Statistical analysis plan for early goal-directed therapy using a physiological
            holistic view - the ANDROMEDA-SHOCK: a randomized controlled trial.

Hernández, Glenn; Cavalcanti, Alexandre Biasi; Ospina-Tascón, Gustavo Adolfo; Dubin, Arnaldo; Hurtado, Francisco Javier; Damiani, Lucas Petri; Friedman, Gilberto; Castro, Ricardo; Alegría, Leyla; Cecconi, Maurizio; Teboul, Jean‐Louis; Bakker, Jan

doi:10.5935/0103-507x.20180041

Cited by 10 publications

(14 citation statements)

References 16 publications

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“…Subgroup analyses, with Cox proportional hazards adjusted for the same covariates as in the main model, were conducted to assess interactions between treatment effect and the following prespecified baseline characteristics: lactate levels (>4.0 vs ≤4.0 mmol/L); APACHE II score (<25 vs ≥25); SOFA score (<10 vs ≥10); source of infection (confirmed vs unconfirmed); variation of lactate level between first measurement and baseline measurement (≥10% vs <10%). 16 Several additional post hoc sensitivity analyses listed in the eMethods in Supplement 2, including per protocol analyses, were performed. Furthermore, in a post hoc analysis, we assessed whether treatment effect on the primary outcome might differ across sites using a Cox proportional hazards model adjusted for the same covariates as the main model and a treatment × site interaction term.…”

Section: Discussionmentioning

confidence: 99%

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock

Hernández

Ospina-Tascón

Damiani

et al. 2019

JAMA

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IMPORTANCE Abnormal peripheral perfusion after septic shock resuscitation has been associated with organ dysfunction and mortality. The potential role of the clinical assessment of peripheral perfusion as a target during resuscitation in early septic shock has not been established. OBJECTIVE To determine if a peripheral perfusion-targeted resuscitation during early septic shock in adults is more effective than a lactate level-targeted resuscitation for reducing mortality. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized trial conducted at 28 intensive care units in 5 countries. Four-hundred twenty-four patients with septic shock were included between March 2017 and March 2018. The last date of follow-up was June 12, 2018. INTERVENTIONS Patients were randomized to a step-by-step resuscitation protocol aimed at either normalizing capillary refill time (n = 212) or normalizing or decreasing lactate levels at rates greater than 20% per 2 hours (n = 212), during an 8-hour intervention period. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 28 days. Secondary outcomes were organ dysfunction at 72 hours after randomization, as assessed by Sequential Organ Failure Assessment (SOFA) score (range, 0 [best] to 24 [worst]); death within 90 days; mechanical ventilation-, renal replacement therapy-, and vasopressor-free days within 28 days; intensive care unit and hospital length of stay. RESULTS Among 424 patients randomized (mean age, 63 years; 226 [53%] women), 416 (98%) completed the trial. By day 28, 74 patients (34.9%) in the peripheral perfusion group and 92 patients (43.4%) in the lactate group had died (hazard ratio, 0.75 [95% CI, 0.55 to 1.02]; P = .06; risk difference, −8.5% [95% CI, −18.2% to 1.2%]). Peripheral perfusion-targeted resuscitation was associated with less organ dysfunction at 72 hours (mean SOFA score, 5.6 [SD, 4.3] vs 6.6 [SD, 4.7]; mean difference, −1.00 [95% CI, −1.97 to −0.02]; P = .045). There were no significant differences in the other 6 secondary outcomes. No protocol-related serious adverse reactions were confirmed. CONCLUSIONS AND RELEVANCE Among patients with septic shock, a resuscitation strategy targeting normalization of capillary refill time, compared with a strategy targeting serum lactate levels, did not reduce all-cause 28-day mortality.

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Section: Discussionmentioning

confidence: 99%

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock

Hernández

Ospina-Tascón

Damiani

et al. 2019

JAMA

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496

380

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“…Of this sample, 242 (70%) patients were categorized as fluid responders. These FR+ patients had received a pre-protocol fluid loading of 26.7 vs. 26.8 [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] mL/kg (p = 0.8) in FR− patients. Baseline demographic and severity characteristics of groups are shown in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…The complete protocol, statistical analysis, and main results of the ANDROMEDA-SHOCK trial have been previously published [30][31][32]. Institutional review boards at each participating center approved the study.…”

Section: Methodsmentioning

confidence: 99%

Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial

et al. 2020

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Background: Fluid boluses are administered to septic shock patients with the purpose of increasing cardiac output as a means to restore tissue perfusion. Unfortunately, fluid therapy has a narrow therapeutic index, and therefore, several approaches to increase safety have been proposed. Fluid responsiveness (FR) assessment might predict which patients will effectively increase cardiac output after a fluid bolus (FR+), thus preventing potentially harmful fluid administration in non-fluid responsive (FR−) patients. However, there are scarce data on the impact of assessing FR on major outcomes. The recent ANDROMEDA-SHOCK trial included systematic per-protocol assessment of FR. We performed a post hoc analysis of the study dataset with the aim of exploring the relationship between FR status at baseline, attainment of specific targets, and clinically relevant outcomes. Methods: ANDROMEDA-SHOCK compared the effect of peripheral perfusion-vs. lactate-targeted resuscitation on 28-day mortality. FR was assessed before each fluid bolus and periodically thereafter. FR+ and FR− subgroups, independent of the original randomization, were compared for fluid administration, achievement of resuscitation targets, vasoactive agents use, and major outcomes such as organ dysfunction and support, length of stay, and 28day mortality. Results: FR could be determined in 348 patients at baseline. Two hundred and forty-two patients (70%) were categorized as fluid responders. Both groups achieved comparable successful resuscitation targets, although nonfluid responders received less resuscitation fluids (0 [0-500] vs. 1500 [1000-2500] mL; p 0.0001), exhibited less positive fluid balances, but received more vasopressor testing. No difference in clinically relevant outcomes between FR+ and FR− patients was found, including 24-h SOFA score (9 [5-12] vs. 8 [5-11], p = 0.4), need for MV (78% vs. 72%, p = 0.16), need for RRT (18% vs. 21%, p = 0.7), ICU-LOS (6 [3-11] vs. 6 [3-16] days, p = 0.2), and 28-day mortality (40% vs. 36%, p = 0.5). Only thirteen patients remained fluid responsive along the intervention period. Conclusions: Systematic assessment allowed determination of fluid responsiveness status in more than 80% of patients with early septic shock. Fluid boluses could be stopped in non-fluid responsive patients without any negative impact on clinical relevant outcomes. Our results suggest that fluid resuscitation might be safely guided by FR assessment in septic shock patients.

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“…Moreover, in a previous pilot study, fluid resuscitation could be safely withheld in septic shock patients with normalized peripheral perfusion, a fact that was associated with less organ dysfunction [9]. In ANDROMEDA-SHOCK, CRT was assessed every 30 min and lactate every 2 h during the intervention period of 8 h [10,11]. Accordingly, and considering the published evidence, the first time-point where the impact of resuscitation could be compared between study arms was as early as at 2 h (T2).…”

Section: Introductionmentioning

confidence: 99%

A lactate-targeted resuscitation strategy may be associated with higher mortality in patients with septic shock and normal capillary refill time: a post hoc analysis of the ANDROMEDA-SHOCK study

Kattan

Hernández

Ospina-Tascón

et al. 2020

Ann. Intensive Care

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Background: Capillary refill time (CRT) may improve more rapidly than lactate in response to increments in systemic flow. Therefore, it can be assessed more frequently during septic shock (SS) resuscitation. Hyperlactatemia, in contrast, exhibits a slower recovery in SS survivors, probably explained by the delayed resolution of non-hypoperfusion-related sources. Thus, targeting lactate normalization may be associated with impaired outcomes. The ANDROMEDA-SHOCK trial compared CRT-versus lactate-targeted resuscitation in early SS. CRT-targeted resuscitation associated with lower mortality and organ dysfunction; mechanisms were not investigated. CRT was assessed every 30 min and lactate every 2 h during the 8-h intervention period, allowing a first comparison between groups at 2 h (T2). Our primary aim was to determine if SS patients evolving with normal CRT at T2 after randomization (T0) exhibited a higher mortality and organ dysfunction when allocated to the LT arm than when randomized to the CRT arm. Our secondary aim was to determine if those patients with normal CRT at T2 had received more therapeutic interventions when randomized to the LT arm. To address these issues, we performed a post hoc analysis of the ANDROMEDA-SHOCK dataset. Results: Patients randomized to the lactate arm at T0, evolving with normal CRT at T2 exhibited significantly higher mortality than patients with normal CRT at T2 initially allocated to CRT (40 vs 23%, p = 0.009). These results replicated at T8 and T24. LT arm received significantly more resuscitative interventions (fluid boluses: 1000[500-2000] vs. 500[0-1500], p = 0.004; norepinephrine test in previously hypertensive patients: 43 (35) vs. 19 (19), p = 0.001; and inodilators: 16 (13) vs. 3 (3), p = 0.003). A multivariate logistic regression of patients with normal CRT at T2, including APACHE-II, baseline lactate, cumulative fluids administered since emergency admission, source of infection, and randomization group) confirmed that allocation to LT group was a statistically significant determinant of 28-day mortality (OR 3.3; 95%CI[1.5-7.1]); p = 0.003).

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Statistical analysis plan for early goal-directed therapy using a physiological holistic view - the ANDROMEDA-SHOCK: a randomized controlled trial.

Cited by 10 publications

References 16 publications

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock

Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial

A lactate-targeted resuscitation strategy may be associated with higher mortality in patients with septic shock and normal capillary refill time: a post hoc analysis of the ANDROMEDA-SHOCK study

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