Clinical Science and Molecular Medicine (1977) 52, 61-14.
Acid-base and respiratory changes after prolonged exposure to 1%carbon dioxide B. J. W. P I N G R E E Tenth Submarine Squadron, Royal Navy, and Department of Bioengineering, University of Strathclyde, Scotland
(Received 13 June 1975; accepted 19 August 1976)
Key words : acid-base equilibrium, blood gas analysis, hypercapnia.
summary 1. The acid-base and respiratory status of fifteen healthy male subjects living in an atmosphere of 1% COz in air was studied over the course of 44 days, during an operational patrol in a nuclear submarine. 2. Observations were made during a control period before exposureto COr,at 4 day intervals during the patrol, and finally during the period after its completion. Samples of arterial blood from each subject were analysed for Pa,cor, pH and Poz immediately after collection. Concurrently mixed expired Pcozand Poz,together with minute volume and respiratory rate, were measured. 3. A mild uncompensated respiratory acidosis in which arterial pH was depressed by 0.02 pH unit was demonstrated throughout the period of exposure to COz.This was associated with an acute rise in Pa,co, of 0.14 kPa, accompanied by an increase in minute volume from 11.5 to 15 I/min. By mid-patrol minute ventilation had returned to control value and a further elevation in Pa,cor of 0.31 kPa was detected together with a rise in plasma bicarbonate of almost 1 mmol/l. 4. On return to air after completion of the patrol, the acid-base changes appeared to be quickly reversed. Minute volume decreased slightly initially, but it too subsequently returned to the control value. A fall in Pa,or of about 2.5 kPa was recorded at this time, together with a reductionin f o r d vital capacity of 8%.
Introduction In recent years interest has grown in the physiological problems associated with the operation of undersea and space vehicles. As a consequence of this it has been necessary to define a maximum acceptable limit for the atmospheric COz concentration in such vehicles to permit safe prolonged exposure. This has stimulated a number of studies into chronic hypercapnia in man at COr concentrations of up to 4% over periods of from 3 to 56 days (Chapin, Otis & Rahn, 1955; Schaefer, Hastings, Carey & Nichols, 1963; Glatte, Motsay & Welch, 1967; Clark, Sinclair & Welch, 1971). Of these studies the one most comparable in scope with this present work is that of Schaefer et al. (1963), in which twenty-one subjects were exposed to 1.5% CO, for 42 days. Schaefer et al. (1963) demonstrated the wellestablished acute sequelae of exposure to a raised ambient COz concentration. Thus for his subjects there was an initial rise in mean PA,CO~ of 0.25 kPa together with a fall in venous blood pH of 0.06 unit and an elevation in minute ventilation of approximately 1 1 min-I m-z. After some 23 days, adaptation (defined by a compensation of the respiratory acidosis) had occurred. On the basis of this and other work, Schaefer (1961) postulated a triple-tolerance concept to account for changes he had shown after chronic exposure to various COz concentrations. For COz concentrations of 3% down
Correspondence: Dr B. J. W.Pingree. G. D. Searle and Co.Ltd, High Wycombe, Bucks., U.K.
67
68
B. J , W. Pingree
to 0.8% this concept envisages slow adaptive processes in electrolyte exchange and acid-base regulation which might induce pathophysiological states on greatly prolonged exposure. For COz concentrations below 05-04% Schaefer (1961) suggests that no significant adaptive changes occur, although he states that this last concentration is not yet fully established. For prolonged submarine operations it is desirable that this last concentration described by Schaefer is closely studied even if it should require work similar to Schaefer’s at COz concentrations only slightly less than 1 5 % . Thus it is important to know whether there is indeed a COz threshold below which adaptive changes no longer occur and whether the threshold can be accurately quantified. In current nuclear submarine practice COz can be conveniently kept to between 0.5 and 1% but far greater demands are made on air-purification machinery if COz concentrations of less than 05% are required. Only detailed knowledge of the physiological response to prolonged exposure to low concentrations of COz will indicate whether the effort should be made to reduce operating COz concentrations. In support of the limits proposed by Schaefer for his lowest COz concentration, Peck (1971) was unable to detect any evidence of respiratory acidosis during a submarine patrol in which atmospheric COz had a mean value of 0.85%. This work, however, was based on measurements in arterialized capillary and venous blood, and was confined to blood-gas and pH analysis, with some plasma electrolyte study, there being no measurement of respiratory minute volume. The present investigation was done to establish whether acute or adaptive acid-base and respiratory processes are stimulated during prolonged exposure to concentrations of COz of approximately 1 %, as existed during an operational submarine patrol. In this work advantage was taken of recent developments in blood gasanalysis equipment to measure arterial blood samples immediately they had been taken, in apparatus installed aboard the submarine. By the use of arterial blood it was envisaged that a possible source of variability in the data of some earlier workers, who had used venous or capillary samples, would be eliminated. This consideration was important in view of the small changes, if any, it was expected might occur.
Methods Subjects
Fifteen healthy male volunteers acted as subjects in this study. They worked in various departments within the submarine and they had each undertaken from nil to five previous nuclear submarine patrols. No subject had been on a patrol during the 3 months before the start of this study. The subjects’ ages ranged from 21 to 37 years. There was no history of respiratory disease in any volunteer and none was under treatment for any medical condition at the time of the start of the experiment. Such medication as was prescribed to subjects during the study consisted of no more than the very occasional paracetamol for headache. Diet was unrestricted and was of a varied and generally balanced nature but dietary analysis was not carried out in this work. Full subject data are presented in Table 1. Consent was obtained from each subject to undertake the procedures contemplated after explanation of their nature, purpose and risks. The protocol for the study was approved by the Flag Officer Submarines, Royal Navy. Atmosphere
During the patrol the PcoZvaried between 0.8 and 1.2kPa but was generally close to 0.93 kPa. The ambient pressure in the vessel was maintained in the region of 106 kPa, giving a nominal C o t concentration of 1%. Oxygen concentration was maintained between 19 and 22% and carbon monoxide was less than 20 p.p.m. At no time during the 44days patrol was the submarine ventilated with outside air. Experimental procedure
Specimens of radial arterial blood and mixed expired air were collected for analysis from each subject during a control period before the start of the patrol. This procedure was repeated at 4 days intervals as the patrol progressed until the vessel was opened to the air when it surfaced after 44 days at the end of the patrol. There were then three further sampling occasions, at 12 days, 36 days and 3 months after completion of the patrol. The post-patrol measurements were restricted by the unavailability of some of the subjects during this period.
Age (years) Height (m) Weight (kg) Surface area (Dubois, mz) Smoking habit (cigaretteslday) Forced vital capacity bcfore patrol (1 BTPS) Forced vital capacity after patrol (l BTPS) No. of previous patrols 3.9 3.3 2
5.4 46 1
5.3
4.9 5
24 1.78 76.5 1.94 0
21 1.88 80.8 2.07 25
24 1.78 66.2 1.84 0
3
2
1
4.4 2
3-9 2
4.8 2
5.1 1
3.7 2
4.5 2
5.2 5.1
48
3.1
4.5
4.2
5.5
4 02
34 1.80 68.2 1.87 20
20 1.75 66.8 1.81 20
23 1.70 64.4 1.76 10
25 1.70 66.8 1.77 25
29 1.85 69.8 1.94
22 1.73 79.5 1.94 20
24 1.73 66.5 1.79 20
10
9
8
7
6
5
4
Subject no.
TABLE 1. Data for the subjects of the study
4.1
27 1.70 79.0 1.91 0
11
5.1
37 1.78 64.4 1.82 20
12
5.3
22 1.88 89.5 216 0
13
3.9
32 1.70 63.5 1.73 15
14
4.8
402
31 1.80 65.0 1.84
2
9
3
3 E $
5
h
3
70
B. J. W. Pingree
Samples were taken from seated subjects after they had first rested and then accustomed themselves to the collection apparatus by a period of breathing on open circuit. Their mixed expired air was collected over 4 min and the respiratory rate during this collection period recorded. As soon as the expired air had been collected a sample of radial arterial blood was taken and immediately analysed for Pco2, pH and Po1 in a Radiometer BMS3 blood gasanalysis apparatus. Blood sampling was performed under local anaesthesia to reduce the discomfort occasioned by arterial puncture. This precaution was desirable for the subjects who were to undergo a series of such punctures, and also to reduce any hyperventilation which might otherwise be provoked. The measuring cuvette in the BMS3 equipment was surrounded by a water bath maintained at a constant 37°C. When the measurements on blood had been completed the apparatus was used to determine the Pcoz and Po1 of a small sample of the mixed expired air, the volume of the remainder then being measured in a dry gas meter. The composition of the atmosphere in the submarine at the time of sampling was determined by a Beckman gas chromatograph installed as part of the vessel’s routine atmospheric monitoring equipment. This same apparatus was also used to obtain a continuous record of ambient CO, throughout the patrol. The Pcoz and Poz electrodes were calibrated immediately before blood sampling from each subject. Calibration was done with bottled gas mixtures analysed by Haldane’s method (duplicate analyses within 0.03%). The pH electrode was calibrated with Radiometer precision buffer solutions of pH 7.383 +0.005 and 6.841 k0.005, at 37°C. Plasma [HCOs-] was derived from P C Oand ~ pH data using the Siggaard-Andersen (1963) alignment nomogram. The electrode system was assessed by tonometry in the Department of Medicine, University of Edinburgh. For the C o t electrode, mean blood-gas difference at tonometer gas Pco2of 6.34 kPa was 3.99 x kPa, with a coefficient of variation on duplicate measurements of the same blood sample of 1.4% (five sets of duplicate determinations). For the Oz electrode, mean blood-gas difference at tonometer gas Pozof 15.79 kPa was 9.45 x 10- kPa, with a coefficient of variation on duplicate measurements of the same blood
sample of 2.4% (nine sets of determinations). For further details of this work see Pingree (1973). Statistical methods A two-factor analysis of variance was made from the data, using the interaction of subjects by times to test the significance between times. The times considered were control, the initial and final halves of the exposure period and the post-patrol period after return to air. For these periods the mean value of the variables for each subject was taken to be the best approximation to the true value. This approach was necessary because of the absence of data for some subjects on occasions when radial stab was unsuccessful. Additionally Schaefer’s triple-tolerance hypothesis would suggest adaptive changes to be occurring after some 3-4 weeks’ exposure, or roughly half way through the patrol. Thus bearing in mind the necessity for meaning of subject data mentioned, it was decided to divide the patrol into initial and final halves in the analysis of variance. More complete data were obtained for the control and exposure periods than for the postexposure period when a number of subjects was unavailable. Accordingly the conclusions made for this period are generally less precise. The results for subject no. 11, who did not participate after the fourth sampling occasion, were disregarded in the analysis. Details of the analysis of variance appear in Pingree (1973).
Results Acid-base measurements The data recorded for arterial Pco2, pH and [HC03-] are summarized in Fig. 1. Pa,co2 in the initial half of the exposure period was significantly elevated by 0.13 kPa ( P < 0.05),relative to a control value of 5.09 kPa. A further significant rise to 0.46 kPa above control was demonstrated in the latter half of the period of exposure ( P < 0.001). On return to air blood samples taken at the first sampling occasion showed that Pa,co2 remained elevated 0.13 kPa above control (P< 0.01), but this elevation was not sustained, there being no significant difference between control and the postexposure period taken overall (P < 0.05).
Response to mild chronic hypercapnia -Air
71
I
T l. T
0 4
8 12 16 20 24 28 32 36 40
Time (days) FIG.1. Time-course of acid-base and respiratory variables for the fifteen subjects studied. Mean values are plotted. with f 1 SD limits indicated by horizontal bars.
Arterial pH was depressed during exposure to (P< 0.01). There was no significant difference (P
Acid-base and respiratory changes after prolonged exposure to 1%carbon dioxide B. J. W. P I N G R E E Tenth Submarine Squadron, Royal Navy, and Department of Bioengineering, University of Strathclyde, Scotland
(Received 13 June 1975; accepted 19 August 1976)
Key words : acid-base equilibrium, blood gas analysis, hypercapnia.
summary 1. The acid-base and respiratory status of fifteen healthy male subjects living in an atmosphere of 1% COz in air was studied over the course of 44 days, during an operational patrol in a nuclear submarine. 2. Observations were made during a control period before exposureto COr,at 4 day intervals during the patrol, and finally during the period after its completion. Samples of arterial blood from each subject were analysed for Pa,cor, pH and Poz immediately after collection. Concurrently mixed expired Pcozand Poz,together with minute volume and respiratory rate, were measured. 3. A mild uncompensated respiratory acidosis in which arterial pH was depressed by 0.02 pH unit was demonstrated throughout the period of exposure to COz.This was associated with an acute rise in Pa,co, of 0.14 kPa, accompanied by an increase in minute volume from 11.5 to 15 I/min. By mid-patrol minute ventilation had returned to control value and a further elevation in Pa,cor of 0.31 kPa was detected together with a rise in plasma bicarbonate of almost 1 mmol/l. 4. On return to air after completion of the patrol, the acid-base changes appeared to be quickly reversed. Minute volume decreased slightly initially, but it too subsequently returned to the control value. A fall in Pa,or of about 2.5 kPa was recorded at this time, together with a reductionin f o r d vital capacity of 8%.
Introduction In recent years interest has grown in the physiological problems associated with the operation of undersea and space vehicles. As a consequence of this it has been necessary to define a maximum acceptable limit for the atmospheric COz concentration in such vehicles to permit safe prolonged exposure. This has stimulated a number of studies into chronic hypercapnia in man at COr concentrations of up to 4% over periods of from 3 to 56 days (Chapin, Otis & Rahn, 1955; Schaefer, Hastings, Carey & Nichols, 1963; Glatte, Motsay & Welch, 1967; Clark, Sinclair & Welch, 1971). Of these studies the one most comparable in scope with this present work is that of Schaefer et al. (1963), in which twenty-one subjects were exposed to 1.5% CO, for 42 days. Schaefer et al. (1963) demonstrated the wellestablished acute sequelae of exposure to a raised ambient COz concentration. Thus for his subjects there was an initial rise in mean PA,CO~ of 0.25 kPa together with a fall in venous blood pH of 0.06 unit and an elevation in minute ventilation of approximately 1 1 min-I m-z. After some 23 days, adaptation (defined by a compensation of the respiratory acidosis) had occurred. On the basis of this and other work, Schaefer (1961) postulated a triple-tolerance concept to account for changes he had shown after chronic exposure to various COz concentrations. For COz concentrations of 3% down
Correspondence: Dr B. J. W.Pingree. G. D. Searle and Co.Ltd, High Wycombe, Bucks., U.K.
67
68
B. J , W. Pingree
to 0.8% this concept envisages slow adaptive processes in electrolyte exchange and acid-base regulation which might induce pathophysiological states on greatly prolonged exposure. For COz concentrations below 05-04% Schaefer (1961) suggests that no significant adaptive changes occur, although he states that this last concentration is not yet fully established. For prolonged submarine operations it is desirable that this last concentration described by Schaefer is closely studied even if it should require work similar to Schaefer’s at COz concentrations only slightly less than 1 5 % . Thus it is important to know whether there is indeed a COz threshold below which adaptive changes no longer occur and whether the threshold can be accurately quantified. In current nuclear submarine practice COz can be conveniently kept to between 0.5 and 1% but far greater demands are made on air-purification machinery if COz concentrations of less than 05% are required. Only detailed knowledge of the physiological response to prolonged exposure to low concentrations of COz will indicate whether the effort should be made to reduce operating COz concentrations. In support of the limits proposed by Schaefer for his lowest COz concentration, Peck (1971) was unable to detect any evidence of respiratory acidosis during a submarine patrol in which atmospheric COz had a mean value of 0.85%. This work, however, was based on measurements in arterialized capillary and venous blood, and was confined to blood-gas and pH analysis, with some plasma electrolyte study, there being no measurement of respiratory minute volume. The present investigation was done to establish whether acute or adaptive acid-base and respiratory processes are stimulated during prolonged exposure to concentrations of COz of approximately 1 %, as existed during an operational submarine patrol. In this work advantage was taken of recent developments in blood gasanalysis equipment to measure arterial blood samples immediately they had been taken, in apparatus installed aboard the submarine. By the use of arterial blood it was envisaged that a possible source of variability in the data of some earlier workers, who had used venous or capillary samples, would be eliminated. This consideration was important in view of the small changes, if any, it was expected might occur.
Methods Subjects
Fifteen healthy male volunteers acted as subjects in this study. They worked in various departments within the submarine and they had each undertaken from nil to five previous nuclear submarine patrols. No subject had been on a patrol during the 3 months before the start of this study. The subjects’ ages ranged from 21 to 37 years. There was no history of respiratory disease in any volunteer and none was under treatment for any medical condition at the time of the start of the experiment. Such medication as was prescribed to subjects during the study consisted of no more than the very occasional paracetamol for headache. Diet was unrestricted and was of a varied and generally balanced nature but dietary analysis was not carried out in this work. Full subject data are presented in Table 1. Consent was obtained from each subject to undertake the procedures contemplated after explanation of their nature, purpose and risks. The protocol for the study was approved by the Flag Officer Submarines, Royal Navy. Atmosphere
During the patrol the PcoZvaried between 0.8 and 1.2kPa but was generally close to 0.93 kPa. The ambient pressure in the vessel was maintained in the region of 106 kPa, giving a nominal C o t concentration of 1%. Oxygen concentration was maintained between 19 and 22% and carbon monoxide was less than 20 p.p.m. At no time during the 44days patrol was the submarine ventilated with outside air. Experimental procedure
Specimens of radial arterial blood and mixed expired air were collected for analysis from each subject during a control period before the start of the patrol. This procedure was repeated at 4 days intervals as the patrol progressed until the vessel was opened to the air when it surfaced after 44 days at the end of the patrol. There were then three further sampling occasions, at 12 days, 36 days and 3 months after completion of the patrol. The post-patrol measurements were restricted by the unavailability of some of the subjects during this period.
Age (years) Height (m) Weight (kg) Surface area (Dubois, mz) Smoking habit (cigaretteslday) Forced vital capacity bcfore patrol (1 BTPS) Forced vital capacity after patrol (l BTPS) No. of previous patrols 3.9 3.3 2
5.4 46 1
5.3
4.9 5
24 1.78 76.5 1.94 0
21 1.88 80.8 2.07 25
24 1.78 66.2 1.84 0
3
2
1
4.4 2
3-9 2
4.8 2
5.1 1
3.7 2
4.5 2
5.2 5.1
48
3.1
4.5
4.2
5.5
4 02
34 1.80 68.2 1.87 20
20 1.75 66.8 1.81 20
23 1.70 64.4 1.76 10
25 1.70 66.8 1.77 25
29 1.85 69.8 1.94
22 1.73 79.5 1.94 20
24 1.73 66.5 1.79 20
10
9
8
7
6
5
4
Subject no.
TABLE 1. Data for the subjects of the study
4.1
27 1.70 79.0 1.91 0
11
5.1
37 1.78 64.4 1.82 20
12
5.3
22 1.88 89.5 216 0
13
3.9
32 1.70 63.5 1.73 15
14
4.8
402
31 1.80 65.0 1.84
2
9
3
3 E $
5
h
3
70
B. J. W. Pingree
Samples were taken from seated subjects after they had first rested and then accustomed themselves to the collection apparatus by a period of breathing on open circuit. Their mixed expired air was collected over 4 min and the respiratory rate during this collection period recorded. As soon as the expired air had been collected a sample of radial arterial blood was taken and immediately analysed for Pco2, pH and Po1 in a Radiometer BMS3 blood gasanalysis apparatus. Blood sampling was performed under local anaesthesia to reduce the discomfort occasioned by arterial puncture. This precaution was desirable for the subjects who were to undergo a series of such punctures, and also to reduce any hyperventilation which might otherwise be provoked. The measuring cuvette in the BMS3 equipment was surrounded by a water bath maintained at a constant 37°C. When the measurements on blood had been completed the apparatus was used to determine the Pcoz and Po1 of a small sample of the mixed expired air, the volume of the remainder then being measured in a dry gas meter. The composition of the atmosphere in the submarine at the time of sampling was determined by a Beckman gas chromatograph installed as part of the vessel’s routine atmospheric monitoring equipment. This same apparatus was also used to obtain a continuous record of ambient CO, throughout the patrol. The Pcoz and Poz electrodes were calibrated immediately before blood sampling from each subject. Calibration was done with bottled gas mixtures analysed by Haldane’s method (duplicate analyses within 0.03%). The pH electrode was calibrated with Radiometer precision buffer solutions of pH 7.383 +0.005 and 6.841 k0.005, at 37°C. Plasma [HCOs-] was derived from P C Oand ~ pH data using the Siggaard-Andersen (1963) alignment nomogram. The electrode system was assessed by tonometry in the Department of Medicine, University of Edinburgh. For the C o t electrode, mean blood-gas difference at tonometer gas Pco2of 6.34 kPa was 3.99 x kPa, with a coefficient of variation on duplicate measurements of the same blood sample of 1.4% (five sets of duplicate determinations). For the Oz electrode, mean blood-gas difference at tonometer gas Pozof 15.79 kPa was 9.45 x 10- kPa, with a coefficient of variation on duplicate measurements of the same blood
sample of 2.4% (nine sets of determinations). For further details of this work see Pingree (1973). Statistical methods A two-factor analysis of variance was made from the data, using the interaction of subjects by times to test the significance between times. The times considered were control, the initial and final halves of the exposure period and the post-patrol period after return to air. For these periods the mean value of the variables for each subject was taken to be the best approximation to the true value. This approach was necessary because of the absence of data for some subjects on occasions when radial stab was unsuccessful. Additionally Schaefer’s triple-tolerance hypothesis would suggest adaptive changes to be occurring after some 3-4 weeks’ exposure, or roughly half way through the patrol. Thus bearing in mind the necessity for meaning of subject data mentioned, it was decided to divide the patrol into initial and final halves in the analysis of variance. More complete data were obtained for the control and exposure periods than for the postexposure period when a number of subjects was unavailable. Accordingly the conclusions made for this period are generally less precise. The results for subject no. 11, who did not participate after the fourth sampling occasion, were disregarded in the analysis. Details of the analysis of variance appear in Pingree (1973).
Results Acid-base measurements The data recorded for arterial Pco2, pH and [HC03-] are summarized in Fig. 1. Pa,co2 in the initial half of the exposure period was significantly elevated by 0.13 kPa ( P < 0.05),relative to a control value of 5.09 kPa. A further significant rise to 0.46 kPa above control was demonstrated in the latter half of the period of exposure ( P < 0.001). On return to air blood samples taken at the first sampling occasion showed that Pa,co2 remained elevated 0.13 kPa above control (P< 0.01), but this elevation was not sustained, there being no significant difference between control and the postexposure period taken overall (P < 0.05).
Response to mild chronic hypercapnia -Air
71
I
T l. T
0 4
8 12 16 20 24 28 32 36 40
Time (days) FIG.1. Time-course of acid-base and respiratory variables for the fifteen subjects studied. Mean values are plotted. with f 1 SD limits indicated by horizontal bars.
Arterial pH was depressed during exposure to (P< 0.01). There was no significant difference (P
