Septic shock: The initial moments and beyond

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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.


  • 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.



Considerably fewer patients who develop sepsis are dying of it now, thanks to a number of studies of how to reverse sepsis-induced tissue hypoxia.1 The greatest strides in improving outcomes have been attributed to better early management, which includes prompt recognition of sepsis, rapid initiation of antimicrobial therapy, elimination of the source of infection, and early goal-directed therapy. Thus, even though the incidence of severe sepsis and septic shock is increasing,2,3 the Surviving Sepsis Campaign has documented a significant decrease in unadjusted mortality rates (37% to 30.8%) associated with the bundled approach in the management of sepsis.4 (We will talk about this later in the article.)

This review will summarize the evidence for the early management of septic shock and will evaluate the various treatment decisions beyond the initial phases of resuscitation.


Sepsis syndrome starts with an infection that leads to a proinflammatory state with a complex interaction between anti-inflammatory and proinflammatory mediators, enhanced coagulation, and impaired fibrinolysis.5,6

Sepsis induces vasodilation by way of inappropriate activation of vasodilatory mechanisms (increased synthesis of nitric oxide and vasopressin deficiency) and failure of vasoconstrictor mechanisms (activation of ATP-sensitive potassium channels in vascular smooth muscle).7 Thus, the hemodynamic abnormalities are multifactorial, and the resultant tissue hypoperfusion further contributes to the proinflammatory and procoagulant state, precipitating multiorgan dysfunction and, often, death.


  • Sepsis—infection together with systemic manifestation of inflammatory response
  • Severe sepsis—sepsis plus induced organ dysfunction or evidence of tissue hypoperfusion
  • Septic shock—sepsis-induced hypotension persisting despite adequate fluid resuscitation.


Early in the course of septic shock, the physician’s job is to:

  • Recognize it promptly
  • Begin empiric antibiotic therapy quickly
  • Eliminate the source of infection, if applicable, eg, by removing an infected central venous catheter
  • Give fluid resuscitation, titrated to specific goals
  • Give vasopressor therapy to maintain blood pressure, organ perfusion, and oxygen delivery (Table 1).

The line between “early” and “late” is not clear. Traditionally, it has been drawn at 6 hours from presentation, and this cutoff was used in some of the studies we will discuss here.

Recognizing severe sepsis early in its course

The diagnosis of severe sepsis may be challenging, since up to 40% of patients may present with cryptic shock. These patients may not be hemodynamically compromised but may show evidence of tissue hypoxia, eg, an elevated serum lactate concentration or a low central venous oxygen saturation (Scvo2), or both.8 In view of this, much effort has gone into finding a biomarker that, in addition to clinical features, can help identify patients in an early stage of sepsis.

Procalcitonin levels rise in response to severe bacterial infection,9 and they correlate with sepsis-related organ failure scores and outcomes.10,11 Thus, the serum procalcitonin level may help in assessing the severity of sepsis, especially when combined with standard clinical and laboratory variables. However, controversy exists about the threshold to use in making decisions about antibiotic therapy and the value of this test in differentiating severe noninfectious inflammatory reactions from infectious causes of shock.12 Therefore, it is not widely used in clinical practice.

Serum lactate has been used for decades as a marker of tissue hypoperfusion. It is typically elevated in patients with severe sepsis and septic shock, and although the hyperlactatemia could be a result of global hypoperfusion, it can also be secondary to sepsis-induced mitochondrial dysfunction,13 impaired pyruvate dehydrogenase activity,14 increased aerobic glycolysis by catecholamine-stimulated sodium-potassium pump hyperactivity,15 and even impaired clearance.16

But whatever the mechanism, elevated lactate in severe sepsis and septic shock predicts a poor outcome and may help guide aggressive resuscitation. In fact, early lactate clearance (ie, normalization of an elevated value on repeat testing within the first 6 hours) is associated with better outcomes in patients with severe sepsis and septic shock.17,18

Panels of biomarkers. A literature search revealed over 3,000 papers on 178 different biomarkers in sepsis.19 Many of these biomarkers lack sufficient specificity and sensitivity for clinical use, and thus some investigators have suggested using a panel of them to enhance their predictive ability. Shapiro et al20 evaluated 971 patients admitted to the emergency department with suspected infection and discovered that a panel of three biomarkers (neutrophil gelatinase-associated lipocalin, protein C, and interleukin-1 receptor antagonist) was highly predictive of severe sepsis, septic shock, and death.


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