Respiratory depression is a side effect of many medications used for anesthesia during and after surgery, especially opioids. The reported incidence of opioid-related respiratory depression from a meta-analysis by Gupta et al. estimated 5 cases per 1000 patients, roughly 0.5% [1]. Although the incidence is low, respiratory depression can be fatal, making it an important adverse effect for anesthesiologists to consider. Other potential side effects include hypotension, hypercarbia from hypoventilation, bradycardia, and postoperative nausea and vomiting.

The most likely time for respiratory depression to occur is in the post-operative care unit. Respiratory depression tends to occur right after opioid administration. Patients should be monitored acutely after surgery in the post-operative unit for muscular rigidity, fall in chest wall compliance, hypoventilation, respiratory acidosis, and hypotension. Risk remains high for the first 12 hours after surgery and remains elevated for the first 24 hours, possibly due to a delayed phenomenon where fentanyl reenters the plasma from adipose tissue, muscle, and the GI tract [2]. Patients who develop hypothermia and acidosis in the post-operative period are more likely to develop delayed respiratory depression [3]. Patients should be counseled about these risks, especially if they are undergoing outpatient surgery where they are less likely to be closely monitored after going home.

It is imperative to consider the patient’s risk factors for respiratory depression. In the meta-analysis by Gupta et al., the most common risk factors for opioid-induced respiratory depression were cardiac disease, respiratory disease, or obstructive sleep apnea. Beyond controlling for these risk factors, it is difficult to predict the timing or severity of respiratory depression due to multiple contributing factors such as comorbidities and concomitant medications [4]. These risk factors should be addressed in a preoperative meeting and the patient should be counseled on their increased risk for adverse events.

Another important step is to consider the dosage given. Typically, opioid dosing is based on body weight. High doses of intraoperative opioids (32 mg morphine equivalents) are associated with increased hospital readmission risk compared to lower doses (8 mg morphine equivalents) [4]. Dosage should be reduced in older patients or patients with impaired renal, hepatic, or pulmonary function. Previous opioid usage should be considered in case there is tolerance.

Opioid reversal is typically done with naloxone (brand name Narcan), an opioid receptor antagonist. However, along with reversing respiratory depression, naloxone reverses analgesia which makes it important to carefully titrate the dose to preserve analgesic effects. Another reason to slowly reverse opioids is a rare side effect of a sympathetic surge causing hypertension, tachycardia, and flash pulmonary edema. The recommended initial naloxone dose is 40 mg IV, titrating up as necessary to 400 mg. If prolonged respiratory depression continues despite naloxone reversal, mechanical intubation should be considered.

There is increasing interest in counteracting respiratory depression with non-opioid stimulants like dopamine, AMPA, NMDA receptor antagonists, and nicotinic acetylcholine. Studies have mostly been done in the laboratory on rats or in veterinary medicine with other animals [5]. More research needs to be done with preclinical data before they become used in clinical practice.

References 

1. ​​Gupta K, Nagappa M, Prasad A, Abrahamyan L, Wong J, Weingarten TN, Chung F. Risk factors for opioid-induced respiratory depression in surgical patients: a systematic review and meta-analyses. BMJ Open. 2018 Dec 14;8(12):e024086. doi: 10.1136/bmjopen-2018-024086. PMID: 30552274; PMCID: PMC6303633. 

1. Weingarten TN, Warner LL, Sprung J. Timing of postoperative respiratory emergencies: when do they really occur? Curr Opin Anaesthesiol. 2017 Feb;30(1):156-162. doi: 10.1097/ACO.0000000000000401. PMID: 27685799. 

1. Klausner JM, Caspi J, Lelcuk S, Khazam A, Marin G, Hechtman HB, Rozin RR. Delayed muscular rigidity and respiratory depression following fentanyl anesthesia. Arch Surg. 1988 Jan;123(1):66-7. doi: 10.1001/archsurg.1988.01400250076013. PMID: 3337659. 

1. Long DR, Lihn AL, Friedrich S, Scheffenbichler FT, Safavi KC, Burns SM, Schneider JC, Grabitz SD, Houle TT, Eikermann M. Association between intraoperative opioid administration and 30-day readmission: a pre-specified analysis of registry data from a healthcare network in New England. Br J Anaesth. 2018 May;120(5):1090-1102. doi: 10.1016/j.bja.2017.12.044. Epub 2018 Mar 9. PMID: 29661386. 

1. Imam MZ, Kuo A, Smith MT. Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants. F1000Res. 2020 Feb 7;9:F1000 Faculty Rev-91. doi: 10.12688/f1000research.21738.1. PMID: 32089833; PMCID: PMC7008602.