Anesthesia Patient Safety Foundation Section Editor: Sorin J. Brull
E Review Article CME
Chronic Opioid Use and Central Sleep Apnea: A Review of the Prevalence, Mechanisms, and Perioperative Considerations Denis Correa, MBBS, MD,* Robert J. Farney, MD,† Frances Chung, MBBS, FRCPC,* Arun Prasad, MBBS, FRCA, FRCPC,* David Lam, BMSc,* and Jean Wong, MD, FRCPC* BACKGROUND: Chronic opioid use has been associated with the development of sleep-disordered breathing (SDB) such as central sleep apnea (CSA). Patients receiving chronic opioids may suffer from unrecognized sleep apnea that contributes to opioid-overdose death. Currently, information regarding the perioperative management of patients with chronic opioid-associated CSA is limited. The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight their prevalence, mechanisms, risk factors, and perioperative management. METHODS: We searched Medline (1983–2014), Medline In-Process and other nonindexed citations (July 2014), EMBASE (1983–2014), the Cochrane Database of Systematic Reviews (January 2005–2014), the Cochrane Central Registry of Controlled Trials (July 2014), and PubMed basic search for new materials (1983–2014). Anesthesia and Sleep Medicine meeting abstracts were also searched for relevant articles. We included all prospective, retrospective studies and case reports in which CSA and chronic opioid use was confirmed by polysomnography. CSA was defined as the absence of airflow for ≥10 seconds with the absence of breathing efforts. A Central Apnea Index ≥5 events/h was considered significant. RESULTS: The search strategy yielded 8 studies which included 560 patients. The overall prevalence of CSA in patients taking chronic opioids was high (24%). The morphine equivalent daily dose (MEDD) was strongly associated with the severity of the SDB, predominantly CSA, with an MEDD of >200 mg being a threshold of particular concern. Concurrent use of benzodiazepines or hypnotics was associated with the severity of CSA in one study. Body mass index was inversely related to the severity of SDB. There were various recommendations regarding the best type of positive airway pressure therapy for the treatment of opioid-associated CSA. Continuous positive airway pressure may be ineffective in eliminating, or may even increase, CSA. Adaptive servoventilation and bilevel positive airway pressure ventilation were effective according to some reports. CONCLUSIONS: The overall prevalence of CSA in patients taking chronic opioids was 24%. The most important risk factors for severity of CSA were an MEDD >200 mg, and low or normal body mass index. Continuous positive airway pressure is often ineffective for treating CSA. Limited data are available on the perioperative management of patients with CSA associated with chronic opioid use. Further prospective studies on the perioperative risks and management of these patients are needed. (Anesth Analg 2015;120:1273–85)
O
pioids are the cornerstone for managing moderate to severe acute postoperative pain. The potential for acute respiratory suppression and death caused by
From the *Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; and †University of Utah Health Sciences Center, Intermountain Sleep Disorders Center, Intermountain Healthcare, LDS Hospital, Salt Lake City, Utah. Accepted for publication December 2, 2014.
Funding: Supported by Department of Anesthesia, Toronto Western Hospital, University Health Network, University of Toronto. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). Reprints will not be available from the authors. Address correspondence to Jean Wong, MD, FRCPC, Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, 2McL-405, 399 Bathurst St., Toronto, Ontario, Canada M5T 2S8. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000672
June 2015 • Volume 120 • Number 6
opioids is well known; however, the relationship between sleep and opioid toxicity has only recently been described.–8 Opioids are associated with various sleep-induced respiratory disturbances such as central sleep apnea (CSA),1,2,4–7 other types of abnormal breathing patterns,1–3,8 and hypoxemia.1–3,5,8 Most studies in the anesthesiology literature have assessed the impact of acute parenteral opioid administration on metrics such as respiratory rate and ventilatory response to hypoxia or hypercapnia in normal healthy subjects and in the awake state.9–11 However, many patients taking chronic opioids may suffer from significant unrecognized central and obstructive sleep-disordered breathing (SDB) that may result in increased morbidity and mortality.12–14 Of special concern is the possibility of fatal complications in patients undergoing outpatient surgery or who are discharged after a short hospital stay and are receiving acute or increased opioids without oxygen therapy or monitoring. Satisfactory arterial oxygen saturation while breathing room air, having www.anesthesia-analgesia.org 1273
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E REVIEW ARTICLE a normal respiratory rate, and the absence of subjective respiratory symptoms while awake provide no assurance that a lethal respiratory abnormality will not occur once the patient goes to sleep at home. Information regarding the perioperative management of patients with SDB associated with chronic opioids is limited. The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight the prevalence, mechanisms, risk factors, and perioperative management. Other sleep-induced respiratory disturbances, such as obstructive sleep apnea (OSA) syndrome and obesity hypoventilation syndrome, and the cardiotoxicity of opioids will not be reviewed in this paper.
also high (range 42%–85%) mean of 70%, and severity was in the moderate category (AHI ≥15 to 200 mg/d, and 61% patients with MEDD 10/h; however, 4 studies showed that there was no interaction,4,6–8 and there was no information in the other 3 reports.1,3,5 The effect of concurrent medications and chronic opioid-associated CSA was assessed in each of the studies,1–6,8 with the exception of the report by Jungquist et al.,7 and no relationship was observed. The synergy between opioids and sleep deprivation, as might occur in the perioperative environment, also seems plausible and relevant; however, none of the studies has addressed this point. It is almost impossible to exclude concurrent use of various medications as risk factors. Therefore, until more definitive studies can be performed, it would be prudent to avoid potentially exacerbating medications. The relationship with nonobese status is particularly interesting and has not been thoroughly investigated. The increase in central apneas in patients with lower BMI may be because the dosage was prescribed according to general guideline with a dose range and not as a milligram per kilogram basis. It is possible that patients with smaller BMIs may have a relative overdose versus patients with higher BMIs because of a difference in effect site concentration based on differences in pharmacokinetics.
Do Patients with Opioid-Associated CSA Have Higher Morbidity and Mortality?
The effect of opioid-associated CSA on morbidity and mortality has not been well characterized because long-term studies are not available. The current practice of chronic pain management is to use multiple analgesic medications at reduced doses to take advantage of their synergetic effect; however, there are no data to indicate whether this practice alters the risk of ataxic breathing, sleep apnea, or unanticipated death during sleep. Ideally, polysomnography should be performed if symptoms are observed. Whether the treatment of opioidassociated CSA prevents sleep-related mortality is unclear.
Therapy for Opioid-Associated CSA
Management of patients with opioid-related CSA is extremely challenging.25 Practice parameters with an evidence-based literature review of therapy for CSA was recently published46; however, there are no consensus guidelines that
anesthesia & analgesia
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Chronic Opioid Use and Central Sleep Apnea
define indications and therapy for opioid-related breathing disorders. The main options available include: withdrawal of opioids,47,48 reducing opioid dose, selecting an opioid that may have less toxicity (e.g., buprenorphine in lieu of methadone),49–51 greater use of non-opioid analgesics, supplemental oxygen, pharmacologic therapy (e.g., acetazolamide, theophylline, carbon dioxide), positional therapy,52 avoidance of potentially aggravating concurrent drugs, and PAP. It is extremely important to identify and treat those with OSA and those who are using chronic opioids because there may be substantial interactions (e.g., increased upper airway resistance, hypoxemia, and blunted ventilatory and arousal responses). For the perioperative period, the 2 major therapeutic modalities are oxygen and PAP.
Oxygen
The effectiveness of oxygen for OSA53 and in the treatment of certain types of CSA, primarily Cheyne-Stokes breathing associated with heart failure, has been reviewed.46 However, the role of oxygen therapy for hypoxemia or CSA specifically related to opioids has not been established. Of note, nonapneic hypoxemia can occur during wakefulness in patients without cardiopulmonary disease and who are receiving chronic opioids with and without sleep apnea.3,5,54 More than 10% of patients on chronic opioids demonstrated resting awake and asleep hypoxemia without apnea.5 In a case series report by Farney et al.,55 oxygen supplementation corrected hypoxemia; however, Biots/ataxic breathing persisted. Despite the beneficial effects on arterial oxygen saturation, patients using opioids chronically already have a reduced arousal/ventilatory response hypercarbia. Therefore, oxygen therapy could potentiate hypoventilation or prolong central apneas/hypopneas. Conversely, opioids can stabilize breathing if the arousal threshold is low and respiratory controller gain is high associated with pain, so that oxygen therapy is unlikely to cause respiratory suppression. Unfortunately, these phenotypes may be indistinguishable based on anatomy or the specific opioid being used. We are unaware of any study in which the effect of oxygen on central apneas or ataxic breathing has been systematically assessed. Accordingly, oxygen therapy to treat hypoxemia due to opioids (with or without central apneas) appears prudent; however, patients need to be monitored very closely in the perioperative period because of multiple, potentially interactive factors. Adjunctive oxygen, in particular, may be necessary, in addition to PAP therapy, for optimal resolution of CSA and hypoxemia due to opioids.56
PAP Therapy
There are 4 PAP modalities: (1) continuous positive airway pressure (CPAP); (2) bilevel positive airway pressure (BPAP); (3) automatic self-adjusting positive airway pressure (APAP); and (4) servo-controlled ventilation (ASV or BPAP adapt). (See Table 4 for detailed comparison.) Except for servo-controlled ventilation, practice parameters have been published for all of these modalities for therapy of OSA and CSA not associated with chronic opioid use.57–59 Continuous Positive Airway Pressure CPAP devices maintain a CPAP with adjustable flow generated by fan-driven or turbine systems to stent the upper
June 2015 • Volume 120 • Number 6
airway open and to increase functional residual capacity. A pressure adjusted to abolish flow limitation is prescribed. CPAP can be autotitrated or fixed. In either case, the pressure is adjusted to abolish flow limitation and is thus several cm H2O higher than closing pressure, which is the pressure at which the airway closes completely. Furthermore, the pressure is not determined by PSG. It can be determined during PSG, but can also be determined under other circumstances, such as autotitration at home. Patients with sleep apnea related to opioids often have obstructive events, providing a logical basis for use of CPAP. Five retrospective studies60–64 (Table 4) showed that CPAP therapy does not eliminate or may even increase central apneas.60–63 The use of opioids does not preclude a favorable response to CPAP, but adjunctive oxygen or alternative PAP modalities will be required in most cases. Bilevel Positive Airway Pressure These devices permit independent adjustment of inspiratory positive airway pressure and expiratory positive airway pressure to target the obstructive and central SDB events. There are different modes of BPAP: Spontaneous (S Mode), Timed (T Mode), and Spontaneous/Timed Mode (ST Mode). In BPAP-ST Mode, a “backup” rate is also set to ensure that patients still receive a minimal number of breaths per minute if they fail to breathe spontaneously. BPAP (S or ST Mode) alone, or with a backup rate and/or oxygen, was effective for treating CSA unresponsive to CPAP62,65,66 (Table 4). A recent systematic review also reported the effectiveness of BPAP in eliminating CSA in 62% and ASV in 58% of patients taking chronic opioids.67 Servo-Controlled Ventilation Adaptive servoventilation is a relatively new approach in treating CSA, mainly in patients with congestive heart failure or complex apnea related to overtitration with CPAP. Based on an internal algorithm and a moving window sampling of the patient’s minute ventilation, ASV uses a preset or autotitrating end-expiratory pressure to eliminate any obstructive apneas or hypopneas, and it generates variable inspiratory pressure support (usually in the range of 3–10 cm H2O) on a breath-by-breath basis above the expiratory pressure to regulate ventilation to prevent hypocapnicinduced central apneas. Pressure support increases as ventilation wanes and decreases as it waxes. ASV appears to successfully treat CSA associated with chronic opioid use unresponsive to CPAP60,61,63,66 (Table 4).
Perioperative Management
Unlike OSA, the perioperative risk due to CSA syndromes is unknown. Diagnostic studies for CSA are not standard, and the possibility of opioid-induced SDB, such as CSA, may not even be considered. Based on our review, none of the usual risk factors for OSA has been useful for screening patients for opioid-induced CSA. However, the following factors should raise concern: (1) the clinical context identified in these studies (i.e., patients receiving methadone or buprenorphine for opioid addiction, patients being treated for chronic pain, and patients who have risk factors or diagnosis of OSA and are also receiving chronic opioids); (2) any patient being treated with an MEDD ≥ 200 mg/d; and (3) patients with low or normal BMI. Although
www.anesthesia-analgesia.org 1281
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E REVIEW ARTICLE Table 4. Positive Airway Pressure Therapy Author Population N F, % Sleep apnea 22 59 Farney et al.56 (2008) Obstructive apneas were eliminated with both CPAP and ASV; however central apneas increased with CPAP. With ASV, central apneas were reduced but hypopneas, hypoxemia, and ataxic breathing persisted. Sleep apnea 5 20 Javaheri et al.57 (2008) CPAP eliminated obstructive apneas; however, central apneas increased. ASV was effective however hypopneas persisted.
Sleep apnea 6 33 Alattar et al.61 (2009) CPAP failed to eliminate central apneas in 5 patients and appeared to be effective in 1 patient but at a high intolerable level. BPAP with backup rate effective 3 of 4 patients but needed oxygen to treat nocturnal hypoxemia. Sleep apnea 44 50 Guilleminault et al.58 (2010) Central apneas were not present on baseline but emerged with CPAP therapy and persisted with BPAP until backup rate was used. Sleep apnea 41 ? Chowdhuri et al.51 (2012) Complete descriptive statistics were not reported for the opioid subgroup. This study shows the benefit of multimodality therapy (i.e., PAP and O2). Sleep apnea 47 51 Ramar et al.59 (2012) The opioid patients represent a subpopulation of a group of patients with central apnea due to congestive heart failure and central or complex sleep apnea related to opioids. Complete descriptive data for the opioid patients were not reported. Sleep apnea 34 ? Troitino et al.55 (2013) Almost all subjects were male (study conducted in a Veterans Affairs population). Only 24% were successfully treated with CPAP. Neither BPAP-ST or servoventilation achieved success in more than 67% and 60%, respectively. Complete descriptive statistics were only reported for baseline study of the entire population with opioid-induced central apneas. Descriptive statistics for therapy refer only to those who were successfully treated and not all patients treated with specific PAP. Sleep apnea 20 35 Javaheri et al.60 (2014) CPAP testing was abandoned after the failure in 9 cases even after continued therapy 4–8 wk.
Parameter N AHI OAI CAI HI Parameter N AHI OAI CAI HI Parameter N AHI OAI CAI
Respiratory findings Baseline CPAP 22 18 66.6 ± 37.3 70.1 ± 32.6 25.8 ± 23.7 10.7 ± 12.4 26.4 ± 25.1 48.1 ± 27.1 14.5 ± 14.5 11.3 ± 9.1 Baseline CPAP 5 4 70 ± 19 55 ± 25 6±7 1±2 26 ± 27 37 ± 21 36 ± 15 16 ± 7 Baseline Baseline 6 4 51.5 ± 27.7 60.2 ± 30.9 13.3 ± 17.2 15.9 ± 21.5 34.2 ± 12.6 38.4 ± 13.7
Parameter Baseline N 44 AHI 43.9 ± 1.19 CAI 0.64 ± 1.36 Outcome CPAP N 41 AHI
E Review Article CME
Chronic Opioid Use and Central Sleep Apnea: A Review of the Prevalence, Mechanisms, and Perioperative Considerations Denis Correa, MBBS, MD,* Robert J. Farney, MD,† Frances Chung, MBBS, FRCPC,* Arun Prasad, MBBS, FRCA, FRCPC,* David Lam, BMSc,* and Jean Wong, MD, FRCPC* BACKGROUND: Chronic opioid use has been associated with the development of sleep-disordered breathing (SDB) such as central sleep apnea (CSA). Patients receiving chronic opioids may suffer from unrecognized sleep apnea that contributes to opioid-overdose death. Currently, information regarding the perioperative management of patients with chronic opioid-associated CSA is limited. The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight their prevalence, mechanisms, risk factors, and perioperative management. METHODS: We searched Medline (1983–2014), Medline In-Process and other nonindexed citations (July 2014), EMBASE (1983–2014), the Cochrane Database of Systematic Reviews (January 2005–2014), the Cochrane Central Registry of Controlled Trials (July 2014), and PubMed basic search for new materials (1983–2014). Anesthesia and Sleep Medicine meeting abstracts were also searched for relevant articles. We included all prospective, retrospective studies and case reports in which CSA and chronic opioid use was confirmed by polysomnography. CSA was defined as the absence of airflow for ≥10 seconds with the absence of breathing efforts. A Central Apnea Index ≥5 events/h was considered significant. RESULTS: The search strategy yielded 8 studies which included 560 patients. The overall prevalence of CSA in patients taking chronic opioids was high (24%). The morphine equivalent daily dose (MEDD) was strongly associated with the severity of the SDB, predominantly CSA, with an MEDD of >200 mg being a threshold of particular concern. Concurrent use of benzodiazepines or hypnotics was associated with the severity of CSA in one study. Body mass index was inversely related to the severity of SDB. There were various recommendations regarding the best type of positive airway pressure therapy for the treatment of opioid-associated CSA. Continuous positive airway pressure may be ineffective in eliminating, or may even increase, CSA. Adaptive servoventilation and bilevel positive airway pressure ventilation were effective according to some reports. CONCLUSIONS: The overall prevalence of CSA in patients taking chronic opioids was 24%. The most important risk factors for severity of CSA were an MEDD >200 mg, and low or normal body mass index. Continuous positive airway pressure is often ineffective for treating CSA. Limited data are available on the perioperative management of patients with CSA associated with chronic opioid use. Further prospective studies on the perioperative risks and management of these patients are needed. (Anesth Analg 2015;120:1273–85)
O
pioids are the cornerstone for managing moderate to severe acute postoperative pain. The potential for acute respiratory suppression and death caused by
From the *Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; and †University of Utah Health Sciences Center, Intermountain Sleep Disorders Center, Intermountain Healthcare, LDS Hospital, Salt Lake City, Utah. Accepted for publication December 2, 2014.
Funding: Supported by Department of Anesthesia, Toronto Western Hospital, University Health Network, University of Toronto. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.anesthesia-analgesia.org). Reprints will not be available from the authors. Address correspondence to Jean Wong, MD, FRCPC, Department of Anesthesiology, Toronto Western Hospital, University Health Network, University of Toronto, 2McL-405, 399 Bathurst St., Toronto, Ontario, Canada M5T 2S8. Address e-mail to [email protected]. Copyright © 2015 International Anesthesia Research Society DOI: 10.1213/ANE.0000000000000672
June 2015 • Volume 120 • Number 6
opioids is well known; however, the relationship between sleep and opioid toxicity has only recently been described.–8 Opioids are associated with various sleep-induced respiratory disturbances such as central sleep apnea (CSA),1,2,4–7 other types of abnormal breathing patterns,1–3,8 and hypoxemia.1–3,5,8 Most studies in the anesthesiology literature have assessed the impact of acute parenteral opioid administration on metrics such as respiratory rate and ventilatory response to hypoxia or hypercapnia in normal healthy subjects and in the awake state.9–11 However, many patients taking chronic opioids may suffer from significant unrecognized central and obstructive sleep-disordered breathing (SDB) that may result in increased morbidity and mortality.12–14 Of special concern is the possibility of fatal complications in patients undergoing outpatient surgery or who are discharged after a short hospital stay and are receiving acute or increased opioids without oxygen therapy or monitoring. Satisfactory arterial oxygen saturation while breathing room air, having www.anesthesia-analgesia.org 1273
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E REVIEW ARTICLE a normal respiratory rate, and the absence of subjective respiratory symptoms while awake provide no assurance that a lethal respiratory abnormality will not occur once the patient goes to sleep at home. Information regarding the perioperative management of patients with SDB associated with chronic opioids is limited. The objectives of this review are to define the clinical manifestations of SDB associated with chronic opioid therapy, especially CSA, and to highlight the prevalence, mechanisms, risk factors, and perioperative management. Other sleep-induced respiratory disturbances, such as obstructive sleep apnea (OSA) syndrome and obesity hypoventilation syndrome, and the cardiotoxicity of opioids will not be reviewed in this paper.
also high (range 42%–85%) mean of 70%, and severity was in the moderate category (AHI ≥15 to 200 mg/d, and 61% patients with MEDD 10/h; however, 4 studies showed that there was no interaction,4,6–8 and there was no information in the other 3 reports.1,3,5 The effect of concurrent medications and chronic opioid-associated CSA was assessed in each of the studies,1–6,8 with the exception of the report by Jungquist et al.,7 and no relationship was observed. The synergy between opioids and sleep deprivation, as might occur in the perioperative environment, also seems plausible and relevant; however, none of the studies has addressed this point. It is almost impossible to exclude concurrent use of various medications as risk factors. Therefore, until more definitive studies can be performed, it would be prudent to avoid potentially exacerbating medications. The relationship with nonobese status is particularly interesting and has not been thoroughly investigated. The increase in central apneas in patients with lower BMI may be because the dosage was prescribed according to general guideline with a dose range and not as a milligram per kilogram basis. It is possible that patients with smaller BMIs may have a relative overdose versus patients with higher BMIs because of a difference in effect site concentration based on differences in pharmacokinetics.
Do Patients with Opioid-Associated CSA Have Higher Morbidity and Mortality?
The effect of opioid-associated CSA on morbidity and mortality has not been well characterized because long-term studies are not available. The current practice of chronic pain management is to use multiple analgesic medications at reduced doses to take advantage of their synergetic effect; however, there are no data to indicate whether this practice alters the risk of ataxic breathing, sleep apnea, or unanticipated death during sleep. Ideally, polysomnography should be performed if symptoms are observed. Whether the treatment of opioidassociated CSA prevents sleep-related mortality is unclear.
Therapy for Opioid-Associated CSA
Management of patients with opioid-related CSA is extremely challenging.25 Practice parameters with an evidence-based literature review of therapy for CSA was recently published46; however, there are no consensus guidelines that
anesthesia & analgesia
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
Chronic Opioid Use and Central Sleep Apnea
define indications and therapy for opioid-related breathing disorders. The main options available include: withdrawal of opioids,47,48 reducing opioid dose, selecting an opioid that may have less toxicity (e.g., buprenorphine in lieu of methadone),49–51 greater use of non-opioid analgesics, supplemental oxygen, pharmacologic therapy (e.g., acetazolamide, theophylline, carbon dioxide), positional therapy,52 avoidance of potentially aggravating concurrent drugs, and PAP. It is extremely important to identify and treat those with OSA and those who are using chronic opioids because there may be substantial interactions (e.g., increased upper airway resistance, hypoxemia, and blunted ventilatory and arousal responses). For the perioperative period, the 2 major therapeutic modalities are oxygen and PAP.
Oxygen
The effectiveness of oxygen for OSA53 and in the treatment of certain types of CSA, primarily Cheyne-Stokes breathing associated with heart failure, has been reviewed.46 However, the role of oxygen therapy for hypoxemia or CSA specifically related to opioids has not been established. Of note, nonapneic hypoxemia can occur during wakefulness in patients without cardiopulmonary disease and who are receiving chronic opioids with and without sleep apnea.3,5,54 More than 10% of patients on chronic opioids demonstrated resting awake and asleep hypoxemia without apnea.5 In a case series report by Farney et al.,55 oxygen supplementation corrected hypoxemia; however, Biots/ataxic breathing persisted. Despite the beneficial effects on arterial oxygen saturation, patients using opioids chronically already have a reduced arousal/ventilatory response hypercarbia. Therefore, oxygen therapy could potentiate hypoventilation or prolong central apneas/hypopneas. Conversely, opioids can stabilize breathing if the arousal threshold is low and respiratory controller gain is high associated with pain, so that oxygen therapy is unlikely to cause respiratory suppression. Unfortunately, these phenotypes may be indistinguishable based on anatomy or the specific opioid being used. We are unaware of any study in which the effect of oxygen on central apneas or ataxic breathing has been systematically assessed. Accordingly, oxygen therapy to treat hypoxemia due to opioids (with or without central apneas) appears prudent; however, patients need to be monitored very closely in the perioperative period because of multiple, potentially interactive factors. Adjunctive oxygen, in particular, may be necessary, in addition to PAP therapy, for optimal resolution of CSA and hypoxemia due to opioids.56
PAP Therapy
There are 4 PAP modalities: (1) continuous positive airway pressure (CPAP); (2) bilevel positive airway pressure (BPAP); (3) automatic self-adjusting positive airway pressure (APAP); and (4) servo-controlled ventilation (ASV or BPAP adapt). (See Table 4 for detailed comparison.) Except for servo-controlled ventilation, practice parameters have been published for all of these modalities for therapy of OSA and CSA not associated with chronic opioid use.57–59 Continuous Positive Airway Pressure CPAP devices maintain a CPAP with adjustable flow generated by fan-driven or turbine systems to stent the upper
June 2015 • Volume 120 • Number 6
airway open and to increase functional residual capacity. A pressure adjusted to abolish flow limitation is prescribed. CPAP can be autotitrated or fixed. In either case, the pressure is adjusted to abolish flow limitation and is thus several cm H2O higher than closing pressure, which is the pressure at which the airway closes completely. Furthermore, the pressure is not determined by PSG. It can be determined during PSG, but can also be determined under other circumstances, such as autotitration at home. Patients with sleep apnea related to opioids often have obstructive events, providing a logical basis for use of CPAP. Five retrospective studies60–64 (Table 4) showed that CPAP therapy does not eliminate or may even increase central apneas.60–63 The use of opioids does not preclude a favorable response to CPAP, but adjunctive oxygen or alternative PAP modalities will be required in most cases. Bilevel Positive Airway Pressure These devices permit independent adjustment of inspiratory positive airway pressure and expiratory positive airway pressure to target the obstructive and central SDB events. There are different modes of BPAP: Spontaneous (S Mode), Timed (T Mode), and Spontaneous/Timed Mode (ST Mode). In BPAP-ST Mode, a “backup” rate is also set to ensure that patients still receive a minimal number of breaths per minute if they fail to breathe spontaneously. BPAP (S or ST Mode) alone, or with a backup rate and/or oxygen, was effective for treating CSA unresponsive to CPAP62,65,66 (Table 4). A recent systematic review also reported the effectiveness of BPAP in eliminating CSA in 62% and ASV in 58% of patients taking chronic opioids.67 Servo-Controlled Ventilation Adaptive servoventilation is a relatively new approach in treating CSA, mainly in patients with congestive heart failure or complex apnea related to overtitration with CPAP. Based on an internal algorithm and a moving window sampling of the patient’s minute ventilation, ASV uses a preset or autotitrating end-expiratory pressure to eliminate any obstructive apneas or hypopneas, and it generates variable inspiratory pressure support (usually in the range of 3–10 cm H2O) on a breath-by-breath basis above the expiratory pressure to regulate ventilation to prevent hypocapnicinduced central apneas. Pressure support increases as ventilation wanes and decreases as it waxes. ASV appears to successfully treat CSA associated with chronic opioid use unresponsive to CPAP60,61,63,66 (Table 4).
Perioperative Management
Unlike OSA, the perioperative risk due to CSA syndromes is unknown. Diagnostic studies for CSA are not standard, and the possibility of opioid-induced SDB, such as CSA, may not even be considered. Based on our review, none of the usual risk factors for OSA has been useful for screening patients for opioid-induced CSA. However, the following factors should raise concern: (1) the clinical context identified in these studies (i.e., patients receiving methadone or buprenorphine for opioid addiction, patients being treated for chronic pain, and patients who have risk factors or diagnosis of OSA and are also receiving chronic opioids); (2) any patient being treated with an MEDD ≥ 200 mg/d; and (3) patients with low or normal BMI. Although
www.anesthesia-analgesia.org 1281
Copyright © 2015 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
E REVIEW ARTICLE Table 4. Positive Airway Pressure Therapy Author Population N F, % Sleep apnea 22 59 Farney et al.56 (2008) Obstructive apneas were eliminated with both CPAP and ASV; however central apneas increased with CPAP. With ASV, central apneas were reduced but hypopneas, hypoxemia, and ataxic breathing persisted. Sleep apnea 5 20 Javaheri et al.57 (2008) CPAP eliminated obstructive apneas; however, central apneas increased. ASV was effective however hypopneas persisted.
Sleep apnea 6 33 Alattar et al.61 (2009) CPAP failed to eliminate central apneas in 5 patients and appeared to be effective in 1 patient but at a high intolerable level. BPAP with backup rate effective 3 of 4 patients but needed oxygen to treat nocturnal hypoxemia. Sleep apnea 44 50 Guilleminault et al.58 (2010) Central apneas were not present on baseline but emerged with CPAP therapy and persisted with BPAP until backup rate was used. Sleep apnea 41 ? Chowdhuri et al.51 (2012) Complete descriptive statistics were not reported for the opioid subgroup. This study shows the benefit of multimodality therapy (i.e., PAP and O2). Sleep apnea 47 51 Ramar et al.59 (2012) The opioid patients represent a subpopulation of a group of patients with central apnea due to congestive heart failure and central or complex sleep apnea related to opioids. Complete descriptive data for the opioid patients were not reported. Sleep apnea 34 ? Troitino et al.55 (2013) Almost all subjects were male (study conducted in a Veterans Affairs population). Only 24% were successfully treated with CPAP. Neither BPAP-ST or servoventilation achieved success in more than 67% and 60%, respectively. Complete descriptive statistics were only reported for baseline study of the entire population with opioid-induced central apneas. Descriptive statistics for therapy refer only to those who were successfully treated and not all patients treated with specific PAP. Sleep apnea 20 35 Javaheri et al.60 (2014) CPAP testing was abandoned after the failure in 9 cases even after continued therapy 4–8 wk.
Parameter N AHI OAI CAI HI Parameter N AHI OAI CAI HI Parameter N AHI OAI CAI
Respiratory findings Baseline CPAP 22 18 66.6 ± 37.3 70.1 ± 32.6 25.8 ± 23.7 10.7 ± 12.4 26.4 ± 25.1 48.1 ± 27.1 14.5 ± 14.5 11.3 ± 9.1 Baseline CPAP 5 4 70 ± 19 55 ± 25 6±7 1±2 26 ± 27 37 ± 21 36 ± 15 16 ± 7 Baseline Baseline 6 4 51.5 ± 27.7 60.2 ± 30.9 13.3 ± 17.2 15.9 ± 21.5 34.2 ± 12.6 38.4 ± 13.7
Parameter Baseline N 44 AHI 43.9 ± 1.19 CAI 0.64 ± 1.36 Outcome CPAP N 41 AHI
