Introduction: The Persistent Debate of Blood Pressure Targets
The management of septic shock remains one of the most complex challenges in critical care medicine. For decades, clinicians have grappled with the optimal Mean Arterial Pressure (MAP) target to ensure adequate organ perfusion without inducing the toxic effects of excessive vasopressor use. While the Surviving Sepsis Campaign guidelines generally recommend a minimum MAP of 65 mmHg, the question of whether certain patient subgroups benefit from higher targets (80-85 mmHg) has persisted. A landmark study in this field, the SEPSIS-PAM trial, previously suggested no overall mortality benefit for higher targets, though it hinted at potential renal benefits in patients with chronic hypertension. However, the ‘one-size-fits-all’ approach in sepsis is increasingly under scrutiny. A recent post-hoc analysis by Pirracchio et al., published in Intensive Care Medicine (2025), provides a deeper dive into the heterogeneity of treatment effects (HTE), asking a critical question: Does the clinical trajectory of the patient dictate the success or failure of a higher blood pressure target?
Highlights
1. No significant heterogeneity of treatment effect (HTE) was found based on baseline patient characteristics, suggesting that pre-existing conditions (other than perhaps chronic hypertension) do not clearly identify who should receive higher MAP targets.
2. A higher MAP target is associated with increased mortality if reaching that target requires high doses of norepinephrine.
3. The failure of skin mottling to resolve within 24 hours while pursuing a higher MAP target is a potent signal of increased mortality risk.
4. Pursuit of higher MAP targets should be individualized based on physiological responsiveness rather than rigid adherence to numerical goals.
Background: The Legacy of SEPSIS-PAM
The original SEPSIS-PAM (Sepsis and Mean Arterial Pressure) trial was a multicenter, pragmatic randomized controlled trial that enrolled 776 patients with septic shock. Patients were randomized to either a low-target group (MAP 65-70 mmHg) or a high-target group (MAP 80-85 mmHg). The primary endpoint, mortality at 28 days, showed no significant difference between the two groups (36.6% in the high-target group vs. 34.0% in the low-target group). Despite these results, clinical practice remains varied. Some clinicians argue that higher pressures are necessary to ‘open’ the microcirculation, while others fear the iatrogenic harm of high-dose catecholamines, including arrhythmias, myocardial ischemia, and metabolic derangements. The recent analysis by Pirracchio and colleagues sought to resolve these conflicting perspectives by examining how the patient’s immediate response to treatment influences the ultimate outcome.
Study Design and Methodology
Population and Outcomes
The study analyzed the original 776 patients from the SEPSIS-PAM cohort. The primary outcome remained mortality at day 28, with secondary outcomes including 90-day mortality, the incidence of acute kidney injury (AKI) based on KDIGO criteria, the need for renal replacement therapy (RRT), and vasopressor-free days. The researchers aimed to identify whether specific baseline variables—such as age, severity scores, or prior hypertension—interacted with the MAP target to affect survival.
Statistical Framework: Testing for Heterogeneity
What sets this analysis apart is its sophisticated statistical approach. The investigators used a ‘sweep’ p-value to test for HTE across various baseline characteristics. Furthermore, they employed a multimediation analysis. This technique allowed them to estimate how much of the treatment’s effect on mortality was ‘mediated’ by post-randomization variables, such as the dose of norepinephrine required to hit the target, lactate levels, urine output, and the mottling score (a clinical marker of peripheral perfusion).
Key Findings: No One-Size-Fits-All but Clear Signals of Harm
Baseline Characteristics and HTE
The first major finding of the study was the lack of evidence for HTE based on baseline characteristics. The sweep p-value of 0.664 (95% CI: 0.633-0.673) indicates that no single baseline factor—including the much-discussed history of chronic hypertension—statistically predicted a better response to a higher MAP target in terms of 28-day mortality. This suggests that clinicians cannot simply look at a patient’s history to decide on a higher target; the decision must be more dynamic.
The Role of Mediators: Norepinephrine and Mottling
The most provocative results emerged from the mediation analysis. While the direct effect of a higher MAP target on mortality was not significant (Risk Difference [RD] = 0.017; p = 0.62), the ‘indirect’ effects through physiological mediators were telling. If achieving a higher MAP required high doses of norepinephrine at 24 hours, this was associated with a significant increase in mortality (RD = 0.027; 95% CI 0.012-0.047). Similarly, if the higher MAP target did not result in the resolution of skin mottling by 24 hours, the risk of death increased (RD = 0.012; 95% CI 0.001-0.026).
In simpler terms: when we push the blood pressure up using high doses of vasopressors, but the patient’s microcirculation (reflected by skin mottling) does not improve, we are likely causing more harm than good. The ‘cost’ of the higher MAP—in the form of catecholamine toxicity—outweighs the benefit of the higher pressure.
Expert Commentary: Interpreting the Biological Plausibility
The findings by Pirracchio et al. align with the growing understanding of ‘macro-micro dissociation’ in sepsis. In many patients, blood pressure (a macro-hemodynamic variable) can be successfully restored to ‘normal’ or ‘high-normal’ levels, yet the microcirculation remains paralyzed by inflammation, endothelial dysfunction, and microthrombi. When clinicians use escalating doses of norepinephrine to reach a MAP of 80 mmHg in a patient whose microvasculature is unresponsive, the result is excessive vasoconstriction. This can lead to decreased tissue perfusion in the gut, extremities, and even the heart itself, despite a seemingly ‘good’ number on the monitor.
Furthermore, the study reinforces the importance of skin mottling as a ‘window’ into the patient’s physiological state. Mottling reflects poor skin perfusion and is strongly correlated with organ dysfunction. If pushing the MAP higher doesn’t clear the mottling, it suggests that the vasopressor is merely increasing afterload without improving the flow where it matters most.
Clinical Implications: Moving Toward Physiological Responsiveness
How should these findings change bedside practice? For the attending intensivist, the message is clear: the MAP target should not be a static goal. If a patient is randomized or assigned to a higher target, but their norepinephrine requirements are climbing rapidly without a concomitant improvement in perfusion markers (like lactate clearance, urine output, or mottling resolution), the target should likely be downgraded to a standard 65 mmHg.
This study advocates for a ‘response-guided’ hemodynamic strategy. Instead of asking ‘What should the MAP be?’, clinicians should ask ‘What is the cost of reaching this MAP, and is the patient’s physiology actually improving?’. If the ‘vasopressor load’ becomes too high, the iatrogenic risk becomes the primary driver of mortality.
Conclusion: The End of the High MAP Era?
The post-hoc analysis of SEPSIS-PAM by Pirracchio and colleagues provides a nuanced conclusion to a decade-old debate. It suggests that while there is no evidence of a specific subgroup that universally benefits from higher MAP targets at the outset, there is clear evidence of harm in those who require excessive pharmacological support to reach those targets. In the era of precision medicine, the ‘precision’ in hemodynamic management may not lie in the patient’s history, but in their real-time physiological response to intervention. The pursuit of higher blood pressure must be abandoned the moment it becomes a source of catecholamine-induced injury.
Funding and ClinicalTrials.gov
The SEPSIS-PAM trial was supported by the French Ministry of Health (Programme Hospitalier de Recherche Clinique 2009). The trial is registered at ClinicalTrials.gov under the identifier NCT01149278.
References
Pirracchio R, Fong N, Legrand M. Heterogeneity in the response to a high vs low mean arterial pressure target in patients with septic shock: a post hoc analysis of a randomized controlled trial. Intensive Care Med. 2025 Oct;51(10):1775-1783. doi: 10.1007/s00134-025-08104-8.
Asfar P, Meziani F, Hamel JF, et al. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014;370(17):1583-1593. doi:10.1056/NEJMoa1312173.
