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EFFECT OF I.V. MIDAZOLAM ON THE VENTILATORY RESPONSE TO SUSTAINED HYPOXIA IN MAN
British Journal of Anaesthesia 1991; 66: 454-457
EFFECT OF I.V. MIDAZOLAM ON THE VENTILATORY RESPONSE TO SUSTAINED HYPOXIA IN MAN A. DAHAN AND D. S. WARD
SUMMARY
SUBJECTS AND METHODS
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
We studied five healthy male subjects (mean age 24 yr, mean body weight 77 kg) with no history of cardiovascular or respiratory disease. Informed consent was obtained and the local subjects protection committee approved the study. All subjects were naive to respiratory physiology and unaware of the purpose of this study, but had participated before in other respiratory studies. They were asked to refrain from stimulants for at least 12 h before the experiment. The subjects breathed via a mouthpiece and wore a noseclip. The oxygen and carbon dioxide KEY WORDS concentrations and the gas flow of the inspired Hypnotics: midazolam. Ventilation: hypoxic response. and expired gas were measured with a mass spectrometer (Perkin Elmer 1100 MGA, U.S.A.) The sudden imposition of isocapnic hypoxia and a turbine flow meter (VMM-1, Sensor results in a rapid increase in ventilation in awake Medics, U.S.A.), respectively. The ECG was man. However, this initial period of hyper- monitored and a pulse oximeter (Ohmeda Biox ventilation is usually not sustained longer than 3700, U.S.A.) used to measure arterial oxygen 5 min and is followed by a slow decrease in saturation via an ear probe. The tidal volume, ventilation ( F E ) that reaches a new steady state ventilatory frequency, F E and end-tidal partial F E after 15-20 min [1, 2]. The initial increase in pressures of carbon dioxide (ft'co,) and oxygen F E is driven by peripheral chemoreceptors, while (PE' OJ ) were calculated by a computer and stored the subsequent decrease has a central origin [3]. It on a breath-to-breath basis using the TIDAL has been suggested that the release or accumu- software package [8]. lation, or both, of inhibitory neuromodulators The mouthpiece and flowmeter were connected such as y-aminobutyric acid (GABA) and to a gas mixing chamber. The gas flow to the adenosine in the brainstem during exposure to chamber was controlled by two servo valves, by moderate hypoxia is the main cause of the hypoxic which the flows of oxygen and carbon dioxide ventilatory depression [4—6]. could be set individually as desired. The main Until recently, only the effects of drugs on the flow of gas in the mixing chamber consisted of acute hyperventilatory response have been stud- nitrogen, room air, or both. The computer ied. The effects on prolonged hypoxia have been provided control signals to the servo valves, so investigated only rarely. Midazolam, in common with other benzodiazepines, potentiates the effects of GABA [7] and thus could potentially change ALBERT DAHAN, M.D., PH.D., Department of Anestbcsiology, the ventilatory response to sustained hypoxia. We University of Leiden, PO Box 9600, 2300 RC Leiden, The DENHAM S. WARD, M.D., PH.D., Department of therefore investigated the effect of midazolam on Netherlands. Anesthesiology, UCLA School of Medicine, Los Angeles, CA the development of hypoxic ventilatory change in 90024-1778, U.S.A. Accepted for Publication: October 30, man. 1990. The ventilatory response to isocapnic, sustained hypoxia is characterized by initial hyperventilation followed by ventilatory decline. The ventilatory response to isocapnic sustained hypoxia during i.v. administration of midazolam was assessed in five healthy subjects. Compared with control experiments, the hyperventilatory effect of hypoxia was not decreased following administration of midazolam. The hypoxic ventilatory change was significantly greater with midazolam because of a decrease in tidal volume.
MIDAZOLAM AND HYPOXAEMIC VENTILATORY RESPONSE
455
TABLE I. Ventilatory response to hypoxia (mean (SD)). A = 3-min period before hypoxia; B = 3-min period following the first 2 min of hypoxia; C = 12—15 min of hypoxia. P ^ 0.05 compared with * period A or ^period B Period A
Period B
Period C
6.16(0.55) 6.27 (0.39)
6.08 (0.54) 6.23(0.41)
6.11 (0.58) 6.21 (0.42)
14.52 (0.09) 14.53 (0.05)
7.02 (0.06)* 6.93 (0.08)*
7.02 (0.03)* 7.03 (0.07)*
12.20(5.21) 8.45 (3.23)
21.49(10.96)* 15.24 (6.34)*
19.19(8.52)* 9.28 (3.57)t
0.96 (0.26) 0.71 (0.23)
1.43(0.44)* 1.01 (0.34)*
1.28(0.42)* 0.77 (0.24)+
13.93 (3.94) 13.97 (0.76)
15.74(3.97)* 16.55 (2.85)
16.16(2.67)* 14.35(1.90)
PE'CO, (kPa)
that the composition of the inspiratory gas mixture could be adjusted to permit PE'COI and PE' O to follow a specific dynamic pattern in time. After the subjects arrived at the laboratory, an i.v. infusion of normal saline 100 ml h"1 was started. Subsequently, the subjects rested for 30 min. Following this rest period, a control hypoxic experiment was performed. Subsequently, an infusion of midazolam 0.025 mg kg"1 was given over 10 min, followed by a continuous infusion of 1.0 mg/70 kg h"1. Thirty minutes after the start of the infusion, a second experiment was performed. The experiments consisted of a 5-min period of steady state ventilation during which PE'OI was held constant at 14.5 kPa, followed by a rapid decrease in PE' OJ to 7 kPa, which was maintained constant for 20 min. Each hypoxic episode was followed by inhalation of 100% oxygen for 7 min to eliminate residual effects of hypoxia [4]. During the control experiment, PE'COI w a s increased to slightly greater than resting value and kept constant at this value during both control and midazolam experiments (PE'CO, 5.5—6.2 kPa between subjects), to anticipate the development of hypercapnia after infusion of midazolam and to maintain control of PE'CO, even if VE decreased to less than the normoxic value.
period following the first 2 min of hypoxia (period B), and 12-15 min of the hypoxic period (period C). The prolonged hypoxia caused some subjects to become restless towards the end of the period, particularly during the control studies. As this occurred generally during the last 5 min, this period was excluded from analysis. Data were subjected to two-way analysis of variance with post-hoc multiple comparisons with Newman-Keuls test and paired t test as appropriate using the SOLO (BMDP Inc.) computer package. P < 0.05 was taken as significant. RESULTS
All subjects became lightly sedated during the administration of midazolam, but remained easily rousable. None experienced any side effects and all had partial amnesia for the procedure. The mean values of the variables for the periods A, B and C are shown in table I. During the control experiments, all but one subject showed the typical biphasic response after exposure to hypoxia. The mean initial increase in VE of 9.3 litre min"1 was followed by a small decrease of 2.3 litre min"1. During the midazolam experiments, the mean ventilatory increase of 6.8 litre min"1 was followed by a decrease of 5.9 litre min"1, which resulted in an almost comData analysis plete return of VE to its initial value. In three For statistical comparisons, we calculated the subjects VE was reduced in period C to less than mean of the breath-to-breath values of the 3-min that of period A. One subject showed no deperiod before • hypoxia (period A), the 3-min pression in his control experiment (fig. 1).
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
Control Midazolam PE' O , (kPa) Control Midazolam VE (litre min"1) Control Midazolam Tidal volume (litre) Control Midazolam Ventilatory frequency (b.p.m.) Control Midazolam
BRITISH JOURNAL OF ANAESTHESIA
456
Control 15.0-,
viidazolam
•
• f 12.5
a
•
15.012.5
10.0-
•
•
•
7.5
o
ID
. •
•
1 10.0=
• •
•
7.5 • • •
•
5.0-
t
2.5
. . • • • '
t
2.5
0240
280 720 Time (s)
960
0
1200
240
280 720 Time (s)
960
1200
FIG. 1. Comparison of the ventilatory response to sustained isocapnic hypoxia in control and midazolam studies in a single subject. Each point represents a 60-s average of the brcath-to-breath values. At time I = 300 s (arrows), hypoxia was induced. TABLE II. Mean (SD) changes in Pfi'o, and PE'Q, (Period B - period A)
(Period C - period B)
Control Midazolam
-0.08(0.12) -0.04 (0.05)
-0.03(0.10) 0.02 (0.06)
Control Midazolam
-7.50(0.14) -7.60(0.08)
-0.00 (0.05) -0.11 (0.12)
The ventilatory increase from period A to period B did not differ significantly between control and midazolam experiments. However, the subsequent decrease from period B to period C, expressed as the ratio of ventilatory decrease to ventilatory increase, was greater in the midazolam group (96 % vs 18 %, P = 0.01). Visual inspection of the dynamics of the ventilatory response revealed that, in the four subjects who showed a decrease in the control experiments, the onset of decrease occurred at 4-6 min, while in the midazolam experiments it was at 1-3 min. The control of PE' COI and PE'Ot in these experiments is important, because of the pronounced effect of their interaction on ventilation. The relatively large SD of PE' COI in the different periods in table I reflect inter-subject variability and not changes with time in one subject. This is shown in table II, where the average changes in PE' COJ and PE'O, for the three periods are given. PE' COJ was slightly greater during the midazolam experiments than during the control experiments (approximately 0.1 kPa).
DISCUSSION
Hypoxic hyperventilation. Although the acute ventilatory response to hypoxia was decreased with midazolam, it was not statistically significant in our group of subjects. This is at variance with the findings of Alexander and Gross [9], who found a reduced response after midazolam O.lmgkg"1 i.v. administered over 5 min. The i.m. administration of diazepam 10 mg resulted also in a marked decrease in hyperventilatory response to hypoxia [10]. The discrepancy between these findings and ours may have been caused by several mechanisms: the small number of subjects in our study; the smaller dose used in our study, which caused less sedation; the slightly greater PE'COf in our midazolam experiments compared with the control experiments, which may have masked the decrease in the initial hyperventilation; and the use of a ramp hypoxic test, compared with the step hypoxic test we used. We found that the onset of ventilatory depression in the midazolam experiments was faster than that
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
0
MIDAZOLAM AND HYPOXAEMIC VENTILATORY RESPONSE
[9], and we suggest that the oxygenation of patients receiving sedative doses of midazolam should be monitored and the inspired oxygen concentration increased. ACKNOWLEDGEMENTS A. D. was supported by grants from the Netherlands Organisation for the Advancement of Pure Research (NWO) and the Anesthesia Education Foundation (Los Angeles, California). REFERENCES 1. Kagawa S, Stafford MJ, Waggener TB, Severinghaus JW. No effect of naloxone on hypoxia-induccd ventilatory depression in adults. Journal of Applied Physiology 1982; 52: 1030-1034. 2. Easton PA, Slykerman LJ, Anthonisen NR. Ventilatory response to sustained hypoxia in normal man Journal of Applied Physiology 1986; 61: 906-911. 3. Vizek M, Pickett CK, Weil JV. Biphasic ventilatory response of adult cats to sustained hypoxia has central origin. Journal of Applied Physiology 1987; 63: 1658-1664. 4. Easton PA, Slykerman LJ, Anthonisen NR. Recovery of ventilatory response to hypoxia in normal adults. Journal of Applied Physiology 1988; 64: 521-528. 5. Neubauer JA, Melton JE, Edelman NH. Modulation of respiration during brain hypoxia. Journal of Applied Physiology 1990; 68: 441-451. 6. Kneussle MP, Pappaginopoulos P, Hoop B, Kaseris H. Reversible depression of ventilation and cardiovascular function by ventriculocisternal perfusion with ir-aminobutyric acid in dogs. American Review of Respiratory Disease 1986; 133: 1024-1028. 7. Haefly WE. Benzodiazepines. International Anesthesiology Climes 1988; 26: 262-272. 8. Jenkins JS, Valcke CP, Ward DS. A programmable system for acquisition and reduction of respiratory physiological data. Annals of Biomedical Engineering 1989; 17: 93-108. 9. Alexander CM, Gross JB. Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesthesia and Analgesia 1988; 76: 377-382. 10. Lakshminarayan S, Sahn SA, Hudson LD, Weil JV. Effect of diazepam on ventilatory responses. Clinical Pharmacology and Therapeutics 1976; 20: 178-183. 11. Suzuki A, Nishimura M, Yamamoto H, Miyamoto K, Kishi F, Kawakami Y. No effect of brain blood flow on ventilatory depression during sustained hypoxia. Journal of Applied Physiology 1989; 66: 1674-1678.
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
in the control group. It is therefore possible that, in contrast with their control group, by using a ramp decline in PE'O,, Alexander and Gross encountered the effects of hypoxic depression in their midazolam group. Hypoxic ventilatory decrease. The magnitude of the hypoxic ventilatory decrease in our control group (18% of the initial increase) was smaller than the 64% decrease reported by Easton, Slykerman and Anthonisen [2]. However, it is similar to that found by Suzuki and colleagues [11], who reported that VE tended to decrease more clearly during sustained hypoxia in subjects with reduced hyperventilatory responses, whereas the change in VE was less apparent in subjects with increased hyperventilatory responses. Most of our subjects were in the latter group. There are several possible mechanisms for the increase in the hypoxic ventilatory decrease observed in the midazolam experiments: an effect of the control experiment on the effects of midazolam; an effect of midazolam on the hypoxic peripheral chemoreceptor activation; an interaction of midazolam with the GABA-benzodiazepine receptor complex in the brain stem during hypoxia [7]; and an effect of midazolam on supra-pontine structures. Although none of the above can be excluded, the potentiation of the effect of GABA by midazolam during exposure to hypoxia is the most likely explanation for our observations. The further decrease in tidal volume with midazolam (table I) is typical for the GABAmediated depression of VE [6]. Our study supports the hypothesis that the ventilatory decrease with hypoxia results, at least partly, from accumulation of the neuromodulator GABA. The effect of midazolam on the hypoxic ventilatory decrease has some important clinical implications. Patients receiving sedative doses of midazolam who develop hypoxaemia may react with initial hyperventilation. Sustained hypoxaemia would result in decreased ventilatory drive and a further decrease in oxygenation. Midazolam obscures the usual clinical signs of hypoxaemia
457
EFFECT OF I.V. MIDAZOLAM ON THE VENTILATORY RESPONSE TO SUSTAINED HYPOXIA IN MAN A. DAHAN AND D. S. WARD
SUMMARY
SUBJECTS AND METHODS
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
We studied five healthy male subjects (mean age 24 yr, mean body weight 77 kg) with no history of cardiovascular or respiratory disease. Informed consent was obtained and the local subjects protection committee approved the study. All subjects were naive to respiratory physiology and unaware of the purpose of this study, but had participated before in other respiratory studies. They were asked to refrain from stimulants for at least 12 h before the experiment. The subjects breathed via a mouthpiece and wore a noseclip. The oxygen and carbon dioxide KEY WORDS concentrations and the gas flow of the inspired Hypnotics: midazolam. Ventilation: hypoxic response. and expired gas were measured with a mass spectrometer (Perkin Elmer 1100 MGA, U.S.A.) The sudden imposition of isocapnic hypoxia and a turbine flow meter (VMM-1, Sensor results in a rapid increase in ventilation in awake Medics, U.S.A.), respectively. The ECG was man. However, this initial period of hyper- monitored and a pulse oximeter (Ohmeda Biox ventilation is usually not sustained longer than 3700, U.S.A.) used to measure arterial oxygen 5 min and is followed by a slow decrease in saturation via an ear probe. The tidal volume, ventilation ( F E ) that reaches a new steady state ventilatory frequency, F E and end-tidal partial F E after 15-20 min [1, 2]. The initial increase in pressures of carbon dioxide (ft'co,) and oxygen F E is driven by peripheral chemoreceptors, while (PE' OJ ) were calculated by a computer and stored the subsequent decrease has a central origin [3]. It on a breath-to-breath basis using the TIDAL has been suggested that the release or accumu- software package [8]. lation, or both, of inhibitory neuromodulators The mouthpiece and flowmeter were connected such as y-aminobutyric acid (GABA) and to a gas mixing chamber. The gas flow to the adenosine in the brainstem during exposure to chamber was controlled by two servo valves, by moderate hypoxia is the main cause of the hypoxic which the flows of oxygen and carbon dioxide ventilatory depression [4—6]. could be set individually as desired. The main Until recently, only the effects of drugs on the flow of gas in the mixing chamber consisted of acute hyperventilatory response have been stud- nitrogen, room air, or both. The computer ied. The effects on prolonged hypoxia have been provided control signals to the servo valves, so investigated only rarely. Midazolam, in common with other benzodiazepines, potentiates the effects of GABA [7] and thus could potentially change ALBERT DAHAN, M.D., PH.D., Department of Anestbcsiology, the ventilatory response to sustained hypoxia. We University of Leiden, PO Box 9600, 2300 RC Leiden, The DENHAM S. WARD, M.D., PH.D., Department of therefore investigated the effect of midazolam on Netherlands. Anesthesiology, UCLA School of Medicine, Los Angeles, CA the development of hypoxic ventilatory change in 90024-1778, U.S.A. Accepted for Publication: October 30, man. 1990. The ventilatory response to isocapnic, sustained hypoxia is characterized by initial hyperventilation followed by ventilatory decline. The ventilatory response to isocapnic sustained hypoxia during i.v. administration of midazolam was assessed in five healthy subjects. Compared with control experiments, the hyperventilatory effect of hypoxia was not decreased following administration of midazolam. The hypoxic ventilatory change was significantly greater with midazolam because of a decrease in tidal volume.
MIDAZOLAM AND HYPOXAEMIC VENTILATORY RESPONSE
455
TABLE I. Ventilatory response to hypoxia (mean (SD)). A = 3-min period before hypoxia; B = 3-min period following the first 2 min of hypoxia; C = 12—15 min of hypoxia. P ^ 0.05 compared with * period A or ^period B Period A
Period B
Period C
6.16(0.55) 6.27 (0.39)
6.08 (0.54) 6.23(0.41)
6.11 (0.58) 6.21 (0.42)
14.52 (0.09) 14.53 (0.05)
7.02 (0.06)* 6.93 (0.08)*
7.02 (0.03)* 7.03 (0.07)*
12.20(5.21) 8.45 (3.23)
21.49(10.96)* 15.24 (6.34)*
19.19(8.52)* 9.28 (3.57)t
0.96 (0.26) 0.71 (0.23)
1.43(0.44)* 1.01 (0.34)*
1.28(0.42)* 0.77 (0.24)+
13.93 (3.94) 13.97 (0.76)
15.74(3.97)* 16.55 (2.85)
16.16(2.67)* 14.35(1.90)
PE'CO, (kPa)
that the composition of the inspiratory gas mixture could be adjusted to permit PE'COI and PE' O to follow a specific dynamic pattern in time. After the subjects arrived at the laboratory, an i.v. infusion of normal saline 100 ml h"1 was started. Subsequently, the subjects rested for 30 min. Following this rest period, a control hypoxic experiment was performed. Subsequently, an infusion of midazolam 0.025 mg kg"1 was given over 10 min, followed by a continuous infusion of 1.0 mg/70 kg h"1. Thirty minutes after the start of the infusion, a second experiment was performed. The experiments consisted of a 5-min period of steady state ventilation during which PE'OI was held constant at 14.5 kPa, followed by a rapid decrease in PE' OJ to 7 kPa, which was maintained constant for 20 min. Each hypoxic episode was followed by inhalation of 100% oxygen for 7 min to eliminate residual effects of hypoxia [4]. During the control experiment, PE'COI w a s increased to slightly greater than resting value and kept constant at this value during both control and midazolam experiments (PE'CO, 5.5—6.2 kPa between subjects), to anticipate the development of hypercapnia after infusion of midazolam and to maintain control of PE'CO, even if VE decreased to less than the normoxic value.
period following the first 2 min of hypoxia (period B), and 12-15 min of the hypoxic period (period C). The prolonged hypoxia caused some subjects to become restless towards the end of the period, particularly during the control studies. As this occurred generally during the last 5 min, this period was excluded from analysis. Data were subjected to two-way analysis of variance with post-hoc multiple comparisons with Newman-Keuls test and paired t test as appropriate using the SOLO (BMDP Inc.) computer package. P < 0.05 was taken as significant. RESULTS
All subjects became lightly sedated during the administration of midazolam, but remained easily rousable. None experienced any side effects and all had partial amnesia for the procedure. The mean values of the variables for the periods A, B and C are shown in table I. During the control experiments, all but one subject showed the typical biphasic response after exposure to hypoxia. The mean initial increase in VE of 9.3 litre min"1 was followed by a small decrease of 2.3 litre min"1. During the midazolam experiments, the mean ventilatory increase of 6.8 litre min"1 was followed by a decrease of 5.9 litre min"1, which resulted in an almost comData analysis plete return of VE to its initial value. In three For statistical comparisons, we calculated the subjects VE was reduced in period C to less than mean of the breath-to-breath values of the 3-min that of period A. One subject showed no deperiod before • hypoxia (period A), the 3-min pression in his control experiment (fig. 1).
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
Control Midazolam PE' O , (kPa) Control Midazolam VE (litre min"1) Control Midazolam Tidal volume (litre) Control Midazolam Ventilatory frequency (b.p.m.) Control Midazolam
BRITISH JOURNAL OF ANAESTHESIA
456
Control 15.0-,
viidazolam
•
• f 12.5
a
•
15.012.5
10.0-
•
•
•
7.5
o
ID
. •
•
1 10.0=
• •
•
7.5 • • •
•
5.0-
t
2.5
. . • • • '
t
2.5
0240
280 720 Time (s)
960
0
1200
240
280 720 Time (s)
960
1200
FIG. 1. Comparison of the ventilatory response to sustained isocapnic hypoxia in control and midazolam studies in a single subject. Each point represents a 60-s average of the brcath-to-breath values. At time I = 300 s (arrows), hypoxia was induced. TABLE II. Mean (SD) changes in Pfi'o, and PE'Q, (Period B - period A)
(Period C - period B)
Control Midazolam
-0.08(0.12) -0.04 (0.05)
-0.03(0.10) 0.02 (0.06)
Control Midazolam
-7.50(0.14) -7.60(0.08)
-0.00 (0.05) -0.11 (0.12)
The ventilatory increase from period A to period B did not differ significantly between control and midazolam experiments. However, the subsequent decrease from period B to period C, expressed as the ratio of ventilatory decrease to ventilatory increase, was greater in the midazolam group (96 % vs 18 %, P = 0.01). Visual inspection of the dynamics of the ventilatory response revealed that, in the four subjects who showed a decrease in the control experiments, the onset of decrease occurred at 4-6 min, while in the midazolam experiments it was at 1-3 min. The control of PE' COI and PE'Ot in these experiments is important, because of the pronounced effect of their interaction on ventilation. The relatively large SD of PE' COI in the different periods in table I reflect inter-subject variability and not changes with time in one subject. This is shown in table II, where the average changes in PE' COJ and PE'O, for the three periods are given. PE' COJ was slightly greater during the midazolam experiments than during the control experiments (approximately 0.1 kPa).
DISCUSSION
Hypoxic hyperventilation. Although the acute ventilatory response to hypoxia was decreased with midazolam, it was not statistically significant in our group of subjects. This is at variance with the findings of Alexander and Gross [9], who found a reduced response after midazolam O.lmgkg"1 i.v. administered over 5 min. The i.m. administration of diazepam 10 mg resulted also in a marked decrease in hyperventilatory response to hypoxia [10]. The discrepancy between these findings and ours may have been caused by several mechanisms: the small number of subjects in our study; the smaller dose used in our study, which caused less sedation; the slightly greater PE'COf in our midazolam experiments compared with the control experiments, which may have masked the decrease in the initial hyperventilation; and the use of a ramp hypoxic test, compared with the step hypoxic test we used. We found that the onset of ventilatory depression in the midazolam experiments was faster than that
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
0
MIDAZOLAM AND HYPOXAEMIC VENTILATORY RESPONSE
[9], and we suggest that the oxygenation of patients receiving sedative doses of midazolam should be monitored and the inspired oxygen concentration increased. ACKNOWLEDGEMENTS A. D. was supported by grants from the Netherlands Organisation for the Advancement of Pure Research (NWO) and the Anesthesia Education Foundation (Los Angeles, California). REFERENCES 1. Kagawa S, Stafford MJ, Waggener TB, Severinghaus JW. No effect of naloxone on hypoxia-induccd ventilatory depression in adults. Journal of Applied Physiology 1982; 52: 1030-1034. 2. Easton PA, Slykerman LJ, Anthonisen NR. Ventilatory response to sustained hypoxia in normal man Journal of Applied Physiology 1986; 61: 906-911. 3. Vizek M, Pickett CK, Weil JV. Biphasic ventilatory response of adult cats to sustained hypoxia has central origin. Journal of Applied Physiology 1987; 63: 1658-1664. 4. Easton PA, Slykerman LJ, Anthonisen NR. Recovery of ventilatory response to hypoxia in normal adults. Journal of Applied Physiology 1988; 64: 521-528. 5. Neubauer JA, Melton JE, Edelman NH. Modulation of respiration during brain hypoxia. Journal of Applied Physiology 1990; 68: 441-451. 6. Kneussle MP, Pappaginopoulos P, Hoop B, Kaseris H. Reversible depression of ventilation and cardiovascular function by ventriculocisternal perfusion with ir-aminobutyric acid in dogs. American Review of Respiratory Disease 1986; 133: 1024-1028. 7. Haefly WE. Benzodiazepines. International Anesthesiology Climes 1988; 26: 262-272. 8. Jenkins JS, Valcke CP, Ward DS. A programmable system for acquisition and reduction of respiratory physiological data. Annals of Biomedical Engineering 1989; 17: 93-108. 9. Alexander CM, Gross JB. Sedative doses of midazolam depress hypoxic ventilatory responses in humans. Anesthesia and Analgesia 1988; 76: 377-382. 10. Lakshminarayan S, Sahn SA, Hudson LD, Weil JV. Effect of diazepam on ventilatory responses. Clinical Pharmacology and Therapeutics 1976; 20: 178-183. 11. Suzuki A, Nishimura M, Yamamoto H, Miyamoto K, Kishi F, Kawakami Y. No effect of brain blood flow on ventilatory depression during sustained hypoxia. Journal of Applied Physiology 1989; 66: 1674-1678.
Downloaded from http://bja.oxfordjournals.org/ at UB Giessen on May 5, 2015
in the control group. It is therefore possible that, in contrast with their control group, by using a ramp decline in PE'O,, Alexander and Gross encountered the effects of hypoxic depression in their midazolam group. Hypoxic ventilatory decrease. The magnitude of the hypoxic ventilatory decrease in our control group (18% of the initial increase) was smaller than the 64% decrease reported by Easton, Slykerman and Anthonisen [2]. However, it is similar to that found by Suzuki and colleagues [11], who reported that VE tended to decrease more clearly during sustained hypoxia in subjects with reduced hyperventilatory responses, whereas the change in VE was less apparent in subjects with increased hyperventilatory responses. Most of our subjects were in the latter group. There are several possible mechanisms for the increase in the hypoxic ventilatory decrease observed in the midazolam experiments: an effect of the control experiment on the effects of midazolam; an effect of midazolam on the hypoxic peripheral chemoreceptor activation; an interaction of midazolam with the GABA-benzodiazepine receptor complex in the brain stem during hypoxia [7]; and an effect of midazolam on supra-pontine structures. Although none of the above can be excluded, the potentiation of the effect of GABA by midazolam during exposure to hypoxia is the most likely explanation for our observations. The further decrease in tidal volume with midazolam (table I) is typical for the GABAmediated depression of VE [6]. Our study supports the hypothesis that the ventilatory decrease with hypoxia results, at least partly, from accumulation of the neuromodulator GABA. The effect of midazolam on the hypoxic ventilatory decrease has some important clinical implications. Patients receiving sedative doses of midazolam who develop hypoxaemia may react with initial hyperventilation. Sustained hypoxaemia would result in decreased ventilatory drive and a further decrease in oxygenation. Midazolam obscures the usual clinical signs of hypoxaemia
457