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Effects on pulmonary function of daily exposure to dry or humidified hyperbaric oxygen
Respiration Physiology 108 (1997) 241 – 246
Effects on pulmonary function of daily exposure to dry or humidified hyperbaric oxygen A. Shupak *, A. Abramovich, Y. Adir, I. Goldenberg, Y. Ramon, P. Halpern, A. Ariel Israel Na6al Medical Institute, IDF Medical Corps, P.O. Box 8040, Haifa 31080, Israel Accepted 10 March 1997
Abstract The purpose of this study was to examine the effects of breathing dry or humidified hyperbaric oxygen on pulmonary function. Pulmonary function tests were performed before and after each of 10 hyperbaric oxygen exposures at 2.5 atmospheres absolute (ATA) for 95 min in a group of 13 patients treated daily by hyperbaric oxygen for problem wounds. Patients breathed dry oxygen during five successive sessions and humidified oxygen during the remaining five. No differences were found between forced vital capacities (FVC) and maximal expiratory flows before and after hyperbaric oxygen exposure while breathing dry or humidified oxygen. Significant differences were found for the changes in the percentage of FVC expired in 1 s (FEV1%) and mean forced mid-expiratory flow rate during the middle half of the FVC (FEF25 – 75%) on day 1 alone: decrements of 1.42 and 2.96%, respectively, under dry oxygen, vs. increments of 3.93 and 34.4%, respectively, for humidified oxygen. Day-to-day decrements in the percent changes in FEV1% and FEF25 – 75% were observed while breathing humidified hyperbaric oxygen. These results demonstrate that repeated daily exposure to humidified hyperbaric oxygen abolishes the initial beneficial effect of humidification on peripheral airways flow characteristics. © 1997 Elsevier Science B.V. Keywords: Function test; Dry vs. humidified hyperbaric oxygen; Humidification; Hyperbaric oxygen; Lung
1. Introduction Repeated daily exposure to hyperbaric oxygen (HBO) at 2.5 atmospheres absolute (ATA) for * Corresponding author. Tel.: +972 4 8693040; fax: + 972 4 8693240.
90–120 min is widely employed in the combined treatment of problem wounds (Thom, 1992). The oxygen delivered to the patients is kept dry to prevent corrosion and icing in the gas storage and supply system. To reduce the risk of bronchoconstriction due to the airway hyper-reactivity, airway epithelial damage and inflammation that may
0034-5687/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 4 - 5 6 8 7 ( 9 7 ) 0 0 0 2 2 - 4
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A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
be produced by inhaling dry respiratory gases, humidifiers can be introduced on the ambient pressure side of the oxygen supply system (O’Cain et al., 1980; Barbet et al., 1988; Thorsen et al., 1992; Murchie et al., 1993). Although overt pulmonary oxygen toxicity is unlikely on this protocol and the cumulative effects of HBO are considered negligible for daily exposure (Clark, 1993), no study has been made of dayto-day variability in pulmonary function tests during the course of HBO therapy. Contradictory pulmonary effects of breathing humidified gas have also been reported. Breathing humidified air during a single air-dive prevented the flow limitation in the small airways associated with dry air, and was considered by the divers to be more comfortable (Thorsen et al., 1992), while breathing humidified oxygen during a chamber dive significantly increases both the wet and dry weights of rodent lungs, indicating exacerbation of pulmonary oxygen toxicity (Lin and Jamieson, 1993). The purpose of this study was to examine the daily and day-to-day effects of dry and humid HBO breathing on pulmonary function tests in a group of patients receiving routine HBO therapy.
2. Patients and methods
2.1. Patients Thirteen patients, 42 – 63 years of age, receiving daily HBO treatment for problem wounds, participated in the study after giving their written informed consent. All were non-smokers, had a negative history of chronic pulmonary disease, no pathological findings on physical examination of the respiratory system, and normal anterior–posterior and lateral chest roentgenograms.
2.2. HBO administration Subjects were randomly assigned to the dry and humidified oxygen treatment groups in a cross-over design, breathing dry oxygen during
five successive sessions and humidified oxygen during the remaining five sessions. The study protocol was approved by the local Helsinki committee. HBO was administered once daily in a multilock chamber compressed by air to an absolute pressure of 2.5 ATA for 95 min. Each treatment session was composed of two 40 min intervals of oxygen breathing, separated by 5 min of air breathing. The temperature inside the chamber was maintained at approximately 23°C. Oxygen was inhaled via a full face mask fitted with a demand valve and an expiratory overboard dumping system. To establish humid conditions, the inspired oxygen was passed through a bubble humidifier. Relative humidity was measured with a humidity thermistor (Tecnologic, Vigevano, Italy) at the output of the humidifier, and was maintained at 70–80%.
2.3. Pulmonary function tests Pulmonary function tests were performed at ambient pressure breathing room air, immediately before and 5–20 min after each HBO exposure on the first 10 treatment days. On the day preceding the first HBO session, each subject was repeatedly trained in the performance of pulmonary function tests until reproducibility of the results was achieved, according to the American Thoracic Society recommendations (American Thoracic Society, 1995). Forced vital capacities (FVC) and maximal expiratory flows were measured immediately after calibration of the spirometer (ST-250, Fukuda Sangyo, Japan), and validated according to the American Thoracic Society recommendations (American Thoracic Society, 1995). The respiratory parameters recorded included forced vital capacity (FVC), volume expired in 1 s (FEV1), percentage of FVC expired in 1 s (FEV1%), peak expiratory flow rate (PEF), and forced mid-expiratory flow rate (FEF25 – 75%). A minimum of three attempts was made for each spirometry session. Only the results of the best test, defined according to the highest value obtained by the summation of FEV1 and FVC, were taken into consideration. All values were corrected to BTPS conditions.
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
2.4. Symptoms of oxygen toxicity After each HBO exposure, the study participants were specifically asked about symptoms that have previously been related to pulmonary oxygen toxicity. These symptoms include retrosternal irritation on inspiration, chest tightness or pain, cough, and dyspnoea (Clark and Lambertsen, 1971).
2.5. Statistical analysis Pulmonary function values obtained before and after HBO exposure were compared separately for the dry and humidified oxygen groups using the paired t-test. Differences in daily measurements between the groups were evaluated by the twosample t-test. The significance of day-to-day variations in the test results was calculated by repeated measures one-way analysis of variance (ANOVA), and the source of significant differences between the days by the Tukey test for the pairwise comparison of means. Statistical analysis was carried out using SAS software (SAS Institute, Cary, NC) on an IBM-compatible personal computer.
3. Results
3.1. Symptoms of oxygen toxicity No symptoms related to pulmonary oxygen toxicity were reported by the patients during the study.
3.2. Changes in pulmonary function tests No differences were found on any of the days between the average forced vital capacities (FVC) and maximal expiratory flows measured before or after HBO exposure while breathing dry oxygen. The only significant change observed after humidified HBO breathing was an increase in the average absolute value for FEF25 – 75% on day 1: 3.43 l/min before and 4.59 l/min after the HBO session (p=0.03, paired t-test).
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When the percent changes in pulmonary function tests after HBO exposure were compared, significant differences were noted in the changes in FEV1% and FEF25 – 75% on day 1 alone; a decrement of 1.4291.63 (SE) and 2.969 6.31 in FEV1% and FEF25 – 75%, respectively, under dry oxygen vs. an increment of 3.93 9 2.29 (SE) and 34.49 12.5 in FEV1% and FEF25 – 75%, respectively, for humidified oxygen (p=0.03, p =0.006, respectively, two-sample t-test) (Table 1). In the dry HBO group, no significant daily variations were found in the percent change in pulmonary function tests following HBO exposure. However, significant decrements in the percent changes in FEV1% and FEF25 – 75% were observed while breathing humidified HBO (p= 0.03 and p=0.005, respectively, one-way repeated measures ANOVA) (Figs. 1 and 2, Table 1). These differences between the days were attributed to the variance between day 1 and day 4 (Tukey test).
4. Discussion Significant differences were found between the average changes in FEV1% and FEF25 – 75% under dry HBO relative to baseline measurements, and the average changes in the same parameters while breathing humidified HBO. This observation was documented only for the first session. While no significant day-to-day variability could be found in any of the pulmonary function tests measured for the dry oxygen group, repeated HBO humidification was associated with a decrease in the relative post-exposure increments in FEV1% and FEF25 – 75% observed for the first humidified HBO exposure. Previous animal models and human studies investigating the pulmonary effects of breathing humidified normobaric oxygen or hyperbaric air during a single exposure support our findings regarding the short-term advantage of oxygen humidification. Rats exposed to 0.94 ATA dry normobaric oxygen for 48 h showed significant bronchial epithelial thickening, was prevented by oxygen humidification (Murchie et al., 1993). Anaesthetized dogs ventilated at 1 ATA for
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
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Table 1 Pulmonary function test changes (%) after HBO exposure: humidified vs. dry oxygen breathing (mean9SE) FCV Day 1 Humidified Dry Day 2 Humidified Dry Day 3 Humidified Dry Day 4 Humidified Dry Day 5 Humidified Dry
FEV1
FEV1%a
PEF
FEFb25 – 75%
−2.02 93.10 4.5896.04
1.109 2.29 2.619 4.93
3.93 92.29 −1.42 9 1.63c
8.39 9 8.25 15.44 9 16.2
34.42 9 12.6 −2.96 9 6.31d
0.799 2.08 1.189 1.90
2.559 3.56 0.919 1.66
−1.4891.66 0.92 90.92
1.09 9 8.07 0.3 9 4.05
1.79 9 9.36 5.26 9 8.97
2.5292.35 0.3892.41
2.109 2.62 1.389 2.44
−0.41 9 0.98 1.18 91.78
0.12 9 5.39 0.03 9 4.54
2.55 94.00 10.82 98.21
5.869 5.39 1.239 2.70
−1.129 0.72 1.069 2.58
−3.24 91.45 −0.62 91.42
0.66 98.32 −4.28 93.02
−8.58 9 6.42 4.56 9 6.93
1.939 1.82 1.209 3.32
1.679 2.18 −0.279 2.14
−0.53 91.31 −0.99 91.69
1.37 9 11.0 −6.11 9 4.37
−2.87 9 2.51 7.17 9 6.86
a
P = 0.03 (repeated measures ANOVA) for day-to-day variations when breathing humidified oxygen. P =0.005 (repeated measures ANOVA) for day-to-day variations when breathing humidified oxygen. c P = 0.03 (two-sample t-test). d P =0.006 (two-sample t-test). b
12 h showed less of a decrease in surfactant activity when breathing humidified oxygen compared with animals ventilated with dry oxygen (Motlagh et al., 1969). However, in another study using similar animals breathing oxygen at 1 ATA for 7 h, potentiation of pulmonary toxicity, as evaluated by pulmonary vein PO2 values, was reported to result from oxygen humidification (Ching et al., 1973).
Two previous human studies compared the changes in pulmonary function tests measured before and after dry or humidified compressed air-dives (Thorsen et al., 1992; Ronnestad et al., 1994). Dry air and oxy-helium dives to pressures of 1.16–5.94 ATA for 30 min to 4 h were associated with significant reductions in FEV1 and FEF25 – 75%. Such changes were not found for dives to the same depths and bottom times on humi-
Fig. 1. Day-to-day variations in FEV1% after dry and humidified HBO exposure. Data are presented as mean9SE.
Fig. 2. Day-to-day variations in FEF25 – 75% after dry and humidified HBO exposure. Data are presented as mean 9 SE.
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
dified air or oxy-helium. For the shallower humidified air dives, relative increments were reported in FEV1 and FEF25 – 75%, matching our observation regarding the relative changes in FEV1% and FEF25 – 75% after the first humidified HBO session. Although the subjects of the above mentioned studies were, like our patients, all non-smokers, with no history, physical or baseline pulmonary function findings indicating bronchoconstriction, in their case as well, humidification of the breathing gas improved airway flow characteristics relative to baseline measurements. The mechanism of improved pulmonary airflow characteristics following a single exposure to a humidified hyperoxic gas mixture has not yet been investigated or elucidated. Breathing dry air results in bronchoconstriction, probably due to osmolarity changes affecting the fluid lining of the airways (Anderson, 1992). It is believed that these changes cause stimulation of autonomic nerve endings or the release of an as yet unidentified mediator, inducing a bronchomotor response, because the latter may be prevented by the administration of cholinergic antagonists (Anderson et al., 1979; Wilson et al., 1984). One may speculate that contrasting osmolarity changes facilitated by breathing highly humidified oxygen produced the bronchodilatation observed in the present study. One mediator which might be involved in the suggested response is nitric oxide, which has a well documented smooth muscle relaxation effect (Gaston et al., 1994). Repeated daily HBO exposures may result in the accumulation of oxygenderived free radicals, which overwhelm existing scavenger systems. The reaction of these free radicals with nitric oxide to produce various nitrogen oxides would lead to the disappearance of the temporary bronchodilatory effect observed after the first HBO session. The results of a recently published rodent model suggest that oxygen humidification might affect the development of pulmonary oxygen toxicity to different degrees according to the pressure applied and the duration of the exposure (Lin and Jamieson, 1993). Mice which breathed humidified oxygen for 30 min at pressures of 5.1 – 5.8 ATA had significant increases in wet and dry lung weights compared with animals breathing dry
245
oxygen. This observation was interpreted as a sign of enhanced pulmonary oxygen toxicity under humid conditions. In contrast to this, rats exposed to normobaric hyperoxia for 68–72 h had a decreased mortality rate, lower lung weights, and less pleural effusion under humid conditions when compared with a group of similar animals breathing dry oxygen (Lin and Jamieson, 1993). In spite of the fact that in the present study no symptoms related to pulmonary oxygen toxicity were reported by the patients in either group, gradual but significant decrements in FEV1% and FEF25 – 75% normalised values were found after repeated humidified HBO exposures. It is known that despite the absence of clinical symptomatology, the biochemical effects of oxygen toxicity are initiated concurrently with the elevation of PO2 (Lambertsen, 1978). Deterioration in lung mechanical function precedes the clinical symptoms of pulmonary oxygen toxicity, and abnormal pulmonary function has been reported to persist for as long as 11 days after the disappearance of such symptoms (Clark and Lambertsen, 1971). The initial exposure interval represents an asymptomatic period of slowly developing toxicity, from which recovery is considered to be rapid and complete on return to normoxia (Clark, 1993). However, our results imply that when a course of daily 95 min sessions of 2.5 ATA humidified HBO is in question, cumulative effects of pulmonary oxygen toxicity might persist. These may abolish the initial benefits of oxygen humidification on pulmonary flow characteristics observed after the first HBO session. We were unable to find any previous study comparing the pulmonary effects of dry vs. humidified oxygen in patients receiving daily HBO treatments on one of the protocols recommended by the Undersea and Hyperbaric Medical Society for problem wounds (Thom, 1992). The only study examining changes in pulmonary function tests after humidified oxygen breathing at 2.5 ATA employed a single continuous oxygen exposure lasting 5.7 h. The greatest changes found were an average drop of 30% in FEF25 – 75% and 20% in maximal expiratory flow rate at 50% of FVC (MEF50%), indicating increased resistance of the peripheral airways (Clark, 1988, 1993). Although the daily oxygen
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
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breathing period employed in our study was much shorter (two intervals of 40 min separated by a 5 min air break), these observations are comparable to the gradual decline observed in FEV1% and FEF25 – 75% in the course of our study when the patients were breathing humidified oxygen, reaching maximal decrements of 3.2 and 8.6%, respectively. FEV1% contains both the effort-dependent and effort-independent parts of the flow – volume loop, whereas FEF25 – 75% is effort-independent, and a decrease in its value relative to the baseline measurement represents flow limitation in the peripheral airways (McFadden and Linden, 1972). Our results show that although patients might benefit from oxygen humidification during a single HBO session with regard to airway flow characteristics, this advantage might disappear during successive HBO treatments. We suggest that the practice of breathing humidified gas during routine daily HBO therapy protocols over a prolonged period should be reconsidered.
Acknowledgements The authors are indebted to Esther Eilender and Richard Lincoln for their assistance in the preparation of the manuscript.
References American Thoracic Society, 1995. Standardization of Spirometry, 1994 Update. Am. J. Resp. Crit. Care Med. 152, 1107 – 1136. Anderson, S.D., Seale, J.P., Ferris, L., Schoeffel, R., Lindsay, D.A., 1979. An evaluation of pharmacotherapy for exercise-induced asthma. J. Allergy Clin. Immunol. 64, 612– 624. Anderson, S.D., 1992. Asthma provoked by exercise, hyperventilation, and the inhalation of non-isotonic aerosols. In: Barnes, P.J., Rodger, I.W., Thomson, N.C. (Eds.), Asthma: Basic Mechanisms and Clinical Management, 2nd ed. Academic Press, London, pp. 473–490. Barbet, J.P., Chauveau, M., Labbe, S., Lockhart, A., 1988. Breathing dry air causes acute epithelial damage and infl-
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ammation of the guinea pig trachea. J. Appl. Physiol. 64, 1851 – 1857. Ching, N., Kazigo, J.M., Hicks, R.G., Nealon, T.F. Jr., 1973. Potentiation of oxygen toxicity by excessive levels of humidification. Surg. Forum 24, 222 – 223. Clark, J.M., Lambertsen, C.J., 1971. Pulmonary oxygen toxicity: a review. Pharmacol. Rev. 23, 37 – 133. Clark, J.M., 1988. Extension of oxygen tolerance. Proceedings of a symposium in honor of Christian J. Lambertsen, M.D.. Exp. Lung Res. 14 (Suppl.), 863 – 1058. Clark, J.M., 1993. Oxygen toxicity. In: Bennett, P.B., Elliott, D.H. (Eds.), The Physiology and Medicine of Diving, 4th ed. W.B. Saunders, London, pp. 121 – 169. Gaston, B., Drazen, J.M., Loscalzo, J., Stamler, J.S., 1994. The biology of nitrogen oxides in the airways. Am. J. Resp. Crit. Care Med. 149, 538 – 551. Lambertsen, C.J., 1978. Effects of hyperoxia on organs and their tissues. In: Robin, E.D. (Ed.), Extrapulmonary Manifestations of Respiratory Disease (Lung Biology in Health and Disease, vol. 8), Marcel Dekker, New York, pp. 239 – 303. Lin, Y., Jamieson, D., 1993. Effect of humidity on hyperoxic toxicity. J. Appl. Physiol. 75, 1980 – 1983. McFadden, E.R. Jr., Linden, D.A., 1972. A reduction in maximum mid-expiratory flow rate. A spirographic manifestation of small airway disease. Am. J. Med. 52, 725 – 737. Motlagh, F.A., Kaufman, S.Z., Giusti, R., Cramer, M., Garzon, A.A., Karlson, K.E., 1969. Electron microscopic appearance and surface tensions properties of the lungs ventilated with dry or humid air or oxygen. Surg. Forum 20, 219 – 220. Murchie, P., Johnston, P.W., Ross, J.A.S., Godden, D.J., 1993. Effects of hyperoxia on bronchial wall dimensions and lung mechanics in rats. Acta Physiol. Scand. 148, 363 – 370. O’Cain, C.F., Dowling, N.B., Slutsky, A.S., Hensley, M.J., Strohl, K.P., McFadden, E.R. Jr., Ingram, R.H. Jr., 1980. Airway effects of respiratory heat loss in normal subjects. J. Appl. Physiol. 49, 875 – 880. Ronnestad, I., Thorsen, E., Segadal, K., Hope, A., 1994. Bronchial response to breathing dry gas at 3.7 MPa ambient pressure. Eur. J. Appl. Physiol. 69, 32 – 35. Thom, S.R., 1992. Hyperbaric Oxygen Therapy: a Committee Report. Undersea and Hyperbaric Medical Society, UHMS publication no. 30 CR, HBO, Bethesda, MD. Thorsen, E., Ronnestad, I., Segadal, K., Hope, A., 1992. Respiratory effects of warm and dry air at increased ambient pressure. Undersea Biomed. Res. 19, 73 – 83. Wilson, N., Dixon, C., Silverman, M., 1984. Bronchial responsiveness to hyperventilation in children asthma: inhibition by ipratropium bromide. Thorax 39, 588 – 593.
Effects on pulmonary function of daily exposure to dry or humidified hyperbaric oxygen A. Shupak *, A. Abramovich, Y. Adir, I. Goldenberg, Y. Ramon, P. Halpern, A. Ariel Israel Na6al Medical Institute, IDF Medical Corps, P.O. Box 8040, Haifa 31080, Israel Accepted 10 March 1997
Abstract The purpose of this study was to examine the effects of breathing dry or humidified hyperbaric oxygen on pulmonary function. Pulmonary function tests were performed before and after each of 10 hyperbaric oxygen exposures at 2.5 atmospheres absolute (ATA) for 95 min in a group of 13 patients treated daily by hyperbaric oxygen for problem wounds. Patients breathed dry oxygen during five successive sessions and humidified oxygen during the remaining five. No differences were found between forced vital capacities (FVC) and maximal expiratory flows before and after hyperbaric oxygen exposure while breathing dry or humidified oxygen. Significant differences were found for the changes in the percentage of FVC expired in 1 s (FEV1%) and mean forced mid-expiratory flow rate during the middle half of the FVC (FEF25 – 75%) on day 1 alone: decrements of 1.42 and 2.96%, respectively, under dry oxygen, vs. increments of 3.93 and 34.4%, respectively, for humidified oxygen. Day-to-day decrements in the percent changes in FEV1% and FEF25 – 75% were observed while breathing humidified hyperbaric oxygen. These results demonstrate that repeated daily exposure to humidified hyperbaric oxygen abolishes the initial beneficial effect of humidification on peripheral airways flow characteristics. © 1997 Elsevier Science B.V. Keywords: Function test; Dry vs. humidified hyperbaric oxygen; Humidification; Hyperbaric oxygen; Lung
1. Introduction Repeated daily exposure to hyperbaric oxygen (HBO) at 2.5 atmospheres absolute (ATA) for * Corresponding author. Tel.: +972 4 8693040; fax: + 972 4 8693240.
90–120 min is widely employed in the combined treatment of problem wounds (Thom, 1992). The oxygen delivered to the patients is kept dry to prevent corrosion and icing in the gas storage and supply system. To reduce the risk of bronchoconstriction due to the airway hyper-reactivity, airway epithelial damage and inflammation that may
0034-5687/97/$17.00 © 1997 Elsevier Science B.V. All rights reserved. PII S 0 0 4 - 5 6 8 7 ( 9 7 ) 0 0 0 2 2 - 4
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A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
be produced by inhaling dry respiratory gases, humidifiers can be introduced on the ambient pressure side of the oxygen supply system (O’Cain et al., 1980; Barbet et al., 1988; Thorsen et al., 1992; Murchie et al., 1993). Although overt pulmonary oxygen toxicity is unlikely on this protocol and the cumulative effects of HBO are considered negligible for daily exposure (Clark, 1993), no study has been made of dayto-day variability in pulmonary function tests during the course of HBO therapy. Contradictory pulmonary effects of breathing humidified gas have also been reported. Breathing humidified air during a single air-dive prevented the flow limitation in the small airways associated with dry air, and was considered by the divers to be more comfortable (Thorsen et al., 1992), while breathing humidified oxygen during a chamber dive significantly increases both the wet and dry weights of rodent lungs, indicating exacerbation of pulmonary oxygen toxicity (Lin and Jamieson, 1993). The purpose of this study was to examine the daily and day-to-day effects of dry and humid HBO breathing on pulmonary function tests in a group of patients receiving routine HBO therapy.
2. Patients and methods
2.1. Patients Thirteen patients, 42 – 63 years of age, receiving daily HBO treatment for problem wounds, participated in the study after giving their written informed consent. All were non-smokers, had a negative history of chronic pulmonary disease, no pathological findings on physical examination of the respiratory system, and normal anterior–posterior and lateral chest roentgenograms.
2.2. HBO administration Subjects were randomly assigned to the dry and humidified oxygen treatment groups in a cross-over design, breathing dry oxygen during
five successive sessions and humidified oxygen during the remaining five sessions. The study protocol was approved by the local Helsinki committee. HBO was administered once daily in a multilock chamber compressed by air to an absolute pressure of 2.5 ATA for 95 min. Each treatment session was composed of two 40 min intervals of oxygen breathing, separated by 5 min of air breathing. The temperature inside the chamber was maintained at approximately 23°C. Oxygen was inhaled via a full face mask fitted with a demand valve and an expiratory overboard dumping system. To establish humid conditions, the inspired oxygen was passed through a bubble humidifier. Relative humidity was measured with a humidity thermistor (Tecnologic, Vigevano, Italy) at the output of the humidifier, and was maintained at 70–80%.
2.3. Pulmonary function tests Pulmonary function tests were performed at ambient pressure breathing room air, immediately before and 5–20 min after each HBO exposure on the first 10 treatment days. On the day preceding the first HBO session, each subject was repeatedly trained in the performance of pulmonary function tests until reproducibility of the results was achieved, according to the American Thoracic Society recommendations (American Thoracic Society, 1995). Forced vital capacities (FVC) and maximal expiratory flows were measured immediately after calibration of the spirometer (ST-250, Fukuda Sangyo, Japan), and validated according to the American Thoracic Society recommendations (American Thoracic Society, 1995). The respiratory parameters recorded included forced vital capacity (FVC), volume expired in 1 s (FEV1), percentage of FVC expired in 1 s (FEV1%), peak expiratory flow rate (PEF), and forced mid-expiratory flow rate (FEF25 – 75%). A minimum of three attempts was made for each spirometry session. Only the results of the best test, defined according to the highest value obtained by the summation of FEV1 and FVC, were taken into consideration. All values were corrected to BTPS conditions.
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
2.4. Symptoms of oxygen toxicity After each HBO exposure, the study participants were specifically asked about symptoms that have previously been related to pulmonary oxygen toxicity. These symptoms include retrosternal irritation on inspiration, chest tightness or pain, cough, and dyspnoea (Clark and Lambertsen, 1971).
2.5. Statistical analysis Pulmonary function values obtained before and after HBO exposure were compared separately for the dry and humidified oxygen groups using the paired t-test. Differences in daily measurements between the groups were evaluated by the twosample t-test. The significance of day-to-day variations in the test results was calculated by repeated measures one-way analysis of variance (ANOVA), and the source of significant differences between the days by the Tukey test for the pairwise comparison of means. Statistical analysis was carried out using SAS software (SAS Institute, Cary, NC) on an IBM-compatible personal computer.
3. Results
3.1. Symptoms of oxygen toxicity No symptoms related to pulmonary oxygen toxicity were reported by the patients during the study.
3.2. Changes in pulmonary function tests No differences were found on any of the days between the average forced vital capacities (FVC) and maximal expiratory flows measured before or after HBO exposure while breathing dry oxygen. The only significant change observed after humidified HBO breathing was an increase in the average absolute value for FEF25 – 75% on day 1: 3.43 l/min before and 4.59 l/min after the HBO session (p=0.03, paired t-test).
243
When the percent changes in pulmonary function tests after HBO exposure were compared, significant differences were noted in the changes in FEV1% and FEF25 – 75% on day 1 alone; a decrement of 1.4291.63 (SE) and 2.969 6.31 in FEV1% and FEF25 – 75%, respectively, under dry oxygen vs. an increment of 3.93 9 2.29 (SE) and 34.49 12.5 in FEV1% and FEF25 – 75%, respectively, for humidified oxygen (p=0.03, p =0.006, respectively, two-sample t-test) (Table 1). In the dry HBO group, no significant daily variations were found in the percent change in pulmonary function tests following HBO exposure. However, significant decrements in the percent changes in FEV1% and FEF25 – 75% were observed while breathing humidified HBO (p= 0.03 and p=0.005, respectively, one-way repeated measures ANOVA) (Figs. 1 and 2, Table 1). These differences between the days were attributed to the variance between day 1 and day 4 (Tukey test).
4. Discussion Significant differences were found between the average changes in FEV1% and FEF25 – 75% under dry HBO relative to baseline measurements, and the average changes in the same parameters while breathing humidified HBO. This observation was documented only for the first session. While no significant day-to-day variability could be found in any of the pulmonary function tests measured for the dry oxygen group, repeated HBO humidification was associated with a decrease in the relative post-exposure increments in FEV1% and FEF25 – 75% observed for the first humidified HBO exposure. Previous animal models and human studies investigating the pulmonary effects of breathing humidified normobaric oxygen or hyperbaric air during a single exposure support our findings regarding the short-term advantage of oxygen humidification. Rats exposed to 0.94 ATA dry normobaric oxygen for 48 h showed significant bronchial epithelial thickening, was prevented by oxygen humidification (Murchie et al., 1993). Anaesthetized dogs ventilated at 1 ATA for
A. Shupak et al. / Respiration Physiology 108 (1997) 241–246
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Table 1 Pulmonary function test changes (%) after HBO exposure: humidified vs. dry oxygen breathing (mean9SE) FCV Day 1 Humidified Dry Day 2 Humidified Dry Day 3 Humidified Dry Day 4 Humidified Dry Day 5 Humidified Dry
FEV1
FEV1%a
PEF
FEFb25 – 75%
−2.02 93.10 4.5896.04
1.109 2.29 2.619 4.93
3.93 92.29 −1.42 9 1.63c
8.39 9 8.25 15.44 9 16.2
34.42 9 12.6 −2.96 9 6.31d
0.799 2.08 1.189 1.90
2.559 3.56 0.919 1.66
−1.4891.66 0.92 90.92
1.09 9 8.07 0.3 9 4.05
1.79 9 9.36 5.26 9 8.97
2.5292.35 0.3892.41
2.109 2.62 1.389 2.44
−0.41 9 0.98 1.18 91.78
0.12 9 5.39 0.03 9 4.54
2.55 94.00 10.82 98.21
5.869 5.39 1.239 2.70
−1.129 0.72 1.069 2.58
−3.24 91.45 −0.62 91.42
0.66 98.32 −4.28 93.02
−8.58 9 6.42 4.56 9 6.93
1.939 1.82 1.209 3.32
1.679 2.18 −0.279 2.14
−0.53 91.31 −0.99 91.69
1.37 9 11.0 −6.11 9 4.37
−2.87 9 2.51 7.17 9 6.86
a
P = 0.03 (repeated measures ANOVA) for day-to-day variations when breathing humidified oxygen. P =0.005 (repeated measures ANOVA) for day-to-day variations when breathing humidified oxygen. c P = 0.03 (two-sample t-test). d P =0.006 (two-sample t-test). b
12 h showed less of a decrease in surfactant activity when breathing humidified oxygen compared with animals ventilated with dry oxygen (Motlagh et al., 1969). However, in another study using similar animals breathing oxygen at 1 ATA for 7 h, potentiation of pulmonary toxicity, as evaluated by pulmonary vein PO2 values, was reported to result from oxygen humidification (Ching et al., 1973).
Two previous human studies compared the changes in pulmonary function tests measured before and after dry or humidified compressed air-dives (Thorsen et al., 1992; Ronnestad et al., 1994). Dry air and oxy-helium dives to pressures of 1.16–5.94 ATA for 30 min to 4 h were associated with significant reductions in FEV1 and FEF25 – 75%. Such changes were not found for dives to the same depths and bottom times on humi-
Fig. 1. Day-to-day variations in FEV1% after dry and humidified HBO exposure. Data are presented as mean9SE.
Fig. 2. Day-to-day variations in FEF25 – 75% after dry and humidified HBO exposure. Data are presented as mean 9 SE.
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dified air or oxy-helium. For the shallower humidified air dives, relative increments were reported in FEV1 and FEF25 – 75%, matching our observation regarding the relative changes in FEV1% and FEF25 – 75% after the first humidified HBO session. Although the subjects of the above mentioned studies were, like our patients, all non-smokers, with no history, physical or baseline pulmonary function findings indicating bronchoconstriction, in their case as well, humidification of the breathing gas improved airway flow characteristics relative to baseline measurements. The mechanism of improved pulmonary airflow characteristics following a single exposure to a humidified hyperoxic gas mixture has not yet been investigated or elucidated. Breathing dry air results in bronchoconstriction, probably due to osmolarity changes affecting the fluid lining of the airways (Anderson, 1992). It is believed that these changes cause stimulation of autonomic nerve endings or the release of an as yet unidentified mediator, inducing a bronchomotor response, because the latter may be prevented by the administration of cholinergic antagonists (Anderson et al., 1979; Wilson et al., 1984). One may speculate that contrasting osmolarity changes facilitated by breathing highly humidified oxygen produced the bronchodilatation observed in the present study. One mediator which might be involved in the suggested response is nitric oxide, which has a well documented smooth muscle relaxation effect (Gaston et al., 1994). Repeated daily HBO exposures may result in the accumulation of oxygenderived free radicals, which overwhelm existing scavenger systems. The reaction of these free radicals with nitric oxide to produce various nitrogen oxides would lead to the disappearance of the temporary bronchodilatory effect observed after the first HBO session. The results of a recently published rodent model suggest that oxygen humidification might affect the development of pulmonary oxygen toxicity to different degrees according to the pressure applied and the duration of the exposure (Lin and Jamieson, 1993). Mice which breathed humidified oxygen for 30 min at pressures of 5.1 – 5.8 ATA had significant increases in wet and dry lung weights compared with animals breathing dry
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oxygen. This observation was interpreted as a sign of enhanced pulmonary oxygen toxicity under humid conditions. In contrast to this, rats exposed to normobaric hyperoxia for 68–72 h had a decreased mortality rate, lower lung weights, and less pleural effusion under humid conditions when compared with a group of similar animals breathing dry oxygen (Lin and Jamieson, 1993). In spite of the fact that in the present study no symptoms related to pulmonary oxygen toxicity were reported by the patients in either group, gradual but significant decrements in FEV1% and FEF25 – 75% normalised values were found after repeated humidified HBO exposures. It is known that despite the absence of clinical symptomatology, the biochemical effects of oxygen toxicity are initiated concurrently with the elevation of PO2 (Lambertsen, 1978). Deterioration in lung mechanical function precedes the clinical symptoms of pulmonary oxygen toxicity, and abnormal pulmonary function has been reported to persist for as long as 11 days after the disappearance of such symptoms (Clark and Lambertsen, 1971). The initial exposure interval represents an asymptomatic period of slowly developing toxicity, from which recovery is considered to be rapid and complete on return to normoxia (Clark, 1993). However, our results imply that when a course of daily 95 min sessions of 2.5 ATA humidified HBO is in question, cumulative effects of pulmonary oxygen toxicity might persist. These may abolish the initial benefits of oxygen humidification on pulmonary flow characteristics observed after the first HBO session. We were unable to find any previous study comparing the pulmonary effects of dry vs. humidified oxygen in patients receiving daily HBO treatments on one of the protocols recommended by the Undersea and Hyperbaric Medical Society for problem wounds (Thom, 1992). The only study examining changes in pulmonary function tests after humidified oxygen breathing at 2.5 ATA employed a single continuous oxygen exposure lasting 5.7 h. The greatest changes found were an average drop of 30% in FEF25 – 75% and 20% in maximal expiratory flow rate at 50% of FVC (MEF50%), indicating increased resistance of the peripheral airways (Clark, 1988, 1993). Although the daily oxygen
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breathing period employed in our study was much shorter (two intervals of 40 min separated by a 5 min air break), these observations are comparable to the gradual decline observed in FEV1% and FEF25 – 75% in the course of our study when the patients were breathing humidified oxygen, reaching maximal decrements of 3.2 and 8.6%, respectively. FEV1% contains both the effort-dependent and effort-independent parts of the flow – volume loop, whereas FEF25 – 75% is effort-independent, and a decrease in its value relative to the baseline measurement represents flow limitation in the peripheral airways (McFadden and Linden, 1972). Our results show that although patients might benefit from oxygen humidification during a single HBO session with regard to airway flow characteristics, this advantage might disappear during successive HBO treatments. We suggest that the practice of breathing humidified gas during routine daily HBO therapy protocols over a prolonged period should be reconsidered.
Acknowledgements The authors are indebted to Esther Eilender and Richard Lincoln for their assistance in the preparation of the manuscript.
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