More Advances in the Prevention and Treatment of Sepsis/Septic Shock

Abstracts & Commentary

Synopsis: Maintenance of a normal blood glucose level in critically ill surgical intensive care patients is associated with a reduced mortality, especially deaths due to multi-organ system failure with a proven septic focus. Patients with severe sepsis and septic shock aggressively managed immediately on presentation according to a protocol with the goal of balancing oxygen delivery and demand have improved survival.

Sources: Van den Berghe G, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367; Rivers E, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-1377.

Van den Berghe and colleagues in Leuven, Belgium, performed an open controlled trial to determine the effect on clinical outcome of aggressive maintenance of normal blood glucose levels in adult patients admitted to a largely surgical (including 63% cardiac surgery) intensive care unit (ICU). Patients requiring mechanical ventilation were randomized to receive either conventional or intensive insulin therapy. The former group received a continuous insulin infusion if their blood glucose exceeded 215 mg/dL, with adjustments to maintain the level between 180 and 200 mg/dL. In the intensive treatment group, an insulin infusion was initiated if the blood glucose exceeded 110 mg/dL and the target range was 80-110 mg/dL.

The study was discontinued when a planned interim analysis demonstrated superiority of intensive insulin therapy. Although the mortality rates during the first 5 days of ICU care were almost identical, examination of patients who required more than 5 days of such care revealed that intensive insulin therapy was associated with an adjusted (for multiple interim analyses) risk reduction of 32% (95% CI, 2-55%; P < 0.04). Intensive insulin therapy was most effective in reducing mortality from multiple organ system failure in the presence of a septic focus, decreasing it from 33 of 783 (4.2%) in the conventional therapy group to 8 of 765 (1.0%) in the aggressive management arm.

Intensive insulin therapy was also associated with a 46% reduction (95% CI, 25-67%) in episodes of septicemia and concomitant reduction in prolonged use of antibiotics. Among those who did develop bacteremia, mortality was lower (12.5%) in the intensive management arm than in those receiving conventional insulin therapy (29.5%). Intensive insulin therapy was also associated with a reduced incidence of critical illness polyneuropathy as well as a reduced incidence of renal impairment and hyperbilirubinemia and a reduced duration of mechanical ventilation. Intensive insulin therapy was well tolerated.

Rivers and colleagues in Detroit enrolled 263 adult patients arriving in the emergency department (ED) with severe sepsis or septic shock in a trial examining the potential benefit of immediate goal-directed management (GDM) (see Table). Subjects were randomized to receive GDM in the ED for the first 6 hours or to receive standard therapy prior to transfer to an ICU. Patients with evidence of systemic inflammatory response syndrome and a systolic blood pressure < 90 mm Hg despite a defined fluid challenge or with hyperlactemia were eligible if all of a large number of exclusion criteria were absent.

Table
Goal-Directed Management Protocol

A 500 mL bolus of crystalloid given every 30 minutes to achieve a central venous pressure (CVP) of 8-12 mm Hg.
If the mean arterial pressure (MAP) < 65 mm Hg, give vasopressors to maintain MAP > 65 mm Hg.
If MAP > 90 mm Hg, give vasodilators to maintain MAP < 90 mm Hg.
If central venous O2 saturation (CVO2sat) < 70%, give RBC transfusion to maintain hematocrit > 30 vol%.
If, after optimization of CVP, MAP, and hematocrit the CVO2sat < 70%, administer dobutamine with adjustments* to maintain CVO2sat > 70%.
If unable to achieve hemodynamic optimization, reduce oxygen consumption by mechanical ventilation and sedation.
*2.5 µg/kg/min, increasing by 2.5 µg/kg/min every 30 minutes until CVO2sat > 70% or until a maximum dose of 20 µg/kg/min is reached. Decrease dose or discontinue dobutamine infusion if MAP < 65 mm Hg or heart rate > 120 beats/min.

The in-hospital mortality rate was significantly lower in the patients receiving GDM than in those receiving standard care (30.5% vs 46.5%; P = 0.009). This reduced mortality was associated with a higher mean CVO2sat, lower lactate concentration, lower base deficit, and higher arterial pH, as well as less severe organ dysfunction.

Comment by Stan Deresinski, MD, FACP

Van den Berghe et al provide strong evidence that maintenance of a blood glucose within a narrow range of 80-110 mg/dL is safe and is associated with a reduced risk of bacteremia as well as reduced mortality, especially sepsis-associated mortality, in selected critical care patients. At the same time, Rivers et al provide similarly strong evidence that, in patients who present with severe sepsis or septic shock, strictly protocol-driven management aimed at achieving defined hemodynamic goals is also associated with significantly reduced mortality. Although each of these studies have some drawbacks, the evidence they provide is sufficiently compelling to affect the practice of critical care medicine pending the completion of confirmatory trials.

Previous studies of the role of hemodynamic optimization, in which patients were enrolled as much as 72 hours after ICU admission, failed to demonstrate benefit. This delay was also frequently characteristic of several other studies with negative outcomes, including those involving antiTNF strategies. Relatively early intervention was characteristic of the other recently reported successful intervention in sepsis and septic shock. In that study, in which administration of human recombinant activated protein C (drotrecogin alfa activated) was associated with a reduction in the relative risk of death of 19.4% and an absolute reduction of 6.1%, the mean time from first organ dysfunction to the start of infusion was 17.5 hours.1-3 The lesson appears clear—early intervention is more likely to be successful than delayed intervention.

Thus, current data provide evidence that points to effective strategies in the prevention and management of severe sepsis and septic shock. This evidence includes the following:

• Maintenance of normal blood sugar in surgical intensive care patients is associated with a reduced risk of bacteremia and of multi-organ system dysfunction with a septic focus.

• In patients who develop severe sepsis or septic shock, early aggressive goal-directed management is associated with reduced mortality.

• Administration of human recombinant activated protein C to patients older than the age of 50 with sepsis and organ system dysfunction with high Apache scores significantly reduces mortality.

References

1. Bernard GR, et al. N Engl J Med. 2001;344:699-709.

2. Deresinski SC. Infectious Disease Alert. 2001;20:81-82.

3. http://www.fda.gov. Accessed November 21, 2001.

Dr. Deresinski, Clinical Professor of Medicine, Stanford; Director, AIDS Community Research Consortium; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.