Abstract
Background
Postoperative opioid-induced respiratory depression and oversedation can lead to fatal events and increase perioperative mortality. In reports from major academic centers, naloxone administration has been used as a proxy for severe opioid overdose. Herein, we studied the incidence, clinical characteristics, and outcomes of postoperative naloxone use in a mid-size community hospital.
Methods
This was a retrospective review of adult patients who received naloxone within 48 postoperative hours between July 9, 2017, and May 31, 2022.
Results
During the study timeframe, a total of 23,362 surgical procedures were performed and a total of 19 patients received naloxone (8 in the recovery room, 11 on hospital wards), with an incidence of 8.1 [95% confidence interval 4.9–12.7] per 10,000 anesthetics. In 12 cases (63%), naloxone was indicated for oversedation, and in 7 cases (37%), for opioid-induced respiratory depression. All patients received naloxone within the first 24 postoperative hours. While all patients survived the opioid-related adverse event, 2 patients were intubated, 1 developed stress-induced cardiomyopathy, and 5 required intensive care unit admission.
Conclusion
The rate of early postoperative opioid-induced respiratory depression or oversedation in our community hospital was low; however, these patients often require a substantial escalation of medical management.
Keywords: Naloxone, opioid toxicity, oversedation, respiratory depression
Postoperative opioid-induced respiratory depression (OIRD) and severe oversedation can negatively affect patients’ outcome and result in increased mortality.1 Because OIRD-related complications and opioid-induced oversedation are preventable events, this topic remains of interest for academic research,2–4 for development of perioperative guidelines,5,6 and for healthcare regulations.7,8 Academic research has focused on the incidence, temporal patterns, risk factors, and outcomes of OIRD or oversedation using a variety of study designs, ranging from nursing observations9 and continuous respiratory monitoring technologies2,3 to counting naloxone administration as a surrogate marker for opioid overdose.10 Naloxone administration is considered a marker of severe OIRD, because its use is typically reserved for the most severe cases of opioid-induced overdose. While the use of naloxone was used as a marker of OIRD in reports from large academic centers,4,11 it remains unknown whether these results can be generalized to community hospital practices. To address this knowledge gap, we conducted a review of postoperative naloxone administrations in a mid-sized community surgical practice in order to a) determine the incidence of ORID/oversedation, b) characterize clinical circumstances for its use, and c) describe patient outcomes.
METHODS
This study was approved by the Mayo Clinic Institutional Review Board (identification number 22-004248), which provided the authors with a waiver for patient authorization of release of protected health information. This study adheres to the applicable STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.
This was a retrospective observational study of naloxone administration within the first 48 postoperative hours. Cases were identified by reviewing the community hospital pharmacy database. Identified patients underwent detailed chart review of preoperative clinical characteristics, the perioperative period, and patient outcomes following naloxone administration.
Included were adult patients (≥18 years) who underwent elective procedures with general anesthesia at a single institution from July 9, 2017 to May 31, 2022 and were administered naloxone within the first 48 postoperative hours. Patients who received naloxone to facilitate tracheal extubation or postoperatively to treat opioid-induced pruritus were excluded. The 48 postoperative hour time window was selected to identify perioperative oversedation and respiratory depression events.
The electronic medical records were manually reviewed, and data were abstracted by a single abstractor (ORN). Preoperative variables included demographics (age, sex, body mass index), American Society of Anesthesiologist Physical Status Score, and selected comorbidities, namely history of cardiovascular disease, pulmonary disease, diabetes mellitus, central nervous system disease (stroke, dementia), and chronic (at home, preoperative) use of sedating medications (opioid analgesics, gabapentinoids). Perioperative variables included in the review were the type and duration of surgical procedure and use of midazolam, gabapentinoids, and opioids.12 The clinical circumstances regarding the naloxone administration were reviewed for indication, other interventions, and outcomes. Nursing notes were examined prior to naloxone administration to determine the last recorded sedation assessment (determined by the Richmond Agitation Sedation Scale [RASS] score,13 a 10-point scale that ranges from +4 [combative] to −5 [unarousable]) and pulmonary function (last recorded respiratory rate and oxyhemoglobin saturation). Rate of postoperative naloxone administration per 10,000 general anesthetics was calculated. Data were summarized using descriptive statistics.
RESULTS
During the study period, 23,362 adult patients underwent general anesthesia. Of those, 19 received naloxone following tracheal extubation, yielding an incidence of 8.1 [95% confidence interval 4.9–12.7] per 10,000 anesthetics. The median dose of naloxone was 0.2 mg (interquartile range 0.16–0.2). Naloxone was administered in 8 patients (42%) in the postanesthesia care unit (PACU) and 11 (58%) on general hospital wards. Of these 11 cases, 9 received naloxone within the first 12 postoperative hours, and all administration occurred within first 24 postoperative hours (Figure 1).
Figure 1.
Timing of naloxone administration.
Clinical details of patients and procedural characteristics are summarized in Table 1. The cases were more likely to be females (14/19, 77%), the mean age was 67 years (standard deviation ±10), and the body mass index was 30.3 kg/m2 (±6.3). A substantial burden of chronic comorbidities was recorded in the majority of patients, and 7 patients (37%, 4 female and 3 male) had obstructive sleep apnea. The mean duration of anesthesia was 175 (±58) minutes. Preoperatively midazolam was used in 14 cases (74%), and gabapentin in 6 cases (32%), while intraoperatively 8 patients (42%) received long-acting opioids. Of note, 5 patients who did not receive preoperative gabapentin as a part of anesthetic management had gabapentin on a list of their home medications; however, we do not have information on the timing of their last preoperative dose.
Table 1.
Characteristics and outcome of 19 perioperative patients who received naloxone following tracheal extubation
| Pt #, Sex, ASA PS, Age (yr), BMI | Comorbidities, Home use of opioids or GABAa |
Surgery type, duration (min),
Intraoperative medications |
Time to naloxone administration (min)b, Indication for naloxone administration, Additional interventions |
|---|---|---|---|
| PACU CASES | |||
| 20031. ♀, II 54; 28.5 |
DM II | Urology, 204; Sev, Roc/Sug Mid (2), Fent (350), HM (1.0) |
22, respiratory depression |
| 2. ♀, II 61; 31.2 |
GABA | Orthopedic, 123; Sev, Roc/Sug Mid (2), Fent (250) |
64, respiratory depression |
| 3. ♀, II 42; 30.4 |
None | Gynecology, 134; Sev, Roc/Sug Mid (2), Fent (150), GABA |
65, sedation |
| 4. ♀, II 72; 33.6 |
None | Orthopedic, 155; Sev, Roc/Sug Mid (2), Fent (200), HM (1.2) |
70, sedation |
| 5. ♂, III 72; 31.0 |
HTN, asthma, DM II OSA |
General, 247; Sev, Roc/Neo + Glyc Mid (2), Fent (200), HM (0.8) |
85, sedation BiPAP |
| 6. ♀, II 69; 25.6 |
HTN, asthma, DM II OSA; hydrocodone, GABA |
General, 94 Sevo, Roc/Sug Mid (2), Fent (150) |
88, respiratory depression BiPAP, unplanned ICU admission |
| 7. ♀, III 77; 42.9 |
HTN, VHD, CKD, DM II OSA, GABA |
Urology, 234; Sev, Roc/Sug Fent (200) |
160, sedation; unplanned ICU admission |
| 8. ♂, II 65; 26.6 |
None | Orthopedic, 190 Sev; Mid (2), Fent (100), HM (2) |
165, respiratory depression |
| WARD CASES | |||
| 9. ♂, IV 66; 41.8 |
HTN, CHF, PVD, CKD, COPD, Home oxygen, DM II, OSA; oxycodone, tramadol, GABA | General, 91 Sev, Roc/Sug Mid (2), Fent (100) |
66, sedation endotracheal intubation, ICU admission |
| 10. ♂, II 77; 28.2 |
HTN | Orthopedic, 190; Des, Roc/Neo + Glyc Mid (2), Fent (250), HM (1.0) |
79, sedation |
| 11. ♀, II 54; 32.4 |
HTN | Orthopedic, 287; Sev, Roc/Sug; Mid (2), Fent (350), HM (0.8), GABA | 128, sedation |
| 12. ♀, III 62; 22.9 |
CAD, HTN, PVD, CKD, DM II, MoD; OSA; GABA | General, 97; Sev, Roc/Sug Mid (2), Fent (100), GABA |
150, sedation; reinitiated home BiPAP |
| 13. ♀, III 64; 15.5 |
CAD, COPD, home oxygen hydrocodone |
Orthopedic, 114 Des, Roc/Sug; Fent (200) |
158, respiratory depression |
| 14. ♀, III 80; 36.5 |
CAD, HTN, CHF, CKD GABA |
Neurologic, 236 Sev; Fent (100) |
172, sedation; CPRc, endotracheal intubation, ICU admission stressed induced cardiomyopathy with EF 38% |
| 15. ♀, II 79; 29.5 |
HTN, CKD, trauma | Orthopedic, 156; Sev, Roc/Sug Fent (200), GABA |
255, sedation |
| 16. ♀, II 64; 26.3 |
None | Orthopedic, 247; Sev, Roc/Sug Mid (2), Fent (200), HM (1.0), GABA |
283, respiratory depression |
| 17. ♀, III 71; 25.7 |
HTN, DM II | General, 186; Des, Roc/Neo + Glyc Mid (2), Fent (100), HM (2.0) |
310, respiratory depression |
| 18. ♀, III 80; 31.7 |
HTN, CHF OSA |
General, 173; Sev, Roc/Sug Fent (100) |
780, sedation BiPAP, ICU admission |
| 19. ♂, IV 57; 34.9 |
PVD, CKD, DM II, home oxygen; OSA; oxycodone, GABA | General, 169; Sev, Rocu/Neo + Glyc Mid (2), Fent (100), GABA |
1425, sedation |
All patients had a full recovery. ASA PS indicates American Society of Anesthesiologists physical status; BiPAP, bilevel positive airway pressure; BMI, body mass index (kg/m2); CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CPR, cardiopulmonary resuscitation; Des, desflurane; DM, diabetes mellitus; EF, ejection fraction; Fent, fentanyl (dose in mcg); GABA, gabapentin; Glyc, glycopyrrolate; HM, hydromorphone (dose in mg); HTN, hypertension; Mid, midazolam (dose in mg); Neo, neostigmine; OSA, obstructive sleep apnea; Pt #, patient number; PVD, peripheral vascular disease; Roc, rocuronium; Sev, sevoflurane; Sug, Sugammadex; VHD, valvular heart disease.
aRefers to chronic use of opioids, gabapentin, or pregabalin prior to surgery.
bThe time to naloxone administration was calculated from the time of end of surgery.
cPatient developed pulseless electrical activity cardiac arrest. In addition to naloxone, CPR was initiated and after 10 minutes of resuscitation return of spontaneous circulation was achieved.
The indications for naloxone administration were reported as respiratory depression in 7 patients (37%) and excessive sedation in 12 (63%). Nursing documentation prior to naloxone administration indicated that 5 (26%) patients were drowsy to mildly sedated (RASS = −1 to − 2), and 11 (58%) were moderately sedated to comatose (RASS = −3 to −5). Nine (47%) patients had bradypnea (breathing rate < 10 breaths per minute) with one patient being apneic; and two patients were hypoxemic (oxyhemoglobin saturations 72% and 58%, respectively). After naloxone administration, 5 (26%) patients were admitted to the intensive care unit and of these, 2 patients (11%) required tracheal intubation with mechanical ventilation and 3 (16%) required application of continuous noninvasive positive pressure ventilation.
One patient who was tracheally intubated and short-term (2 hours) mechanically ventilated was an 80-year-old woman who underwent lumbar spine fusion surgery. She was found unresponsive/obtunded 2 hours following admission to the general hospital ward. She was administered 0.2 mg naloxone but shortly afterwards developed pulseless electrical activity. Ten minutes of cardiopulmonary resuscitation resulted in return of spontaneous circulation; however, she was diagnosed with resuscitation-induced stress cardiomyopathy (ejection fraction decreased from 60% preoperatively to 38% after resuscitation). The second intubated patient was a 66-year-old man on hemodialysis who underwent debridement of a perineal wound. One hour after arrival to the general floor he became obtunded. He was administered 0.4 mg naloxone and underwent intubation with mechanical ventilation. He was extubated the following day without sequelae.
DISCUSSION
The main findings of our study are that the rate of severe postoperative OIRD or oversedation, as assessed from administration of naloxone, was low, but when present, it required substantial healthcare resources and invasive treatments (e.g., intubation, mechanical ventilation, resuscitation) and in some patients resulted in unplanned admission to the critical care units for additional treatment and/or monitoring.
In our mid-size community hospital the rate of naloxone administration for postoperative OIRD or oversedation was 8 per 10,000 general anesthetics, which is in the lower range compared to other studies (Table 2). For example, a study from a major academic hospital within 100 miles of our medical center reported a comparable incidence of naloxone treatments, 5.9 per 10,000 general anesthetics.15 A combination of data from Weingarten et al4 and Deljou et al14 demonstrated a similar low rate (15.8 and 11.6, respectively).10,16 However, other studies from major tertiary centers have reported a much higher rate of naloxone administration,11,17,18 ranging from 18 to 53 cases over 10,000 surgical patients. Interestingly, these studies looked at naloxone administration over an extended postoperative period, which could have contributed to the reported higher rate.
Table 2.
Incidence of postoperative naloxone administration for respiratory depression and/or oversedation
| References | Clinical setting Timing of naloxone administration |
Number of cases/ total number of patients |
Incidence (rate/10,000 cases) |
|---|---|---|---|
| Weingarten et al4 | Academic medical center Surgical ward—postoperative 48 h |
134/84,553 | 15.8 |
| Deljou et al14 | Academic medical center Surgical ward—postoperative 48 h |
128/110,019 | 11.6 |
| Valencia Morales et al15 | Academic medical center Surgical ward—postoperative 48 h |
63/106,807 | 5.9 |
| Gordon and Pellino11 | Academic medical center Surgical ward—5 postoperative days |
56/10,511 | 53.3 |
| Khelemsky et al16 | Academic medical center PACU—postoperative 72 h |
433/442,699 | 9.78 |
| Rosenfeld et al17 | Academic medical center Surgical ward/ICU—entire hospitalization |
108/28,151 | 53.28 |
| Eckstrand et al18 | Academic medical center Surgical ward/ICU—entire hospitalization |
69/36,533 | 18.89 |
| Ramachandran et al19 | Academic medical center PACU/Surgical ward—entire hospitalization |
32/87,650 | 3.65 |
ICU indicates intensive care unit; PACU, postoperative care unit.
Adapted from Weingarten and Sprung.10
In our study, all naloxone administrations occurred within the first 24 hours after discharge to hospital wards, which is consistent with the reports from other academic centers.10 A similar temporal pattern of naloxone administrations has been reported by other studies,4,10,14,16 with the majority of opioid-induced adverse events occurring shortly after PACU discharge to hospital wards. Studies that employed monitoring of respiratory patterns with thoracic bioimpedance20 and bedside capnography21 reported that respiratory depression usually manifests early following discharge from PACU to wards. Another trend noted in our study, also reported by others,14,15,22 is that the recorded indication for naloxone administration was more often noted as oversedation than respiratory depression. Data from studies that used continuous respiratory monitoring have found that the majority of episodes of postoperative respiratory depression manifest as intermittent apnea or bradypnea,2,21 but when healthcare providers evaluate such patients they note oversedation but not respiratory depression.2,3,22 For example, a closed claim analysis of postoperative OIRD found that in the majority of litigated cases nurses indicated oversedation but not respiratory depression in evaluations antecedent to the critical event.1 One theory to explain why healthcare staff often do not appreciate OIRD with traditional means is that when patients are awoken during vital signs assessment respiratory effort is regained and thus not clinically appreciated.10
Although all of our patients recovered from respiratory episodes, these rare adverse events may have severe consequences. For example, one patient developed stress-induced cardiomyopathy after resuscitation, two patients were tracheally intubated, and five (26%) patients were transferred to the higher level of care for treatment and monitoring. This observation is in agreement with reports from the quaternary medical center, i.e., that patients treated for severe respiratory depression often trigger additional comprehensive treatments that may require admission to the critical care unit.14,15
While opioids need to be used with extreme caution because of possible severe adverse events such as respiration depression, postoperative pain still needs to be treated properly since inadequate management of postoperative pain can increase patients’ morbidity, negatively impair functioning and quality of life, delay recovery time, prolong duration of opioid use, and increase healthcare costs.23
While our study lacked the power to identify risk factors for postoperative respiratory depression/oversedation, it is worth noting that those who received naloxone were mostly women, were over the age of 60 years (84%), were overweight, and had an elevated burden of comorbidities. In addition, 14 cases (74%) received preoperative midazolam, all received a substantial amount of fentanyl, 8 in addition to fentanyl received the long-acting opioid hydromorphone, and 11 (58%) received gabapentinoids, all of which may produce a compounding effect on development of OIRD and oversedation. For example, 11 patients (58%) received gabapentin either immediately preoperatively or were taking it as a part of their chronic home therapy. While in our study we could not elicit a cause-effect relationship, studies utilizing multicenter databases have found that gabapentin and pregabalin, when used as part of multimodal enhanced recovery analgesic pathways, may be associated with increased risk of severe respiratory complications,24–28 and for this reason the Food and Drug Administration recently issued a black box warning for their perioperative use.
This study has limitations inherent to its retrospective observational design. Importantly, the sample size was insufficiently powered to allow analysis of variables potentially associated with risk for OIRD. Further, we relied on naloxone as a proxy for OIRD or oversedation, and we cannot exclude the possibility that naloxone was administered empirically to acutely decompensating patients when the underlying etiology was a clinically unrelated event. Furthermore, our incidence of postoperative opioid toxicity likely represents an underestimate of the OIRD/oversedation rates, since less severe cases could have been managed without the use of naloxone.
In conclusion, the rate of OIRD or oversedation attributed to opioids was low; however, when present, patients needed substantial escalation of postoperative care, including a high rate of admissions to the critical care unit.
Funding Statement
This study was supported by the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Health System, Eau Claire, Wisconsin. Toby N. Weingarten receives consulting and speaking fees from Medtronic and Merck.
DISCLOSURE STATEMENT
This study was supported by the Department of Anesthesiology and Perioperative Medicine, Mayo Clinic Health System, Eau Claire, Wisconsin. Toby N. Weingarten receives consulting and speaking fees from Medtronic, Merck. All other authors have no conflicts of interest.
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