Incidence of postoperative opioid-induced respiratory depression episodes in patients on room air or supplemental oxygen: a post-hoc analysis of the PRODIGY trial.

BACKGROUND: Supplemental oxygen (SO) potentiates opioid-induced respiratory depression (OIRD) in experiments on healthy volunteers. Our objective was to examine the relationship between SO and OIRD in patients on surgical units. METHODS: This post-hoc analysis utilized a portion of the observational PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) trial dataset (202 patients, two trial sites), which involved blinded continuous pulse oximetry and capnography monitoring of postsurgical patients on surgical units. OIRD incidence was determined for patients receiving room air (RA), intermittent SO, or continuous SO. Generalized estimating equation (GEE) models, with a Poisson distribution, a log-link function and time of exposure as offset, were used to compare the incidence of OIRD when patients were receiving SO vs RA. RESULTS: Within the analysis cohort, 74 patients were always on RA, 88 on intermittent and 40 on continuous SO. Compared with when on RA, when receiving SO patients had a higher risk for all OIRD episodes (incidence rate ratio [IRR] 2.7, 95% confidence interval [CI] 1.4-5.1), apnea episodes (IRR 2.8, 95% CI 1.5-5.2), and bradypnea episodes (IRR 3.0, 95% CI 1.2-7.9). Patients with high or intermediate PRODIGY scores had higher IRRs of OIRD episodes when receiving SO, compared with RA (IRR 4.5, 95% CI 2.2-9.6 and IRR 2.3, 95% CI 1.1-4.9, for high and intermediate scores, respectively). CONCLUSIONS: Despite oxygen desaturation events not differing between SO and RA, SO may clinically promote OIRD. Clinicians should be aware that postoperative patients receiving SO therapy remain at increased risk for apnea and bradypnea. TRIAL REGISTRATION: Clinicaltrials.gov: NCT02811302, registered June 23, 2016.

Pharmacologically Induced Ventilatory Depression in the Postoperative Patient: A Sleep-Wake State-Dependent Perspective.

Pharmacologically induced ventilatory depression (PIVD) is a common postoperative complication with a spectrum of severity ranging from mild hypoventilation to severe ventilatory depression, potentially leading to anoxic brain injury and death. Recent studies, using continuous monitoring technologies, have revealed alarming rates of previously undetected severe episodes of postoperative ventilatory depression, rendering the recognition of such episodes by the standard intermittent assessment practice, quite problematic. This imprecise description of the epidemiologic landscape of PIVD has thus stymied efforts to understand better its pathophysiology and quantify relevant risk factors for this postoperative complication. The residual effects of various perianesthetic agents on ventilatory control, as well as the multiple interactions of these drugs with patient-related factors and phenotypes, make postoperative recovery of ventilation after surgery and anesthesia a highly complex physiological event. The sleep-wake, state-dependent variation in the control of ventilation seems to play a central role in the mechanisms potentially enhancing the risk for PIVD. Herein, we discuss emerging evidence regarding the epidemiology, risk factors, and potential mechanisms of PIVD.

Non-steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea.

BACKGROUND: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls. METHODS: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit. RESULTS: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%. CONCLUSIONS: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 µg · kg of ideal body weight per minute.

Opioids for Acute Pain Management in Patients With Obstructive Sleep Apnea: A Systematic Review.

The intrinsic nature of opioids to suppress respiratory function is of particular concern among patients with obstructive sleep apnea (OSA). The association of OSA with increased perioperative risk has raised the question of whether patients with OSA are at higher risk for opioid-induced respiratory depression (OIRD) compared to the general population. The aims of this systematic review were to summarize current evidence with respect to perioperative OIRD, changes in sleep-disordered breathing, and alterations in pain and opioid sensitivity in patients with OSA. A systematic literature search of studies published between 1946 and October 2017 was performed utilizing the following databases: Medline, ePub Ahead of Print/Medline In-process, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed-NOT-Medline and ClinicalTrials.Gov. Of 4321 initial studies, 40 met the inclusion criteria. The Oxford level of evidence was assessed. Overall, high-quality evidence on the comparative impact of acute opioid analgesia in OSA versus non-OSA patients is lacking. The current body of evidence is burdened by significant limitations including risk of bias and large heterogeneity among studies with regard to OSA severity, perioperative settings, outcome definitions, and the presence or absence of various perioperative drivers. These factors complicate an accurate interpretation and robust analysis of the true complication risk. Nevertheless, there is some consistency among studies with regard to a detrimental effect of opioids in the presence of OSA. Notably, the initial 24 hours after opioid administration appear to be most critical with regard to life-threatening OIRD. Further, OSA-related increased pain perception and enhanced opioid sensitivity could predispose patients with OSA to a higher risk for OIRD without overdosing. While high-quality evidence is needed, retrospective analyses indicate that critical, life-threatening OIRD may be preventable with a more cautious approach to opioid use, including adequate monitoring.

Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea.

The purpose of the Society of Anesthesia and Sleep Medicine Guideline on Intraoperative Management of Adult Patients With Obstructive Sleep Apnea (OSA) is to present recommendations based on current scientific evidence. This guideline seeks to address questions regarding the intraoperative care of patients with OSA, including airway management, anesthetic drug and agent effects, and choice of anesthesia type. Given the paucity of high-quality studies with regard to study design and execution in this perioperative field, recommendations were to a large part developed by subject-matter experts through consensus processes, taking into account the current scientific knowledge base and quality of evidence. This guideline may not be suitable for all clinical settings and patients and is not intended to define standards of care or absolute requirements for patient care; thus, assessment of appropriateness should be made on an individualized basis. Adherence to this guideline cannot guarantee successful outcomes, but recommendations should rather aid health care professionals and institutions to formulate plans and develop protocols for the improvement of the perioperative care of patients with OSA, considering patient-related factors, interventions, and resource availability. Given the groundwork of a comprehensive systematic literature review, these recommendations reflect the current state of knowledge and its interpretation by a group of experts at the time of publication. While periodic reevaluations of literature are needed, novel scientific evidence between updates should be taken into account. Deviations in practice from the guideline may be justifiable and should not be interpreted as a basis for claims of negligence.

Preoperative Treatment of Obstructive Sleep Apnea With Positive Airway Pressure is Associated With Decreased Incidence of Atrial Fibrillation After Cardiac Surgery.

OBJECTIVE: Based on clinical studies in the nonsurgical population that positive airway pressure (PAP) therapy for patients with obstructive sleep apnea (OSA) provides benefits for those with atrial fibrillation, the authors tested the hypothesis that PAP in patients with OSA reduces the incidence of postoperative atrial fibrillation (POAF) after cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: The study comprised 192 patients in sinus rhythm preoperatively who were undergoing nontransplantation or ventricular assist device implantation cardiac surgery requiring cardiopulmonary bypass but not requiring systemic circulatory arrest, with documented PAP adherence from January 2008 to October 2015. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: POAF was defined as atrial fibrillation requiring therapeutic intervention. Of the 192 patients with OSA, 104 (54%) were documented to be PAP-adherent and 88 (46%) were reported to be PAP-nonadherent. Among PAP users, 49 (47%) developed POAF; among PAP nonusers, 59 (66%) developed POAF. The adjusted hazard ratio was 0.59 (95% confidence interval 0.40-0.86, p<0.01). No differences were observed in intensive care unit length of stay (4.0±3.4 days for PAP-adherent group v 5.0±6.2 days for PAP-nonadherent group; p = 0.22) or hospital length of stay (10.7±6.6 days for PAP-adherent group v 10.9±7.3 days for PAP nonadherent group; p = 0.56). A lower median postoperative creatinine rise was observed in PAP-adherent patients (18.2% [8.3%-37.5%) v 31.3% [13.3%-50%]; p< 0.01). CONCLUSION: Preoperative PAP use in patients with OSA was associated with a decreased rate of POAF after cardiac surgery.

Society of Anesthesia and Sleep Medicine Guidelines on Preoperative Screening and Assessment of Adult Patients With Obstructive Sleep Apnea.

The purpose of the Society of Anesthesia and Sleep Medicine guideline on preoperative screening and assessment of adult patients with obstructive sleep apnea (OSA) is to present recommendations based on the available clinical evidence on the topic where possible. As very few well-performed randomized studies in this field of perioperative care are available, most of the recommendations were developed by experts in the field through consensus processes involving utilization of evidence grading to indicate the level of evidence upon which recommendations were based. This guideline may not be appropriate for all clinical situations and all patients. The decision whether to follow these recommendations must be made by a responsible physician on an individual basis. Protocols should be developed by individual institutions taking into account the patients' conditions, extent of interventions and available resources. This practice guideline is not intended to define standards of care or represent absolute requirements for patient care. The adherence to these guidelines cannot in any way guarantee successful outcomes and is rather meant to help individuals and institutions formulate plans to better deal with the challenges posed by perioperative patients with OSA. These recommendations reflect the current state of knowledge and its interpretation by a group of experts in the field at the time of publication. While these guidelines will be periodically updated, new information that becomes available between updates should be taken into account. Deviations in practice from guidelines may be justifiable and such deviations should not be interpreted as a basis for claims of negligence.

Obstructive sleep apnea, pain, and opioids: is the riddle solved?

PURPOSE OF REVIEW: Perioperative opioid-based pain management of patients suffering from obstructive sleep apnea (OSA) may present challenges because of concerns over severe ventilatory compromise. The interaction between intermittent hypoxia, sleep fragmentation, pain, and opioid responses in OSA, is complex and warrants a special focus of perioperative outcomes research. RECENT FINDINGS: Life-threatening opioid-related respiratory events are rare. Epidemiologic evidence suggests that OSA together with other serious renal and heart disease, is among those conditions predisposing patients for opioid-induced ventilatory impairment (OIVI) in the postoperative period. Both intermittent hypoxia and sleep fragmentation, two distinct components of OSA, enhance pain. Intermittent hypoxia may also potentiate opioid analgesic effects. Activation of major inflammatory pathways may be responsible for the effects of sleep disruption and intermittent hypoxia on pain and opioid analgesia. Recent experimental evidence supports that these, seemingly contrasting, phenotypes of pain-increasing and opioid-enhancing effects of intermittent hypoxia, are not mutually exclusive. Although the effect of intermittent hypoxia on OIVI has not been elucidated, opioids worsen postoperative sleep-disordered breathing in OSA patients. A subset of these patients, characterized by decreased chemoreflex responsiveness and high arousal thresholds, might be at higher risk for OIVI. SUMMARY: OSA may complicate opioid-based perioperative management of pain by altering both pain processing and sensitivity to opioid effect.

Relationship between chronic intermittent hypoxia and intraoperative mean arterial pressure in obstructive sleep apnea patients having laparoscopic bariatric surgery.

BACKGROUND: Recurrent nocturnal hypoxemia in obstructive sleep apnea enhances sympathetic function, decreases baroreceptor sensitivity, and weakens peripheral vascular responses to adrenergic signals. The authors hypothesized that the percentage of total sleep time spent at oxyhemoglobin saturation (SaO2) less than 90% and minimum nocturnal SaO2 on preoperative polysomnography are associated with decreased intraoperative mean arterial pressure. METHODS: The authors examined the records of all patients who had laparoscopic bariatric surgery at Cleveland Clinic between 2005 and 2009 and an available polysomnography study. The authors assessed the relationships between the percentage of total sleep time spent at SaO2 less than 90% and minimum nocturnal SaO2, and the time-weighted average of mean arterial pressure. The authors used multivariable regression models to adjust for prespecified clinical confounders. RESULTS: Two hundred eighty-one patients were included in the analysis. The average change in the time-weighted average of mean arterial pressure was -0.02 (97.5% CI, -0.08, 0.04) mmHg for each 1% absolute increase in the percentage of sleep time spent at SaO2 less than 90% (P = 0.50). The average change was -0.13 (97.5% CI, -0.27, 0.01) mmHg, for each 1% absolute decrease in the minimum SaO2 (P = 0.04 > significance criterion of 0.025, Bonferroni correction). An unplanned analysis estimated 1% absolute decrease in minimum SaO2 was associated with -0.22 (98.75% CI, -0.39, -0.04) mmHg, change in mean arterial pressure (P = 0.002) in the time period between endotracheal intubation and trocar insertion. CONCLUSION: Recurrent nocturnal hypoxemia in obstructive sleep apnea is not a risk marker for intraoperative hypotension.

Nocturnal intermittent hypoxia is independently associated with pain in subjects suffering from sleep-disordered breathing.

BACKGROUND: On the basis of experimental and clinical evidence, the authors hypothesized that nocturnal hypoxemia would be associated with pain reports in subjects suffering from sleep-disordered breathing, independently of sleep fragmentation and inflammation. METHODS: After obtaining institutional approval and access to the Cleveland Family Study phenotype and genotype data, the authors used proportional odds regression to examine the association between arterial desaturation and four different types of pain, as well as their composite measure, sequentially adjusted for: (1) clinical characteristics and (2) sleep fragmentation and inflammation. The authors also examined the association of selected candidate single-nucleotide polymorphisms with pain reports. RESULTS: Decreased minimum nocturnal arterial saturation increased the odds for morning headache (adjusted odds ratio per SD=1.36; 95% CI [1.08-1.71]; P=0.009), headache disrupting sleep (1.29 [1.10-1.51]; P=0.002), and chest pain while in bed (1.37 [1.10-1.70]; P=0.004). A decrease in the minimum nocturnal saturation from 92 to 75% approximately doubled the odds for pain. One single-nucleotide polymorphism for the α 1 chain of collagen type XI (COL11A1-rs1676486) gene was significantly associated with headache disrupting sleep (odds ratio=1.72 [1.01-2.94]; P=0.038), pain disrupting sleep (odds ratio=1.85 [1.04-3.28]; P=0.018), and pain composite (odds ratio=1.89 [1.14-3.14]; P=0.001). CONCLUSION: Nocturnal arterial desaturation may be associated with an increased pain in subjects with sleep-disordered breathing, independently of sleep fragmentation and inflammation.

Bispectral index dynamics during propofol hypnosis is similar in red-haired and dark-haired subjects.

BACKGROUND: We have previously shown that red hair is associated with increased desflurane requirement for immobility, compared with dark hair. The effect of red hair on IV anesthetic requirement remains unknown. We tested the hypothesis that the propofol concentration in the effect site associated with half maximal electroencephalogram response, Ce50, is at least 50% higher in subjects with red hair. METHODS: We modeled the propofol concentration versus electroencephalogram response relationship using a 2-step approach in 29 healthy dark- and red-haired volunteers receiving a propofol infusion to produce loss of consciousness. Bispectral Index (BIS) was the measure of drug effect. The parameters of a 3-compartment pharmacokinetic model were fit to measured arterial propofol concentrations. The relationship between effect-site propofol concentration (Ce) and BIS was characterized using a sigmoid Emax model. Model performance and accuracy of the estimated parameters were evaluated using accepted metrics and bootstrap resampling. The effect of hair color on the Ce50 for BIS response in the final model was assessed using a threshold of 6.63 (P<0.01) in reduction of -2 log likelihood. The influence of body weight on the model was also assessed. RESULTS: The inclusion of hair color as a model covariate did not improve either the pharmacokinetic or the pharmacodynamic model. A separate analysis for the dark- and red-haired subjects estimated a median (95% confidence interval) Ce50 BIS of 2.71 µg/mL (2.28-3.36 µg/mL) and 2.57 µg/mL (1.68-3.60 µg/mL), respectively. Body weight was a significant covariate for the CL1 and V1. CONCLUSIONS: Red hair phenotype does not affect the pharmacokinetics or pharmacodynamics of propofol.

The effect of hyperoxia on ventilation during recovery from general anesthesia: A randomized pilot study for a parallel randomized controlled trial.

STUDY OBJECTIVE: While supplemental O2 inhalation corrects hypoxemia, its effect on post-anesthesia ventilation remains unknown. This pilot trial tested the hypothesis that hyperoxia increases the time spent with a transcutaneous PCO2 (TcPCO2) > 45 mmHg, compared with standard O2 supplementation. DESIGN: Single-blinded, parallel two-arm randomized pilot trial. SETTING: University hospital. PATIENTS: 20 patients undergoing robotic-assisted laparoscopic nephrectomy. MEASUREMENTS: After institutional approval and informed consent, patients were randomized to receive O2 titrated to arterial saturation (SpO2): 90-94% (Conservative O2, N =10), or to SpO2 > 96% (Liberal O2, N = 10) for up to 90 min after anesthesia. Continuous TcPCO2, respiratory inductance plethysmography (RIP), and SpO2, were recorded. We calculated the percentage of time at TcPCO2 > 45 mmHg for each patient and compared the two groups using analysis of covariance, adjusting for sex, age, and body mass index. We also estimated the sample size required to detect the between-group difference observed in this pilot trial. RIP signals were used to calculate apnea/hypopnea index (AHI), which was then compared between two groups. MAIN RESULTS: The mean percentage of time with a TcPCO2 > 45 mmHg was 80.6% for the Conservative O2 (N=9) and 61.2% for the Liberal O2 (N=10) group [between-group difference of 19.4% (95% CI: -18.7% to 57.6%), P = 0.140]. With an observed effect size of 0.73, we estimated that 30 participants per group are required, to demonstrate this difference with a power of 80% at a two-sided alpha of 5%. Means SpO2 were 94.5% and 99.9% for the Conservative O2 and the Liberal O2 groups, respectively. AHI was significantly higher in the Conservative O2, compared with the Liberal O2 group (median AHI: 16 vs. 3; P = 0.0014). CONCLUSIONS: Hyperoxia in the post-anesthesia period reduced the time spent at TcPCO2 > 45 mmHg and significantly decreased AHI, while mean SpO2 ranged inside the a priori defined limits. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04723433.

Reinforcement learning versus proportional-integral-derivative control of hypnosis in a simulated intraoperative patient.

BACKGROUND: Research has demonstrated the efficacy of closed-loop control of anesthesia using bispectral index (BIS) as the controlled variable. Model-based and proportional-integral-derivative (PID) controllers outperform manual control. We investigated the application of reinforcement learning (RL), an intelligent systems control method, to closed-loop BIS-guided, propofol-induced hypnosis in simulated intraoperative patients. We also compared the performance of the RL agent against that of a conventional PID controller. METHODS: The RL and PID controllers were evaluated during propofol induction and maintenance of hypnosis. The patient-hypnotic episodes were designed to challenge both controllers with varying degrees of interindividual variation and noxious surgical stimulation. Each controller was tested in 1000 simulated patients, and control performance was assessed by calculating the median performance error (MDPE), median absolute performance error (MDAPE), Wobble, and Divergence for each controller group. A separate analysis was performed for the induction and maintenance phases of hypnosis. RESULTS: During maintenance, RL control demonstrated an MDPE of -1% and an MDAPE of 3.75%, with 80% of the time at BIS(target) ± 5. The PID controller yielded a MDPE of -8.5% and an MDAPE of 8.6%, with 57% of the time at BIS(target) ± 5. In comparison, the MDAPE in the worst-controlled patient of the RL group was observed to be almost half that of the worst-controlled patient in the PID group. CONCLUSIONS: When compared with the PID controller, RL control resulted in slower induction but less overshoot and faster attainment of steady state. No difference in interindividual patient variation and noxious destabilizing challenge on control performance was observed between the 2 patient groups.

Reinforcement learning: a novel method for optimal control of propofol-induced hypnosis.

Reinforcement learning (RL) is an intelligent systems technique with a history of success in difficult robotic control problems. Similar machine learning techniques, such as artificial neural networks and fuzzy logic, have been successfully applied to clinical control problems. Although RL presents a mathematically robust method of achieving optimal control in systems challenged with noise, nonlinearity, time delay, and uncertainty, no application of RL in clinical anesthesia has been reported.

The performance of compartmental and physiologically based recirculatory pharmacokinetic models for propofol: a comparison using bolus, continuous, and target-controlled infusion data.

BACKGROUND: With the growing use of pharmacokinetic (PK)-driven drug delivery and/or drug advisory displays, identifying the PK model that best characterizes propofol plasma concentration (Cp) across a variety of dosing conditions would be useful. We tested the accuracy of 3 compartmental models and 1 physiologically based recirculatory PK model for propofol to predict the time course of propofol Cp using concentration-time data originated from studies that used different infusion schemes. METHODS: Three compartmental PK models for propofol, called the "Marsh," the "Schnider," and the "Schüttler" models, and 1 physiologically based recirculatory model called the "Upton" model, were used to simulate the time course of propofol Cp. To test the accuracy of the models, we used published measured plasma concentration data that originated from studies of manual (bolus and short infusion) and computer-controlled (target-controlled infusion [TCI] and long infusion) propofol dosing schemes. Measured/predicted (M/P) propofol Cp plots were constructed for each dataset. Bias and inaccuracy of each model were assessed by median prediction error (MDPE) and median absolute prediction error (MDAPE), respectively. RESULTS: The M/P propofol Cp in the 4 PK models revealed bias in all 3 compartmental models during the bolus and short infusion regimens. In the long infusion, a worse M/P propofol Cp at higher concentration was seen for the Marsh and the Schüttler models than for the 2 other models. Less biased M/P propofol Cp was found for all models during TCI. In the bolus group, after 1 min, a clear overprediction was seen for all 3 compartmental models for the entire 5 min; however, this initial error resolved after 4 min in the Schnider model. The Upton model did not predict propofol Cp accurately (major overprediction) during the first minute. During the bolus and short infusion, the Marsh model demonstrated worse MDPE and MDAPE compared with the 3 other models. During short infusion, MDAPE for the Schnider and Schüttler models was better than the Upton and the Marsh models. All models showed similar MDPE and MDAPE during TCI simulations. During long infusion, the Marsh and the Schüttler models underestimated the higher plasma concentrations. CONCLUSION: When combining the performance during various infusion regimens, it seems that the Schnider model, although still not perfect, is the recommended model to be used for TCI and advisory displays.

Neuromuscular block differentially affects immobility and cortical activation at near-minimum alveolar concentration anesthesia.

BACKGROUND: Anesthesia-induced immobility and cortical suppression are governed by anatomically separate, but interacting, areas of the central nervous system. Consequently, larger volatile anesthetic concentrations are required to suppress cortical activation than to abolish movement in response to noxious stimulation. We examined the effect of decreased afferent input, as produced by neuromuscular block (NMB), on immobility and cortical activation, as measured by bispectral index (BIS) of the electrocardiogram, in the presence of noxious stimulation during approximately minimum alveolar concentrations (MACs) of desflurane anesthesia. METHODS: The effect of NMB on the median effective end-tidal concentration of desflurane (EtDes(50), or MAC(tetanus)) for immobility was estimated using the up-and-down method and isolated forearm technique in 24 healthy volunteers. Each volunteer sequentially received saline, mivacurium, and succinylcholine in a randomized order, while EtDes concentration during each of the treatments was determined based on the movement response of the previous volunteer on the same treatment. Nonlinear mixed-effects modeling was used to evaluate the effect of NMB on BIS versus EtDes concentration relationship at baseline and after noxious stimulation, while the frontal electromyogram (EMG(BIS)) effect on BIS was also modeled as a covariate. Cardiovascular responses to noxious stimulation were compared across treatments. RESULTS: Succinylcholine and mivacurium significantly reduced MAC(tetanus) (95% confidence interval) from 5.00% (4.85%-5.13%), during saline, to 4.05% (3.81%-4.29%) and 3.84% (3.60%-4.08%), respectively. Noxious stimulation significantly, although minimally, increased BIS response during all treatments. Succinylcholine increased BIS independently of an effect on EMG(BIS). Succinylcholine administration increased cardiovascular activity. Interestingly, although cardiovascular reaction to the noxious event was ablated by mivacurium, cortical response, as determined by BIS, was retained. CONCLUSIONS: Both succinylcholine and mivacurium enhanced immobility during near-MAC anesthesia. All treatments were associated with a small, although significant, BIS increase in response to noxious stimulation, whereas succinylcholine increased BIS independently of noxious stimulation or EMG(BIS). Mivacurium suppressed autonomic response to a noxious event.

Automated responsiveness monitor to titrate propofol sedation.

BACKGROUND: In previous studies, we showed that failure to respond to automated responsiveness monitor (ARM) precedes potentially serious sedation-related adversities associated with loss of responsiveness, and that the ARM was not susceptible to false-positive responses. It remains unknown, however, whether loss and return of response to the ARM occur at similar sedation levels. We hypothesized that loss and return of response to the ARM occur at similar sedation levels in individual subjects, independent of the propofol effect titration scheme. METHODS: Twenty-one healthy volunteers aged 20-45 yr underwent propofol sedation using an effect-site target-controlled infusion system and two different dosing protocol schemes. In all, we increased propofol effect-site concentration (Ce) until loss of response to the ARM occurred. Subsequently, the propofol Ce was decreased either by a fixed percentage (20%, 30%, 40%, 50%, 60%, and 70%; fixed percentage protocol, n = 10) or by a linear deramping (0.1, 0.2, and 0.3 microg x mL(-1) x min(-1); deramping protocol, n = 11) until the ARM response returned. Consequently, the propofol Ce was maintained at the new target for a 6-min interval (Ce plateau) during which arterial samples for propofol determination were obtained, and a clinical assessment of sedation (Observer's Assessment of Alertness/Sedation [OAA/S] score) performed. Each participant in the two protocols experienced each percentage or deramping rate of Ce decrease in random order. The assumption of steady state was tested by plotting the limits of agreement between the starting and ending plasma concentration (Cp) at each Ce plateau. The probability of response to the ARM as a function of propofol Ce, Bispectral Index (BIS) of the electroencephalogram, and OAA/S score was estimated, whereas the effect of the protocol type on these estimates was evaluated using the nested model approach (NONMEM). The combined effect of propofol Ce and BIS on the probability for ARM response was also evaluated using a fractional probability model (P(BIS/Ce)). RESULTS: The measured propofol Cp at the beginning and the end of the Ce plateau was almost identical. The Ce50 of propofol for responding to the ARM was 1.73 (95% confidence interval: 1.55-2.10) microg/mL, whereas the corresponding BIS50 was 75 (71.3-77). The OAA/S50 probability for ARM response was 12.5/20 (12-13.4). A fractional probability (P(BIS/Ce)) model for the combined effect of BIS and Ce fitted the data best, with an estimated contribution for BIS of 63%. Loss and return of ARM response occurred at similar sedation levels in individual subjects. CONCLUSIONS: Reproducible ARM dynamics in individual subjects compares favorably with clinical and electroencephalogram sedation end points and suggests that the ARM could be used as an independent instrumental guide of drug effect during propofol-only sedation.

Lower-body warming mimics the normal epidural-induced reduction in the shivering threshold.

BACKGROUND: Neuraxial anesthesia reduces the shivering threshold approximately 0.6 degrees C. This effect might be mediated by an apparent (as opposed to actual) increase in lower body temperature. Accordingly, sufficient lower body warming should result in thermoregulatory inhibition comparable to that exerted by epidural anesthesia. We tested the hypothesis that increasing leg skin temperature to 38 degrees C mimics the normal approximately 0.6 degrees C reduction in the shivering threshold during epidural anesthesia. METHODS: Shivering threshold during internal body cooling was determined in nine female volunteers on two separate days: one unanesthetized control day, and one day with a T10-11 epidural block. On each study day, lower body skin temperature was maintained near 38 degrees C and upper body skin temperature near 33 degrees C. We assessed equivalency of the shivering thresholds on the control and epidural days using the two one-sided tests method. RESULTS: The thresholds on the control (35.8 degrees C +/- 0.5 degrees C; mean +/- sd) and epidural (35.8 degrees C +/- 0.5 degrees C) days were shown to be equivalent because the 95% CI for the difference in means, 0.0 (-0.4, 0.4), was within our prespecified limits of -0.6 degrees C to +0.6 degrees C (P < 0.025 for both one-sided equivalency tests). CONCLUSIONS: Lower body warming mimics the normal epidural-induced reduction in the shivering threshold. Our results support a mechanism based on increased apparent lower body skin temperature during neuraxial anesthesia.

Knowledge Gaps in the Perioperative Management of Adults with Obstructive Sleep Apnea and Obesity Hypoventilation Syndrome. An Official American Thoracic Society Workshop Report.

The purpose of this workshop was to identify knowledge gaps in the perioperative management of obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS). A single-day meeting was held at the American Thoracic Society Conference in May, 2016, with representation from many specialties, including anesthesiology, perioperative medicine, sleep, and respiratory medicine. Further research is urgently needed as we look to improve health outcomes for these patients and reduce health care costs. There is currently insufficient evidence to guide screening and optimization of OSA and OHS in the perioperative setting to achieve these objectives. Patients who are at greatest risk of respiratory or cardiac complications related to OSA and OHS are not well defined, and the effectiveness of monitoring and other interventions remains to be determined. Centers involved in sleep research need to develop collaborative networks to allow multicenter studies to address the knowledge gaps identified below.