THE CASE FOR STANDARDIZING VASOPRESSOR DOSING UNITS Norepinephrine is well-established as the cornerstone of initial vasoactive therapy for most forms of shock, including septic shock (1,2). Its role is fundamental in supporting life-sustaining cardiovascular function when fluid resuscitation alone fails to achieve hemodynamic stability. While there is strong consensus supporting norepinephrine as the first-line agent for circulatory shock (1) and that its doses should be reported in its molecular form (3), there appears to be little agreement on which dosing units should be utilized. Both weight-based dosing (WBD) and non-weight-based dosing (NWBD) units are used clinically and are considered acceptable conventions by major drug references for norepinephrine (Table 1) (4,5). In North America, clinicians are generally accustomed to dosing norepinephrine in either mcg/kg/min or mcg/min (6,7), while additional NWBD units (e.g., mg/hr, mL/hr) are often reported across Europe and other parts of the world (3,8). Despite these differences, the short-acting nature of norepinephrine has generated a “titrate to effect” mentality, rendering many clinicians seemingly unaware—or indifferent—to how dosing units influence clinical care at bedside. Table 1. - Comparison of Weight-Based vs Non-Weight-Based Norepinephrine Dosing Approaches Weight-Based Norepinephrine Dosing Units Non-Weight-Based Norepinephrine Dosing Units Examples• mcg/kg/min Pros• Individualized• Precise titration for low body weight Cons• Excessive exposure in obesity• False “maximum” dose in low body weight• Which weight? (total body weight, ideal body weight, etc.) Examples• mcg/min• mg/hr• mL/hr Pros• Standardized• Limit potential for errors Cons• False “maximum” dose in obesity• Less precise titration in low body weight The absence of standardized dosing units contributes to variability in drug exposure, assessment of treatment response, and decisions to escalate to secondary or salvage therapies (9,10). These inconsistencies extend beyond stylistic or regional practice differences, directly influencing therapeutic decision-making, interpretation of evidence, prognostication, and patient safety. This is especially relevant at the extremes of body weight, where drug exposure patterns may intersect with outcome differences reported in obesity (11). In this issue of Critical Care Medicine, a joint Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) taskforce report the results of an international Delphi process to establish a consensus definition of refractory septic shock (12). As such efforts incorporate vasoactive therapy intensity as a defining domain, the precision with which norepinephrine exposure is expressed becomes not merely academic but operationally critical. Without clarity in dosing units, even consensus-derived definitions may be variably interpreted when translated into bedside practice across institutions that conceptualize vasopressor dose differently. In this commentary, we seek to highlight the vast discrepancy that exists with dosing unit practices, the consequences of failing to recognize the implications of such inconsistencies, and potential solutions necessary for the critical care community. EVIDENCE OF DOSING UNIT VARIABILITY Surveys conducted across nations, institutions, and clinical specialties consistently highlight significant variability in vasopressor dosing units and practices, particularly in the use of WBD versus NWBD for norepinephrine (eTable 1,https://links.lww.com/CCM/H956). North American institutions appear divided, with both mcg/kg/min and mcg/min commonly reported (6,7,13,14). NWBD appears more common internationally, although expressed in varying dosing units (mg/hr or mL/hr) (3,8). A 2022 survey of ESICM members notably found that while no respondents reported WBD use, norepinephrine thresholds for adding a second-line vasopressor were expressed in mcg/kg/min, indicating a disconnect between theoretical concepts and real-world application. Additionally, 26% of respondents reported using several norepinephrine concentrations, further complicating volumetric dosing units (e.g., mL/hr) (8). CONSEQUENCES OF DOSING UNIT HETEROGENEITY Prognostication Norepinephrine dosing units expressed have the potential to influence the timing of escalation to second-line therapies, total norepinephrine exposure, perceived severity of shock, and communication about prognosis and care preferences. A 2019 U.S. pharmacist survey revealed stark differences in maximum allowable doses: institutions using NWBD reported mean maximum norepinephrine doses of 59 ± 54 mcg/min, while institutions using WBD permitted nearly twice that amount at 1.7 ± 1.2 mcg/kg/min (equivalent to approximately 113 ± 84 mcg/min for a 70 kg patient) (7). Life-sustaining measures may be withdrawn for a patient at an institution using NWBD once the norepinephrine dose reaches 60 mcg/min, while care for the same patient at an institution using WBD would continue to escalate using doses of norepinephrine that exceed the equivalent of 115 mcg/min. This discrepancy underscores substantial interinstitutional variation in thresholds that define futility or treatment limitation, revealing significant national differences in how patients are managed and when life-sustaining therapies are withdrawn. A 2024 international survey of almost 600 critical care providers further emphasized these disparities. Scaled to a 70-kg patient, institutions using WBD reported median norepinephrine “soft maximum” doses equivalent to 70 mcg/min (35–210 mcg/min), whereas NWBD sites reported a narrower median of 30 mcg/min (30–50 mcg/min). Ranges were also notably broader for institutions using WBD, spanning from 0.2 to 10 mcg/kg/min (14−700 mcg/min for a 70-kg patient) compared with NWBD ranges of 20 to 400 mcg/min. Hard maximums were used in just one in five institutions but still varied widely, from 34−205 mcg/min (WBD equivalent in a 70-kg patient) and 50 to 210 mcg/min (NWBD) (14). Escalation Many institutions have established norepinephrine dose thresholds to guide initiation, modification, or exclusion of adjunctive therapies, including secondary vasopressors (e.g., vasopressin, angiotensin II), corticosteroids, or other agents used for “refractory” shock (e.g., nitric oxide modulators such as methylene blue or hydroxocobalamin). These thresholds are also commonly used to assess the potential futility of advanced interventions, such as mechanical circulatory support with extracorporeal membrane oxygenation. Given the cost, availability, and adverse-effect profiles of adjunctive agents, their use warrants careful consideration. In a 2021 study, Bosch et al (10) found that initiation of vasopressin and corticosteroids tended to occur at higher norepinephrine doses when using WBD units compared with NWBD units, suggesting that patients in different institutions might receive different interventions for the same clinical scenario. Thus, what one clinician considers “high-dose” norepinephrine may be viewed as moderate by another, depending solely on the dosing units utilized at that institution (Figure 1). Without an objective assessment of responsiveness, treatment decisions may drift toward premature escalation or withdrawal, or toward delayed initiation of critical interventions, each with clinically meaningful consequences.Figure 1.: Comparison of weight-based (A) and non-weight-based (B) norepinephrine thresholds. These figures illustrate how commonly applied norepinephrine thresholds translate into either absolute (mcg/min) or relative (mcg/kg/min) doses across patients of varying body size, depending on the dosing units used. Actions provided at each threshold are for illustration purposes only and do not represent recommendations.Challenges in Defining and Identifying “Refractory Shock” Thresholds used to define refractory shock, catecholamine resistance, and “high-dose norepinephrine” vary widely (15). Observational studies report mortality exceeding 80% in patients requiring norepinephrine doses beyond 1 mcg/kg/min (16,17), yet a global survey revealed that a second vasopressor is often not initiated until doses of 0.5 mcg/kg/min or above, underscoring the absence of a universal benchmark (8). Categorical thresholds have been proposed to help stratify shock severity and guide therapy escalation (e.g., 0.4 as high) (18). Other studies have incorporated norepinephrine equivalents as a composite exposure metric to support prognostication and triage decisions (19). Recent international consensus efforts have incorporated vasoactive therapy intensity into a standardized definition of refractory septic shock (12). While necessary and commendable, such approaches implicitly treat weight as a neutral scalar. A threshold expressed in mcg/kg/min, however, is definitionally distinct from one operationalized in mcg/min. A norepinephrine dose of 1 mcg/kg/min represents 50 mcg/min in a 50-kg patient and 100 mcg/min in a 100-kg patient. An institution applying a fixed threshold of 100 mcg/min would therefore use a more permissive standard in lighter patients and a more restrictive one in heavier patients. As a result, identical numeric thresholds may correspond to substantially different catecholamine exposures, triggering escalation or futility determinations at different points along a patient’s disease trajectory. Impact on Research and Guideline Interpretation Accounting for variation in patient traits and treatment delivery through standardized measures enhances both the interpretability of research and the translation of its findings into clinical guidelines. Inconsistencies in vasopressor dosing units, however, complicate the use of cumulative exposure indices like norepinephrine equivalents and the vasoactive-inotropic score, which are increasingly integrated into models predicting mortality and organ dysfunction such as SOFA-2 and MAVIC (20–23). Dose conversions are especially error-prone and can introduce up to 10% dosing error for every 10 kg deviation from assumed weight (24). Inconsistency in dosing units also complicates the interpretation and comparability of landmark vasopressor trials and subsequent guideline recommendations. The VASST trial reported norepinephrine dosing in mcg/min (25), whereas the ATHOS-3 trial used norepinephrine equivalents expressed in mcg/kg/min (26). Current Surviving Sepsis Campaign guidelines state that vasopressin is typically initiated when norepinephrine reaches 0.2–0.5 mcg/kg/min; in practice, this spans 10-25 mcg/min at 50 kg and 20-50 mcg/min at 100 kg, producing broad catecholamine exposure across body weights (1). Studies evaluating the initiation of vasopressin or angiotensin II frequently use norepinephrine dose as surrogate for shock severity (27,28). To apply observational data suggesting 10 mcg/min of norepinephrine as a threshold for adding vasopressin, adjunctive therapy would start at 0.2 mcg/kg/min in a 50-kg patient and as early as 0.1 mcg/kg/min in a 100-kg patient (27). An Analogy: Standardizing Dose Reporting from Salt Formulations The dosing unit dilemma parallels recent efforts to standardize norepinephrine dose reporting arising from various norepinephrine formulations across the world. While norepinephrine is available as a conjugated tartrate, bitartrate, or hydrochloride salt formulation in various regions of the world, labeling practices—and consequently dosage reporting—may obscure true norepinephrine dose exposure. Because 2 mg of norepinephrine tartrate contains 1 mg of norepinephrine base (i.e., pharmaceutically active component), discrepancies in how doses are reported have distorted perceptions of dose intensity and disease severity (3). A modeling study by Morales et al. (29) demonstrated that at a threshold of 1 mcg/kg/min, predicted mortality of 83% using norepinephrine base but only 54% using norepinephrine tartrate. Acknowledgment of the potential implications sparked a coordinated effort by international societies to standardize norepinephrine dose reporting as base equivalents across prescribing, research, and guidelines development (3). This example demonstrates how even seemingly small inconsistencies in formulation or dosing units can significantly influence outcomes, perceptions of severity, and therapeutic decisions. The same rationale must now be applied to dosing conventions. Without alignment between WBD and NWBD, clinical inequities, research ambiguities, and practice inefficiencies risk being perpetuated. CALL TO ACTION: TOWARD STANDARDIZATION Addressing discrepancies in dose unit expression demands a concerted, international, multidisciplinary effort. Where retrospective studies have fallen short, prospective trials are urgently needed to compare WBD and NWBD strategies in terms of clinical outcomes such as time to hemodynamic stability, vasopressor exposure, organ dysfunction, adverse events, and mortality (30–34). Equally important is the understanding of how each of these dosing units influence clinical decision-making and perceived therapeutic response. While local efforts to standardize vasopressor dosing units and dilution concentrations for continuous infusions have shown promise to address potential operational errors, broader alignment is needed (35,36). We urge leading critical care organizations—such as SCCM and ESICM—along with national pharmacy groups to prioritize vasopressor dosing standardization and establish evidence-based, consensus guidelines after identifying the optimal strategy. CONCLUSION Norepinephrine is a cornerstone of critical care pharmacotherapy used every day in ICUs around the world, yet the dosing units utilized remain fragmented, inconsistent, and often institution dependent. This heterogeneity creates meaningful disparities in care, confounds clinical trial interpretation, and undermines the ability to generate and apply robust evidence. The recent success of initiatives standardizing norepinephrine dose reporting in the setting of salt formulations sets an important precedent. As professional societies work to establish a standardized definition of refractory septic shock, alignment of vasopressor dosing units represents a necessary parallel effort. In critical care, where precision saves lives, clarity begins with learning how to see the consequences of what we treat as interchangeable. Now is the time to align our practices, strengthen our research, and ensure that the care we provide is as consistent as it is evidence-based.
Rudoni et al. (2026) studied this question.