapy: Stopping therapy is only recommended in children with complete resolution of the disease. Close follow-up is warranted, including evaluation for fever, hepatosplenomegaly, neurological abnormalities, cytopenia, as well as elevation of ferritin, serum transaminases, and sCD25.

Prognosis
Primary HLH is invariably fatal if untreated, with a median survival of only 2 months. Secondary HLH is also aggressive

with a quoted mortality of 50%. Reports indicate that EBVassociated HLH can have fatality rates as high as 40%. With the introduction of a standard treatment protocol in 1994, the 5-year survival of HLH had improved markedly, from 5-22% to 55%. Prompt initiation of treatment is important. Prompt initiation of treatment and use of the treatment protocol improves survival. (30-31)

Conclusions
Haemophagocytic lymphohistiocytosis is a rare but highly fatal disease if not diagnosed and treated early. The diagnosis should be considered in children with persistent fever, organomegaly, and cytopaenia. Elevated serum ferritin and the presence of haemophagocytosis in bone marrow samples may help to establish the diagnosis. Diagnostic guidelines and effective treatment are available. Prompt diagnosis and initiation of treatment can improve prognosis, thus there is a need for heightened awareness of this disease entity.

References
1. Favara BE, Feller AC, Pauli M, et al. Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997; 29: 157-66. 2. Filipovich AH. Hemophagocytic lymphohistiocytosis: a lethal disorder of immune regulation. J Pediatr 1997; 130: 337-8. 3. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48: 124-131. 4. Filipovich AH. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders. Immunol Allergy Clin North Am 2008; 28: 293-313. 5. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80: 428-35. 6. Farquhar JW, Claireaux AE. Familial haemophagocytic reticulosis. Arch Dis Child. 1952; 27: 519-525. 7. Janka G. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983; 140: 221-30. 8. Katano H, Cohen JI. Perforin and lymphohistiocytic proliferative disorders. Br J Haematol. 2005; 128: 739750. 9. Janka G, Imashuku S, Elinder G, Schneider M, Henter JI. Infection- and malignancy-associated hemophagocytic syndromes. Secondary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am. 1998; 12: 435-444. 10. Feldmann J, Callebaut I, Raposo G, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in 21

a form of familial hemophagocytic lymphohistiocytosis (FHL3).Cell. 2003; 115: 461-473. 11. Menasche G, Feldmann J, Fischer A, de Sainte Basile G. Primary hemophagocytic syndromes point to a direct link between lymphocyte cytotoxicity and homeostasis. Immunol Rev. 2005; 203: 165-179. 12. Zur Stadt U, Schmidt S, Kasper B, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005; 14: 827-834. 13. Ohadi M, Lalloz MR, Sham P, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet. 1999; 64: 165-171. 14. Sailler L, Duchayne E, Marchou B, Brousset P, Pris J, Massip P, et al. Aspects etiologiques des hemophagocytoses reactionnelles: etude retrospective chez 99 patients. Rev Med Interne 1997; 18: 855- 864. 15. Menasche G, Pastural E, Feldmann J, et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet. 2000; 25:173176. 16. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocytic Society. Semin Oncol 1991; 18: 29-33. 17. Rieux-Laucat F, Le deist F, De Saint Basile G. Autoimmune lymphoproliferative syndrome and perforin. N Engl J Med 2005; 352: 306-307. 18. Hafsteinsdottir S, Jonmundsson GK, Kristinsson Jr, et al. Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation. Acta Paediatr 2002; 91: 974-977. 19. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, BaderMeunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001; 40: 1285-1292. 20. Arico M, Danesino C, Pende D, Moretta L. Pathogenesis of haemophagocytic lymphohistiocytosis. Br J Haematol 2001;114:761-769. 21. Schneider EM, Lorenz I, Muller-Rosenberg M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer cell induced apoptosis. Blood 2002; 100: 2891-2898. 22. Imashuku S, Teramura T, Morimoto A, Hibi S. Recent developments in the management of hemophagocytic lymphohistiocytosis. Expert Opin Pharmacother 2001; 2: 1437-1448. 23. Horne AC, Janka G, Egeler RM, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis. Br J Haematol 2005; 129: 622630. 24. Fischer A, Cerf-Bensussan N, Blanche S, et al. Allogeneic bone marrow transplantation for erythrophagocytic

lymphohistiocytosis. J Pediatr 1986; 108: 267270. 25. Jabado N, de Graeff-Meeder ER, Cavazzana-Calvo M, et al. Treatment of familial hemophagocytic lymphohistiocytosis with bone marrow transplantation from HLA genetically nonidentical donors. Blood 1997; 90: 47434748. 26. Ambruso DR, Hays T, Zwartjes WJ, et al. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer 1980; 45: 25162520 27. Fischer A, Virelizier JL, Arenzana-Seisdedos F, et al. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation. Pediatrics 1985; 76: 263268. 28. Henter J-I, Samuelsson-Horne AC, Arico M, et al.

Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002; 100:23672373. 29. Al-LamkiZ, WaliYA, PathareA, et al.Clinical and genetic studies of familial hemophagocytic lymphohistiocytosis in Oman: Need for early treatment. Pediatr Hematol Oncol 2003; 20: 603609. 30. Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol 2002; 44: 259-272. 31. Henter JI. Treatment protocol of the Second International HLH Study 2004. Haemophagocytic Lymphohistiocytosis Study Group. Histiocyte Society; 2004.Med Pediatr oncol 1997; 28: 342-347.

22

Case Report

Pheochromocytoma: A Case Report and Review of Literature

Vikram Gagneja Fellow, Pediatric Critical Care, Department of Pediatrics, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi

A case of pheochromocytoma is presented who had complicated pre and peri operative period followed by complete recovery.

Figure 1: MRI- showing right adrenal mass

Case report
A 13yrs old boy presented with sudden onset of headache, vomiting and irritability since last 12 hours. He had a history of previous hospital admission 1 year back with complaints of fever, seizure and altered sensorium and was treated as a case of meningo-encephalitis. He had shock requiring mutilple inotropes. Echocardiography (ECHO) done at that time showed ejection fraction of 45% which improved subsequently. After discharge, there was no neurological deficit, but used to complain of intermittent headache and cold peripheries. At present admission child was irritable with cold and sweaty peripheries. His heart rate was 130/minute, respiratory rate 28/minute, capillary filling time >5 seconds, SpO2 94% and non-invasive blood pressure 210/116 mmHg (mean 158 mmHg). His systemic examination was normal except fundus examination which revealed grade 2 hypertensive changes. This time ECHO showed left ventricular ejection fraction of 50% with concentric left ventricular hypertrophy with normal right ventricular systolic function. Ultrasonography of abdomen showed right adrenal mass. He was managed as a case of hypertensive emergency with sodium nitroprusside drip (started with 0.05mcg/kg/min to maximum dose of 0.2mcg/kg/min). As there were features of excess catecholamine release in the form of labiality in blood pressure, cold and clammy peripheries with right suprarenal mass, possibility of pheochromocytoma was kept which was confirmed by high urine metanephrines3141.3 ug/24hrs (normal 71-395) and Normetanephrines5069.28ug/g creat (normal 45-324) levels. MRI abdomen showed a large mass (6.5 x 4.6 cm) in the right adrenal gland. Vascular supply to the right suprarenal mass was directly arising from aorta and from a branch arising from the right main renal artery. Pre-operation patient was started on alpha blockers (phenoxybenzamine) and gradually nitroprusside drip was tapered off. Phenoxybenzamine dose was gradually hiked up till the sign of alpha blockade in the form tachycardia and postural hypotension appeared and once alpha blockade was achieved beta blockers were also added. Patient was also allowed to take libral salt and fluid intake before surgery. 23

Figure 2: Gross feature of excised tumour

During surgery patient had gone into shock requiring fluid boluses and nor-epinephrine drip. Post op blood pressure was controlled with oral antihypertensive and stopped once BP stabilized. Repeat urine metaneprine levels had come down after 6 weeks.

Review of Literature
Pheochromocytomas are tumours arising from the catecholamine-producing chromaffin cells in the adrenal medulla. Tumours arising in extra-adrenal sympathetic and parasympathetic paraganglia are closely related and are classified as extra-adrenal paragangliomas. Phaeochromocytomas and extraadrenal sympathetic paragangliomas usually secrete catecholamines, whereas parasympathetic paragangliomas of the head and neck are usually non-functioning.

Clinical Presentation
Pheochromocytomas are thought to be responsible for 1% of childhood hypertension (1). The incidence of malignant phaeochromocytoma is approximately 0.02 per million

children (2). Reports from three studies of 24, 50 and 58 paediatric patients suggest a varying malignancy rate of 25%, 56% and 12%, respectively (3-5). The same three studies report bilateral pheochromocytoma in 25%, 32% and 34% and extra-adrenal functional catecholaminesecreting tumours in 8%, 18% and 22%, respectively. Pheochromocytoma may present in a variety of ways ranging from vague symptoms to a hypertensive emergency. Symptoms may include headache, sweating, flushing, palpitations, blurred vision, syncope, panic attacks, tremor, gastrointestinal disturbance and weight loss. Pham et al report that 30% present with symptoms of mass effect or as an incidental finding on imaging (6). Some tumors may remain undiagnosed before death (7). Hypertension is the most consistent sign, which is sustained and without paroxysms in 63% (3). Complications include cardiomyopathy, hypertensive crisis, accidents, convulsions, mass effect and multiorgan failure.

MRI and CT are good modalities for identifying a lesion. In a study of 236 adult patients, these techniques failed to detect 0% and 5.8%, respectively, of benign paragangliomas (14). However, they lack specificity. Functional imaging with 123 I-labelled MIBG scintigraphy may lack sensitivity (8090%), but has high specificity (98%) (15). Abnormal neuroectodermal tissue takes up the isotope and gives a focal area of increased uptake on the scan. This is useful for confirming the presence of chromaffin tissue and aids in locating extra-adrenal paragangliomas or multiple synchronous primaries. Functional [18F] fluoro-2deoxyglucose/6-[18F]fluorodopamine positron emission tomography has produced promising results, suggesting that multimodality imaging is appropriate in tumours that are difficult to localise (16,17). MIBG studies with correlative single photon emission CT/CT fusion imaging are beneficial in cases where the diagnosis is equivocal and can increase the diagnostic certainty by up to 90% (18). However, the increased radiation exposure should be considered (19).

Investigations
Confirmation of the diagnosis requires the demonstration of inappropriate production of catecholamines (norepinephrine and epinephrine). This has traditionally been achieved by measuring 24 h urinary excretion of total metanephrines and catecholamines (8,9). The plasma concentrations of norepinephrine and epinephrine are determined by the release of these substances from the adrenal gland dependent on sympathoadrenal tone, whereas the concentrations of plasma metanephrines, their metabolites, are due to the metabolism of epinephrine and norepinephrine within the chromaffin cells and subsequent continuous release, which is far less dependent on sympathoadrenal tone. The two processes are independent of each other (10,11). Measurement of fractionated metanephrines (normetanephrine and metanephrine measured separately) in urine or plasma provides better diagnostic sensitivity than measurement of the parent catecholamines (12). Measurement of 24 h urinary total metanephrines and catecholamines (sensitivity 90%; specificity 98%) is appropriate when the patient is at low risk of pheochromocytoma (isolated hypertension), whereas measurement of fractionated plasma metanephrines (sensitivity 97%; specificity 85%) may be the test of choice when the patient is at greater risk (genetic predisposition or adrenal mass) (13). Lenders et al have suggested that demonstration of normal plasma fractionated metanephrines can virtually exclude a diagnosis of a phaeochromocytoma (12). Successful management of pheochromocytoma depends on high-quality imaging to accurately localise the tumour and stage the extent of disease. The choice of imaging modality depends on the level of suspicion determined by biochemical evidence, previous history of a pheochromocytoma, and inherited predisposition. 24

Genetics
Tr a d i t i o n a l t e a c h i n g s u g g e s t e d t h a t 1 0 % o f pheochromocytomas are familial. Recent advances in molecular genetics, however, have revealed an identifiable germline mutation in up to 59% (27/48) of apparently sporadic pheochromocytomas presenting at 18 years or younger and in 70% of those presenting before 10 years of age. The inherited predisposition may be attributable to a germline gene alteration in the VHL, SDHB, SDHD, MEN2 or NF1 genes.

Preoperative Management
Pheochromocytoma may present as an emergency. Management is symptom-dependent usually requiring pharmacological intervention to block the effects of high concentrations of circulating catecholamines. Hypertensive crisis is the most common emergency associated with pheochromocytoma and may be defined as high blood pressure resulting in life threatening emergencies or compromises of vital organ function. Blood pressure should be controlled at a rate sufficient to reduce toxicity, but avoiding acute hypoperfusion of vital organs. This should be undertaken in a setting where invasive monitoring is available to assess the central nervous system, cardiac and renal function. Intravenous agents are preferable under these circumstances, to allow adjustment of infusion rate according to response. A continuous infusion of phentolamine or sodium nitroprusside is preferable (20). Intravenous labetalol by bolus injection, followed by continuous infusion, may also be used (21). In patients with hypertension but without signs of end organ damage, oral anti-hypertensive drugs can be considered.

Surgery is the curative option for most patients. Preoperative preparation is important in order to minimise the complications arising from surgery and may take several weeks. Induction of anaesthesia and manipulation of the tumour causes unpredictable release of catecholamines, which may result in hypertensive crisis, stroke and arrhythmias. To prevent these problems, patients must undergo pharmacological blockade of catecholamine synthesis or effects before surgery (22). Routine preoperative -adrenoceptor blockade opposes catecholamine- induced vasoconstriction and its sequelae. A -adrenoceptor blocker is added to oppose the reflex tachycardia often associated with blockade. blockade alone can be dangerous and is contraindicated, because it does not prevent, and can actually augment, effects of catecholamines at adrenoceptors, resulting in hypertensive crisis. It is important that, if -adrenoceptor blockers are used, they should be used only after adequate pretreatment with -adrenoceptor antagonists. Adequate blockade is indicated by normotension or the development of side effects such as orthostatic hypotension, tachycardia, nasal congestion, nausea and abdominal pain. A retrospective review of blockade with phenoxybenzamine, prazosin or doxazosin in preoperative preparation concluded that surgery is safe with each of these drugs (23). - Methyl-para-tyrosine (metyrosine) competitively inhibits tyrosine hydroxylase, the ratelimiting step in catecholamine biosynthesis. Treatment with metyrosine reduces tumour stores of catecholamines, decreases the need for intraoperative antihypertensive drugs, lowers intraoperative fluid requirements, and attenuates blood loss (24) A combination of metyrosine, phenoxybenzamine, blocker and liberal salt intake starting 1014 days before surgery leads to better control of blood pressure and decreases surgical risks. Combined medical blockade also allows relaxation of the constricted vascular tree and expansion of the reduced plasma volume, thus avoiding hypotension after sudden diffuse vasodilation at the time of tumour removal. Intravenous fluids 24 h before surgery may be necessary to hydrate and ensure adequate blood volume. Alternative agents and approaches have been used successfully in limited settings. The oral calcium channel blocker, nicardipine (310 days before surgery), has been used to control intraoperative blood pressure, but it did not prevent all haemodynamic instability during tumour resection (25). Angiotensin-converting enzyme inhibitors have also been used successfully to manage hypertension in older patients with phaeochromocytoma (26).

crisis during tumour manipulation and severe hypotension after removal. Premedication may be necessary to ensure that the patient is calm in the anaesthetic room. Invasive monitoring of BP should be started before induction of anaesthesia. A combined general anaesthetic and epidural technique is useful both during the operation (to reduce the effects of vasoactive substances released during tumour handling) and for postoperative analgesia. Acute episodes of hypertension during surgery can be controlled with sodium nitroprusside by infusion. Hypotension may occur when venous drainage of the tumour is removed; infusions of dobutamine and/or norepinephrine may be required to maintain normotension for a variable period after surgery.

Surgical Management
Traditionally, open surgery for an adrenal or abdominal/ pelvic (organ of Zuckerkandl) primary tumour (95% of cases) permits full inspection of the lesion and, in cases of suspected malignancy, the opportunity to assess loco-regional disease, vascular element invasion and metastases. Thoracic tumours can be approached via a muscle-sparing thoracotomy. Those located in rarer sites include the head/neck, urinary bladder or central nervous system. The latter will require neurosurgical expertise. Advantages of open operation are that complete tumour resection is facilitated with early isolation and control of venous drainage, thereby minimising systemic catecholamine release (27). Paravertebral sympathetic chain paragangliomas and retrocaval extra-adrenal tumours can be particularly challenging, with careful dissection and mobilisation of great vessels required to expose the hidden offending lesion. Vascular reconstruction may be needed in these technically demanding scenarios. Ex vivo techniques (bench surgery) have recently been described by transplant surgeons to achieve resection of tumours located in close proximity to the portal triad anatomy and inferior vena cava (28). Total adrenalectomy for bilateral tumours carries substantial morbidity, with long-term requirement for steroid hormone replacement therapy, risks of osteoporosis, and Addisonian crises if patient compliance lapses. Adrenal cortical sparing procedures have been advocated for patients with bilateral tumours (29). Advances in minimally invasive surgery have increased the feasibility and safety of laparoscopic adrenalectomy for non-malignant tumours (<10 cm), with expanding indications for a laparoscopic approach in childhood (30). This strategy has also been used recently to resect the extra-adrenal tumours (31).

Anaesthetic Management and Complication During Surgery

Meticulous anaesthesia throughout the operative procedure is crucial to reduce the risk of hypertensive 25

Histopathology

Histopathological examination of the tumour is essential to confirm the diagnosis and site of origin and to assess features that may indicate a greater likelihood of malignancy or syndromic disease. Pheochromocytomas and extra-adrenal paragangliomas can have identical histological appearances. Microscopic evaluation of peri-adrenal tumours is therefore important to confirm extra adrenal origin, which is associated with an increased risk of malignancy (32). Differentiation from other tumour types is usually straightforward with the use of immunohistochemistry (33). Occasionally, composite tumours with areas of ganglioneuroma or ganglioneuroblastoma are identified (32). Biological behaviour of these tumours cannot be accurately predicted on the basis of histopathological features. Malignancy can only be diagnosed with documented metastatic disease in a site where chromaffin cells are usually absent, to exclude the possibility of a synchronous or metachronous primary tumour. Recent systematic attempts to quantify risk of malignancy on the basis of histopathological features have included paediatric patients in both benign and malignant groups (32). These studies use a combination of factors, such as growth pattern, necrosis, mitotic rate and tumour cellularity, to predict the likelihood of malignant behaviour. Although none are perfectly predictive, they represent the best evidence currently available for stratifying risk, and some features are incorporated into the reporting guidelines of the Royal College of Pathologists and the Association of Directors of Anatomic and Surgical Pathology in the USA (34). Tumour expression of many other proteins, including tenascin, cyclo-oxygenase-2 and vascular endothelial growth factor, has been found to correlate with malignant behaviour (35). There is a greatly increased risk of malignancy in the context of SDHB mutation, and extra-adrenal location is increased in SDHD and SDHB mutations and in VHL syndrome (36).

at other sites. It is partly determined by the underlying genetic condition if present. Screening schedules for the different genetic disorders remain controversial and should be overseen by a pediatric endocrinologist or person with the relevant expertise. Initial follow-up should include 6-monthly measurement of blood pressure and urinary catecholamines. Annual follow-up may be appropriate later and for children in whom a gene alteration is not identified; whether they require further imaging and its frequency are contentious issues. Children who have undergone bilateral adrenalectomy require regular assessment to monitor adequacy of steroid replacement. If a second or recurrent phaeochromocytoma is identified, investigation is as for the initial presentation. If a mutation was not identified initially, a clinical geneticist should review the child again. If a gene alteration is identified, family members should be offered a referral to the clinical genetics department. Liaison between the paediatric and adult sectors is vital to ensure continued screening (2).

References
1. Pickard JL, Ross G, Silver D. Coexisting extraadrenal pheochromocytoma and renal artery stenosis: A case report and review of the pathophysiology. J Pediatr Surg 1995; 30: 16131615. 2. British Society of Paediatric Endocrinology & Diabetes. Paediatric Endocrine Tumours. A Multidisciplinary Consensus Statement of Best Practice from a Working Group Convened Under the Auspices of the BSPED and UKCCSG, 2005. 3. Barontini M, Levin G, Sanso G. Characteristics of pheochromocytoma in a 4- to 20- year-old population. Ann NY Acad Sci 2006; 1073: 3037. 4. Pe r e l Y, S c h l u m b e r g e r M , A l o s N , e t a l . Pheochromocytoma and paraganglioma in children: a report of 24 cases of the French Society of Pediatric Oncology. Pediatr Hematol Oncol 1997; 14: 413422. 5. Beltsevich DG, Kuznetsov NS, Kazaryan AM, et al. Pheochromocytoma surgery: epidemiologic peculiarities in children. World J Surg 2004; 28:592596. 6. P h a m T H , M o i r C , T h o m p s o n G B , e t a l . Pheochromocytoma and paraganglioma in children: a review of medical and surgical management at a tertiary care centre. Pediatrics 2006; 118: 11091117. 7. M c N e i l A R , B l o k B H , K o e l m e ye r T D, e t a l. Phaeochromocytomas discovered during coronial autopsies in Sydney, Melbourne and Auckland. Aust NZ J Med 2000; 30: 648652. 8. Bravo EL, Tarazi RC, Gifford RW, et al. Circulating and urinary catecholamines in pheochromocytoma. Diagnostic and pathophysiologic implications. N Engl J Med 1979; 301:682686. 9. Young WF Jr. Pheochromocytoma and primary aldosteronism: diagnostic approaches. Endocrinol Metab Clin North Am 1997; 26: 801827. 10. Eisenhofer G, Keiser K, Friberg P, et al. Plasma 26

Management of Malignant Pheochromocytoma

Surgical excision remains the treatment of choice for malignant disease, but medical treatments have been explored in adults using 131I-labelled MIBG57 and somatostatin analogues and combination chemotherapy (37,38). 131I-labelled MIBG is the most promising of these, leading to an increase in survival for those responding in the first 6 months of treatment. It has been suggested that myeloablative chemotherapy with stem cell rescue may have a place in the treatment for malignant disease, but it is yet to be fully evaluated.

Follow-Up
Lifelong follow-up is required to detect the possible development of metachronous tumours and tumours

metanephrines are markers of pheochromocytoma produced by catechol-O-methyltransferase within tumours. J Clin Endocrinol Metab 1998; 83:21752185. 11. Eisenhofer G, Goldstein GS, Kopin IJ, et al. Pheochromocytoma: rediscovery as a catecholaminemetabolising tumours. Endocr Pathol 2003; 14: 193212. 12. Lenders JWM, Keiser HR, Goldstein DS, et al. Plasma metanephrines in the diagnosis of pheochromocytoma. Ann Intern Med 1995; 123: 101109. 13. Sawka AM, Ravinder JR, Singh J, et al. A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. Clin Endocrinol Metab 2003; 88: 553558. 14. Erickson D, Kudva YC, Ebersold MJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab 2001; 86: 52105216. 15. Dahnert W. Radiology review manual. 5th edn. Philadelphia, PA: Lippincott Williams and Wilkins, 2003; 935936. 16. Esfandiari NH, Shulkin BL, Bui C, et al. Multimodality imaging of malignant pheochromocytoma. Clin Nucl Med 2006; 31: 822825. 17. Timmers HG, Kozupa A, Chen CC, et al. Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated phaeochromocytoma and paraganglioma. J Clin Orthod 2007; 25: 22622269. 18. Rozovsky K, Koplewitz BZ, Krausz Y, et al. Added value of SPEC T/C T for correlation of MIBG scintigraphy and diagnostic CT in neuroblastoma and pheochromocytoma. AJR Am J Roentgenol 2008; 190: 10851090. 19. G elfand MJ, Lemen LC. PET/CT and SPECT/CT dosimetry in children: the challenge to the pediatric imager. Semin Nucl Med 2007; 37: 391398. 20. Brouwers FM, Eisenhofer G, Lenders, JWM. Emergencies caused by pheochromocytoma, neuroblastoma, or ganglioneuroma. Endocrinol Metab Clin N Am 2006; 35: 699724. 21. Groshonq T. Hypertensive crisis in children. Pediatr Ann 1996; 25: 368371. 22. W a l t h e r M M , K e i s e r H R , L i n e h a n W M . Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 1999; 17: 3539. 23. Kocak S, Aydintug S, Canakci N. Alpha blockade in preoperative preparation of patients with pheochromocytomas. Int Surg 2002; 87: 191194.

24. Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromoctyoma with the use of metyrosine. Ann Surg 1990; 212: 621628. 25. Lebuffe G, Dosseh ED, Tek G, et al. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas. Anaesthesia 2005; 60: 439444. 26. Sheps DG, Jiang NS, Klee GG. Recent developments in the diagnosis and treatment of pheochromocytoma. Mayo Clin Proc 1990; 65: 88-95. 27. Skinner MA, Safford SD. Endocrine disorders and tumours. In: Ashcraft KW, Holcomb III GW, Murphy JP, eds. Pediatric surgery. Philadelphia: Elsevier Saunders,2005. 28. Fusai G, Steinberg R, Prachalias A, et al. Ex vivo surgery for extraadrenal pheochromocytoma. Pediatr Surg Int 2006; 22: 282285. 29. Ludwig AD, Feig DI, Brandt ML, et al. Recent advances in the diagnosis and treatment of pheochromocytoma in children. Am J Surg 2007; 194:792796. 30. Gagner M, Lacroix A, Bolte E. Laparoscopic adrenalec tomy in Cushings syndrome and pheochromocytoma. N Engl J Med 1992; 327: 1033. 31. Kravarusic D, Pinto-Rojas A, Al-Assiri A, et al. Laparoscopic resection of extraadrenal pheochromocytoma: case report and review of the literature in pediatric patients. J Pediatr Surg 2007; 42: 17801784. 32. Linnoila RI, Keiser HR, Steinberg SM, et al. Histopathology of benign versus malignant sympathoadrenal paragangliomas: clinicopathologic study of 120 cases including unusual histologic features. Hum Pathol 1990; 21: 11681180. 33. Tischler AS, Kimura N, McNicol AM. Pathology of pheochromocytoma and extraadrenal paraganglioma. Ann NY Acad Sci 2006; 1073: 557570. 34. Association of Directors of Anatomic and Surgical Pathology. Checklist for adrenal cortical carcinoma and phaeochromocytoma, November 2003. 35. Salmenkivi K, Haglund C, Arola J, et al. Increased expression of tenascin in pheochromocytomas correlates with malignancy. Am J Surg Pathol 2001; 25: 14191423. 36. Amar L, Bertherat J, Baudin E, et al. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 88128818. 37. Duet M, Guichard J, Rizzo N, et al. Are somatostatin analogs therapeutic alternatives in the management of head and neck paragangliomas? Laryngoscope 2005; 115: 13811384. 38. Scholz T, Eisenhofer G, Pacak K, et al. Clinical review: current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 2007; 92: 12171225.

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Technology Update

Jugular Venous Bulb Oxygen Saturation Monitoring

Devinder Chhonker Fellow, Pediatric Critical Care, Department of Pediatrics, Sir Ganga Ram Hospital, New Delhi

Introduction
Jugular venous bulb oxygen saturation (SjvO2) refers to the oxygen saturation of venous blood in the jugular bulb located at the base of the skull. Sjvo2 monitoring is currently suggested in patients with severe head trauma as a global measure of adequacy of the cerebral blood flow (CBF) to metabolic requirements. Oxygenation of cerebral venous outflow has been investigated as a neuromonitor for more than 60 years (13). SjvO2 in normal volunteers first was obtained by Gibbs et al in 1942 (1). It provides an indirect assessment of cerebral oxygen use and can be used to guide physiologic management decision in a variety of clinical situation.

Virtually all of the blood from the brain drains into the internal jugular veins. Blood from subcortical areas tends to flow into the left internal jugular vein while blood from the cortical areas tends to drain into the right. Approximately 2/3 of the blood in the internal jugular vein is thought to come from the ipsilateral hemisphere and 1/3 from the contralateral hemisphere (4-6). Contribution of the extra-cranial circulation is estimated to range from 0-6.6%. This is exacerbated if the blood is contaminated with blood from the facial vein which joins the internal jugular vein a few cm. below the jugular bulb. Catheter placement In patient with injury involving both the hemisphere, the catheter is usually placed on the side of dominant drainage, usually the right (7, 8). The dominant side may be determined by comparing the intracranial pressure (ICP) increase caused by manual compression of each internal jugular vein (9), by computerized tomographic assessment of jugular foramen size (10), or by ultrasonography to compare internal jugular vein size. The assumption of the compression technique is that a greater ICP increase on one side is the result of occlusion of a larger portion of the cerebral outflow, and therefore more reflective of global conditions. It is controversial, which side is to be chosen for placement of catheter in case of unilateral head injury. The head of the patient is positioned horizontally or slightly downward while keeping the intracranial pressure below 20 mmHg. The internal jugular vein is cannulated between the two heads of sternocleidomastoid muscle or at the level of the cricoid ring. The catheter is advanced towards the base of skull until resistance is met at the jugular bulb (about 12-15 cm). Alternatively, a catheter may be inserted via an introducer to a distance equal to that measured from the point of insertion to the level of the mastoid process (approximately the level of the jugular bulb) or until resistance is met . Position of the catheter is confirmed by X-ray neck antero-posterior or lateral view. The tip of the catheter should be above the C1/C2 intervertebral disc (11) (Figure 2). SjvO2 can be measured continuously using a fibreoptic catheter and reflectance oximetry (12-14) or intermittently by drawing samples from the catheter and measuring saturation with a cooximeter. If the intermittent method is used care must be taken with sampling to prevent aspiration of blood from the facial vein (extra cranial contamination). 28

Placement of SjvO2 catheter

Anatomy The internal jugular vein exits the skull and continues its course, within the carotid sheath, beneath the sternocleidomastoid muscle in a posterolateral approximation to the carotid artery. The jugular bulb is the dilated portion of the jugular vein just below the base of the skull and is the preferred site for blood sampling (Figure 1).

Figure 1: Anatomy of internal jugular vein in the neck

Figure 2: X-ray neck lateral view showing the position of internal jugular catheter

Table 1: Causes of low and high jugular venous saturation

Result Low SjvO2 Interpretation Increased brain oxygen extraction due to systemic arterial hypoxia Low CBF from hypotension, vasospasm or ICP Increased brain metabolic demand in fever, seizure

High SjvO2 Hyperaemia Failure of oxygen extraction Grossly low CBF in high ICP CBF Cerebral blood flow, ICP intracranial pressure

Physiology
Clinical measurements of SjvO2 reflect the balance of oxygen supply and consumption of the brain. Factors affecting SjvO2 include CBF, cerebral oxygen consumption, arterial oxygen content, (CaO 2 ) and haemoglobin concentration. The Fick equation describes the relationship between cerebral blood flow (CBF), arterial CaO 2 and venous oxygen content CjO2 and cerebral metabolic rate for oxygen (CMRO2): CMRO2 = CBF x CaO2-CjO2 The difference in oxygen content between arterial and jugular venous blood is expressed by the term (CaO2 CjvO2) or AjvDO2. By rearranging the above equation it is apparent that: AjvDO2 = CMRO2/CBF Normally, AjvDO2 is stable at 48 mL O2/100 mL blood (15,16). If CMRO2 remains constant, changes in AjvDO2 should reflect changes in CBF. If AjvDO2 is <4 mL O2/100 mL blood, it is assumed that CBF is luxuriant. If AjvO2 >8 mL O2/100 mL blood suggests ischemia. Many factors affect the relationship of CMRO2 and oxygen delivery (figure 3). Simplistically, when cerebral oxygen Figure 3: Mechanisms of low and high jugular venous saturation

demand exceeds supply, the brain extracts oxygen from hemoglobin, resulting in a decreased oxygen saturation of the blood in the jugular bulb. If CBF is constant then CMRO2 decides the amount of oxygen to be extracted by brain from blood. Jugular venous oxygen saturation is normally approximately 55%75% (1), which is lower than systemic mixed venous oxygen saturation. As SjVO2 is a global measure, SjVO2 monitoring has high specificity but low sensitivity for ischemia, i.e., a normal saturation may not reflect focal areas of ischemia, but a low saturation is indicative of low flow (Figure 3) (Table 1).

Clinical applications
Perez et al (17) demonstrated that jugular venous monitoring may aid in predicting the neurologic outcome of children with severe traumatic brain injury. Ranucci et al (18) showed continuous monitoring of jugular venous saturation during cardiopulmonary bypass may offer a predictive index for major morbidity after cardiac operations in pediatric patients. Sheinberg et (19) conducted a study which evaluated, the continuous measurement of SjvO2 with a fiberoptic catheter as a method of detecting cerebral ischemia after head injury. The incidence of jugular venous oxygen desaturation found in this study suggests that continuous monitoring of SjvO2 may be of clinical value in patients with head injury. Jugular venous oximetry is most often used in patients with head injuries for neurosurgical procedures and for cardiovascular procedures for (17,18) Early diagnosis of ischemia Optimizing hyperventilation therapy Guiding fluid management and oxygenation Optimizing perfusion pressure Detecting arterial-venous fistula Barbiturate induced cerebral metabolic suppression SjvO2 measurement is associated with certain complications related mainly to vessel catheterization and few sampling limitations (19) (Table 2). SjvO2 is a very promising parameter for neurocritically ill patients monitoring. Few studies have shown benefits 29

Table 2: Limitations and complications of jugular venous saturation monitoring

Limitations Poor correlation of concomitant values obtained from cerebral oximeter to an IJV sample Complications Carotid arteries puncture (14.5%) Thrombosis (40% subclinical) Haematoma formation

Possibility of extracerebral Raised ICP (rare) contamination False negative value with Infection focal ischemia

but more large sample size, randomized studies are required to assess the outcome benefits especially in pediatric population.

References
1. Gibbs EL, Lennox WG, Nims LF, et al. Arterial and cerebral venous blood: arterial-venous differences in man. J Biol Chem 1942;144:325332. 2. Lennox WG, Gibbs FA, Gibbs EL. Relationship of unconsciousness to cerebral blood flow and to anoxemia. Arch Neurol Psychiat 1935;34: 10011013. 3. Ferris E, Engel G, Stevens C, Logan M. The validity of internal jugular venous blood in studies of cerebral metabolism and blood flow in man. Am J Physiol 1946; 147:517521. 4. Shenkin GA, Harmel MH, Kety SS. Dynamic anatomy of the cerebral circulation. Arch Neurol Psychiatry 1948; 60:240252. 5. Gibbs EL, Lennox WG, Gibbs FA. Bilateral internal jugular blood: comparison of A-V differences, oxygendextrose ratios and respiratory quotients. Am J Psychiatry 1945; 102:184190. 6. Lassen NA. Cerebral blood flow and oxygen consumption in man. Physiol Rev 1959; 39: 183238. 7. Robertson CS, Narayan RK, Gokosla ZL, et al. Cerebral arteriovenous oxygen difference as an estimation of cerebral blood flow in comatose patients. J Neurosurg 1989;70: 222230. 8. Cowan F, Thoresen M. Ultrasound study of the cranial venous system in the human new-born infant and the adult. Acta Physiol 1983; 117:131137. 9. Dearden NM. Jugular bulb venous oxygen saturation in the management of severe head injury. Curr Opin Anesthesiol 1991; 4:279286.

10. Stochetti N, Paparella A, Bridelli F, et al. Cerebral venous oxygen saturation studied with bilateral samples in the internal jugular veins. Neurosurgery 1994; 34: 3844. 11. Bankier AA, Fleischman D, Windisch A, et al. Position of jugular oxygen saturation catheter in patients with head trauma: assessment by use of plain films. Am J Roentgenol 1995; 164:437441. 12. Howard L, Gopinath SP, Uzura M, et al. Evaluation of a new fiberoptic catheter for monitoring jugular venous oxygen saturation. Neurosurgery 1999;44: 12801285. 13. Andrews PJD, Dearden NM, Miller JD. Jugular bulb cannulation: description of a cannulation technique and validation of a new continuous monitor. Br J Anaesth 1991; 67:553558. 14. Nakajima T, Ohsumi H, Kuro M. Accuracy of continuous jugular bulb venous oximetry during cardiopulmonary bypass. Anesth Analg 1993; 77:11111115. 15. Souter M, Andrews P. A review of jugular venous oximetry. Intensive Care World 1996; 13:3238. 16. Ritter A, Robertson C. Cerebral metabolism. Neurosurg Clin North Am 1994; 5: 633645. 17. Alten, Jeffrey MD; Mariscalco, M Michele MD, Critical appraisal of Perez et al: Jugular venous oxygen saturation or arteriovenous difference of lactate content and outcome in children with severe traumatic brain injury. Pediatr Crit Care Med 2005; 6: 480-482. 18. Ranucci et al. Central venous oxygen saturation and blood lactate levels during cardiopulmonary bypass are associated with outcome after pediatric cardiac surgery. CriticalCare 2010, 14:R149doi:10.1186/cc9217 19. Sheinberg M, Kanter MJ, Robertson CS, et al. Continuous monitoring of jugular venous oxygen saturation in head-injured patients. J Neurosurg. 1992; 77:162-163. 20. Thiagarajan A, Goverdhan PD, Chari P, et al. The effect of hyperventilation and hyperoxia on cerebral venous oxygen saturation in patients with traumatic brain injury. Anesth Analg 1998; 87:850853. 21. Guidelines for the management of severe head injury. Washington, DC: Brain Trauma Foundation, 1995. 22. Stochetti N, Barbagallo M, Gordon CR, et al. Arteriojugular difference of oxygen and intracranial pressure in comatose, head injured patients: technical aspects and complications. Minerva Anesthesiol 1991; 57:319326. 23. Rodrigues MG, Salgado DR, Resende VM, et al. Complications of monitoring of jugular bulb venous saturation. Critical Care 2003, 7(S3): P79doi:10.1186/ cc2275

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