Septic shock: The initial moments and beyond

Adding catecholamines

The optimal time point or vasopressor dose at which to consider initiating additional therapies is unknown. However, the Vasopressin and Septic Shock Trial (VASST) provides some insight.⁵¹

This study compared two strategies: escalating doses of norepinephrine vs adding vasopressin to norepinephrine. Overall, adding vasopressin showed no benefit in terms of a lower mortality rate. However, in the subgroup of patients with norepinephrine requirements of 5 to 14 μg/min at study enrollment (ie, a low dose, reflecting less-severe sepsis) vasopressin was associated with a lower 28-day mortality rate (26.5% vs 35.7%, P = .05) and 90-day mortality rate (35.8% vs 46.1%, P = .04). Benefit was also noted in patients with other markers of lower disease severity such as low lactate levels or having received a single vasopressor at baseline.⁵¹

Although subgroup analyses should not generally be used to guide treatment decisions, a prospective trial may never be done to evaluate adding vasopressin to catecholamines earlier vs later. Thus, clinicians who choose to use vasopressin may consider starting this therapy when catecholamine doses are relatively low or before profound hyperlactatemia from prolonged tissue hypoxia has developed.

There is less evidence to guide clinicians who are considering adding a different catecholamine. The theoretical concerns of splanchnic ischemia and cardiac arrhythmia associated with higher doses of catecholamines are usually the impetus to limit a single catecholamine to a “maximum” dose. However, studies that have evaluated combination catecholamine therapies have generally studied combinations of vasopressors with inotropes and lacked standardization in their protocols, thus making them difficult to interpret.^52–54 One could also argue that additional catecholamine therapies, which all function similarly, may have additive effects and cause even more adverse effects. As such, adding another vasopressor should be reserved for patients experiencing noticeable adverse effects (such as tachycardia) on first-line therapy.

Inotropic support

Left ventricular function should be assessed in all patients who continue to be hypotensive despite adequate fluid resuscitation and vasopressor therapy. In a study of patients with septic shock in whom echocardiography was performed daily for the first 3 days of hemodynamic support, new-onset left ventricular hypokinesia was found in 26 (39%) of 67 patients on presentation and in an additional 14 patients (21%) after at least 24 hours of norepinephrine.⁵⁵ Adding inotropic support with dobutamine or epinephrine led to decreases in vasopressor dose and enhanced left ventricular ejection fraction.

In short, left ventricular hypokinesia is common in septic shock, may occur at presentation or after a period of vasopressor support, and is usually correctable with the addition of inotropic support.

Corticosteroids

Beyond hemodynamic support with fluids and catecholamines or vasopressin (or both), clinicians should also consider adjunctive corticosteroid therapy. However, for many years the issue has been controversial for patients with severe sepsis and septic shock.

Annane et al⁵⁶ conducted a large, multicenter, randomized, double-blind, placebocontrolled trial to assess the effect of low doses of corticosteroids in patients with refractory septic shock. Overall, the 28-day mortality rate was 61% in the treatment group and 55% in the placebo group, which was not statistically significant (adjusted odds ratio 0.65, 95% confidence interval 0.39–1.07, P value .09). However, when separated by response to cosyntropin stimulation, those with a change in cortisol of 9 ug/dL or less (nonresponders) randomized to receive corticosteroids had significantly higher survival rates in the short term (28 days) and the long term (1 year). The positive results of this study led to the adoption of low-dose hydrocortisone as standard practice in most patients with septic shock.⁵⁷

But then, to evaluate the effects of corticosteroids in a broader intensive-care population with septic shock, another trial was designed: the Corticosteroid Therapy of Septic Shock (CORTICUS) trial.⁵⁸ Surprisingly, this multicenter, randomized, double-blind, placebo-controlled trial found no significant difference in survival between the group that received hydrocortisone and the placebo group, regardless of response to a cosyntropin stimulation test.

Taking into account the above studies and other randomized controlled trials, the 2012 Surviving Sepsis Campaign guidelines and the International Task Force for the Diagnosis and Management of Corticosteroid Insufficiency in Critically Ill Adult Patients recommend intravenous hydrocortisone therapy in adults with septic shock whose blood pressure responds poorly to fluid resuscitation and vasopressor therapy. These consensus statements do not recommend the cosyntropin stimulation test to identify patients with septic shock who should receive corticosteroids.^22,59 The guidelines, however, do not explicitly define poor response to initial therapy.

Of note, in the Annane study, which found a lower mortality rate with corticosteroids, the patients were severely ill, with a mean baseline norepinephrine dose of 1.1 μg/kg/min. In contrast, in the CORTICUS study (which found no benefit of hydrocortisone), patients had lower baseline vasopressor doses, with a mean norepinephrine dose of 0.5 μg/kg/min.

While corticosteroids are associated with a higher rate of shock reversal 7 days after initiation, ⁵⁹ this has not translated into a consistent reduction in the death rate. If a clinician is considering adding corticosteroids to decrease the risk of death, it would seem prudent to add this therapy in patients receiving norepinephrine in doses above 0.5 μg/kg/min.

The ideal sequence and combination of the above therapies including fluids, catecholamine vasopressors, vasopressin, inotropes, and vasopressors have not been elucidated. However, some preliminary evidence suggests an advantage with the combination of vasopressin and corticosteroids. In a subgroup analysis of the VASST study, in patients who received corticosteroids, the combination of vasopressin plus norepinephrine was associated with a lower 28-day mortality rate than with norepinephrine alone (35.9% vs 44.7%, P = .03).⁶⁰ These findings have been replicated in other studies,^61,62 prompting suggestions for a study of vasopressin with and without corticosteroids in patients on norepinephrine to elucidate the role of each therapy individually and in combination.

Tight glycemic control

As with corticosteroids, the pendulum for tight glycemic control in critically ill patients has swung widely in recent years. Enthusiasm was high at first after the publication of a study by van den Berghe et al, which described a 3.4% absolute reduction in mortality with intensive insulin therapy to maintain blood glucose at or below 110 mg/dL.⁶³ However, the significant benefits found in this study were never replicated.

In fact, recent evidence suggests that tight glycemic control is associated with no benefit and a higher risk of hypoglycemia.^34,64 In the largest randomized controlled trial of this topic, with more than 6,000 patients, intensive insulin therapy with a target blood glucose level of 81 to 108 mg/dL was associated with a significantly higher mortality rate (odds ratio 1.14, 95% confidence interval 1.02–1.28, P = .02) than with a target glucose level of less than 180 mg/dL.⁶⁵ Furthermore, in a recent follow-up analysis,⁶⁶ moderate hypoglycemia (serum glucose 41–70 mg/dL) and severe hypoglycemia (serum glucose < 41 mg/dL) were associated with a higher rate of death in a dose-response relationship.⁶⁶

Taking this information together, clinicians should be aware that there is no additional benefit in lowering blood glucose below the range of 140 to 180 mg/dL, and that doing so may be harmful.

Drotecogin alfa

Drotecogin alfa (Xigris) was another adjunctive therapy that has fallen from favor. It was approved for the treatment of severe sepsis in light of promising findings in initial studies.⁶⁷

However, on October 25, 2011, drotecogin alfa was voluntarily withdrawn from the market by the manufacturer after another study found no beneficial effect on the mortality rates at 28 days or at 90 days.⁶⁸ Furthermore, no difference could be found regarding any predetermined primary or secondary outcome measures.

Continued antibiotic therapy

The decision whether to continue initial empiric antimicrobial coverage, broaden it, or de-escalate must be faced for all patients with septic shock, and is ultimately clinical.

The serum procalcitonin level has been proposed to guide antibiotic discontinuation in several clinical settings, although there are still questions about the safety of such an approach. The largest randomized trial published to date reported that a procalcitoninguided strategy to treat suspected bacterial infections in nonsurgical patients could reduce antibiotic exposure with no apparent adverse outcomes.⁶⁹ On the other hand, other data discourage the use of procalcitonin-guided antimicrobial escalation, as this approach did not improve survival and worsened organ function and length of stay in the intensive care unit.⁷⁰

The Surviving Sepsis Campaign guidelines recommend combination antibiotic therapy for no longer than 3 to 5 days and limiting the duration of antibiotics in most cases to 7 to 10 days.²²

TRIALS ARE ONGOING

The understanding of the pathophysiology and treatment of sepsis has greatly advanced over the last decade. Adoption of evidence-based protocols for managing patients with septic shock has improved outcomes. Nevertheless, many multicenter trials are being conducted worldwide to look into some of the most controversial therapies, and their results will guide therapy in the future.