Treating Sepsis: An Update on the Latest Therapies, Part 1

Sushma K. Cribbs, MD and Greg S. Martin, MD, MSc

| June 2, 2009

Dr Cribbs is a senior fellow and Dr Martin is assistant professor of medicine, division of pulmonary, allergy, and critical care medicine, Emory University School of Medicine, Atlanta.

Corticosteroids
The past decade has seen a considerable debate and the emergence of new evidence regarding the use of corticosteroids in septic shock. In the past, randomized clinical trials and meta-analyses have shown that high-dose corticosteroid therapy is ineffective in patients with severe sepsis or septic shock.^93-96 Until recently, there was 1 multicenter randomized controlled trial that suggested better shock reversal and a survival benefit in patients with vasopressor-unresponsive septic shock and relative adrenal insufficiency, defined as a post–adrenocorticotropic hormone (ACTH) cortisol level increase of 9 µg/dL or less.⁹⁷ Two smaller, single-center studies also suggested that there was a greater incidence of shock reversal with corticosteroids.^98,99

A large European multicenter trial, Corticosteroid Therapy of Septic Shock (CORTICUS), randomized 499 patients with septic shock to receive either low-dose hydrocortisone(Drug information on hydrocortisone) therapy or placebo for 5 days.¹⁰⁰ The authors concluded that at 28 days, there was no significant difference in mortality between patients in the 2 treatment groups, irrespective of any response to ACTH.¹⁰⁰ While corticosteroids hastened the reversal of septic shock, they were also associated with a greater risk of nosocomial infections and recurrent sepsis.¹⁰⁰ These results suggest that ACTH stimulation testing is not useful in predicting which patients with sepsis may benefit from corticosteroids and that corticosteroid therapy in general does not improve clinical outcomes in patients with septic shock.

Corticosteroids are not without adverse effects. These drugs are immunosuppressive, potentially leading to secondary infections and impaired wound healing, and can cause myopathy, hyperglycemia, and hypernatremia.^98-100 Thus, corticosteroid therapy should be discontinued as early as possible.⁴¹ However, to date no study has compared a fixed duration of corticosteroid therapy followed by tapering over several days^92,93 or abrupt discontinuation⁹¹ with tapering therapy after shock resolution,⁹⁹ so it remains uncertain whether outcome is affected by tapering of corticosteroids.

However, despite these controversies, corticosteroids are still suggested only for patients with septic shock, since no studies suggest a benefit in patients with less severe forms of sepsis whose blood pressure is poorly responsive to fluids and vasopressor therapy.⁴¹

Treatment of anemia in sepsis
Anemia is a common feature among critically ill patients with sepsis who frequently require transfusions of PRBCs.¹⁰¹ Hemoglobin concentrations typically decline during the first few days of an ICU stay, but while they tend to stabilize in patients without sepsis, hemoglobin concentrations continue to decline in patients with sepsis.¹⁰² To date, the optimum hemoglobin level in patients with sepsis has not been evaluated, but it certainly varies according to the phase (early vs late) of sepsis.

Two main randomized controlled trials have evaluated transfusion strategies in patients with sepsis.^1,103 Early goal-directed therapy includes transfusion of PRBCs to a target hematocrit level of 30% or higher during the first 6 hours of resuscitation for septic shock.¹ Although not limited to patients with sepsis, the Transfusion Requirements in Critical Care (TRICC) trial compared 2 transfusion strategies in 838 euvolemic critically ill patients.¹⁰³ After initial resuscitation, the patients were randomized to either a restrictive (maintenance of hemoglobin level of 7.0 to 9.0 g/dL with a threshold of 7.0 g/dL) or a liberal (maintenance of hemoglobin level of 10.0 to 12.0 g/dL with a threshold of 10.0 g/dL) transfusion strategy that was adhered to throughout the patient’s ICU stay.

There was no difference in 30-day all-cause mortality between the 2 groups overall, but there was improved survival in the younger and less severely ill patients.¹⁰³ Sepsis was the primary diagnosis in only 5% of patients, limiting the interpretation of these results for this population. Together, these studies suggest that PRBC transfusion is valuable during the early stage of sepsis as opposed to later stages when patients are more likely to be euvolemic—transfusion to a hematocrit level of 30% or higher decreases mortality during the first 6 hours of resuscitation, while maintenance of hemoglobin levels of 7.0 to 9.0 g/dL is adequate after initial resuscitation.

Recombinant human erythropoietin(Drug information on erythropoietin) has also been evaluated as a therapy for critically ill anemic patients. Patients with sepsis exhibit inappropriately low levels of erythropoietin,^104,105 and 2 previous trials involving critically ill patients showed that erythropoietin therapy reduced red cell transfusions but did not decrease mortality.^106,107

In a large randomized trial of 1460 patients, of which 13% had sepsis, erythropoietin therapy did not reduce the incidence of PRBC transfusion among critically ill patients.¹⁰⁸ While mortality was reduced in the trauma patients, the incidence of thrombotic events was increased in all patients who received erythropoietin therapy.¹⁰⁸ As such, current guidelines do not recommend erythropoietin for the treatment of anemia associated with sepsis.⁴¹

[Editor’s note: In part 2, Drs Cribbs and Martin will continue their review of the management of sepsis.]

Pages: 1 2 3 4

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Treating Sepsis: An Update on the Latest Therapies, Part 1

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