Our systematic review yielded 18 articles describing the effects of sedatives and anesthetics on perioperative respiratory events, medication requirements, hemodynamics, postoperative pain, emergence, and hospital stay in patients with OSA. Few adverse effects were reported when patients with known OSA underwent elective surgery with the currently available sedatives and anesthetics. These reports were limited by the number of patients, their level of evidence, and the uniformity of reporting of outcomes.
Benzodiazepines depress central nervous system (CNS) activity and increase the level of inspiratory effort required to cause arousal after sleep in OSA patients. Studies in vivo
and in vitro
have described gamma amino butyric acid (GABA) A and N
-methyl-D-aspartate (NMDA) receptors in the cortex, thalamus, brain stem, and striatum as important targets of hypnotic drugs.[45
] The administration of midazolam markedly increases supraglottic upper airway resistance and induces central apnea followed by obstructive apneic events.[47
] Benzodiazepines decrease the arousal response to hypoxia and hypercarbia and thereby increase the duration of apnea.[48
] Even a small dose of triazolam (0.25 mg), a benzodiazepine, has been shown to increase apneic duration and worsen oxygen saturation in patients with severe OSA.[49
] Similarly, the administration of pentobarbital, a barbiturate in healthy volunteers increases upper airway resistance and end-tidal CO2
concentration when compared to placebo.[50
Eight patients with undiagnosed OSA undergoing middle ear surgery with midazolam and fentanyl had impaired upper airway patency.[33
] These patients were retrospectively diagnosed as having OSA by polysomnography. Also, intraoperative snoring causing uvular edema in the postoperative period was reported when propofol was administered with midazolam and fentanyl for sedation.[32
] This edema could be due to synergistic respiratory depression caused by midazolam in conjunction with a preexisting dysfunctional airway in OSA patients. Every effort should be made to minimize the use of sedatives in OSA patients to minimize adverse events. With its sedative properties and elimination half-life of 2 h, midazolam should be avoided or only small doses should be used in OSA patients. Preoperative screening of patients with the STOP-Bang questionnaire may have alerted the anesthesiologists to the possibility of OSA and direct the appropriate perioperative management.[23
In a retrospective study of elective non-cardiac surgical procedures, respiratory complications were more frequent in patients with OSA (44%) versus those without OSA (28%).[11
] Of these respiratory complications, oxygen desaturation was the major adverse event.[11
] In another retrospective study of patients undergoing hip or knee replacement surgery, significantly higher postoperative complications occurred in OSA patients versus non-OSA patients.[10
] A recent retrospective cohort study of 65,774 OSA patients undergoing orthopedic procedures and 51,509 OSA patients undergoing general surgical procedures found that OSA patients had significantly higher pulmonary complications like aspiration pneumonia, acute respiratory distress syndrome, and intubation/mechanical ventilation.[51
] Due to the small patient numbers, our systematic review in OSA patients showed only eight cases of temporary interruption of middle ear surgery and one case of uvular edema with intraoperative snoring with the use of sedatives.
Inhalational anesthetic agents have shown variable responses during emergence in OSA patients. In a randomized prospective study involving 24 OSA patients, the use of propofol and isoflurane in upper airway surgery delayed recovery of respiration with a drop in oxygen saturation.[29
] This may be due to the quantified effects of sub-anesthetic concentrations of inhalational anesthetics on the human ventilatory response to hypoxia.[52
] However, further studies evaluating its effects on respiratory events are warranted. Faster emergence after bariatric surgery was described with sevoflurane over isoflurane.[53
] Similar effects were noticed with desflurane over isoflurane or propofol.[54
The administration of propofol in healthy volunteers has been shown to produce a sleep-like state with slow waves on electroencephalogram (EEG) and decreased consciousness even in the presence of high gamma activity.[55
] However, there is no data on the effects of propofol and EEG changes with known OSA patients.
Ketamine anesthesia abolishes the coupling between loss of consciousness and upper dilator muscle dysfunction and thereby protects upper airway patency in OSA patients.[30
] Ketamine was used as an effective sedating agent for a tracheostomy procedure in an OSA patient who was refractory to lorazepam sedation. Concentration-dependant relaxation of the trachealis muscle has been described in animal studies,[57
] but its effect on OSA patients needs to be evaluated. Ketamine may offer advantages of maintaining upper airway patency in OSA patients and further studies are warranted.
Clonidine decreases perioperative anesthetic and analgesic requirements in OSA patients. It increases the slow-wave activity (delta) and attenuates the physiological alpha fluctuations and thereby causes sedation and lower bispectral index scores (BIS).[59
] Administration of clonidine preoperatively has been shown to potentiate the effects of anesthetics[60
] and decrease the requirement of propofol.[61
Studies on the analgesic potency of clonidine did not show consistent results, ranging from minor analgesic effects to significant opioid sparing effect.[62
] However, superior analgesia with significant opioid sparing effect has been described in OSA patients with preoperative clonidine.[27
] The reduced opioid requirement with clonidine in OSA patients could be due to upregulation of mu opioid receptors in the brainstem caused by continuous hypoxemia as described in a hypoxic animal model.[64
] The use of clonidine in OSA patients has shown less oxygen desaturation in the postoperative period. The combination of REM sleep suppression and reduced use of opioids with clonidine may have reduced oxygen desaturation indices.[27
There may be a theoretical advantage of using dexmedetomidine in OSA patients. The use of dexmedetomidine stimulates receptors in the locus coeruleus causing sedation and analgesia by stimulating spinal cord receptors.[66
] Dexmedetomidine infusion causes a mild decrease in minute ventilation and an increase in PaCO2
; however, these effects are much less pronounced than with opioids and are similar to those seen during profound sleep.[67
] The use of dexmedetomidine reduces the propofol and morphine requirements during bispectral index-guided sedation[68
] and reduces the requirement of midazolam by 80% and morphine by 50% when compared to placebo.[69
] There are no RCTs with the use of dexmedetomidine in OSA patients. Most of the published data are from case reports and retrospective chart review.[35
] Though dexmedetomidine was shown to be advantageous over currently used sedatives and anesthetics in case reports, well-designed studies involving large numbers of OSA patients are warranted.
There is limited data on the length of hospital stay in OSA patients with the currently used sedatives and anesthetics. However, a significantly prolonged hospital stay has been described in OSA patients compared with patients without OSA after non-cardiac, hip, or knee replacement surgeries.[10
The results of our review must be interpreted with caution due to several limitations. There was a lack of studies that clearly had the objective of determining the effects of sedatives and anesthetics on respiratory events, hemodynamic changes, medication requirements, pain, emergence, and hospital stay. Thus, we included the case reports and case series. In these studies, there was also a lack of reported adverse effects from sedatives or anesthetics may result from the limited number of patients. As well, there was a lack of uniformity in the outcomes assessed. However, it is difficult to perform large prospective studies in the OSA patient population because there may be increased vigilance by clinicians to avoid adverse events. The rarity of adverse events may necessitate reporting of adverse events with patient registry, events through case series or outcomes databases from multiple centers with detailed reporting of patient characteristics, drug doses, and other contributory factors.
In conclusion, based on the results of our systematic review, there were adverse effects reported when patients with known OSA underwent elective surgery with the currently available sedatives and anesthetics. Impaired airway patency in eight undiagnosed OSA patients, and uvular edema with intraoperative snoring in a known OSA patient with sedation using midazolam, have been described. Caution is suggested with the use of benzodiazepines. However, these reports are limited by the number of patients, their level of reported evidence, and the uniformity of reporting of outcomes. There is a need for further trials with large numbers and uniform reporting of outcomes.