In this episode, I’ll discuss acetazolamide’s use as a respiratory stimulant in ICU patients.
Acetazolamide is a carbonic anhydrase inhibitor that has indications for use in altitude sickness, edema, and elevated intraocular pressure. However, acetazolamide also has potentially useful properties as a respiratory stimulant for certain ICU patients.
Patients recovering from a severe exacerbation of chronic obstructive pulmonary disease (COPD) often have difficulty weaning from mechanical ventilation. Metabolic alkalosis is a common finding in this patient population. The phrase given to metabolic alkalosis in COPD patients after mechanical ventilation is post-hypercapnic alkalosis.
Acetazolamide can reverse metabolic alkalosis, working in part by reducing the tubular reabsorption of bicarbonate. An additional effect is the inhibition of H+ secretion in the distal tubule. This leads to an alkaline diuresis, greatly increasing the amount of filtered bicarbonate that is eliminated in the urine. The maximum effect is reached at 24 hours, when about 5 mmol/L of bicarbonate is eliminated and blood pH can be expected to drop by somewhere between 0.05 to 0.1.
It is the metabolic acidosis from this effect of acetazolamide that has the potential to act as a respiratory stimulant. Chemoreceptors, both peripheral and central become stimulated by the acidosis and this can result in increased minute ventilation. The PaCO2 will decrease by about 5 mmHg. It is important to note that this effect will only occur if the ventilator settings do not place a limitation on the tidal volume or the respiratory rate.
The concomitant use of furosemide or corticosteroids can blunt the acidosis related effects of acetazolamide. This is because both furosemide and corticosteroids can increase H+ secretion at the distal tubule, reversing part of the effects of acetazolamide.
The exact dose to use and benefits to expect from acetazolamide as a respiratory stimulant in COPD patients have not been clearly defined in the available literature. Several studies have shown the effects of 500 mg of IV acetazolamide on surrogate endpoints such as blood pH and bicarbonate levels. One study compared acetazolamide 500 mg as a single dose with 250 mg every 6 hours for 4 doses. Within 72 hours the single dose reversed metabolic alkalosis just as well as the multiple-dose regimen.
Another study demonstrated that in the presence of furosemide the acetazolamide dose needed to be doubled to 500 mg IV twice daily to achieve the same 5 mmol/L decrease in bicarbonate as when furosemide was not present.
The failure of 500 mg daily doses of acetazolamide to achieve a meaningful difference vs historical controls to weaning COPD patients from mechanical ventilation has led to the use of higher doses in recent studies. The largest randomized controlled study to date was in nearly 400 mechanically ventilated COPD patients who received either 500 mg IV twice daily of acetazolamide or placebo. The dose of acetazolamide was doubled to 1000 mg IV twice daily if furosemide was also used. Metabolic alkalosis was corrected more frequently in the acetazolamide group but unfortunately, there was no difference in duration of mechanical ventilation. One possible explanation for this was the study was not adequately powered to detect a small difference in outcomes between groups.
The main adverse effect to watch for is the development of hypokalemia, and acetazolamide should be avoided in patients with cirrhosis due to hepatic encephalopathy or severe renal or hepatic dysfunction due to drug accumulation.
Because the available data is not conclusive, guidelines do not recommend routinely using acetazolamide as a respiratory stimulant. However, hospital pharmacists should be aware that acetazolamide may be employed in select patients with metabolic alkalosis and difficulty weaning from the ventilator. If this is the case, the pharmacist can also be vigilant for concomitant medications that would blunt the effects of acetazolamide, especially furosemide.
To get a free 2-page pdf of what a pharmacist should know about mechanical ventilation go to my free download area at pharmacyjoe.com/free, it’s number 6 on the list.
If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.