Septic shock: The initial moments and beyond

Starting empiric antibiotic therapy early

As soon as severe sepsis and septic shock are recognized, it is imperative that adequate empiric antibiotic treatment be started, along with infectious source control if applicable.²¹ The Surviving Sepsis Campaign guidelines recommend starting intravenous antibiotics as early as possible—within the first hour of recognition of severe sepsis with or without septic shock.²²

Kumar et al,²³ in a multicenter retrospective study of patients with septic shock, found that each hour of delay in giving appropriate antimicrobial agents in the first 6 hours from the onset of hypotension was associated with a 7.6% decrease in the in-hospital survival rate.

In a similar study,²⁴ the same investigators analyzed data from 5,715 septic shock patients regarding the impact of starting the right antimicrobial therapy. Appropriate antimicrobial agents (ie, those having in vitro activity against the isolated pathogens) were given in 80.1% of cases, and the survival rate in those who received appropriate antibiotics was drastically higher than in those who received inappropriate ones (52.0% vs 10.3%, P < .0001).

In addition, two recent studies evaluated the importance of early empiric antibiotic therapy in conjunction with resuscitative protocols.^25,26 In a preplanned analysis of early antimicrobial use in a study comparing lactate clearance and Scvo₂ as goals of therapy, Puskarich et al²⁶ found that fewer patients who received antibiotics before shock was recognized (according to formal criteria) died. Similarly, in a retrospective study in patients presenting to the emergency department and treated with early goal-directed therapy (defined below), Gaieski et al²⁵ found that the mortality rate was drastically lower when antibiotics were started within 1 hour of either triage or initiation of early goal-directed therapy.

In short, it is imperative to promptly start the most appropriate broad-spectrum antibiotics to target the most likely pathogens based on site of infection, patient risk of multidrug-resistant pathogens, and local susceptibility patterns.

Goal-directed resuscitative therapy

As with antimicrobial therapy, resuscitative therapy should be started early and directed at defined goals.

Rivers et al²⁷ conducted a randomized, controlled study in patients with severe sepsis or septic shock presenting to an emergency department of an urban teaching hospital. The patients were at high risk and had either persistent hypotension after a fluid challenge or serum lactate levels of 4 mmol/L or higher.

Two hundred sixty patients were randomized to receive either early goal-directed therapy in a protocol aimed at maximizing the intravascular volume and correcting global tissue hypoxia or standard therapy in the first 6 hours after presentation. The goals in the goal-directed therapy group were:

• Central venous pressure 8 to 12 mm Hg (achieved with aggressive fluid resuscitation with crystalloids)
• Mean arterial blood pressure greater than 65 mm Hg (maintained with vasoactive drugs, if necessary)
• Scvo₂ above 70%. To achieve this third goal, packed red blood cells were infused to reach a target hematocrit of greater than 30%. For patients with a hematocrit higher than 30% but still with an Scvo₂ less than 70%, inotropic agents were added and titrated to the Scvo₂ goal of 70%.

Goal-directed therapy reduced the in-hospital mortality rate by 16% (the mortality rates were 30.5% in the goal-directed group and 46.5% in the standard therapy group, P = .009) and also reduced the 28- and 60-day mortality rates by similar proportions.²⁷

Subsequent studies of a protocol for early recognition and treatment of sepsis have concluded that early aggressive fluid resuscitation decreases the ensuing need for vasopressor support.²⁸ A resuscitation strategy based on early goal-directed therapy is a major component of the initial resuscitation bundle recommended by the Surviving Sepsis Campaign.²² (A “bundle” refers to the implementation of a core set of recommendations involving the simultaneous adaptation of a number of interventions.)

Areas of debate. However, concerns have been raised about the design of the study by Rivers et al and the mortality rate in the control group, which was higher than one would expect from the patients’ Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.²⁹ In particular, the bundled approach they used precludes the ability to differentiate which interventions were responsible for the outcome benefits. Indeed, there were two major interventions in the early goal-directed therapy group: a protocol for achieving the goals described and the use of Scvo₂ as a goal.

Aggressive fluid resuscitation is considered the most critical aspect of all the major interventions, and there is little argument on its value. The debate centers on central venous pressure as a preload marker, since after the publication of the early goal-directed therapy trial,²⁷ several studies showed that central venous pressure may not be a valid measure to predict fluid responsiveness (discussed later in this paper).^30,31

The choice of colloids or crystalloids for fluid resuscitation is another area of debate. Clinical evidence suggests that albumin is equivalent to normal saline in a heterogeneous intensive care unit population,³² but subgroup analyses suggest albumin may be superior in patients with septic shock.³³ Studies are ongoing (NCT00707122, NCT01337934, and NCT00318942). The use of hydroxyethyl starch in severe sepsis is associated with higher rates of acute renal failure and need for renal replacement therapy than Ringer’s lactate,³⁴ and is generally not recommended. This is further substantiated by two recent randomized controlled studies, which found that the use of hydroxyethyl starch for fluid resuscitation in severe sepsis, compared with crystalloids, did not reduce the mortality rate (and even increased it in one study), and was associated with more need for renal replacement therapy.^35,36

The use of Scvo₂ is yet another topic of debate, and other monitoring variables have been evaluated. A recent study assessed the noninferiority of incorporating venous lactate clearance into the early goal-directed therapy protocol vs Scvo₂.³⁷ Both groups had identical goals for central venous pressure and mean arterial pressure but differed in the use of lactate clearance (defined as at least a 10% decline) or Scvo₂ (> 70%) as the goal for improving tissue hypoxia. There were no significant differences between groups in their in-hospital mortality rates (17% in the lactate clearance group vs 23% in the Scvo₂ group; criteria for noninferiority met). This suggests that lactate may be an alternative to Scvo₂ as a goal in early goal-directed therapy. However, a secondary analysis of the data revealed a lack of concordance in achieving lactate clearance and Scvo₂ goals, which suggests that these parameters may be measuring distinct physiologic processes.³⁸ Since the hemodynamic profiles of septic shock patients are complex, it may be prudent to use both of these markers of resuscitation until further studies are completed.

Given the debate, a number of prospective randomized trials are under way to evaluate resuscitative interventions. These include the Protocolized Care for Early Septic Shock trial (NCT00510835), the Australasian Resuscitation in Sepsis Evaluation trial (NCT00975793), and the Protocolised Management of Sepsis (ProMISe) trial in the United Kingdom (ISRCTN 36307479). These three trials will evaluate, collectively, close to 4,000 patients and will provide considerable insights into resuscitative interventions in septic shock.