Acute mountain sickness occurs in man following rapid ascent to HA. The exact causes and mechanism of the development of AMS are unknown. Acetazolamide, a carbonic anhydrase inhibitor drug, is believed to be effective in preventing and ameliorating AMS;[3-5] however, the mechanism by which acetazolamide does so is unclear. It has been suggested that the mechanism may be related to improved oxygenation by inducing an increase in ventilation. Whether the increase in ventilation with acetazolamide is due to an altered baseline level of ventilation, or whether respiratory chemosensitivity to [CO.sub.2] or hypoxia is also altered during HA exposure is unknown. In addition, we previously have shown that the increase in ventilation which occurs following exposures to HA primarily is due to an increase in respiratory frequency, with little changein Vr, and it would be of interest to know whether the increased ventilation with administration of acetazolamide following HA exposure is associated with changes in the ventilatory pattern.
The present work was undertaken to examine, in a double-blind study, the effects of acetazolamide, given in a dose known to ameliorate AMS, on ventilation and respiratory chemosensitivity during HA exposure.
This was a double-blind study, comparing acetazolamide tablets to placebo tablets (ascorbic acid). Twelve healthy, male subjects (mean age [+ or -] SD = 20.3 [+ or -] 1.4 years) were selected for the study; none of them had any history or clinical evidence of cardiopulmonary or other systemis disease. Informed consent was obtained from each subject.
Measurements were made at SL in Rawalpindi, Pakistan (altitude 518 m) and following rapid transport (<8 h) to HA at 4,450 m in the Karakorum mountains. The subjects were randomly divided into two groups of six subjects each; in all subjects, baseline measurements were performed on two successive days at SL; following the measurements on the second day, the subjects were given either the placebo tablets (ascorbic acid, 500 mg), one tablet twice daily (group 1) or acetazolamide tablets, 250 mg twice daily (group 2) in a double-blind fashion, and measurements at SL were again made on the next day. The subjects were then transported by road, with an overnight stop, to the HA study site. The actual change from altitudes of lesss than 1,000 m to the final study altitude of 4,450 m occurred within 8 h. Studies at HA were performed starting at 32 h and 56 h after arrival.
Studies consisted of clinical observation, and measurements of resting ventilation and the ventilatory responses to [CO.sub.2] hypoxia and hyperoxia.
Clinical observation for AMS consisted of evaluation of dizzinees, nausea/vomiting and headache on a grade of 0 to 2 (-, +, ++); subjects also were examined by auscultation for the presence of pulmonary edema.
Resting ventilation was measured with the subjects seated, breathing through a Hans-Rudolph low deadspace (18 ml) one-way valve, to the inspiratory side of which was attached a pneumotachograph; the differential pressure signal from the pneumotachygraph was measured with a pressure transducer (Validyne PM15) and amplified and recorded (Messrs Gould, Inc, model 2400). The flow signal also was electronically integrated to volume and recorded. The [CO.sub.2] concentration was continuously measured at the mouth, using a [CO.sub.2] analyzer (Instrumentation Laboratory, model IL 200) and recorded. After it was ascertained that the seated subject was comfortable and at rest, a recording of resting ventilation and ventilatory pattern was made for a minimum of at least 30 breaths on each occasion.
The [SaO.sub.2] was measured noninvasively by means of an ear oximeter (Ohmeda BIOX 2). The mixed venous [Pco.sub.2] was measured by a standard re-breathing technique; the [PaCO.sub.2] was calculated from the measured mixed venous [Pco.sub.2]. The [PaO.sub.2] was calculated, using the alveolar air equation, from the measured inspired [Po.sub.2] and the calculated [PaCo.sub.2].
The steady state [CO.sub.2] response was measured at SL using a calibrated gas mixture of 4.95 percent [CO.sub.2] in oxygen, and at high altitude using a calibrated gas mixture of 11.13 percent [CO.sub.2] in oxygen. The differences in the two gas mixtures were chosen so that the inhaled [Pco.sub.2] was closely similar between SL and HA. A Douglas bag was filled with the [CO.sub.2] gas mixture and, without the subject's knowledge, was added to the inspiratory side of the circuit . The subject was allowed to continue to breathe the [CO.sub.2] mixture until it was judged that the end-tidal [CO.sub.2], measured by a [CO.sub.2] analyzer (Instrumentation Laboratory, model IL 200), and ventilation had become relatively constant; this usually took 5 to 7 min. At this point, ventilation and ventilatory pattern were recorded.
The ventilatory response to hypoxia was measured at SL and the response to hyperoxia was measured both at SL and HA. For these responses, the Douglas bag was filled either with 100 percent [O.sub.2] (hyperoxic response) or with a gas mixture of 12.65 percent [O.sub.2] in air (hypoxic response); this level of hypoxic gas mixture was chosen to approximate the [Po.sub.2] of inspired air at HA. The subjects was switched to breathing the Douglas bag without his knowledge and was allowed to breathe from the bag for 7 to 10 min and a recording of ventilation was made, for a minimum of 30 breaths, after ascertaining that the ventilatory and end-tidal [CO.sub.2] levels were stable.
Statistical analysis was performed by means of paired t tests within each group of subjects and unpaired t tests between the two groups.
The two groups were closely matched in anthropometric parameters: Placebo group - age, 20.7 [+ or -] 1.4 years; height, 174.2 [+ or -] 5.3 cm; weight, 62.4 [+ or -] 4.1 kg. Drug group - age, 20.2 [+ or -] 1.5 years; height, 178.3 [+ or -] 2.9 cm; weight, 65.2 [+ or -] 6.0 kg.
While AMS was more severe and more frequent (Table 1) in the placebo group, symptoms still occurred in the drug group. None of the subjects exhibited any signs of pulmonary edema. In the placebo group, valid data on ventilation and [CO.sub.2] responses were only available in five subjects, since subjects 2 had to be excluded due to severe mountain sickness.
[TABULAR DATA OMITTED]
In the placebo group, there were no significant differences in the measured [PvCO.sub.2], [PetCO.sub.2] or the calculated [PaCO.sub.2] and [PaO.sub.2] between the control day and day 1 at SL (Table 2.). On the other hand, in the drug group, there was a significant (p<0.01) increase in [PaO.sub.2] due to an increase in alveolar ventilation at SL (as evidenced by significant decreases in [PvCO.sub.2], [PetCO.sub.2] and [PaCO.sub.2] following acetazolamide therapy on day 1. As expected, at HA there were significant (p<0.01) decreases in [SaO.sub.2] and [PaO.sub.] and increases in alveolar ventilation and VE in both groups.
Within each group, there were no significant differences in measured ventilatory parameters at rest between the two days at SL (Table 2); at HA, in both groups VE rose significantly (p<0.05), and this increase was entirely due to an increase in respiratory frequency.
Between the two groups, there were no significant differences in [SaO.sub.2], [PvCO.sub.2] or [PetCO.sub.2] at SL, although alveolar ventilation (as indicated by [PVCO.sub.2], [PETCO.sub.2] and the calculated [PaCO.sub.2]) was higher in the drug group on day 1 (Table 2). At HA, [PvCO.sub.2], [PetCO.sub.2] and the calculated [PaCO.sub.2] were significantly (p<0.01) lower, and ventilation [SaO.sub.2] and [PaO.sub.2] were significantly (p<0.01) higher in the drug group, compared with the placebo group.
[TABULAR DATA OMITTED]
There was a significant (p<0.05) ventilatory response to [CO.sub.2] in each group, both at SL and at HA; however, there were no differences in the responses to [CO.sub.2] between the two groups either at SL or HA (Table 3). The actual Ve achieved in response to [CO.sub.2] was significantly greater (p<0.05) at HA in both groups compared with the corresponding SL values, and this was due to a significantly increased (p<0.05) respiratory frequency. However, the percentage of change from the baseline resting value at HA was not significantly different from the percentage of change from the baseline resting value at SL in either group.
At SL, there were no significant changes in Ve or ventilatory pattern in response to hyperoxia in either group (Table 3). In both groups, there was a significant ventilatory response to hypoxia (Table 3), but this did not differ between the groups. AT HA, in response to hyperoxia, there was no significant change in ventilation in either group; however, the ventilatory pattern changed in the drug group: VT decreased significantly in response to 100 percent [O.sub.2] and this change was significantly different from the placebo group.
[TABULAR DATA OMITTED]
The results of the present study indicate that acetazolamide exerts its beneficial effects on the symptoms of AMS in association with an increase in resting alveolar ventilation and oxygenation. However, acetazolamide in therapeutic doses previously shown to ameliorate AMS[3-5] does not alter ventilatory chemoresponsiveness.
Acute mountain sickness is the term applied to a constellation of symptoms, first described in writing by a Chinese official, ca 37 BC, consisting of anorexia, nausea, headache and vomiting, which occurs in healthy subjects within 4 to 8 h after ascent to HA. The precise cause of this symptom is unknown.
In a number of clinical studies,[3-5] acetazolamide pretreatment has been shown to ameliorate the symptoms of AMS, and the clinical observations in the present study are in accord with these previous findings; however, the present study, as well as most previous studies[3-5], indicate that acetazolamide pretreatment does not completely prevent AMS and, in some subjects, AMS may be quite severe despite acetazolamide treatment, as in subject 10 in the present study (Table 1).
Acetazolamide is a specific potent inhibitor of carbonic anhydrasae in the blood, brain and other tissues;[9,10] this results in [CO.sub.2] retention in the tissue and a metabolic acidosis; it also causes an increase in cerebral extracellular fluid [Pco.sub.2] and (H) + . This results in a stimulation of ventilation, presumably via both peripheral and central chemoreceptors, thus lowering [PaCO.sub.2] and increasing [PaO.sub.].
Studies at sea level examining the effects of acetazolamide on arterial blood gas values in normal human subjects at rest are surprisingly few;[11-13] these studies found no significant overall changes in [PaCO.sub.2], even though later workers have quoted these studies as indicating a significant stimulations of ventilation. However, it is to be noted that these studies[12,13] included very small numbers of subjects, between two and four subjects, with no control group. The present study noted a significnt increase in alveolar ventilation at SL following acetazolamide therapy; and these findings are consistent with animal studies and the known in vitro actions of acetazolamide.[15,16]
Whereas both [PaO.sub.2] [17,18] and [PAO.sub.2] [19,20] have been found to be increased with acetazolamide treatment in comparison with control subjects at HA, the reported effects on alveolar ventilation and [PaCO.sub.2] are conflicting. Cain and Dunn found no significant differences in [PaCO.sub.2] either at SL or HA between control subjects and those on acetazolamide; Evans et al did not begin acetazolamide therapy at sea level but reported no significant differences in [PaCO.sub.2] at HA between control subjects and those on acetazolamide therapy. In contrast, two other studies[17,20] noted significant differences in [PaCO.sub.2] between control and acetazolamide-treated groups at HA; unfortunately, these latter two studies did not measure [Pco.sub.2] or [Po.sub.2] values at SL in the two groups.
In the present study, evidence of change in alveolar ventilation is based on changes in Ve and measured [PetCO.sub.2] and [PvCO.sub.2], and the calculated [PaCO.sub.2], derived from the measured [PvCO.sub.2]. It could be argued that the relationship between [PvCO.sub.2] and [PaCO.sub.2] is altered by changes in acid-base status, cardiac output, and [SaO.sub.2]; however, the measured [PetCO.sub.2] values closely paralleled the calculated [PaCO.sub.2] values and provide confidence in these data. Further confirmation is provided by the closely related changes in the measured Ve and [SaO.sub.2] and the calculated [PaO.sub.2].
Our data indicate that acetazolamide therapy results in an increase in alveolar and minute ventilation, [SaO.sub.2] [PaO.sub.2] at SL and HA; this effect does not appear to be increased at HA, implying that acetazolamide induces a change in the baseline level of ventilation. Since there was no difference in ventilation responses to hypoxia between the two groups at SL, the differences in ventilation at HA between the groups are unlikely to be due to differences in the intrinsic ventilatory responsiveness to hypoxia.
It could be argued that a more specific evaluation of the hypoxic ventilatory response at SL could have been obtained under isocapnic conditions; however, recent reports[21,22] indicate that the ventilatory response varies with the duration of the hypoxic challenge. In view of this, it is unlikely that the conventional measurement of the acute, isocapnic hypoxic ventilatory response would provide more useful information than the technique used in the present study. Indeed, we chose to preferentially measure the steady state, poikilocapnic ventilatory response for the very reason that it more closely mimics the actual hypoxic stimulus at high altitude.
Our results confirm our previous findings that the increase in ventilation with exposure to HA is primarily mediated by a significant increase in respiratory frequency with little change in tidal volume. Acetazolamide treatment does not significantly alter this ventilatory pattern at HA.
Since acetazolamide treatment alters the acid/base status of the internal milieu, it was of interest to study whether, in causing an acidosis, it also alters ventilatory responsiveness to [CO.sub.2]. In the present study, we examined the hyperoxic [CO.sub.2] response at SL and at HA in order to avoid the confounding effects of hypoxia. The results suggest that acetazolamide treatment does not alter the ventilatory response to [Co.sub.2] at SL or at HA. While the absolute Ve achieved in response to hypoxic [CO.sub.2] stimulation was significantly greater at HA in both groups, this was primarily a reflection of the increased resting ventilation, since the percentage of change from baseline ventilation at HA was similar to the percentage of change from baseline ventilation at SL. However, while it would be reasonable to interpret these results as indicating that acetazolamide treatment alters the baseline level of ventilation, but does not alter respiratory chemosensitivity, there was a trend toward a greater ventilatory response to [CO.sub.2] in the drug group. Further, it is possible that the lack of a significant statistical difference reflects the relatively small numbers of subjects in each group.
The absence of any significant change in ventilation in response to acute hypoxia in the placebo group at HA is in accordance with our previous findings. The change in ventilatory pattern in response to hyperoxia in the acetazolamide treatment group is surprising and the mechanism is nuclear.
Studies[24,25] have shown that acetazolamide treatment improves the periodic breathing and [O.sub.2] desaturation which occurs during sleep at HA. None of these studies is directly comparable in data or intent to the present work, in that none of them report data on the same subjects at SL and AT HA, and the HA studies were performed on well-acclimatized subjects during sleep. Nevertheless, Hackett et al also did not find any difference between acetazolamide treatment compared with placebo in the ventilatory response to hypoxia at HA.
It is generally held that the primary stimulus for the development of AMS must be the reduced ambient [Po.sub.2] at increasing altitude. The tissue hypoxia which results may impair cellular function affecting cellular oxidative processes, and it may that the symptoms of AMS are a consequence of these changes. However, it could be argued that, if this is the primary cause of AMS, then similar symptoms should occur in patients who rapidly develop hypoxemia at SL; clinical experience indicates that this is not so: patients with acute hypoxic respiratory failure, eg, due to ARDS or pulmonary embolism, do not usually develop headache, nausea or vomiting. Clearly, therefore, other factors are at work. Alterations in fluid balance have been implicated in AMS; fluid retention has been proposed as the culprit.[26-28] However, the rapid onset of AMS - within 4 h, in many cases - makes it very unlikely that any significant fluid retention can develop in this time period; furthermore, patients at SL, who develop acute oliguric renal failure do not exhibit the symptoms of AMS. Another suggestion is a shift of intracellular fluid to the extracellular space, in response to hypoxia, but the data remain inconclusive. Another factor that has been implicated is an increase in cerebral blood flow; however, recent studies imply that this is unlikely to be a casual factor. Furthermore, while acetazolamide is known to increase cerebral blood flow, this action does not appear to be related to its beneficial effect in AMS.
The fact that AMS occurs initially following ascent to HA, and the symptoms abate 24 to 48 h, suggests either that the body adjust to the factors responsible or that these factors themselves decrease or disappear. While the changes in [PaO.sub.2] and [PaCO.sub.2] persists with continued sojourn at HA, the acute change in acid-base status toward alkalinity gradually reverts. Therefore, the possibility exists that AMS is the result of the acute development of arterial tissue and CSF alkalinity in association with hypoxemia. Although Sutton et al have shown an inverse correlation between arterial pH and severity of AMS, their analysis did not examine whether this correlation remained after adjusting for [PaO.sub.2]; the data suggest otherwise. The beneficial effects of acetazolamide could possibly be explained on the basis of an increased alveolar ventilation, and better arterial oxygenation for a given arterial pH.
In summary, the present study results confirm previous findings on the efficacy of acetazolamide treatment in partial amelioration, but not complete effectiveness, in preventing AMS. The results further confirm that acetazolamide treatment results in a lower baseline resting [PaCO.sub.2] and higher resting minute and alveolar ventilations and [PaO.sub.2] and SL and HA; this is achieved without significantly altering the ventilatory pattern changes which occur on exposure to HA. Finally, respiratory chemosensitivity to [CO.sub.2] is not altered at SL or HA by accetazolamide treatment.
 Gilbert DL. The first documented report of mountain sickness: the China or headache mountain story. Respir Physiol 1983; 52:315-26  Johnson TS, Rock PB. Current concepts: acute mountain sickness. N Engl J Med 1988; 319:841-45  Greene MK, Keer AM, McIntosh IB, Prescott RJ. Acetazolamide in prevention of acute mountain sickness; a double-blind controlled cross-over study. Br Med J 1981; 283:811-13  Hackett PH, Rennie D, Levine HD. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976; 2:11:1149-54  Larson EB, Roach RC, SChoene RB, Hornbein TF. Acute mountain sickness and acetazolamide. JAMA 1982; 248:328-32  Burki NK. Effects of acute exposure to high altitude on ventilatory drive and respiratory pattern. J Appl Physiol: Respirant Environ Exercise Physiol 1984; 56:1027-31  Burki NK. Resting ventilatory pattern, mouth occlusion pressure, and effect of aminophylline in asthma and chronic airways obstruction. Chest 1979; 765:629-35  McEvoy JDS, Jones NL, Campbell EJM. Mixed venous and arterial [PCO.sub.2]. Br Med J 1974; 2:687-90  Hauser D, Astrup J, Lassen NA, Betz E. Brain carbonic acidosis after acetazolamide. Acta Physiol Scand 1975; 93:385-90  Swenson ER. The respiratory aspects of carbonic anyhydrase. Ann NY Acad Sci 1984; 429:547-60  Becker EL, Hodler JE, Fishman AP. Effect of carbonic anhydrase inhibitor (6063) on arterial-alveolar [CO.sub.2] gradient in man. Proc Soc Exp Med Biol 1953; 84:193-95  Galdson M. Respiratory and renal effects of a carbonic anhydrase inhibitor (Diamox) on acid-base balance in normal man and in patients with respiratory acidosis. Am J Me 195; 19:516-32  Nadell J. The effects of the carbonic anhydrase inhibitor "6063" on electrolytes and acid-base balance in two normal subjects and two patients with respiratory acidosis. J Clin Invest 1953; 32:622-29  Skaturd JB, Dempsey JA. Relative effectiveness of acetazolamide versus medroxyprogesterone acetate in correction of chronic carbon dioxide retention. Am Rev Respir Dis 1983; 127:405-12  Carter ET, Clark RT. Respiratory effects of carbonic anhydrase inhibition in the trained anesthetized dog. J Appl Physiol 1958; 13:42-26  Tomashefski JF, Chinn HI, Clark RT. Effect of carbonic anhydrase inhibition on respiration. Am J Physiol 1954; 177:451-54  Birmingham Medical Research Expeditionary Society Mountain Sickness study group. Acetazolamine in control of acute mountain sickness. Lancet 1981; Jan:180-83  Evans WO, Robinson SM, Horstman DH, Jackson RE, Weiskopf. Amelioration of the symptoms of acute mountain sickness by staging and acetazolamide. Aviat Space Environ Med 1976; 47:512-16  Cain SM, Dunn JE. Low doses of acetozolamide to aid accommodation of men to altitude. J Appl Physiol 1966; 21:1195-1200  Forward SA, Landowne M, Follansbee JN, Hansen JE. Effect of acetazolamide on acute mountain sickness. N Engl J Med 1968; 279:839-45  Bender PR, WEil JV, Reeves JT, Moore LG. Breathing pattern in hypoxic exposures of varying duration. J Appl Physiol 1987; 62:640-45  Easton PA, Slykerman LJ, Anthonisen NR. Ventilatory response to sustained hypoxia in normal adults. J Appl Physiol 1986; 61:906-11  Rebuck AS, Campbell EJM. A clinical method for assessing the ventilatory response to hypoxia. Am Rev Respir Dis 1974; 109:345-50  HAckett PH, Roach RC, Harrison GL, Schocne RB, Mills WJ. Respiratory stimulants and sleep periodic breathing at high altitude. Am Rev Respir Dis 1987; 135:896-98  Sutton JR, Gray GW, Houston CS, Powles ACP. Effects of duration at altitude and acetazolamide on ventilation and oxygenation during sleep. Sleep 1980; 3:455-64  Milledge JS. Acute mountain sickness (Editorial). Thorax 1983; 38:641-45  Hackett PH, Rennie D. Hofmeister SE, Grover RF, Grover EB, Reeves JT. Fluid retention and relative hypoventilation in acute mountain sickness. Respiration 1982; 43:321-29  Singh I, Khanna PK, Srivastava MC, Madan LM, Roy SB, Subramanyam CSV. Acute mountain sickness. N Engl J Med 1969; 280:175-84  Hansen JE, Evans. WO. A hypothesis regarding the pathophysiology of acute mountain sickness. ARch Environ Health 1970; 21:666-69  Reeves JT, Moore LG, McCullough RG, Harrison G, Tranmer BI, Micco AJ, et al. Headache at high alititude is not related to internal carotid arterial blood velocity. J Appl Physiol 1985; 59:909-15  Enrenreich DL, Burns Alman RW, Fazekas JF. Influence of acetazolamide on cerebral blood flow. Arch Neurol 1961; 5:227-32  Wright AD, Brandwell AR, Jensen J, Lassen N. Cerebral blood flow in acute mountain sickness and treatment with acetozolamide. Clin Sci 1988; 74(suppl 18):1P  Haldane JS, Kellas AM, Hennaway EL. Experiments on acclimatization to reduced atmospheric pressure. J Physiol 1919; 53:181-206  Sutton JR, Bryan AC, Gray GW, Horton ES, Rebuck AS, Woodley W,et al. Pulmonary gas exchange in acute mountain sickness. Aviat Space Environ Med 1976; 47:1032-37
COPYRIGHT 1992 American College of Chest Physicians
COPYRIGHT 2004 Gale Group