Faculty Bibliography

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.

PURPOSE OF REVIEW/OBJECTIVE:Currently, the treatment of patients with shock is focused on the clinical symptoms of shock. In the early phase, this is usually limited to heart rate, blood pressure, lactate levels and urine output. However, as the ultimate goal of resuscitation is the improvement in microcirculatory perfusion the question is whether these currently used signs of shock and the improvement in these signs actually correspond to the changes in the microcirculation. RECENT FINDINGS/RESULTS:Recent studies have shown that during the development of shock the deterioration in the macrocirculatory parameters are followed by the deterioration of microcirculatory perfusion. However, in many cases the restoration of adequate macrocirculatory parameters is frequently not associated with improvement in microcirculatory perfusion. This relates not only to the cause of shock, where there are some differences between different forms of shock, but also to the type of treatment. SUMMARY/CONCLUSIONS:The improvement in macrohemodynamics during the resuscitation is not consistently followed by subsequent changes in the microcirculation. This may result in both over-resuscitation and under-resuscitation leading to increased morbidity and mortality. In this article the principles of coherence and the monitoring of the microcirculation are reviewed.

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details.

INTRODUCTION/BACKGROUND:Post-extubation dysphagia is commonly observed in ICU patients and associated with increased aspiration rates, delayed resumption of oral intake/ malnutrition, prolonged ICU and hospital length of stay, decreased quality of life, and increased mortality. Conventional therapeutic approaches are limited. Pharyngeal electrical stimulation (PES) was previously shown to improve swallowing function and airway safety in severely dysphagic tracheostomised stroke patients. METHODS:In a multi-center, single-blind, 1:1 randomized controlled study, up to 400 (360 evaluable) mixed emergency adult ICU patients with recent extubation following mechanical ventilation and confirmed oropharyngeal dysphagia will be enrolled at investigational academic ICUs. Primary objective is to evaluate the effectiveness of PES in reducing the severity of unsafe swallows. Patients will be randomized to receive PES (or sham) treatment on 3 consecutive days in addition to best supportive care. Primary endpoint is a composite of 2 endpoints with hierarchy based on clinical priorities: DISCUSSION:: This study will evaluate the effects of PES on swallowing safety in critically ill ICU patients post mechanical ventilation with oropharyngeal dysphagia.

RATIONALE AND OBJECTIVES/OBJECTIVE:Acidosis and hyperlactatemia predict outcome in critically ill patients. We assessed BE and pH for risk prediction capabilities in a sub-group of septic patients in the MIMIC-III database. METHODS:Associations with mortality were assessed by logistic regression analysis in 5586 septic patients. Baseline parameters, lactate concentrations, pH, and BE were analyzed at baseline and after 6 hours. MEASUREMENTS AND MAIN RESULTS/RESULTS:We combined acidosis (defined as either BE ≤-6 and/or pH ≤7.3) and hyperlactatemia and split the cohort into three subgroups: low-risk (no acidosis and lactate <2.3 mmol/L; n = 2294), medium-risk (either acidosis or lactate >2.3 mmol/L; n = 2125) and high-risk (both acidosis and lactate >2.3 mmol/L; n = 1167). Mortality was 14%, 20% and 38% (p<0.001) in low-risk, medium-risk and high-risk patients, respectively. The predictiveness of this model (AUC 0.63 95%CI 0.61-0.65) was higher compared to acidosis (AUC 0.59 95%CI 0.57-0.61; p<0.001) and lactate >2.3 mmol/L (AUC 0.60 95%CI 0.58-0.62; p<0.001) alone. Hyperlactatemia alone was only moderately predictive for acidosis (AUC 0.60 95%CI 0.59-0.62). CONCLUSIONS:Acidosis and hyperlactatemia can occur independently to a certain degree. Combining acidosis and hyperlactatemia in a model yielded higher predictiveness for ICU-mortality. Septic patients with acidosis should be treated even more aggressively in the future.

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.

There is a tight relationship between lactate levels (and its changes over time) with morbidity and mortality and the presence of tissue hypoxia/hypoperfusion in both models of shock and clinical studies. These findings have placed lactate in the center of guiding resuscitation in patients with increased lactate levels. However, given the complex metabolism and clearance of lactate, especially in sepsis, the actual use of lactate is more complex than suggested by some guidelines. By using other markers of tissue hypoperfusion together with lactate levels provides a more solid framework to guide the initial hours of resuscitation.

BACKGROUND:Over the last decade, multiple large randomized controlled trials have studied alternative transfusion strategies in critically ill patients, demonstrating the safety of restrictive transfusion strategies. Due to the lack of international guidelines specific for the intensive care unit (ICU), we hypothesized that a large heterogeneity in transfusion practice in this patient population exists. The aims of this study were to describe the current transfusion practices and identify the knowledge gaps. METHODS:An online, anonymous, worldwide survey among ICU physicians was performed evaluating red blood cell, platelet and plasma transfusion practices. Furthermore, the presence of a hospital- or ICU-specific transfusion guideline was asked. Only completed surveys were analysed. RESULTS:cells/L IQR (10-25) in asymptomatic patients, but at a higher count prior to invasive procedures (p < 0.001). In patients with an international normalized ratio (INR) > 3, 43% and 57% of the respondents would consider plasma transfusion without any upcoming procedures or prior to a planned invasive procedure, respectively. Finally, doctors with base specialty in anaesthesiology transfused critically ill patients more liberally compared to internal medicine physicians. CONCLUSION/CONCLUSIONS:Red blood cell transfusion practice for the general ICU population is restrictive, while for different subpopulations, higher Hb thresholds are applied. Furthermore, practice in plasma and platelet transfusion is heterogeneous, and local transfusion guidelines are lacking in the majority of the ICUs.