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Predictors of Delayed Postoperative Respiratory Depression Assessed from Naloxone Administration

Weingarten, Toby N. MD*; Herasevich, Vitaly MD, PhD*; McGlinch, Maria C.*; Beatty, Nicole C. MD*; Christensen, Erin D. RN; Hannifan, Susan K. RN; Koenig, Amy E. RN§; Klanke, Justin MD*; Zhu, Xun MD*; Gali, Bhargavi MD*; Schroeder, Darrell R. MS; Sprung, Juraj MD, PhD*

doi: 10.1213/ANE.0000000000000792
Patient Safety: Research Report

BACKGROUND: The aim of this study was to identify patient and procedural characteristics associated with postoperative respiratory depression or sedation requiring naloxone intervention.

METHODS: We identified patients who received naloxone to reverse opioid-induced respiratory depression or sedation within 48 hours after discharge from anesthetic care (transfer from the postanesthesia care unit or transfer from the operating room to postoperative areas) between July 1, 2008, and June 30, 2010. Patients were matched to 2 control subjects based on age, sex, and exact type of procedure performed during the same year. A chart review was performed to identify patient, anesthetic, and surgical factors that may be associated with risk for intervention requiring naloxone. In addition, we identified all patients who developed adverse respiratory events (hypoventilation, apnea, oxyhemoglobin desaturation, pain/sedation mismatch) during phase 1 anesthesia recovery. We performed conditional logistic regression taking into account the 1:2 matched set case–control study design to assess patient and procedural characteristics associated with naloxone use.

RESULTS: We identified 134 naloxone administrations, 58% within 12 hours of discharge from anesthesia care, with an incidence of 1.6 per 1000 (95% confidence interval [CI], 1.3–1.9) anesthetics. The presence of obstructive sleep apnea (odds ratio [OR] = 2.45; 95% CI, 1.27–4.66; P = 0.008) and diagnosis of an adverse respiratory event in the postanesthesia recovery room (OR = 5.11; 95% CI, 2.32–11.27; P < 0.001) were associated with an increased risk for requiring naloxone to treat respiratory depression or sedation after discharge from anesthesia care. After discharge from anesthesia care, patients administered naloxone used a greater median dose of opioids (10 [interquartile range, 0–47.1] vs 5 [0–24.8] IV morphine equivalents, P = 0.020) and more medications with sedating side effects (n = 41 [31%] vs 24 [9%]; P < 0.001).

CONCLUSIONS: Obstructive sleep apnea and adverse respiratory events in the recovery room are harbingers of increased risk for respiratory depression or sedation requiring naloxone after discharge from anesthesia care. Also, patients administered naloxone received more opioids and other sedating medications after discharge from anesthetic care. Our findings suggest that these patients may benefit from more careful monitoring after being discharged from anesthesia care.

Published ahead of print May 19, 2015

From the *Department of Anesthesiology, Nursing Thoracic/Vascular ICU and Mayo School of Health Sciences, Mayo School of Health Sciences, §Nursing Pediatric ICU and Mayo School of Health Sciences, and Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.

Accepted for publication February 17, 2015.

Published ahead of print May 19, 2015

Funding: The Department of Anesthesiology, College of Medicine, Mayo Clinic, Rochester, MN. Research reported in this publication was also supported by the National Institute on Aging of the National Institutes of Health under Award Number R01AG034676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Toby N. Weingarten, MD, Department of Anesthesiology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Address e-mail to weingarten.toby@mayo.edu.

Etiologies for postoperative respiratory failure can be broadly categorized into either hypoventilatory or hypoxic respiratory failure. In the general surgical adult patient, hypoventilatory respiratory failure is typically thought to be secondary to oversedation from anesthetic and analgesic medications, preexisting sleep-disordered breathing conditions (e.g., obstructive sleep apnea [OSA]), or a combination, because patients with OSA are more sensitive to respiratory depression from these medications. OSA is a common sleep breathing disorder with an estimated prevalence of 17% and 9% among middle-aged men and women, respectively,1 with approximately 90% of cases undiagnosed.2 Mirroring the obesity epidemic, there has been a substantial increase in the prevalence of OSA in the general population.1

Pain management standards set by the Joint Commission on Accreditation of Healthcare Organizations3 have emphasized the importance of adequate pain control in hospitalized patients. These standards have resulted in a substantial increase in perioperative opioid administration to control postoperative pain4 as well as an increase in the incidence of opioid-induced oversedation.5 The Institute for Safe Medication Practices has raised concerns that this practice shift has resulted in an increase in the number of cases of oversedation and fatal respiratory depression events.6 Thus, clinicians are faced with having to balance the competing priorities of delivering adequate postoperative pain control and avoiding opioid-induced side effects,7 especially in patients with a high prevalence of OSA.

Although there are numerous methods for assessing opioid-induced respiratory depression,8 naloxone administration has been proposed as a surrogate marker for an episode of overnarcotization.9 Several studies have examined preoperative risk factors and the administration of naloxone in the postoperative period since the publication of Joint Commission standards.9–11 These have found that older age, presence of comorbidities such as OSA, and use of medications such as benzodiazepines were all associated with an increased risk for postoperative naloxone administration.

As an added layer of safety for patients recovering from anesthesia during phase 1 recovery, our institution has adopted a formal screening process for 4 types of adverse respiratory events: hypoventilation, apnea, oxyhemoglobin desaturation, and pain/sedation mismatch and termed them respiratory-specific events.12,13 In our institution, patients who experience these events were found to have more postoperative respiratory complications and more episodes of oxyhemoglobin desaturations.12,13 However, whether these events are associated with an increased rate of respiratory depression or excessive sedation have not been studied. Our primary aim was to assess whether preclinical characteristics and various perioperative variables, including respiratory-specific events during phase 1 recovery, were associated with naloxone administration after discharge from anesthesia care within 48 hours of dismissal from the postanesthesia care unit (PACU) or transfer from the operating room to the postoperative area.

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METHODS

This study was approved by the Mayo Clinic, Rochester, MN, institutional review board. Consistent with Minnesota Statute 144.295, we included only patients who have provided authorization for research use of their medical records (historically >95% of Mayo Clinic patients).14

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Study Design

This study used a retrospective case–control design that assessed patient and procedural characteristics associated with the requirement of postoperative naloxone administration.

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Study Setting

This study was set at a large academic tertiary care facility.

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Population Studied

An electronic search of the institutional medical records was performed from July 1, 2008, to June 30, 2010, to identify adult patients who 1) underwent general anesthesia whose tracheas were extubated either in the operating room or in the PACU; and 2) received naloxone within 48 hours of dismissal from anesthetic care (dismissal from a PACU or transfer from the operating room to a postoperative area [i.e., postsurgical ward, intensive care unit, progressive care unit]).15,16 Patients administered naloxone in the operating room, procedural room, or PACU were excluded. Patients who remained tracheally intubated after dismissal from anesthetic care and transferred to an intensive care unit were also excluded. Patients were also excluded if naloxone was administered to treat opioid-induced pruritus. The 48-hour time window was selected to allow identification of risk factors directly related to the perioperative course. For each patient who was administered naloxone, we used our medical record database to identify 2 control patients who underwent general anesthesia in the same year but who did not receive naloxone in the first 48 hours after dismissal from anesthesia care. The cases and control subjects were matched on age, sex, and exact type of procedure (based on International Classification of Diseases, 9th Revision procedure code).

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Data Abstraction

Electronic medical records were abstracted for demographics, comorbid conditions, preoperative, intraoperative and postoperative variables, postoperative course, and complications. Overall physical status was assessed from the American Society of Anesthesiologists physical status score. Comorbid conditions were defined as cardiovascular disease: coronary artery disease (myocardial infarction, coronary stent placement, or cardiac bypass surgery); congestive heart failure (or ejection fraction <40%); moderate to severe valvular disease; or peripheral vascular disease—pulmonary disease: OSA; chronic obstructive pulmonary disease or asthma; use of home oxygen; or other severe pulmonary disease (i.e., malignancy; restrictive pulmonary disease, or pulmonary hypertension)—neurologic disease: cerebrovascular disease (i.e., stroke, previous carotid surgery); dementia (i.e., Alzheimer disease); movement disorders (i.e., Parkinson disease)—or malignancy; diabetes mellitus (taking oral agents or insulin); and preoperative use of benzodiazepines or opioids. Preoperative use of benzodiazepines and opioids was defined as regular (chronic) use of these medications as indicated in the medical record and does not include limited use of these medications for immediate preoperative anxiolysis or analgesia.

The anesthetic and surgical records were reviewed for surgical procedure, anesthetic technique (general anesthesia with or without neuraxial analgesia), and duration of anesthesia; benzodiazepine, ketamine use, and systemic opioid analgesics were recorded (during procedure and phase 1 recovery). The doses of systemic opioid analgesics were converted to IV morphine equivalents (MEs) using published guidelines.17,18 If used, the dose of remifentanil was not considered for calculating IV MEs because of its ultrashort duration. Because of different pharmacokinetic profiles between the lipophilic opioid fentanyl and the other commonly used opioids, a separate variable was created to indicate those patients who received any “long-acting” opioids (i.e., hydromorphone, morphine, or oxymorphone); however, in these patients, fentanyl was also taken into account for ME calculations. For those patients admitted to the PACU for phase 1 recovery, we reviewed the duration of PACU stay for the occurrence of respiratory-specific events. During phase 1 recovery, registered nurses continuously monitored patients for 4 types of respiratory-specific events: hypoventilation (3 episodes of <8 respirations/min), apnea (episode of apnea ≥10 seconds), hypoxemia (3 episodes of oxyhemoglobin desaturations as measured by pulse oximetry (<90% with or without nasal cannula), and “pain/sedation mismatch” (defined as Richmond Agitation Sedation Score19 = −3 to −5 and a numeric pain score >5 [from a scale 0 to 10 {worst pain imaginable}]).12,13 Any patient who has a respiratory-specific event must have a subsequent 60-minute period free of further events to be transferred to a nonmonitored ward. Patients who had repeated events were discharged to an advanced monitored care setting or were continuously monitored for oxyhemoglobin desaturation via a pulse oximetry monitored by telemetry. Otherwise, discharge criteria for phase 1 recovery were based on standard discharge criteria.20

For patients who received naloxone, postoperative opioids were recorded from the time of discharge from anesthetic control to the time of naloxone administration. For control patients, the perioperative opioid administration from the time of anesthesia discharge to the time naloxone administration for the matched case was recorded. Postoperative opioids were then converted to IV ME and adjusted for time by dividing by the number of hours between anesthesia discharge to naloxone administration (or corresponding time for control patients; IV ME mg/h). In addition to postoperative opioids, the postoperative administration of other medications with sedating properties (benzodiazepines, gabapentinoids [gabapentin, pregabalin], sleep aids [zolpidem, tricyclic, or sedating antidepressants], spasmolytics [cyclobenzaprine], and antihistamines) was recorded. If naloxone administration was recorded, the primary indication for administration was recorded and categorized as treatment for isolated respiratory depression, oversedation, or cardiovascular collapse. Other interventions in addition to administration of naloxone were recorded.

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Outcomes

Postoperative complications within the first 30 postoperative days of the surgery were reported. Information was obtained from medical records from the index hospitalization, rehospitalization, or outpatient visits. Postoperative complications included myocardial infarction, cerebrovascular event, sepsis or multiorgan failure, or death. Hospital length of stay and 30-day mortality were recorded.

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Statistical Analyses

Data are summarized using mean ± standard deviation or median (25th, 75th percentiles) for continuous variables and frequency percentages for nominal variables. Of patients who received naloxone, characteristics were compared between full unit (0.4 mg) and titrated doses (<0.4 mg) using the Fisher exact test or χ2 test. Analyses to assess characteristics potentially associated with naloxone use were performed using conditional logistic regression, taking into account the 1:2 matched set case–control study design. Preoperative characteristics listed in Table 1 with evidence of an association in the univariate analysis (P ≤ 0.05) and all perioperative characteristics listed in Table 2 were assessed with the exception of age, sex, and type of procedure because these were matching variables in the study design. Body mass index, anesthesia duration, and opioid dose (intraoperative and recovery room) were modeled as continuous variables, and all other characteristics were modeled as nominal variables. The variable indicating IV opioid dose represents the ME in milligrams administered intraoperatively and during phase 1 recovery and includes both fentanyl and long-acting opioids. To account for differences in the pharmacokinetics of fentanyl and long-acting opioids, an additional variable was introduced indicating whether patients received any long-acting opioid. For the continuous variables, the assumption of linearity in the logit was assessed using the Box-Tidwell test, and no evidence of nonlinearity was detected. In addition to assessing each characteristic individually (univariate analyses), 2 multivariable analyses were performed. For the first multivariable analysis, all 134 matched sets were included and all preoperative characteristics found to be statistically significant on univariate analysis were included as explanatory variables in the model along with anesthetic technique and duration, any use of benzodiazepines, any use of ketamine, opioid dose, and whether any long-acting opioid was used. The second multivariable analysis was restricted to 122 matched sets where the case and at least 1 matched control subject went to the PACU and included an additional binary explanatory variable indicating whether the patient experienced respiratory events in the PACU. Two-tailed P values are reported and are not adjusted for multiple comparisons. Analyses were performed using SAS statistical software (version 9.2; SAS Institute, Inc., Cary, NC).

Table 1

Table 1

Table 2

Table 2

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RESULTS

During the study period, 84,533 patients underwent general anesthesia. Of those, 135 received naloxone for respiratory depression after general anesthesia and after tracheal extubation and dismissal from anesthetic care. One patient did not provide authorization for study inclusion in retrospective studies and was excluded from analysis. The estimated rate of naloxone administration was 1.6 per 1000 (95% confidence interval [CI], 1.3–1.9) anesthetics.

Tables 1 and 2 summarize the baseline clinical presentation and the perioperative course, respectively, of cases and control subjects. Results from multivariable models assessing clinical and procedural characteristics potentially associated with naloxone administration are presented in Table 3. From the multivariable analysis that includes all cases and control subjects, the presence of OSA (odds ratio [OR] = 2.45; 95% CI, 1.27–4.66; P = 0.008) was associated with an increased risk of receiving naloxone. When restricted to patients who received phase 1 recovery in the PACU, those experiencing respiratory-specific events had a higher risk for subsequently receiving naloxone (OR, 5.11; 95% CI, 2.32–11.27; P < 0.001). After discharge, patients who received naloxone were administered larger doses of opioids and were more frequently administered than other sedating medications (Table 4). Patients who were regularly using opioid medications preoperatively had increased use of postoperative opioids.

Table 3

Table 3

Table 4

Table 4

The majority (n = 78 [58%]) of naloxone administrations occurred during the first 12 hours after surgery, and 110 (82%) occurred within the first 24 hours (Fig. 1). The mean dose of naloxone was 0.32 ± 0.23 mg with 64 (48%) receiving 0.4 mg naloxone. Naloxone was administered on a standard postoperative ward to 111 cases (83%) and in an advance monitored setting (i.e., intensive care unit) 23 (17%) cases. The indications for its administration included treatment of respiratory depression (n = 70 [52%]) or excessive sedation (n = 58 [43%]) as part of cardiopulmonary resuscitation (n = 2 [2%]) or for unclear indication (n = 4 [3%]). There was no correlation between the dose of opioid administered during surgery and postanesthesia recovery and dose of administered naloxone (Fig. 2). Median length of stay was longer in the naloxone group, but the rate of serious morbidity and mortality was similar between cases and control subjects (Table 4).

Figure 1

Figure 1

Figure 2

Figure 2

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DISCUSSION

Our most important finding was that the patients who developed specific respiratory events in the recovery room had approximately a 5-fold increased likelihood for receiving naloxone after discharge from anesthesia care. Another important finding is that a preoperative diagnosis of OSA was also associated with respiratory depression or sedation that required naloxone administration. Our findings suggest that these patients may benefit from more careful monitoring after being discharged from anesthesia care.

The rate of naloxone administration in our study was similar to the lower estimate of postoperative naloxone administration reported in a meta-analysis that included 10 studies and 55,404 patients (0.3%; 95% CI, 0.1%–1.3%).8 However, these studies were published before 2000,8 and thus predated the Joint Commission pain standards, which changed the way postoperative pain is managed.4 In addition, that meta-analysis was heavily weighted by patients who received epidural analgesia (91.4%) compared with our study in which <15% of our cases and control subjects received a form of neuraxial analgesia. A more recent study from the current era of Joint Commission pain standards reported that 4.3 per 1000 adult patients who underwent anesthesia (95% CI, 3.0–5.4) received naloxone within 2 days after discharge from anesthetic care (the rate of epidural use in that cohort was 19.7%).9 Although speculative, one reason that our naloxone administration was lower may be because patients in our practice who experience respiratory-specific events during phase 1 recovery require an additional 60-minute evaluation and must be free of further events before discharge to a standard postoperative ward.12,13 This practice could provide an additional layer of safety. Nonetheless, it is important to note that most naloxone administrations occurred within 12 hours of discharge from anesthetic care and those who experienced respiratory events in the PACU were at increased risk for requiring naloxone. This suggests that our added layer of safety in PACU is certainly not foolproof in preventing subsequent severe respiratory depression after discharge from anesthesia care. Other studies have also found that naloxone is typically administered in the earlier postoperative period.9–11

It is not surprising that our patients with a preoperative diagnosis of OSA had a higher risk for developing postoperative respiratory depression requiring naloxone. Similarly, patients who had respiratory-specific events in the recovery room were also at increased risk. The rate of postoperative opioid administration among patients in the naloxone group was greater than that in control subjects, which was observed before by Gordon and Pellino.9 The rate of administration of other medications with sedating side effects was also greater in the naloxone group. Although this study is not designed to examine potential associations with these medications and naloxone administration, it does raise concerns for a potential association between perioperative polypharmacy and postoperative respiratory depression and oversedation. It is notable that patients who regularly used preoperative opioids had greater postoperative opioid use; however, this patient subset was not found to be at increased risk for naloxone administration.

Patients who were administered naloxone in this study had longer hospital stays than control subjects. Others have observed that patients who experience opioid-induced adverse events have longer hospital stays and greater hospitalization costs.21 However, in this study, we cannot determine whether the longer hospitalization was a direct result of the opioid-induced respiratory depression or other patient or surgical factors.

A substantial proportion of patients in this cohort received 0.4 mg naloxone, which is the unit dose of naloxone stored in standard emergency drug kits (i.e., code carts). In this retrospective study, it is difficult to ascertain all the specific circumstances under which naloxone was administered and how providers decided to administer a specific dose. However, the high percentage of patients receiving the full 0.4-mg naloxone dose may suggest unfamiliarity with the fact that this drug should ideally be titrated to effect. A 0.4-mg dose of naloxone given as a bolus is sufficient to produce an abstinence syndrome, leaving patients in severe pain that may induce sympathetic surge, which can be associated with pulmonary edema, asystole, and seizures.22–25 To avoid these complications, gradual titration of naloxone by 0.04-mg increments to reverse opioid-induced respiratory depression without untoward effects on analgesia has been recommended.26

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Limitations

This study has all the inherent limitations of a retrospective research design. Importantly, we relied on the administration of naloxone as a surrogate marker for opioid-induced respiratory depression or severe sedation. Undoubtedly, less severe cases may have been treated with more conservative methods such as withholding opioids until the patient became more alert or alternatively by using noninvasive respiratory ventilation devices. Therefore, our study does not report the rate at which postoperative respiratory depression occurs in our surgical population. It is plausible that our practice of prolonging the duration of phase 1 recovery for patients experiencing respirator-specific events could have resulted in a relatively low incidence of postoperative naloxone administrations. The pharmacokinetic profiles of various opioids used in the perioperative period differ substantially and add uncertainty to calculating MEs. To address this shortcoming, we introduced a dichotomous variable to indicate whether a patient received a long-acting opioid (i.e., hydromorphone, oxymorphone, morphine) during the perioperative period and included this in the multivariable analysis. This study is not powered to evaluate whether patients requiring naloxone have increased major postoperative morbidity or mortality, and therefore, the lack of association in this study should not be used as evidence that there is a possible association. Another limitation of this study is the lack of detailed records to determine the chronicity of outpatient opioid and benzodiazepine use. The assumption was made that the use of these medications was regular if they were documented in the patient’s medical record and were not recently prescribed for an acute condition (i.e., recent traumatic injury now undergoing surgical repair).

In conclusion, OSA and respirator-specific events during phase 1 recovery are associated with an increased likelihood of naloxone administration for opioid-induced respiratory depression. Detecting respirator-specific events in the recovery room may be a method for identifying patients who may require an increased level of postdischarge monitoring. The potential benefits of this preemptive approach will need to be assessed in future studies.

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DISCLOSURES

Name: Toby N. Weingarten, MD.

Contribution: This author helped design the study, conduct the study, collect data, review the analysis reported in this manuscript, and prepare the manuscript.

Attestation: Toby N. Weingarten approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.

Name: Vitaly Herasevich, MD, PhD.

Contribution: This author helped design the study, conduct the study, collect data, review the analysis reported in this manuscript, and prepare the manuscript.

Attestation: Vitaly Herasevich approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

Name: Maria C. McGlinch.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Maria C. McGlinch approved the final manuscript.

Name: Nicole C. Beatty, MD.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Nicole C. Beatty approved the final manuscript.

Name: Erin D. Christensen, RN.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Erin D. Christensen approved the final manuscript.

Name: Susan K. Hannifan, RN.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Susan K. Hannifan approved the final manuscript.

Name: Amy E. Koenig, RN.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Amy E. Koenig approved the final manuscript.

Name: Justin Klanke, MD.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Justin Klanke approved the final manuscript.

Name: Xun Zhu, MD.

Contribution: This author helped collect data and prepare the manuscript.

Attestation: Xun Zhu approved the final manuscript.

Name: Bhargavi Gali, MD.

Contribution: This author helped review the analysis reported in this manuscript and prepare the manuscript.

Attestation: Bhargavi Gali approved the final manuscript.

Name: Darrell R. Schroeder, MS.

Contribution: This author helped design the study, conduct the study, review the analysis reported in this manuscript, and prepare the manuscript.

Attestation: Darrell R. Schroeder approved the final manuscript.

Name: Juraj Sprung, MD, PhD.

Contribution: This author helped design the study, review the analysis reported in this manuscript, and prepare the manuscript.

Attestation: Juraj Sprung approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.

This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).

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