Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Immediate Norepinephrine in Endotoxic Shock: Effects on Regional and Microcirculatory Flow.

OBJECTIVES: To investigate the effects of immediate start of norepinephrine versus initial fluid loading followed by norepinephrine on macro hemodynamics, regional splanchnic and intestinal microcirculatory flows in endotoxic shock. DESIGN: Animal experimental study. SETTING: University translational research laboratory. SUBJECTS: Fifteen Landrace pigs. INTERVENTIONS: Shock was induced by escalating dose of lipopolysaccharide. Animals were allocated to immediate start of norepinephrine (i-NE) ( n = 6) versus mandatory 1-hour fluid loading (30 mL/kg) followed by norepinephrine (i-FL) ( n = 6). Once mean arterial pressure greater than or equal to 75 mm Hg was, respectively, achieved, successive mini-fluid boluses of 4 mL/kg of Ringer Lactate were given whenever: a) arterial lactate greater than 2.0 mmol/L or decrease less than 10% per 30 min and b) fluid responsiveness was judged to be positive. Three additional animals were used as controls (Sham) ( n = 3). Time × group interactions were evaluated by repeated-measures analysis of variance. MEASUREMENTS AND MAIN RESULTS: Hypotension was significantly shorter in i-NE group (7.5 min [5.5-22.0 min] vs 49.3 min [29.5-60.0 min]; p < 0.001). Regional mesenteric and microcirculatory flows at jejunal mucosa and serosa were significantly higher in i-NE group at 4 and 6 hours after initiation of therapy ( p = 0.011, p = 0.032, and p = 0.017, respectively). Misdistribution of intestinal microcirculatory blood flow at the onset of shock was significantly reversed in i-NE group ( p < 0.001), which agreed with dynamic changes in mesenteric-lactate levels ( p = 0.01) and venous-to-arterial carbon dioxide differences ( p = 0.001). Animals allocated to i-NE showed significantly higher global end-diastolic volumes ( p = 0.015) and required significantly less resuscitation fluids ( p < 0.001) and lower doses of norepinephrine ( p = 0.001) at the end of the experiment. Pulmonary vascular permeability and extravascular lung water indexes were significantly lower in i-NE group ( p = 0.021 and p = 0.004, respectively). CONCLUSIONS: In endotoxemic shock, immediate start of norepinephrine significantly improved regional splanchnic and intestinal microcirculatory flows when compared with mandatory fixed-dose fluid loading preceding norepinephrine. Immediate norepinephrine strategy was related with less resuscitation fluids and lower vasopressor doses at the end of the experiment.

How to assess tissue oxygenation?

PURPOSE OF REVIEW: To discuss the different techniques used to assess tissue oxygenation in critically ill patients. RECENT FINDINGS: While historically the analysis of oxygen consumption (VO2)/oxygen delivery (DO2) relationships has provided important information, methodological limitations prevent its use at bedside. PO2 measurements, while attractive, are unfortunately of limited value in the presence of microvascular blood flow heterogeneity which is observed in many critically ill conditions including sepsis. Surrogates of tissue oxygenation are hence used. Elevated lactate levels may suggest inadequate tissue oxygenation, but other sources than tissue hypoxia can also contribute to hyperlactatemia so that lactate measurements should be used in combination with other measurements of tissue oxygenation. Venous O2 saturation can be used to evaluate the adequacy of DO2 in respect to VO2, but it can be misleading normal or even high in sepsis. Measurements of Pv-aCO2 and computation of Pv-aCO2/CavO2 are very promising as physiologically sound, easy to measure, rapidly respond to therapy, and are associated with outcome. An elevated Pv-aCO2 reflects an impaired tissue perfusion while an increased Pv-aCO2/CavO2 ratio reflects tissue dysoxia. SUMMARY: Recent studies have highlighted the interest of surrogate measurements of tissue oxygenation and in particular PCO2 gradients.

Perspectives on peripheral perfusion assessment.

PURPOSE OF REVIEW: The ANDROMEDA-SHOCK trial positioned capillary refill time (CRT) assessment as a novel resuscitation target for septic shock.The purpose of this article is to summarize pathophysiological determinants of CRT, review new technical developments on peripheral perfusion assessment, and explore recent evidence on the role of CRT monitoring in septic shock and other critical conditions. RECENT FINDINGS: A growing body of evidence supports the role of peripheral perfusion assessment as a warning and prognostic signal in a variety of clinical conditions among severely ill patients. Recent physiological studies demonstrated a rapid improvement of CRT after a single fluid bolus or a passive leg raising maneuver, a fact which may have diagnostic and therapeutic implications. Moreover, a couple of posthoc analyses of ANDROMEDA-SHOCK trial, reinforce that a normal CRT at the start of septic shock resuscitation, or its rapid normalization, thereafter may be associated with significant better outcomes. SUMMARY: Recent data confirm the relevance of peripheral perfusion assessment in septic shock and other conditions in critically ill patients. Future studies should confirm these findings, and test the potential contribution of technological devices to assess peripheral perfusion.

Evidence for a personalized early start of norepinephrine in septic shock.

During septic shock, vasopressor infusion is usually started only after having corrected the hypovolaemic component of circulatory failure, even in the most severe patients. However, earlier administration of norepinephrine, simultaneously with fluid resuscitation, should be considered in some cases. Duration and depth of hypotension strongly worsen outcomes in septic shock patients. However, the response of arterial pressure to volume expansion is inconstant, delayed, and transitory. In the case of profound, life-threatening hypotension, relying only on fluids to restore blood pressure may unduly prolong hypotension and organ hypoperfusion. Conversely, norepinephrine rapidly increases and better stabilizes arterial pressure. By binding venous adrenergic receptors, it transforms part of the unstressed blood volume into stressed blood volume. It increases the mean systemic filling pressure and increases the fluid-induced increase in mean systemic filling pressure, as observed in septic shock patients. This may improve end-organ perfusion, as shown by some animal studies. Two observational studies comparing early vs. later administration of norepinephrine in septic shock patients using a propensity score showed that early administration reduced the administered fluid volume and day-28 mortality. Conversely, in another propensity score-based study, norepinephrine administration within the first hour following shock diagnosis increased day-28 mortality. The only randomized controlled study that compared the early administration of norepinephrine alone to a placebo showed that the early continuous administration of norepinephrine at a fixed dose of 0.05 µg/kg/min, with norepinephrine added in open label, showed that shock control was achieved more often than in the placebo group. The choice of starting norepinephrine administration early should be adapted to the patient's condition. Logically, it should first be addressed to patients with profound hypotension, when the arterial tone is very low, as suggested by a low diastolic blood pressure (e.g. ≤ 40 mmHg), or by a high diastolic shock index (heart rate/diastolic blood pressure) (e.g. ≥ 3). Early administration of norepinephrine should also be considered in patients in whom fluid accumulation is likely to occur or in whom fluid accumulation would be particularly deleterious (in case of acute respiratory distress syndrome or intra-abdominal hypertension for example).

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.

A plea for personalization of the hemodynamic management of septic shock.

Although guidelines provide excellent expert guidance for managing patients with septic shock, they leave room for personalization according to patients' condition. Hemodynamic monitoring depends on the evolution phase: salvage, optimization, stabilization, and de-escalation. Initially during the salvage phase, monitoring to identify shock etiology and severity should include arterial pressure and lactate measurements together with clinical examination, particularly skin mottling and capillary refill time. Low diastolic blood pressure may trigger vasopressor initiation. At this stage, echocardiography may be useful to identify significant cardiac dysfunction. During the optimization phase, echocardiographic monitoring should be pursued and completed by the assessment of tissue perfusion through central or mixed-venous oxygen saturation, lactate, and carbon dioxide veno-arterial gradient. Transpulmonary thermodilution and the pulmonary artery catheter should be considered in the most severe patients. Fluid therapy also depends on shock phases. While administered liberally during the resuscitation phase, fluid responsiveness should be assessed during the optimization phase. During stabilization, fluid infusion should be minimized. In the de-escalation phase, safe fluid withdrawal could be achieved by ensuring tissue perfusion is preserved. Norepinephrine is recommended as first-line vasopressor therapy, while vasopressin may be preferred in some patients. Essential questions remain regarding optimal vasopressor selection, combination therapy, and the most effective and safest escalation. Serum renin and the angiotensin I/II ratio may identify patients who benefit most from angiotensin II. The optimal therapeutic strategy for shock requiring high-dose vasopressors is scant. In all cases, vasopressor therapy should be individualized, based on clinical evaluation and blood flow measurements to avoid excessive vasoconstriction. Inotropes should be considered in patients with decreased cardiac contractility associated with impaired tissue perfusion. Based on pharmacologic properties, we suggest as the first test a limited dose of dobutamine, to add enoximone or milrinone in the second line and substitute or add levosimendan if inefficient. Regarding adjunctive therapies, while hydrocortisone is nowadays advised in patients receiving high doses of vasopressors, patients responding to corticosteroids may be identified in the future by the analysis of selected cytokines or specific transcriptomic endotypes. To conclude, although some general rules apply for shock management, a personalized approach should be considered for hemodynamic monitoring and support.

Effects of a Resuscitation Strategy Targeting Peripheral Perfusion Status versus Serum Lactate Levels among Patients with Septic Shock. A Bayesian Reanalysis of the ANDROMEDA-SHOCK Trial.

Rationale: A recent randomized controlled trial showed that a peripheral perfusion-guided resuscitation strategy was associated with lower mortality and less organ dysfunction when compared with lactate-guided resuscitation strategy in patients with septic shock, but the difference in the primary outcome, 28-day mortality, did not reach the proposed statistical significance threshold (P = 0.06). We tested different analytic methods to aid in the interpretation of these results.Objectives: To reassess the results of the ANDROMEDA-SHOCK trial using both Bayesian and frequentist frameworks.Methods: All patients recruited in ANDROMEDA-SHOCK were included. Both a post hoc Bayesian analysis and a mixed logistic regression analysis were performed. The Bayesian analysis included four different priors (optimistic, neutral, null, and pessimistic) for mortality endpoints. The probability of having a Sequential Organ Failure Assessment in the lowest quartile at 72 hours was assessed using Bayesian networks.Measurements and Main Results: In the Bayesian analysis, the posterior probability that a peripheral perfusion-targeted resuscitation strategy is superior to lactate-targeted resuscitation at 28 days was above 90% for all priors; the probability of benefit at 90 days was above 90% for all but the pessimistic prior. Using an optimistic prior, posterior median odds ratios were 0.61 (95% credible interval, 0.41-0.90) and 0.68 (95% credible interval, 0.47-1.01) for 28-day and 90-day mortality, respectively. The comparable frequentist odds ratios for 28-day and 90-day mortality were 0.61 (95% confidence interval [CI], 0.38-0.92) and 0.70 (95% CI, 0.45-1.08), respectively. The odds that that patients in the peripheral perfusion-targeted resuscitation arm had Sequential Organ Failure Assessment scores in the lower quartile at 72 hours was 1.55 (95% CI, 1.02-2.37).Conclusions: Peripheral perfusion-targeted resuscitation may result in lower mortality and faster resolution of organ dysfunction when compared with a lactate-targeted resuscitation strategy.

Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial.

IMPORTANCE: The effect of high-flow oxygen therapy vs conventional oxygen therapy has not been established in the setting of severe COVID-19. OBJECTIVE: To determine the effect of high-flow oxygen therapy through a nasal cannula compared with conventional oxygen therapy on need for endotracheal intubation and clinical recovery in severe COVID-19. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label clinical trial conducted in emergency and intensive care units in 3 hospitals in Colombia. A total of 220 adults with respiratory distress and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 200 due to COVID-19 were randomized from August 2020 to January 2021, with last follow-up on February 10, 2021. INTERVENTIONS: Patients were randomly assigned to receive high-flow oxygen through a nasal cannula (n = 109) or conventional oxygen therapy (n = 111). MAIN OUTCOMES AND MEASURES: The co-primary outcomes were need for intubation and time to clinical recovery until day 28 as assessed by a 7-category ordinal scale (range, 1-7, with higher scores indicating a worse condition). Effects of treatments were calculated with a Cox proportional hazards model adjusted for hypoxemia severity, age, and comorbidities. RESULTS: Among 220 randomized patients, 199 were included in the analysis (median age, 60 years; n = 65 women [32.7%]). Intubation occurred in 34 (34.3%) randomized to high-flow oxygen therapy and in 51 (51.0%) randomized to conventional oxygen therapy (hazard ratio, 0.62; 95% CI, 0.39-0.96; P = .03). The median time to clinical recovery within 28 days was 11 (IQR, 9-14) days in patients randomized to high-flow oxygen therapy vs 14 (IQR, 11-19) days in those randomized to conventional oxygen therapy (hazard ratio, 1.39; 95% CI, 1.00-1.92; P = .047). Suspected bacterial pneumonia occurred in 13 patients (13.1%) randomized to high-flow oxygen and in 17 (17.0%) of those randomized to conventional oxygen therapy, while bacteremia was detected in 7 (7.1%) vs 11 (11.0%), respectively. CONCLUSIONS AND RELEVANCE: Among patients with severe COVID-19, use of high-flow oxygen through a nasal cannula significantly decreased need for mechanical ventilation support and time to clinical recovery compared with conventional low-flow oxygen therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04609462.

Septic shock: a microcirculation disease.

PURPOSE OF REVIEW: The aim of this study was to discuss the implication of microvascular dysfunction in septic shock. RECENT FINDINGS: Resuscitation of sepsis has focused on systemic haemodynamics and, more recently, on peripheral perfusion indices. However, central microvascular perfusion is altered in sepsis and these alterations often persist despite normalization of various macro haemodynamic resuscitative goals. Endothelial dysfunction is a key element in sepsis pathophysiology. It is responsible for the sepsis-induced hypotension. In addition, endothelial dysfunction is also implicated involved in the activation of inflammation and coagulation processes leading to amplification of the septic response and development of organ dysfunction. It also promotes an increase in permeability, mostly at venular side, and impairs microvascular perfusion and hence tissue oxygenation.Microvascular alterations are characterized by heterogeneity in blood flow distribution, with adequately perfused areas in close vicinity to not perfused areas, thus characterizing the distributive nature of septic shock. Such microvascular alterations have profound implications, as these are associated with organ dysfunction and unfavourable outcomes. Also, the response to therapy is highly variable and cannot be predicted by systemic hemodynamic assessment and hence cannot be detected by classical haemodynamic tools. SUMMARY: Microcirculation is a key element in the pathophysiology of sepsis. Even if microcirculation-targeted therapy is not yet ready for the prime time, understanding the processes implicated in microvascular dysfunction is important to prevent chasing systemic hemodynamic variables when this does not contribute to improve tissue perfusion.

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

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 28-day 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 non-fluid 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. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03078712. Registered retrospectively on March 13, 2017.

Effects of very early start of norepinephrine in patients with septic shock: a propensity score-based analysis.

BACKGROUND: Optimal timing for the start of vasopressors (VP) in septic shock has not been widely studied since it is assumed that fluids must be administered in advance. We sought to evaluate whether a very early start of VP, even without completing the initial fluid loading, might impact clinical outcomes in septic shock. METHODS: A total of 337 patients with sepsis requiring VP support for at least 6 h were initially selected from a prospectively collected database in a 90-bed mixed-ICU during a 24-month period. They were classified into very-early (VE-VPs) or delayed vasopressor start (D-VPs) categories according to whether norepinephrine was initiated or not within/before the next hour of the first resuscitative fluid load. Then, VE-VPs (n = 93) patients were 1:1 propensity matched to D-VPs (n = 93) based on age; source of admission (emergency room, general wards, intensive care unit); chronic and acute comorbidities; and lactate, heart rate, systolic, and diastolic pressure at vasopressor start. A risk-adjusted Cox proportional hazard model was fitted to assess the association between VE-VPs and day 28 mortality. Finally, a sensitivity analysis was performed also including those patients requiring VP support for less than 6 h. RESULTS: Patients subjected to VE-VPs received significantly less resuscitation fluids at vasopressor starting (0[0-510] vs. 1500[650-2300] mL, p < 0.001) and during the first 8 h of resuscitation (1100[500-1900] vs. 2600[1600-3800] mL, p < 0.001), with no significant increase in acute renal failure and/or renal replacement therapy requirements. VE-VPs was related with significant lower net fluid balances 8 and 24 h after VPs. VE-VPs was also associated with a significant reduction in the risk of death compared to D-VPs (HR 0.31, CI95% 0.17-0.57, p < 0.001) at day 28. Such association was maintained after including patients receiving vasopressors for < 6 h. CONCLUSION: A very early start of vasopressor support seems to be safe, might limit the amount of fluids to resuscitate septic shock, and could lead to better clinical outcomes.

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.

The practice of intensive care in Latin America: a survey of academic intensivists.

BACKGROUND: Intensive care medicine is a relatively young discipline that has rapidly grown into a full-fledged medical subspecialty. Intensivists are responsible for managing an ever-increasing number of patients with complex, life-threatening diseases. Several factors may influence their performance, including age, training, experience, workload, and socioeconomic context. The aim of this study was to examine individual- and work-related aspects of the Latin American intensivist workforce, mainly with academic appointments, which might influence the quality of care provided. In consequence, we conducted a cross-sectional study of intensivists at public and private academic and nonacademic Latin American intensive care units (ICUs) through a web-based electronic survey submitted by email. Questions about personal aspects, work-related topics, and general clinical workflow were incorporated. RESULTS: Our study comprised 735 survey respondents (53% return rate) with the following country-specific breakdown: Brazil (29%); Argentina (19%); Chile (17%); Uruguay (12%); Ecuador (9%); Mexico (7%); Colombia (5%); and Bolivia, Peru, Guatemala, and Paraguay combined (2%). Latin American intensivists were predominantly male (68%) young adults (median age, 40 [IQR, 35-48] years) with a median clinical ICU experience of 10 (IQR, 5-20) years. The median weekly workload was 60 (IQR, 47-70) h. ICU formal training was between 2 and 4 years. Only 63% of academic ICUs performed multidisciplinary rounds. Most intensivists (85%) reported adequate conditions to manage patients with septic shock in their units. Unsatisfactory conditions were attributed to insufficient technology (11%), laboratory support (5%), imaging resources (5%), and drug shortages (5%). Seventy percent of intensivists participated in research, and 54% read scientific studies regularly, whereas 32% read no more than one scientific study per month. Research grants and pharmaceutical sponsorship are unusual funding sources in Latin America. Although Latin American intensivists are mostly unsatisfied with their income (81%), only a minority (27%) considered changing to another specialty before retirement. CONCLUSIONS: Latin American intensivists constitute a predominantly young adult workforce, mostly formally trained, have a high workload, and most are interested in research. They are under important limitations owing to resource constraints and overt dissatisfaction. Latin America may be representative of other world areas with similar challenges for intensivists. Specific initiatives aimed at addressing these situations need to be devised to improve the quality of critical care delivery in Latin America.

Organizational Issues, Structure, and Processes of Care in 257 ICUs in Latin America: A Study From the Latin America Intensive Care Network.

OBJECTIVE: Latin America bears an important burden of critical care disease, yet the information about it is scarce. Our objective was to describe structure, organization, processes of care, and research activities in Latin-American ICUs. DESIGN: Web-based survey submitted to ICU directors. SETTINGS: ICUs located in nine Latin-American countries. SUBJECTS: Individual ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred fifty-seven of 498 (52%) of submitted surveys responded: 51% from Brazil, 17% Chile, 13% Argentina, 6% Ecuador, 5% Uruguay, 3% Colombia, and 5% between Mexico, Peru, and Paraguay. Seventy-nine percent of participating hospitals had less than 500 beds; most were public (59%) and academic (66%). ICUs were mainly medical-surgical (75%); number of beds was evenly distributed in the entire cohort; 77% had 24/7 intensivists; 46% had a physician-to-patient ratio between 1:4 and 7; and 69% had a nurse-to-patient ratio of 1 ≥ 2.1. The 24/7 presence of other specialists was deficient. Protocols in use averaged 9 ± 3. Brazil (vs the rest) had larger hospitals and ICUs and more quality, surveillance, and prevention committees, but fewer 24/7 intensivists and poorer nurse-to-patient ratio. Although standard monitoring, laboratory, and imaging practices were almost universal, more complex measurements and treatments and portable equipment were scarce after standard working hours, and in public hospitals. Mortality was 17.8%, without differences between countries. CONCLUSIONS: This multinational study shows major concerns in the delivery of critical care across Latin America, particularly in human resources. Technology was suboptimal, especially in public hospitals. A 24/7 availability of supporting specialists and of key procedures was inadequate. Mortality was high in comparison to high-income countries.

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.

Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock.

BACKGROUND: Persistent hyperlactatemia during septic shock is multifactorial. Hypoperfusion-related anaerobic production and adrenergic-driven aerobic generation together with impaired lactate clearance have been implicated. An excessive adrenergic response could contribute to persistent hyperlactatemia and adrenergic modulation might be beneficial. We assessed the effects of dexmedetomidine and esmolol on hemodynamics, lactate generation, and exogenous lactate clearance during endotoxin-induced septic shock. METHODS: Eighteen anesthetized and mechanically ventilated sheep were subjected to a multimodal hemodynamic/perfusion assessment including hepatic and portal vein catheterizations, total hepatic blood flow, and muscle microdialysis. After monitoring, all received a bolus and continuous infusion of endotoxin. After 1 h they were volume resuscitated, and then randomized to endotoxin-control, endotoxin-dexmedetomidine (sequential doses of 0.5 and 1.0 µg/k/h) or endotoxin-esmolol (titrated to decrease basal heart rate by 20 %) groups. Samples were taken at four time points, and exogenous lactate clearance using an intravenous administration of sodium L-lactate (1 mmol/kg) was performed at the end of the experiments. RESULTS: Dexmedetomidine and esmolol were hemodynamically well tolerated. The dexmedetomidine group exhibited lower epinephrine levels, but no difference in muscle lactate. Despite progressive hypotension in all groups, both dexmedetomidine and esmolol were associated with lower arterial and portal vein lactate levels. Exogenous lactate clearance was significantly higher in the dexmedetomidine and esmolol groups. CONCLUSIONS: Dexmedetomidine and esmolol were associated with lower arterial and portal lactate levels, and less impairment of exogenous lactate clearance in a model of septic shock. The use of dexmedetomidine and esmolol appears to be associated with beneficial effects on gut lactate generation and lactate clearance and exhibits no negative impact on systemic hemodynamics.