research is still needed. Crit Care Med 2010; 38:683– 684 8.

Machado FR, Mazza BF: Improving mortality in sepsis: Analysis of clinical trials. Shock 2010;34(Suppl 1):54 –58 9. Jones AE, Brown MD, Trzeciak S, et al: The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: A metaanalysis. Crit Care Med 2008; 36:2734 –2739 10. Trzeciak S, Dellinger RP, Abate NL, et al: Translating research to clinical practice: A 1-year experience with implementing early goal-directed therapy for septic shock in the emergency department. Chest 2006; 129: 225–232

11. Shapiro NI, Howell MD, Talmor D, et al: Implementation and outcomes of the Multiple Urgent Sepsis Therapies (MUST) protocol. Crit Care Med 2006; 34:1025–1032 12. Jones AE, Focht A, Horton JM, et al: Prospective external validation of the clinical effectiveness of an emergency department-based early goal-directed therapy protocol for severe sepsis and septic shock. Chest 2007; 132:425– 432 13. Nichol AD, Egi M, Pettila V, et al: Relative hyperlactatemia and hospital mortality in critically ill patients: A retrospective multicentre study. Crit Care 2010; 14:R25 14. Nguyen HB, Rivers EP, Knoblich BP, et al:

Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637–1642 15. Bakker J, Gris P, Coffernils M, et al: Serial blood lactate levels can predict the development of multiple organ failure following septic shock. Am J Surg 1996; 171:221–226 16. Arnold RC, Shapiro NI, Jones AE, et al: Multicenter study of early lactate clearance as a determinant of survival in patients with presumed sepsis. Shock 2009; 32:35–39 17. Jones AE, Shapiro NI, Trzeciak S, et al: Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: A randomized clinical trial. JAMA 2010; 303:739 –746

Stop filling patients against central venous pressure, please!*
n this issue of Critical Care Medicine, Boyd and colleagues (1) present the results of their study examining fluid balance during resuscitation of patients suffering from septic shock. The investigators studied 778 patients originally enrolled in the Vasopressin And Septic Shock Trial (2) who had septic shock and who were receiving a minimum of 5 g of noradrenaline per minute. The main objective was to determine whether central venous pressure and fluid balance following resuscitation for septic shock was associated with mortality. The study design was a retrospective review of the use of intravenous fluids during the first 4 days of care in the intensive care unit. After correcting for age and Acute Physiology Assessment and Chronic Health Evaluation II score, a more positive fluid balance at both 12 hrs and day 4 correlated significantly with increased mortality. Furthermore, central venous pressure was found to be an unreliable marker of fluid balance. Boyd and colleagues (1) present provocative data on a hot topic in intensive care medicine. The current Surviving Sepsis Guidelines (3) are based on the protocol first applied by Rivers et a1 (4),

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*See also p. 259. Key Words: septic shock; severe sepsis; fluid resuscitation; sepsis guidelines The author has not disclosed any potential conflicts of interest. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e318205c375

where they aimed to achieve mean arterial pressure of 65 mm Hg, central venous pressure of 8 –12 mm Hg, urine output of 0.5 mL/kg/hr, and a central venous oxygen saturation of 70% during the early phase of resuscitation. By administration of antibiotics and a strict adherence to this early goal-directed therapy protocol, Rivers et al (4) demonstrated a highly favorable outcome. In this new study, Boyd and colleagues (1) link a negative outcome to those who became fluid overloaded. This finding is also in line with the results from the European survey of critically ill patients with sepsis, where a positive fluid balance was found to be associated with increased mortality (5). Furthermore, positive fluid balance has also been shown to increase time spent on mechanical ventilation and a trend toward increased mortality in patients with acute lung injury (6). These and other studies highlight the need for a closer monitoring and evaluation of current practice. How should we monitor patients suffering from severe sepsis and septic shock? How should we specifically monitor fluid balance in septic patients receiving early goal-directed therapy, and how should fluid responsiveness be assessed? Current sepsis guidelines focus on targeting an optimum delivery of oxygen to the body through preload optimization, initiation of timely and appropriate vasopressor and inotropic support (3). For decades central venous pressure has been known to be a poor parameter for fluid balance. Dr. Swan’s group presented data on this issue nearly 40 yrs ago (7), and experimental and human studies

have consistently confirmed a very poor correlation between central venous pressure and preload (8). Although central venous pressure is a fairly good estimate of right atrial pressure, it bears little relation to right ventricular end-diastolic volume, right ventricular stroke volume, and left ventricular preload (9). Accordingly, fluid resuscitation in septic patients must be guided by other parameters than central venous pressure alone, as it might mislead clinicians to either overfill or underfill septic patients (10). Accordingly, the present study should urge us to review current guidelines and discuss alternatives to central venous pressure as a target parameter for fluid resuscitation. To date no randomized controlled trials have been designed to study dosing of intravenous fluids in patients suffering from septic shock. The present data were corrected for age and Acute Physiology Assessment and Chronic Health Evaluation II score, yet this does not necessarily mean that these patients were equally ill. Two patients with identical Acute Physiology Assessment and Chronic Health Evaluation II scores might respond differently to fluids. One patient may well be reversed by fluids and the other not. Fluid responsiveness could thus serve as a measure of illness, indirectly reflecting the degree of inflammation and capillary leak. Unfortunately, failure to reverse septic shock with fluids may thus lead us to give even more fluids, leading to further organ failure and death. The present study links a positive fluid balance and elevated central venous pressure to inCrit Care Med 2011 Vol. 39, No. 2

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creased mortality but did not actually show a causal relationship. This is of course a weakness of retrospective studies. A prospective, randomized study of a liberal vs. restrictive fluid management strategy will be required to definitely prove any causal relationship between fluid balance and mortality inpatient with severe sepsis and septic shock. In any case, we should continue to monitor patients and administrate fluids guided by parameters that can provide us with accurate information on current hemodynamic and oxygen transport status. Most centers would thus advocate the use of calibrated devices offering intermittent or continuous cardiac index monitoring and monitor oxygen transport data via arterial and central venous blood gases, as well as performing repeated bedside clinical assessments. Dynamic responses to volume challenge by using either stroke volume variation or pulse pressure variation are both highly sensitive and specific for preload responsiveness in mechanical ventilated patients, whereas the passive straight leg test should be used in spontaneously breathing patients (11). However, arrhythmias, spontaneous breathing efforts, as well as low tidal volumes are known to reduce accuracy of these two parameters (12). Accordingly, data must be interpreted with these limitations in mind. Echocardiographic

methods for assessment of cardiac function and fluid responsiveness provide useful complimentary information in this context. However, we should remind ourselves that no single parameter should be evaluated in isolation. Resuscitation from severe sepsis and septic shock remains a dynamic clinical challenge. Indeed, fluids do make a difference and that is why we should stop filling patients against central venous pressure. Lars Marius Ytrebø, MD University Hospital of North Norway Tromso, Norway

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REFERENCES
1. Boyd JH, Forbes J, Nakada T, et al: Fluid resuscitation in septic shock: A positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med 2011; 39:259 –265 2. Russell JA, Walley KR, Singer J, et al: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877– 887 3. Dellinger RP, Levy MM, Carlet JM, et al: Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 2008; 34:17– 60 4. Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368 –1377 5. Vincent JL, Sakr Y, Sprung CL, et al: Sepsis 9.

10.

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in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34: 344 –353 National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al: Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006; 354:2564 –2575 Forrester JS, Diamond G, McHugh TJ, et al: Filling pressures in the right and left sides of the heart in acute myocardial infarction. A reappraisal of central-venous-pressure monitoring. N Engl J Med 1971; 285:190 –193 Marik PE, Baram M, Vahid B: Does central venous pressure predict fluid responsiveness? A systematic review of the literature and the tale of seven mares. Chest 2008; 134:172–178 Osman D, Ridel C, Ray P, et al: Cardiac filling pressures are not appropriate to predict hemodynamic response to volume challenge. Crit Care Med 2007; 35:64 – 68 Perel A: Bench-to-bedside review: The initial hemodynamic resuscitation of the septic patient according to Surviving Sepsis Campaign guidelines– does one size fit all? Crit Care 2008; 12:223 Marik PE: Techniques for assessment of intravascular volume in critically ill patients. J Intensive Care Med 2009; 24:329 –337 Marik PE, Cavallazzi R, Vasu T, et al: Dynamic changes in arterial waveform derived variables and fluid responsiveness in mechanically ventilated patients: A systematic review of the literature. Crit Care Med 2009; 37:2642–2647

What is the evidence for glucose control in children undergoing cardiac surgery?*
ritically ill patients commonly develop transient, stress-induced hyperglycemia, which historically was presumed to be adaptive and generally not treated. However, triggered in large part by the publication of the landmark Leuven University Hospital adult surgical intensive

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*See also p. 266. Key Words: pediatrics; intensive care; hyperglycemia; cardiovascular surgery. The author has not disclosed any potential conflicts of interest. Copyright © 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e318205c2f1

care unit trial, which found that the use of insulin to achieve normoglycemia was associated with decreased mortality, the topic has been the focus on substantial investigation and debate over the last decade (1). Numerous observational studies in various critically ill adult patient populations have found associations between hyperglycemia and adverse outcomes. Mechanisms of critical illness-related glucose toxicity described in adults include proinflammatory effects and immunoparesis as well as mitochondrial, endothelial, and neuronal dysfunction, among others (2– 4). However, in recent years, the initial enthusiasm for tight glycemic control during critical illness in adults

has been tempered by the fact that two multicenter adult trials have been terminated prematurely for lack of efficacy and safety concerns related to excessive rates of hypoglycemia (5, 6). Even more concerning were the findings of a third multicenter trial in which patients assigned to tight glycemic control had increased mortality compared with the control group, in whom the glucose target range was 144 –180 mg/dL (7). Differences in nutritional support, nursing expertise, glucose target ranges, and measurement systems may explain some of the discrepant findings. Similar to adult data, the majority of observational studies in children under397

Crit Care Med 2011 Vol. 39, No. 2

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