Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing

doi:10.1016/0034-5687(91)90104-Q

Respiration Physiology

Volume 86, Issue 3, December 1991, Pages 333-343

Respiration Physiolo...

https://doi.org/10.1016/0034-5687(91)90104-Q Get rights and content

Abstract

The efficacy of carbonic anhydrase (CA) inhibitors in amelioration of periodic breathing during sleep at high altitude is not fully understood. Although CA is present in anumber of tissues, we hypothesized that selective renal CA inhibition without physiologically important inhibition of other tissue CA, may be sufficient alone by its generation of a mild metabolic acidosis to stimulate ventilation and prevent periodic breathing. We studied benzolamide (3 mg/kg), a selective inhibitor of renal CA, in 4 climbers on ventilation and ventilatory responses at sea level and on arterial O₂ saturation (Sa_O₂%) and periodic breathing during sleep at altitude. At sea level, ventilation increased and Pa_O₂ rose accompanied by a mild metabolic acidosis. The isocapnic hypoxic ventilatory response was unchanged but the hyperoxic hypercapnic ventilatory response rose 40%. At high altitude (4400 m), daytime Sa_O₂% improved from 81 to 85 and venous plasma HCO₃ fell from 18.9 to 14.8 mM. During sleep, mean Sa_O₂% rose from 76 to 80 and periodic breathing decreased 75%. We conclude that metabolic acidosis occurring with all CA inhibitors is one of the major stimulant actions of these drugs on ventilation while awake and during sleep at high altitude.

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CA inhibitors improve sleep-disordered breathing via several mechanisms. These include a reduced reabsorption of bicarbonate in the proximal tubule of the kidney, promotion of diuresis, increased cerebral blood flow, and a stimulation of ventilation via metabolic acidosis.77 Consequently, CA inhibitors induce a left-shift of the hypercapnic/ventilatory response curve, reduce apnea threshold, and stabilize breathing.78
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There have been a number of studies that have used pharmacological manipulation at high altitude to improve periodic breathing, including acetazolamide, dexamethasone, various hypnotics and theophylline. Oral acetazolamide has been shown by a number of authors to effectively suppress CSA by 50–80% at high altitude (Hackett et al., 1987; Sutton et al., 1980, 1979; Swenson et al., 1991). The efficacy of carbonic anhydrase (CA) inhibitors is the result of ventilatory stimulation and better arterial oxygenation driven by the metabolic acidosis and the slight CO2 retention from vascular CA IV inhibition and any partial red cell CA inhibition.
We provide an updated review on the current understanding of breathing and sleep at high altitude in humans. We conclude that: (1) progressive changes in pH initiated by the respiratory alkalosis do not underlie early (<48 h) ventilatory acclimatization to hypoxia (VAH) because this still proceeds in the absence of such alkalosis; (2) for VAH of longer duration (>48 h), complex cellular and neurochemical re-organization occurs both in the peripheral chemoreceptors as well as within the central nervous system. The latter is likely influenced by central acid-base changes secondary to the extent of the initial respiratory responses to initial exposure to high altitude; (3) sleep at high altitude is disturbed by various factors, but principally by periodic breathing; (4) the extent of periodic breathing during sleep at altitude intensifies with duration and severity of exposure; (5) complex interactions between hypoxic-induced enhancement in peripheral and central chemoreflexes and cerebral blood flow – leading to higher loop gain and breathing instability – underpin this development of periodic breathing during sleep; (6) because periodic breathing may elevate rather than reduce mean SaO₂ during sleep, this may represent an adaptive rather than maladaptive response; (7) although oral acetazolamide is an effective means to reduce periodic breathing by 50–80%, recent studies using positive airway pressure devices to increase dead space, hyponotics and theophylline are emerging but appear less practical and effective compared to acetazolamide. Finally, we suggest avenues for future research, and discuss implications for understanding sleep pathology.
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Furthermore, obesity is a risk factor for both IIH and OSA and may be a possible link between them [17–20]; indeed, one treatment option for IIH is weight reduction [21]. In addition, carbon anhydrase inhibitors such as acetazolamide that reduce the production of cerebrospinal fluid [22,23] and increase ventilatory drive [24,25] also lead to a reduction in arterial carbon dioxide tension (hypocapnia) and, consequently, reduced intracranial pressure [26]. The limitations of the study are the relatively small number of patients and lack of full evaluation by polysomnograpy.
Idiopathic intracranial hypertension may be associated with sleep apnea. This study evaluated the incidence of sleep breathing disorders in patients with idiopathic intracranial hypertension.
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Mean age of the study group was 32.6 ± 12.2 years and of the control group, 37.0 ± 12.9 years. Neither group had significant findings of hypoxia or hypercarbia during sleep, and there were no between-group differences in mean carbon dioxide level (patients, 35.8 ± 4.41 mmHg; controls, 37.6 ± 4.38 mmHg; p > 0.02) or minimal oxygen saturation (96.35 ± 1.99% and 5.69 ± 1.71%, respectively; p > 0.02). The study group had significantly more events of apnea (CO₂) per hour of sleep than the control group (1.21 ± 1.38 and 0.92 ± 0.56, respectively; p = 0.02), although values were still within normal range (<5/hr).
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Citation Excerpt :
As a carbonic anhydrase inhibitor, the drug promotes renal bicarbonate excretion, thus counteracting the hypoxia-induced respiratory alkalosis.22 The resulting reduction in pH stimulates ventilation and augments the hypercapnic ventilatory response.23,24 Hyperventilation dampens periodic breathing by moving the Paco2 on the isometabolic hyperbola to a steeper portion so that a larger overshoot in ventilation is required to reduce the Paco2 by a given amount (Fig 4).
Many patients with obstructive sleep apnea syndrome (OSA) are unable or unwilling to use continuous positive airway pressure (CPAP) therapy when traveling to the mountains for work or recreation even though they risk pronounced hypoxemia and exacerbation of sleep apnea. Because the treatment of OSA at altitude has not been established, we tested the hypothesis that acetazolamide improves hypoxemia, sleep, and breathing disturbances in otherwise untreated patients with OSA at altitude.
Forty-five patients with OSA on long-term CPAP, median age 64 years, living at < 600 m underwent a placebo-controlled, double-blind, crossover trial randomized for the sequence of drug and altitude exposure (490 m, 1,860 m, and 2,590 m). Patients spent two 3-day periods at altitude and a 2-week wash-out period at < 600 m. At altitude, patients discontinued CPAP and received acetazolamide 2 × 250 mg daily or placebo. Polysomnography, vigilance, and symptoms were evaluated.
At 490 m, off CPAP, median nocturnal oxygen saturation was 93%, and the apnea/hypopnea index was 51.2/h. On placebo at 1,860 m and 2,590 m, the corresponding values were 89% and 85% and 63.6/h and 86.2/h, respectively (P < .01 vs 490 m, both instances). On acetazolamide at 1,860 m and 2,590 m, oxygen saturation was higher (91% and 88%) and apnea/hypopnea indices were lower (48.0/h and 61.4/h) than on placebo (P < .01 all instances). Acetazolamide reduced nocturnal transcutaneous Pco₂, improved sleep efficiency and subjective insomnia, and prevented excessive BP elevations at altitude.
In patients with OSA discontinuing CPAP during an altitude sojourn, acetazolamide improves oxygenation, breathing disturbances, and sleep quality by stimulating ventilation. Therefore, patients with OSA may benefit from acetazolamide at altitude if CPAP therapy is not feasible.
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View full text

Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing

Abstract

Respir. Physiol.

Biochem. Pharmacol.

Respir. Physiol.

Mechanisms of hypoxia induced periodic breathing during sleep in humans

J. Physiol. (Lond.)

The effect of maintained ammonium chloride acidosis on the relation between pulmonary ventilation and alveolar oxygen and carbon dioxide in man

Q.J. Exp. Physiol.

Respiration and cerebral blood flow in metabolic acidosis and alkalosis in humans

J. Appl. Physiol.

Fluid retention and relative hypoventilation in acute mountain sickness

Respir. Physiol.

Respiratory stimulants and sleep periodic breathing at high altitude: Almitrine versus acetazolamide

Am. Rev. Respir. Dis.

250 mg acetazolamide intravenously does not increase cerebral blood flow at high altitude

Hastening respiratory acclimatization to altitude with benzolamide (CL 11366)

Aerospace Med.

Acute mountain sickness and acetazolamide: clinical efficacy and effect on ventilation

J. Am. Med. Assoc.

A comparison of the ventilatory response to carbon dioxide by steady state and rebreathing methods during metabolic acidosis and alkalosis

Clin. Sci. Mol. Med.

A simplified micromethod for determination of carbonic anhydrase and its inhibitors

J. Pharmacol. Exp. Ther.

The pharmacology of acetazolamide as related to cerebrospinal fluid and the treatment of hydrocephalus

Bull. Johns Hopkins Hosp.