Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity.

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Deep neuromuscular block does not improve surgical conditions in patients receiving sevoflurane anaesthesia for laparoscopic renal surgery.

BACKGROUND: Deep neuromuscular block is associated with improved working conditions during laparoscopic surgery when propofol is used as a general anaesthetic. However, whether deep neuromuscular block yields similar beneficial effects when anaesthesia is maintained using volatile inhalation anaesthesia has not been systematically investigated. Volatile anaesthetics, as opposed to intravenous agents, potentiate muscle relaxation, which potentially reduces the need for deep neuromuscular block to obtain optimal surgical conditions. We examined whether deep neuromuscular block improves surgical conditions over moderate neuromuscular block during sevoflurane anaesthesia. METHODS: In this single-centre, prospective, randomised, double-blind study, 98 patients scheduled for elective renal surgery were randomised to receive deep (post-tetanic count 1-2 twitches) or a moderate neuromuscular block (train-of-four 1-2 twitches). Anaesthesia was maintained with sevoflurane and titrated to bispectral index values between 40 and 50. Pneumoperitoneum pressure was maintained at 12 mm Hg. The primary outcome was the difference in surgical conditions, scored at 15 min intervals by one of eight blinded surgeons using a 5-point Leiden-Surgical Rating Scale (L-SRS) that scores the quality of the surgical field from extremely poor1 to optimal5. RESULTS: Deep neuromuscular block did not improve surgical conditions compared with moderate neuromuscular block: mean (standard deviation) L-SRS 4.8 (0.3) vs 4.8 (0.4), respectively (P=0.94). Secondary outcomes, including unplanned postoperative readmissions and prolonged hospital admission, were not significantly different. CONCLUSIONS: During sevoflurane anaesthesia, deep neuromuscular block did not improve surgical conditions over moderate neuromuscular block in normal-pressure laparoscopic renal surgery. CLINICAL TRIAL REGISTRATION: NL7844 (www.trialregister.nl).

Reduced postoperative pain using Nociception Level-guided fentanyl dosing during sevoflurane anaesthesia: a randomised controlled trial.

BACKGROUND: The majority of postoperative patients report moderate to severe pain, possibly related to opioid underdosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain. METHODS: In this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU. RESULTS: Median postoperative pain scores were 3.2 (inter-quartile range 1.3-4.3) and 4.8 (3.0-5.3) in NOL-guided and standard care groups, respectively (P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg-1 (NOL-guided group) and 0.09 (0.09) mg kg-1 (control group; P=0.204). During surgery, fentanyl dosing was not different between groups (NOL-guided group: 6.4 [4.2] µg kg-1vs standard care: 6.0 [2.2] µg kg-1, P=0.749), although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group). CONCLUSIONS: Despite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia. CLINICAL TRIAL REGISTRATION: www.trialregister.nl under identifier NL7845.

Does nociception monitor-guided anesthesia affect opioid consumption? A systematic review of randomized controlled trials.

Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the effect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the effect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identified 12 randomized controlled trials that compared one of five different nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgical plethysmographic index was the only monitor for which an intra operative opioid sparing effect was found. For the other monitors, either no effect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent effect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no definitive conclusions regarding the effect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn.Clinical trial number PROSPERO ID 102913.

Cholinergic Chemotransmission and Anesthetic Drug Effects at the Carotid Bodies.

General anesthesia is obtained by administration of potent hypnotics, analgesics and muscle relaxants. Apart from their intended effects (loss of consciousness, pain relief and muscle relaxation), these agents profoundly affect the control of breathing, in part by an effect within the peripheral chemoreflex loop that originates at the carotid bodies. This review assesses the role of cholinergic chemotransmission in the peripheral chemoreflex loop and the mechanisms through which muscle relaxants and hypnotics interfere with peripheral chemosensitivity. Additionally, consequences for clinical practice are discussed.

Nociception-guided versus Standard Care during Remifentanil-Propofol Anesthesia: A Randomized Controlled Trial.

BACKGROUND: The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level-guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication. METHODS: In this single-blinded randomized study, 80 American Society of Anesthesiologists class I-III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level-guided analgesia. In the nociception level-guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events. RESULTS: Compared with standard care, remifentanil administration was reduced in nociception level-guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 µg · kg · min (mean difference, 0.039 µg · kg · min; 95% CI, 0.025-0.052 µg · kg · min; P < 0.001). Among nociception level-guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08-0.77; P = 0.006). In the nociception level-guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40-0.99; P = 0.044). CONCLUSIONS: Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption.

Reversal of Partial Neuromuscular Block and the Ventilatory Response to Hypoxia: A Randomized Controlled Trial in Healthy Volunteers.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: The ventilatory response to hypoxia is a critical reflex that is impaired by neuromuscular blocking drugs. However, the degree to which this reflex is restored after reversal of blockade is unknown. WHAT THIS ARTICLE TELLS US THAT IS NEW: Despite full reversal of neuromuscular blockade at the thumb using different drug classes, this hypoxic chemoreflex is not fully restored. BACKGROUND: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study evaluated the effect of three strategies for reversal of a partial neuromuscular block on ventilatory control in 34 healthy male volunteers on the chemoreflex. The hypothesis was that the hypoxic ventilatory response is fully restored following the return to a train-of-four ratio of 1. METHODS: In this single-center, experimental, randomized, controlled trial, ventilatory responses to 5-min hypoxia (oxygen saturation, 80 ± 2%) and ventilation at hyperoxic isohypercapnia (end-tidal carbon dioxide concentration, 55 mmHg) were obtained at baseline, during rocuronium-induced partial neuromuscular block (train-of-four ratio of 0.7 measured at the adductor pollicis muscle by electromyography), and following reversal until the train-of-four ratio reached unity with placebo (n = 12), 1 mg neostigmine/0.5 mg atropine (n = 11), or 2 mg/kg sugammadex (n = 11). RESULTS: This study confirmed that low-dose rocuronium reduced the ventilatory response to hypoxia from 0.55 ± 0.22 (baseline) to 0.31 ± 0.21 l · min · % (train-of-four ratio, 0.7; P < 0.001). Following full reversal as measured at the thumb, there was persistent residual blunting of the hypoxic ventilatory response (0.45 ± 0.16 l · min · %; train-of-four ratio, 1.0; P < 0.001). Treatment effect was not significant (analysis of covariance, P = 0.299) with chemoreflex impairment in 5 (45%) subjects following sugammadex reversal, in 7 subjects (64%) following neostigmine reversal, and in 10 subjects (83%) after spontaneous reversal to a train-of-four ratio of 1. CONCLUSIONS: Despite full reversal of partial neuromuscular block at the thumb, impairment of the peripheral chemoreflex may persist at train-of-four ratios greater than 0.9 following reversal with neostigmine and sugammadex or spontaneous recovery of the neuromuscular block.

The use of surgical rating scales for the evaluation of surgical working conditions during laparoscopic surgery: a scoping review.

INTRODUCTION: Surgical rating scales (SRSs) enable the surgeon to uniformly quantify surgical working conditions. They are increasingly used as a primary outcome in studies evaluating the effect of anaesthesia or surgery-related interventions on the quality of the surgical work field. SRSs are especially used in laparoscopic surgery due to a renewed interest in deep neuromuscular block. There are however no guidelines regarding the uniform use of SRS and the uniform reporting of results. METHODS: A systematic search was conducted in the databases of PubMed, Web of Science and Embase for studies that reported the use of an SRS to evaluate surgical conditions in laparoscopic surgery. Only original human research in English language with full text availability through the Leiden university library was considered for this review. The full texts of eligible abstracts were independently reviewed by the first and second author. The quality of SRSs and methodology of rating were systematically reviewed. RESULTS: The search yielded 2830 reports, of which 17 were identified using a surgical rating scale (SRS) in laparoscopic surgery. Ten of these reports used a unique SRS, these were systematically appraised for their quality. The overall quality of the SRSs was low: the majority of the scales were poorly described and lacked assessment of inter- and intra-rater reliability. In addition, considerable differences exist in the methodology of rating and the reporting of results. CONCLUSION: There is substantial inconsistency in SRS quality, methodology, and results reporting. The uniform use of high-quality surgical rating scales is needed to improve the quality and reproducibility of future research.

Ability of the nociception level, a multiparameter composite of autonomic signals, to detect noxious stimuli during propofol-remifentanil anesthesia.

BACKGROUND: A novel multidimensional index of nociception, the nociception level (NoL) index, derived from the nonlinear composite of heart rate (HR), HR variability, amplitude of the photoplethysmogram, skin conductance, fluctuations in skin conductance, and their time derivatives, was used to assess nociception during anesthesia. METHODS: Seventy-two American Society of Anesthesiologists I to III patients received propofol (target bispectral index, 45) and one of six remifentanil target concentrations in the range of 0 to 5 ng/ml. The NoL, mean arterial pressure (MAP; derived from a beat-to-beat finger cuff measurement), and HR were measured during nonnoxious, moderate noxious (skin incision), and intense noxious (intubation) stimulation. Values are represented as average (95% CI). RESULTS: NoL, HR, and MAP did not change during nonnoxious events. Incision increased HR by 1.3/min (-0.46 to 3.1/min; not significant), MAP by 7.9 mmHg (-1.9 to 13.0 mmHg; not significant), and NoL by 8.0 (0.4 to 16.0; P < 0.001). Intubation increased HR by 7.0/min (1.4 to 12.0/min; P < 0.001), MAP by 13.0 mmHg (3.1 to 20 mmHg; P < 0.001), and NoL by 18.0 (7.8 to 29.0; P < 0.001). The ΔNoL area under the curve (0.95) of the receiver operating characteristic curve was greater compared with ΔHR (0.84, P < 0.001) and ΔMAP (0.78, P < 0.001). Under nonnociceptive conditions, remifentanil had no effect on NoL, in contrast to HR and MAP that showed a dose-dependent decrease. CONCLUSIONS: The NoL is a reliable measure of moderate and intense noxious stimulation and outperforms HR and MAP in differentiating noxious from nonnoxious stimuli. In contrast to HR and MAP, the NoL was not affected by hemodynamic effects of remifentanil.

The Use of Muscle Relaxants and Reversal Agents in a Setting Without Cost Restrictions: Experience from a Tertiary Academic Hospital in the Netherlands.

Introduction: Muscle relaxants are often given during general anesthesia to facilitate endotracheal intubation. However lingering effects after anesthesia-end may lead to respiratory compromise in the PACU. Strategies to reduce these adverse events include monitoring neuromuscular block, the use of short-acting agents and active pharmacological reversal before extubation. At Leiden University Medical Center (LUMC), a tertiary care academic hospital in the Netherlands, various muscle relaxants and reversal agents are freely available to all clinicians without restrictions. In this setting, we intended to evaluate how patient and surgical characteristics impacted the use of these agents for a variety of non-cardiac surgeries. Material and Methods: This is a retrospective database study of adult patients that had received elective, non-cardiac surgery and general anesthesia with endotracheal intubation between 2016 and 2020 at LUMC in the Netherlands. Exclusion criteria consisted of patients pharmacologically reversed with both sugammadex and neostigmine during the same procedure, diagnosed with myasthenia gravis, receiving pyridostigmine therapy, or with renal failure (eGFR <30 mL.min.1.73m2). Results: We retrieved 23,373 patient records of which 9742 were excluded because one or more exclusion criteria were met. The final cohort consisted of 13,631 cases. Rocuronium was the most commonly used muscle relaxant (88.5%); sugammadex was the most commonly used reversal agent (99.9% of those pharmacologically reversed). Of all cases that received rocuronium as muscle relaxant, 76.9% of patients were not reversed, while 23.1% were reversed with sugammadex. The odds of reversal increased with age, BMI, ASA class (1-3) and shorter duration of surgery. Conclusion: In an unrestricted clinical environment, rocuronium and sugammadex are the preferred agents for muscle relaxation and reversal. Pharmacologic reversal of neuromuscular block was uncommon overall, but more likely in older and obese patients, higher ASA classification and shorter lasting procedures. Sugammadex has largely replaced neostigmine for this purpose.

Intraoperative use of the machine learning-derived nociception level monitor results in less pain in the first 90†min after surgery.

In this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain scores in the post-anesthesia care unit of 1.5 (95% CI 0.8-2.2) points on an 11-point scale. The proportion of patients with severe pain was lower by 70%. Severe postoperative pain remains a significant problem and associates with several adverse outcomes. Here, we determined whether the application of a monitor that detects intraoperative nociceptive events, based on machine learning technology, and treatment of such events reduces pain scores in the post-anesthesia care unit (PACU). To that end, we performed a pooled analysis of two trials in adult patients, undergoing elective major abdominal surgery, on the effect of intraoperative nociception level monitor (NOL)-guided fentanyl dosing on PACU pain was performed. Patients received NOL-guided fentanyl dosing or standard care (fentanyl dosing based on hemodynamic parameters). Goal of the intervention was to keep NOL at values that indicated absence of nociception. The primary endpoint of the study was the median pain score obtained in the first 90 min in the PACU. Pain scores were collected at 15 min intervals on an 11-point Likert scale. Data from 125 patients (55 men, 70 women, age range 21-86 years) were analyzed. Sixty-one patients received NOL-guided fentanyl dosing and 64 standard care. Median PACU pain score was 1.5 points (0.8-2.2) lower in the NOL group compared to the standard care; the proportion of patients with severe pain was 70% lower in the NOL group (p = 0.045). The only significant factor associated with increased odds for severe pain was the standard of care compared to NOL treatment (OR 6.0, 95% CI 1.4 -25.9, p = 0.017). The use of a machine learning-based technology to guide opioid dosing during major abdominal surgery resulted in reduced PACU pain scores with less patients in severe pain.

Are thyrotropin-releasing hormone (TRH) and analog taltirelin viable reversal agents of opioid-induced respiratory depression?

Opioid-induced respiratory depression (OIRD) is a potentially life-threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin-releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH-analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator within the brainstem respiratory network. An additional respiratory excitatory effect may be related to TRH's analeptic effect. In awake and anesthetized rodents, TRH and taltirelin improved morphine- and sufentanil-induced respiratory depression, by causing rapid shallow breathing. This pattern of breathing increases the work of breathing, dead space ventilation, atelectasis, and hypoxia. In awake and anesthetized humans, a continuous infusion of intravenous TRH with doses up to 8 mg, did not reverse sufentanil- or remifentanil-induced respiratory depression. This is related to poor penetration of TRH into the brain compartment but also other causes are discussed. No human data on taltirelin are available. In conclusion, data from animals and human indicate that TRH is not a viable reversal agent of OIRD in awake or anesthetized humans. Further human studies on the efficacy and safety of TRH's more potent and longer lasting analog taltirelin are needed as this agent seems to be a more promising reversal drug.

The impact of deep versus standard neuromuscular block on intraoperative safety during laparoscopic surgery: an international multicenter randomized controlled double-blind strategy trial - EURO-RELAX TRIAL.

BACKGROUND: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established. METHODS: Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. INTERVENTION: Patients will be randomized to a deep NMB (post-tetanic count 1-2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra® classification (i.e., ClassIntra® grade ≥ 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients' quality of recovery. DISCUSSION: This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04124757 (EURO-RELAX); registration URL: https://clinicaltrials.gov/ct2/show/NCT04124757 , registered on October 11th, 2019.

Combining opioids and benzodiazepines: effects on mortality and severe adverse respiratory events.

Opioids and benzodiazepines are increasingly used alone or in combination. However, the combined use of these agents increases the risk for potentially lethal respiratory depression. This review summarizes current evidence on the effects of the combined use of opioids and benzodiazepines on mortality and severe respiratory adverse events. The results of 29 included manuscripts showed that concomitant use of opioids and benzodiazepines increased the risk for these outcomes in most of clinical and non-clinical settings. However, the risk for harm and benefit of the drug combination strongly correlates to its context and there are situations, such as in the hospice setting, where benefits may outweigh the risks.

Pharmacokinetic and pharmacodynamic considerations for NMDA-receptor antagonist ketamine in the treatment of chronic neuropathic pain: an update of the most recent literature.

Introduction: Chronic neuropathic pain (NP) is an incapacitating illness caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP.Areas covered: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine.Expert opinion: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest the efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often ill-defined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.

Recent advances in neuromuscular block during anesthesia.

Muscle relaxation is a routine part of anesthesia and has important advantages. However, the lingering effects of muscle relaxants in the postoperative period have historically been associated with postoperative adverse events. Neuromuscular reversal, together with neuromuscular monitoring, is a recognized strategy to reduce the rate of postoperative residual relaxation but has only marginally improved outcome in the past few decades. Sugammadex, a novel reversal agent with unique encapsulating properties, has changed the landscape of neuromuscular reversal and opened up new opportunities to improve patient care. By quickly and completely reversing any depth of neuromuscular block, it may reduce the rate of residual relaxation and improve respiratory recovery. In addition, sugammadex has made the use of deep neuromuscular block possible during surgery. Deep neuromuscular block may improve surgical working conditions and allow for a reduction in insufflation pressures during selected laparoscopic procedures. However, whether and how this may impact outcomes is not well established.