Critical Care: What You May Have Missed in 2023.

Critical care medicine is a specialty that brings together a truly wide spectrum of patient populations, disease states, and treatment methods. This article highlights 10 important pieces of research from 2023 (and 1 from 2022) in critical care. The literature was screened for new evidence relevant to internal medicine physicians and hospitalists whose focus of practice is not critical care but who may be taking care of seriously ill patients. The articles highlight the diverse spectrum of pathology and interplay of various specialties that go into critical care. Topics include transfusion medicine, fluid resuscitation, safe intubation practices and respiratory failure, and the management of acute ischemic stroke. Several trials are groundbreaking, forcing clinicians to reconsider preexisting dogma and likely adopt new treatment strategies.

Pharmacological agents for procedural sedation and analgesia in the emergency department and intensive care unit: a systematic review and network meta-analysis of randomised trials.

BACKGROUND: We aimed to evaluate the comparative effectiveness and safety of various i.v. pharmacologic agents used for procedural sedation and analgesia (PSA) in the emergency department (ED) and ICU. We performed a systematic review and network meta-analysis to enable direct and indirect comparisons between available medications. METHODS: We searched Medline, EMBASE, Cochrane, and PubMed from inception to 2 March 2023 for RCTs comparing two or more procedural sedation and analgesia medications in all patients (adults and children >30 days of age) requiring emergent procedures in the ED or ICU. We focused on the outcomes of sedation recovery time, patient satisfaction, and adverse events (AEs). We performed frequentist random-effects model network meta-analysis and used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to rate certainty in estimates. RESULTS: We included 82 RCTs (8105 patients, 78 conducted in the ED and four in the ICU) of which 52 studies included adults, 23 included children, and seven included both. Compared with midazolam-opioids, recovery time was shorter with propofol (mean difference 16.3 min, 95% confidence interval [CI] 8.4-24.3 fewer minutes; high certainty), and patient satisfaction was better with ketamine-propofol (mean difference 1.5 points, 95% CI 0.3-2.6 points, high certainty). Regarding AEs, compared with midazolam-opioids, respiratory AEs were less frequent with ketamine (relative risk [RR] 0.55, 95% CI 0.32-0.96; high certainty), gastrointestinal AEs were more common with ketamine-midazolam (RR 3.08, 95% CI 1.15-8.27; high certainty), and neurological AEs were more common with ketamine-propofol (RR 3.68, 95% CI 1.08-12.53; high certainty). CONCLUSION: When considering procedural sedation and analgesia in the ED and ICU, compared with midazolam-opioids, sedation recovery time is shorter with propofol, patient satisfaction is better with ketamine-propofol, and respiratory adverse events are less common with ketamine.

Intracranial hemorrhage in patients treated for SARS-CoV-2 with extracorporeal membrane oxygenation: A systematic review and meta-analysis.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is routinely used in patients with severe respiratory failure and has been increasingly needed during the COVID-19 pandemic. In patients treated with ECMO, significant intracranial hemorrhage (ICH) risk exists due to circuit characteristics, anticoagulation, and disease characteristics. ICH risk may be substantially higher in COVID-19 patients than patients treated with ECMO for other indications. METHODS: We systematically reviewed current literature regarding ICH during ECMO treatment of COVID-19. We utilized Embase, MEDLINE, and Cochrane Library databases. Meta-analysis was performed for included comparative studies. Quality assessment was performed using MINORS criteria. RESULTS: A total of 54 studies with 4000 ECMO patients were included, all retrospective. Risk of bias was increased via MINORS score primarily due to retrospective designs. ICH was more likely in COVID-19 patients (RR 1.72, 95% CI 1.23, 2.42). Mortality among COVID patients on ECMO with ICH was 64.0%, compared with 41% in patients without ICH (RR1.9, 95% 1.44, 2.51). CONCLUSION: This study suggests increased hemorrhage rates in COVID-19 patients on ECMO compared to similar controls. Hemorrhage reduction strategies may include atypical anticoagulants, conservative anticoagulation strategies, or biotechnology advances in circuit design and surface coatings.

In Silico Models for Hepatotoxicity.

In this chapter, we review the state of the art of predicting human hepatotoxicity using in silico techniques. There has been significant progress in this area over the past 20 years but there are still some challenges ahead. Principally, these challenges are our partial understanding of a very complex biochemical system and our ability to emulate that in a predictive capacity. Here, we provide an overview of the published modeling approaches in this area to date and discuss their design, strengths and weaknesses. It is interesting to note the diversity in modeling approaches, whether they be statistical algorithms or evidenced-based approaches including structural alerts and pharmacophore models. Irrespective of modeling approach, it appears a common theme of access to appropriate, relevant, and high-quality data is a limitation to all and is likely to continue to be the focus of future research.

Can the Addition of NT-proBNP and Glucose Measurements Improve the Prognostication of High-Sensitivity Cardiac Troponin Measurements for Patients with Suspected Acute Coronary Syndrome?

Guidelines published in 2021 have supported natriuretic peptide (NP) testing for the prognostication in patients with acute coronary syndrome (ACS) and for the diagnosis of chronic and acute heart failure (HF). Our objective was to determine if the addition of N-terminal pro B-type NP (NT-proBNP) and glucose to high-sensitivity cardiac troponin (hs-cTn) could better identify emergency department (ED) patients with potential ACS at low- and high-risk for a serious cardiovascular outcome over the next 72 h. The presentation sample in two different ED cohorts which enrolled patients with symptoms suggestive of ACS within six hours of pain onset (Cohort-1, n = 126 and Cohort-2, n = 143) that had Abbott hs-cTnI, Roche hs-cTnT, NT-proBNP and glucose were evaluated for NT-proBNP alone and combined with hs-cTn and glucose for the primary outcome (composite which included death, myocardial infarction, HF, serious arrhythmia and refractory angina) via receiver-operating characteristic (ROC) curve analyses with area under the curve (AUC) and diagnostic estimates derived. The AUC for NT-proBNP for the primary outcome was 0.68 (95% confidence interval (CI): 0.59-0.76) and 0.75 (95%CI: 0.67-0.82) in Cohort-1 and 2, respectively, with the 125 ng/L cutoff yielding a higher sensitivity (≥75%) as compared to the 300 ng/L cutoff (≥58%). Using the 125 ng/L cutoff for NT-proBNP with the published glucose and hs-cTn cutoffs for risk-stratification produced a new score (GuIDER score for Glucose, Injury and Dysfunction in the Emergency-setting for cardiovascular-Risk) and yielded higher AUCs as compared to NT-proBNP (p < 0.05). GuIDER scores of 0 and 5 using either hs-cTnI/T yielded sensitivity estimates of 100% and specificity estimates > 92% for the primary outcome. A secondary analysis assessing MI alone in the overall population (combined Cohorts 1 and 2) also achieved 100% sensitivity for MI with a GuIDER cutoff ≥ 2, ruling-out 48% (Roche) and 38% (Abbott) of the population at presentation for MI. Additional studies are needed for the GuIDER score in both the acute and ambulatory setting to further refine the utility, however, the preliminary findings reported here may present a pathway forward for inclusion of NP testing for ruling-out serious cardiac events and MI in the emergency setting.

Diagnostic Performance of Serial High-Sensitivity Cardiac Troponin Measurements in the Emergency Setting.

Serial high-sensitivity cardiac troponin (hsTn) testing in the emergency department (ED) and the intensive cardiac care unit may assist physicians in ruling out or ruling in acute myocardial infarction (MI). There are three major algorithms proposed for high-sensitivity cardiac troponin I (hsTnI) using serial measurements while incorporating absolute concentration changes for MI or death following ED presentation. We sought to determine the diagnostic estimates of these three algorithms and if one was superior in two different Canadian ED patient cohorts with serial hsTnI measurements. An undifferentiated ED population (Cohort-1) and an ED population with symptoms suggestive of acute coronary syndrome (ACS; Cohort-2) were clinically managed with non-hsTn testing with the hsTnI testing performed in real-time with physicians blinded to these results (i.e., hsTnI not reported). The three algorithms evaluated were the European Society of Cardiology (ESC), the High-STEACS pathway, and the COMPASS-MI algorithm. The diagnostic estimates were derived for each algorithm for the 30-day MI/death outcome for the rule-out and rule-in arm in each cohort and compared to proposed diagnostic benchmarks (i.e., sensitivity ≥ 99.0% and specificity ≥ 90.0%) with 95% confidence intervals (CI). In Cohort-1 (n = 2966 patients, 15.3% had outcome) and Cohort-2 (n = 935 patients, 15.6% had outcome), the algorithm that obtained the highest sensitivity (97.8%; 95% CI: 96.0-98.9 and 98.6%; 95% CI: 95.1-99.8, respectively) in both cohorts was COMPASS-MI. Only Cohort-2 with both the ESC and COMPASS-MI algorithms exceeded the specificity benchmark (97.0%; 95% CI: 95.5-98.0 and 96.7%; 95% CI: 95.2-97.8, respectively). Patient selection for serial hsTnI testing will affect specificity estimates, with no algorithm achieving a sensitivity ≥ 99% for 30-day MI or death.

Disagreement between Cardiac Troponin Tests Yielding a Higher Incidence of Myocardial Injury in the Emergency Setting.

Differences in patient classification of myocardial injury between high-sensitivity cardiac troponin (hs-cTn) assays have largely been attributed to assay design and analytical sensitivity aspects. Our objective was to compare Ortho Clinical Diagnostics' (OCD) hs-cTnI assay to OCD's contemporary/conventional assay (cTnI ES) and another hs-cTnI assay (Abbott hs-cTnI) in samples obtained from different emergency departments (EDs). Two different sample types were evaluated (lithium heparin and ethylenediaminetetraacetic acid (EDTA) plasma) in a non-selected ED population (study 1, n = 469 samples) and in patients for which ED physicians ordered cardiac troponin testing (study 2, n = 1147 samples), from five different EDs. The incidence of injury in study 1 was higher with the OCD hs-cTnI assay (30.9%; 95% CI: 26.9 to 35.2) compared to that of the Abbott hs-cTnI (17.3%; 95% CI: 14.1 to 21.0) and the OCD cTnI ES (15.4%; 95% CI: 12.4 to 18.9) assays, with repeat testing identifying 4.8% (95% CI: 3.0 to 7.5) of the OCD hs-cTnI results with poor reproducibility. In study 2, 4.6% (95% CI: 3.5 to 6.0) of the results were not reported for the OCD hs-cTnI assay (i.e., poor reproducibility) with 12.7% (95%CI: 8.7 to 17.8) of the OCD hs-cTnI results positive for injury being negative for injury with the Abbott hs-cTnI assay. In summary, the OCD hs-cTnI assay yields higher rates of biochemical injury with a higher rate of poor reproducible results in different ED populations.

Levetiracetam Versus Phenytoin or Fosphenytoin for Second-Line Treatment of Pediatric Status Epilepticus: A Meta-Analysis.

OBJECTIVE: To synthesize the available evidence examining the efficacy and safety of levetiracetam compared with phenytoin or fosphenytoin in benzodiazepine-refractory pediatric status epilepticus. DATA SOURCES: We searched (from inception until April 27, 2020) Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials. STUDY SELECTION: Two reviewers, independently and in duplicate, screened citations and manuscripts for eligible randomized controlled trials. DATA EXTRACTION AND SYNTHESIS: Independently and in duplicate, we performed data abstraction, risk of bias assessment, and certainty assessment using Grading of Recommendations, Assessment, Development, and Evaluation. We performed meta-analyses using random-effect models or, if insufficient data, presented findings narratively. RESULTS: We identified seven randomized controlled trials (n = 1,575). Pooled analysis demonstrated low certainty evidence for no difference of levetiracetam on time to seizure cessation (mean difference, -3.11 min; 95% CI, -6.67 to 0.45), early seizure cessation (relative risk, 1.09, 95% CI, 0.95-1.26), or late seizure cessation (relative risk, 1.05; 95% CI, 0.93-1.18). Adverse event outcomes were limited by low event numbers. We found low certainty evidence for less respiratory depression with levetiracetam (relative risk, 0.28; 95% CI, 0.12-0.69). CONCLUSIONS: The efficacy of levetiracetam is comparable with phenytoin or fosphenytoin in children with benzodiazepine-refractory status epilepticus (low certainty evidence). Levetiracetam may cause less respiratory depression. Clinicians and guideline developers should weigh safety profiles when choosing between these agents.

Prediction of Human Lethal Doses and Concentrations of MEIC Chemicals from Rodent LD50 Values: An Attempt to Make Some Reparation.

The prediction of human toxicities from animal toxicity tests is often poor, and is now discouraged and in some cases banned, especially those involving the LD50 test. However, there is a vast number of historical LD50 data in both public and in-house repositories that are being put to little use. This study examined the correlations between human lethality (doses and concentrations) of 36 MEIC chemicals and the median values of a large number of mouse and rat LD50 values obtained for four different routes of administration. The best correlations were found with mouse and rat intraperitoneal LD50 values (r2 = 0.838 and 0.810 for human lethal dose, and r2 = 0.753 and 0.785 for human lethal concentration). The results show that excellent prediction of human lethal dose and concentration can be made, for this series of chemicals at least, by using uncurated rodent LD50 values, thus offering some reparation for the millions of rodent lives sacrificed in LD50 testing.

Development of a Gaussian Process - feature selection model to characterise (poly)dimethylsiloxane (Silastic® ) membrane permeation.

OBJECTIVES: The current study aims to determine the effect of physicochemical descriptor selection on models of polydimethylsiloxane permeation. METHODS: A total of 2942 descriptors were calculated for a data set of 77 chemicals. Data were processed to remove redundancy, single values, imbalanced and highly correlated data, yielding 1363 relevant descriptors. For four independent test sets, feature selection methods were applied and modelled via a variety of Machine Learning methods. KEY FINDINGS: Two sets of molecular descriptors which can provide improved predictions, compared to existing models, have been identified. Best permeation predictions were found with Gaussian Process methods. The molecular descriptors describe lipophilicity, partial charge and hydrogen bonding as key determinants of PDMS permeation. CONCLUSIONS: This study highlights important considerations in the development of relevant models and in the construction and use of the data sets used in such studies, particularly that highly correlated descriptors should be removed from data sets. Predictive models are improved by the methodology adopted in this study, notably the systematic evaluation of descriptors, rather than simply using any and all available descriptors, often based empirically on in vitro experiments. Such findings also have clear relevance to a number of other fields.

BET 2: Ability of a normal gait examination to rule out cerebellar stroke in acute vertigo.

A short-cut review was carried out to establish whether a normal gait examination can rule out cerebellar stroke in patients with acute vertigo. 16 studies were relevant to the question. The author, year and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that a normal gait examination cannot rule out a cerebellar stroke but the presence of an abnormal gait can be associated.

Preoperative and Postoperative Assessment of Rectus Abdominis Muscle Size and Function following DIEP Flap Surgery.

BACKGROUND: Prospective evaluation of rectus abdominis muscle function after deep inferior epigastric artery perforator (DIEP) flap breast reconstruction is limited. Elimination of muscle harvest with this procedure is theoretically associated with preservation of rectus abdominis function and minimization of abdominal wall morbidity. In this study, the authors evaluate the change in rectus abdominis muscle size and function after DIEP flap surgery. METHODS: Patients undergoing unilateral DIEP flap surgery were recruited prospectively. Using computed tomography, the change in preoperative to postoperative rectus abdominis muscle size was compared between the operative side rectus abdominis muscle and the contralateral, nonoperative control rectus abdominis. Postoperative muscle integrity and contractility were evaluated using ultrasound by comparing the change in rectus abdominis muscle dimensions between contractile and relaxed states. The BREAST-Q was used to score patients' subjective satisfaction. Clinical and radiographic hernia rates were also calculated. RESULTS: Analysis of 26 paired rectus abdominis muscles revealed no significant change in muscle size from preoperative to postoperative values. Furthermore, dimensional change from contractile to relaxed states postoperatively was similar for paired operative and nonoperative rectus abdominis muscles. BREAST-Q scores indicated a high degree of satisfaction in abdominal well-being, breast satisfaction, and surgical experience domains. There were no clinical or radiographic abdominal wall hernias noted. CONCLUSIONS: The DIEP flap is an effective surgical procedure with minimal abdominal wall morbidity that is associated with no measurable loss in rectus abdominis size and contractile function postoperatively. Patients are highly satisfied with their abdominal function postoperatively using this technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Expansion of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells that Stimulate Limb Revascularization.

Uncompromised by chronic disease-related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra-muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (<0.5%) of these cells. Our goal was to generate a clinically-translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro-angiogenic potency. Purified UCB ALDHhi cells were expanded >18-fold over 6-days under serum-free conditions. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, only 15.1% ± 1.3% of progeny maintained high ALDH-activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7-fold), CD34+ /CD133+ cells (2.8-fold), and hematopoietic colony forming cells (7.7-fold). Remarkably, injection of expanded progeny accelerated recovery of perfusion and improved limb usage in immunodeficient mice with femoral artery ligation-induced limb ischemia. At 7 or 28 days post-transplantation, mice transplanted with expanded ALDHhi cells showed augmented endothelial cell proliferation and increased capillary density compared to controls. Expanded cells maintained pro-angiogenic mRNA expression and secreted angiogenesis-associated growth factors, chemokines, and matrix modifying proteins. Coculture with expanded cells augmented human microvascular endothelial cell survival and tubule formation under serum-starved, growth factor-reduced conditions. Expanded UCB-derived ALDHhi cells represent an alternative to autologous bone marrow as an accessible source of pro-angiogenic hematopoietic progenitor cells for the refinement of vascular regeneration-inductive therapies. Stem Cells Translational Medicine 2017;6:1607-1619.

In Silico Models for Hepatotoxicity.

In this chapter we review the challenges of predicting human hepatotoxicity. Principally, this is our partial understanding of a very complex biochemical system and our ability to emulate that in a predictive capacity. We give an overview of the published modeling approaches in this area to date and discuss their design, strengths, and weaknesses. It is interesting to note the shift during the period of this review in the direction of evidenced-based approaches including structural alerts and pharmacophore models. Proposals on how best to utilize the data emerging from modeling studies are also discussed.

Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models.

The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models. To address this issue we propose a scheme for the verification of in silico models that enables end users and modellers to assess the scientific validity of models in accordance with the principles of good computer modelling practice. We report here the implementation of the scheme within the Innovative Medicines Initiative project "eTOX" (electronic toxicity) and its application to the in silico models developed within the frame of this project.

Pragmatic approaches to using computational methods to predict xenobiotic metabolism.

In this study the performance of a selection of computational models for the prediction of metabolites and/or sites of metabolism was investigated. These included models incorporated in the MetaPrint2D-React, Meteor, and SMARTCyp software. The algorithms were assessed using two data sets: one a homogeneous data set of 28 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and paracetamol (DS1) and the second a diverse data set of 30 top-selling drugs (DS2). The prediction of metabolites for the diverse data set (DS2) was better than for the more homogeneous DS1 for each model, indicating that some areas of chemical space may be better represented than others in the data used to develop and train the models. The study also identified compounds for which none of the packages could predict metabolites, again indicating areas of chemical space where more information is needed. Pragmatic approaches to using metabolism prediction software have also been proposed based on the results described here. These approaches include using cutoff values instead of restrictive reasoning settings in Meteor to reduce the output with little loss of sensitivity and for directing metabolite prediction by preselection based on likely sites of metabolism.