Surgical procedures are routinely performed as an alternative to continuous positive airway pressure treatment in patients with obstructive sleep apnea (OSA). However, the response to surgery is often variable. Instability of the respiratory control during sleep (or high loop gain) has been associated with poor surgical results in previous research. Acetazolamide (AZM), a carbonic anhydrase inhibitor, has shown potential in reducing loop gain without affecting other physiological OSA traits. In this protocol the investigators will evaluate the clinical efficacy of AZM add-on therapy to surgical procedures in patients with OSA.

Seventy-four patients with diagnosed moderate to severe OSA will be equally (1:1) randomized to AZM (250 mg twice daily) or placebo add-on therapy after surgery. Two surgical procedures will be performed throughout the study: barbed reposition pharyngoplasty (BRP) and upper airway stimulation (UAS) using electrical neurostimulation of the hypoglossal nerve.

Treatment allocation will occur after a satisfactory recovery in patients undergoing BRP and after titration of the device settings in patients treated with UAS. Treatment outcome will be assessed approximately 10 weeks thereafter by in-laboratory polysomnography. Two on-site follow-up visits will be scheduled to assess adherence and adverse events. The maximum treatment duration per participant will amount to 16 weeks.

Besides the aforementioned core clinical part, the study protocol will also include an optional exploratory part prior to surgery, assessing the physiological OSA traits and airflow features by means of polysomnography and drug-induced sleep endoscopy research measurements.

Inclusion Criteria:

• Diagnosis of moderate to severe OSA (i.e. 15≤ AHI <65 events per hour)
• Eligibility for either BRP or UAS surgery
• Fitness for general anesthesia (ASA ≤2)
• Capability of giving informed consent and willingness to undergo surgery

Exclusion Criteria:

• Craniofacial anomalies affecting the UA

• Body mass index (BMI) >35 kg/m²

• General contra-indications for surgery

• Central sleep apnea (defined as central AHI ≥5 events per hour)

• Contra-indications related to acetazolamide treatment

  • Hypersensitivity to sulfonamides or acetazolamide
  • Renal impairment (eGFR <60 ml/min/1.73m²), electrolyte imbalances (sodium levels <135 mmol/L or potassium levels <3.5 mmol/L) and/or adrenocortical insufficiency
  • Clinically significant neurological, metabolic (including diabetes mellitus type 1 or 2), hepatic (alanine transaminase or aspartate transaminase >2 times the upper limit of normal) and/or hematological disease
  • Chronic obstructive pulmonary disease
  • Closed-angle glaucoma
  • Professional driving or handling complex machinery due to the potential risk of exaggerated daytime sleepiness

• Concomitant intake of drugs that influence breathing, sleep, arousal and/or muscle physiology

• Inability of the patient to understand and/or comply to the study procedures

• Active psychiatric disease (psychotic illness, major depression, anxiety attacks, and alcohol or drug abuse) which prevents compliance with the requirements of the research setting

• Pregnancy or willing to become pregnant