Septic shock: The initial moments and beyond
ABSTRACTOur understanding of the pathophysiology and treatment of sepsis has advanced over the last decade, and evidence-based protocols have improved its outcomes. Here, we review its management in the first hours and afterward, including topics of ongoing study and debate.
KEY POINTS
- Managing septic shock in the first 6 hours involves prompt recognition, empiric antibiotic therapy, elimination of the source of infection (if applicable), fluid resuscitation titrated to specific goals, and vasopressor therapy.
- A number of biomarkers have been proposed to help recognize septic shock early in its course.
- A delay in starting appropriate antibiotic treatment is associated with higher risk of death.
- The ideal measure of the adequacy of fluid resuscitation remains a topic of study and debate.
- Preliminary studies suggest that norepinephrine should be the initial vasopressor.
- Management after the first 6 hours is less well defined. Decisions in this period include whether to give further fluid resuscitation, further and additional hemodynamic therapies, adjunctive therapies, and antibiotics.
Vasopressors: Which one to use?
If fluid therapy does not restore perfusion, vasopressors should be promptly initiated, as the longer that hypotension goes on, the lower the survival rate.39
But which vasopressor should be used? The early goal-directed therapy protocol used in the study by Rivers et al27 did not specify which vasopressor should be used to keep the mean arterial pressure above 65 mm Hg.
The Surviving Sepsis Campaign22 recommends norepinephrine as the first-choice vasopressor, with dopamine as an alternative only in selected patients, such as those with absolute or relative bradycardia.
The guidelines also recommend epinephrine to be added to or substituted for norepinephrine when an additional catecholamine is needed to maintain adequate blood pressure.22 Furthermore, vasopressin at a dose of 0.03 units/min can be added to norepinephrine with the intent of raising the blood pressure or decreasing the norepinephrine requirement. Higher doses of vasopressin should be reserved for salvage therapy.
Regarding phenylephrine, the guidelines recommend against its use except when norepinephrine use is associated with significant tachyarrhythmias, cardiac output is known to be higher, or as a salvage therapy.22
This is a topic of debate, with recent clinical studies offering further insight.
De Backer et al40 compared the effects of dopamine vs norepinephrine for the treatment of shock in 1,679 patients, 62% of whom had septic shock. Overall, there was a trend towards better outcomes with norepinephrine, but no significant difference in mortality rates at 28 days (52.5% with dopamine vs 48.5% with norepinephrine, P = .10). Importantly, fewer patients who were randomized to norepinephrine developed arrhythmias (12.4% vs 24.1%, P < .001), and the norepinephrine group required fewer days of study drug (11.0 vs 12.5, P = .01) and open-label vasopressors (12.6 vs 14.2, P = .007). Of note, patients with cardiogenic shock randomized to norepinephrine had a significantly lower mortality rate than those randomized to dopamine. Although no significant difference in outcome was found between the two vasopressors in the subgroup of patients with septic shock, the overall improvements in secondary surrogate markers suggest that norepinephrine should be the first-line agent.
Norepinephrine has also been compared with “secondary” vasopressors. Annane et al,41 in a prospective multicenter randomized controlled study, evaluated the effect of norepinephrine plus dobutamine vs epinephrine alone in managing septic shock. There was no significant difference in the primary outcome measure of 28-day mortality (34% with norepinephrine plus dobutamine vs 40% with epinephrine alone, P = .31). However, the study was powered to evaluate for an absolute risk reduction of 20% in the mortality rate, which would be a big reduction. A smaller reduction in the mortality rate, which would not have been statistically significant in this study, might still be considered clinically significant. Furthermore, the group randomized to norepinephrine plus dobutamine had more vasopressor-free days (20 days vs 22 days, P = .05) and less acidosis on days 1 to 4 than the group randomized to epinephrine.
Norepinephrine was also compared with phenylephrine as a first-line vasopressor in a randomized controlled trial in 32 patients with septic shock. No difference was found in cardiopulmonary performance, global oxygen transport, or regional hemodynamics between phenylephrine and norepinephrine.42
While encouraging, these preliminary data need to be verified in a larger randomized controlled trial with concrete outcome measures before being clinically adapted. Taken together, the above studies suggest that norepinephrine should be the initial vasopressor of choice for patients with septic shock.
CONTINUED MANAGEMENT OF SEPTIC SHOCK
How to manage septic shock after the initial stages is much less defined.
Uncertainty persists about the importance of achieving the early goals of resuscitation in patients who did not reach them in the initial 6 hours of treatment. Although there are data suggesting that extending the goals beyond the initial 6 hours may be beneficial, clinicians should use caution when interpreting these results in light of the observational design of the studies.43,44 For the purpose of this discussion, “continued management” of septic shock will mean after the first 6 hours and after all the early goals are met.
The clinical decisions necessary after the initial stages of resuscitation include:
- Whether further fluid resuscitation is needed
- Assessment for further and additional hemodynamic therapies
- Consideration of adjunctive therapies
- Reevaluation of antibiotic choices (Table 2).
Is more fluid needed? How can we tell?
There is considerable debate about the ideal method for assessing fluid responsiveness. In fact, one of the criticisms of the early goal-directed therapy study27 was that it used central venous pressure as a marker of fluid responsiveness.
Several studies have shown that central venous pressure or pulmonary artery occlusion pressure may not be valid measures of fluid responsiveness.45 In fact, in a retrospective study of 150 volume challenges, the area under the receiver-operating-characteristics curve of central venous pressure as a marker of fluid responsiveness was only 0.58. (Recall that the closer the area under the curve is to 1.0, the better the test; a value of 0.50 is the same as chance.) The area under the curve for pulmonary artery occlusion pressure was 0.63.46
In contrast, several dynamic indices have been proposed to better guide fluid resuscitation in mechanically ventilated patients.31 These are based on changes in stroke volume, aortic blood flow, or arterial pulse pressure in response to the ventilator cycle or passive leg-raising. A detailed review of these markers can be found elsewhere,31 but taken together, they have a sensitivity and specificity of over 90% for predicting fluid responsiveness. Clinicians may consider using dynamic markers of fluid responsiveness to determine when to give additional fluids, particularly after the first 6 hours of shock, in which data supporting the use of central venous pressure are lacking.
Optimal use of fluids is particularly important, since some studies suggest that “overresuscitation” has negative consequences. In a multicenter observational study of 1,177 patients with sepsis, after adjusting for a number of comorbidities and baseline severity of illness, the cumulative fluid balance in the first 72 hours after the onset of sepsis was independently associated with a worse mortality rate.47
Furthermore, in a retrospective analysis of a randomized controlled trial of vasopressin in conjunction with norepinephrine for septic shock, patients in the highest quartile of fluid balance (more fluid in than out) at 12 hours and 4 days after presentation had significantly higher mortality rates than those in the lowest two quartiles.48 The worse outcome with a positive fluid balance might be explained by worsening oxygenation and prolonged mechanical ventilation, as demonstrated by the Fluid and Catheter Treatment Trial in patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS).49 Indeed, when fluid balance in patients with septic shockinduced ALI/ARDS was evaluated, patients with both adequate initial fluid resuscitation and conservative late fluid management had a lower mortality rate than those with either one alone.50
In view of these findings, especially beyond the initial hours of resuscitation, clinicians should remember that further unnecessary fluid administration may have detrimental effects. Therefore, given the superior predictive abilities of dynamic markers of fluid responsiveness, these should be used to determine the need for further fluid boluses.
In cases in which patients are no longer fluid-responsive and need increasing levels of hemodynamic support, clinicians still have a number of options. These include increasing the current vasopressor dose or starting an additional therapy such as an alternative catecholamine vasopressor, vasopressin, inotropic therapy, or an adjunctive therapy such as a corticosteroid. The intervention could also be a combination of the above choices.
