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

Najib T. Ayas, Cheryl R. Laratta, John M. Coleman, Anthony G. Doufas, Matthias Eikermann, Peter C. Gay, Daniel J. Gottlieb, Indira Gurubhagavatula, David R. Hillman, Roop Kaw, Atul Malhotra, Babak Mokhlesi, Timothy I. Morgenthaler, Sairam Parthasarathy, Satya Krishna Ramachandran, Kingman P. Strohl, Patrick J. Strollo, Michael J. Twery, Phyllis C. Zee, and Frances F. Chung; on behalf of the ATS Assembly on Sleep and Respiratory Neurobiology

THIS OFFICIAL WORKSHOP REPORT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED OCTOBER 2017. This official American Thoracic Society Workshop Report was endorsed by the Canadian Sleep Society November 2017 and by the Canadian Thoracic Society December 2017.

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

Ann Am Thorac Soc Vol 15, No 2, pp 117–126, Feb 2018 Copyright © 2018 by the American Thoracic Society DOI: 10.1513/AnnalsATS.201711-888WS Internet address: www.atsjournals.org

Contents Methods of Obstructive Sleep Apnea Committee Composition and Obesity Hypoventilation Overview Workshop Structure and Syndrome Key Knowledge Gap Literature Review Perioperative Use of Positive 1. How can we identify patients Document Development Airway Pressure with obstructive sleep apnea or Perioperative Outcomes of Obesity Hypoventilation obesity hypoventilation Patients with Sleep- Syndrome in the syndrome at highest risk of disordered Breathing Perioperative postoperative cardiopulmonary Screening for Obstructive Sleep Period complications? Apnea in Surgical Patients Opioids and the Surgical Patient 2. How do we prevent Obstructive Sleep Apnea with Obstructive Sleep Apnea postoperative cardiopulmonary Endotypes and Potential The Use of Administrative complications in patients with Relevance in the Databases and Patient obstructive sleep apnea or Perioperative Registries obesity hypoventilation Period Patient Safety and Healthcare syndrome? Role of Algorithms in the Management Considerations Introduction Perioperative Management Conclusions

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Overview postoperative cardiopulmonary iv. Are there nonopioid analgesic complications? strategies (e.g., nonsteroidal A. Can we risk stratify patients for antiinflammatories, peripheral/ Perioperative management of sleep- perioperative complications related to epidural use of local anesthetics) disordered breathing, such as obstructive or novel strategies (e.g., respiratory sleep apnea (OSA) and obesity OSA or OHS? stimulants) that can be employed hypoventilation syndrome (OHS), is an area B. Is there any safe threshold of in patients with OSA or OHS to of patient care that requires improvement opioid therapy in patients fi mitigate risk? due to the risk of morbidity and mortality identi ed as high risk of having v. Are there patient (or family) from sleep-disordered breathing in the OSA or OHS? educational tools and interventions perioperative period (1). Adverse C. What clinical or physiologic markers that can be employed to improve perioperative outcomes of patients with (serum bicarbonate, troponin levels, fl patient outcomes? OSA or OHS include anoxic brain injury preoperative in ammatory markers, B. Key questions related to monitoring in or death in rare circumstances (2), and may etc.) predict opioid sensitivity or the perioperative setting include: be preventable. During the development postoperative cardiopulmonary i. How do we risk stratify patients of the Society of Anesthesia and Sleep complications? with OSA to identify patients who Medicine (SASM) Guidelines on D. Do particular physiologic endotypes of may not require monitoring (low Preoperative Screening and Assessment of OSA predict opioid sensitivity or risk of postoperative Adult Patients with Obstructive Sleep postoperative cardiopulmonary complications)? Apnea, hereafter referred to as the SASM complications? ii. What duration and components of guidelines, it became clear that further E. Can assessments in postanesthesia care monitoring are critical to mitigate research was necessary to improve the unit (PACU) provide additional value risk? quality and strength of the clinical in reducing adverse outcomes upon iii. Once optimized detection and recommendations. Further research on discharge? alarm thresholds are determined, OSA and OHS in the perioperative F. Are polysomnography (PSG) or how do we train our workforce setting is urgently needed as we look to ambulatory studies useful in risk and use our electronic health improve health outcomes for these stratifying patients before surgery? That records to optimize outcomes and patients, and reduce health care costs that is, do these tests help to predict which resource utilization? arise from postoperative monitoring, patients may be at increased risk after cardiopulmonary complications, increased surgery and help to direct length of stay (LOS) in intensive care, and management? increased LOS in hospital. There is little 2. How do we prevent postoperative Introduction evidence to guide screening and treatment cardiopulmonary complications in patients of sleep-disordered breathing in the with obstructive sleep apnea or obesity TheprevalenceofOSAis10%–20% in adult perioperative setting to achieve these hypoventilation syndrome? surgical patients (3, 4) and up to 70% before objectives. Patients who are at greatest risk A. Key questions related to positive airway bariatric surgery (5). Postoperatively, there of respiratory or cardiac complications pressure therapy in the perioperative are physiologic changes in sleep architecture related to OSA or OHS are not well defined, setting include: and an increase in the apnea–hypopnea index and the effectiveness of monitoring and i. Does it confer benefits beyond (AHI) in both patients with and without OSA other interventions remains to be those of enhanced monitoring (6). The most severe arterial oxygen determined. Centers involved in sleep strategies? desaturations and highest AHI occur on research need to develop collaborative ii. When does continuous positive Night 3 postoperatively, and have been networks to allow multicenter studies to airway pressure (CPAP) attributed in part to a gradual increase in address the research questions identified administration reduce risks: is rapid eye movement sleep and a reduction in below. postoperative administration the use of supplemental oxygen after the sufficient, or is preoperative initial postoperative night (6). Numerous Key Knowledge Gaps initiation of CPAP needed, and, if variables influence sleep-disordered breathing so, for how long preoperatively? in the perioperative period, including the 1. How can we identify patients with iii. Which ventilatory strategies would be anesthetic, upper airway injury after obstructive sleep apnea or obesity most effective in treating intubation, fluid shifts, pain medications, and hypoventilation syndrome at highest risk of postoperative OSA? the administration of oxygen.

ORCID IDs: 0000-0003-0259-7464 (N.T.A.); 0000-0002-7656-0173 (C.R.L.); 0000-0003-1268-0106 (M.E.); 0000-0002-9391-2011 (P.C.G.); 0000-0001-7712-7729 (R.K.); 0000-0001-9664-4182 (A.M.); 0000-0001-8135-5433 (B.M.); 0000-0002-2614-3793 (T.I.M.); 0000-0002-1128-3005 (S.P.); 0000-0002-7176-6375 (S.K.R.); 0000-0001-7740-9013 (K.P.S.); 0000-0002-2065-9641 (P.J.S.); 0000-0001-6296-6685 (P.C.Z.); 0000-0001-9576-3606 (F.F.C.). Correspondence and requests for reprints should be addressed to Najib T. Ayas, M.D., M.P.H., Leon Judah Blackmore Centre for Sleep Disorders UBC Hospital, Purdy Pavillion Room G34A, 2211 Wesbrook Mall Vancouver, BC, V6T 2B5 Canada. E-mail: [email protected].

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Moderate-quality evidence patients. During the planning of this discussion within each topic were performed predominantly from large cohort studies workshop, which was originally organized independently by each presenter. After a suggests that patients with OSA have a two- to discuss primarily OSA, it was identified short presentation, the presenter and Chairs to three-times increased risk of that a particularly high-risk group in the facilitated a discussion with all workshop cardiopulmonary complications after perioperative period are patients with OHS, participants to achieve consensus regarding surgery (7, 8); the absolute risk varies which often coexists with OSA. As a result, key limitations in knowledge within each between studies, in part related to thiswasincludedasaspecific objective to topic. After the final presentation, the variability in the definitions of OSA and address within the workshop. Of note, the Chairs facilitated a discussion among all postoperative outcomes. Retrospective workshop did not include discussion of issues participants of key knowledge gaps, which studies that have required a preoperative pertaining to patients undergoing elective resulted in the final list of knowledge gaps diagnosis of OSA, or confirmed diagnosis surgeries to correct OSA (i.e., upper airway and recommended key questions outlined of OSA by PSG, provide estimates of surgery). in the major conclusions. postoperative complications of 14%–49% versus 2.6%–31% of control subjects (7, 9, Document Development 10). Prospective or retrospective cohort Methods The recommendations were collated by studies evaluating noncardiac surgery the chair after review of audiotapes and suggest that patients with OSA have an This single-day workshop was held on May PowerPoint presentations available odds ratio (OR) of 2.07 (95% confidence 13, 2016 at the American Thoracic Society from all presentations and discussions. interval [CI] = 1.23–3.50) for cardiac events Conference in San Francisco, California. This was reviewed with workshop (3.76% vs. 1.69%), an OR of 2.43 (95% CI The workshop was chaired by N. Ayas and participants by e-mail and by two 1.34–4.39) for respiratory failure (1.96% vs. F. Chung, hereafter referred to as the Chairs. teleconferences in the fall of 2016. 0.70%), and a nonsignificantly higher The structure of this workshop report was Questions at the end of each section odds of reintubation (0.92% vs. 0.63%) conceived as an initiative to complement the were those discussed within the in the postoperative period (7). More recently published SASM guidelines (1). workshop, included in the document to heterogeneous data suggest an OR of The Chairs brought together researchers provide the reader with a sense of the 2.27 (95% CI = 1.20–4.26) for desaturation, from anesthesia, sleep medicine, and directions of interest. Consensus and an OR of 2.81 (95% CI = 1.46–5.43) respirology to identify the limitations of the regarding key knowledge gaps outlined for intensive care unit (ICU) transfer current evidence, important areas for in the OVERVIEW was reached by all (5.09% vs. 1.57%) (7). A retrospective further research, and strategies to overcome members of the workshop before cohort study suggests that the perioperative barriers to research in patients with OSA. submission. morbidity experienced by patients with The workshop was funded by the American unrecognized OHS is even higher than that Thoracic Society without additional experienced by patients with OSA (11). industry or other funding. Conflict of Perioperative Outcomes of Across hospitals, there is substantial interest statements were reviewed by the Patients with Sleep- variability in the management of these Chairs to ensure that significant bias could disordered Breathing patients. Due to the evidence supporting be avoided. physiologic worsening of OSA in the In observational and interventional studies, perioperative period, and the increased Committee Composition the evaluation of the particular perioperative complication risk attributed A total of 12 clinician-scientists in perioperative outcomes to further our to OSA and OHS, the perioperative respiratory and nonrespiratory sleep understanding of impact of sleep- management of sleep-disordered breathing medicine or anesthesiology were selected by disordered breathing is still under debate. is now considered an important patient the Chairs for invitation due to their A recent systematic review outlined some safety initiative (12). A systematic analysis expertise in the field of OSA or OHS and ofthecommonlyusedoutcomesinthe was recently completed creating the basis perioperative management. One invited literature (8). Outcomes discussed are for the SASM guidelines (1). During the clinician-scientist was unable to participate outlined in Table 1. Outcomes that extend creation of these guidelines, numerous due to time constraints. In addition, a beyond cardiopulmonary outcomes, such limitations in our knowledge on how to hospital administrator and a representative as delirium, may be important, but were identify and manage OSA perioperatively from the National Institutes of Health with not addressed. were identified. An additional drive significant research expertise were invited so Respiratory outcomes are an important to better understand perioperative that resource management and funding category. OSA is a risk factor for postoperative management of sleep-disordered breathing were considered in all discussions. respiratory failure rate, which is a patient is that OSA-related perioperative safety indicator (7); the definition is based on complications are increasingly linked to Workshop Structure and the International Classification of Diseases malpractice lawsuits with severe financial Literature Review codes(14).Basedonthisdefinition, penalties (2, 13). Further research in this A total of 10 participants were invited to approximately 1.0%–1.5% of patients will area is urgently needed. review and present in their areas of expertise develop postoperative respiratory failure The purpose of this workshop was to on a list of topics selected by the Chairs with (15), with significant comorbidity in 50%, identify knowledge gaps in the perioperative input from the committee. Search strategies, and an estimated mortality of 23% (14). management of OSA and OHS in adult inclusion and exclusion criteria, and areas of The utility of desaturation as an intermediate

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Table 1. Potential outcomes for evaluation of the impact of obstructive sleep apnea on OSA per se. As such, integrating other perioperative outcomes in an observational study or clinical trial clinical aspects into screening tools should be considered, such as type of surgery, Outcome Category Relevant Outcomes mode of anesthesia; requirement of opioids, and other comorbidities. In Pulmonary complications Acute respiratory failure (11, 19, 21, 77, 78) addition, it is unclear what proportion of Reintubation (9–11, 19, 37, 77, 78) perioperative complications is attributable Pneumonia (3, 21, 37, 77, 79, 80) to OSA or OHS as opposed to associated Pulmonary embolism (3, 37, 77, 79, 80) comorbidities (e.g., obesity, coronary Prolonged mechanical ventilation (11) Desaturation (9, 10, 78, 79) artery disease). Determining the Cardiac complications Arrhythmias (including atrial fibrillation) (9, 10, 19, attributable risk may give an indication of 21, 37, 79) what is potentially reversible with Heart failure (9–11, 81) interventions. Screening questionnaires Cardiac arrest (9, 21, 37) Myocardial infarction (3, 9–11, 21, 37, 78–80) should be considered strategically for those Biomarkers Troponin (82) with a moderate/high or low pretest Clinical outcomes Mortality (3, 81) probability of disease, depending on Hospital length of stay (3, 19) whether the goal is to confirm (i.e., obtain a Medical emergency team responses very high posttest probability) or exclude ICU admission (3, 10, 78) ICU length of stay (3, 78) disease (i.e., obtain a very low posttest Health care costs (19) probability). Health care utilization (3, 21, 80) There was substantial discussion about fi Definition of abbreviation risk strati cation of patients in the PACU. : ICU = intensive care unit. Not all patients who have clinically important OSA after surgery are identified by outcome was debated, as this is a they are associated with robust clinical preoperative screening tools; in addition, “characteristic” of OSA. However, severe outcomes perioperatively. That is, they may some patients with no or mild OSA may desaturation may be a reasonable outcome serve as a risk indicator for the infrequent develop apnea postoperatively secondary to measure, especially if it is associated with clinical outcomes. physiologic challenges from opioids or additional resources utilization (e.g., medical intravenous fluids. Monitoring in the PACU emergency team activation). However, further has the potential to evaluate if a patient has work is needed to identify desaturation Screening for Obstructive failed an anesthetic/opioid “stress test,” and thresholds that are relevant. Sleep Apnea in thereby may identify patients at risk of Postoperative cardiac outcomes are also Surgical Patients further adverse events on the ward. Gali and important, given the association between OSA colleagues (26) found that recurrent PACU and cardiac disease (16). However, there Many tools have been used to detect risk of “events” (apnea, bradypnea, oxygen are many comorbidities that are potential OSA, including the STOP-Bang score, desaturation, pain sedation mismatch in two confounders, such as obesity, diabetes, perioperative sleep apnea prediction score, of three 30-min evaluation periods) in dyslipidemia, coronary artery disease, and Berlin questionnaire, and American Society patients at high risk of OSA were associated increasing age. Pulmonary edema is an of Anesthesiologists checklist (1). A STOP- with postoperative respiratory complications, important cause of postoperative respiratory Bang score of 3 or greater has high such as ICU admissions for a respiratory failure(17,18).Postoperativeatrialfibrillation sensitivity and modest specificity for indication, the need for respiratory therapy in cardiothoracic surgery is common, even OSA, and is associated with an increased beyond standard postoperative clinical up to 30 days postoperatively, and may be risk of perioperative complications (1). practice, the need for noninvasive ventilatory increased in patients with OSA (19, 20). One The use of a higher STOP-Bang threshold support, or the development of large national database study reported (e.g., >5) may be more appropriate in postoperative pneumonia. More research to increased rates of shock and cardiac arrest populations with a lower prevalence of determine how PACU monitoring could postoperatively in patients with OSA when OSA (25). help to risk stratify and identify patients who identifying patients with OSA with The utility of confirmatory testing in need more intensive monitoring would be International Classification of Diseases patients identified at high risk of OSA or useful. Potential interventions during the data (21). OHS during preoperative screening is initial postoperative period (e.g., during Approximately 9% of patients have unclear. PSG is often challenging to monitoring in the PACU) will have to asymptomatic elevations of troponin after schedule before surgery, and ambulatory consider the challenges inherent in noncardiac surgery. Even without meeting technologies may be more useful, and increasing the use of resources in a high- criteria for myocardial infarction (22), should be studied in this context. acuity setting. Similarly, interventions that patients with increased postoperative The objective of preoperative screening can only be implemented in high-acuity troponins are at higher risk of complications was addressed. Some argue that it is settings,suchasanICU,areunlikelytobe (23) and 30-day mortality (24). Troponin more important to identify patients available to sufficient patients to make a and other cardiac biomarkers may be useful at increased risk of postoperative dramatic reduction in adverse postoperative intermediate outcomes to study, especially if complications rather than the presence of outcomes.

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Obstructive Sleep Apnea was recognized. This approach would ambulatory testing has not been extensively Endotypes and Potential require in-depth physiological studies until studied as a preoperative strategy to mitigate Relevance in the endotyping can be accomplished with less perioperative risk. Perioperative Period time-intensive studies or through PSG. The Enhanced monitoring strategies are development of noninvasive and readily being considered. This has been captured in Understanding the different endotypes available physiological studies or clinical algorithms that prespecify increased underlying the phenotype of OSA may prediction models that can characterize monitoring time in the PACU for those result in more personalized screening, patients who have high-risk endotypes of identified as high risk. Wireless continuous monitoring, and therapy. An endotype, OSA is an important area of research, as this pulse oximetry/pulse rate monitoring fi in this context, is a subtype of OSA strategy could then be employed by system with direct noti cations through a defined by a unique or distinctive function numerous health care providers to improve pager system is another possible monitoring or pathophysiologic mechanism (27). There care if outcome data were supportive. strategy being tested. The threshold oxygen , are multiple mechanistic pathways that saturation was set low ( 82%) because of fi can lead to OSA (e.g., compromised signi cant false positives above this anatomy, dilator muscle dysfunction, low Role of Algorithms in the threshold. It is not clear how cost effective arousal threshold, elevated loop gain, Perioperative Management of this was, and various process barriers were inadequate lung volume tethering, and Obstructive Sleep Apnea or encountered that are elaborated upon in the vascular leak) that are potentially relevant Obesity Hypoventilation section PATIENT SAFETY AND HEALTHCARE in a perioperative setting (27). Syndrome MANAGEMENT CONSIDERATIONS. The role of Arousal threshold is an important capnography for postoperative monitoring consideration. Arousal threshold is defined There are limited published data on has been considered. Barriers encountered using esophageal/epiglottic pressure before algorithms of care to identify or manage with implementing algorithms with patients with OSA. The protocols are often capnography were frequent. Interpretation electroencephalogram arousal; however, instituted as quality-improvement initiatives, of the signals was challenging, given the lack arousal threshold can be estimated using a and thus may not be published. For example, of a secured airway and the discrepancy recently validated multivariate model that modifications in anesthetic practice with a between nasal/mouth capture end-tidal uses PSG data (28). Low arousal thresholds reduction in doses of opioids with carbon dioxide and arterial partial pressure can prevent the accumulation of respiratory multimodal analgesia and regional anesthesia of carbon dioxide, particularly when the stimuli, resulting in reduced activation of technique may reduce postoperative risk in patient is on oxygen therapy or has an genioglossus postoperatively. Though patients with OSA independently of targeted elevated respiratory rate. The increased skill highly speculative and theoretical, in these algorithms. Many challenges that are faced by and training requirement to appropriately patients, increasing the arousal threshold researchers evaluating algorithms were apply end-tidal carbon dioxide monitoring is with sedatives or allowing a low level of raised. In many centers, a minority of also a substantial challenge. carbon dioxide retention postoperatively patients attend a preoperative clinic, which Intervention strategies are a final may increase the genioglossus muscle limits opportunity for patient identification suggested component of the algorithms in activation and decrease apneas (29, 30). before surgery. There needs to be substantial use. Educational interventions may be a However, individuals with high arousal support from surgical services. Many useful component of management algorithms. threshold may be especially prone to questions potentially inform us about the Educational interventions may be targeted adverse sedative effects of anesthetic agents value of algorithms of care: How much OSA toward increasing positive airway pressure and opioids if profound hypoxemia and confers risk? What is the best screening test? use before surgery. As an example of a hypercapnia were to develop before arousal. What is the most cost-effective postoperative method that has been tried, patients with a Dilator muscle control may be possible monitoring strategy? What is the best pre-existing diagnosis of OSA were contacted to manipulate to improve OSA intervention or therapy, and how should it be preoperatively, and were advised to use CPAP perioperatively. The genioglossus muscle is implemented? Three protocols from the for 2 weeks before surgery and to bring CPAP stimulated with an increased partial University of Pittsburgh Medical Centre and to the hospital. For patients identified as pressure of carbon dioxide in combination Northwestern University were discussed in having a high risk of OSA, family and patient with a mechanoreceptor load (31). These this presentation, and key features of these education regarding OSA and risks with combinations of stimuli can activate the algorithms, and the barriers encountered, are surgery is another possibility that is being genioglossus during stable sleep, and may outlined subsequently here. explored. Incentive spirometry, use of local or represent a therapeutic target to stabilize Strategies to increase the detection rate regional anesthesia if possible, minimizing breathing in predisposed individuals. of patients at risk of OSA or OHS are opioid use, and prespecified PACU protocols Methods of percutaneous stimulation of the ongoing. One strategy under evaluation is to are possible interventions that require more hypoglossal nerve are now being studied in screen patients diagnosed without OSA with study. CPAP or automatic positive airway this context as well (32). a STOP-Bang score administered on the day pressure (APAP) initiation in the pre- or In the discussion, the potential utility in of surgery; if the patient scored 5 or greater, postoperative period is further discussed in the further defining endotypes of OSA and the anesthesiologist was made aware and an subsequent section. Use of perioperative determining whether these would OSA wrist band applied. Preoperative sleep oxygen improves oxygenation and AHI on predispose to postoperative opioid testing was a challenge, as many patients postoperative Nights 1–3 (33); however, a sensitivity and postoperative complications would not attend a PSG appointment, and subset of patients retain carbon dioxide with

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AMERICAN THORACIC SOCIETY DOCUMENTS this therapy for unclear reasons (33). The role pressure therapy in the postoperative hyperventilate during the sampling) (48). of supplemental oxygen postoperatively period, one study suggests that 18% of The use of serum bicarbonate in addition to requires further study. patients spent at least 30 minutes with the STOP-Bang questionnaire may identify oxygen saturations less than 90% the night potential patients with OHS (49). after surgery, despite use of their prescribed Compared with patients with OSA Perioperative Use of Positive positive airway pressure therapy (43). alone, in the perioperative setting, patients Airway Pressure Furtherworkneedstobedoneto with OHS have an increased risk of determine how and when to effectively respiratory failure (OR = 10.9; 95% CI = Optimization of OSA treatment implement positive airway pressure. A number 3.7–32.3), heart failure (OR = 5.4; 95% CI = preoperatively is thought to be high-quality of potential questions were discussed. What 1.9–15.7), prolonged intubation (OR = 3.1; care. Because CPAP may have significant are the barriers to CPAP adherence in the 95% CI = 0.6–15.3), tracheostomy (OR = long-term benefits in terms of perioperative setting? Can patient adherence 3.8; 95% CI = 1.7–8.6), and ICU transfer improvements in quality of life, preoperative and positive airway pressure effectiveness be (OR = 10.9; 95% CI = 3.7–32.3) (11). clinics provide an opportunity for increased with educational resources (e.g., Patients with OHS also have longer ICU identification of patients with undiagnosed digital tablets)? Should other respiratory LOS and hospital LOS (11). Thus, the OSA who may symptomatically benefit support interventions be examined either in perioperative management of OHS requires from treatment (34–36). Two recent isolation or bundled with positive airway expertise and attention (50). matched observational studies using large pressure? For example, could flags for OSA Research questions proposed included administrative databases suggest benefits of (similar to an allergy alert) be used to alert the following. How should we screen CPAP use perioperatively in patients with pharmacy/nurses/medical staff, initiate for unrecognized OHS? How should we diagnosed and undiagnosed OSA (21, 37); automatic orders (e.g., block certain drugs, approach patients with OHS who are however, limitations exist in these studies such as bolus opioids/certain hypnotics), nonadherent to positive airway pressure? (discussed in a subsequent section). In one improve gas exchange (stimulation, frequent How safe is postoperative supplemental study, patients diagnosed with OSA with a vitals and sedation scale assessments, raise oxygen in patients with OHS? What are the CPAP prescription had reduced risk of headofthebed,oxygen),andidentify best monitoring strategies for patients with cardiovascular adverse events compared hypercapnia early? Is there a role for targeted hypercapnia? How can we avoid management with patients with undiagnosed OSA positive airway pressure therapy to very pitfalls, such as over-diuresis or excessive (OR = 0.34; 95% CI = 0.15–0.77; P = 0.009) high–risk groups, such as patients with severe oxygen supplementation that may worsen (21). In another study, patients with OSA, patients with OHS, or patients with hypoventilation? What is the ideal positive documented OSA without therapy or uncontrolled systemic diseases, such as airway pressure strategy in patients with suspected OSA had more frequent pulmonary hypertension? What is the OHS? Could respiratory stimulants be useful? cardiopulmonary complications compared medicolegal liability and patient safety factors with patients with OSA with positive airway to consider when starting positive airway pressure therapy (risk-adjusted rates of pressure in the hospital? Opioids and the Surgical 6.7% vs. 4%; P = 0.001) (37). In addition, Patient with Obstructive there are data to support the use of CPAP Sleep Apnea to modulate the respiratory depressant Obesity Hypoventilation effects of opioids given for pain (38). Syndrome in the Although postoperative hypoxemia due to In randomized trials, the institution of Perioperative Period opioid analgesia is common and persistent positive airway pressure perioperatively has (51, 52), life-threatening, opioid-induced not been highly effective. Meta-analysis of To be diagnosed with OHS, the patient respiratory depression (OIRD) is an clinical trials, including data from 904 should have a body mass index of 30 kg/m2 uncommon event (53). Nevertheless, a patients, suggests that postoperative CPAP or greater an arterial partial pressure of closed-claims analysis by the American results in a reduction in AHI, a trend to a carbon dioxide of 45 mm Hg or greater Society of Anesthesiologists (54) has reduction in LOS, but no significant impact during wakefulness, and exclusion of other identified OSA and OSA-related on postoperative adverse events (39). The causes of hypercapnia (44). Approximately phenotypes as common conditions among lack of clear improvement in outcomes 90% of patients with OHS have patients who suffered brain damage or died might be due to low adherence to positive concomitant OSA (45). OHS is estimated to in a setting of postoperative OIRD, thus airway pressure therapy (2.4–4.6 h/night) occur in 1/160 adults (46). OHS should be potentially implicating OSA as a risk (40–42). In addition, full resolution of suspected in very obese patients (46), obese marker for unwanted respiratory effects in sleep-disordered breathing may not occur patients with an increased serum the context of opioid administration. with positive airway pressure (39). There bicarbonate (>27 mEq/L) (47), room air The interaction between several are three prospective trials evaluating the hypoxemia while resting, persistent anatomical (e.g., pharyngeal airway institution of empiric positive airway hypoxemia during PSG, or when a dimensions) (55) and functional (i.e., gain pressure postoperatively, in patients with restrictive ventilatory defect is present. An of respiratory control, arousal threshold, undiagnosed or untreated OSA; all three elevated serum bicarbonate or base excess responsiveness of the airway dilator muscles) studies used automatic positive airway may be a better marker of prolonged endotypes (27) at multiple levels of breathing pressure (36, 39). In those continuing hypoventilation as opposed to daytime regulation is of central importance in the previously prescribed positive airway arterial blood gases (patients may development of apnea–hypopnea in patients

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with OSA (see also OSA ENDOTYPES AND phrenic nerve stimulation [68, 69], and events in the intraoperative period are POTENTIAL RELEVANCE IN THE PERIOPERATIVE elevated body position [70]), especially given difficult to control for (e.g., blood loss, PERIOD)(16,56–59). As a result, increasing that CPAP use is challenging in the intraoperative fluid requirements), but can arousal threshold with hypnotics (30), and/or perioperative setting? Do other affect outcomes substantially. There may be suppressing chemoreflex sensitivity by oxygen comorbidities, such as congestive heart opportunities to leverage existing datasets; inhalation (60), improved apnea severity in failure (71, 72) or diabetes (73), affect opioid for example, linking sleep study data to certain groups of patients. Because opioids sensitivity and the development of sleep- perioperative datasets to examine the impact can exert similar actions via their sedative and disordered breathing postoperatively? Can of disease severity or other PSG data (e.g., chemoreception-suppressing effects, it is we more faithfully define OSA endotypes to sleep stages). Incorporating other data reasonable to hypothesize that the respiratory better understand the variability in the streams, such as nursing records and the behavior of patients with OSA under opioids, respiratory and analgesic response to opioids electronic medical record (EMR), has as well as their vulnerability to OIRD, may in this patient population? potential to increase postoperative depend on the effect of opioids on individual respiratory and cardiac event capture. OSA endotypes, and that knowing the latter may help in predicting the former. The Use of Administrative Insupportofthishypothesisisalsothe Databases and Patient Safety and Healthcare substantial variability in the observed Patient Registries Management Considerations respiratory effects of opioids in patients with OSA (61–64), where both harmful (62) and Patient registries and administrative All healthcare institutions seek to avoid beneficial (63) effects on apnea severity datasets have numerous advantages and patient harm; however, they are also interested during sleep have been demonstrated. disadvantages. Advantages include the large in resource utilization, as all centers are Characteristically, in a randomized, placebo- sample size, reduced costs, and data resource limited. When harm occurs, costs can controlled trial, Bernards and colleagues (64) reflecting patients in the real world as be substantial. Pulmonary complications are have shown a dramatic increase of central opposed to selected cohorts. The large of particular interest due to their inclusion in apnea (from 0.8 to 43 events/h) in only 4 out sample size is especially advantageous in the “pay for performance” programs, and of 10 patients with moderate OSA who study of infrequent postoperative outcomes, respiratory outcomes are a component of received an opioid infusion during PSG, the adjustment for multiple confounders, many publicly reported safety metrics. emphasizing the existing variability in the and to examine subgroups of patients. The fundamental process to reduce respiratory response to opioids in this The disadvantages include the OSA- or OHS-attributable complications population. Although differences in the study observational design, difficulty in controlling extends from patients to procedure to primary methods might have been responsible for for confounders or comorbidities, and prevention of OSA complications to detection of these heterogeneous findings, the endotypic analyses that are limited to database entries. deteriorationtorecoveryafterdeterioration. variability of OSA condition is also a possible This may compromise the ability to control Resources consumed per patient generally explanation (65). for relevant confounders (e.g., body mass increase along this process, with prevention Presently, our strategies to mitigate index, OSA severity, CPAP adherence) if being less costly per patient than rescue after a OIRD in patients with OSA, should not they were not included in the dataset. complication has occurred. However, current differ from general measures that apply to Identification of outcomes may be preoperative OSA screening tools have a high non-OSA populations, like the use of short- challenging, as it can be difficult to false-positive rate, leading to a waste of resources, acting anesthetic agents to reduce differentiate preexisting diagnoses from new as systems deploy funds and personnel to somnolence postoperatively and the diagnoses. For the assessment of treatment enhanced monitoring and treatment of patients adoption of nonopioid-based analgesia, effectiveness, confounding by indication and who are not truly at increased risk for OSA- or including nonsteroidal antiinflammatory adherence are significant potential issues. OHS-related complications. agents and/or regional anesthesia, to reduce OSA severity is rarely included in these From the standpoint of monitoring/ opioid requirement. Furthermore, although research studies, nor is it often known if these detection of events postoperatively, there are the application of positive airway pressure, patients are treated for OSA or OHS. There three different types of alarms: 1) event an airway-stabilizing treatment, has been are no validated algorithms with good alarms (e.g., arrhythmia); 2) parameter shown to reduce apnea severity (41) and performance characteristics to identify OSA violation (vital signs); and 3) technical mitigate the impairing effects of opioids on within administrative data; therefore, the alarm (poor signal, intravenous tubing). ventilation (38) in postoperative patients performance characteristics of the algorithms Alarms are meant to err on the safe side; with OSA, this treatment modality requires used are not known, although these studies however, poor specificity can lead to alarm further investigation as a preventive are still thought to have value (74, 75). fatigue, and some consider this the number measure against OIRD, especially when Databases enriched for factors leading one hazard of health technology. There are considering issues like opioid-induced to or reflecting perioperative OSA unintended consequences of monitoring central apnea (64), or the emergence of complications would be useful. More work is interventions: significant waste of resources central apnea in CPAP-naive patients (66). required to better understand which for false-positive alarms, alarm fatigue, In the discussion, the following questions exposures (e.g., OSA severity measures), clerical burden, nurse turnover, diversion of were also raised. Could pharmacotherapy or outcomes, and confounders are important resources, and patient delirium/sleep loss. other therapies to stimulate the respiratory to record. One major confounder that needs Alarm thresholds for oximetry are system be useful (e.g., ampakines [67], to be considered is surgical complexity; commonly set to 90%, but there are few

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AMERICAN THORACIC SOCIETY DOCUMENTS data supporting this (76). A threshold close of adverse outcomes, such as those with committee for Bayer; served as a consultant for to 80% for desaturation was suggested to OHS, high-risk surgery (e.g., spinal, Nightbalance; received honorarium from Philips Respironics; received honorarium and travel minimize false positives. upper abdominal), or particular OSA support from Vapotherm; holds a patent for a There is insufficient evidence to know endotypes. home-based heliox system with carbon dioxide if monitoring affects clinical outcomes. Key knowledge gaps are summarized in removal. S.K.R. received research support from Comparative effectiveness studies of the OVERVIEW section. Much work has Merck; served on an advisory committee for interventions with collection of health services been accomplished already in this exciting Medtronic. K.P.S. served as a speaker for and fi received research support from Inspire Medical outcomes (e.g., workload, total costs of acute eld. However, many knowledge gaps have Systems; served on an advisory committee for care episode, and LOS) would be useful. been identified and highlighted. It is Sommetrics. P.J.S. received research support clearly now time to systematically address from Inspire Medical Systems and PinMed; these gaps given the importance of this served as a consultant for Itamar Medical, ResMed and Separation Design Group; served Conclusions area. Collaboration and strategic use of on an advisory committee and received research resources will lend itself to research support from Jazz Pharmaceuticals; Numerous knowledge gaps have been more rapid improvement in patient served on the general medical committee for identified and highlighted. Given that care and improvement in patient the National Football League; reviewed complications are rare events, identification outcomes. n educational videos for EMMI. P.C.Z. served as a fi consultant for Sanofi; served on an advisory of a suf cient number of patients with OSA committee for Aptalis Pharma and Pernix to answer the important research questions Therapeutics; received research support from This official Workshop Report was prepared by Technogel and X (a division of Alphabet, Inc.); will require collaborative research networks. an ad hoc subcommittee of the ATS Assembly served as a consultant and on an advisory A specific high-risk cohort of interest may on Sleep and Respiratory Neurobiology. committee for Merck; served as a consultant be individuals with OHS. Agreement on a Members of the subcommittee are as follows: and received research support from Eisai and minimal set of data elements to be collected NAJIB T. AYAS, M.D., M.P.H. (Co-Chair) Jazz Pharmaceuticals; served as a consultant, in prospective cohort studies would facilitate FRANCES F. CHUNG, M.B.B.S. (Co-Chair) on an advisory committee and received multisite collaboration and meta-analysis of JOHN M. COLEMAN, M.D. research support from Philips Respironics and Vanda Pharmaceuticals; owns stocks, stock independent studies. ANTHONY G. DOUFAS, M.D., PH.D. options or other ownerships interests in Teva As life-threatening postoperative MATTHIAS EIKERMANN, M.D., PH.D. PETER C. GAY, M.D. Pharmaceuticals; has the following patents complications are rare events, analysis of pending U.S. Serial Nos. 62/038,700 & PCT/ – DANIEL J. GOTTLIEB, M.D., M.P.H. causal factors lends itself to case control INDIRA GURUBHAGAVATULA, M.D., M.P.H. US2015/045273 (phase-locked loop to enhance slow wave sleep) and U.S. Serial No: 62/515,361. studies. Detailed physiologic endotyping DAVID R. HILLMAN, M.B. ROOP KAW, M.D. J.M.C., A.G.D., P.C.G., D.J.G., I.G., R.K., C.R.L., that is not possible in large cohort studies A.M., T.I.M., M.J.T. reported no relationships with could identify pathophysiologic mechanisms CHERYL R. LARATTA, M.D. ATUL MALHOTRA, M.D. relevant commercial interests. that increase risk of perioperative BABAK MOKHLESI, M.D., M.Sc. Workshop speakers are as follows: complications of OSA. Although these studies TIMOTHY I. MORGENTHALER, M.D. F. F. Chung, M.B.B.S. would necessarily exclude those with the most SAIRAM PARTHASARATHY, M.D. J. M. Coleman, M.D. severe complication (death), deep physiologic SATYA KRISHNA RAMACHANDRAN, M.D. KINGMAN P. STROHL, M.D. A. G. Doufas, M.D. endotyping of survivors of postoperative PATRICK J. STROLLO, M.D. P. C. Gay, M.D. respiratory failure and an appropriately MICHAEL J. TWERY,PH.D. R. Kaw, M.D. selected control group may be an efficient PHYLLIS C. ZEE, M.D., PH.D. A. Malhotra, M.D. B. Mokhlesi, M.D., M.Sc. approach to identifying characteristics that T. I. Morgenthaler, M.D. increase risk of postoperative respiratory Author disclosures: N.T.A. served on an S. K. Ramachandran, M.D. complications, such as opioid sensitivity, advisory committee for Bresotec. F.F.C. P. J. Strollo, M.D. airway anatomy, arousal threshold, and other received research support from Acacia and Other participants are as follows: components of ventilatory control. Such case– Medtronic; received research support from the ResMed Foundation to develop the STOP- M. Eikermann, M.D. control studies might also be nested within Bang questionnaire which is proprietary to D. J. Gottlieb, M.D., M.P.H. larger cohort studies, facilitating choice of an University Health Network. M.E. served on an I. Gurubhagavatula, M.D., M.P.H. advisory committee and served as a speaker for appropriate control group. These studies may D. R. Hillman, M.B. Merck; owns stocks, stock options or improve risk stratification and lead to novel C. R. Laratta, M.D. other ownerships interests in Calabash S. Parthasarathy, M.D. targeted therapies. Biotechnology. D.R.H. received research K. P. Strohl, M.D. The evaluation of interventions that support from Nyxoah, Oventus and ResMed; M. J. Twery, Ph.D. served on an advisory committee for can optimize safety in this population is also P. C. Zee, M.D., Ph.D. important. Testing a bundled approach to Sommetrics. B.M. served on an advisory care (e.g., an algorithm of care including committee for Itamar Medical; received research support from Philips Respironics; monitoring, positive airway pressure, served as a speaker for Zephyr Medical Acknowledgment: The authors acknowledge education, and other respiratory supports) Technologies; served as an expert witness in the important work of the Society of Anesthesia rather than each component individually medical malpractice lawsuits for Roetzel and and Sleep Medicine (SASM) for their recent might be more useful in initial clinical trials, as Andress Law Firm. S.P. served as an author for clinical guideline, which helped prompt the UpToDate; received research support from discussion surrounding these knowledge gaps. this may be more likely to be effective in Niveus Medical Inc., Philips Respironics and Of note, several of the workshop committee improving outcomes. Initial intervention trials Younes Sleep Technologies; served as a members, including the Chairs, were part of the should likely focus on patients at highest risk speaker for Merck; served on an advisory SASM guideline development.

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