Why sedative hypnotics often fail in development.

PURPOSE OF REVIEW: Drug development to support anaesthesia and sedation has been slow with few candidates emerging from preclinical discovery and limited innovation beyond attempted reformulation of existing compounds. RECENT FINDINGS: The market is well supported by low-cost generic products and development compounds have not been shown to improve patient outcomes or possess other distinctive characteristics to justify the cost of development. SUMMARY: To make progress in a large-volume, low margin and highly competitive environment requires meaningful advances in relevant basic science. Opportunities exist, but probably require bolder initiatives than further attempts at reformulation or fiddling with the structure of propofol. Extending development ambitions to include nonanaesthesiologist providers challenges professional boundaries but may facilitate cost-effective changes in patterns of care.

A new pharmacological approach for tracheal intubation?

Anaesthesia induced with remimazolam and a fentanyl-series opioid can be reversed with flumazenil and naloxone. Concomitant paralysis with rocuronium can facilitate tracheal intubation whilst being reversible with sugammadex. Together, this combination might offer full reversibility of a 'routine' or a 'rapid-sequence' induction anaesthesia. Whether this is useful, or even safe, requires careful evaluation.

Is adamgammadex the brother of sugammadex or the next generation of reversal agent?

Sugammadex is now in widespread use to reverse the neuromuscular blocking effects of rocuronium. Adverse effects from sugammadex are rare, but anaphylactic and cardiovascular reactions to the drug have been reported. In an attempt to reduce such side-effects, a modified gamma-cyclodextrin, adamgammadex, has been developed. Phase 3 clinical trials suggest that it is slightly less potent than sugammadex and has a non-inferior speed of onset. In a multicentre trial of 310 patients, there was a suggestion of a lower incidence of allergic responses and recurarisation after adamgammadex compared with sugammadex. The clinical implications of this study are discussed in this editorial.

Clinical features and outcomes of hospitalised patients with COVID-19 and Parkinsonian disorders: A multicentre UK-based study.

BACKGROUND: Parkinson's disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson's disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear. OBJECTIVE: To investigate clinical profiles and outcomes of people with Parkinson's disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study. METHODS: A retrospective cohort study of Parkinson's disease patients with a positive SARS-CoV-2 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson's disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate. RESULTS: Data from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day all-cause mortality rate was 38.4%; male sex, increased age and frailty, Parkinson's dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge. CONCLUSIONS: This first, multicentre, UK-based study on people with Parkinson's disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.

Potential responses to remifentanil supply shortages.

Rapid elimination of remifentanil facilitates application of intense opioid effect during general anaesthesia whilst maintaining prompt emergence. Interruptions in remifentanil supply mean clinicians must relearn titration of pharmacokinetically longer-acting opioids to achieve appropriate levels of opioid effect whilst maintaining acceptable recovery times. Opioid-free anaesthesia is achievable for many minor and intermediate surgical procedures for which remifentanil might have been used previously.

Avoiding kidney damage in ICU sedation with sevoflurane: use isoflurane instead.

Intensive care unit (ICU) sedation with sevoflurane is associated with nephrogenic diabetes insipidus. Given that isoflurane is now licenced (in Europe) for ICU sedation and has Investigational New Drug status in the USA, evidence indicates that clinicians should stop using sevoflurane in this indication except in the context of clinical trials.

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.

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review.

Anaesthesiologists and non-anaesthesiologist sedationists have a limited set of available i.v. hypnotics, further reduced by the withdrawal of thiopental in the USA and its near disappearance in Europe. Meanwhile, demand for sedation increases and new clinical groups are using what traditionally are anaesthesiologists' drugs. Improved understanding of the determinants of perioperative morbidity and mortality has spotlighted hypotension as a potent cause of patient harm, and practice must be adjusted to respect this. High-dose propofol sedation may be harmful, and a critical reappraisal of drug choices and doses is needed. The development of remimazolam, initially for procedural sedation, allows reconsideration of benzodiazepines as the hypnotic component of a general anaesthetic even if their characterisation as i.v. anaesthetics is questionable. Early data suggest that a combination of remimazolam and remifentanil can induce and maintain anaesthesia. Further work is needed to define use cases for this technique and to determine the impact on patient outcomes.

Remimazolam for anaesthesia or sedation.

PURPOSE OF REVIEW: Anaesthesia and sedation are ubiquitous in contemporary medical practice. Developments in anaesthetic pharmacology are targeted on reducing physiological disturbance whilst maintaining or improving titrateability, recovery profile and patient experience. Remimazolam is a new short-acting benzodiazepine in the final stages of clinical development. RECENT FINDINGS: Clinical experience with remimazolam comprises volunteer studies and a limited number of clinical investigations. In addition, laboratory investigations explore the implications of its 'soft drug' pharmacology. SUMMARY: Remimazolam provides effective procedural sedation with superior success rates and recovery profile when compared to midazolam. Comparisons with propofol are required. Preliminary studies suggest potential for using remimazolam as the hypnotic component of general anaesthesia. Definitive studies are awaited. As a benzodiazepine, remimazolam could be evaluated as an anticonvulsant and for intensive care sedation.

Molecular Mechanisms Linking Autonomic Dysfunction and Impaired Cardiac Contractility in Critical Illness.

OBJECTIVES: Molecular mechanisms linking autonomic dysfunction with poorer clinical outcomes in critical illness remain unclear. We hypothesized that baroreflex dysfunction alone is sufficient to cause cardiac impairment through neurohormonal activation of (nicotinamide adenine dinucleotide phosphate oxidase dependent) oxidative stress resulting in increased expression of G-protein-coupled receptor kinase 2, a key negative regulator of cardiac function. DESIGN: Laboratory/clinical investigations. SETTING: University laboratory/medical centers. SUBJECTS: Adult rats; wild-type/nicotinamide adenine dinucleotide phosphate oxidase subunit-2-deficient mice; elective surgical patients. INTERVENTIONS: Cardiac performance was assessed by transthoracic echocardiography following experimental baroreflex dysfunction (sino-aortic denervation) in rats and mice. Immunoblots assessed G-protein-coupled receptor recycling proteins expression in rodent cardiomyocytes and patient mononuclear leukocytes. In surgical patients, heart rate recovery after cardiopulmonary exercise testing, time/frequency measures of parasympathetic variables were related to the presence/absence of baroreflex dysfunction (defined by spontaneous baroreflex sensitivity of <6 ms mm Hg). The associations of baroreflex dysfunction with intraoperative cardiac function and outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Experimental baroreflex dysfunction in rats and mice resulted in impaired cardiac contractility and upregulation of G-protein-coupled receptor kinase 2 expression. In mice, genetic deficiency of gp91 nicotinamide adenine dinucleotide phosphate oxidase subunit-2 prevented upregulation of G-protein-coupled receptor kinase 2 expression in conditions of baroreflex dysfunction and preserved cardiac function. Baroreflex dysfunction was present in 81 of 249 patients (32.5%) and was characterized by lower parasympathetic tone and increased G-protein-coupled receptor kinase 2 expression in mononuclear leukocytes. Baroreflex dysfunction in patients was also associated with impaired intraoperative cardiac contractility. Critical illness and mortality were more frequent in surgical patients with baroreflex dysfunction (relative risk, 1.66 [95% CI, 1.16-2.39]; p = 0.006). CONCLUSIONS: Reduced baroreflex sensitivity is associated with nicotinamide adenine dinucleotide phosphate oxidase subunit-2-mediated upregulation of G-protein-coupled receptor kinase 2 expression in cardiomyocytes and impaired cardiac contractility. Autonomic dysfunction predisposes patients to the development of critical illness and increases mortality.

Severe Nausea and Vomiting in the Evaluation of Nitrous Oxide in the Gas Mixture for Anesthesia II Trial.

BACKGROUND: The Evaluation of Nitrous oxide in the Gas Mixture for Anesthesia II trial randomly assigned 7,112 noncardiac surgery patients to a nitrous oxide or nitrous oxide-free anesthetic; severe postoperative nausea and vomiting (PONV) was a prespecified secondary end point. Thus, the authors evaluated the association between nitrous oxide, severe PONV, and effectiveness of PONV prophylaxis in this setting. METHODS: Univariate and multivariate analyses of patient, surgical, and other perioperative characteristics were used to identify the risk factors for severe PONV and to measure the impact of severe PONV on patient outcomes. RESULTS: Avoiding nitrous oxide reduced the risk of severe PONV (11 vs. 15%; risk ratio [RR], 0.74 [95% CI, 0.63 to 0.84]; P < 0.001), with a stronger effect in Asian patients (RR, 0.55 [95% CI, 0.43 to 0.69]; interaction P = 0.004) but lower effect in those who received PONV prophylaxis (RR, 0.89 [95% CI, 0.76 to 1.05]; P = 0.18). Gastrointestinal surgery was associated with an increased risk of severe PONV when compared with most other types of surgery (P < 0.001). Patients with severe PONV had lower quality of recovery scores (10.4 [95% CI, 10.2 to 10.7] vs. 13.1 [95% CI, 13.0 to 13.2], P < 0.0005); severe PONV was associated with postoperative fever (15 vs. 20%, P = 0.001). Patients with severe PONV had a longer hospital stay (adjusted hazard ratio, 1.14 [95% CI, 1.05 to 1.23], P = 0.002). CONCLUSIONS: The increased risk of PONV with nitrous oxide is near eliminated by antiemetic prophylaxis. Severe PONV, which is seen in more than 10% of patients, is associated with postoperative fever, poor quality of recovery, and prolonged hospitalization.

Sympathetic autonomic dysfunction and impaired cardiovascular performance in higher risk surgical patients: implications for perioperative sympatholysis.

OBJECTIVE: Recent perioperative trials have highlighted the urgent need for a better understanding of why sympatholytic drugs intended to reduce myocardial injury are paradoxically associated with harm (stroke, myocardial infarction). We hypothesised that following a standardised autonomic challenge, a subset of patients may demonstrate excessive sympathetic activation which is associated with exercise-induced ischaemia and impaired cardiac output. METHODS: Heart rate rise during unloaded pedalling (zero workload) prior to the onset of cardiopulmonary exercise testing (CPET) was measured in 2 observation cohorts of elective surgical patients. The primary outcome was exercise-evoked, ECG-defined ischaemia (>1 mm depression; lead II) associated with an exaggerated increase in heart rate (EHRR ≥12 bpm based on prognostic data for all-cause cardiac death in preceding epidemiological studies). Secondary outcomes included cardiopulmonary performance (oxygen pulse (surrogate for left ventricular stroke volume), peak oxygen consumption (VO2peak), anaerobic threshold (AT)) and perioperative heart rate. RESULTS: EHRR was present in 40.4-42.7% in both centres (n=232, n=586 patients). Patients with EHRR had higher heart rates perioperatively (p<0.05). Significant ST segment depression during CPET was more common in EHRR patients (relative risk 1.7 (95% CI 1.3 to 2.1); p<0.001). EHRR was associated with 11% (95%CI 7% to 15%) lower predicted oxygen pulse (p<0.0001), consistent with impaired left ventricular function. CONCLUSIONS: EHRR is common and associated with ECG-defined ischaemia and impaired cardiac performance. Perioperative sympatholysis may further detrimentally affect cardiac output in patients with this phenotype.