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.

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.

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.

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.

Intraoperative Tonic-Clonic Seizure Under General Anesthesia Captured by Electroencephalography: A Case Report.

We present the case of a 34-year-old man undergoing craniotomy for arteriovenous malformation resection under general anesthesia who suffered a tonic-clonic seizure captured by intraoperative electroencephalograph. The seizure was extinguished with a propofol bolus. This patient had no previous history of seizures, and no precipitating cause was identified. Intraoperative electroencephalographic seizures under general anesthesia have been recorded previously in the literature, but our observation is the first to demonstrate this with overt motor manifestations. We also discuss the differential diagnosis of an intraoperative seizure under general anesthesia and provide guidance to the anesthesiologist who encounters this event.

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.

Insomnia From Drug Treatments: Evidence From Meta-analyses of Randomized Trials and Concordance With Prescribing Information.

OBJECTIVE: To determine whether drugs used to treat diverse conditions cause insomnia symptoms and whether their prescription information is concordant with this evidence. METHODS: We conducted a survey of meta-analyses (Cochrane Database of Systematic Reviews) and comparisons with package inserts compiled in the Physicians' Desk Reference (PDR). We identified randomized controlled trials (RCTs) in which any drug had been evaluated vs placebo and sleep had been assessed. We collectively referred to insomnia-related outcomes as sleep disturbance. We also searched the PDR to identify any insomnia symptoms listed for drugs with RCT evidence available. RESULTS: Seventy-four Cochrane systematic reviews corresponding to 274 RCTs assessed 88 drugs in 27 different conditions, providing evidence on 109 drug-condition pairs. Of these 88 drugs, 5 decreased sleep problems and 19 increased sleep problems; 64 drugs had no nominally statistically significant effect on sleep. Acetylcholinesterase inhibitors, dopamine agonists, and selective serotonin reuptake inhibitors were the drug classes most importantly associated with sleep disturbance. Of 35 drugs that included disturbed sleep as an adverse effect in the PDR, only 14 had RCT evidence supporting such effect, and 2 had evidence of increasing and decreasing sleep problems in RCTs, although this was not shown in the PDR. We identified weak concordance between the PDR and RCTs (weighted κ=0.31; P<.001). CONCLUSION: The RCTs offer substantial evidence about the common effects of drugs on the risk of sleep disturbance; currently, prescription information only partially agrees with the available randomized evidence.

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.

Chronic intermittent hypoxia is independently associated with reduced postoperative opioid consumption in bariatric patients suffering from sleep-disordered breathing.

BACKGROUND: Evidence suggests that recurrent nocturnal hypoxemia may affect pain response and/or the sensitivity to opioid analgesia. We tested the hypothesis that nocturnal hypoxemia, quantified by sleep time spent at an arterial saturation (SaO2) < 90% and minimum nocturnal SaO2 on polysomnography, are associated with decreased pain and reduced opioid consumption during the initial 72 postoperative hours in patients having laparoscopic bariatric surgery. METHODS: With Institutional Review Board approval, we examined the records of all patients who underwent laparoscopic bariatric surgery between 2004 and 2010 and had an available nocturnal polysomnography study. We assessed the relationships between the time-weighted average of pain score and total opioid consumption during the initial 72 postoperative hours, and: (a) the percentage of total sleep time spent at SaO2 < 90%, (b) the minimum nocturnal SaO2, and (c) the number of apnea/hypopnea episodes per hour of sleep. We used multivariable regression models to adjust for both clinical and sleep-related confounders. RESULTS: Two hundred eighteen patients were included in the analysis. Percentage of total sleep time spent at SaO2 < 90% was inversely associated with total postoperative opioid consumption; a 5-%- absolute increase in the former would relatively decrease median opioid consumption by 16% (98.75% CI: 2% to 28%, P = 0.006). However, the percentage of total sleep time spent at SaO2 < 90% was not associated with pain. The minimum nocturnal SaO2 was associated neither with total postoperative opioid consumption nor with pain. In addition, neither pain nor total opioid consumption was significantly associated with the number of apnea/hypopnea episodes per hour of sleep. CONCLUSIONS: Preoperative nocturnal intermittent hypoxia may enhance sensitivity to opioids.

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.

Experimental pain and opioid analgesia in volunteers at high risk for obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA. METHODS: After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an µ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil. RESULTS: Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1ß and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1ß, P = 0.0218; TNF-α, P = 0.0276). CONCLUSIONS: Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency. TRIAL REGISTRATION: Clinicaltrials.gov NCT00672737.

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.

Concordance of sleep and pain outcomes of diverse interventions: an umbrella review.

BACKGROUND/OBJECTIVE: Pain influences sleep and vice versa. We performed an umbrella review of meta-analyses on treatments for diverse conditions in order to examine whether diverse medical treatments for different conditions have similar or divergent effects on pain and sleep. METHODS: We searched published systematic reviews with meta-analyses in the Cochrane Database of Systematic Reviews until October 20, 2011. We identified randomized trials (or meta-analyses thereof, when >1 trial was available) where both pain and sleep outcomes were examined. Pain outcomes were categorized as headache, musculoskeletal, abdominal, pelvic, generic or other pain. Sleep outcomes included insomnia, sleep disruption, and sleep disturbance. We estimated odds ratios for all outcomes and evaluated the concordance in the direction of effects between sleep and various types of pain and the correlation of treatment effects between sleep and pain outcomes. RESULTS: 151 comparisons with 385 different trials met our eligibility criteria. 96 comparisons had concordant direction of effects between each pain outcome and sleep, while in 55 the effect estimates were in opposite directions (P<0.0001). In the 20 comparisons with largest amount of evidence, the experimental drug always had worse sleep outcomes and tended to have worse pain outcomes in 17/20 cases. For headache and musculoskeletal pain, 69 comparisons showed concordant direction of effects with sleep outcomes and 36 showed discordant direction (P<0.0001). For the other 4 pain types there were overall 27 vs. 19 pairs with concordant vs. discordant direction of effects (P = 0.095). There was a weak correlation of the treatment effect sizes for sleep vs. headache/musculoskeletal pain (r = 0.17, P = 0.092). CONCLUSIONS: Medical interventions tend to have effects in the same direction for pain and sleep outcomes, but exceptions occur. Concordance is primarily seen for sleep and headache or musculoskeletal pain where many drugs may both disturb sleep and cause pain.