Variables influencing the prediction of fluid responsiveness: a systematic review and meta-analysis.

INTRODUCTION: Prediction of fluid responsiveness in acutely ill patients might be influenced by a number of clinical and technical factors. We aim to identify variables potentially modifying the operative performance of fluid responsiveness predictors commonly used in clinical practice. METHODS: A sensitive strategy was conducted in the Medline and Embase databases to search for prospective studies assessing the operative performance of pulse pressure variation, stroke volume variation, passive leg raising (PLR), end-expiratory occlusion test (EEOT), mini-fluid challenge, and tidal volume challenge to predict fluid responsiveness in critically ill and acutely ill surgical patients published between January 1999 and February 2023. Adjusted diagnostic odds ratios (DORs) were calculated by subgroup analyses (inverse variance method) and meta-regression (test of moderators). Variables potentially modifying the operative performance of such predictor tests were classified as technical and clinical. RESULTS: A total of 149 studies were included in the analysis. The volume used during fluid loading, the method used to assess variations in macrovascular flow (cardiac output, stroke volume, aortic blood flow, volume‒time integral, etc.) in response to PLR/EEOT, and the apneic time selected during the EEOT were identified as technical variables modifying the operative performance of such fluid responsiveness predictor tests (p < 0.05 for all adjusted vs. unadjusted DORs). In addition, the operative performance of fluid responsiveness predictors was also influenced by clinical variables such as the positive end-expiratory pressure (in the case of EEOT) and the dose of norepinephrine used during the fluid responsiveness assessment for PLR and EEOT (for all adjusted vs. unadjusted DORs). CONCLUSION: Prediction of fluid responsiveness in critically and acutely ill patients is strongly influenced by a number of technical and clinical aspects. Such factors should be considered for individual intervention decisions.

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.

Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: The effects of recruitment maneuvers and positive end-expiratory pressure (PEEP) titration on clinical outcomes in patients with acute respiratory distress syndrome (ARDS) remain uncertain. Objective: To determine if lung recruitment associated with PEEP titration according to the best respiratory-system compliance decreases 28-day mortality of patients with moderate to severe ARDS compared with a conventional low-PEEP strategy. Design, Setting, and Participants: Multicenter, randomized trial conducted at 120 intensive care units (ICUs) from 9 countries from November 17, 2011, through April 25, 2017, enrolling adults with moderate to severe ARDS. Interventions: An experimental strategy with a lung recruitment maneuver and PEEP titration according to the best respiratory-system compliance (n = 501; experimental group) or a control strategy of low PEEP (n = 509). All patients received volume-assist control mode until weaning. Main Outcomes and Measures: The primary outcome was all-cause mortality until 28 days. Secondary outcomes were length of ICU and hospital stay; ventilator-free days through day 28; pneumothorax requiring drainage within 7 days; barotrauma within 7 days; and ICU, in-hospital, and 6-month mortality. Results: A total of 1010 patients (37.5% female; mean [SD] age, 50.9 [17.4] years) were enrolled and followed up. At 28 days, 277 of 501 patients (55.3%) in the experimental group and 251 of 509 patients (49.3%) in the control group had died (hazard ratio [HR], 1.20; 95% CI, 1.01 to 1.42; P = .041). Compared with the control group, the experimental group strategy increased 6-month mortality (65.3% vs 59.9%; HR, 1.18; 95% CI, 1.01 to 1.38; P = .04), decreased the number of mean ventilator-free days (5.3 vs 6.4; difference, -1.1; 95% CI, -2.1 to -0.1; P = .03), increased the risk of pneumothorax requiring drainage (3.2% vs 1.2%; difference, 2.0%; 95% CI, 0.0% to 4.0%; P = .03), and the risk of barotrauma (5.6% vs 1.6%; difference, 4.0%; 95% CI, 1.5% to 6.5%; P = .001). There were no significant differences in the length of ICU stay, length of hospital stay, ICU mortality, and in-hospital mortality. Conclusions and Relevance: In patients with moderate to severe ARDS, a strategy with lung recruitment and titrated PEEP compared with low PEEP increased 28-day all-cause mortality. These findings do not support the routine use of lung recruitment maneuver and PEEP titration in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01374022.

Predictive value of dynamic arterial elastance for vasopressor withdrawal: a systematic review and meta-analysis.

BACKGROUND: Dynamic arterial elastance (Eadyn) has been investigated for its ability to predict hypotension during the weaning of vasopressors. Our study focused on assessing Eadyn's performance in the context of critically ill adult patients admitted to the intensive care unit, regardless of diagnosis. MAIN BODY: Our study was conducted in accordance with the Preferred Reported Items for Systematic Reviews and Meta-Analysis checklist. The protocol was registered in PROSPERO (CRD42023421462) on May 26, 2023. We included prospective observational studies from the MEDLINE and Embase databases through May 2023. Five studies involving 183 patients were included in the quantitative analysis. We extracted data related to patient clinical characteristics, and information about Eadyn measurement methods, results, and norepinephrine dose. Most patients (76%) were diagnosed with septic shock, while the remaining patients required norepinephrine for other reasons. The average pressure responsiveness rate was 36.20%. The synthesized results yielded an area under the curve of 0.85, with a sensitivity of 0.87 (95% CI 0.74-0.93), specificity of 0.76 (95% CI 0.68-0.83), and diagnostic odds ratio of 19.07 (95% CI 8.47-42.92). Subgroup analyses indicated no variations in the Eadyn based on norepinephrine dosage, the Eadyn measurement device, or the Eadyn diagnostic cutoff to predict cessation of vasopressor support. CONCLUSIONS: Eadyn, evaluated through subgroup analyses, demonstrated good predictive ability for the discontinuation of vasopressor support in critically ill patients.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan.

BACKGROUND: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. OBJECTIVE: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. METHODS: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. OUTCOMES: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. CONCLUSION: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

Hypertonic saline infusion does not improve the chance of primary fascial closure after damage control laparotomy: a randomized controlled trial.

BACKGROUND: Previous observational studies showed higher rates of abdominal wall closure with the use of hypertonic saline in trauma patients with abdominal injuries. However, no randomized controlled trials have been performed on this matter. This double-blind randomized clinical trial assessed the effect of 3% hypertonic saline (HS) solution on primary fascial closure and the timing of abdominal wall closure among patients who underwent damage control laparotomy for bleeding control. METHODS: Double-blind randomized clinical trial. Patients with abdominal injuries requiring damage control laparotomy (DCL) were randomly allocated to receive a 72-h infusion (rate: 50 mL/h) of 3% HS or 0.9 N isotonic saline (NS) after the index DCL. The primary endpoint was the proportion of patients with abdominal wall closure in the first seven days after the index DCL. RESULTS: The study was suspended in the first interim analysis because of futility. A total of 52 patients were included. Of these, 27 and 25 were randomly allocated to NS and HS, respectively. There were no significant differences in the rates of abdominal wall closure between groups (HS: 19 [79.2%] vs. NS: 17 [70.8%]; p = 0.71). In contrast, significantly higher hypernatremia rates were observed in the HS group (HS: 11 [44%] vs. NS: 1 [3.7%]; p < 0.001). CONCLUSION: This double-blind randomized clinical trial showed no benefit of HS solution in primary fascial closure rates. Patients randomized to HS had higher sodium concentrations after the first day and were more likely to present hypernatremia. We do not recommend using HS in patients undergoing damage control laparotomy. Trial registration The trial protocol was registered in clinicaltrials.gov (identifier: NCT02542241).

Hemodynamic phenotype-based, capillary refill time-targeted resuscitation in early septic shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial study protocol. / Ressuscitação direcionada ao tempo de enchimento capilar baseada em fenótipo hemodinâmico no choque séptico precoce: protocolo de estudo do ensaio clínico randomizado ANDROMEDA-SHOCK-2.

BACKGROUND: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock. METHODS: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy. CONCLUSIONS: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

INTRODUçÃO: A reversão precoce da hipoperfusão tecidual induzida é essencial para a sobrevida no choque séptico. No entanto, falta consenso sobre a melhor estratégia de ressuscitação inicial, uma vez que intervenções destinadas a toda a população com choque séptico podem produzir administração desnecessária de líquidos. Este artigo relata a justificativa, o delineamento e o plano de análise do estudo ANDROMEDA-2, que visa determinar se uma estratégia guiada por perfusão periférica, que consiste na ressuscitação guiada pelo tempo de enchimento capilar com base em fenótipos clínicos e hemodinâmicos, está associada a uma diminuição no desfecho composto de mortalidade, tempo até a interrupção ao suporte de órgãos e tempo de internação em comparação com o atendimento padrão em pacientes com choque séptico precoce (< 4 horas do diagnóstico). METÓDOS: O estudo ANDROMEDA-2 é um ensaio clínico randomizado controlado multinacional e multicêntrico. No grupo de intervenção, o tempo de enchimento capilar será medido a cada hora, durante 6 horas. Se estiver anormal, os pacientes serão alocados em um algoritmo, começando com a avaliação da pressão de pulso. Pacientes com pressão de pulso inferior a 40mmHg serão testados quanto à capacidade de resposta a líquidos e receberão líquidos de acordo. Em pacientes com pressão de pulso > 40mmHg, norepinefrina será titulada para manter a pressão arterial diastólica > 50mmHg. Os pacientes que não normalizarem o tempo de enchimento capilar após as etapas anteriores serão submetidos à ecocardiografia de cuidados intensivos para avaliação da disfunção cardíaca e posterior manejo. Por fim, serão realizados testes com vasopressores e inodilatadores para otimizar ainda mais a perfusão. Um tamanho de amostra de 1.500 pacientes fornecerá 88% de poder para demonstrar a superioridade da estratégia direcionada ao tempo de enchimento capilar. CONCLUSÃO: Se for demonstrado que o direcionamento ao tempo de enchimento capilar é uma estratégia melhor, os processos de atendimento na ressuscitação do choque séptico podem ser otimizados com ferramentas usadas à beira do leito.

Changes of operative performance of pulse pressure variation as a predictor of fluid responsiveness in endotoxin shock.

Several limitations regarding pulse pressure variation (PPV) use have been reported. Our aim was to describe changes in the PPV operative performance as a predictor of fluid responsiveness during the development of a swine endotoxin shock model and to assess hemodynamic variables associated with PPV changes. A swine porcine endotoxin shock model was established (Escherichia Coli 055:B5 endotoxin) in 7 pigs, and 3 pigs were included in the control group. The endotoxin was infused until the mean arterial pressure (MAP) dropped below 50 mmHg (TH0); then, the model animal was reanimated with fluids and vasopressors. We performed fluid challenges every hour for 6 h. ROC curve analysis and a linear mixed model were performed. The area under the curve of PPV decreased from 0.95 (0.81-1.00) to 0.60 (0.17-1.00) at TH0. Its cutoff increased from 10.5 to 22.00% at TH0. PPV showed an inverse relationship with stroke volume, mean systemic filling pressure, MAP, and systemic vascular resistance (SVR) (p < 0.001, AIC = 111.85). The PPV operative performance as a predictor of fluid responsiveness decreased with the progression of shock. This could lead to an inverse association between PPV and the following variables: MAP and SVR.

Impact of red blood cell transfusion on oxygen transport and metabolism in patients with sepsis and septic shock: a systematic review and meta-analysis. / Impacto da transfusão de eritrócitos no transporte e no metabolismo de oxigênio em pacientes com sepse e choque séptico: uma revisão sistemática e metanálise.

Red blood cell transfusion is thought to improve cell respiration during septic shock. Nevertheless, its acute impact on oxygen transport and metabolism in this condition remains highly debatable. The objective of this study was to evaluate the impact of red blood cell transfusion on microcirculation and oxygen metabolism in patients with sepsis and septic shock. We conducted a search in the MEDLINE®, Elsevier and Scopus databases. We included studies conducted in adult humans with sepsis and septic shock. A systematic review and meta-analysis were performed using the DerSimonian and Laird random-effects model. A p value < 0.05 was considered significant. Nineteen manuscripts with 428 patients were included in the analysis. Red blood cell transfusions were associated with an increase in the pooled mean venous oxygen saturation of 3.7% (p < 0.001), a decrease in oxygen extraction ratio of -6.98 (p < 0.001) and had no significant effect on the cardiac index (0.02L/minute; p = 0,96). Similar results were obtained in studies including simultaneous measurements of venous oxygen saturation, oxygen extraction ratio, and cardiac index. Red blood cell transfusions led to a significant increase in the proportion of perfused small vessels (2.85%; p = 0.553), while tissue oxygenation parameters revealed a significant increase in the tissue hemoglobin index (1.66; p = 0.018). Individual studies reported significant improvements in tissue oxygenation and sublingual microcirculatory parameters in patients with deranged microcirculation at baseline. Red blood cell transfusions seemed to improve systemic oxygen metabolism with apparent independence from cardiac index variations. Some beneficial effects have been observed for tissue oxygenation and microcirculation parameters, particularly in patients with more severe alterations at baseline. More studies are necessary to evaluate their clinical impact and to individualize transfusion decisions.

Considera-se que a transfusão de eritrócitos melhora a respiração celular durante o choque séptico. Contudo, seu impacto agudo no transporte e no metabolismo de oxigênio nessa condição ainda é amplamente debatido. O objetivo deste estudo foi avaliar o impacto da transfusão de eritrócitos na microcirculação e no metabolismo do oxigênio em pacientes com sepse e choque séptico. Conduzimos um levantamento nas bases de dados MEDLINE®, Elsevier e Scopus. Incluímos estudos realizados com seres humanos adultos com sepse e choque séptico. Realizamos uma revisão sistemática e metanálise com utilização do modelo de efeitos aleatórios de DerSimonian e Laird. Consideramos significante valor de p < 0,05. Incluíram-se na análise 19 manuscritos, correspondentes a 428 pacientes. As transfusões de eritrócitos se associaram com aumento de 3,7% na média combinada de saturação venosa mista de oxigênio (p < 0,001), diminuição de razão de extração de oxigênio de -6,98 (p < 0,001) e nenhum efeito significante no índice cardíaco (0,02 L/minuto; p = 0,96). Obtiveram-se resultados similares em estudos que incluíram mensurações simultâneas de saturação venosa mista de oxigênio, razão de extração de oxigênio e índice cardíaco. As transfusões de eritrócitos levaram a aumento significante na proporção de pequenos vasos perfundidos (2,85%; p = 0,553), enquanto os parâmetros de oxigenação tissular revelaram aumento significante no índice de hemoglobina tissular (1,66; p = 0,018). Estudos individuais relataram melhoras significantes na oxigenação tissular e nos parâmetros microcirculatórios sublinguais em pacientes com microcirculação alterada na avaliação inicial. A transfusão de eritrócitos pareceu melhorar o metabolismo sistêmico de oxigênio com aparente independência de variações no débito cardíaco. Observaram-se alguns efeitos benéficos para a oxigenação tissular e parâmetros microcirculatórios, em particular em pacientes com alterações iniciais mais graves. São necessários mais estudos para avaliar seu impacto clínico e individualizar as decisões relativas à transfusão.

Predictors of fluid responsiveness in critically ill patients mechanically ventilated at low tidal volumes: systematic review and meta-analysis.

INTRODUCTION: Dynamic predictors of fluid responsiveness have shown good performance in mechanically ventilated patients at tidal volumes (Vt) > 8 mL kg-1. Nevertheless, most critically ill conditions demand lower Vt. We sought to evaluate the operative performance of several predictors of fluid responsiveness at Vt ≤ 8 mL kg-1 by using meta-regression and subgroup analyses. METHODS: A sensitive search was conducted in the Embase and MEDLINE databases. We searched for studies prospectively assessing the operative performance of pulse pressure variation (PPV), stroke volume variation (SVV), end-expiratory occlusion test (EEOT), passive leg raising (PLR), inferior vena cava respiratory variability (Δ-IVC), mini-fluid challenge (m-FC), and tidal volume challenge (VtC), to predict fluid responsiveness in adult patients mechanically ventilated at Vt ≤ 8 ml kg-1, without respiratory effort and arrhythmias, published between 1999 and 2020. Operative performance was assessed using hierarchical and bivariate analyses, while subgroup analysis was used to evaluate variations in their operative performance and sources of heterogeneity. A sensitivity analysis based on the methodological quality of the studies included (QUADAS-2) was also performed. RESULTS: A total of 33 studies involving 1,352 patients were included for analysis. Areas under the curve (AUC) values for predictors of fluid responsiveness were: for PPV = 0.82, Δ-IVC = 0.86, SVV = 0.90, m-FC = 0.84, PLR = 0.84, EEOT = 0.92, and VtC = 0.92. According to subgroup analyses, variations in methods to measure cardiac output and in turn, to classify patients as responders or non-responders significantly influence the performance of PPV and SVV (p < 0.05). Operative performance of PPV was also significantly affected by the compliance of the respiratory system (p = 0.05), while type of patient (p < 0.01) and thresholds used to determine responsiveness significantly affected the predictability of SVV (p = 0.05). Similarly, volume of fluids infused to determine variation in cardiac output, significantly affected the performance of SVV (p = 0.01) and PLR (p < 0.01). Sensitivity analysis showed no variations in operative performance of PPV (p = 0.39), SVV (p = 0.23) and EEOT (p = 0.15). CONCLUSION: Most predictors of fluid responsiveness reliably predict the response of cardiac output to volume expansion in adult patients mechanically ventilated at tidal volumes ≤ 8 ml kg-1. Nevertheless, technical and clinical variables might clearly influence on their operative performance.

Use of Pulse Pressure Variation as Predictor of Fluid Responsiveness in Patients Ventilated With Low Tidal Volume: A Systematic Review and Meta-Analysis.

INTRODUCTION: Pulse pressure variation (PPV) has been shown to be useful to predict fluid responsiveness in patients ventilated at tidal volume (Vt) >8 mL kg-1. Nevertheless, most conditions in critical care force to use lower Vt. Thus, we sought to evaluate the operative performance of PPV when a Vt ⩽8 mL kg-1 is used during mechanical ventilation support. METHODS: We searched PubMed and Embase databases for articles evaluating the operative performance of PPV as a predictor of fluid responsiveness in critical care and perioperative adult patients ventilated with tidal volume ⩽8 mL kg-1 without respiratory effort and arrhythmias, between January 1990 and January 2019. We included cohort and cross-sectional studies. Two authors performed an Independently selection using predefined terms of search. The fitted data of sensitivity, specificity, and area under the curve (AUC) were assessed by bivariate and hierarchical analyses. RESULTS: We retrieved 19 trials with a total of 777 patients and a total of 935 fluid challenges. The fitted sensitivity of PPV to predict fluid responsiveness during mechanical ventilation at Vt ⩽8 mL kg-1 was 0.65 (95% confidence interval [CI]: 0.57-0.73), the specificity was 0.79 (95% CI: 0.73-0.84), and the AUC was 0.75. The diagnostic odds ratio was 5.5 (95% CI: 3.08-10.01, P < .001) by the random-effects model. CONCLUSIONS: Pulse pressure variation shows a fair operative performance as a predictor of fluid responsiveness in critical care and perioperative patients ventilated with a tidal volume ⩽8 mL kg-1 without respiratory effort and arrhythmias.

Impact of Using a Novel Gastric Feeding Tube Adaptor on Patient's Comfort and Air Leaks During Non-invasive Mechanical Ventilation.

INTRODUCTION: The presence of oral or naso-enteral probes during non-invasive mechanical ventilation (NIMV) increases the risk of leakage and patient discomfort. The objective of this study was to evaluate the effectiveness of a novel tube adapter for NIMV (TA-NIMV) in relation to leakage and comfort level. METHODS: A non-randomized quasi-experimental design was performed in an adult intensive care unit of a highly complex hospital, in which patients were their own controls. We included adult patients who required NIV with oronasal mask and who simultaneously had oral or naso-enteric tubes. The interventions were as follows: every participant received two therapies, one with the TA-NIMV and one conventional therapy of NIMV (CT-NIMV). Comfort could be evaluated in 99 patients with a Glasgow Coma Scale of 15. The outcomes of interest was the average percentage of air leak and patient comfort during each intervention. RESULTS: 196 patients were included in the study during a 16-month period. The mean air leak percentage was 9.2% [standard deviation (SD), 7.7] during TA-NIMV and 32.5% (SD, 12.5) during CT-NIMV (p<0.001). 84.9% reported being comfortable or very comfortable during TA-VMNI. 66.7% Uncomfortable or Very uncomfortable during CT-NIMV (p<0.001). CONCLUSION: Higher comfort levels and lower air leakage volume percentages were achieved using the TA-NIMV than those achieved by CT-NIMV.

Effects of hydrocortisone on microcirculatory alterations in patients with septic shock.

OBJECTIVE: To evaluate the effects of hydrocortisone on microcirculatory blood flow alterations in patients with septic shock. DESIGN: Prospective, open-label study. SETTING: A 31-bed, medico-surgical intensive care unit of a university hospital. PATIENTS: Twenty patients with septic shock. INTERVENTIONS: Intravenous hydrocortisone (50 mg/6 hr). MEASUREMENTS AND MAIN RESULTS: An orthogonal polarization spectral device (Cytoscan ARII, Cytometrics; Philadelphia, PA) was used to investigate the sublingual microcirculation in 20 patients who received so-called "stress doses" of hydrocortisone as part of their management for septic shock. Hemodynamic measurements and orthogonal polarization spectral images were obtained before administration of the first dose (50 mg) of hydrocortisone and 1, 2, 4, and 24 hours later. Measurements were also made before an adrenocorticotropic hormone (ACTH) test, whenever performed. Global hemodynamic variables were similar at all study time points. Microcirculatory variables improved slightly already at 1 hour after the start of hydrocortisone administration. In particular, perfused vessel density increased from 5.7 (4.8-6.4) to 7.2 (6.5-9.0)n/mm, p < 0.01, which was due to combined increases in small vessel density from 5.2 (4.6-6.2) to 6.0 (5.1-7.5)n/mm, p < 0.01, and in the proportion of perfused vessels from 82.1 (68.7-88.0) to 89.2 (83.4-92.6)%, p < 0.01. There were no differences in microcirculatory variables during hydrocortisone administration between ACTH test responders and nonresponders. CONCLUSIONS: The administration of moderate doses of hydrocortisone in septic shock results in a modest but consistent improvement in capillary perfusion, independent of the response to the ACTH test. The mechanisms underlying this effect need to be elucidated.

Efectos del reto de líquidos sobre el acople ventrículo arterial en un biomodelo porcino de choque endotóxico / The effect of fluid challenge on ventriculo-arterial coupling in an endotoxic shock swine bio-model

Introducción: el reto de líquidos es una prueba que consiste en administrarlos y medir la respuesta hemodinámica mediante el cambio del gasto cardíaco (GC), aunque solo medir el GC resulta insuficiente. El acople ventrículo-arterial (AVA) (elastancia arterial efectiva/ elastancia telesistólica: Eae/Ets) aparece como una variable que evalúa el estado cardiocirculatorio en forma integral. Objetivo: evaluar el AVA en un biomodelo de choque endotóxico y durante retos de líquidos. Materiales y métodos: biomodelo de choque endotóxico (9 porcinos). Se midieron variables hemodinámicas cada hora desde un tiempo 0 (T0) hasta T6. Se realizaron 5 retos de líquidos entre T0 y T4. El tiempo de hipotensión se denominó TH0. Se calcularon diferencias de medianas de variables entre T0-T4. Se clasificaron los retos en dos grupos según el delta del AVA (AVA posreto-AVA prerreto), en ΔAVA≤0 o >0, se midieron variables antes y después de cada reto. Se determinó la relación lactato/piruvato (L/P) en T0, T3 y T6, se establecieron correlaciones entre la diferencia LP T6-T0 y de variables hemodinámicas. Resultados: el AVA aumentó (1.58 a 2,02, p=0.042) por incremento en la Eae (1.74 a 2,55; p=0.017). El grupo ΔAVA≤0 elevó el GC (4.32 a 5,46, p=0.032) y el poder cardíaco (PC) (0.61 a 0,77, p=0,028). El Δ L/P se correlacionó con el Δ del índice de choque sistólico y diastólico (r=0.73), pero no con el del AVA. Conclusión: durante el choque endotóxico el AVA aumentó de manera significativa. Durante el reto de líquidos el grupo Δ AVA≤0, elevó el GC y PC. El Δ L/P no se correlacionó con variables del AVA.

Introduction: fluid challenges (FCs) consist of measuring hemodynamic response through changes in cardiac output (CO) after fluid administration, although only measuring CO proves insufficient. Ventriculo-arterial coupling (V-A) (effective arterial elastance / tele-systolic elastance: E(a)/Ets) are variables used for a comprehensive cardiac and circulatory status appraisal. Objective: to evaluate V-A in an endotoxic shock bio-model by FCs. Materials and methods: an endotoxic shock bio-model (9 pigs). Hemodynamic variables were measured every hour from time 0 (T0) to T6. Five FCs were performed between T0 and T4. Hypotension time was referred to as HT. The median differences in variables between T0-T4 were calculated. Challenges were classified into two groups according to V-A delta (post-challenge V-A - pre-challenge V-A). In ΔV-A≤0 o>0, variables were measured before and after each FC. The lactate to pyruvate (L/P) ratio was determined at T0, T3 and T6. Correlations between the LP T6-T0 difference and hemodynamic variables, were established. Results: V-A increased (1.58 to 2,02, p=0.042) as Eae increased (1.74 to 2.55; p=0.017). CO (4.32 to 5.46, p=0.032) and cardiac power (CP) (0.61 to 0.77, p=0,028) increased, in the ΔV-AC≤0 group. The ΔLP correlated with the systolic and diastolic shock index (r=0.73), but not with V-A. Conclusion: V-A increased significantly during endotoxic shock. The ΔAVA≤0 group, showed elevated CO and CP during FC. ΔLP did not correlate with any of the V-A variables.

Prospective, randomized, controlled trial assessing the effects of a driving pressure-limiting strategy for patients with acute respiratory distress syndrome due to community-acquired pneumonia (STAMINA trial): protocol and statistical analysis plan / Estudo randomizado prospectivo e controlado de avaliação dos efeitos de uma estratégia de limitação da driving pressure em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade (estudo STAMINA): protocolo e plano de análise estatística

ABSTRACT Background: Driving pressure has been suggested to be the main driver of ventilator-induced lung injury and mortality in observational studies of acute respiratory distress syndrome. Whether a driving pressure-limiting strategy can improve clinical outcomes is unclear. Objective: To describe the protocol and statistical analysis plan that will be used to test whether a driving pressure-limiting strategy including positive end-expiratory pressure titration according to the best respiratory compliance and reduction in tidal volume is superior to a standard strategy involving the use of the ARDSNet low-positive end-expiratory pressure table in terms of increasing the number of ventilator-free days in patients with acute respiratory distress syndrome due to community-acquired pneumonia. Methods: The ventilator STrAtegy for coMmunIty acquired pNeumoniA (STAMINA) study is a randomized, multicenter, open-label trial that compares a driving pressure-limiting strategy to the ARDSnet low-positive end-expiratory pressure table in patients with moderate-to-severe acute respiratory distress syndrome due to community-acquired pneumonia admitted to intensive care units. We expect to recruit 500 patients from 20 Brazilian and 2 Colombian intensive care units. They will be randomized to a driving pressure-limiting strategy group or to a standard strategy using the ARDSNet low-positive end-expiratory pressure table. In the driving pressure-limiting strategy group, positive end-expiratory pressure will be titrated according to the best respiratory system compliance. Outcomes: The primary outcome is the number of ventilator-free days within 28 days. The secondary outcomes are in-hospital and intensive care unit mortality and the need for rescue therapies such as extracorporeal life support, recruitment maneuvers and inhaled nitric oxide. Conclusion: STAMINA is designed to provide evidence on whether a driving pressure-limiting strategy is superior to the ARDSNet low-positive end-expiratory pressure table strategy for increasing the number of ventilator-free days within 28 days in patients with moderate-to-severe acute respiratory distress syndrome. Here, we describe the rationale, design and status of the trial.

RESUMO Contexto: Em estudos observacionais sobre a síndrome do desconforto respiratório agudo, sugeriu-se que a driving pressure é o principal fator de lesão pulmonar induzida por ventilador e de mortalidade. Não está claro se uma estratégia de limitação da driving pressure pode melhorar os desfechos clínicos. Objetivo: Descrever o protocolo e o plano de análise estatística que serão usados para testar se uma estratégia de limitação da driving pressure envolvendo a titulação da pressão positiva expiratória final de acordo com a melhor complacência respiratória e a redução do volume corrente é superior a uma estratégia padrão envolvendo o uso da tabela de pressão positiva expiratória final baixa do protocolo ARDSNet, em termos de aumento do número de dias sem ventilador em pacientes com síndrome do desconforto respiratório agudo devido à pneumonia adquirida na comunidade. Métodos: O estudo STAMINA (ventilator STrAtegy for coMmunIty acquired pNeumoniA) é randomizado, multicêntrico e aberto e compara uma estratégia de limitação da driving pressure com a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet em pacientes com síndrome do desconforto respiratório agudo moderada a grave devido à pneumonia adquirida na comunidade internados em unidades de terapia intensiva. Esperamos recrutar 500 pacientes de 20 unidades de terapia intensiva brasileiras e duas colombianas. Eles serão randomizados para um grupo da estratégia de limitação da driving pressure ou para um grupo de estratégia padrão usando a tabela de pressão positiva expiratória final baixa do protocolo ARDSnet. No grupo da estratégia de limitação da driving pressure, a pressão positiva expiratória final será titulada de acordo com a melhor complacência do sistema respiratório. Desfechos: O desfecho primário é o número de dias sem ventilador em 28 dias. Os desfechos secundários são a mortalidade hospitalar e na unidade de terapia intensiva e a necessidade de terapias de resgate, como suporte de vida extracorpóreo, manobras de recrutamento e óxido nítrico inalado. Conclusão: O STAMINA foi projetado para fornecer evidências sobre se uma estratégia de limitação da driving pressure é superior à estratégia da tabela de pressão positiva expiratória final baixa do protocolo ARDSnet para aumentar o número de dias sem ventilador em 28 dias em pacientes com síndrome do desconforto respiratório agudo moderada a grave. Aqui, descrevemos a justificativa, o desenho e o status do estudo.

How microcirculation data have changed my clinical practice.

PURPOSE OF REVIEW: The present review discusses how microcirculation assessment, which was recently made feasible, has altered clinical practice. RECENT FINDINGS: Experimental data have provided important information on microcirculation alterations in disease states. Recent advances in imaging techniques have allowed microcirculation studies in critically ill patients. Derangements in microcirculation are variable and unpredictable, associated with organ dysfunction and outcome, and can be improved by therapeutic interventions. Recent studies not only confirm the beneficial effects of some drugs on the microcirculation, but also suggest new mechanisms of actions of these drugs. In particular, the interaction between the endothelial surface and circulating cells, and especially white blood cells, seems to be crucial. Although these imaging techniques provide important information, these remain difficult to implement at the bedside. Assessment of vasoreactivity using transient occlusion tests and indirect measurements of microvascular blood flow with laser Doppler or near infrared spectroscopy may be good alternatives. SUMMARY: Microcirculation alterations are present in shock states, mainly septic shock, and can have a prognostic role and be the target of therapeutic interventions. To date, microcirculation analysis remains in the field of clinical investigation, but recently interesting clinical data have encouraged assessment of the microcirculation at the bedside.

Microcirculatory blood flow derangements during severe preeclampsia and HELLP syndrome.

OBJECTIVE: To evaluate the microcirculatory blood flow in severe preeclampsia and compare it with healthy pregnant and non-pregnant women controls, using a portable intravital-microscopy technique. METHODS: Using a side-stream dark field (SDF) device, we prospectively evaluated the sublingual microcirculatory blood flow before placental delivery in 40 women with severe preeclampsia (PE-group) complicated (n=8) or not (n=32) with HELLP syndrome, 40 healthy pregnant women (HP-group) matched by gestational and chronological age, and 20 healthy non-pregnant women (NP-group). Microvessels were classified as large or small using a cutoff value of 20µm and those with continuous flow were considered as normal while sluggish, intermittent and stopped flows were considered as abnormal. We computed the proportion of well-perfused small vessels (PPV), and total and functional capillary densities (TCD and FCD) were calculated according to the total number and quantity of well-perfused small vessels per area unit, respectively. RESULTS: Total capillary densities were significantly higher in all pregnant women when compared to non-pregnant controls. The PE-group exhibited, however, significantly lower TCD compared with the HP-group. Meanwhile, significant decreases in PPV and FCD were observed in the PE-group, with deeper alterations in those with coexisting HELLP syndrome. These altered PPVs were significant although incompletely reversed after placental delivery in pregnancies complicated by HELLP syndrome, while capillary densities remained unaltered at least during very early post-delivery period. CONCLUSIONS: Substantial distributive microcirculatory blood flow alterations and restricted capillary densities are observed in preeclampsia, suggesting a key role for microvascular dysfunction in the pathophysiology of this condition.

Ressuscitação direcionada ao tempo de enchimento capilar baseada em fenótipo hemodinâmico no choque séptico precoce: protocolo de estudo do ensaio clínico randomizado ANDROMEDA-SHOCK-2 / Hemodynamic phenotype-based, capillary refill time-targeted resuscitation in early septic shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial study protocol

RESUMO Introdução: A reversão precoce da hipoperfusão tecidual induzida é essencial para a sobrevida no choque séptico. No entanto, falta consenso sobre a melhor estratégia de ressuscitação inicial, uma vez que intervenções destinadas a toda a população com choque séptico podem produzir administração desnecessária de líquidos. Este artigo relata a justificativa, o delineamento e o plano de análise do estudo ANDROMEDA-2, que visa determinar se uma estratégia guiada por perfusão periférica, que consiste na ressuscitação guiada pelo tempo de enchimento capilar com base em fenótipos clínicos e hemodinâmicos, está associada a uma diminuição no desfecho composto de mortalidade, tempo até a interrupção ao suporte de órgãos e tempo de internação em comparação com o atendimento padrão em pacientes com choque séptico precoce (< 4 horas do diagnóstico). Metódos: O estudo ANDROMEDA-2 é um ensaio clínico randomizado controlado multinacional e multicêntrico. No grupo de intervenção, o tempo de enchimento capilar será medido a cada hora, durante 6 horas. Se estiver anormal, os pacientes serão alocados em um algoritmo, começando com a avaliação da pressão de pulso. Pacientes com pressão de pulso inferior a 40mmHg serão testados quanto à capacidade de resposta a líquidos e receberão líquidos de acordo. Em pacientes com pressão de pulso > 40mmHg, norepinefrina será titulada para manter a pressão arterial diastólica > 50mmHg. Os pacientes que não normalizarem o tempo de enchimento capilar após as etapas anteriores serão submetidos à ecocardiografia de cuidados intensivos para avaliação da disfunção cardíaca e posterior manejo. Por fim, serão realizados testes com vasopressores e inodilatadores para otimizar ainda mais a perfusão. Um tamanho de amostra de 1.500 pacientes fornecerá 88% de poder para demonstrar a superioridade da estratégia direcionada ao tempo de enchimento capilar. Conclusão: Se for demonstrado que o direcionamento ao tempo de enchimento capilar é uma estratégia melhor, os processos de atendimento na ressuscitação do choque séptico podem ser otimizados com ferramentas usadas à beira do leito.

ABSTRACT Background: Early reversion of sepsis-induced tissue hypoperfusion is essential for survival in septic shock. However, consensus regarding the best initial resuscitation strategy is lacking given that interventions designed for the entire population with septic shock might produce unnecessary fluid administration. This article reports the rationale, study design and analysis plan of the ANDROMEDA-2 study, which aims to determine whether a peripheral perfusion-guided strategy consisting of capillary refill time-targeted resuscitation based on clinical and hemodynamic phenotypes is associated with a decrease in a composite outcome of mortality, time to organ support cessation, and hospital length of stay compared to standard care in patients with early (< 4 hours of diagnosis) septic shock. Methods: The ANDROMEDA-2 study is a multicenter, multinational randomized controlled trial. In the intervention group, capillary refill time will be measured hourly for 6 hours. If abnormal, patients will enter an algorithm starting with pulse pressure assessment. Patients with pulse pressure less than 40mmHg will be tested for fluid responsiveness and receive fluids accordingly. In patients with pulse pressure > 40mmHg, norepinephrine will be titrated to maintain diastolic arterial pressure > 50mmHg. Patients who fail to normalize capillary refill time after the previous steps will be subjected to critical care echocardiography for cardiac dysfunction evaluation and subsequent management. Finally, vasopressor and inodilator tests will be performed to further optimize perfusion. A sample size of 1,500 patients will provide 88% power to demonstrate superiority of the capillary refill time-targeted strategy. Conclusions: If hemodynamic phenotype-based, capillary refill time-targeted resuscitation demonstrates to be a superior strategy, care processes in septic shock resuscitation can be optimized with bedside tools.

Impacto da transfusão de eritrócitos no transporte e no metabolismo de oxigênio em pacientes com sepse e choque séptico: uma revisão sistemática e metanálise / Impact of red blood cell transfusion on oxygen transport and metabolism in patients with sepsis and septic shock: a systematic review and meta-analysis

RESUMO Considera-se que a transfusão de eritrócitos melhora a respiração celular durante o choque séptico. Contudo, seu impacto agudo no transporte e no metabolismo de oxigênio nessa condição ainda é amplamente debatido. O objetivo deste estudo foi avaliar o impacto da transfusão de eritrócitos na microcirculação e no metabolismo do oxigênio em pacientes com sepse e choque séptico. Conduzimos um levantamento nas bases de dados MEDLINE®, Elsevier e Scopus. Incluímos estudos realizados com seres humanos adultos com sepse e choque séptico. Realizamos uma revisão sistemática e metanálise com utilização do modelo de efeitos aleatórios de DerSimonian e Laird. Consideramos significante valor de p < 0,05. Incluíram-se na análise 19 manuscritos, correspondentes a 428 pacientes. As transfusões de eritrócitos se associaram com aumento de 3,7% na média combinada de saturação venosa mista de oxigênio (p < 0,001), diminuição de razão de extração de oxigênio de -6,98 (p < 0,001) e nenhum efeito significante no índice cardíaco (0,02 L/minuto; p = 0,96). Obtiveram-se resultados similares em estudos que incluíram mensurações simultâneas de saturação venosa mista de oxigênio, razão de extração de oxigênio e índice cardíaco. As transfusões de eritrócitos levaram a aumento significante na proporção de pequenos vasos perfundidos (2,85%; p = 0,553), enquanto os parâmetros de oxigenação tissular revelaram aumento significante no índice de hemoglobina tissular (1,66; p = 0,018). Estudos individuais relataram melhoras significantes na oxigenação tissular e nos parâmetros microcirculatórios sublinguais em pacientes com microcirculação alterada na avaliação inicial. A transfusão de eritrócitos pareceu melhorar o metabolismo sistêmico de oxigênio com aparente independência de variações no débito cardíaco. Observaram-se alguns efeitos benéficos para a oxigenação tissular e parâmetros microcirculatórios, em particular em pacientes com alterações iniciais mais graves. São necessários mais estudos para avaliar seu impacto clínico e individualizar as decisões relativas à transfusão.

ABSTRACT Red blood cell transfusion is thought to improve cell respiration during septic shock. Nevertheless, its acute impact on oxygen transport and metabolism in this condition remains highly debatable. The objective of this study was to evaluate the impact of red blood cell transfusion on microcirculation and oxygen metabolism in patients with sepsis and septic shock. We conducted a search in the MEDLINE®, Elsevier and Scopus databases. We included studies conducted in adult humans with sepsis and septic shock. A systematic review and meta-analysis were performed using the DerSimonian and Laird random-effects model. A p value < 0.05 was considered significant. Nineteen manuscripts with 428 patients were included in the analysis. Red blood cell transfusions were associated with an increase in the pooled mean venous oxygen saturation of 3.7% (p < 0.001), a decrease in oxygen extraction ratio of -6.98 (p < 0.001) and had no significant effect on the cardiac index (0.02L/minute; p = 0,96). Similar results were obtained in studies including simultaneous measurements of venous oxygen saturation, oxygen extraction ratio, and cardiac index. Red blood cell transfusions led to a significant increase in the proportion of perfused small vessels (2.85%; p = 0.553), while tissue oxygenation parameters revealed a significant increase in the tissue hemoglobin index (1.66; p = 0.018). Individual studies reported significant improvements in tissue oxygenation and sublingual microcirculatory parameters in patients with deranged microcirculation at baseline. Red blood cell transfusions seemed to improve systemic oxygen metabolism with apparent independence from cardiac index variations. Some beneficial effects have been observed for tissue oxygenation and microcirculation parameters, particularly in patients with more severe alterations at baseline. More studies are necessary to evaluate their clinical impact and to individualize transfusion decisions.