Key Point:

The Surviving Sepsis Campaign has developed guidelines for the management of sepsis and septic shock; the guidelines’ major goal is a substantial reduction in sepsis-related mortality.

ORLANDO, FLA—Evidence-based guidelines for the management of sepsis and septic shock have just been released.[1] These guidelines evaluate the continuum of care required by sepsis patients, beginning with initial fluid resuscitation and antibiotic selection. They also address such controversial topics as corticosteroid use and blood glucose control.

The new guidelines were put together by a committee of experts from 11 international organizations, explained Mitchell M. Levy, MD, at the annual meeting of the Society of Critical Care Medicine. These experts worked under the auspices of the Surviving Sepsis Campaign, which is administered jointly by the Society of Critical Care Medicine, the European Society of Intensive Care Medicine, and the International Sepsis Forum. The recommendations were graded from A through E based on the quality of the supporting data (see box below).

The next major challenge, said Dr. Levy, an Associate Professor of Medicine at Brown University in Providence, Rhode Island, is to get clinicians to implement the guidelines, a goal that will require extensive promotion and clinician education. The aim is to reduce sepsis-related mortality by 25% over the next five years.

After much discussion, the guidelines committee agreed to advise seven days’ treatment with 200 to 300 mg/d of hydrocortisone for septic shock patients who require vasopressors for blood pressure maintenance despite adequate fluid replacement. The drug can be administered in three or four divided doses or by continuous infusion. However, this recommendation was rated only Grade C because no large randomized trials with clear results were available to support it.

“This was one of two areas in which we could not get 100% consensus,” noted R. Philip Dellinger, MD, lead author of the guidelines. In fact, said Dr. Dellinger, the only way to get the group to agree to any recommendation about corticosteroid use was to include caveats about adrenal stimulation tests, dosage tapering, and the possible addition of fludrocortisone to the regimen.

The committee was more comfortable recommending that hydrocortisone doses above 300 mg/d should not be used to treat septic shock. Two randomized clinical trials and two meta-analyses have shown that such high doses are ineffective or possibly harmful (Grade A).

Another difficult issue was the target blood glucose level. Dr. Dellinger, Director of Critical Care Medicine at Cooper University Hospital in Camden, New Jersey, explained that some members of the guidelines committee wanted to recommend tight blood glucose control—levels kept within the 80- to 110-mg/dL range associated with the best outcomes in one study. However, others were concerned that many community hospitals would not be able to adhere to this stringent standard. Thus, the group eventually decided to recommend that, once the patient is stabilized, blood glucose levels be maintained below 150 mg/dL (Grade D).

Fluid resuscitation of a patient with severe sepsis or sepsis-induced tissue hypoperfusion should not be delayed pending admission to the intensive care unit (Grade B). Either crystalloids or colloids can be used (Grade C). However, if early goal-directed therapy does not reach the targeted oxygen saturation ( greater than or equal to 70%), red blood cell transfusion or dobutamine administration should be considered (Grade B).

Dobutamine use may also be appropriate for patients with low cardiac output despite fluid resuscitation (Grade E). However, it is inappropriate to attempt to increase the cardiac index to an arbitrary, predefined elevated level (Grade A). Vasopressors should be added if blood pressure or organ perfusion remain low (Grade E). Either norepinephrine or dopamine can be used as a first-line agent (Grade D); vasopressin should not be substituted as a first-line agent, although it can be added for patients with refractory shock (Grade E).

The guidelines stress the importance of performing appropriate blood cultures before starting antimicrobial therapy. At least one specimen should be obtained percutaneously; others should be drawn through each vascular access device that has been in place for 48 hours or longer (Grade D).

Ideally, antibiotics should be started within one hour of when sepsis is first recognized (Grade E). However, Dr. Dellinger acknowledged that some hospitals may have to adopt special procedures to achieve this goal.

Broad-spectrum coverage is recommended initially (Grade D). The antimicrobial regimen should be reassessed after 48 to 72 hours, once the causative organism and its susceptibility have been defined; a narrow-spectrum antibiotic can then be substituted, if appropriate, to prevent the development of resistance, reduce toxicity, and minimize costs (Grade E).

The new guidelines also address the use of other therapies. Recombinant human activated protein C is recommended for sepsis patients who are at high risk of death, as long as no absolute contraindications to its use are present, or relative contraindications do not outweigh potential benefit (Grade B). Sedation for mechanically ventilated patients should be administered using a protocol, and a daily interruption or lightening of sedation should be included (Grade B). Neuromuscular blockers should be avoided, if possible (Grade E). Bicarbonate should not be given to improve hemodynamics or reduce vasopressor requirements (if the patient’s pH is greater than or equal to 7.15) (Grade C).

Prophylaxis against deep venous thrombosis (with unfractionated or low-molecular-weight heparin and/or a mechanical device) is recommended for patients with severe sepsis (Grade A). Similarly, prophylaxis against stress ulcers (preferably, with H2 antagonists) should be given (Grade A).

In addition, the guidelines include a number of recommendations about mechanical ventilation and renal replacement, as well as advice on limiting life support. Although it can be difficult, said Dr. Dellinger, physicians need to discuss prognosis and its impact on care with sepsis patients and their families. “Decisions for less aggressive support or withdrawal of support may be in the patient’s best interest,” he noted.

Grading the Sepsis Recommendations

The recommendations in the new sepsis/septic shock guidelines were graded based on the strength of the underlying evidence. Listed below are the recommendations that are supported by at least two large randomized trials with clear-cut results (grade A) or at least one such trial (grade B). The other recommendations in the guidelines are supported only by small randomized trials with uncertain results (grade C), by nonrandomized studies with contemporaneous controls (grade D), or by expert opinion in conjunction with nonrandomized studies with historical controls, uncontrolled studies, or case series (grade E).

Grade A recommendations

• Hydrocorticosone doses above 300 mg/d should not be used to treat septic shock. • Increasing cardiac index to achieve an arbitrarily predefined elevated level is not appropriate. • A spontaneous breathing trial, in conjunction with a weaning protocol, should be used to gauge patients’ readiness for extubation. • Prophylaxis against deep venous thrombosis and stress ulcers should be given to patients with severe sepsis.

Grade B recommendations

• Early goal-directed resuscitation should be administered to patients with severe sepsis or sepsis-induced tissue hypoperfusion; targets include central venous pressure between 8 and 12 mm Hg, mean arterial pressure of 65 mm Hg or higher, central or mixed venous oxygen saturation of 70% or higher, and urine output of 0.5 ml/kg/hr or higher. • Red blood cells and/or dobutamine should be given when early goal-directed therapy cannot achieve the oxygen saturation target. • Once tissue hypoperfusion has resolved, red blood cell transfusions should be used only when hemoglobin decreases below 7.0 g/dL or extenuating circumstances (eg, acute hemorrhage) are present. • Low-dose dopamine should not be used for renal protection. • Recombinant human activated protein C should be given to sepsis patients at high risk of death as long as no absolute contraindications to its use are present; in patients with relative contraindications, the benefits and risks must be assessed on an individual basis. • Erythropoietin should not be used to treat anemia related to severe sepsis unless another accepted reason for its administration is present. • Antithrombin use is not recommended. • High tidal volumes coupled with high plateau pressures should be avoided; the goals are a tidal volume of about 6 mL/kg and an end-inspiratory plateau pressure below 30 cm H2O. • Sedation protocols should be used to guide treatment of mechanically ventilated patients; the protocol should include a daily interruption/lightening of sedation. • In hemodynamically stable patients with acute renal failure, continuous venovenous hemofiltration and intermittent hemodialysis are equally effective. In hemodynamically unstable patients, continuous hemofiltation provides easier management of fluid balance.

—Timothy Begany

Reference
1.Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-873.

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