No benefit from higher mean arterial pressure in most with septic shock

Mar 29, 2014

In Septic Shock, Goal of MAP > 65 mm Hg Remains Standard

In the 13 years since Rivers et al published their seminal paper that established “early goal directed therapy” for sepsis as the standard of care, treatment for severe sepsis and septic shock have evolved dramatically. Newer research questions the wisdom of liberally transfusing blood into critically ill patients and the use of dobutamine as a perfusion-enhancing agent. Further, new technologies and techniques including pulse-pressure variation, trans-esophageal echocardiography and inferior vena cava diameter have emerged as more nuanced (if not yet well-validated) means of assessing volume responsiveness for patients in shock, as compared to the crude, oft-maligned measure of central venous pressure. We entered a new era of sepsis care last week with the publication of the ProCESS trial, which refutes the mortality benefits seen with protocolized early goal directed therapy in Rivers et al, and confirms that early antibiotics and fluid resuscitation are the cornerstones of initial management of severe sepsis and septic shock. That brings us to the question, how valid is the blood pressure goal utilized in Rivers et al? Rivers et al used a mean arterial pressure (MAP) > 65 mm Hg as the target for their study. The MAP target of 65 mm Hg was selected on the basis of data from retrospective studies that showed no improvement in lactate clearance with targeting higher MAP numbers. However, it's hard to judge to what extent the MAP goals played in any survival benefits attributable to the EGDT bundle, since both the control and intervention arms in the study reported MAP values of 65 mm Hg or more. There is evidence to suggest targeting higher MAP could increase disease related events and mortality -- but other studies have suggested targeting a higher MAP 72-82 mm Hg may protect against renal failure. What's the proper target for mean arterial pressure in severe sepsis and septic shock? Pierre Asfar et al recently published SEPSISPAM, a large multicenter randomized trial asking that question; their results are in the March 18, 2014 New England Journal of Medicine.

What They Did

Randomized 776 patients into two groups- one with MAP target of 65-70 mm Hg (the “low-target group”) and another with MAP target of 80-85 mm Hg (the “high target group”). These blood pressure targets were maintained for a maximum of five days or until the time the patient was weaned from vasopressor support. If the pressure targets were not reached, the group assignments were not changed and they were still included in the study groups on an intention-to-treat basis.
The primary outcome was death from any cause at 28 days and secondary outcomes were 90-day mortality, days alive and free from organ dysfunction by day 28, and the length of stay in the intensive care unit (ICU) and hospital.
For patients in the high-target group, a reduction in vasopressor dose to target MAP between 65-70 mm of Hg was permitted if any other side effects of high vasopressor dose became obvious. These included bleeding with at least 2 units packed red blood cells, myocardial infarction, ventricular arrhythmia, poorly tolerated supraventricular arrhythmia, mesenteric or distal limb ischemia.

What They Found

There was no difference in the mortality rate at 28 days or at 90 days: 36.5% in the high target vs 34.0% in the low target group and 43.7% vs 42.3 % respectively.
None of the secondary outcome variables were different; there was no difference in length of ICU days, need for mechanical ventilation or in the organ failure score by day 7.
The incidence of atrial fibrillation was significantly higher in the high-target group (~7% vs ~3%).
Among those patients with a history of hypertension, fewer developed doubling of their baseline creatinine if treated to a high MAP target (39% vs 52%). Incidence of renal failure requiring renal replacement therapy was also significantly lower in the high-target group (32% vs 42%) among such patients.

What It Means

There is no apparent benefit to targeting a mean arterial pressure > 65 mm Hg in most patients with septic shock. Targeting higher MAPs would result in unnecessarily longer and greater infusions of vasopressors, which was not discernibly harmful here, but arguably should be avoided on the basis of parsimony (using the fewest medicines at the lowest possible dose, a key principle of medicine). Having said that, patients with chronic hypertension or atherosclerosis might benefit from a higher MAP target, and the signal is convincing enough here that higher MAPs should probably be recommended for such patients.

Limitations of the Study

The study was underpowered to detect differences in incidence of infrequent side effects arising from use of vasopressors such as myocardial infarctions. Hence we might be underestimating the potential risks associated with targeting a higher MAP.
Even though atrial fibrillation was more common within the high-target group, it could not be directly ascribed to the effect of higher doses of vasopressors that were administered to target a higher MAP. There could be other confounding variables impacting the result.
The achieved MAPs were fairly close in both the subgroups (between 70-75 mm of Hg for the low-target group and 85-90 mm of Hg for the high target group). This might have obscured any potential benefit (or harm) that could have come from targeting a higher MAP.

Clinical Takeaway: The established target of mean arterial pressure > 65 mm Hg remains the standard for most patients with septic shock; there is no clear benefit to targeting a higher MAP (80-85 mm of Hg) for most patients, and there might be unmeasured risks. A higher MAP target could be helpful in patients in septic shock with a history of hypertension or atherosclerosis. Pierre Asfar et al. High versus Low Blood-Pressure Target in Patients with Septic Shock. N Engl J Med March 18, 2014; DOI: 10.1056/NEJMoa1312173