Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit.

BACKGROUND: Studies that have evaluated the use of intravenous vitamin C in adults with sepsis who were receiving vasopressor therapy in the intensive care unit (ICU) have shown mixed results with respect to the risk of death and organ dysfunction. METHODS: In this randomized, placebo-controlled trial, we assigned adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving a vasopressor to receive an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28. RESULTS: A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). The primary outcome occurred in 191 of 429 patients (44.5%) in the vitamin C group and in 167 of 434 patients (38.5%) in the control group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P = 0.01). At 28 days, death had occurred in 152 of 429 patients (35.4%) in the vitamin C group and in 137 of 434 patients (31.6%) in the placebo group (risk ratio, 1.17; 95% CI, 0.98 to 1.40) and persistent organ dysfunction in 39 of 429 patients (9.1%) and 30 of 434 patients (6.9%), respectively (risk ratio, 1.30; 95% CI, 0.83 to 2.05). Findings were similar in the two groups regarding organ-dysfunction scores, biomarkers, 6-month survival, health-related quality of life, stage 3 acute kidney injury, and hypoglycemic episodes. In the vitamin C group, one patient had a severe hypoglycemic episode and another had a serious anaphylaxis event. CONCLUSIONS: In adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. (Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.).

Extubation Advisor: Implementation and Evaluation of A Novel Extubation Clinical Decision Support Tool.

IMPORTANCE: Extubation Advisor (EA) is a novel software tool that generates a synoptic report for each Spontaneous Breathing Trial (SBT) conducted to inform extubation decision-making. OBJECTIVES: To assess bedside EA implementation, perceptions of utility, and identify barriers and facilitators of use. DESIGN, SETTING AND PARTICIPANTS: We conducted a phase I mixed-methods interventional study in three mixed intensive care unit (ICUs) in two academic hospitals. We interviewed critical care physicians (MDs) and respiratory therapists (RTs) regarding user-centered design principles and usability. ANALYSIS: We evaluated our ability to consent participants (feasibility threshold 50%), capture complete data (threshold 90%), generate and review EA reports in real-time (thresholds 75% and 80%, respectively), and MD perception of tool usefulness (6-point Likert scale). We analyzed interview transcripts using inductive coding to identify facilitators and barriers to EA implementation and perceived benefit of tool use. RESULTS: We enrolled 31 patients who underwent 70 SBTs. Although consent rates [31/31 (100%], complete data capture [68/68 (100%)], and EA report generation [68/70 (97.1%)] exceeded feasibility thresholds, reports were reviewed by MDs for [55/70 (78.6%)] SBTs. Mean MD usefulness score was 4.0/6. Based on feedback obtained from 36 interviews (15 MDs, 21 RTs), we revised the EA report twice and identified facilitators (ability to track patient progress, enhance extubation decision-making, and provide support in resource-limited settings) and barriers (resource constraints, need for education) to tool implementation. Half of respondents (9 MDs, 9 RTs; combined 50%) perceived definite or potential benefit to EA tool use. CONCLUSION: This is the first study of a waveform-based variability-derived, predictive clinical decision support tool evaluated in adult ICUs. Our findings support the feasibility of integrating the EA tool into bedside workflow. Clinical trials are needed to assess the utility of the EA tool in practice and its impact on extubation decision-making and outcomes. TRIAL REGISTRATION: NCT04708509.

Predictors of Noninvasive Ventilation Failure in the Post-Extubation Period: A Systematic Review and Meta-Analysis.

OBJECTIVES: To identify factors associated with failure of noninvasive ventilation (NIV) in the post-extubation period. DATA SOURCES: We searched Embase Classic +, MEDLINE, and the Cochrane Database of Systematic Reviews from inception to February 28, 2022. STUDY SELECTION: We included English language studies that provided predictors of post-extubation NIV failure necessitating reintubation. DATA EXTRACTION: Two authors conducted data abstraction and risk-of-bias assessments independently. We used a random-effects model to pool binary and continuous data and summarized estimates of effect using odds ratios (ORs) mean difference (MD), respectively. We used the Quality in Prognosis Studies tool to assess risk of bias and the Grading of Recommendations, Assessment, Development and Evaluations to assess certainty. DATA SYNTHESIS: We included 25 studies ( n = 2,327). Illness-related factors associated with increased odds of post-extubation NIV failure were higher critical illness severity (OR, 3.56; 95% CI, 1.96-6.45; high certainty) and a diagnosis of pneumonia (OR, 6.16; 95% CI, 2.59-14.66; moderate certainty). Clinical and biochemical factors associated with moderate certainty of increased risk of NIV failure post-extubation include higher respiratory rate (MD, 1.54; 95% CI, 0.61-2.47), higher heart rate (MD, 4.46; 95% CI, 1.67-7.25), lower Pa o2 :F io2 (MD, -30.78; 95% CI, -50.02 to -11.54) 1-hour after NIV initiation, and higher rapid shallow breathing index (MD, 15.21; 95% CI, 12.04-18.38) prior to NIV start. Elevated body mass index was the only patient-related factor that may be associated with a protective effect (OR, 0.21; 95% CI, 0.09-0.52; moderate certainty) on post-extubation NIV failure. CONCLUSIONS: We identified several prognostic factors before and 1 hour after NIV initiation associated with increased risk of NIV failure in the post-extubation period. Well-designed prospective studies are required to confirm the prognostic importance of these factors to help further guide clinical decision-making.

Use of multidisciplinary positive deviance seminars to improve efficiency in a high-volume arthroplasty practice: a pilot study.

BACKGROUND: Positive deviance (PD) seminars, which have shown excellent results in improving the quality of surgical practices, use individual performance feedback to identify team members who outperform their peers; the strategies from those with exemplary performance are used to improve team members' practices. Our study aimed to use the PD approach with arthroplasty surgeons and nurses to identify multidisciplinary strategies and recommendations to improve operating room (OR) efficiency. METHODS: We recruited 5 surgeons who performed high-volume primary arthroplasty and had participated in 4-joint rooms since 2012, and 29 nurses who had participated in 4-joint rooms and in at least 16 cases in our data set. Three 1-hour PD sessions were held in February and March 2021: 1 with surgeons, 1 with nurses, and 1 with both surgeons and nurses to select recommendations for implementation. The sessions were led by a member of the nonorthopedic surgical faculty who was familiar with the subjects discussed and with PD seminars. To determine the success of the recommendations, we compared OR efficiency before and after implementation. We defined success as performance of 4 joint procedures within 8 hours. RESULTS: Eleven recommendations were recorded from the session with nurses and 7 from the session with surgeons, of which 11 were selected for implementation. During the month after implementation, there were great improvements across all time intervals of surgical procedures, with the greatest improvements seen in mean anesthesia preparation time in the room (4.51 min [26.3%]), mean procedure duration (9.75 min [14.0%]) and mean anesthesia finish time (5.78 min [44.0%]) (all p < 0.001). The total time saved per day was 49.84 minutes; this led to a success rate of 69.0%, a relative increase of 73.8% from our 2012-2020 success rate of 39.7% (p < 0.001). CONCLUSION: The recommendations and increased motivation owing to the individualized feedback reduced time spent per case, allowing more days to finish on time. Positive deviance seminars offer an inexpensive, efficient and collegial means for process improvement in the OR.

Continuous Monitoring of Entropy Production and Entropy Flow in Humans Exercising under Heat Stress.

Complex living systems, such as the human organism, are characterized by their self-organized and dissipative behaviors, where irreversible processes continuously produce entropy internally and export it to the environment; however, a means by which to measure human entropy production and entropy flow over time is not well-studied. In this article, we leverage prior experimental data to introduce an experimental approach for the continuous measurement of external entropy flow (released to the environment) and internal entropy production (within the body), using direct and indirect calorimetry, respectively, for humans exercising under heat stress. Direct calorimetry, performed with a whole-body modified Snellen calorimeter, was used to measure the external heat dissipation from the change in temperature and relative humidity between the air outflow and inflow, from which was derived the rates of entropy flow of the body. Indirect calorimetry, which measures oxygen consumption and carbon dioxide production from inspired and expired gases, was used to monitor internal entropy production. A two-compartment entropy flow model was used to calculate the rates of internal entropy production and external entropy flow for 11 middle-aged men during a schedule of alternating exercise and resting bouts at a fixed metabolic heat production rate. We measured a resting internal entropy production rate of (0.18 ± 0.01) W/(K·m2) during heat stress only, which is in agreement with published measurements. This research introduces an approach for the real-time monitoring of entropy production and entropy flow in humans, and aims for an improved understanding of human health and illness based on non-equilibrium thermodynamics.

Economic feasibility of a novel tool to assist extubation decision-making: an early health economic modeling.

OBJECTIVES: To estimate the minimum percent change in failed extubation to make a tool designed to reduce extubation failure (Extubation Advisor [EA]) economically viable. METHODS: We conducted an early return on investment (ROI) analysis using data from intubated intensive care unit (ICU) patients at a large Canadian tertiary care hospital. We obtained input parameters from the hospital database and published literature. We ran generalized linear models to estimate the attributable length of stay, total hospital cost, and time to subsequent extubation attempt following failure. We developed a Markov model to estimate the expected ROI and performed probabilistic sensitivity analyses to assess the robustness of findings. Costs were presented in 2020 Canadian dollars (C$). RESULTS: The model estimated a 1 percent reduction in failed extubation could save the hospital C$289 per intubated patient (95 percent CI: 197, 459). A large center seeing 2,500 intubated ICU patients per year could save C$723,124/year/percent reduction in failed extubation. At the current annual price of C$164,221, the EA tool must reduce extubation failure by at least 0.24 percent (95 percent CI: .14, .41) to make the tool cost-effective at our site. CONCLUSIONS: Clinical decision-support tools like the EA may play an important role in reducing healthcare costs by reducing the rate of extubation failure, a costly event in the ICU.

Can Early Warning Systems Enhance Detection of High Risk Patients by Rapid Response Teams?

PURPOSE: We sought to evaluate if incorporating an early warning system (EWS), the Visensia Safety Index (VSI) and the National Early Warning Systems 2 (NEWS2), may lead to earlier identification of rapid response team (RRT) patients. METHODS: This was a retrospective study (2015-2018) of patients experiencing RRT activation within a tertiary care network. We evaluated the proportion of patients with an EWS alert prior to RRT activation and their associated outcomes (primary: hospital mortality). RESULTS: There were 6,346 RRT activations over the study period. Of these, 2042 (50.8%) patients would have had a VSI alert prior to RRT activation, with a median advanced time of 3.6 (IQR 0.5-12.8) hours, compared to 2351 (58.4%) patients and 9.8 (IQR 2.0-18.7) hours for NEWS2. Patients with a potential alert prior to RRT activation had an increased odds of mortality for both VSI (OR 1.2, 95%CI 1.1-1.3) and NEWS2 (OR 2.7, 95% CI 2.4-3.1). Prognostic accuracy for hospital mortality was similar between groups. CONCLUSION: Utilization of an EWS by an RRT has potential to provide earlier recognition of deterioration and mortality risk among hospitalized inpatients.

Variability Predictors of Vasospasm in Subarachnoid Hemorrhage: A Feasibility Study.

BACKGROUND: Mean cerebral blood flow velocity (mean-CBFV) obtained from Transcranial Doppler (TCD) poorly predicts cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage (aSAH). Variability descriptors of mean-CBFV obtained during extended TCD recordings may improve this prediction. We assessed the feasibility of generating reliable linear and non-linear descriptors of mean-CBFV variability using extended recordings in aSAH patients and in healthy controls. We also explored which of those metrics might have the ability to discriminate between aSAH patients and healthy controls, and among patients who would go on to develop vasospasm and those who would not. METHODS: Bilateral mean-CBFV, blood pressure, and heart rate were continuously recorded for 40 minutes in aSAH patients (n = 8) within the first 5 days after ictus, in age-matched healthy controls (n = 8) and in additional young controls (n = 8). We obtained linear [standard deviation, coefficient of variations, and the very-low (0.003-0.040 Hz), low (0.040-0.150 Hz), and high-frequency (0.15-0.4 Hz) power spectra] and non-linear (Fractality, deterministic Chaos analyses) variability metrics. RESULTS: We successfully obtained TCD recordings from patients and healthy controls and calculated the desired metrics of mean-CBFV variability. Differences were appreciable between aSAH patients and healthy controls, as well as between aSAH patients who later developed vasospasm and those who did not. CONCLUSIONS: A 40-minute TCD recording provides reliable variability metrics in aSAH patients and healthy controls. Future studies are required to determine if mean-CBFV variability metrics remain stable over time, and whether they may serve to identify patients who are at greatest risk of developing cerebral vasospasm after aSAH.

Interventions to prevent anastomotic leak after esophageal surgery: a systematic review and meta-analysis.

BACKGROUND: Anastomotic leakage (AL) is a common and serious complication following esophagectomy. We aimed to provide an up-to-date review and critical appraisal of the efficacy and safety of all previous interventions aiming to reduce AL risk. METHODS: We searched MEDLINE and Embase from 1946 to January 2019 for randomized controlled trials (RCTs) evaluating interventions to minimize esophagogastric AL. Pooled risk ratios (RR) for AL were obtained using a random effects model. RESULTS: Two reviewers screened 441 abstracts and identified 17 RCTs eligible for inclusion; 11 studies were meta-analyzed. Omentoplasty significantly reduced the risk of AL by 78% [RR: 0.22; 95% CI: 0.10, 0.50] compared to conventional anastomosis (3 studies, n = 611 patients). Early removal of NG tube significantly reduced the risk of AL by 62% [RR: 0.38; 95% CI: 0.02, 0.65] compared to prolonged NG tube removal (2 studies, n = 293 patients); Stapled anastomosis did not significantly reduce the risk of AL [RR: 0.92; 95% CI: 0.45, 1.87] compared to hand-sewn anastomosis (6 studies, n = 1454 patients). The quality of evidence was high for omentoplasty (vs. conventional anastomosis), moderate for early NG tube removal (vs. prolonged NG tube removal), and very low for stapled anastomosis (vs. hand-sewn anastomosis). CONCLUSIONS: This is the first meta-analysis to summarize the graded quality of evidence for all RCT interventions designed to reduce the risk of AL following esophagectomy. Our findings demonstrated that omentoplasty significantly reduced the risk of AL with a high quality of evidence. Although early NG tube removal significantly reduced AL risk, there is a need for further research to strengthen the quality of evidence for this finding. Evidence profiles presented in our review may help inform the development of future clinical practice recommendations. Systematic review registration: CRD42019127181.

Correction to: Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative­intent Resection for Lung Cancer.

The original version of this article unfortunately contained a mistake in author names. The given and family names of all the authors was transposed. The author names are corrected with this correction. The original article has been corrected.

Postoperative Adverse Events are Associated with Oncologic Recurrence Following Curative-intent Resection for Lung Cancer.

BACKGROUND: Up to 50% of patients suffer short-term postoperative adverse events (AEs) and metastatic recurrence in the long-term following curative-intent lung cancer resection. The association between AEs, particularly infectious in nature, and disease recurrence is controversial. We sought to evaluate the association of postoperative AEs on risk of developing recurrence and recurrence-free survival (RFS) following curative-intent lung resection surgery. METHODS: All lung cancer resections at a single institution (January 2008-July 2015) were included, with prospective collection of AEs using the Thoracic Morbidity & Mortality System. Cox proportional hazards models were used to estimate the effect of AEs on recurrence, with results presented as hazard ratio (HR) with 95% confidence interval (CI). An a priori, clinically driven approach to predictor variable selection was used. Kaplan-Meier curves were used examine the relationship between AE and RFS. p < 0.05 was considered statistically significant. RESULTS: 892 patients underwent curative-intent resection. 342 (38.3%) patients experienced an AE; 69 (7.7%) patients developed infectious AEs. 17.6% (n = 157) of patients had disease recurrence after mean follow-up of 26.5 months. Severe (Grade IV) AEs were associated with increased risk of recurrence (3.40; 95% CI 1.56-7.41) and a trend to decreased RFS. Major infectious AEs were associated with increased risk of recurrence (HR 1.71; CI 1.05-2.8) and earlier time to recurrence (no infectious AE 66 months, minor infectious 41 months, major infectious 54 months; p = 0.02). CONCLUSION: For patients undergoing curative-intent lung cancer resection, postoperative AEs associated with critical illness or major infection were associated with increased risk of oncologic recurrence.

Age differences in cardiac autonomic regulation during intermittent exercise in the heat.

PURPOSE: This study aimed to detect potential differences in heart-rate variability (HRV) during a moderate-intensity intermittent exercise in the heat among physically active young (25.8 ± 1.9 years), middle-aged (43.5 ± 2.8 years), and older (62.9 ± 3.7 years) men. METHODS: Thirty-three participants (11/group) performed four successive bouts of 15-min cycling at a moderate fixed rate of metabolic heat production of ~ 400 W; each separated by a 15-min recovery with 1 h of final recovery in a hot and dry environment (35 °C, 20% relative humidity). Twelve HRV indices were computed that have been commonly described in the literature, and characterized various domains of the variability and complexity of heart rate. RESULTS: Cardiac autonomic regulation during intermittent exercise in the heat, as well as during pre-exercise rest and recovery was significantly affected by age, as changes were observed among the three different aged groups in five indices (p ≤ 0.05). Similarly, time influenced cardiac autonomic regulation as three indices showed changes across time (p ≤ 0.05) during intermittent exercise, whilst five indices displayed significant changes (p ≤ 0.05) during rest and recovery in the heat. CONCLUSIONS: This study supports that moderate-intensity intermittent exercise in the heat is associated with significant cardiac autonomic dysregulation in older men, as compared to young and middle-aged men, yet it highlights the importance of developing preventative health strategies for heat-related illness in aged individuals.

Heart rate variability in older workers during work under the Threshold Limit Values for heat exposure.

BACKGROUND: The Threshold Limit Values (TLV) of the American Conference of Governmental and Industrial Hygienists indicate the levels of heat stress that all workers may be repeatedly exposed to without adverse health effects. In this study, we evaluated heart rate variability (HRV) during moderate-to-heavy work performed continuously or according to different TLV work-rest (WR) allocations in healthy physically active older workers. METHODS: Nine healthy older (58 ± 5 years) males performed three different 120-minute conditions in accordance with TLV guidelines for moderate-to-heavy intensity work (360 W fixed rate of heat production) in different wet-bulb globe temperatures (WBGT): continuous cycling at 28°C WBGT (CON), as well as intermitted work performed at WR of 3:1 in 29°C WBGT (WR3:1), and at WR of 1:1 at 30°C (WR1:1). Rectal temperature and HRV (3-lead electrocardiogram [ECG]) were assessed throughout. RESULTS: Coefficient of Variation, Poincaré SD2, and Shannon Entropy were decreased during the CON compared with the WR3:1 when core temperature exceeded 38°C and after 1 hour of continuous work (P < .05). Also, 4 of the 12 HRV indices studied were reduced at CON compared with WR1:1 after 2 hours of accumulated work time (P < .05). Participants worked longer before core temperature reached 38°C during the WR1:1 and the WR3:1, compared with CON (P < .05). CONCLUSIONS: Incorporating breaks during moderate-to-heavy work in the heat for older adults can reduce autonomic stress and prolong the work performed at safe core temperature levels. The TLV WR1:1 provides increased cardiac protection for older workers, as compared with the CON and the WR3:1.

Predictors of mortality and cost among surgical patients requiring rapid response team activation.

Background: Prior studies of rapid response team (RRT) implementation for surgical patients have demonstrated mixed results with respect to reductions in poor outcomes. The aim of this study was to identify predictors of in-hospital mortality and hospital costs among surgical inpatients requiring RRT activation. Methods: We analyzed data prospectively collected from May 2012 to May 2016 at The Ottawa Hospital. We included patients who were at least 18 years of age, who were admitted to hospital, who received either preoperative or postoperative care, and and who required RRT activation. We created a multivariable logistic regression model to describe mortality predictors and a multivariable generalized linear model to describe cost predictors. Results: We included 1507 patients. The in-hospital mortality rate was 15.9%. The patient-related factors most strongly associated with mortality included an Elixhauser Comorbidity Index score of 20 or higher (odds ratio [OR] 3.60, 95% confidence interval [CI] 1.96-6.60) and care designations excluding admission to the intensive care unit and cardiopulmonary resuscitation (OR 3.52, 95% CI 2.25-5.52). The strongest surgical predictors included neurosurgical admission (OR 2.09, 95% CI 1.17-3.75), emergent surgery (OR 2.04, 95% CI 1.37-3.03) and occurrence of 2 or more operations (OR 1.73, 95% CI 1.21-2.46). Among RRT factors, occurrence of 2 or more RRT assessments (OR 2.01, 95% CI 1.44-2.80) conferred the highest mortality. Increased cost was strongly associated with admitting service, multiple surgeries, multiple RRT assessments and medical comorbidity. Conclusion: RRT activation among surgical inpatients identifies a population at high risk of death. We identified several predictors of mortality and cost, which represent opportunities for future quality improvement and patient safety initiatives.

Contexte: Les études sur la mobilisation d'équipes d'intervention rapide (EIR) auprès de patients en chirurgie ont donné des résultats mitigés quant à la réduction des issues négatives. La présente étude visait à déterminer les facteurs prédictifs de coûts pour les hôpitaux et de mortalité chez les patients en chirurgie nécessitant la mobilisation d'une EIR. Méthodes: Nous avons analysé des données recueillies de manière prospective de mai 2012 à mai 2016 à l'Hôpital d'Ottawa. Nous avons inclus les patients hospitalisés de 18 ans et plus qui ont reçu des soins préopératoires ou postopératoires et qui ont nécessité l'intervention d'une EIR. Nous avons ensuite créé un modèle de régression logistique multivariée pour décrire les facteurs prédictifs de mortalité et un modèle linéaire généralisé multivarié pour décrire les facteurs prédictifs de coûts. Résultats: Nous avons retenus 1507 patients. Le taux global de mortalité à l'hôpital était de 15,9 %. Les principaux facteurs de mortalité liés au patient étaient un indice de comorbidité d'Elixhauser supérieur ou égal à 20 (rapport de cotes [RC] 3,60, intervalle de confiance [IC] à 95 % 1,96­6,60) et des objectifs de soins excluant l'admission à l'unité des soins intensifs et la réanimation cardiorespiratoire (RC 3,52, IC à 95 % 2,25­5,52). Les principaux facteurs prédictifs liés aux interventions sont l'admission en neurochirurgie (RC 2,09, IC à 95 % 1,17­3,75), l'intervention chirurgicale d'urgence (RC 2,04, IC à 95 % 1,37­3,03) et le fait d'avoir subi au moins 2 opérations (RC 1,73, IC à 95 % 1,21­2,46). Parmi les facteurs liés aux EIR, la tenue d'au moins 2 évaluations par l'EIR s'accompagnait du mortalité le plus élevé (RC 2,01, IC à 95 % 1,44­2,80). L'augmentation des coûts était étroitement associée au service d'admission, aux interventions chirurgicales multiples, aux évaluations multiples par l'EIR et à la comorbidité médicale. Conclusion: La mobilisation d'EIR auprès de patients en chirurgie permet de mettre en évidence une population à risque élevé de décès. Nous avons découvert plusieurs facteurs prédictifs de mortalité et de coûts, dont on pourra se servir pour améliorer la qualité des soins et la sécurité des patients.

Optimizing Our Patients' Entropy Production as Therapy? Hypotheses Originating from the Physics of Physiology.

Understanding how nature drives entropy production offers novel insights regarding patient care. Whilst energy is always preserved and energy gradients irreversibly dissipate (thus producing entropy), increasing evidence suggests that they do so in the most optimal means possible. For living complex non-equilibrium systems to create a healthy internal emergent order, they must continuously produce entropy over time. The Maximum Entropy Production Principle (MEPP) highlights nature's drive for non-equilibrium systems to augment their entropy production if possible. This physical drive is hypothesized to be responsible for the spontaneous formation of fractal structures in space (e.g., multi-scale self-similar tree-like vascular structures that optimize delivery to and clearance from an organ system) and time (e.g., complex heart and respiratory rate variability); both are ubiquitous and essential for physiology and health. Second, human entropy production, measured by heat production divided by temperature, is hypothesized to relate to both metabolism and consciousness, dissipating oxidative energy gradients and reducing information into meaning and memory, respectively. Third, both MEPP and natural selection are hypothesized to drive enhanced functioning and adaptability, selecting states with robust basilar entropy production, as well as the capacity to enhance entropy production in response to exercise, heat stress, and illness. Finally, a targeted focus on optimizing our patients' entropy production has the potential to improve health and clinical outcomes. With the implications of developing a novel understanding of health, illness, and treatment strategies, further exploration of this uncharted ground will offer value.

Necrotizing Soft Tissue Infection: Diagnostic Accuracy of Physical Examination, Imaging, and LRINEC Score: A Systematic Review and Meta-Analysis.

OBJECTIVE: We sought to summarize accuracy of physical examination, imaging, and Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score in diagnosis of necrotizing soft tissue infection (NSTI) in adults with a soft tissue infection clinically concerning for NSTI. SUMMARY OF BACKGROUND DATA: NSTI is a life-threatening diagnosis. Delay to diagnosis and surgical management is associated with increased mortality. METHODS: We searched 6 databases from inception through November 2017. We included English-language studies reporting diagnostic accuracy of testing or LRINEC Score. Outcome was NSTI confirmed by surgery or histopathology. Two reviewers screened all citations and extracted data independently. Summary measures were obtained from the Hierarchical Summary Receiver Operating Characteristic model. RESULTS: From 2,290 citations, we included 23 studies (n = 5982). Of physical examination signs, pooled sensitivity and specificity for fever was 46.0% and 77.0% respectively, for hemorrhagic bullae 25.2% and 95.8%, and for hypotension 21.0% and 97.7%. Computed tomography (CT) had sensitivity of 88.5% and specificity of 93.3%, while plain radiography had sensitivity of 48.9% and specificity of 94.0%. Finally, LRINEC ≥ 6 had sensitivity of 68.2% and specificity of 84.8%, while LRINEC ≥ 8 had sensitivity of 40.8% and specificity of 94.9%. CONCLUSIONS: Absence of any 1 physical examination feature (eg, fever or hypotension) is not sufficient to rule-out NSTI. CT is superior to plain radiography. LRINEC had poor sensitivity, and should not be used to rule-out NSTI. Given the poor sensitivity of these tests, a high clinical suspicion warrants early surgical consultation for definitive diagnosis and management.

Frequency of Screening for Weaning From Mechanical Ventilation: Two Contemporaneous Proof-of-Principle Randomized Controlled Trials.

OBJECTIVES: It is unknown whether more frequent screening of invasively ventilated patients, identifies patients earlier for a spontaneous breathing trial, and shortens the duration of ventilation. We assessed the feasibility of conducting a large trial to evaluate screening frequency in critically ill adults in the North American context. DESIGN: We conducted two contemporaneous, multicenter, pilot, randomized controlled trials (the LibeRation from MEchanicaL VEntilAtion and ScrEening Frequency [RELEASE] and Screening Elderly PatieNts For InclusiOn in a Weaning [SENIOR] trials) to address concerns regarding the potential for higher enrollment, fewer adverse events, and better outcomes in younger patients. SETTING: Ten and 11 ICUs in Canada, respectively. PATIENTS: Parallel trials of younger (RELEASE < 65 yr) and older (SENIOR ≥ 65 yr) critically ill adults invasively ventilated for at least 24 hours. INTERVENTIONS: Each trial compared once daily screening to "at least twice daily" screening led by respiratory therapists. MEASUREMENTS AND MAIN RESULTS: In both trials, we evaluated recruitment (aim: 1-2 patients/month/ICU) and consent rates, reasons for trial exclusion, protocol adherence (target: ≥ 80%), crossovers (aim: ≤ 10%), and the effect of the alternative screening frequencies on adverse events and clinical outcomes. We included 155 patients (53 patients [23 once daily, 30 at least twice daily] in RELEASE and 102 patients [54 once daily, 48 at least twice daily] in SENIOR). Between trials, we found similar recruitment rates (1.32 and 1.26 patients/month/ICU) and reasons for trial exclusion, high consent and protocol adherence rates (> 92%), infrequent crossovers, and few adverse events. Although underpowered, at least twice daily screening was associated with a nonsignificantly faster time to successful extubation and more successful extubations but significantly increased use of noninvasive ventilation in both trials combined. CONCLUSIONS: Similar recruitment and consent rates, few adverse events, and comparable outcomes in younger and older patients support conduct of a single large trial in North American ICUs assessing the net clinical benefits associated with more frequent screening.

Frailty and Associated Outcomes and Resource Utilization Among Older ICU Patients With Suspected Infection.

OBJECTIVES: Suspected infection and sepsis are common conditions seen among older ICU patients. Frailty has prognostic importance among critically ill patients, but its impact on outcomes and resource utilization in older patients with suspected infection is unknown. We sought to evaluate the association between patient frailty (defined as a Clinical Frailty Scale ≥ 5) and outcomes of critically ill patients with suspected infection. We also evaluated the association between frailty and the quick Sequential Organ Failure Assessment score. DESIGN: Analysis of a prospectively collected registry. SETTING: Two hospitals within a single tertiary care level hospital system between 2011 and 2016. PATIENTS: We analyzed 1,510 patients 65 years old or older (at the time of ICU admission) and with suspected infection at the time of ICU admission. Of these, 507 (33.6%) were categorized as "frail" (Clinical Frailty Scale ≥ 5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality. A total of 558 patients (37.0%) died in-hospital. Frailty was associated with increased risk of in-hospital death (adjusted odds ratio, 1.81 [95% CIs, 1.34-2.49]). Frailty was also associated with higher likelihood of discharge to long-term care (adjusted odds ratio, 2.06 [95% CI, 1.50-2.64]) and higher likelihood of readmission within 30 days (adjusted odds ratio, 1.83 [95% CI, 1.38-2.34]). Frail patients had increased ICU resource utilization and total costs. The combination of frailty and quick Sequential Organ Failure Assessment greater than or equal to 2 further increased the risk of death (adjusted odds ratio, 7.54 [95% CI, 5.82-9.90]). CONCLUSIONS: The presence of frailty among older ICU patients with suspected infection is associated with increased mortality, discharge to long-term care, hospital readmission, resource utilization, and costs. This work highlights the importance of clinical frailty in risk stratification of older ICU patients with suspected infection.

Heart rate variability dynamics during treatment for exertional heat strain when immediate response is not possible.

NEW FINDINGS: What is the central question of this study? Does a delay in cold water immersion treatment affect the cardiac autonomic control of exertionally heat-strained individuals? What is the main finding and its importance? Cold water immersion is effective for treating exertionally heat-strained individuals even when treatment is commenced with a significant delay. However, that treatment delay leads to only partial/transient restoration of cardiac autonomic control. Therefore, we recommend that exertional heatstroke patients are continuously monitored for several hours even after core temperature has returned to normal values. ABSTRACT: Immediate cold water immersion (CWI) is the gold-standard treatment for exertional heatstroke. In the field, however, treatment is often delayed, primarily owing to a delayed paramedic response and/or inaccurate diagnosis. We examined the effect of treatment (reduction of rectal temperature to 37.5°C) delays of 5 (short), 20 (moderate) and 40 (prolonged) min on cardiac autonomic control [as assessed via heart rate variability (HRV)] in eight exertionally heat-strained (40.0°C rectal temperature) individuals. Eleven HRV indices were computed that have been described commonly in the literature and characterize almost all known domains of the variability and complexity of the cardiopulmonary system. We found that the cardiac autonomic control (as assessed via HRV) of exertionally heat-strained individuals was significantly affected by the amount of time it took for the CWI treatment to be applied. Six out of 11 HRV indices studied, from all variability domains, displayed strong (P ≤ 0.005) time × delay interaction effects. Moreover, the number of significantly (P ≤ 0.005) abnormal (i.e. different from the short delay) HRV indices more than doubled (seven versus 15) from the moderate delay to the prolonged delay. Finally, our results demonstrated that a CWI treatment applied with delays of 20 and, primarily, 40 min did not lead to a full restoration of cardiac autonomic control of exertionally heat-strained individuals. In conclusion, this study supports CWI for treating exertionally heat-strained individuals even when applied with prolonged delay, but it highlights the importance of continued cardiac monitoring of patients who have suffered exertional heatstroke for several hours after restoration of core temperature to normal.

Prognostic accuracy of the Hamilton Early Warning Score (HEWS) and the National Early Warning Score 2 (NEWS2) among hospitalized patients assessed by a rapid response team.

BACKGROUND: Rapid response teams (RRTs) respond to hospitalized patients experiencing clinical deterioration and help determine subsequent management and disposition. We sought to evaluate and compare the prognostic accuracy of the Hamilton Early Warning Score (HEWS) and the National Early Warning Score 2 (NEWS2) for prediction of in-hospital mortality following RRT activation. We secondarily evaluated a subgroup of patients with suspected infection. METHODS: We retrospectively analyzed prospectively collected data (2012-2016) of consecutive RRT patients from two hospitals. The primary outcome was in-hospital mortality. We calculated the number needed to examine (NNE), which indicates the number of patients that need to be evaluated in order to detect one future death. RESULTS: Five thousand four hundred ninety-one patients were included, of whom 1837 (33.5%) died in-hospital. Mean age was 67.4 years, and 51.6% were male. A HEWS above the low-risk threshold (≥ 5) had a sensitivity of 75.9% (95% confidence interval (CI) 73.9-77.9) and specificity of 67.6% (95% CI 66.1-69.1) for mortality, with a NNE of 1.84. A NEWS2 above the low-risk threshold (≥ 5) had a sensitivity of 84.5% (95% CI 82.8-86.2), and specificity of 49.0% (95% CI: 47.4-50.7), with a NNE of 2.20. The area under the receiver operating characteristic curve (AUROC) was 0.76 (95% CI 0.75-0.77) for HEWS and 0.72 (95% CI: 0.71-0.74) for NEWS2. Among suspected infection patients (n = 1708), AUROC for HEWS was 0.79 (95% CI 0.76-0.81) and for NEWS2, 0.75 (95% CI 0.73-0.78). CONCLUSIONS: The HEWS has comparable clinical accuracy to NEWS2 for prediction of in-hospital mortality among RRT patients.