Position Paper on the Reporting of Norepinephrine Formulations in Critical Care from the Society of Critical Care Medicine and European Society of Intensive Care Medicine Joint Task Force

Abstract

Objectives: To provide guidance on the reporting of norepinephrine formulation labeling, reporting in publications, and use in clinical practice. Design: Review and task force position statements with necessary guidance. Setting: A series of group conference calls were conducted from August 2023 to October 2023, along with a review of the available evidence and scope of the problem. Subjects: A task force of multinational and multidisciplinary critical care experts assembled by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. Interventions: The implications of a variation in norepinephrine labeled as conjugated salt (i.e., bitartrate or tartrate) or base drug in terms of effective concentration of norepinephrine were examined, and guidance was provided. Measurements and Main Results: There were significant implications for clinical care, dose calculations for enrollment in clinical trials, and results of datasets reporting maximal norepinephrine equivalents. These differences were especially important in the setting of collaborative efforts across countries with reported differences. Conclusions: A joint task force position statement was created outlining the scope of norepinephrine-dose formulation variations, and implications for research, patient safety, and clinical care. The task force advocated for a uniform norepinephrine-base formulation for global use, and offered advice aimed at appropriate stakeholders.

Norepinephrine dose reporting: are we looking at different sides of the same coin?

“…Given these potentially dangerous clinical implications, we agree with Wieruszewski et al that there is no reason to delay the prospective implementation of a standardized reporting to norepinephrine base [6], especially with the forthcoming results of large multinational randomized controlled studies on septic shock [7].…”

Knowing the ropes of vasopressor dosing: a focus on norepinephrine

“…Recent data have highlighted the relative safety of short term (< 48 h), low dose (< 15 mcg/min) administration of norepinephrine diluted at 64 mcg/mL through peripheral intravenous access [ 9 ], notwithstanding, administration through central venous access is still hegemonic and advisable in current ICU practice. There is significant worldwide variability on drug formulations, as norepinephrine can be found either as tartrate, bitartrate or hydrochloride salts, with different molecular weights and potency equivalence to norepinephrine base, being tartrate the weakest formulation [ 10 ]. Similarly, there is heterogeneity of practice on how to titrate the drug infusion, either using absolute (i.e., mcg/min) or weighted values (i.e., mcg/kg/min).…”

“…However, this heterogeneity could impact the interpretation and exchangeability of clinical data, design and execution of research, and compliance with expert’s recommendations. Thus, homogenization and consensus should be sought [ 10 , 11 ].…”

The impact of norepinephrine dose reporting heterogeneity on mortality prediction in septic shock patients

“…Several salt formulations of NE (tartrate, bitartrate, or hydrochloride) are available in worldwide markets, with the preparation used varying between and even within countries [ 9 ]. Each salt has unique conversion rates to norepinephrine base, the drug's active molecule [ 10 , 11 ]. A recent expert consensus raised awareness of the heterogeneity of NE dose reporting, as clinicians and researchers often fail to specify whether the administered doses are reported as salt or as its base molecule equivalent [ 10 ].…”

“…Each salt has unique conversion rates to norepinephrine base, the drug's active molecule [ 10 , 11 ]. A recent expert consensus raised awareness of the heterogeneity of NE dose reporting, as clinicians and researchers often fail to specify whether the administered doses are reported as salt or as its base molecule equivalent [ 10 ]. In fact, two large surveys showed that around 50% of respondents are unaware of on which formulation is NE reported locally and, therefore, administered in their practice [ 12 ], leading to potential guideline interpretation disagreements between practitioners [ 13 ].…”