Trajectories of mean arterial pressure/norepinephrine equivalent dose index in patients with septic shock receiving low-dose hydrocortisone: a retrospective cohort study in Thailand

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Acute Crit Care. 2026;41(1):107-116

Publication date (electronic) : 2026 February 9

doi : https://doi.org/10.4266/acc.000125

Auttawut Chalermwutanon¹, Sawangjit Saejaow², Veerapong Vattanavanit^,3

¹Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand

²Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand

³Critical Care Medicine Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand

Corresponding author: Veerapong Vattanavanit Critical Care Medicine Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110, Thailand Tel: +66-7445-1452 Fax: +66-7428-1457 Email: vveerapong@gmail.com

Received 2024 December 23; Revised 2025 November 1; Accepted 2025 November 5.

Abstract

INTRODUCTION

Septic shock, a medical emergency characterized by severe infection, leads to reduced blood flow and oxygen delivery to tissues. This condition is frequently encountered in intensive care units (ICUs) and is recognized by the World Health Organization as a significant global public health issue. Approximately 85% of sepsis cases and sepsis-related deaths occur in low-to-middle-income countries [1]. A systematic review reported a sepsis-related hospital mortality rate of 27% globally [2]. In Thailand, the prevalence of shock among patients with sepsis is 30.5%, with a 28-day mortality rate of 38% [3].

The use of corticosteroids in septic shock has been debated and researched for more than four decades. The benefits of corticosteroids remain controversial owing to varying patient selection criteria, types and doses of corticosteroids, and differences in administration duration, leading to inconsistent primary outcomes regarding mortality. However, secondary outcomes have consistently shown that corticosteroids reduce the duration of vasopressor use [4,5]. Current treatment guidelines for septic shock, based on the 2021 guidelines of the Surviving Sepsis Campaign, recommend the use of intravenous corticosteroids in patients who require escalating doses of vasopressors [6].

Recently, the ratio of mean arterial pressure (MAP) to norepinephrine equivalent dose (NEQ), known as the MAP/NEQ index, has been introduced as a novel marker for assessing septic shock severity. The MAP/NEQ demonstrated improved prognostic validity compared with commonly used sepsis severity scores and vasopressor dose alone [7]. The MAP/NEQ has been used to predict early mortality in patients with shock treated with vasopressors [8] and to determine the appropriate timing for initiating enteral nutrition in patients with shock [9].

As corticosteroids reduce the duration of vasopressor use, this can be expected to influence the trajectory of the MAP/NEQ index over time after the initiation of hydrocortisone administration. In this study, we aimed to characterize hemodynamic response trajectories in patients with septic shock receiving low-dose hydrocortisone in real-world clinical practice rather than to test treatment efficacy in a trial setting. We hypothesized that tracking the MAP/NEQ index trajectories after starting low-dose intravenous hydrocortisone treatment would predict septic shock recovery and in-hospital mortality.

MATERIALS AND METHODS

The study was approved by the Human Ethics Committee of the Faculty of Medicine at Prince of Songkla University (No. 66-281-14-4). All methods were performed in accordance with the relevant guidelines and regulations, and the study adhered to the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective study design.

RESULTS

In this study, 265 patients with septic shock admitted to the MICU were eligible for inclusion. After excluding 62 patients (4 with adrenal insufficiency, 32 with preexisting steroid treatment, 4 receiving a different steroid dose, and 22 with incomplete data), 203 patients were included in the study cohort. A flowchart of the patient selection process is shown in Figure 1. The baseline characteristics according to primary outcome are presented in Supplementary Table 1. Type of infection, positive hemoculture, amount of intravenous fluid, appropriate antibiotic use, and severity score significantly affected mortality.

Figure 1.

Study flowchart showing patient screening and enrollment. ICU: intensive care unit.

Model comparison using the BIC, the log Bayes factor, and minimum group membership favored the model with three trajectories as having the optimal fit. By contrast, the models with two- or four-groups yielded poorer BIC values and included implausibly small subgroups (Supplementary Table 2). The assessment of model adequacy for the three-trajectory model is presented in Supplementary Table 3. The average posterior probabilities for all trajectory groups exceeded the recommended cutoff of 0.7, indicating acceptable classification quality.

Figure 2 illustrates the MAP/NEQ trajectories measured at 0, 6, 12, 24, 48, and 72 hours after hydrocortisone administration. The study population was categorized into three distinct patterns of unchanged (n=156, 76.8%), gradually increased (n=29, 14.3%), and rapidly increased (n=18, 8.9%). Distinct trajectories emerged within the first 6 hours and were clearly separated by 24 hours. Patients whose MAP/NEQ index increased above 500 mm Hg/µg/kg/min during this early period generally followed favorable (gradually or rapidly increasing) trajectories, whereas those remaining below 300 mm Hg/µg/kg/min typically belonged to the unchanged, non-responder group.

Figure 2.

Trajectories of the MAP/NEQ index measured at 0, 6, 12, 24, 48, and 72 hours after hydrocortisone initiation. Three distinct patterns were identified: group 1 (blue), unchanged (non-responders, 76.8%); group 2 (red), gradually increased (delayed responders, 14.3%); and group 3 (green), rapidly increased (early responders, 8.9%). Divergence between trajectories became evident at 6 hours and was clearly pronounced by 24 hours. MAP: mean arterial pressure; NEQ: norepinephrine equivalent dose.

The baseline characteristics of the MAP/NEQ trajectory groups are presented in Table 1. The median patient age was 69 years, and 53.2% of the patients were male. Significant differences among the three groups were observed in terms of catheter-associated urinary tract infection, baseline SOFA score, non-cardiovascular SOFA score, initial lactate level, MAP/NEQ index at the time of starting hydrocortisone treatment, shock reversal rate, time to shock reversal, occurrence of hypernatremia, and in-hospital mortality.

Table 1.

Patient characteristics according to the MAP/NEQ index trajectories

The hemodynamic variables and vasoactive agents used at the time of shock diagnosis and initiation of hydrocortisone treatment are detailed in Table 2. The initial median MAP/NEQ index was 1,103.1 mm Hg/µg/kg/min, with no significant differences among the three groups. However, after initiating hydrocortisone treatment, the median MAP/NEQ indices for the unchanged and gradually increased groups were 245.4 mm Hg/µg/kg/min and 432.2 mm Hg/µg/kg/min, respectively, which were significantly lower than the median MAP/NEQ index of 1,318.5 mm Hg/µg/kg/min for the rapidly increased group.

Table 2.

Hemodynamic variables at the time of shock diagnosis and of starting hydrocortisone according to the MAP/NEQ index trajectories

Table 3 shows the associations between MAP/NEQ index trajectory groups and mortality. Compared with the unchanged group, the gradually increased and rapidly increased groups were significantly associated with a lower risk of mortality after adjusting for confounders (OR, 0.15; 95% CI, 0.05–0.40; P<0.001 and OR, 0.29; 95% CI, 0.09-0.92; P=0.035, respectively).

Table 3.

ORs of in-hospital mortality according to the MAP/NEQ index trajectories

DISCUSSION

This study focused on analyzing MAP/NEQ index trajectories in patients with septic shock receiving low-dose hydrocortisone as part of clinical care. Hydrocortisone was considered adjunctive therapy rather than an intervention under investigation. We identified three MAP/NEQ index trajectories after initiating hydrocortisone treatment. The groups with an increased MAP/NEQ index, whether gradual or rapid, were significantly associated with a lower risk of in-hospital mortality and higher rates of shock reversal than the unchanged group.

To the best of our knowledge, this is the first study to evaluate the trajectories of hemodynamic responses to low-dose bolus hydrocortisone using the MAP/NEQ index. Previous studies have examined hemodynamic responses to various hydrocortisone preparations. For instance, Bargate et al. found that, in patients with septic shock, a bolus of hydrocortisone with fludrocortisone increased the systolic blood pressure, diastolic blood pressure, and MAP within 2–4 hours of steroid initiation [18]. Similarly, Keh et al. [19] observed an increase in MAP on day 1 and a decrease in norepinephrine requirements with continuous hydrocortisone administration. Our study used the MAP/NEQ index, which represents the ratio of blood pressure to vasopressor dose and is analogous to the PaO₂/FiO₂ ratio used in respiratory physiology [7]. Our results showed that the MAP/NEQ index trajectories were notably different 24 hours after starting hydrocortisone treatment. The increase in MAP and decrease in NEQ can be attributed to the effects of hydrocortisone, which include direct effects on vascular tone, left ventricular afterload, immunologic effects, and levels of endothelial glucocorticoid receptors that reduce vasoplegia [20].

Our study reflects the real-life practice of using low-dose hydrocortisone for septic shock, with a median of 7 hours from septic shock onset to steroid administration. This aligns with guidelines recommending the initiation of steroids in patients treated with vasopressors for a minimum of 4 hours. The median NEQ dose was 0.25 µg/kg/min, which is consistent with the guideline-recommended dose for corticosteroids [6]. The median time from septic shock onset to shock reversal was 3 days, similar to that in the hydrocortisone group in the Adjunctive Corticosteroid Treatment in Critically Ill Patients with Septic Shock trial [21]. We used intermittent bolus doses of hydrocortisone for ease of administration, which have been associated with higher shock reversal rates on day 7 than continuous infusion [22].

We identified three patterns of MAP/NEQ index response to hydrocortisone. Unfortunately, most patients (76%) exhibited an unchanged pattern, potentially because the patients were steroid non-responders or were severely ill. This lack of response might reflect tissue resistance to glucocorticoids at the receptor level [23], genetic variability in glucocorticoid receptor sensitivity [24], or irreversible vasoplegia occurring in the late phase of septic shock. Previous studies have provided information on corticosteroid responders. For example, the corticosteroid therapy of septic shock study reported that 46.7% of patients with septic shock were steroid non-responders, which was defined as the absence of a response to a corticotropin test [14]. Similarly, a Thai study reported a non-responsiveness rate of 55.2% among patients with septic shock [25]. No benefit was found in using steroids in patients without a sufficient response in the adrenocorticotropic hormone (ACTH) stimulation test, defined as an increase ≤ 9 μg/dl in cortisol 30–60 minutes after ACTH administration. Therefore, steroid responsiveness might not be an appropriate index for hemodynamic response to hydrocortisone. Patients in our study appeared to be more severely affected than those in previous studies, as indicated by a mortality rate of 56.2% in patients with septic shock, compared to ≤50% in two recent major randomized trials of steroid use in septic shock [13,21].

An original study by Bosch et al. [7] reported the prognostic validity of the MAP/NEQ index using MIMIC-III and an electronic ICU database. The MAP/NEQ index within 24 hours of ICU admission ranged from 39 to 8,396 mm Hg/µg/kg/min in the MIMIC-III database. Tertiles were used to create MAP/NEQ cutoffs of < 136, 136–324, and ≥325 mm Hg/µg/kg/min, classified as severe, moderate, and mild severity, respectively. A previous study by Yang et al. [8] identified the MAP/NEQ index as an early mortality predictor in patients with shock using the MIMIC-IV database. Higher MAP/NEQ indices were associated with shorter hospital stays and lower mortality rates. A MAP/NEQ index ≤183 mm Hg/µg/kg/min was linked to a significantly increased mortality risk.

The MAP/NEQ index in our study was higher than those reported in previous studies by Bosch et al. [7] and Yang et al. [8] because we used a different NEQ formula. Previous studies used a formula developed in 2008 that included only norepinephrine, dopamine, epinephrine, and phenylephrine. The units for most vasoactive agents were µg/min, except for dopamine, which was measured in µg/kg/min with a conversion ratio of 1:2. Recently, Kotani et al. [12] updated the NEQ formula to include new vasopressors such as vasopressin and angiotensin II, suggesting its extension for use with the MAP/NEQ index. The updated formula uses units of µg/kg/min, with a conversion ratio of 1:100 for dopamine. This approach yields smaller denominator values and consequently higher MAP/NEQ ratios than those reported in earlier studies. Subsequent studies have shown that the updated NEQ formula demonstrated favorable predictive performance for mortality risk in patients with sepsis in ICUs [26] and supports its use in settings involving alternative vasoactive agents, such as angiotensin II [27] and methylene blue [28]. Our results suggest that using a single MAP/NEQ index as a prognostic marker in patients with septic shock receiving hydrocortisone can be more effective when measured at the time of starting hydrocortisone treatment than at the time of septic shock diagnosis.

The gradually and rapidly increased trajectory groups demonstrated better outcomes in terms of shock reversal, supporting the MAP/NEQ index as a reliable indicator of hemodynamic recovery in patients receiving hydrocortisone. In our study, MAP/NEQ trajectories were associated with both in-hospital mortality and shock reversal outcomes. Hydrocortisone use can lead to metabolic complications such as hyperglycemia and hypernatremia, both of which can worsen patient outcomes. In our study, hyperglycemia (≥150 mg/dl) occurred in approximately 60% of patients after initiation of hydrocortisone administration. Previous evidence suggests that a stable mean blood glucose level between 120 and 140 mg/dl is associated with lower ICU mortality and reduced hypoglycemia risk in patients with sepsis but without diabetes [29]. Hypernatremia (≥150 mEq/L) was observed mainly in the unchanged MAP/NEQ group and has been linked to poor prognosis in septic shock [30]. These findings suggest that, in patients who remain hemodynamically unchanged after 24–48 hours, the development of hypernatremia or persistent hyperglycemia should prompt reconsideration or discontinuation of hydrocortisone to avoid harm. Serial MAP/NEQ monitoring every 6–12 hours can help identify early steroid responders, whereas a persistently flat trajectory, characterized by MAP/NEQ values less than 300 mm Hg/µg/kg/min after 24–48 hours, should prompt reassessment of therapy. This trajectory-based approach could be incorporated into sepsis protocols to guide the timely escalation or de-escalation of corticosteroid treatment.

Our study has several limitations. First, its nature as a single-center study might introduce selection bias. Second, the limited sample size might have reduced the statistical power of the association analysis. Third, rapid hemodynamic fluctuations might have been missed because of the 6-hour data collection intervals. Fourth, data on potential confounders influencing mortality outcomes might not have been fully adjusted. Although fluid balance is an important confounder, only the total volume of fluid resuscitation was recorded because net balance was not preplanned in the study protocol. Moreover, other inflammatory markers, such as C-reactive protein and procalcitonin, were not routinely measured in our hospital. We acknowledge that the observed associations might reflect residual confounding or reverse causality; therefore, the trajectory–mortality relationship should be interpreted as prognostic rather than causal, given the retrospective design and lack of randomization. Fifth, only patients receiving bolus hydrocortisone were included; hence, the findings should not be directly extrapolated to continuous infusion regimens. Finally, the rapidly increased trajectory group, representing less than 10% of the cohort, might have reduced statistical stability and widened CIs, although model adequacy indices support the robustness of the trajectory classification.

In conclusion, three MAP/NEQ index trajectories in patients receiving hydrocortisone were identified using GBTMs. The rapidly and gradually increased trajectory patterns were associated with lower mortality and higher shock reversal than the unchanged trajectory pattern. The MAP/NEQ index trajectory patterns demonstrated the utility of MAP/NEQ index measurement in predicting outcomes in patients with septic shock receiving hydrocortisone. However, our results require further investigation with larger sample sizes and various populations.

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