Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial

Introduction

Sleep is impaired in people who have recently arrived at high altitude. 1 2 Impairment is caused by a combination of factors, which include being in a new environment, the low temperature, general discomfort, and development of acute mountain sickness. A feature of sleep at high altitude is periods of awakening or arousal that are associated with pronounced oxygen desaturation and periodic breathing.3^–7 These episodes of periodic breathing may cause more unconsolidated sleep, which may lead to further episodes of periodic breathing.8 Consequently, daytime symptoms of drowsiness and reduced performance may occur.9 The use of benzodiazepine hypnotics may lessen the effects of periodic breathing and desaturation. 7 8

This study compared the effects of a comparatively low dose (10 mg) of the short acting benzodiazepine temazepam with placebo on the sleep patterns of subjects recently arrived at high altitude.

Subjects and methods

Shortly after arrival at 5300 m on Mount Everest nine men and two women (age range 26-46) were randomly selected from the 78 members of the British Mount Everest Medical Expedition. All participants gave informed consent. The study was approved by the Oxford regional ethics committee. A coin was tossed to randomly allocate participants to either temazepam (Norton Pharmaceuticals, Essex) or placebo (Advisory Services, London) on the first night followed by the other treatment on the second night. Participants were unaware which treatment they were given. However, the investigator was aware of participants' allocation at the time treatment was given because of the different sizes of tablets, but was not aware when data were analysed. Arterial oxygen saturation was measured continuously during the night (every 5 s) with a pulse oximeter and finger probe (Minolta Pulseox 7, De Vilbiss, Middlesex). Each morning quality of sleep was appraised subjectively by direct questioning.

The data on saturation and pulse rate were downloaded to a computer and analysed to find the mean saturation values and variation in saturation (the number of times saturation dropped >4% below mean value). Values were analysed with a paired, two tailed Student's t test (Statview SE and Graphics, version 1.04, Abacus Concepts, Berkeley, CA). P<0.05 was considered significant.

Results

Six participants took temazepam on the first night and placebo on the second and five took placebo on the first and temazepam on the second. The mean duration of recordings made during sleep was 408 minutes (SD 35 min). Length of recording was limited by sleep duration or oximeter battery life (whichever was shorter).

Mean arterial oxygen saturation —Temazepam had no significant effect on mean oxygen saturation during sleep when compared with placebo (table). The difference of 1.05% was not significant using a paired t test (P=0.54, df=10, 95% confidence interval −4.73 to 2.65). However, when participants took temazepam there was a significant decrease in the number of times that saturation fell >4% below the mean (P=0.0036); there were 25.81 fewer falls per hour that were >4% below the mean when participants took temazepam when compared with placebo (df=10, 10.7 falls per hour on temazepam v 40.9 falls per hour on placebo).The effect was more pronounced in the early hours of sleep. These effects were found regardless of whether participants were assigned to take temazepam or placebo first (figure).

Arterial oxygen saturation during 8 hours of sleep in one participant while taking placebo or temazepam. Each horizontal bar represents 1 hour of sleep

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Subjective changes in sleep —All participants reported an improvement in sleep when taking temazepam. Improvements noted included a quicker onset of sleep, better quality of sleep, fewer awakenings and less awareness of periodic breathing, and feeling more rested the next day. No participants complained of drowsiness the day after taking temazepam.

Discussion

In this study the use of temazepam during sleep at high altitude improved the subjective quality of sleep without reducing arterial oxygen saturation. The use of various benzodiazepines at high altitude has been considered in several previous studies.10^–14 Many of these have used high doses and long acting preparations which led to heavy sedation and marked desaturation. 11 14 There is, however, evidence that small doses of benzodiazepines may be beneficial in reducing central sleep apnoeas in susceptible patients.8

The reduction in the number of episodes of desaturation is in part due to the sedative effects of temazepam; these effects produce longer periods of consolidated sleep and lead to fewer of the arousals that are usually associated with sleep apnoea.8 By stabilising sleep and reducing the number of arousals, episodes of periodic breathing are similarly reduced. This leads to an improvement in the quality of sleep and a reduction in both the number of times desaturation occurs during sleep and the amount of desaturation that occurs. In this study the reduction in desaturation was more pronounced in the earlier hours of sleep when temazepam has its strongest effect. By the end of sleep its effect has weakened and saturation values become similar to those found in participants taking placebo.

Though this study suggests an important role for temazepam in reducing periods of desaturation during sleep at altitude it does not elucidate the mechanism by which this occurs. The dose required to produce an effect on desaturation is lower than that needed to produce adequate sedation for sleep at sea level. Although the sedative role of temazepam is important, temazepam is probably affecting desaturation by another pharmacological action. It may act directly by suppressing respiratory receptors or indirectly by affecting cerebral pH. This is analogous to the improvements in saturation found using carbonic anhydrase inhibitors such as acetazolamide.13