Personalized Hemodynamic Resuscitation Targeting Capillary R

Visão geral

https://jamanetwork.com/journals/jama/fullarticle/2840823

Key Points

Resumo Detalhado do Estudo ANDROMEDA-SHOCK-2

🎯 Pergunta Principal

Uma estratégia personalizada de ressuscitação hemodinâmica baseada no tempo de reenchimento capilar (TRC) melhora os desfechos em pacientes com choque séptico inicial comparado ao cuidado usual?

📊 Principais Achados

Em um ensaio clínico com 1.467 pacientes em 86 UTIs, a estratégia personalizada mostrou benefício significativo no desfecho composto hierárquico que incluiu:

O win ratio foi de 1,16, indicando superioridade da intervenção.

💡 Significado Clínico

A estratégia personalizada de ressuscitação hemodinâmica visando normalizar o TRC melhora os desfechos centrados no paciente no choque séptico inicial.

🔬 Metodologia

Desenho: Ensaio clínico randomizado multicêntrico

Período: Março 2022 a Abril 2025, com seguimento até Julho 2025

Locais: 86 centros em 19 países (Américas, Europa e Ásia)

População: 1.467 pacientes (idade média 66 anos, 43,3% mulheres)

⚙️ Grupos de Intervenção

Grupo Intervenção (n=720): Protocolo CRT-PHR incluindo avaliação de:

Grupo Controle (n=747): Cuidado usual

📈 Resultados Primários

Desfecho composto hierárquico avaliado em 28 dias:

Total de vitórias: 131.131 (48,9%) no grupo intervenção vs 112.787 (42,1%) no controle

✅ Conclusão

Entre pacientes com choque séptico inicial, o protocolo personalizado de ressuscitação hemodinâmica baseado no TRC foi superior ao cuidado usual, principalmente devido à menor duração do suporte vital.

Question Does a personalized hemodynamic resuscitation strategy targeting capillary refill time normalization improve outcomes in early septic shock compared with usual care?

Findings In this randomized clinical trial including 1467 patients with septic shock treated in 86 intensive care units, a personalized hemodynamic resuscitation strategy had a significant beneficial effect on the composite hierarchical outcome comprising mortality, duration of vital support, and length of stay through 28 days after randomization, compared with usual care (win ratio, 1.16).

Meaning A personalized hemodynamic resuscitation strategy targeting capillary refill time normalization improves patient-centered outcomes in early septic shock.

Abstract

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Trial of Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock

Visual Abstract.

Importance The optimal strategy for hemodynamic resuscitation in early septic shock remains uncertain.

Objective To determine the effect of a personalized hemodynamic resuscitation protocol targeting capillary refill time (CRT-PHR) on a hierarchical composite outcome of mortality, duration of vital support, and length of hospital stay.

Design, Setting, and Participants This randomized clinical trial was conducted in 86 centers in 19 countries. Patients within the first 4 hours of septic shock were included between March 2022 and April 2025, with last follow-up in July 2025.

Interventions Patients were randomized to undergo CRT-PHR (n = 720), including assessment of pulse pressure, diastolic arterial pressure, fluid responsiveness, and bedside echocardiography, to tailor fluids, vasopressors, and inotropes, vs usual care (n = 747).

Main Outcomes and Measures The primary outcome was a hierarchical composite of mortality, duration of vital support (vasoactives, mechanical ventilation, and kidney replacement therapy), and length of hospital stay assessed at 28 days. A win ratio was calculated for the primary outcome by comparing all possible patient pairs, starting with the first event in the hierarchy and stratified by median APACHE (Acute Physiology and Chronic Health Evaluation) II score at admission. Secondary outcomes were mortality, vital support–free days, and length of hospital stay at 28 days.

Results From 1501 randomized patients, 1467 were included in the primary analysis (mean age, 66 [17] years; 43.3% female). There were 131 131 wins (48.9%) in the CRT-PHR group vs 112 787 (42.1%) in the usual care group for the hierarchical composite primary outcome, with a win ratio of 1.16 (95% CI, 1.02-1.33; P = .04). Individual wins for death were 19.1% vs 17.8%; duration of vital support, 26.4% vs 21.1%; and length of hospital stay, 3.4% vs 3.2% in the intervention vs usual care groups, respectively.

Conclusions and Relevance Among patients with early septic shock, a personalized hemodynamic resuscitation protocol targeting capillary refill time was superior to usual care for the primary composite outcome, primarily due to a lower duration of vital support.

Trial Registration ClinicalTrials.gov Identifier: NCT05057611

Introduction

Research in septic shock has been focused on determining the best resuscitation strategy to reduce mortality and improve patient-centered outcomes. Unfortunately, the optimal management of fluids and vasoactive agents remains uncertain.1 One possible explanation lies in the substantial heterogeneity of patients with septic shock, which may limit the effectiveness of nonpersonalized resuscitation strategies.2 Indeed, recent trials comparing liberal vs restrictive fluid administration3 or high vs low mean arterial pressure (MAP) targets4 have failed to improve patient-centered outcomes. Accordingly, how to personalize hemodynamic resuscitation in septic shock is a research priority raised by experts and recent guidelines.5-7

Septic shock resuscitation relies on the assumption that hemodynamic optimization will improve tissue perfusion and revert cell metabolic derangements.6 Assessment of capillary refill time (CRT) may identify tissue hypoperfusion,8,9 while its evolution could reflect the progress of resuscitation.10 In the ANDROMEDA-SHOCK trial, CRT-targeted resuscitation was associated with faster recovery of organ dysfunction, less fluid administration,11 and higher likelihood of survival12 compared with lactate-targeted resuscitation.

Diverse pathogenic mechanisms, such as hypovolemia, vasoplegia, and cardiac dysfunction, are involved and overlap in septic shock.2 Identifying the predominant hemodynamic pattern is challenging, especially when advanced monitoring is not available and initial resuscitative decisions have to be taken immediately after intensive care admission. Analysis of simple clinical physiological signals at the bedside may be helpful. For instance, a low diastolic arterial pressure (DAP) reflects decreased vascular tone, while a narrow pulse pressure may be associated with a low stroke volume.13,14 However, the impact of integrating personalized hemodynamic interventions with CRT as a resuscitation target during early stages of septic shock has not been previously studied.

Building on this, the ANDROMEDA-SHOCK-2 trial designed and assessed the efficacy of a personalized hemodynamic resuscitation (PHR) protocol incorporating sequential multilayered assessments of diverse physiological signals to tailor fluids, vasopressors, and inotropes, targeting CRT normalization. The study aimed to compare the effect of this strategy vs usual care on a hierarchical composite outcome of mortality, duration of vital support, and length of hospital stay in patients with early septic shock.

Methods

Trial Design, Setting, and Oversight

ANDROMEDA-SHOCK-2 was an investigator-generated, multicenter, randomized clinical trial comparing a personalized hemodynamic resuscitation protocol targeting capillary refill time (CRT-PHR) vs usual care in patients with early septic shock. The trial was conducted in 86 intensive care units across 19 countries from the Americas, Europe, and Asia between March 2022 and April 2025, with last follow-up in July 2025. The trial protocol15 and statistical analysis plan16 are available in Supplement 1. The trial was overseen by an independent data and safety monitoring board, with 2 interim analyses performed after 200 and 1125 patients were enrolled.16 The trial was approved by the institutional review board at each participating site. Written informed consent was obtained from patients or their legal authorized representatives according to local regulations. The trial is reported in accordance with the 2025 Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.17

Patients and Eligibility Criteria

Consecutive adult patients (aged ≥18 years) with septic shock were considered eligible. Septic shock was defined as suspected or confirmed infection, plus hyperlactatemia (≥2.0 mmol/L), and requirement of norepinephrine to maintain a MAP of at least 65 mm Hg after an intravenous fluid load of at least 1000 mL.18 Patients could be identified within the intensive care unit, emergency department, operating theater, or hospital wards. Patients were recruited up to 4 hours after inclusion criteria were met. Exclusion criteria and full definitions are available in Supplement 1.

Randomization

Participants were randomized in a 1:1 ratio to the CRT-PHR or usual care group (Figure 1), with stratification by center and using permuted blocks of variable size, using a web-based system (Castor EDC). Allocation concealment was ensured through central randomization. The trial was unblinded to patients and clinicians.

Figure 1. Flow of Participants in the ANDROMEDA-SHOCK-2 Trial

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ARDS indicates acute respiratory distress syndrome; CRT, capillary refill time; CRT-PHR, capillary refill time personalized hemodynamic resuscitation.

aAssessed by the treating clinician.

bDue to peripheral vascular disease, hypothermia, darker skin tone, or rheumatological diseases, such as Raynaud syndrome.

c Reasons included not meeting inclusion criteria (n = 1), liver cirrhosis (n = 2), imminent surgery or acute dialytic procedure within 6-hour period (n = 1), active bleeding at randomization (n = 1), severe ARDS at randomization (n = 1), randomized beyond 4-hour window following septic shock diagnosis (n = 3), and refractory shock at randomization (n = 1).

dReasons included not meeting inclusion criteria (n = 1), liver cirrhosis (n = 1), imminent surgery or acute dialytic procedure within 6-hour period (n = 1), and refractory shock at randomization (n = 1).

Trial Procedures

The steering committee developed the CRT-PHR algorithm through a consensus process based on physiological and clinical data regarding peripheral perfusion as a resuscitation target,11 interpretation of macrohemodynamic patterns,2,19,20 individual response to fluids,21 and selective use of critical care echocardiography.22

The CRT-PHR algorithm was based on 4 fundamental pillars: (1) CRT normalization as the target of hemodynamic resuscitation; (2) baseline identification of individual hemodynamic patterns of cardiovascular dysfunction (persistent hypovolemia, vasoplegia, and cardiac dysfunction) by simple clinical tools (pulse pressure and DAP) and basic bedside echocardiography, followed by specific interventions; (3) systematic fluid-responsiveness assessment before any fluid resuscitation; and (4) 2 acute (1-hour) hemodynamic tests: a trial of a higher MAP target and a trial of a fixed low-dose dobutamine.

CRT Assessment

CRT was assessed by applying firm pressure to the ventral surface of the distal phalanx of a finger, using a glass microscope slide. The pressure was increased until the skin was blank, maintained for 10 seconds, and then released. The time required to return to the normal skin color was measured with a chronometer and a refill time longer than 3 seconds was defined as abnormal.

CRT-PHR Overview

Patients randomized to the CRT-PHR group underwent a sequential multilayered personalized resuscitation during a 6-hour study period aimed at normalizing CRT (Figure 2). Patients with a normal CRT at baseline did not receive further resuscitative interventions unless CRT became abnormal during subsequent hourly assessments within the 6-hour time frame. Patients with abnormal CRT received CRT-PHR implemented in 2 progressive tiers.

Figure 2. Capillary Refill Time Personalized Hemodynamic Resuscitation (CRT-PHR) Algorithm

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CRT indicates capillary refill time.

aPerform successive fluid challenges until CRT normalizes, fluid responsiveness becomes negative, or safety limits are met.

bIf patient already received dobutamine due to cardiac dysfunction treatment, skip this step.

Tier 1 started with the evaluation of pulse pressure. In those patients with a pulse pressure less than 40 mm Hg, fluid responsiveness was assessed, and in those patients identified as fluid responsive, a 500-mL fluid bolus (of crystalloid or colloid) was administered in 30 minutes and CRT reassessed. If still abnormal, a second fluid bolus was administered in fluid-responsive patients. Meanwhile, in those with a pulse pressure of 40 mm Hg or higher and a simultaneous DAP less than 50 mm Hg, norepinephrine was titrated to reach a DAP of 50 mm Hg or higher (DAP adjustment). If these tier 1 interventions failed to normalize CRT, the patient moved to tier 2.

Tier 2 started with basic echocardiography to rule out cardiac dysfunction. In patients with right or left ventricular dysfunction, general treatment recommendations were provided and interventions recorded (right/left ventricular optimization), although no mandatory therapy was part of the CRT-PHR algorithm (Supplement 1). If this intervention failed to normalize CRT or cardiac dysfunction was ruled out, fluid responsiveness was reassessed and further fluid boluses were administered in fluid-responsive patients until normalizing CRT, reaching safety limits, or the patient became unresponsive, whichever came first. If the CRT goal was not achieved, a MAP test was performed only in patients who were chronic hypertensive, by transiently increasing norepinephrine to attain a MAP of 80 to 85 mm Hg for 1 hour. If the CRT goal was met, this MAP level was maintained throughout the 6-hour study period. Otherwise, norepinephrine was decreased to the previous dose and the patient moved to a dobutamine test with a fixed low dose (5 µg/kg/min) for 1 hour. Dobutamine was maintained only in those with normalized CRT.

In all CRT-PHR stages, normalization of CRT prompted hourly reassessments until protocol completion, without additional resuscitative interventions, while standard goals of care were maintained in accordance with recent guideline recommendations.12 The clinical team could override the CRT-PHR if deemed in the patient’s best interest.

The usual care group was treated according to local protocols and/or international guidelines.23 Fluid-responsiveness assessment and echocardiography were allowed but not mandated. CRT measurements were only requested at baseline and at 6 hours.

Protocol Training and Adherence

Before recruitment began, all participating clinicians at each site (medical operators) completed mandatory training on trial procedures and protocol implementation. Training included instructional videos and manuals, case-based exercises with fictitious patients, and virtual sessions with the study coordinating center. If a patient was randomized to the CRT-PHR group, trained medical operators executed the protocol. Meanwhile, patients allocated to the usual care group were resuscitated by attending intensivists, who oversaw all care-related decisions. After the 6-hour study period, clinical management of both groups was at the discretion of the attending physicians.

Protocol adherence was audited by a dedicated team from the Fundación Valle del Lili, who identified protocol deviations and nonadherence (protocol violations) by weekly case-by-case analysis of recruited patients in the CRT-PHR group, according to predefined critical nodes of the algorithm (Supplement 1). In all these cases, participant centers received early feedback from the team.

Outcomes

The primary outcome was a hierarchical composite outcome: (1) all-cause mortality within 28 days, (2) duration of vital support (vasoactives, mechanical ventilation, and kidney replacement therapy) truncated at day 28, and (3) length of hospital stay truncated at day 28. Duration of vital support was defined as the time between randomization and the cessation of all vital support. For patients who resumed vital support, the time of final support cessation was the end of the last period.

Secondary outcomes tested in hierarchical order were (1) all-cause mortality, (2) vital support–free days within 28 days (defined as the number of days between randomization and 28 days after randomization, in which the patient is alive and not requiring cardiovascular, respiratory, and/or kidney support), and (3) length of hospital stay (defined as the number of days between randomization and the day of hospital discharge or death, truncated at day 28). Tertiary outcomes are described at length in Supplement 1. Patients were followed up until day 90 since randomization or death.

Statistical Analysis

For the usual care group, we assumed a 28-day mortality of 39%, mean (SD) number of days needing life support truncated at 28 days among survivors of 5.6 (6.7) and a length of hospital stay truncated at 28 days among survivors of 15.6 (10.1) days, based on the ANDROMEDA-SHOCK trial.11 We considered that the intervention group would reduce mortality to 33%, shorten mean (SD) days using life support among survivors to 4.3 (6.2), and shorten length of hospital stay among survivors to 14 (9.9) days. Using the win ratio method with these 3 components and with 1500 patients enrolled, the trial had a power of 88% to show superiority in the hierarchical composite outcome for a 2-sided α of .05. Because substantial loss to follow-up was not expected in this setting, no adjustment was made to the sample size for potential attrition.

Analysis of treatment effect considered an intention-to-treat population, defined as all participants who adhered to inclusion and exclusion criteria, were randomized, and consented to participate. The primary outcome was analyzed using the stratified win ratio method, using treatment as a fixed effect, with median Acute Physiology and Chronic Health Evaluation (APACHE) II score as a stratifying variable.24 The stratified win ratio could be expressed as the proportion of pairwise comparisons for which the intervention won over the control, divided by the proportion of pairwise comparisons for which the control won, considering the hierarchical ordering of the outcomes. We considered death within 28 days as a binary event, and if both patients in a pair died, it was classified as an early tie and no further primary hierarchical outcomes were considered. The bootstrap resampling method was used to calculate the 95% CI for the win ratio and P value for the hypothesis test.

Secondary outcomes were analyzed with a gatekeeping procedure to preserve overall type I error at .05. Thus, the assessment of statistical significance of secondary outcomes was performed only if the preceding outcome in the hierarchy met the threshold for statistical significance and is further detailed in the statistical analysis plan (Supplement 1). No adjustment for multiple comparisons was applied for analyses of tertiary outcomes and subgroups. Thus, these results should be interpreted as exploratory. All analyses were performed using R version 4.2.3 software (R Foundation).

Results

Patient Characteristics

We enrolled 1501 patients (eFigure 1 and eTable 1 in Supplement 2). Geographical distribution of recruited patients included the Americas (n = 816), Europe (n = 609), and Asia (n = 76). A total of 744 patients were randomized to the CRT-PHR group and 757 to the usual care group. Twenty patients withdrew consent, while 14 were incorrectly randomized, leaving a final cohort of 1467 patients for the analysis: 720 in the CRT-PHR group and 747 in the usual care group (Figure 1). Patients had similar clinical-demographic characteristics at baseline (Table 1) (eTable 2 in Supplement 2).

Table 1. Patient Characteristics at Baseline

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Protocol Interventions

During the 6-hour study period, a higher percentage of patients normalized CRT in the CRT-PHR group compared with usual care (85.9% vs 61.7%). For those patients who normalized CRT in the CRT-PHR group, this was achieved in 65% and 35% of patients during tiers 1 and 2, respectively. Personalized hemodynamic interventions performed and the number of patients normalizing CRT after each intervention are shown in eFigure 2 and eTable 3 in Supplement 2. In the CRT-PHR group, a total of 262 patients (36.4%) started and remained with a normal CRT throughout the study period, whereby they did not receive further hemodynamic interventions. In the usual care group, 62% of patients had fluid responsiveness assessed at any time point, while 68% had basic echocardiography assessments.

Overall, patients randomized to the CRT-PHR group received less resuscitation fluids (595 mL vs 847 mL; mean difference, −251 mL [95% CI, −316 to −187]), received more dobutamine (84/684 [12.3%] vs 37/694 [5.3%]; difference, 7.0% [95% CI, 4.0%-9.9%]), had lower central venous pressure (9.1 mm Hg vs 9.8 mm Hg; mean difference, −0.6 mm Hg [95% CI, −1.1 to −0.1]), and had lower lactate levels (3.2 mmol/L vs 3.5 mmol/L; mean difference, −0.3 mmol/L [95% CI, −0.5 to −0.1]) by the end of the 6-hour study period compared with usual care (Table 2) (eTables 4 and 5 in Supplement 2).

Table 2. Hemodynamic Therapies and Resuscitation-Related Variables at Hour 6

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Patients with normal CRT at baseline who were randomized to the CRT-PHR group had less fluid-responsiveness assessments (71/286 [24.8%] vs 155/269 [57.6%]; difference, −32.8% [95% CI, −40.5% to −25.1%]) and received less resuscitation fluids (210 mL vs 441 mL; mean difference, −231 mL [95% CI, −312 to −150]) compared with the usual care group (eTable 6 in Supplement 2). Conversely, among patients with abnormal CRT at baseline randomized to the CRT-PHR group, fluid-responsiveness assessment (390/408 [95.6%] vs 327/430 [76.1%]; difference, 19.5% [95% CI, 15.0% to 24.0%]) and inotropes administration (72/399 [18.0%] vs 26/427 [6.1%]; difference, 12.0% [95% CI, 7.6%-16.4%]) were more frequent compared with usual care (eTable 6 in Supplement 2). Evolution of hemodynamics and tissue perfusion variables up to day 3 is shown in eTables 4 and 5 in Supplement 2.

In the CRT-PHR group, protocol deviations and violations were observed in 111 of 720 (15%) and 44 of 720 patients (6%), respectively (eFigure 3 and eTable 7 in Supplement 2). DAP augmentation, MAP tests, and dobutamine tests were not conducted due to preemptive safety considerations in 6, 13, and 19 patients, respectively. One dobutamine test had to be stopped because of hypotension, which was reversed after drug discontinuation.

Outcomes

At 28 days after randomization, we observed 131 131 wins (48.9%) for the CRT-PHR group over 112 787 (42.1%) in the usual care group, yielding a stratified win ratio of 1.16 (95% CI, 1.02-1.33; P = .04) (Table 3 and Figure 3). The total number of ties was 24 151 (9.0%). Of the 3 components of the win ratio, duration of vital support yielded the highest number of wins to losses (eTable 8 in Supplement 2); individual wins for death were 19.1% vs 17.8%; duration of vital support, 26.4% vs 21.1%; and length of hospital stay, 3.4% vs 3.2% in the intervention vs usual care groups, respectively.

Table 3. Primary and Secondary Outcomes

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Figure 3. Primary Outcome Analysis

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Distribution of wins, ties, and losses for the CRT-PHR group among both APACHE II strata at each level of the hierarchical primary composite outcome. Every possible pair of participants between groups was compared in a hierarchical fashion with a win, loss, or tie determined by the outcome evaluated at each level of the hierarchy. Percentages are calculated for each level of the hierarchy.

APACHE indicates Acute Physiology and Chronic Health Evaluation; CRT-PHR, capillary refill time personalized hemodynamic resuscitation.

aEarly ties were determined when both participants in the pair died before 28 days following randomization. No further pairwise outcome comparisons were made for early ties.

bTies were determined when both participants survived 28 days or more following randomization.

Among secondary outcomes, there was no significant difference in 28-day mortality between the CRT-PHR and usual care groups (26.5% vs 26.6%; hazard ratio, 0.99 [95% CI, 0.81-1.21]; P = .91). Patients in the CRT-PHR group had a higher number of mean (SD) organ support–free days within 28 days (16.5 [11.3] vs 15.4 [11.4]; proportional odds ratio, 1.28 [95% CI, 1.06-1.54]) and faster decrease in SOFA (Sequential Organ Failure Assessment) score within 7 days compared with the usual care group (eTables 9 and 10 in Supplement 2). Tertiary outcomes are presented in eTable 11 in Supplement 2. Vital support requirements throughout the study period are shown in eTable 12 in Supplement 2. There was no effect modification for the subgroups assessed (eFigure 4 and eTables 13 and 14 in Supplement 2). Use of adjunctive therapies and antimicrobial and surgical source control is shown in eTables 15 and 16 in Supplement 2. A post hoc analysis of treatment effect by participating centers is shown in eFigure 5 in Supplement 2. Five cases of suspected unexpected serious adverse reactions were reported by centers, without differences between groups, but none was considered as likely related to the study protocol.

Discussion

In this trial including patients with early septic shock, a CRT-PHR strategy was superior to usual care on a hierarchical composite outcome of mortality, duration of vital support, and length of hospital stay at day 28. These results were mainly driven by a shorter duration of vital support.

The development of personalized hemodynamic resuscitative strategies is considered a top priority on the septic shock research agenda.5,6 However, there has been limited progress in this direction, explained partly by the extreme complexity of designing and conducting trials in which the intervention process is probably a research objective by itself. When comparing a personalized resuscitation strategy with usual care, there are additional challenges, such as training, monitoring, and data analysis, particularly to assess gradients of interventions between groups. The present trial used a comprehensive approach to address these challenges, opening new perspectives for future studies.

The ANDROMEDA-SHOCK trial established CRT as a valid target for hemodynamic resuscitation in septic shock11,25,26 by using a standardized sequential algorithm, including fluid responsiveness assessment, and MAP and/or dobutamine tests to achieve perfusion goals.21 Although the ANDROMEDA-SHOCK-2 trial might appear to have certain similarities at first glance, the novel CRT-PHR protocol introduced key refinements aimed at personalizing resuscitation.27 This protocol incorporated simple bedside hemodynamic tools, such as pulse pressure, DAP, and basic echocardiography assessments, to identify distinct hemodynamic patterns and tailor resuscitative interventions.28 The CRT-PHR algorithm had a hierarchical structure of increasing complexity, reserving more labor-intensive assessments (eg, echocardiography) for patients with persistent CRT abnormalities after simpler tier 1 interventions. Indeed, only 35% of patients transitioned to tier 2. Additionally, the ANDROMEDA-SHOCK-2 algorithm was operationalized around key actionable nodes that were trainable and auditable by data quality monitoring to further enhance its effectiveness and facilitate transition to clinical practice.

The effectiveness of the CRT-PHR algorithm cannot be attributed to a single intervention (ie, administered resuscitation fluids) but to the dynamic interaction between the individual components, which converged into a higher rate of CRT normalization. Patients in the CRT-PHR group with normal baseline CRT underwent fewer tests and received less fluids and inotropes, suggesting a more efficient resuscitation. Moreover, normalization of CRT after hemodynamic interventions may signal effective tissue reperfusion, allowing clinicians to stop resuscitation.10 Taken together, this may decrease the odds of overresuscitation, organ dysfunction, and organ support requirements, a relevant patient-centered outcome.26 Indeed, the results of ANDROMEDA-SHOCK-2 support these findings (Table 2).

An important element of acute hemodynamic tests is that they are reversible, which can be continued or not according to response, representing real-time personalization of hemodynamic interventions.29 Both the MAP and dobutamine tests presented success rates (CRT normalization) of approximately 50%. Additionally, a novel DAP adjustment was integrated, with the aim of eventually improving coronary perfusion and consequently systemic blood flow to restore abnormal CRT.19 ,20 Even though CRT normalization rates were lower than with the aforementioned tests, overall CRT values decreased considerably even in patients who did not normalize (eTable 3 in Supplement 2). Further research should explore this in more detail.

To comprehensively assess treatment efficacy in critical care trials, composite end points have been increasingly used.30-32 These measures are particularly valuable because binary outcomes, such as mortality, often fail to capture the full spectrum of morbidity, including prolonged organ dysfunction and the need for sustained vital support among survivors. Indeed, the latter is relevant because it directly influences patients’ recovery trajectories, prolongs the emotional burden for families, and carries major implications for health care system capacity and resource allocation. Thus, composite end points provide a granular and useful view of clinical progression, reflecting both patient-centered outcomes and health care resource utilization.33-38 The use of the win ratio method as primary outcome analysis in ANDROMEDA-SHOCK-2 had the advantage to assess treatment effect on a composite outcome, but with hierarchical prioritization.24 In fact, higher weights are placed on outcomes at the top of the hierarchy. Thus, it increased statistical power compared with assessing mortality alone.

Strengths of this study include its generalizability because it was conducted in a diverse range of hospitals across high- and middle-income countries, enhancing external validity. The protocol proved feasible, evidenced by high adherence rates and a low frequency of protocol violations (nonadherence).

Limitations

This study has limitations. First, it was unblinded. However, multiple independent signals favored the CRT-PHR group, highlighting consistency of the observed effects. Second, decisions regarding discontinuation of vasopressors, extubation, and initiation of kidney replacement therapy were made by attending intensivists according to local practice and were not adjudicated. Nonetheless, while variability in clinical decision-making may increase random error, there is no reason to anticipate systematic differences between study groups. Third, the protocol relied on specific measurements, such as CRT testing, that may have been affected by interrater variability; however, this can be mitigated with proper training and standardization. Fluid responsiveness assessment could be challenging in specific scenarios. The study proposed dichotomic thresholds for pulse pressure and DAP that, although physiologically sound, lack prospective clinical validation. Fourth, the protocol may be perceived as labor intensive and impractical in certain clinical contexts. Nonetheless, most patients achieved CRT normalization with tier 1 interventions, and the protocol proved feasible across a broad range of organizational cultures. Fifth, the possibility that more frequent patient assessments in the CRT-PHR group contributed to the observed effect cannot be excluded. However, the reduction in fluid administration, greater use of vasopressors and inotropes at 6 hours, and higher rates of CRT normalization in the CRT-PHR group all point to protocol-specific mechanistic effects as the primary drivers of benefit. Sixth, one could argue that the usual care group may have been unintentionally undertreated. However, this group underwent substantial fluid responsiveness and echocardiographic assessments, received larger volumes of fluids and a similar proportion of adjuvant therapies, and achieved a lower-than-anticipated 28-day mortality, all of which suggest that undertreatment was unlikely. Seventh, even though the low mortality rate observed in both groups could raise concerns about limited power for the primary outcome analysis, the use of the win ratio approach mitigates this risk. Lower mortality rate in both groups decreases the number of ties and, in turn, increases the number of comparisons based on subsequent hierarchical outcomes. Eighth, mandatory training may have led to inadvertent contamination of the usual care group. However, if that was the case, the results may have underestimated the treatment effect. Ninth, variability in standard care practices across centers and countries may have influenced outcomes; however, such heterogeneity reflects real-world conditions and enhances external validity of the results.

Conclusions

Among patients with early septic shock, a personalized hemodynamic resuscitation protocol targeting CRT was superior to usual care for the primary composite outcome of mortality, duration of vital support, and length of hospital stay at day 28, primarily due to a shorter duration of organ support.

Article Information

Accepted for Publication: October 6, 2025.

Published Online: October 29, 2025. doi:10.1001/jama.2025.20402

Corresponding Author: Glenn Hernandez, MD, PhD, Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Avenida Diagonal Paraguay 362, 6510260, Santiago, Chile (glennguru@gmail.com).

Authors/ANDROMEDA-SHOCK-2 Investigators: Glenn Hernandez, MD, PhD; Gustavo A. Ospina-Tascón, MD, PhD; Eduardo Kattan, MD, PhD; Miguel Ibarra-Estrada, MD; Fernando Ramasco, MD, PhD; Nicolás Orozco, MD, MSc; Karla Ramos, RN, MSc; Jose Luis Aldana, MD, MSc; Giorgio Ferri, MD, MSc; Olfa Hamzaoui, MD, PhD; Daniel De Backer, MD, PhD; Jean-Louis Teboul, MD, PhD; Antoine Vieillard-Baron, MD, PhD; Lucas Petri Damiani, PhD; Gustavo A. García-Gallardo, MD; Sebastian Morales, MD; Paula Carmona Garcia, MD, PhD; Rosa Mendez, MD; Thierry Hernandez-Gilsoul, MD, MPH; Orlando R. Pérez-Nieto, MD; Claudia Olea Vielba, MD; Silvia Ramos, MD, PhD; David Dominguez, MD, PhD; Mario Bruna, MD; Sascha David, MD; Pedro D. Wendel-Garcia, MD, MSc; María Galiana-Ivars, MD, MSc; Sheila Nainan Myatra, MD; Antonio Messina, MD, PhD; Maurizio Cecconi, MD, PhD; Mario Pozo, MD; Macarena Amthauer, RN, MSc; Eva Higuera, MD; Zainab Al Duhalib, MD, MSc; Jesús Rico-Feijoo, MD, PhD; Carolina Ferrer-Gómez, MD, PhD; Ana Pérez-Carbonell, MD, PhD; Sara Martinez-Castro, MD, PhD; Francisco Javier Redondo Calvo, MD, PhD; Marc Vives, MD, PhD; Hector Fabio Sanchez, MD, MSc; Iñaki Bilbao, MD; Paula Fernandez, MD; Abdulrahman Al-Fares, MD; Adela Benitez-Cano, MD, PhD; Cecilia Gonzalez, MD; Luis Felipe Reyes, MD, PhD; Job H. Rodriguez-Guillen, MD; Ana Vaz Cristino, MD; Juan Carlos Pendino, MD; Guillermo Ortiz, MD, PhD; Maria Concepción Alonso-Gonzalez, MD, MSc; Gastón Murias, MD; Guadalupe Aguirre-Ávalos, MD, PhD; Leonardo Hernández, MD; Zulay Adriana Calderón Barajas, MD, MSc; Iratxe Zarragoikoetxea, MD, PhD; Xavier Monnet, MD, PhD; Antoine Goury, MD; Tiago Mendonça dos Santos, PhD; Liliana Vallecilla, MD, MSc; Lucas Martins de Lima, BScIT; Erica Sady, BScPT; Leyla Alegria, RN, MSc; Marlies Ostermann, MD, PhD; Jan Bakker, MD, PhD; Alexandre Biasi Cavalcanti, MD, PhD.

Affiliations of Authors/ANDROMEDA-SHOCK-2 Investigators: Departamento de Medicina Intensiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile (Hernandez, Kattan, K. Ramos, Morales, Amthauer, Alegria, Bakker); Red de Salud UC Christus, Santiago, Chile (Hernandez, Kattan); Department of Intensive Care Medicine, Fundación Valle del Lili, Cali, Colombia (Ospina-Tascón, Orozco, Aldana, García-Gallardo, Vallecilla); Translational Research Laboratory in Critical Care Medicine (TransLab CCM), Universidad Icesi, Cali, Colombia (Ospina-Tascón); Unidad de Terapia Intensiva, Hospital Civil Fray Antonio Alcalde, Universidad de Guadalajara, Guadalajara, Jalisco, México (Ibarra-Estrada, Aguirre-Ávalos); Department of Anaesthesiology and Surgical Intensive Care, Hospital Universitario de La Princesa, Madrid, Spain (Ramasco, Mendez); Unidad de Cuidados Intensivos, Hospital Barros Luco Trudeau, Santiago, Chile (Ferri, Hernández); Service de Médecine Intensive-Réanimation polyvalente, Hôpital Robert-Debré, CHU de Reims, Reims, France (Hamzaoui, Goury); Department of Intensive Care Medicine, CHIREC Hospitals, Université Libre de Bruxelles, Brussels, Belgium (De Backer); Faculté de Médecine Paris-Saclay, Université Paris-Saclay, Le Kremlin-Bicêtre, Paris, France (Teboul); Medical and Surgical Intensive Care Unit, GHU Paris-Saclay, Assistance Publique Hôpitaux de Paris, University Hospital Ambroise Paré, Boulogne-Billancourt, France (Vieillard-Baron); Hcor Research Institute, São Paulo, Brazil (Petri Damiani, Mendonça dos Santos, Martins de Lima, Sady, Biasi Cavalcanti); Department of Anesthesiology and Critical Care, Hospital Universitari i Politècnic La Fe, Valencia, Spain (Carmona Garcia, Zarragoikoetxea); Emergency Department, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City, México (Hernandez-Gilsoul); Intensive Care Unit, Hospital General San Juan del Río, Querétaro, México (Pérez-Nieto); Department of Anesthesia and Intensive Care, Hospital Universitario 12 de Octubre, Madrid, Spain (Olea Vielba, Calderón Barajas); Department of Anesthesiology and Resuscitation, Gregorio Marañón University Hospital, Madrid, Spain (S. Ramos); Department of Anesthesiology, Hospital Universitario N.S. de Candelaria, Santa Cruz de Tenerife, Spain (Dominguez); Unidad de Cuidados Intensivos, Hospital de Quilpué, Quilpué, Chile (Bruna); Institute of Intensive Care Medicine, University Hospital Zurich, Zurich, Switzerland (David, Wendel-Garcia); Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care Medicine, Department of Anaesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria (Wendel-Garcia); Anaesthesiology and Reanimation Service, Hospital General Universitario Dr. Balmis, Alicante, Spain (Galiana-Ivars); Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India (Myatra); IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy (Messina, Cecconi); Servicio de Terapia Intensiva, Hospital Británico de Buenos Aires, Buenos Aires, Argentina (Pozo, Murias); Anaesthesiology and Reanimation Service, Complejo Asistencial Universitario de León, León, Spain (Higuera); Critical Care Medicine Department, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia (Al Duhalib); Department of Anesthesia, Río Hortega University Hospital, Valladolid, Spain (Rico-Feijoo); Department of Anesthesia, Critical Care and Pain Unit, University General Hospital, Valencia, Spain (Ferrer-Gómez); Anesthesiology and Critical Care, Hospital General Universitario de Elche, Alicante, Spain (Pérez-Carbonell); Anesthesia and Critical Care Department, Hospital Clínico Universitario de Valencia, Valencia, Spain (Martinez-Castro); Department of Anesthesiology and Critical Care Medicine, University General Hospital, Ciudad Real, Spain (Redondo Calvo); Department of Anesthesia & Critical Care, Clinica Universidad de Navarra, Pamplona, Spain (Vives); Hospital Universitario Departamental de Nariño, Nariño, Colombia (Sanchez); Servicio de Anestesia y Reanimación del Hospital Universitario de Cruces, Barakaldo, Spain (Bilbao); Departamento Medicina Interna, Facultad de Medicina, Universidad de Concepción, Concepción, Chile (Fernandez); Department of Anesthesia, Critical Care Medicine and Pain Medicine and Kuwait Extracorporeal Life Support Program, Al-Amiri Hospital, Ministry of Health, Kuwait City, Kuwait (Al-Fares); Anesthesiology and Intensive Care Department, Hospital del Mar, Barcelona, Spain (Benitez-Cano); Sanatorio Parque, Rosario, Santa Fe, Argentina (Gonzalez); Unisabana Center for Translational Science, School of Medicine, Universidad de La Sabana, Chia, Colombia (Reyes); Critical Care Department, Hospital H+ Querétaro, Querétaro, México (Rodriguez-Guillen); Serviço de Medicina Intensiva, Unidade Local de Saúde de Trás-os-Montes e Alto Douro, Vila Real, Portugal (Cristino); Unidad de Terapia Intensiva, Hospital Provincial del Centenario, Rosario, Santa Fe, Argentina (Pendino); Subred Centro Oriente, Bogota, Colombia (Ortiz); Complejo Hospitalario Universitario de Ourense, Ourense, Spain (Alonso-Gonzalez); Service de Médecine Intensive-Réanimation, Hôpital de Bicêtre, Université Paris-Saclay, AP-HP, Le Kremlin-Bicêtre, Paris, France (Monnet); Insper Institute of Education and Research, São Paulo, Brazil (Mendonça dos Santos); Department of Critical Care, Guy’s and St Thomas’ NHS Foundation Trust, King’s College, London, United Kingdom (Ostermann); Department of Intensive Care, Erasmus University Medical Center, Rotterdam, the Netherlands (Bakker); Postgraduate Program of Anesthesiology, Surgical Sciences, and Perioperative Medicine, Faculty of Medicine, Universidade de São Paulo, São Paulo, Brazil (Biasi Cavalcanti).

Author Contributions: Drs Ospina-Tascón and Biasi Cavalcanti had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Hernandez, Ospina-Tascón, and Kattan contributed equally.

Concept and design: G. Hernandez, Ospina-Tascón, Kattan, Ramasco, De Backer, Teboul, Vieillard-Baron, Damiani, Morales, David, Cecconi, Ferrer-Gómez, Monnet, Mendonca dos Santos, Bakker, Biasi Cavalcanti.

Acquisition, analysis, or interpretation of data: G. Hernandez, Ospina-Tascón, Kattan, Ibarra-Estrada, Ramasco, Orozco, K. Ramos, Aldana Diaz, Ferri, Hamzaoui, De Backer, Teboul, Vieillard-Baron, Damiani, García-Gallardo, Morales, Carmona-Garcia, Méndez Hernández, Hernandez-Gilsoul, Pérez-Nieto, Olea Vielba, S. Ramos, Domínguez García, Bruna, David, Wendel Garcia, Galiana-Ivars, Myatra, Messina, Cecconi, Pozo, Amthauer, Higuera, Al Duhailib, Rico-Feijoo, Pérez-Carbonell, Martinez-Castro, Redondo Calvo, Vives, Sanchez, Bilbao, Fernandez, Al-Fares, Benítez-Cano, Gonzalez, Reyes, Rodriguez-Guillen, Cristino, Pendino, Ortiz Ruiz, Alonso González, Murias, Aguirre-Avalos, L. Hernandez, Calderon Barajas, Zarragoikoetxea, Goury, Mendonca dos Santos, Vallecilla, Martins de Lima, Sady, Alegría, Ostermann, Bakker, Biasi Cavalcanti.

Drafting of the manuscript: G. Hernandez, Ospina-Tascón, Kattan, Ramasco, Orozco, K. Ramos, Teboul, García-Gallardo, Morales, Olea Vielba, Cecconi, Martinez-Castro, Gonzalez, Pendino, Aguirre-Avalos, Vallecilla, Martins de Lima, Alegría, Ostermann, Bakker, Biasi Cavalcanti.

Critical review of the manuscript for important intellectual content: G. Hernandez, Ospina-Tascón, Kattan, Ibarra-Estrada, Ramasco, Aldana Diaz, Ferri, Hamzaoui, De Backer, Teboul, Vieillard-Baron, Damiani, García-Gallardo, Morales, Carmona-Garcia, Méndez Hernández, Hernandez-Gilsoul, Pérez-Nieto, S. Ramos, Domínguez García, Bruna, David, Wendel Garcia, Galiana-Ivars, Myatra, Messina, Cecconi, Pozo, Amthauer, Higuera, Al Duhailib, Rico-Feijoo, Ferrer-Gómez, Pérez-Carbonell, Martinez-Castro, Redondo Calvo, Vives, Sanchez, Bilbao, Fernandez, Al-Fares, Benítez-Cano, Gonzalez, Reyes, Rodriguez-Guillen, Cristino, Ortiz Ruiz, Alonso González, Murias, L. Hernandez, Calderon Barajas, Zarragoikoetxea, Monnet, Goury, Mendonca dos Santos, Sady, Ostermann, Bakker, Biasi Cavalcanti.

Statistical analysis: Ospina-Tascón, Kattan, Orozco, Damiani, García-Gallardo, Morales, Mendonca dos Santos, Martins de Lima, Ostermann, Biasi Cavalcanti.

Obtained funding: Ospina-Tascón, Ramasco, Hamzaoui, Reyes, Bakker.

Administrative, technical, or material support: Ospina-Tascón, Kattan, Ramasco, Orozco, K. Ramos, Aldana Diaz, García-Gallardo, Morales, Carmona-Garcia, Olea Vielba, S. Ramos, Domínguez García, David, Wendel Garcia, Myatra, Amthauer, Al Duhailib, Martinez-Castro, Vives, Bilbao, Fernandez, Al-Fares, Benítez-Cano, Reyes, Rodriguez-Guillen, Murias, L. Hernandez, Calderon Barajas, Vallecilla, Martins de Lima, Alegría, Ostermann, Bakker, Biasi Cavalcanti.

Supervision: G. Hernandez, Ospina-Tascón, Kattan, Ibarra-Estrada, Ramasco, K. Ramos, Aldana Diaz, Ferri, De Backer, Vieillard-Baron, Morales, Carmona-Garcia, Hernandez-Gilsoul, Pérez-Nieto, Olea Vielba, Myatra, Messina, Cecconi, Amthauer, Ferrer-Gómez, Pérez-Carbonell, Martinez-Castro, Redondo Calvo, Vives, Sanchez, Bilbao, Reyes, Rodriguez-Guillen, Zarragoikoetxea, Ostermann, Bakker.

Conflict of Interest Disclosures: Dr Hamzaoui reported receiving grants from French Health Ministry during the conduct of the study and personal fees from AOP Health and Viatris outside the submitted work. Dr De Backer reported receiving personal fees from Viatris and AOP Health and nonfinancial support from Pharmazz outside the submitted work. Dr Teboul reported receiving consulting fees from Edwards Lifesciences and BD-APM outside the submitted work. Dr Messina reported receiving personal fees from Vygon and Edwards Lifesciences outside the submitted work. Dr Monnet reported receiving personal fees from Getinge, Baxter, BD, AOP Health, and Masimo outside the submitted work. Dr Bakker reported receiving grants to his institution from Nihon Kohden; personal fees from Pharmazz, Bayer, Abbott, Radiometer, and Photonics outside the submitted work; and having a patent pending with Delft University of Technology. No other disclosures were reported.

Funding/Support: The study received logistical support from the Pontificia Universidad Católica de Chile, Fundación Valle del Lili, Erasmus University Medical Center Rotterdam, and HCor Research Institute. This study was supported by the Plataforma Instituto de Salud Carlos III (ISCIII) de Soporte para la Investigación Clínica SCReN (Spanish Clinical Research Network), funded by ISCIII through project PT23/00060 and cofunded by the European Union. The French sites were funded by a grant from Programme Hospitalier de Recherche Clinique National–PHRC-N 2021 (Ministère de la Santé, No. AOM 21020). In the United Kingdom, this study was approved and registered as a National Institute for Health and Care Research portfolio study (NIHR ID 62499).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The ANDROMEDA-SHOCK-2 Investigators for the ANDROMEDA Research Network, Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), and Latin American Intensive Care Network (LIVEN) are listed in Supplement 3.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We thank the patients and their families as well as the intensive care unit teams and dedicated colleagues for making this study happen. We also thank the data and safety monitoring board: M. Elizabeth Wilcox, MD (University of Toronto), Wim J. R. Rietdijk, PhD (Erasmus Medical Center), Michelle Ng Gong, MD, MS (Montefiore Medical Center), Phil Dellinger, MD (Cooper Medical School of Rowan University), and Jean Louis Vincent, MD, PhD (Université libre de Bruxelles), for their significant contribution to this work; none of these individuals received compensation for their role in the study.

Referências