By Joe Alcock

Many advances in the care of critically ill patients over time have involved intervening less aggressively. A recent perspective by D’Amico and colleagues (1) builds on that tradition of “less is more.” In Protective Hemodynamics: C.L.E.A.R.! the authors urge caution in treating low blood pressure with fluids or vasopressor medications.  

D’Amico, F., Marmiere, M., Monti, G., & Landoni, G. (2025). Protective Hemodynamics: C.L.E.A.R.! Journal of Cardiothoracic and Vascular Anesthesia, 39(1), 13–19. https://doi.org/10.1053/j.jvca.2024.10.021

In critical care and emergency medicine, controversy exists over how to manage hypotension, or low blood pressure, in our sickest patients. Low blood pressure is associated with higher mortality, and very low blood pressure can herald cardiovascular collapse and death. Because of this, guidelines advise raising blood pressure in critically ill adults by infusing intravenous (IV) fluids or catecholamine vasopressors. However, as D’Amico and colleagues point out in a recent perspective piece, association does not mean causation. Their recent work highlights the possibility of unintended iatrogenic harm when interventions are used to increase blood pressure. 

In 2024, D’Amico and colleagues performed a meta-analysis of higher or lower blood pressure targets in critically ill and surgical patients (2). Patients treated more aggressively to raise the blood pressure died more often than did those whose blood pressures remained lower. This study included RCTs involving both critically ill adults and surgical patients. As they relate, this study “surprisingly demonstrated a reduction in mortality within the lower blood pressure target group (relative risk 0.93; 95% confidence interval, 0.87-0.99; p = 0.03).”  These findings imply we should stop before we rush to treat many of our patients with low blood pressure.

The authors followed this research with a perspective piece arguing for a change in practice for these hypotensive patients. They propose that efforts to treat these surgical and critically ill patients should focus less on increasing blood pressure. Among other recommendations, they argue for adopting an approach of protective hemodynamics – one that minimizes the use of catecholamine vasopressors and avoids the excess use of IV fluids. 

D’Amico and colleagues’ “C.L.E.A.R.” approach is aimed at limit iatrogenic harm from hemodynamic treatments: “Key strategies for protective hemodynamics include customize blood pressure targets, limit catecholamines, enhance flow, adjust fluid balance, and resolve underlying condition.” They advise that some patients with lower blood pressure do not require treatment if they have adequate blood flow. I agree with the authors that a new approach is needed. As we will discuss below, the goal of avoiding iatrogenic harm around blood pressure has implications for evolutionary medicine.

This is not the first time that investigators have showed harm from excess IV fluids in critically ill and injured patients. A landmark randomized controlled trial (RCT) by Bickell and colleagues (3) showed that patients with penetrating trauma (shootings and stabbings) fared worse when they received early IV fluids aimed at stabilizing their blood pressure. The surprising increase in mortality has been attributed to higher blood pressure, along with dilution of clotting factors, that worsened blood loss before it could be fixed in the operating room. 

Later, the FEAST trial (4) studied the effect of fluid resuscitation in hypotensive children with severe febrile illness. This trial, led by Kathryn Maitland, was undertaken in three sub-Saharan countries where the prevailing standard of care did not involve infusions of fluids. The results, published in the New England Journal of Medicine, surprised the investigators performing the study. Giving fluids increased mortality by 40%. Maitland was quoted in Lancet: “Our theory is that the shock response in severe febrile illness is a defense mechanism, and bringing [children] out of this too soon with a fluid bolus can be counterproductive, resulting in later cardiovascular collapse.” Others have argued that the results of FEAST are not generalizable to high income populations.

In 2022, Meyhoff and colleagues (5) tested the question of higher versus lower blood pressure targets in adults with septic shock. 1554 ICU patients were randomized to higher and lower fluid resuscitation treatments; neither group did better or worse. McIntyre and Marshall (6) wrote in an accompanying NEJM editorial: “These findings show that a highly restrictive fluid management strategy is safe and raise important new questions that challenge conventional wisdom regarding the management of shock.”  

Some have interpreted findings like these to advocate for the replacement of fluids with vasopressor drugs that also tend to increase blood pressure. However, vasopressors have their own problems. A meta-analysis by Lamontagne and colleagues (7) showed higher mortality in patients with septic shock randomized to a higher blood pressure target who had received vasopressors for more than 6 hours. If lower blood pressure is itself beneficial (still a hypothesis) in certain conditions, then raising blood pressure by any modality might have adverse effects. 

Evidence suggests that vasodilatory hypotension occurring in some contexts is evolutionarily conserved. Shared hemodynamic responses to infection make mice, dogs, sheep and pigs useful as experimental stand-ins for human sepsis. A primary mechanism of hypotension in critical illness involves vasodilation caused by nitric oxide synthases (NOS). NOS are broadly conserved in metazoans, seen in 33 invertebrate and 63 vertebrate species (8). Nitric oxide produced by NOS has an antimicrobial and antiparasitic role in vertebrates and invertebrates, while also causing vasodilation in mammals (9). Plasmodium falciparum and Yersinia pestis are examples of pathogens that block nitric oxide synthases as part of their virulence program, providing further evidence for a host defense function of nitric oxide (9). Instead of leveraging the antimicrobial effects of NO, drug developers have attempted to reverse septic shock by blocking NOS. That treatment strategy hit a dead end when a higher number of deaths occurred in sepsis patients randomized to the nitric oxide synthase inhibitor 546C88 (10).

These examples suggest that there are tradeoffs around blood pressure in our sickest patients. Low blood pressure has long been seen as a pathological departure from normal homeostasis or a deficiency syndrome (of circulating volume or vascular tone) that needs immediate treatment. It is undeniable that blood pressure that is too low can cause cardiovascular collapse and death. At the same time, work by D’Amico and colleagues highlight the importance of reducing iatrogenic harm when we initiate fluid or vasopressor therapies. Some of these harms may occur because various immune, metabolic, and repair functions work best in conditions of arteriolar vasodilation and lower blood pressure. The implications of that informed speculation will require further testing.  

1. F. D’Amico, M. Marmiere, G. Monti, G. Landoni, Protective Hemodynamics: C.L.E.A.R.! Journal of Cardiothoracic and Vascular Anesthesia 39, 13–19 (2025).

2. F. D’Amico, et al., Low Versus High Blood Pressure Targets in Critically Ill and Surgical Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit Care Med 52, 1427–1438 (2024).

3. W. H. Bickell, et al., Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. The New England journal of medicine 331, 1105–1109 (1994).

4. K. Maitland, et al., Mortality after Fluid Bolus in African Children with Severe Infection. The New England journal of medicine (2011).

5. T. S. Meyhoff, et al., Restriction of Intravenous Fluid in ICU Patients with Septic Shock. N Engl J Med 386, 2459–2470 (2022).

6. L. A. McIntyre, J. C. Marshall, Intravenous Fluids in Septic Shock — More or Less? New England Journal of Medicine 386, 2518–2519 (2022).

7. F. Lamontagne, et al., Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med 42, 542–550 (2016).

8. N. Andreakis, et al., Evolution of the nitric oxide synthase family in metazoans. Mol Biol Evol 28, 163–179 (2011).

9. F. C. Fang, Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2, 820–832 (2004).

10. A. Lopez, et al., Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Critical Care Medicine 32, 21–30 (2004).