To the editor
The study conducted by Ko et al. examines the effect of early norepinephrine administration on septic shock patients with different haemodynamic phenotypes, defined by diastolic blood pressure (DBP) and pulse pressure (PP) measurements [1]. The study successfully introduces a new research idea through its innovative hypothesis-testing approach, which requires us to address specific study points.
A DBP cutoff of < 50 mmHg is conceptually reasonable as a definition of a “vasoplegic phenotype,” based upon previous physiological understandings of septic circulatory shock. Nonetheless, we urge a note of caution. The current study utilizes a single estimation of the non-invasive DBP at the emergency department (ED) triage, which may not be universally accurate in hypotensive, tachycardic, or arrhythmic states. Oscillometric devices are pragmatic but can underestimate or overestimate true arterial pressure in shock states. Although oscillometric devices are useful for obtaining blood pressure, they can frequently underestimate or overestimate true blood pressure levels, especially in shock states. Even minor measurements can change between groups for the analysis of the interaction between DBP and the time to norepinephrine [2].
The definition of “early norepinephrine” as administration within 25 min of triage may also measure system efficiency, rather than purely pharmacologic benefit. In many emergency departments, achieving vasopressor initiation within such a short timeframe depends on rapid triage, early physician recognition, timely vascular access, and streamlined pharmacy workflows. Thus, the observed mortality benefit may partly represent the advantage of high-performing care systems rather than the isolated effect of early norepinephrine. This interpretation is consistent with the existing literature on sepsis, which suggests that timely completion of the sepsis bundle is frequently an indirect measure of the quality of care provided [3].
As with all observational studies, the problem of confounding by indication remains, and it is possible that clinicians may have preferentially initiated norepinephrine earlier in patients perceived as more vasodilated or less tolerant of fluids. Such patients may have had earlier source control, better monitoring, and earlier ICU admission, all of which improve outcomes. We note that granular fluid data (volume, rate, and dynamic fluid responsiveness indices) were unavailable, making it difficult to fully separate the effect of early norepinephrine from broader resuscitation strategies [4].
The secondary stratification by pulse pressure is innovative and physiologically appealing. However, several subgroups had small sample sizes with wide confidence intervals, which limits the robustness of some inferences. The concept that low DBP with wide PP represents “vasoplegia with preserved stroke volume” is biologically plausible but remains speculative without concurrent echocardiographic or invasive hemodynamic validation. Integration of bedside ultrasound in future studies would greatly enhance clinical applicability [5].
We also postulate that in-hospital mortality is an incomplete surrogate for the clinical effect of early norepinephrine. Other endpoints, such as vasopressor-free days, resolution of organ dysfunction, duration of mechanical ventilation, and 90-day survival, may better describe benefit. Additionally, in-hospital mortality is susceptible to bias in institutional discharge practices and end-of-life decisions that differ between centers [6].
In the broader context, this study contributes meaningfully to the ongoing debate regarding early vasopressors versus fluid-first strategies in septic shock. While the CENSER trial suggested potential advantages of earlier norepinephrine, the CLOVERS trial did not demonstrate clear superiority of a restrictive fluid strategy with early pressors. Thus, Ko et al.’s findings should be viewed as complementary and hypothesis-generating rather than definitive, helping refine rather than resolve the question of which patients benefit most from early vasopressor therapy [7, 8].
We believe that the most valuable contribution of this work is to reinforce phenotype-guided resuscitation rather than adherence to a rigid time threshold. Future randomized trials stratified by DBP, PP, and echocardiographic profiles are required to determine whether such precision resuscitation improves outcomes.
In conclusion, Ko et al., by linking early norepinephrine use to readily available hemodynamic markers, refine current understanding of vasopressor timing and underscore the need for more individualized treatment strategies. These findings should encourage prospective, physiology-based trials incorporating detailed hemodynamic assessment to better define which patients derive the greatest benefit from early vasopressor therapy.
Acknowledgements
Not applicable.
Author contributions
Both authors contributed equally. Both authors read and approved the final manuscript.
Funding
Nill.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publications
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Ko R-E, Kang D, Kim WY, et al. Time-to-vasopressors and clinical outcome by level of diastolic blood pressure and pulse pressure in patients with septic shock: a retrospective analysis of prospective multicenter cohort study. Crit Care. 2026. 10.1186/s13054-026-05859-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Meidert AS, Dolch ME, Mühlbauer K, et al. Oscillometric versus invasive blood pressure measurement in patients with shock: a prospective observational study in the emergency department. J Clin Monit Comput. 2021;35(2):387–93. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–247. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Boyd JH, Forbes J, Nakada TA, Walley KR, Russell JA. Fluid resuscitation in septic shock: a positive fluid balance and elevated central venous pressure are associated with increased mortality. Crit Care Med. 2011;39(2):259–65. [DOI] [PubMed] [Google Scholar]
- 5.Geri G, Vignon P, Aubry A, et al. Cardiovascular clusters in septic shock combining clinical and echocardiographic parameters: a post hoc analysis. Intensive Care Med. 2019;45(5):657–67. [DOI] [PubMed] [Google Scholar]
- 6.Vincent JL. Endpoints in sepsis trials: more than just 28-day mortality? Crit Care Med. 2004;32(5 Suppl):S209–13. [DOI] [PubMed] [Google Scholar]
- 7.Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med. 2019;199(9):1097–105. [DOI] [PubMed] [Google Scholar]
- 8.National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network, Shapiro NI, Douglas IS, et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension. N Engl J Med. 2023;388(6):499–510. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.