Early goal-directed resuscitation of patients with septic shock: current evidence and future directions

Abstract

Severe sepsis and septic shock are among the leading causes of mortality in the intensive care unit. Over a decade ago, early goal-directed therapy (EGDT) emerged as a novel approach for reducing sepsis mortality and was incorporated into guidelines published by the international Surviving Sepsis Campaign. In addition to requiring early detection of sepsis and prompt initiation of antibiotics, the EGDT protocol requires invasive patient monitoring to guide resuscitation with intravenous fluids, vasopressors, red cell transfusions, and inotropes. The effect of these measures on patient outcomes, however, remains controversial. Recently, three large randomized trials were undertaken to re-examine the effect of EGDT on morbidity and mortality: the ProCESS trial in the United States, the ARISE trial in Australia and New Zealand, and the ProMISe trial in England. These trials showed that EGDT did not significantly decrease mortality in patients with septic shock compared with usual care. In particular, whereas early administration of antibiotics appeared to increase survival, tailoring resuscitation to static measurements of central venous pressure and central venous oxygen saturation did not confer survival benefit to most patients. In the following review, we examine these findings as well as other evidence from recent randomized trials of goal-directed resuscitation. We also discuss future areas of research and emerging paradigms in sepsis trials.

Fig. 1

Microcirculatory dysfunction in sepsis. The microvascular network undergoes functional and structural changes during inflammatory states such as sepsis and may have a key role in organ dysfunction. Changes include dilation of arterioles, microvascular thrombosis, increased adhesion of leukocytes in venules, and increased vascular permeability. These alterations result in impaired microcirculatory blood flow and tissue perfusion, ultimately leading to organ failure. Techniques for measuring microcirculatory flow in vivo have been previously described but these tools have not yet been rigorously tested for use in patients with sepsis

Fig. 2

Early goal-directed therapy. During the first 6 hours of septic shock, the early goal-directed therapy protocol requires the placement of a central venous catheter with an oximetric port for continuous monitoring of central venous pressure (CVP) and central venous oxygen saturation (ScvO ₂). Resuscitation with intravenous fluids, vasopressors, and packed red blood cells is titrated to specific end-points, including CVP of 8 to 12 mm Hg, mean arterial pressure (MAP) of at least 65 mm Hg, and ScvO₂ of at least 70 %. Inotropic therapy is recommended in patients with low cardiac output despite adequate volume and MAP. Recent controlled clinical trials have challenged the efficacy of this approach for reducing mortality among patients with septic shock. HCT hematocrit

Fig. 3

Measuring fluid responsiveness by cardiac ultrasound. A patient is considered fluid-responsive if left ventricular function falls along the ascending portion of the Frank-Starling curve. Additional fluids given above this zone do not increase cardiac output and worsen the risk of volume overload. Measurement of stroke volume and cardiac output by Doppler ultrasound may allow more accurate estimation of fluid responsiveness in patients receiving intravenous fluid therapy