The best type of fluid replacement and optimal volume of resuscitation in the setting of severe sepsis have been heavily debated but studies have provided guidance to the clinician. One trial comparing 4% albumin with normal saline for fluid resuscitation found no difference in mortality at 28 days. 24 A 2004 meta-analysis similarly found no mortality advantage with the use of colloids compared with the use of crystalloids. 25 The trial of EGDT revealed that patients in the treatment arm received far greater volumes of fluid in the first 6 hours of resuscitation than those in the control arm. In a large study of European ICUs, patients with a positive fluid balance at 72 hours had a poor outcome. 26 In a clinical trial of patients with acute lung injury, the use of a conservative fluid strategy targeting a CVP lower than 4 mm Hg and a pulmonary artery occlusion pressure (PAOP) lower than 8 mm Hg was associated with a fewer number of ICU and ventilators days. 27 The preponderance of data would suggest that aggressive fluid management be done in the acute phase of sepsis, followed by a more conservative phase in the following few days.
On a macroscopic level, sepsis progresses along a spectrum from infectious insult to septic shock and multiorgan dysfunction. 25 Septic shock is a form of distributive shock, manifested in patients by an increase in cardiac output and vasodilation. 24 The oxygen demand of end organs exceeds oxygen delivery, and with the cellular switch from aerobic to anaerobic metabolism, lactate is produced. 28 As oxygen demands remain unmatched, perfusion decreases leading to end organ failure. With each organ system failure, absolute mortality increases by 15%-20%. 27
(NEJM 2008;358(2):125) Intensive Insulin Therapy and Pentastarch Resuscitation in Severe Sepsis Background The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support the choice of either crystalloids or colloids. Methods In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/), or modified Ringer’s lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. Results The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [ mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [ mmol per liter], P ). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, 40 mg per deciliter [ mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (% vs. %, P ), as was the rate of serious adverse events (% vs. %, P=). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer’s lactate. Conclusions The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. ( number, NCT00135473  .)