We gladly thank Wieruszewski et al. for their comment on our recent article about norepinephrine [1]. They highlighted that as long as the norepinephrine base content in preparations is similar, the physiological effects are expected to be the same regardless of the salt formulation [2].

We agree and are aware that drug potency goes beyond salt formulations and involves a complex interaction between molecules and their receptors. For the case of norepinephrine, it is considered an efficacy-driven agonist, meaning that the resulting signals are less attenuated in tissues with lower α1-adrenergic receptor density, compared to affinity-driven agonists (i.e., oxymetazoline) that will become partial agonists or even antagonists in states of lower receptor density [3]. In the article, we avoided to focus on deeper pharmacologic nuances and did not elaborate on the concept of potency; and as mentioned in a response letter [4], we preferred to simplify terms to stress the need for standardized formulation reporting on clinical grounds.

In a significant number of countries, most critical care units do not have dedicated pharmacy departments to ensure the preparations are labeled according to norepinephrine base; this is carried out on-site with vials of any available salt, leaving clinicians unaware of the base molecule equivalency. This can be exemplified in the case of an 80 kg patient who is receiving commercial norepinephrine infusion (16 mg of base equivalent in 250 ml of D5W) at 20 ml/h. As this preparation is labeled and titrated according to the base molecule, the actual base dose is 0.27 mcg/kg/min. However, if the infusion was labeled according to the salt formulation (i.e., 16 mg of tartrate), and administered at the same infusion rate, the actual base molecule norepinephrine dose would only be 0.135 mcg/kg/min. So, regardless of the physiological response at cellular level, the clinical response would indeed be considered as lower/weaker for the latter preparation, with the requirement of an apparent “higher” dose to reach the desired clinical targets. This divergence becomes progressively relevant at higher doses. As illustrated in Fig. 1, the absolute gap of norepinephrine base equivalence becomes wider among the different salt-based dose preparation/labeling.

Fig. 1
figure 1

Relationship between the different salt-based dose reporting strategies and their base molecule equivalents

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Most importantly, norepinephrine dose has known prognostic implications. It has been integrated in several scores for estimating disease severity, and common thresholds for identifying patients at higher risk of death could be misinterpreted in the light of reporting heterogeneity. In fact, since norepinephrine dose is non-linearly correlated with mortality in a dose-dependent fashion [5], dose reporting heterogeneity could bias clinicians’ perception of severity and prognosis, with the risk of triggering either early, delayed or inadequate decisions that could hinder optimal clinical care.

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].