Clinical Science and Molecular Medicine (1975) 49, 33-38.
Effect of ethanol on the ventilatory responses to oxygen and carbon dioxide in man S. A. SAHN, S. LAKSHMINARAYAN, D. J. P I E R S O N A N D J. V. WEIL Division of Pulmonary Medicine and Cardiovascular Pulmonary Research Laboratory, Department of Medicine, and Webb- Waring Lung Institute, University of Colorado Medical Center, Denver, Colorado, U.S.A.
(Received 24 September 1974)
Association, 1968). Higgins (1917) found a variable effect of ethanol on respiratory rate but a reduction in the 'volume of air breathed' in man. Hitchcock (1942) demonstrated that ethanol ingested by man tended to depress the stimulating effect of C 0 2 on respiration. However, in studying the effects of hypoxia on ventilation, he found variable results. Loomis (1952) observed a significant reduction in respiratory rate, minute ventilation (93 and ventilatory response in intact dogs to breathing 10% (v/v)oxygen, when their blood ethanol concentrations were greater than 87 mmol/l (400 mg/lOO ml). In a study of ten severely intoxicated adults brought to an emergency room, Johnstone & Witt (1972) found COa retention only in those patients whose blood ethanol concentrations were greater than 76 mmol/l (350 mg/lOO ml). Johnstone & Reier (1973) showed a shift of the ventilatory response to COz to the right in a dose-dependent manner in normal man after intravenous infusion of ethanol. However, the effects of ethanol on the isocapnic hypoxic ventilatory drive in man have not been reported. We have studied the effects of oral ethanol on the isocapnic hypoxic and normoxic hypercapnic ventilatory drives.
SY 1. Hypoxic and hypercapnic ventilatory drives were measured in eight healthy male subjects before and after ingestion of ethanol, in a dose of 17 mmol/kg body weight. 2. A significant decrease in hypoxic ventilatory drive was observed at 20 min after ethanol (P< 0.05). A significant depression in hypercapnic drive was observed at 70 min after ingestion of ethanol (P< 0.05). The mean peak blood ethanol (24 mmol/l) occurred at 20 min, at which time the lowest mean hypoxic drive was recorded. 3. Ethanol in moderate doses produced a depression of both hypoxic and hypercapnic ventilatory drives in normal subjects. This suggests that ethanol may play a role in the precipitation of acute respiratory failure in certain patients in whom the ventilatory drive is already impaired, as in chronic airways obstruction. Key words: carbon dioxide, control of ventilation, ethanol, hypoxia.
Introduction The qualitative effects of ethanol on the central nervous system are a matter of wide human experience. The depression of the central nervous system initially involves the reticular activating system and advances in an irregular manner, resembling that produced by general anaesthesia (American Medical
Methods The subjects of our study were eight healthy adult male residents of Denver, Colorado (altitude 1600 m), aged 21-35 years. All gave normal spirometric data and none were cigarette smokers. All studies were carried out in the Webb-Waring Lung Institute at the University of Colorado Medical Center in
Correspondence: Dr Steven A. Sahn, C-272, Pulmonary Division, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220, U.S.A.
33
S. A . Sahn et al.
4
-
Hard
{ T e l e f y p e IPunched tope
FIG.1. Diagram of the apparatus used to measure the ventilatory drives (for explanation see the Methods section). Vent. = ventilation.
Denver. Informed consent was obtained from all subjects. Measurement of ventilatory drives The hypoxic ventilatory drive was measured by the method of Weil, Byrne-Quinn, Sodal, Friesen, Underhill, Filley & Grover (1970). A modification of the method of Read (1967) was used to study the hypercapnic drive. The subject breathed through a Rudolph respiratory valve (Collins), from which end-tidal gas was continuously sampled by an infrared CO, analyser (Beckman LB-1) and by a mass spectrometer (end-tidal 0,). Ventilation was measured with a hot-film anemometer (Thermal Systems Inc.), which is a mass flowmeter with an error of less than 5% in the range 0-35 I/min, when calibrated against a standard Tissot spirometer. Outputs from the gas analysers and anemometer were fed into an on-line PDP-8 computer, the data emerging as continuous, real-time oscilloscopic plots of end-tidal P o z , end-tidal Pcoz and VE (Fig. 1). In the hypoxic drive studies, the end-tidal P o , plot was used as a guideline for the gradual addition of N, to the inspired air to produce a gradual fall in end-tidal Poz (alveolar P o 2 ) from 20.7 kPa (155
mmHg) to 5.3 kPa (40 mmHg) over 7 min. End-tidal P c o , guided the addition of C O , to prevent the development of hypocapnia during the period of hyperventilation. Hypercapnic drive was studied with the subject rebreathing from a reservoir bag of 10 litres capacity containing 40% (v/v) oxygen, data collection commencing when the inspired P c o , approached the resting end-tidal value. This generally occurred after 2 or 3 min of rebreathing. End-tidal Pco2 (alveolar Pcoz) then increased from resting levels to approximately 6.7 kPa (50 mmHg) over the subsequent 4-5 min, the end-tidal Po1 being maintained above 20.0 kPa (1 50 mmHg). The hypoxic drive is expressed as a value A , which is a mathematical expression of the hyperbolic function derived from plotting V, in I/min STPD against end-tidal Po2 in mmHg, in eqn. (l), V, =
VE + A/(PA,o, -4.25)
(1)
where 3, is minute ventilation in I/min STPD and P A , o ~is alveolar Po, (in kPa). Parameter $7, is the asymptote for ventilation obtained by extrapolation, and A determines the shape of the curve, so that the higher the value of A , the greater is the hypoxic ventilatory drive. The constant 4.25 kPa (32 mmHg)
35
Ethanol and ventilatory drive
TABLE 1 . Hypoxic ventilatory drive, hypercapnic ventilatory drive and blood ethanol concentrations at various times after ingestion of ethanol Ingestion of ethanol took place over 30 min. Times shown are from the end of the ingestion period. N.S. = not significant (P> 0.05). Hypercapnic ventilatory drive (S)
Hypoxic ventilatory drive (A) Subject
Control") Omin
20 rnin 40min 60 rnin Control 30 rnin 70 min
Concn. of blood ethanol (mmol/l) 0 min
20min 40 min 60 min
~
1 (S.L.) 2 (C.H.) 3 (D.P.) 4 (P.B.) 5 (D.J.) 6 (R.H.) 7 (C.C.) 8 (F.H.) Mean SEM
P different
from control
16.9 9.1 23.3 5.3 6.6 9.0 6.5 164 11.7 2.34
-
15.2 9.3 26.6 3.3 10.1 11.3 1.7 1.2 9.8 3.00
N.S.
15.2 7.9 8.4 2.3 3.6 2.3 1.2 1.6 5.3 1.72
Effect of ethanol on the ventilatory responses to oxygen and carbon dioxide in man S. A. SAHN, S. LAKSHMINARAYAN, D. J. P I E R S O N A N D J. V. WEIL Division of Pulmonary Medicine and Cardiovascular Pulmonary Research Laboratory, Department of Medicine, and Webb- Waring Lung Institute, University of Colorado Medical Center, Denver, Colorado, U.S.A.
(Received 24 September 1974)
Association, 1968). Higgins (1917) found a variable effect of ethanol on respiratory rate but a reduction in the 'volume of air breathed' in man. Hitchcock (1942) demonstrated that ethanol ingested by man tended to depress the stimulating effect of C 0 2 on respiration. However, in studying the effects of hypoxia on ventilation, he found variable results. Loomis (1952) observed a significant reduction in respiratory rate, minute ventilation (93 and ventilatory response in intact dogs to breathing 10% (v/v)oxygen, when their blood ethanol concentrations were greater than 87 mmol/l (400 mg/lOO ml). In a study of ten severely intoxicated adults brought to an emergency room, Johnstone & Witt (1972) found COa retention only in those patients whose blood ethanol concentrations were greater than 76 mmol/l (350 mg/lOO ml). Johnstone & Reier (1973) showed a shift of the ventilatory response to COz to the right in a dose-dependent manner in normal man after intravenous infusion of ethanol. However, the effects of ethanol on the isocapnic hypoxic ventilatory drive in man have not been reported. We have studied the effects of oral ethanol on the isocapnic hypoxic and normoxic hypercapnic ventilatory drives.
SY 1. Hypoxic and hypercapnic ventilatory drives were measured in eight healthy male subjects before and after ingestion of ethanol, in a dose of 17 mmol/kg body weight. 2. A significant decrease in hypoxic ventilatory drive was observed at 20 min after ethanol (P< 0.05). A significant depression in hypercapnic drive was observed at 70 min after ingestion of ethanol (P< 0.05). The mean peak blood ethanol (24 mmol/l) occurred at 20 min, at which time the lowest mean hypoxic drive was recorded. 3. Ethanol in moderate doses produced a depression of both hypoxic and hypercapnic ventilatory drives in normal subjects. This suggests that ethanol may play a role in the precipitation of acute respiratory failure in certain patients in whom the ventilatory drive is already impaired, as in chronic airways obstruction. Key words: carbon dioxide, control of ventilation, ethanol, hypoxia.
Introduction The qualitative effects of ethanol on the central nervous system are a matter of wide human experience. The depression of the central nervous system initially involves the reticular activating system and advances in an irregular manner, resembling that produced by general anaesthesia (American Medical
Methods The subjects of our study were eight healthy adult male residents of Denver, Colorado (altitude 1600 m), aged 21-35 years. All gave normal spirometric data and none were cigarette smokers. All studies were carried out in the Webb-Waring Lung Institute at the University of Colorado Medical Center in
Correspondence: Dr Steven A. Sahn, C-272, Pulmonary Division, University of Colorado Medical Center, 4200 East Ninth Avenue, Denver, Colorado 80220, U.S.A.
33
S. A . Sahn et al.
4
-
Hard
{ T e l e f y p e IPunched tope
FIG.1. Diagram of the apparatus used to measure the ventilatory drives (for explanation see the Methods section). Vent. = ventilation.
Denver. Informed consent was obtained from all subjects. Measurement of ventilatory drives The hypoxic ventilatory drive was measured by the method of Weil, Byrne-Quinn, Sodal, Friesen, Underhill, Filley & Grover (1970). A modification of the method of Read (1967) was used to study the hypercapnic drive. The subject breathed through a Rudolph respiratory valve (Collins), from which end-tidal gas was continuously sampled by an infrared CO, analyser (Beckman LB-1) and by a mass spectrometer (end-tidal 0,). Ventilation was measured with a hot-film anemometer (Thermal Systems Inc.), which is a mass flowmeter with an error of less than 5% in the range 0-35 I/min, when calibrated against a standard Tissot spirometer. Outputs from the gas analysers and anemometer were fed into an on-line PDP-8 computer, the data emerging as continuous, real-time oscilloscopic plots of end-tidal P o z , end-tidal Pcoz and VE (Fig. 1). In the hypoxic drive studies, the end-tidal P o , plot was used as a guideline for the gradual addition of N, to the inspired air to produce a gradual fall in end-tidal Poz (alveolar P o 2 ) from 20.7 kPa (155
mmHg) to 5.3 kPa (40 mmHg) over 7 min. End-tidal P c o , guided the addition of C O , to prevent the development of hypocapnia during the period of hyperventilation. Hypercapnic drive was studied with the subject rebreathing from a reservoir bag of 10 litres capacity containing 40% (v/v) oxygen, data collection commencing when the inspired P c o , approached the resting end-tidal value. This generally occurred after 2 or 3 min of rebreathing. End-tidal Pco2 (alveolar Pcoz) then increased from resting levels to approximately 6.7 kPa (50 mmHg) over the subsequent 4-5 min, the end-tidal Po1 being maintained above 20.0 kPa (1 50 mmHg). The hypoxic drive is expressed as a value A , which is a mathematical expression of the hyperbolic function derived from plotting V, in I/min STPD against end-tidal Po2 in mmHg, in eqn. (l), V, =
VE + A/(PA,o, -4.25)
(1)
where 3, is minute ventilation in I/min STPD and P A , o ~is alveolar Po, (in kPa). Parameter $7, is the asymptote for ventilation obtained by extrapolation, and A determines the shape of the curve, so that the higher the value of A , the greater is the hypoxic ventilatory drive. The constant 4.25 kPa (32 mmHg)
35
Ethanol and ventilatory drive
TABLE 1 . Hypoxic ventilatory drive, hypercapnic ventilatory drive and blood ethanol concentrations at various times after ingestion of ethanol Ingestion of ethanol took place over 30 min. Times shown are from the end of the ingestion period. N.S. = not significant (P> 0.05). Hypercapnic ventilatory drive (S)
Hypoxic ventilatory drive (A) Subject
Control") Omin
20 rnin 40min 60 rnin Control 30 rnin 70 min
Concn. of blood ethanol (mmol/l) 0 min
20min 40 min 60 min
~
1 (S.L.) 2 (C.H.) 3 (D.P.) 4 (P.B.) 5 (D.J.) 6 (R.H.) 7 (C.C.) 8 (F.H.) Mean SEM
P different
from control
16.9 9.1 23.3 5.3 6.6 9.0 6.5 164 11.7 2.34
-
15.2 9.3 26.6 3.3 10.1 11.3 1.7 1.2 9.8 3.00
N.S.
15.2 7.9 8.4 2.3 3.6 2.3 1.2 1.6 5.3 1.72
