Early May Be Better: Early Low-Dose Norepinephrine in Septic Shock

In this issue of the Journal, Permpikul and colleagues (pp. 1097–1105) report on a phase 2 randomized controlled trial (RCT) of early low-dose norepinephrine (NE) in septic shock (1). Arguably the most important finding from studies of antibiotic timing (2, 3) and early goal-direct therapy (3, 4) is that early treatment of septic shock is beneficial. At first, the design may appear odd, but a close reading reveals a neat design that allows early testing of the intervention (early low-dose NE), allowing separation of the treatment groups without denying “standard” care and without forcing any patients to receive “late” NE.

The authors randomized patients to early low-dose NE (n = 155) or placebo infusion (n = 155) plus standard care, which included open-label vasopressors. NE study drug dose was weight-based infused via peripheral intravenous lines in many cases until a dose of 0.05 μg/kg/min was achieved (e.g., 3 μg/min in a 60-kg patient), plus open-label vasopressors and fluid resuscitation, and NE dose was unchanged for 24 hours. The primary outcome was control of shock defined by a composite of mean arterial pressure (MAP) greater than 65 mm Hg plus either urine output greater than 0.5 ml/kg/h or 10% decline in lactate from baseline, reasonable components of a composite, because each is associated with short-term mortality of septic shock (5, 6). Intervention patients had NE started sooner (93 vs. 192 min), indicating that the intervention (early NE) was indeed tested. The primary endpoint was achieved in significantly more of the intervention than control group (76.1% vs. 48.4%); each component of the composite was achieved significantly earlier in the intervention group (i.e., the composite was not driven by one major component). There was a nominally lower mortality in the intervention than control group (15.5% vs. 21.9%; P = 0.15). This phase 2 RCT was not powered for mortality, but it is satisfying to see these short-term mortality results. There was no difference in the fluids administered, but the net fluid balance was not reported. One might have expected that early NE would lower net fluid balance (7). Interestingly, the intervention group had significantly fewer patients with cardiogenic pulmonary edema (14.4% vs. 27.7%) or new-onset arrhythmias (11% vs. 20%). The authors conclude that early low-dose NE was associated with earlier shock control.

This RCT fits a growing body of evidence that vasopressors should probably be started earlier. It aligns with a recent artificial intelligence (AI) study in which the AI clinician recommended more patients with sepsis should have been given vasopressors (17% vs. 30%) (8). Although we should not change practice on the basis of the study by Permpikul and colleagues (1), this trial and other work suggests that we should not delay starting vasopressors. If there is delay inserting a central venous catheter, then one should consider peripheral low-dose dilute NE temporarily rather than delay vasopressor(s). If clinicians delay starting vasopressor(s) because of a lack of critical care bed availability, then again, this RCT suggests they probably should not delay. Managing a patient on a general ward, without vasopressors, hoping that in time blood pressure will improve and thus not require critical care, may lead to worse outcomes for patients.

The investigators should be congratulated for conducting a high-quality trial, with an interesting design, incorporating a blinded placebo infusion in what is a challenging research area. The strengths of the study include computerized randomized controlled design, well-matched patients (although MAP was lower initially in the NE group), the composite primary endpoint, intention-to-treat primary analyses, and the method for organ dysfunction analyses (9). Remarkably, these investigators were able to identify, consent, and randomize patients within 1 hour of meeting inclusion criteria, which is fundamental in examining early treatment.

Limitations are that the effects of NE to increase MAP would have been apparent, and blinding was not 100% possible. Second, many (47%) trial patients not on dialysis or mechanical ventilation were transferred to medical wards for care, which may have increased the risks of protocol violations and adverse events.

The NE group achieved MAP and lactate clearance greater than 10% within 6 hours, and time to target urine output and lactate were lower. Thus, earlier NE may have improved general tissue and renal perfusion; the better urine output could be due to earlier MAP greater than 65 mm Hg and higher early renal perfusion pressure. However, this did not translate into less need for renal replacement therapy.

Early NE may be more effective than later NE because patients have less organ injury, and prevention of organ dysfunction is possible. Early NE may also allow lower doses of NE and so fewer adverse effects, and sustained elevation of NE down-regulates adrenergic receptors, which can further increase NE dose requirements (10) (Figure 1). Early low-dose NE could also beneficially modulate immunity in sepsis (11).

Figure 1.

Norepinephrine (NE, blue) binds to α₁-adrenergic receptors of vascular smooth muscle to induce vasoconstriction and binds to α₁- and β₂-adrenergic receptors on leukocytes to differentially modulate immune response in sepsis. Exposure to NE also downregulates α₁- and β₂-receptor density, which could alter sensitivity to NE, thereby leading to increased infusion doses of NE and greater risk of adverse vascular and immune effects. NF = nuclear factor.

Although there are no clinical predictive biomarkers for response to NE, variants in the β₂-adrenergic receptor gene (12) associated with mortality of septic shock could be predictive biomarkers of response to NE.

What are the wider implications of the current RCT? The RCT by Permpikul and colleagues (1) is similar to prior RCTs of early vasopressin (13) versus NE, NE versus epinephrine (14), NE versus dopamine (15), and vasopressin versus NE in septic shock (16). These RCTs established that NE is superior to dopamine and equivalent to vasopressin and epinephrine. In VANISH (Vasopressin vs. Norepinephrine as Initial Therapy in Septic Shock) (13), early vasopressin was no different regarding mortality than standard care. There was no difference in overall mortality between vasopressin and NE in VASST (Vasopressin and Septic Shock Trial) (16), but vasopressin may have been more effective than NE in patients with less severe shock. A propensity-matched cohort study (17) showed that lower doses of vasopressin were associated with similar outcomes compared with NE. An RCT of early vasopressin and NE versus NE monotherapy found that patients who received early vasopressin and NE achieved MAP of 65 mm Hg faster than those receiving NE monotherapy (18).

Thus, NE remains the primary vasopressor in septic shock, but the existing evidence underlines the importance of early appropriate treatment in sepsis. The current RCT suggests that early low-dose NE may be superior to current standard care. We now need a large multicenter phase 3 RCT of early low-dose NE powered for mortality and organ dysfunction.