The Association Between Intraoperative Compromised Intestinal Integrity and Postoperative Complications in Cancer Patients.

BACKGROUND: Because of perioperative splanchnic hypoperfusion, the gut wall becomes more permeable for intraluminal microbes to enter the splanchnic circulation, possibly contributing to development of complications. Hypoperfusion-related injured enterocytes release intestinal fatty acid binding protein (I-FABP) into plasma, which is used as proxy of intestinal integrity. This study investigates the occurrence of intestinal integrity loss during oncologic surgery, measured by I-FABP change. Secondary the relationship between compromised intestinal integrity, and related variables and complications were studied. METHODS: Patients undergoing oncologic surgery from prospective cohort studies were included. Urine I-FABP samples were collected preoperatively (T0) and at wound closure (T1), and in a subgroup on Day 1 (D1) and Day 2 (D2) postoperatively. I-FABP dynamics were investigated and logistic regression analyses were performed to study the association between I-FABP levels and patient-related, surgical variables and complications. RESULTS: A total of 297 patients were included with median age of 70 years. Median I-FABP value increased from 80.0 pg/mL at T0 (interquartile range [IQR] 38.0-142.0) to 115 pg/mL at T1 (IQR 48.0-198.0) (p < 0.05). Age (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.02-1.08) and anesthesia time (OR 1.13, 95% CI 1.02-1.25) were related to stronger I-FABP increase. When comparing I-FABP change in patients experiencing any complications versus no complications, relative I-FABP change at T1 was 145% of T0 (IQR 86-260) versus 113% (IQR 44-184) respectively (p < 0.05). CONCLUSIONS: A significant change in I-FABP levels was seen perioperatively indicating compromised intestinal integrity. Age and anesthesia time were related to higher I-FABP increase. In patients experiencing postoperative complications, a higher I-FABP increase was found.

Mild and deep hypothermia differentially affect cerebral neuroinflammatory and cold shock response following cardiopulmonary bypass in rat.

INTRODUCTION: Targeted temperature management (TTM) is considered to be a neuroprotective strategy during cardiopulmonary bypass (CPB) assisted procedures, possibly through the activation of cold shock proteins. We therefore investigated the effects of mild compared with deep hypothermia on the neuroinflammatory response and cold shock protein expression after CPB in rats. METHODS: Wistar rats were subjected to 1 hr of mild (33 °C) or deep (18 °C) hypothermia during CPB or sham procedure. PET scan analyses using TSPO ligand [11C]PBR28 were performed on day 1 (short-term) or day 3 and 7 post-procedure (long-term) to assess neuroinflammation. Hippocampal and cortical samples were obtained at day 1 in the short-term group and at day 7 in the long-term group. mRNA expression of M1 and M2 microglia associated cytokines was analysed with RT-PCR. Cold shock protein RNA-binding motive 3 (RBM3) and tyrosine receptor kinase B (TrkB) receptor protein expression were determined with Western Blot and quantified. RESULTS: In both groups target temperature was reached within an hour. Standard uptake values (SUV) of [11C]PBR28 in CPB rats at 1 day and 3 days were similar to that of sham animals. At 7 days after CPB the SUV was significantly higher in amygdala and hippocampal regions of the CPB 18 °C group as compared to the CPB 33 °C group. No differences were observed in the expression of M1 and M2 microglia-related cytokines between TTM 18 °C and 33 °C. RBM3 protein levels in cortex and hippocampus were significantly higher in CPB 33 °C compared to CPB 18 °C and sham 33 °C, at day 1 and day 7, respectively. CONCLUSIONS: TTM at 18 °C increased the neuroinflammatory response in amygdala and hippocampus compared to TTM at 33 °C in rats undergoing a CPB procedure. Additionally, TTM at 33 °C induced increased expression of TrkB and RBM3 in cortex and hippocampus of rats on CPB compared to TTM at 18 °C. Together, these data indicate that neuroinflammation is alleviated by TTM at 33 °C, possibly by recruiting protective mechanisms through cold shock protein induction.

Etomidate versus Ketamine as Prehospital Induction Agent in Patients with Suspected Severe Traumatic Brain Injury.

BACKGROUND: Severe traumatic brain injury is a leading cause of morbidity and mortality among young people around the world. Prehospital care focuses on the prevention and treatment of secondary brain injury and commonly includes tracheal intubation after induction of general anesthesia. The choice of induction agent in this setting is controversial. This study therefore investigated the association between the chosen induction medication etomidate versus S(+)-ketamine and the 30-day mortality in patients with severe traumatic brain injury who received prehospital airway management in the Netherlands. METHODS: This study is a retrospective analysis of the prospectively collected observational data of the Brain Injury: Prehospital Registry of Outcomes, Treatments and Epidemiology of Cerebral Trauma (BRAIN-PROTECT) cohort study. Patients with suspected severe traumatic brain injury who were transported to a participating trauma center and who received etomidate or S(+)-ketamine for prehospital induction of anesthesia for advanced airway management were included. Statistical analyses were performed with multivariable logistic regression and inverse probability of treatment weighting analysis. RESULTS: In total, 1,457 patients were eligible for analysis. No significant association between the administered induction medication and 30-day mortality was observed in unadjusted analyses (32.9% mortality for etomidate versus 33.8% mortality for S(+)-ketamine; P = 0.716; odds ratio, 1.04; 95% CI, 0.83 to 1.32; P = 0.711), as well as after adjustment for potential confounders (odds ratio, 1.08; 95% CI, 0.67 to 1.73; P = 0.765; and risk difference 0.017; 95% CI, -0.051 to 0.084; P = 0.686). Likewise, in planned subgroup analyses for patients with confirmed traumatic brain injury and patients with isolated traumatic brain injury, no significant differences were found. Consistent results were found after multiple imputations of missing data. CONCLUSIONS: The analysis found no evidence for an association between the use of etomidate or S(+)-ketamine as an anesthetic agent for intubation in patients with traumatic brain injury and mortality after 30 days in the prehospital setting, suggesting that the choice of induction agent may not influence the patient mortality rate in this population.

Intraoperative monitoring of the central and peripheral nervous systems: a narrative review.

The central and peripheral nervous systems are the primary target organs during anaesthesia. At the time of the inception of the British Journal of Anaesthesia, monitoring of the central nervous system comprised clinical observation, which provided only limited information. During the 100 yr since then, and particularly in the past few decades, significant progress has been made, providing anaesthetists with tools to obtain real-time assessments of cerebral neurophysiology during surgical procedures. In this narrative review article, we discuss the rationale and uses of electroencephalography, evoked potentials, near-infrared spectroscopy, and transcranial Doppler ultrasonography for intraoperative monitoring of the central and peripheral nervous systems.

Objective clinical registration of tremor, bradykinesia, and rigidity during awake stereotactic neurosurgery: a scoping review.

Tremor, bradykinesia, and rigidity are incapacitating motor symptoms that can be suppressed with stereotactic neurosurgical treatment like deep brain stimulation (DBS) and ablative surgery (e.g., thalamotomy, pallidotomy). Traditionally, clinicians rely on clinical rating scales for intraoperative evaluation of these motor symptoms during awake stereotactic neurosurgery. However, these clinical scales have a relatively high inter-rater variability and rely on experienced raters. Therefore, objective registration (e.g., using movement sensors) is a reasonable extension for intraoperative assessment of tremor, bradykinesia, and rigidity. The main goal of this scoping review is to provide an overview of electronic motor measurements during awake stereotactic neurosurgery. The protocol was based on the PRISMA extension for scoping reviews. After a systematic database search (PubMed, Embase, and Web of Science), articles were screened for relevance. Hundred-and-three articles were subject to detailed screening. Key clinical and technical information was extracted. The inclusion criteria encompassed use of electronic motor measurements during stereotactic neurosurgery performed under local anesthesia. Twenty-three articles were included. These studies had various objectives, including correlating sensor-based outcome measures to clinical scores, identifying optimal DBS electrode positions, and translating clinical assessments to objective assessments. The studies were highly heterogeneous in device choice, sensor location, measurement protocol, design, outcome measures, and data analysis. This review shows that intraoperative quantification of motor symptoms is still limited by variable signal analysis techniques and lacking standardized measurement protocols. However, electronic motor measurements can complement visual evaluations and provide objective confirmation of correct placement of the DBS electrode and/or lesioning. On the long term, this might benefit patient outcomes and provide reliable outcome measures in scientific research.

Consensus guidelines, Delphi methods, and evidence around anaesthetic technique for endoscopic retrograde cholangiopancreatography.

Consensus guidelines on the anaesthetic management of endoscopic retrograde cholangiopancreatography (ERCP) have recently been published. The rigorous synthesis of expert opinion is invaluable when there are limited data, and these guidelines are a significant step forward. This review both guides practice and identifies important research questions. We challenge those working in this field to collaborate and produce the evidence for whether monitored anaesthesia care (MAC) is associated with a lower incidence of adverse events and better outcomes than general anaesthesia for ERCP.

The Association of Physiological and Pharmacological Anesthetic Parameters With Motor-Evoked Potentials: A Multivariable Longitudinal Mixed Model Analysis.

BACKGROUND: During spinal surgery, the motor tracts can be monitored using muscle-recorded transcranial electrical stimulation motor-evoked potentials (mTc-MEPs). We aimed to investigate the association of anesthetic and physiological parameters with mTc-MEPs. METHODS: Intraoperative mTc-MEP amplitudes, mTc-MEP area under the curves (AUC), and anesthetic and physiological measurements were collected retrospectively from the records of 108 consecutive patients undergoing elective spinal surgery. Pharmacological parameters of interest included propofol and opioid concentration, ketamine and noradrenaline infusion rates. Physiological parameters recorded included mean arterial pressure (MAP), bispectral index (BIS), heart rate, hemoglobin O2 saturation, temperature, and Etco2. A forward selection procedure was performed using multivariable mixed model analysis. RESULTS: Data from 75 (69.4%) patients were included. MAP and BIS were significantly associated with mTc-MEP amplitude (P < .001). mTc-MEP amplitudes increased by 6.6% (95% confidence interval [CI], 2.7%-10.4%) per 10 mm Hg increase in MAP and by 2.79% (CI, 2.26%-3.32%) for every unit increase in BIS. MAP (P < .001), BIS (P < .001), heart rate (P = .01), and temperature (P = .02) were significantly associated with mTc-MEP AUC. The AUC increased by 7.5% (CI, 3.3%-11.7%) per 10 mm Hg increase of MAP, by 2.98% (CI, 2.41%-3.54%) per unit increase in BIS, and by 0.68% (CI, 0.13%-1.23%) per beat per minute increase in heart rate. mTc-MEP AUC decreased by 21.4% (CI, -38.11% to -3.98%) per degree increase in temperature. CONCLUSIONS: MAP, BIS, heart rate, and temperature were significantly associated with mTc-MEP amplitude and/or AUC. Maintenance of BIS and MAP at the high normal values may attenuate anesthetic effects on mTc-MEPs.

The Intraoperative Microlesion Effect Positively Correlates With the Short-Term Clinical Effect of Deep Brain Stimulation in Parkinson's Disease.

OBJECTIVE: During the surgical procedure of deep brain stimulation (DBS), insertion of an electrode in the subthalamic nucleus (STN) frequently causes a temporary improvement of motor symptoms, known as the microlesion effect (MLE). The objective of this study was to determine the correlation between the intraoperative MLE and the clinical effect of DBS. MATERIALS AND METHODS: Thirty Parkinson's disease (PD) patients with Movement Disorder Society (MDS) Unified Parkinson's Disease Rating Scale (UPDRS) part III (MDS-UPDRS III) scores during bilateral STN-DBS implantation were included in this retrospective study. MDS-UPDRS III subscores (resting tremor, rigidity, and bradykinesia) of the contralateral upper extremity were used. During surgery, these subscores were assessed directly before and after insertion of the electrode. Also, these subscores were determined in the outpatient clinic after 11 weeks on average (on-stimulation). All assessments were performed in an off-medication state (at least 12 hours of medication washout). RESULTS: Postinsertion MDS-UPDRS motor scores decreased significantly compared to preinsertion scores (p < 0.001 for both hemispheres). The MLE showed a positive correlation with the clinical effect of DBS in both hemispheres (rho = 0.68 for the primarily treated hemisphere, p < 0.001, and rho = 0.59 for the secondarily treated hemisphere, p < 0.01). CONCLUSION: The MLE has a clinically relevant correlation with the effect of DBS in PD patients. These results suggest that the MLE can be relied upon as evidence of a clinically effective DBS electrode placement.

Elevated cerebrospinal fluid glucose levels and diabetes mellitus are associated with activation of the neurotoxic polyol pathway.

AIMS/HYPOTHESIS: During hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations. METHODS: This observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels. RESULTS: Groups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol (p<0.001 and 0.036, respectively). Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels. CONCLUSIONS/INTERPRETATION: Hyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities.

Hypotension during propofol sedation for colonoscopy: a retrospective exploratory analysis and meta-analysis.

BACKGROUND: Intraoperative and postoperative hypotension occur commonly and are associated with organ injury and poor outcomes. Changes in arterial blood pressure (BP) during procedural sedation are not well described. METHODS: Individual patient data from five trials of propofol sedation for colonoscopy and a clinical database were pooled and explored with logistic and linear regression. A literature search and focused meta-analysis compared the incidence of hypotension with propofol and alternative forms of procedural sedation. Hypotensive episodes were characterised by the original authors' definitions (typically systolic BP <90 mm Hg). RESULTS: In pooled individual patient data (n=939), 36% of procedures were associated with episodes of hypotension. Longer periods of propofol sedation and larger propofol doses were associated with longer-lasting and more-profound hypotension. Amongst 380 patients for whom individual BP measurements were available, 107 (28%) experienced systolic BP <90 mm Hg for >5 min, and in 89 (23%) the episodes exceeded 10 min. Meta-analysis of 18 RCTs identified an increased risk ratio for the development of hypotension in procedures where propofol was used compared with the use of etomidate (two studies; n=260; risk ratio [RR] 2.0 [95% confidence interval: 1.37-2.92]; P=0.0003), remimazolam (one study; n=384; RR 2.15 [1.61-2.87]; P=0.0001), midazolam (14 studies; n=2218; RR 1.46 [1.18-1.79]; P=0.0004), or all benzodiazepines (15 studies; n=2602; 1.67 [1.41-1.98]; P<0.00001). Hypotension was less likely with propofol than with dexmedetomidine (one study; n=60; RR 0.24 [0.09-0.62]; P=0.003). CONCLUSIONS: Hypotension is common during propofol sedation for colonoscopy and of a magnitude and duration associated with harm in surgical patients.

Utility of the SmartPilot® View advisory screen to improve anaesthetic drug titration and postoperative outcomes in clinical practice: a two-centre prospective observational trial.

BACKGROUND: The advisory system SmartPilot® View (Drägerwerk AG, Lübeck, Germany) provides real-time, demographically adjusted pharmacodynamic information throughout anaesthesia, including time course of effect-site concentrations of administered drugs and a measure of potency of the combined drug effect termed the "'Noxious Stimulation Response Index' (NSRI). This dual-centre, prospective, observational study assesses whether the availability of SmartPilot® View alters the behaviour of anaesthetic drug titration of anaesthetists and improves the Anaesthesia Quality Score (AQS; percentage of time spent with MAP 60-80 mm Hg and Bispectral Index [BIS] 40-60 [blinded]). METHODS: We recruited 493 patients scheduled for elective surgery in two university centres. A control group (CONTROL; n=170) was enrolled to observe drug titration in current practice. Thereafter, an intervention group was enrolled, for which SmartPilot® View was made available to optimise drug titration (SPV; n=188). The AQS, haemodynamic and hypnotic effects, recovery times, pain scores, and other parameters were compared between groups. RESULTS: There were 358 patients eligible for analysis. Anaesthesia quality score was similar between CONTROL and SPV (median AQS [Q1-Q3]) 25.3% [7.4-41.5%] and 22.2% [8.0-44.4%], respectively; P=0.898). Compared with CONTROL, SPV patients had less severe hypotension and hypertension, less BIS <40, faster tracheal extubation, and lower early postoperative pain scores. CONCLUSIONS: Adding SmartPilot® View information did not affect average drug titration behaviour. However, small improvements in control of MAP and BIS and early recovery suggest improved titration for some patients without increasing the risk of overdosing or underdosing. CLINICAL TRIAL REGISTRATION: NCT01467167.

The association between the inflammatory response following surgery and post-operative delirium in older oncological patients: a prospective cohort study.

INTRODUCTION: Post-operative delirium (POD) is associated with increased morbidity and mortality rates in older patients. Neuroinflammation, the activation of the intrinsic immune system of the brain, seems to be one of the mechanisms behind the development of POD. The aim of this study was to explore the association between the perioperative inflammatory response and the development of POD in a cohort of older oncological patients in need for surgery. METHODS: In this prospective cohort study, patients 65 years and older in need for oncologic surgery were included. Inflammatory markers C-reactive protein (CRP), interleukin-1 beta (IL-1ß), IL-6, IL10 and Neutrophil gelatinase-associated lipocalin (NGAL) were measured in plasma samples pre- and post-operatively. Delirium Observation Screening Scale (DOS) was used as screening instrument for POD in the first week after surgery. In case of positive screening, diagnosis of POD was assessed by a clinician. RESULTS: Between 2010 and 2016, plasma samples of 311 patients with median age of 72 years (range 65-89) were collected. A total of 38 (12%) patients developed POD in the first week after surgery. The perioperative increase in plasma levels of IL-10 and NGAL were associated with POD in multivariate logistic regression analysis (OR 1.33 [1.09-1.63] P = 0.005 and OR 1.30 [1.03-1.64], P = 0.026, respectively). The biomarkers CRP, IL-1ß and IL-6 were not significantly associated with POD. CONCLUSIONS: Increased surgery-evoked inflammatory responses of IL-10 and NGAL are associated with the development of POD in older oncological patients. The outcomes of this study contribute to understanding the aetiology of neuroinflammation and the development of POD.

Comparison of renal region, cerebral and peripheral oxygenation for predicting postoperative renal impairment after CABG.

Patients undergoing coronary artery bypass grafting (CABG) are at risk of developing postoperative renal impairment, amongst others caused by renal ischemia and hypoxia. Intra-operative monitoring of renal region tissue oxygenation (SrtO2) might be a useful tool to detect renal hypoxia and predict postoperative renal impairment. Therefore, the aim of this study was to assess the ability of intra-operative SrtO2 to predict postoperative renal impairment, defined as an increase of serum creatinine concentrations of  > 10% from individual baseline, and compare this with the predictive abilities of peripheral and cerebral tissue oxygenation (SptO2 and SctO2, respectively) and renal specific tissue deoxygenation. Forty-one patients undergoing elective CABG were included. Near-infrared spectroscopy (NIRS) was used to measure renal region, peripheral (thenar muscle) and cerebral tissue oxygenation during surgery. Renal region specific tissue deoxygenation was defined as a proportionally larger decrease in SrtO2 than SptO2. ROC analyses were used to compare predictive abilities. We did not observe an association between tissue oxygenation measured in the renal region and cerebral oxygenation and postoperative renal impairment in this small retrospective study. In contrast, SptO2 decrease > 10% from baseline was a reasonable predictor with an AUROC of 0.767 (95%CI 0.619 to 0.14; p = 0.010). Tissue oxygenation of the renal region, although non-invasively and continuously available, cannot be used in adults to predict postoperative renal impairment after CABG. Instead, peripheral tissue deoxygenation was able to predict postoperative renal impairment, suggesting that SptO2 provides a better indication of 'general' tissue oxygenation status.Registered at ClinicalTrials.gov: NCT01347827, first submitted April 27, 2011.

Intranasal midazolam for the sedation of geriatric patients with care-resistant behaviour during essential dental treatment: An observational study.

OBJECTIVES: To describe the efficacy and safety of intranasal midazolam for sedation during essential dental treatment of geriatric patients with major neurocognitive disorder (MND) and care-resistant behaviour (CRB). BACKGROUND: Dental treatment is often impossible in geriatric MND patients with CRB. Intranasal midazolam may provide a non-invasive sedation method, but there is currently no information on its use in geriatric patients. METHODS: In this observational study, we included geriatric patients with severe MND and CRB needing urgent dental treatment. Each patient received 5 mg midazolam intranasally. Agitation/sedation levels, heart rate, respiration rate and oxygen saturation were recorded at 5-minute intervals. RESULTS: Thirty two patients were included. Mean age was 84 (±7) years. Mean (SD) time to treatment start was 13 (±5) minutes, and mean time to maximum sedation 17 (±11) minutes. Sedation was sufficient to enable dental treatment to be completed in 31 (97%) patients. Anxiolysis/light sedation occurred in 16 (50%) patients, and moderate to deep sedation occurred in 16 (50%) patients. No patients suffered from apnoea, although 3 patients required a chin-lift manoeuvre. Hypoxaemia occurred in 1 of these patients and in 2 other patients without airway obstruction. All patients recovered uneventfully. In a regression model, age, weight and other sedative medication use were found not to be associated with maximum sedation depth. CONCLUSIONS: Of 5 mg intranasal midazolam facilitates treatment of geriatric patients with MND in the comfort of their own environment. More information is needed to guide titration to balance the desired sedation level and patient safety.

Brain death/death by neurologic criteria determination: an update.

PURPOSE OF REVIEW: Brain death, also known as death by neurologic criteria (DNC), is a well-established concept. In this article, we present a short history of the concept and give an overview of recent changes and a practical update on diagnosis and definitions of brain death/DNC. Unresolved issues will be discussed. RECENT FINDINGS: There is variability in brain death/DNC determination worldwide. In recent years, successful attempts have been made to harmonize these criteria and, consequently, to improve public trust in the process and diagnosis. An international multidisciplinary collaboration has been created and it has published minimum criteria, provided guidance for professionals and encouragement to revise or develop guidelines on brain death/DNC worldwide. SUMMARY: There are two sets of criteria for declaration of death. First, if there is neither cardiac output nor respiratory effort, then cardiopulmonary criteria are used. Second, if both the cerebrum and brainstem have completely and permanently lost all functions, and there is a persistent coma, absent brainstem reflexes and no spontaneous respiratory effort, death can be declared on the basis of brain death/DNC. Although attempts to formulate uniform criteria are ongoing, consensus has been reached on the minimum criteria. Some inconsistencies and questions remain.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Modeling the Effect of Excitation on Depth of Anesthesia Monitoring in γ-Aminobutyric Acid Type A Receptor Agonist ABP-700.

BACKGROUND: γ-Aminobutyric acid type A (GABAA) receptor agonists are known to cause involuntary muscle movements. The mechanism of these movements is not known, and its relationship to depth of anesthesia monitoring is unclear. We have explored the effect of involuntary muscle movement on the pharmacokinetic-pharmacodynamic model for the GABAA receptor agonist ABP-700 and its effects on the Bispectral Index (BIS) as well as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores. METHODS: Observations from 350 individuals (220 men, 130 women) were analyzed, comprising 6,312 ABP-700 concentrations, 5,658 ABP-700 metabolite (CPM-acid) concentrations, 25,745 filtered BIS values, and 6,249 MOAA/S scores, and a recirculatory model developed. Various subject covariates and pretreatment with an opioid or a benzodiazepine were explored as covariates. Relationships between BIS and MOAA/S models and involuntary muscle movements were examined. RESULTS: The final model shows that the pharmacokinetics of ABP-700 are characterized by small compartmental volumes and rapid clearance. The BIS model incorporates an effect-site for BIS suppression and a secondary excitatory/disinhibitory effect-site associated with a risk of involuntary muscle movements. The secondary effect-site has a threshold that decreases with age. The MOAA/S model did not show excitatory effects. CONCLUSIONS: The GABAA receptor agonist ABP-700 shows the expected suppressive effects for BIS and MOAA/S, but also disinhibitory effects for BIS associated with involuntary muscle movements and reduced by pretreatment. Our model provides information about involuntary muscle movements that may be useful to improve depth of anesthesia monitoring for GABAA receptor agonists.

PEACHY, another fruitful study.

The results of the PErioperAtive CHildhood ObesitY (PEACHY) study showed an alarmingly high incidence of obesity amongst children presenting for surgical procedures under general anaesthesia in the UK. The study was performed by the Paediatric Anaesthesia Trainee Research Network (PATRN), a network of trainee anaesthetists seeking to quantify important clinical problems. Networks and consortia that facilitate collaboration amongst clinicians and academics working in a wide range of types of hospitals are particularly important in the current era, as they have the potential to gather data rapidly on important clinical problems, and by their size improve the power to identify factors associated with rare complications. Collaboration amongst clinicians within networks instead of competition between clinicians can have wide-ranging benefits that extend beyond research, and can include improvements in training, rapid dissemination of protocols, and knowledge concerning new problems, ultimately improving general standards of care.

Prospective clinical validation of the Eleveld propofol pharmacokinetic-pharmacodynamic model in general anaesthesia.

BACKGROUND: Target-controlled infusion (TCI) systems incorporating pharmacokinetic (PK) or PK-pharmacodynamic (PK-PD) models can be used to facilitate drug administration. Existing models were developed using data from select populations, the use of which is, strictly speaking, limited to these populations. Recently a propofol PK-PD model was developed for a broad population range. The aim of the study was to prospectively validate this model in children, adults, older subjects, and obese adults undergoing general anaesthesia. METHODS: The 25 subjects included in each of four groups were stratified by age and weight. Subjects received propofol through TCI with the Eleveld model, titrated to a bispectral index (BIS) of 40-60. Arterial blood samples were collected at 5, 10, 20, 30, 40, and 60 min after the start of propofol infusion, and every 30 min thereafter, to a maximum of 10 samples. BIS was recorded continuously. Predictive performance was assessed using the Varvel criteria. RESULTS: For PK, the Eleveld model showed a bias < ±20% in children, adults, and obese adults, but a greater bias (-27%) in older subjects. Precision was <30% in all groups. For PD, the bias and wobble were <5 BIS units and the precision was close to 10 BIS units in all groups. Anaesthetists were able to achieve intraoperative BIS values of 40-60 using effect-site target concentrations about 85-140% of the age-adjusted Ce50. CONCLUSIONS: The Eleveld propofol PK-PD model showed predictive precision <30% for arterial plasma concentrations and BIS predictions with a low (population) bias when used in TCI in clinical anaesthesia practice.

Epidemiology, Prehospital Characteristics and Outcomes of Severe Traumatic Brain Injury in The Netherlands: The BRAIN-PROTECT Study.

OBJECTIVE: A thorough understanding of the epidemiology, patient characteristics, trauma mechanisms, and current outcomes among patients with severe traumatic brain injury (TBI) is important as it may inform potential strategies to improve prehospital emergency care. The aim of this study is to describe the prehospital epidemiology, characteristics and outcome of (suspected) severe TBI in the Netherlands. METHODS: The BRAIN-PROTECT study is a prospective observational study on prehospital management of patients with severe TBI in the Netherlands. The study population comprised all consecutive patients with clinical suspicion of TBI and a prehospital GCS score ≤ 8, who were managed by one of the 4 Helicopter Emergency Medical Services (HEMS). Patients were followed-up in 9 trauma centers until 1 year after injury. Planned sub-analyses were performed for patients with "confirmed" and "isolated" TBI. RESULTS: Data from 2,589 patients, of whom 2,117 (81.8%) were transferred to a participating trauma center, were analyzed. The incidence rate of prehospitally suspected and confirmed severe TBI were 3.2 (95% CI: 3.1;3.4) and 2.7 (95% CI: 2.5;2.8) per 100,000 inhabitants per year, respectively. Median patient age was 46 years, 58.4% were involved in traffic crashes, of which 37.4% were bicycle related. 47.6% presented with an initial GCS of 3. The median time from HEMS dispatch to hospital arrival was 54 minutes. The overall 30-day mortality was 39.0% (95% CI: 36.8;41.2). CONCLUSION: This article summarizes the prehospital epidemiology, characteristics and outcome of severe TBI in the Netherlands, and highlights areas in which primary prevention and prehospital care can be improved.