Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study.

BACKGROUND: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. METHODS: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80-85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions). RESULTS: CRT decreased significantly with both tests (from 5 [3.5-7.6] to 4 [2.4-5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3-5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. CONCLUSIONS: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.

Physiological effects of high-flow nasal cannula oxygen therapy after extubation: a randomized crossover study.

BACKGROUND: Prophylactic high-flow nasal cannula (HFNC) oxygen therapy can decrease the risk of extubation failure. It is frequently used in the postextubation phase alone or in combination with noninvasive ventilation. However, its physiological effects in this setting have not been thoroughly investigated. The aim of this study was to determine comprehensively the effects of HFNC applied after extubation on respiratory effort, diaphragm activity, gas exchange, ventilation distribution, and cardiovascular biomarkers. METHODS: This was a prospective randomized crossover physiological study in critically ill patients comparing 1 h of HFNC versus 1 h of standard oxygen after extubation. The main inclusion criteria were mechanical ventilation for at least 48 h due to acute respiratory failure, and extubation after a successful spontaneous breathing trial (SBT). We measured respiratory effort through esophageal/transdiaphragmatic pressures, and diaphragm electrical activity (ΔEAdi). Lung volumes and ventilation distribution were estimated by electrical impedance tomography. Arterial and central venous blood gases were analyzed, as well as cardiac stress biomarkers. RESULTS: We enrolled 22 patients (age 59 ± 17 years; 9 women) who had been intubated for 8 ± 6 days before extubation. Respiratory effort was significantly lower with HFNC than with standard oxygen therapy, as evidenced by esophageal pressure swings (5.3 [4.2-7.1] vs. 7.2 [5.6-10.3] cmH2O; p < 0.001), pressure-time product (85 [67-140] vs. 156 [114-238] cmH2O*s/min; p < 0.001) and ΔEAdi (10 [7-13] vs. 14 [9-16] µV; p = 0.022). In addition, HFNC induced increases in end-expiratory lung volume and PaO2/FiO2 ratio, decreases in respiratory rate and ventilatory ratio, while no changes were observed in systemic hemodynamics, Troponin T, or in amino-terminal pro-B-type natriuretic peptide. CONCLUSIONS: Prophylactic application of HFNC after extubation provides substantial respiratory support and unloads respiratory muscles. Trial registration January 15, 2021. NCT04711759.

Improve sleep in critically ill patients: Study protocol for a randomized controlled trial for a multi-component intervention of environment control in the ICU.

INTRODUCTION: In critically ill patients, sleep and circadian rhythms are greatly altered. These disturbances have been associated with adverse consequences, including increased mortality. Factors associated with the ICU environment, such as exposure to inadequate light and noise levels during the day and night or inflexible schedules of daily care activities, have been described as playing an essential role in sleep disturbances. The main objective of this study is to evaluate the impact of the use of a multifaceted environmental control intervention in the ICU on the quantity and quality of sleep, delirium, and post-intensive care neuropsychological impairment in critically ill patients. METHODS: This is a prospective, parallel-group, randomized trial in 56 critically ill patients once they are starting to recover from their acute illness. Patients will be randomized to receive a multifaceted intervention of environmental control in the ICU (dynamic light therapy, auditory masking, and rationalization of ICU nocturnal patient care activities) or standard care. The protocol will be applied from enrollment until ICU discharge. Baseline parameters, light and noise levels, polysomnography and actigraphy, daily oscillation of plasma concentrations of Melatonin and Cortisol, and questionnaires for the qualitative evaluation of sleep, will be assessed during the study. In addition, all patients will undergo standardized follow-up before hospital discharge and at 6 months to evaluate neuropsychological impairment. DISCUSSION: This study is the first randomized clinical trial in critically ill patients to evaluate the effect of a multicomponent, non-pharmacological environmental control intervention on sleep improvement in ICU patients. The results will provide data about the potential synergistic effects of a combined multi-component environmental intervention in ICU on outcomes in the ICU and long term, and the mechanism of action. TRIAL REGISTRATION: ClinicalTrials.gov, NCT. Registered on January 10, 2023. Last updated on 24 Jan 2023.

Exploring the relationship between capillary refill time, skin blood flow and microcirculatory reactivity during early resuscitation of patients with septic shock: a pilot study.

Capillary refill time (CRT), a costless and widely available tool, has emerged as a promising target to guide septic shock resuscitation. However, it has yet to gain universal acceptance due to its potential inter-observer variability. Standardization of CRT assessment may minimize this problem, but few studies have compared this approach with techniques that directly assess skin blood flow (SBF). Our objective was to determine if an abnormal CRT is associated with impaired SBF and microvascular reactivity in early septic shock patients. Twelve septic shock patients were subjected to multimodal perfusion and hemodynamic monitoring for 24 h. Three time-points (0, 1, and 24 h) were registered for each patient. SBF was measured by laser doppler. We performed a baseline SBF measurement and two microvascular reactivity tests: one with a thermal challenge at 44 °C and other with a vascular occlusion test. Ten healthy volunteers were evaluated to obtain reference values. The patients (median age 70 years) exhibited a 28-day mortality of 50%. Baseline CRT was 3.3 [2.7-7.3] seconds. In pooled data analysis, abnormal CRT presented a significantly lower SBF when compared to normal CRT [44 (13.3-80.3) vs 193.2 (99.4-285) APU, p = 0.0001]. CRT was strongly associated with SBF (R2 0.76, p < 0.0001). An abnormal CRT also was associated with impaired thermal challenge and vascular occlusion tests. Abnormal CRT values observed during early septic shock resuscitation are associated with impaired skin blood flow, and abnormal skin microvascular reactivity. Future studies should confirm these results.

Customized normothermic machine perfusion decreases ischemia-reperfusion injury compared with static cold storage in a porcine model of liver transplantation.

BACKGROUND: Liver transplantation has been demonstrated to be the best treatment for several liver diseases, while grafts are limited. This has caused an increase in waiting lists, making it necessary to find ways to expand the number of organs available for transplantation. Normothermic perfusion (NMP) of liver grafts has been established as an alternative to static cold storage (SCS), but only a small number of perfusion machines are commercially available. METHODS: Using a customized ex situ machine perfusion, we compared the results between ex situ NMP and SCS preservation in a porcine liver transplant model. RESULTS: During NMP, lactate concentrations were 80% lower after the 3-h perfusion period, compared with SCS. Bile production had a 2.5-fold increase during the NMP period. After transplantation, aspartate transaminase (AST) and alanine transaminase (ALT) levels were 35% less in the NMP group, compared to the SCS group. In pathologic analyses of grafts after transplant, tissue oxidation did not change between groups, but the ischemia-reperfusion injury score was lower in the NMP group. CONCLUSION: NMP reduced hepatocellular damage and ischemia-reperfusion injury when compared to SCS using a customized perfusion machine. This could be an alternative for low-income countries to include machine perfusion in their therapeutic options.

Continuous prolonged prone positioning in COVID-19-related ARDS: a multicenter cohort study from Chile.

BACKGROUND: Prone positioning is currently applied in time-limited daily sessions up to 24 h which determines that most patients require several sessions. Although longer prone sessions have been reported, there is scarce evidence about the feasibility and safety of such approach. We analyzed feasibility and safety of a continuous prolonged prone positioning strategy implemented nationwide, in a large cohort of COVID-19 patients in Chile. METHODS: Retrospective cohort study of mechanically ventilated COVID-19 patients with moderate-to-severe acute respiratory distress syndrome (ARDS), conducted in 15 Intensive Care Units, which adhered to a national protocol of continuous prone sessions ≥ 48 h and until PaO2:FiO2 increased above 200 mm Hg. The number and extension of prone sessions were registered, along with relevant physiologic data and adverse events related to prone positioning. The cohort was stratified according to the first prone session duration: Group A, 2-3 days; Group B, 4-5 days; and Group C, > 5 days. Multivariable regression analyses were performed to assess whether the duration of prone sessions could impact safety. RESULTS: We included 417 patients who required a first prone session of 4 (3-5) days, of whom 318 (76.3%) received only one session. During the first prone session the main adverse event was grade 1-2 pressure sores in 97 (23.9%) patients; severe adverse events were infrequent with 17 non-scheduled extubations (4.2%). 90-day mortality was 36.2%. Ninety-eight patients (24%) were classified as group C; they exhibited a more severe ARDS at baseline, as reflected by lower PaO2:FiO2 ratio and higher ventilatory ratio, and had a higher rate of pressure sores (44%) and higher 90-day mortality (48%). However, after adjustment for severity and several relevant confounders, prone session duration was not associated with mortality or pressure sores. CONCLUSIONS: Nationwide implementation of a continuous prolonged prone positioning strategy for COVID-19 ARDS patients was feasible. Minor pressure sores were frequent but within the ranges previously described, while severe adverse events were infrequent. The duration of prone session did not have an adverse effect on safety.

Desarrollo de ventiladores mecánicos en Chile. Crónica de la iniciativa "Un Respiro para Chile", durante la primera ola de la pandemia COVID-19 / Development of mechanical ventilators in Chile. Chronicle of the initiative "Un Respiro para Chile"

At the beginning of the COVID-19 pandemic in Chile, in March 2020, a projection indicated that a significant group of patients with pneumonia would require admission to an Intensive Care Unit and connection to a mechanical ventilator. Therefore, a paucity of these devices and other supplies was predicted. The initiative "Un respiro para Chile" brought together many people and institutions, public and private. In the course of three months, it allowed the design and building of several ventilatory assistance devices, which could be used in critically ill patients.

[Development of mechanical ventilators in Chile. Chronicle of the initiative "Un Respiro para Chile"]. / Desarrollo de ventiladores mecánicos en Chile. Crónica de la iniciativa "Un Respiro para Chile", durante la primera ola de la pandemia COVID-19.

At the beginning of the COVID-19 pandemic in Chile, in March 2020, a projection indicated that a significant group of patients with pneumonia would require admission to an Intensive Care Unit and connection to a mechanical ventilator. Therefore, a paucity of these devices and other supplies was predicted. The initiative "Un respiro para Chile" brought together many people and institutions, public and private. In the course of three months, it allowed the design and building of several ventilatory assistance devices, which could be used in critically ill patients.

Implementation and design of customized ex vivo machine perfusion. Analysis of its first results.

The lack of organs available for transplantation is a global problem. The high mortality rates on the waiting list and the high number of discarded livers are reasons to develop new tools in the preservation and transplantation process. New tools should also be available for low-income countries. This article reports the development of customized normothermic machine perfusion (NMP). An ex vivo dual perfusion machine was designed, composed of a common reservoir organ box (CRO), a centrifugal pump (portal system, low pressure), and a roller pump (arterial system, high pressure). Porcine livers (n = 5) were perfused with an oxygenated normothermic (37℃) strategy for 3 hours. Hemodynamic variables, metabolic parameters, and bile production during preservation were analyzed. Arterial and portal flow remain stable during perfusion. Total bilirubin production was 11.25 mL (4-14.5) at 180 minutes. The median pH value reached 7.32 (7.25-7.4) at 180 minutes. Lactate values decreased progressively to normalization at 120 minutes. This perfusion setup was stable and able to maintain the metabolic activity of a liver graft in a porcine animal model. Design and initial results from this customized NMP are promising for a future clinical application in low-income countries.

Effect of positive end-expiratory pressure on lung injury and haemodynamics during experimental acute respiratory distress syndrome treated with extracorporeal membrane oxygenation and near-apnoeic ventilation.

BACKGROUND: Lung rest has been recommended during extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS). Whether positive end-expiratory pressure (PEEP) confers lung protection during ECMO for severe ARDS is unclear. We compared the effects of three different PEEP levels whilst applying near-apnoeic ventilation in a model of severe ARDS treated with ECMO. METHODS: Acute respiratory distress syndrome was induced in anaesthetised adult male pigs by repeated saline lavage and injurious ventilation for 1.5 h. After ECMO was commenced, the pigs received standardised near-apnoeic ventilation for 24 h to maintain similar driving pressures and were randomly assigned to PEEP of 0, 10, or 20 cm H2O (n=7 per group). Respiratory and haemodynamic data were collected throughout the study. Histological injury was assessed by a pathologist masked to PEEP allocation. Lung oedema was estimated by wet-to-dry-weight ratio. RESULTS: All pigs developed severe ARDS. Oxygenation on ECMO improved with PEEP of 10 or 20 cm H2O, but did not in pigs allocated to PEEP of 0 cm H2O. Haemodynamic collapse refractory to norepinephrine (n=4) and early death (n=3) occurred after PEEP 20 cm H2O. The severity of lung injury was lowest after PEEP of 10 cm H2O in both dependent and non-dependent lung regions, compared with PEEP of 0 or 20 cm H2O. A higher wet-to-dry-weight ratio, indicating worse lung injury, was observed with PEEP of 0 cm H2O. Histological assessment suggested that lung injury was minimised with PEEP of 10 cm H2O. CONCLUSIONS: During near-apnoeic ventilation and ECMO in experimental severe ARDS, 10 cm H2O PEEP minimised lung injury and improved gas exchange without compromising haemodynamic stability.

Effects of capillary refill time-vs. lactate-targeted fluid resuscitation on regional, microcirculatory and hypoxia-related perfusion parameters in septic shock: a randomized controlled trial.

BACKGROUND: Persistent hyperlactatemia has been considered as a signal of tissue hypoperfusion in septic shock patients, but multiple non-hypoperfusion-related pathogenic mechanisms could be involved. Therefore, pursuing lactate normalization may lead to the risk of fluid overload. Peripheral perfusion, assessed by the capillary refill time (CRT), could be an effective alternative resuscitation target as recently demonstrated by the ANDROMEDA-SHOCK trial. We designed the present randomized controlled trial to address the impact of a CRT-targeted (CRT-T) vs. a lactate-targeted (LAC-T) fluid resuscitation strategy on fluid balances within 24 h of septic shock diagnosis. In addition, we compared the effects of both strategies on organ dysfunction, regional and microcirculatory flow, and tissue hypoxia surrogates. RESULTS: Forty-two fluid-responsive septic shock patients were randomized into CRT-T or LAC-T groups. Fluids were administered until target achievement during the 6 h intervention period, or until safety criteria were met. CRT-T was aimed at CRT normalization (≤ 3 s), whereas in LAC-T the goal was lactate normalization (≤ 2 mmol/L) or a 20% decrease every 2 h. Multimodal perfusion monitoring included sublingual microcirculatory assessment; plasma-disappearance rate of indocyanine green; muscle oxygen saturation; central venous-arterial pCO2 gradient/ arterial-venous O2 content difference ratio; and lactate/pyruvate ratio. There was no difference between CRT-T vs. LAC-T in 6 h-fluid boluses (875 [375-2625] vs. 1500 [1000-2000], p = 0.3), or balances (982[249-2833] vs. 15,800 [740-6587, p = 0.2]). CRT-T was associated with a higher achievement of the predefined perfusion target (62 vs. 24, p = 0.03). No significant differences in perfusion-related variables or hypoxia surrogates were observed. CONCLUSIONS: CRT-targeted fluid resuscitation was not superior to a lactate-targeted one on fluid administration or balances. However, it was associated with comparable effects on regional and microcirculatory flow parameters and hypoxia surrogates, and a faster achievement of the predefined resuscitation target. Our data suggest that stopping fluids in patients with CRT ≤ 3 s appears as safe in terms of tissue perfusion. Clinical Trials: ClinicalTrials.gov Identifier: NCT03762005 (Retrospectively registered on December 3rd 2018).

Low Spontaneous Breathing Effort during Extracorporeal Membrane Oxygenation in a Porcine Model of Severe Acute Respiratory Distress Syndrome.

BACKGROUND: A lung rest strategy is recommended during extracorporeal membrane oxygenation in severe acute respiratory distress syndrome (ARDS). However, spontaneous breathing modes are frequently used in this context. The impact of this approach may depend on the intensity of breathing efforts. The authors aimed to determine whether a low spontaneous breathing effort strategy increases lung injury, compared to a controlled near-apneic ventilation, in a porcine severe ARDS model assisted by extracorporeal membrane oxygenation. METHODS: Twelve female pigs were subjected to lung injury by repeated lavages, followed by 2-h injurious ventilation. Thereafter, animals were connected to venovenous extracorporeal membrane oxygenation and during the first 3 h, ventilated with near-apneic ventilation (positive end-expiratory pressure, 10 cm H2O; driving pressure, 10 cm H2O; respiratory rate, 5/min). Then, animals were allocated into (1) near-apneic ventilation, which continued with the previous ventilatory settings; and (2) spontaneous breathing: neuromuscular blockers were stopped, sweep gas flow was decreased until regaining spontaneous efforts, and ventilation was switched to pressure support mode (pressure support, 10 cm H2O; positive end-expiratory pressure, 10 cm H2O). In both groups, sweep gas flow was adjusted to keep Paco2 between 30 and 50 mmHg. Respiratory and hemodynamic as well as electric impedance tomography data were collected. After 24 h, animals were euthanized and lungs extracted for histologic tissue analysis. RESULTS: Compared to near-apneic group, the spontaneous breathing group exhibited a higher respiratory rate (52 ± 17 vs. 5 ± 0 breaths/min; mean difference, 47; 95% CI, 34 to 59; P < 0.001), but similar tidal volume (2.3 ± 0.8 vs. 2.8 ± 0.4 ml/kg; mean difference, 0.6; 95% CI, -0.4 to 1.4; P = 0.983). Extracorporeal membrane oxygenation settings and gas exchange were similar between groups. Dorsal ventilation was higher in the spontaneous breathing group. No differences were observed regarding histologic lung injury. CONCLUSIONS: In an animal model of severe ARDS supported with extracorporeal membrane oxygenation, spontaneous breathing characterized by low-intensity efforts, high respiratory rates, and very low tidal volumes did not result in increased lung injury compared to controlled near-apneic ventilation.

Hypoxia-related parameters during septic shock resuscitation: Pathophysiological determinants and potential clinical implications.

BACKGROUND: Assessment of tissue hypoxia at the bedside has yet to be translated into daily clinical practice in septic shock patients. Perfusion markers are surrogates of deeper physiological phenomena. Lactate-to-pyruvate ratio (LPR) and the ratio between veno-arterial PCO2 difference and Ca-vO2 (ΔPCO2/Ca-vO2) have been proposed as markers of tissue hypoxia, but they have not been compared in the clinical scenario. We studied acute septic shock patients under resuscitation. We wanted to evaluate the relationship of these hypoxia markers with clinical and biochemical markers of hypoperfusion during septic shock resuscitation. METHODS: Secondary analysis of a randomized controlled trial. Septic shock patients were randomized to fluid resuscitation directed to normalization of capillary refill time (CRT) versus normalization or significant lowering of lactate. Multimodal assessment of perfusion was performed at 0, 2, 6 and 24 hours, and included macrohemodynamic and metabolic perfusion variables, CRT, regional flow and hypoxia markers. Patients who attained their pre-specified endpoint at 2-hours were compared to those who did not. RESULTS: Forty-two patients were recruited, median APACHE-II score was 23 [15-31] and 28-day mortality 23%. LPR and ΔPCO2/Ca-vO2 ratio did not correlate during early resuscitation (0-2 h) and the whole study period (24-hours). ΔPCO2/Ca-vO2 ratio derangements were more prevalent than LPR ones, either in the whole cohort (52% vs. 23%), and in association with other perfusion abnormalities. In patients who reached their resuscitation endpoints, the proportion of patients with altered ΔPCO2/Ca-vO2 ratio decreased significantly (66% to 33%, P=0.045), while LPR did not (14% vs. 25%, P=0.34). CONCLUSIONS: Hypoxia markers did not exhibit correlation during resuscitation in septic shock patients. They probably interrogate different pathophysiological processes and mechanisms of dysoxia during early septic shock. Future studies should better elucidate the interaction and clinical role of hypoxia markers during septic shock resuscitation.

Early rise in central venous pressure during a spontaneous breathing trial: A promising test to identify patients at high risk of weaning failure?

BACKGROUND: The spontaneous breathing trial (SBT) assesses the risk of weaning failure by evaluating some physiological responses to the massive venous return increase imposed by discontinuing positive pressure ventilation. This trial can be very demanding for some critically ill patients, inducing excessive physical and cardiovascular stress, including muscle fatigue, heart ischemia and eventually cardiac dysfunction. Extubation failure with emergency reintubation is a serious adverse consequence of a failed weaning process. Some data suggest that as many as 50% of patients that fail weaning do so because of cardiac dysfunction. Unfortunately, monitoring cardiovascular function at the time of the SBT is complex. The aim of our study was to explore if central venous pressure (CVP) changes were related to weaning failure after starting an SBT. We hypothesized that an early rise on CVP could signal a cardiac failure when handling a massive increase on venous return following a discontinuation of positive pressure ventilation. This CVP rise could identify a subset of patients at high risk for extubation failure. METHODS: Two-hundred and four mechanically ventilated patients in whom an SBT was decided were subjected to a monitoring protocol that included blinded assessment of CVP at baseline, and at 2 minutes after starting the trial (CVP-test). Weaning failure was defined as reintubation within 48-hours following extubation. Comparisons between two parametric or non-parametric variables were performed with student T test or Mann Whitney U test, respectively. A logistic multivariate regression was performed to determine the predictive value on extubation failure of usual clinical variables and CVP at 2-min after starting the SBT. RESULTS: One-hundred and sixty-five patients were extubated after the SBT, 11 of whom were reintubated within 48h. Absolute CVP values at 2-minutes, and the change from baseline (dCVP) were significantly higher in patients with extubation failure as compared to those successfully weaned. dCVP was an early predictor for reintubation (OR: 1.70 [1.31,2.19], p<0.001). CONCLUSIONS: An early rise in CVP after starting an SBT was associated with an increased risk of extubation failure. This might represent a warning signal not captured by usual SBT monitoring and could have relevant clinical implications.

Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial.

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. Trial Registration: ClinicalTrials.gov Identifier: NCT03078712.

Near-Apneic Ventilation Decreases Lung Injury and Fibroproliferation in an Acute Respiratory Distress Syndrome Model with Extracorporeal Membrane Oxygenation.

RATIONALE: There is wide variability in mechanical ventilation settings during extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome. Although lung rest is recommended to prevent further injury, there is no evidence to support it. OBJECTIVES: To determine whether near-apneic ventilation decreases lung injury in a pig model of acute respiratory distress syndrome supported with ECMO. METHODS: Pigs (26-36 kg; n = 24) were anesthetized and connected to mechanical ventilation. In 18 animals lung injury was induced by a double-hit consisting of repeated saline lavages followed by 2 hours of injurious ventilation. Then, animals were connected to high-flow venovenous ECMO, and randomized into three groups: 1) nonprotective (positive end-expiratory pressure [PEEP], 5 cm H2O; Vt, 10 ml/kg; respiratory rate, 20 bpm), 2) conventional-protective (PEEP, 10 cm H2O; Vt, 6 ml/kg; respiratory rate, 20 bpm), and 3) near-apneic (PEEP, 10 cm H2O; driving pressure, 10 cm H2O; respiratory rate, 5 bpm). Six other pigs were used as sham. All groups were maintained during the 24-hour study period. MEASUREMENTS AND MAIN RESULTS: Minute ventilation and mechanical power were lower in the near-apneic group, but no differences were observed in oxygenation or compliance. Lung histology revealed less injury in the near-apneic group. Extensive immunohistochemical staining for myofibroblasts and procollagen III was observed in the nonprotective group, with the near-apneic group exhibiting the least alterations. Near-apneic group showed significantly less matrix metalloproteinase-2 and -9 activity. Histologic lung injury and fibroproliferation scores were positively correlated with driving pressure and mechanical power. CONCLUSIONS: In an acute respiratory distress syndrome model supported with ECMO, near-apneic ventilation decreased histologic lung injury and matrix metalloproteinase activity, and prevented the expression of myofibroblast markers.

Plano de análise estatística para o estudo do tratamento precoce baseado em metas com utilização de uma visão fisiológica holística - estudo ANDROMEDA-SHOCK: um estudo randomizado e controlado / Statistical analysis plan for early goal-directed therapy using a physiological holistic view - the ANDROMEDA-SHOCK: a randomized controlled trial

RESUMO Fundamentação: O estudo ANDROMEDA-SHOCK é um estudo internacional, multicêntrico, randomizado e controlado comparando ressuscitação guiada pela perfusão periférica com ressuscitação guiada pelo lactato em pacientes com choque séptico, com a finalidade de testar a hipótese de que a ressuscitação guiada pela perfusão periférica associa-se a menor morbidade e mortalidade. Objetivo: Relatar o plano de análise estatística para o estudo ANDROMEDA-SHOCK. Métodos: Descrevemos o delineamento do estudo, os objetivos primário e secundários, pacientes, métodos de randomização, intervenções, desfechos e tamanho da amostra. Descrevemos nossos planos de análise estatística para os desfechos primários, secundários e terciários. Também descrevemos as análises de subgrupos e sensibilidade. Finalmente, fornecemos detalhes para a apresentação dos resultados, inclusive modelos de tabelas para apresentar as características basais, a evolução das variáveis de hemodinâmica e perfusão, e os efeitos dos tratamentos nos desfechos. Conclusão: Segundo as melhores práticas de pesquisa, relatamos nosso plano de análise estatística e plano de gestão de dados antes do fechamento da base de dados e do início da análise dos dados. Nossa expectativa é que este procedimento previna a ocorrência de vieses na análise e incremente a utilidade dos resultados relatados.

ABSTRACT Background: ANDROMEDA-SHOCK is an international, multicenter, randomized controlled trial comparing peripheral perfusion-targeted resuscitation to lactate-targeted resuscitation in patients with septic shock in order to test the hypothesis that resuscitation targeting peripheral perfusion will be associated with lower morbidity and mortality. Objective: To report the statistical analysis plan for the ANDROMEDA-SHOCK trial. Methods: We describe the trial design, primary and secondary objectives, patients, methods of randomization, interventions, outcomes, and sample size. We describe our planned statistical analysis for the primary, secondary and tertiary outcomes. We also describe the subgroup and sensitivity analyses. Finally, we provide details for presenting our results, including mock tables showing baseline characteristics, the evolution of hemodynamic and perfusion variables, and the effects of treatments on outcomes. Conclusion: According to the best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and initiating the analyses. We anticipate that this procedure will prevent analysis bias and enhance the utility of the reported results.

Statistical analysis plan for early goal-directed therapy using a physiological holistic view - the ANDROMEDA-SHOCK: a randomized controlled trial. / Plano de análise estatística para o estudo do tratamento precoce baseado em metas com utilização de uma visão fisiológica holística - estudo ANDROMEDA-SHOCK: um estudo randomizado e controlado.

BACKGROUND: ANDROMEDA-SHOCK is an international, multicenter, randomized controlled trial comparing peripheral perfusion-targeted resuscitation to lactate-targeted resuscitation in patients with septic shock in order to test the hypothesis that resuscitation targeting peripheral perfusion will be associated with lower morbidity and mortality. OBJECTIVE: To report the statistical analysis plan for the ANDROMEDA-SHOCK trial. METHODS: We describe the trial design, primary and secondary objectives, patients, methods of randomization, interventions, outcomes, and sample size. We describe our planned statistical analysis for the primary, secondary and tertiary outcomes. We also describe the subgroup and sensitivity analyses. Finally, we provide details for presenting our results, including mock tables showing baseline characteristics, the evolution of hemodynamic and perfusion variables, and the effects of treatments on outcomes. CONCLUSION: According to the best trial practice, we report our statistical analysis plan and data management plan prior to locking the database and initiating the analyses. We anticipate that this procedure will prevent analysis bias and enhance the utility of the reported results.

FUNDAMENTAÇÃO: O estudo ANDROMEDA-SHOCK é um estudo internacional, multicêntrico, randomizado e controlado comparando ressuscitação guiada pela perfusão periférica com ressuscitação guiada pelo lactato em pacientes com choque séptico, com a finalidade de testar a hipótese de que a ressuscitação guiada pela perfusão periférica associa-se a menor morbidade e mortalidade. OBJETIVO: Relatar o plano de análise estatística para o estudo ANDROMEDA-SHOCK. MÉTODOS: Descrevemos o delineamento do estudo, os objetivos primário e secundários, pacientes, métodos de randomização, intervenções, desfechos e tamanho da amostra. Descrevemos nossos planos de análise estatística para os desfechos primários, secundários e terciários. Também descrevemos as análises de subgrupos e sensibilidade. Finalmente, fornecemos detalhes para a apresentação dos resultados, inclusive modelos de tabelas para apresentar as características basais, a evolução das variáveis de hemodinâmica e perfusão, e os efeitos dos tratamentos nos desfechos. CONCLUSÃO: Segundo as melhores práticas de pesquisa, relatamos nosso plano de análise estatística e plano de gestão de dados antes do fechamento da base de dados e do início da análise dos dados. Nossa expectativa é que este procedimento previna a ocorrência de vieses na análise e incremente a utilidade dos resultados relatados.