Effect of acetazolamide on ventilatory response in subjects with chronic mountain sickness

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Abstract

Although the effects of acetazolamide (ACZ) on ventilation during acute mountain sickness are well known, there are no studies assessing its effect on ventilatory response in chronic hypoxia. We studied this effect in patients with chronic mountain sickness (CMS). Subjects with CMS, living permanently at 4300 m, were assigned in a randomized, double-blind study to 250 mg/day (n = 9) or to 500 mg/day (n = 9) of ACZ. Resting end-tidal PETO2 and end-tidal PETCO2 were measured before and after 3 weeks of acetazolamide. Ventilatory responses were evaluated by the determination of sensitivity to hypoxia and to CO2. After treatment ventilatory response to hypoxia increased, resting PETCO2 decreased, and ACZ caused a leftward shift in the position, but not a change in the slope of the ventilation (V˙E) versus PETCO2 relationship. There were no differences between the two doses used. ACZ administration provides a beneficial effect on respiratory function of high altitude natives with CMS and thus it can be an effective therapy for the disease.

Introduction

High altitude (HA) natives living at altitude settings have higher minute ventilation (V˙E) and lower end-tidal PCO2 (PETCO2) resting values than sea-level natives living at sea level. Furthermore, HA natives show acute hypoxic ventilatory responses (AHVR) considerably lower than those seen in sea-level natives (Milledge and Lahiri, 1967, Velasquez et al., 1968, Lahiri and Edelman, 1969, Weil et al., 1971). There is no direct proof that alterations in carotid bodies physiology cause the low values for AHVR in HA natives, but interestingly, carotid bodies of HA natives show great hypertrophy (Arias-Stella, 1969). With regard to sensitivity to CO2, under conditions of euoxia (PETO2=100Torr), total ventilatory sensitivity to CO2 and peripheral (fast) chemoreflex sensitivity to CO2 in HA natives is higher than in SL subjects. Hypoxia causes a lower increase in total CO2 sensitivity in HA subjects. Mean values for the time constant of response to CO2 for HA individuals are lower than for SL residents (Fatemian et al., 2003).

In addition, HA natives show increased hemoglobin and hematocrit values as part of a normal response to chronic hypoxia. However, HA natives may lose their adaptation to high altitude and display a variety of clinical symptoms, as well as excessive erythrocytosis. The combination of these features has been defined as chronic mountain sickness (CMS) (Hurtado, 1942, Monge and Whittembury, 1976). This syndrome has primarily been observed in Andean natives living at altitudes above 3,000 m, but it also occurs in almost all the high altitude regions of the world (Winslow and Monge, 1987, Ward et al., 1999). Compared with healthy high altitude natives, patients with CMS living at the same altitude are relatively hypoxic and hypercapnic (Severinghaus et al., 1966, Kryger et al., 1978). In the physiopathological sequence of CMS, these respiratory characteristics of the patients provoke hypoxemia, leading to excessive erythrocytosis (Winslow and Monge, 1987, Monge et al., 1992). We reasoned that these impaired respiratory characteristics may be pharmacologically modified with acetazolamide (ACZ), an inhibitor of carbonic anhydrase.

Carbonic anhydrases belong to a family of ubiquitous metalloenzymes that catalyse predominantly the reversible hydration–dehydration reaction of carbon dioxide to carbonic acid. They play an important role in a broad range of physiological functions including but not limited to respiration, CO2 transport, urinary acidification and ion transfer (Maren, 1967). Inhibition of renal carbonic anhydrase with ACZ leads to an increased urinary excretion of HCO3-, sodium and potassium, and to a decreased urinary excretion of titratable acids and ammonium. The loss of base precedes the development of metabolic acidosis, leading to increase of ventilation, a well-established effect (Skatrud and Dempsey, 1983, Teppema and Dahan, 1999). Thus, ACZ is useful in the prophylaxis of chronic obstructive pulmonary diseases, sleep-disordered breathing syndromes, and acute mountain sickness (Hackett et al., 1987, Burki et al., 1992, Swenson and Hughes, 1993, Bales and Timpe, 2004). By enhancing resting ventilation and ventilatory drive, which is secondary to metabolic acidosis, ACZ improves the blood oxygenation.

Although the effects of ACZ on ventilation in subjects exposed to acute hypoxia and in patients with acute mountain sickness are well documented (Burki et al., 1992, Swenson and Hughes, 1993), there are no studies on its effects on the ventilatory response in subjects with or without CMS who are exposed to chronic hypoxia.

A previous double-blind placebo-controlled study by our group showed that ACZ decreased hematocrit and serum erythropoietin, increased nocturnal arterial O2 saturation, and decreased mean nocturnal heart rate and the number of apnea/hypopnea episodes during sleep in CMS treated subjects (Richalet et al., 2005) when compared to those who received placebo. The overall decrease in erythropoietin was thought to be partly an indirect effect of ACZ through the increase in ventilation and thus in arterial O2 saturation (Richalet et al., 2005).

For patients with CMS, it is important to improve the chemical drive to breath. Thus we aimed to document the effect of clinical doses of ACZ on resting end-tidal PO2 (PETO2), end-tidal PCO2 (PETCO2) and minute ventilation (V˙E), and on the sensitivity of chemoreceptors to decreasing concentrations of inspired O2 fraction and to increasing concentrations of inspired CO2 fraction in subjects with CMS. We specifically aimed to extend our previous findings (Richalet et al., 2005), by comparing now the efficacy of two acetazolamide doses.

Section snippets

Methods

The study was performed in Cerro de Pasco, Peru, at an altitude of 4300 m. It was approved by the ethics committee of Cayetano Heredia University in Lima, Peru. A written informed consent was obtained from all participants before performing any study procedure.

This was a randomized doubled-blind study that compared the effect of two doses of acetazolamide in subjects with CMS, who had undergone a parallel study (Richalet et al., 2005). Subjects were assigned to 250 mg/day or to 500 mg/day of

Results

Subjects in both study groups were closely matched for baseline anthropometric and hematologic parameters (Table 1). From the original 20 subjects enrolled, two patients withdrew prematurely, one in each group, because of reasons not related to the study medication. Thus 18 subjects, 9 in each group, were finally studied. The mean data for resting ventilation, V˙E,PETO2,PETCO2, and SaO2 for all subjects before and after ACZ treatment are shown in Table 2. The drug increased resting ventilation (

Discussion

To our knowledge, this is the first study to assess the chronic effect of ACZ on ventilation and ventilatory control in subjects with CMS. We sought to determine if the chronic inhibition of carbonic anhydrase might show a similar therapeutic efficacy in chronic hypoxia, as it does in subjects exposed to acute hypoxia, due to its effects in improving the blood oxygenation. Our most important findings are that ACZ administered regularly during 3 weeks: (1) increased significantly the ventilatory

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