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THE INFLUENCE OF DOXAPRAM ON POSTOPERATIVE PULMONARY FUNCTION IN PATIENTS UNDERGOING UPPER ABDOMINAL SURGERY
Br.J. Anaesth. (1976), 48, 1197
THE INFLUENCE OF DOXAPRAM ON POSTOPERATIVE PULMONARY FUNCTION IN PATIENTS UNDERGOING UPPER ABDOMINAL SURGERY N. W. LEES, H. B. HOWIE, A. MELLON, A. H. MCKEE AND I. A MCDIARMID SUMMARY
An infusion of doxapram 250 mg in dextrose 5% compared with dextrose 5% alone in patients recovering from upper abdominal surgery was associated with a reduction in the degree of hypoxaemia after operation. This may be the result of a sparing effect on the functional residual capacity.
METHODS
Forty patients admitted to the same surgical unit and undergoing elective upper abdominal surgery for vagotomy and pyloroplasty (23) or cholecystectomy (17) gave consent to the investigations and the administration of doxapram (table I). Patients who were obese or suffered from cardiac or respiratory disease were excluded. They were allocated randomly to one of two groups. Group I received doxapram 250 mg in 500 ml of dextrose 5% in water i.v. during the first 2 h after operation. Group II received the same amount of dextrose 5% without doxapram over the same period. All the patients were anaesthetized using the same technique comprising sodium thiopentone 5 mg/kg and suxamethonium 1 mg/kg. The N. W. LEES, F.F.A.R.C.S.; HELEN B. HOWIE, F.F.A.R.C.S.; ANNE MELLON, F.F.A.R.C.S.; A. H. MCKEE, F.F.A.R.C.S.;
I. A. MCDIARMID, F.F.A.R.C.S.; Departments of Anaesthesia,
Victoria Infirmary, Stobhill General Hospital, and Western Infirmary, Glasgow.
patients were ventilated with 66% nitrous oxide in oxygen and neuromuscular blockade was obtained with pancuronium 0.1 mg/kg. This was antagonized at the end of operation with atropine 1.2 mg and neostigmine 2.5 mg. Up to 10 mg of morphine i.v. was given during the operation. After operation, the inspired oxygen concentration was enriched by administering 3 litre of oxygen via an Edinburgh face mask for 4-6 h. During the first 2 days after operation, all patients received morphine 10 mg i.m. for analgesia every 4 h (Alexander, Parikh and Spence, 1973). Each patient had supervision of breathing exercises once per day by a physiotherapist. TABLE I. Sex and age of the patients in the two groups Operation Group I Cholecystectomy Vagotomy and drainage Group II Cholecystectomy Vagotomy and drainage
Male Female
Mean age (yr + SEM)
3
5
46.4 ±5.16
5 4
6 5
41.6 + 2.06 43.5 + 4.39
7
5
41.7±3.32
Lung function was measured with the patient in a semi-recumbent position on the day before operation and on the 1st, 2nd and 5th days after operation. The first set of measurements was made 24 h after operation. In some patients, a full set of measurements was not obtained. A sample of blood was taken percutaneously from the radial artery for the measurement of PaOs, Pa c o , and pH using standard Radiometer electrodes. All measurements were made with the patients breathing room air. A correction factor of 1.065 was applied to the measurement of PaOi to allow for the difference in the response of the Po 2 electrode to blood and the gas with which it had been calibrated. When appropriate, the samples were corrected for temperature using a Severinghaus slide rule (Severinghaus, 1966).
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
Although many factors are known to influence the severity of hypoxaemia in patients recovering from surgery, the aetiology of the condition is not understood. Alexander and others (1973) have suggested that it is associated with collapse or narrowing of dependent small airways resulting from a reduction in functional residual capacity (FRC). It would seem reasonable to propose that mechanisms which increase the tidal volume might reduce the degree of postoperative hypoxaemia (Winnie et al., 1971). Doxapram is a respiratory stimulant which acts both centrally (Kato and Buckley, 1964) and peripherally (Wang and Hirsch, 1973). We have investigated the effect of an infusion of doxapram on arterial oxygenation in the period following surgery. Patients undergoing upper abdominal surgery were studied, since hypoxaemia after this type of operation is both severe (Diament and Palmer, 1967) and protracted (Spence and Smith, 1971).
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RESULTS
After operation, the arterial Po2 was reduced significantly when compared with the values before surgery in both groups. However, the mean reduction in arterial Po 2 was greater in the control group (group II) than in the doxapram group (group I) on each day after operation (table II). The difference on the 1st day after operation is statistically significant (P < 0.01). Although there was no significant difference in arterial Pco2 between the two groups on any day, in group II there was a small but significant increase in Pa C02 on the 1st and 2nd days after operation compared with the preoperative value (P< 0.02). No such increase occurred in group II (table III). There was no significant difference in the pH values between or within the two groups on any of the days. In group I, the reduction in tidal volume and FRC after operation was less than in the control group. Table IV shows the changes in tidal volume. On the 1st day after operation, the mean control value was 0.47 litre and that of the doxapram group was 0.57 litre. This difference is statistically significant (P< 0.025). A similar pattern of changes was observed in the changes in FRC which are calculated as a percentage reduction compared with the values before surgery (table V). The control group showed a greater percentage reduction in FRC on the 1st and 2nd days after operation. The 2nd day difference is highly significant (P<0.001). The percentage change in CV showed a similar pattern (table VI). In each of the days following surgery, the percentage reduction in CV was less
TABLE II. Mean arterial Po2 (mm Hg) values (and SEM) before and after operation in the control (n = 19) and doxapram (n = 21) groups Day after operation Before operation
Group Control Doxapram
91.6 (2.22) 91.4 (1.98)
1
2
5
69.18* (2.74) 79.6* (2.26)
72.6 (2.85) 76.6 (2.53)
83.0 (3.14) 89.2 (2.53)
* Significant difference between the two groups (P < 0.01). TABLE III. Mean arterial Pco2 (mm Hg) (and SEM) before and after operation Day after operation Before operation
Group Control (n = 19) Doxapram (n = 21)
34.3 (0.90) 36.1 (0.60)
1
2
5
37.5* (0.89) 37.5 (0.99)
38.2* (0.94) 37.1 (0.82)
35.1 (0.90) 36.0 (0.97)
* Significant difference from mean value before operation in the same group (P < 0.05). TABLE IV. Mean tidal volume (litre) (and SEM) before and after operation Day after operation
Group
operation
Control
1
2
5
(0.01)
0.47* (0.03)
0.54 (0.06)
0.56 (0.04)
19
17
16
19
0.62 (0.03)
0.57* (0.03)
0.57 (0.03)
0.59 (0.03)
21
20
18
21
0.7 n:
Doxapram n:
* Significant difference between the two groups (P< 0.025). TABLE V. FRC values before operation (litre) and after operation (expressed as % of measurements before operation). (Means and SEM) Day after operation
Group
operation
Control
3.2
(0.18) n:
Doxapram n:
1
2
5
77.7 (6.42)
76.1* (5.01)
94.2 (5.73) 19 91.0 (4.14) 21
19
17
16
2.85 (0.127)
82.7 (4.36)
94.9* (5.17)
21
20
18
* The difference between the two groups is highly significant on the second day (P< 0.001).
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
The functional residual capacity (FRC) was measured using the closed-circuit helium equilibration technique of Meneely and Kultreider (1949). A Jaeger Spirotest I closed-circuit spirometer was charged with 21% oxygen and 79% helium. Oxygen was added to the circuit via a solenoid valve for the replacement of losses as a result of the patient's metabolic consumption. The concentration of helium was measured using a helium analyser (P. K. Morgan Ltd, Rochester, Kent). Following measurement of FRC, the vital capacity (VC) and its subdivisions were measured using the Spirotest. The closing volume (CV), which is that volume during an expiration following a maximal inspiration at which the dependent airways begin to close, was measured using the xenon-133 method of Dollfuss, Milic-Emili and Bates (1967). These techniques, as used in our laboratory, have been described in detail elsewhere (Alexander et al., 1973).
DOXAPRAM AND LUNG FUNCTION AFTER SURGERY TABLE V I . Closing volume measurements before operation (litre) and after operation {expressed as % of measurements before operation). Means and SEM Day after operation
Group Control n:
Doxapram n:
operation
1
2
5
2.80 (0.19)
85.7 (7.21)
84.0 (7.36)
89.8 (7.83)
19
17
16
19
2.88 (0.19)
87.9 (9.03)
96.2 (9.88)
96.6 (7.14)
21
16
16
21
Differences do not reach statistical significance.
DISCUSSION
Our results suggest that the administration of doxapram 250 mg by infusion over 2 h has a beneficial effect on hypoxaemia after operation as measured by changes in Pa.Ol at 24 h. In association with this, the tidal volume and functional residual capacity are reduced less than would be expected. PaCOa changes in the control group, although statistically significant, probably do not represent significant hypoventilation, since all the Pa C02 values are low. This may represent mild hyperventilation as a result of anxiety. These results are in agreement with those of Winnie and his colleagues (1971) who found an improvement in the PaOa values after intermittent doxapram administration i.v. However, Dobkin, Boyles and Po-Giok (1967) found no difference at 24 h between two groups of patients, one of which received doxapram 300 mg over 2 h. These differences may result from dissimilar anaesthetic techniques. Dobkin's patients were ventilated with up to 1.5% methoxyflurane in a mixture of nitrous oxide in oxygen, whereas the patients in our series were ventilated with nitrous oxide in oxygen and received up to 10 mg of morphine i.v. Doxapram is metabolized very rapidly when given i.v. The effect of a single i.v. dose lasts for 8-10 min (Stephen and Talton, 1964) and blood concentrations decrease rapidly by up to 66% in the 1st hour (Bruce et al., 1965). Because it is metabolized rapidly, it is unlikely that the drug continues to act as a respiratory stimulant 24 h later, and our measured Pa C02 values (table III) tend to support this. Winnie and colleagues
(1971) suggested that the induced hyperventilation reduced atelectasis. Gupta and Dundee (1974) showed that doxapram reduced the respiratory depressant effect of morphine without antagonizing the analgesia, enabling the patients to cough and breathe more deeply. Gawley and others (1976) found that the administration of doxapram 1.5-2.0 mg/kg as an infusion after operation reduced the frequency of cough and expectoration of sputum. The relative sparing effect on FRC and CV associated with doxapram may be the mechanism by which doxapram reduces hypoxaemia after operation, although undoubtedly there are other factors in the aetiology of hypoxaemia following surgery, which doxapram does not influence. The absence of side-effects is in keeping with other studies which showed the absence of cardiac arrythmia (Dobkin, Boyles and Po-Giok Su, 1967) and e.e.g. changes (Menin and Boba, 1966). Stephen reported one patient who exhibited athetoid movement. In all three series, a small increase in arterial pressure and heart rate in association with doxapram was noted.
ACKNOWLEDGEMENTS
This work was supported by a grant from the Secretary of State for Scotland. We are grateful to our surgical and nursing colleagues for their co-operation. We wish to thank Dr A. A. Spence for his help and encouragement, Mrs Martha MacLeod for secretarial help and Miss Sylvia O'Grady for technical assistance.
REFERENCES
Alexander, J. I., Parikh, R. K., and Spence, A. A. (1973). Post-operative analgesia and lung function. A comparison of narcotic analgesia regimen. Br. J. Anaesth., 45, 396. Spence, A. A., Parikh, R. K., and Stuart, B. (1973). The role of airway closure in post-operative hypoxaemia. Br. J. Anaesth., 45, 34. Bruce, R. B., Pitts, J. E., Pinchbeck, F., and Newman, J. (1965). Excretion, distribution and metabolism of doxapram hydrochloride. J. Med. Chem., 8, 157. Diament, A. L., and Palmer, K. N. V. (1967). Venous/ arterial pulmonary shunting as the principal cause of post-operative hypoxaemia. Lancet, 1, 15. Dobkin, A. B., Boyles, P. H., and Po-Giok, Su J. (1967). Comparison of ethamivan and doxapram in the management of post-anesthetic respiratory depression. Anesth. Analg. (Cleve.), 46, 449. Dollfuss, R. E., Milic-Emili, J., and Bates, D. V. (1967). Regional ventilation of the lung studies with boluses of 133
Xenon. Respir. Physiol., 2, 234.
Gawley, T. H., Dundee, J. W., Gupta, P. K., and Jones, C. J. (1976). Role of doxapram in reducing pulmonary complications after major surgery. Br. Med. J., 1, 122.
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
than in the control group. However, these differences did not reach statistical significance. During this study, no side-effects occurred which could be associated with the administration of doxapram.
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BRITISH JOURNAL OF ANAESTHESIA
1200
INFLUENCE DU DOXAPRAM SUR LA FONCTION PULMONAIRE POSTOPERATOIRE DE PATIENTS AYANT SUBI UNE INTERVENTION CHIRURGICALE A LA PARTIE SUPERIEURE DE L'ABDOMEN RESUME
La perfusion de 250 mg de doxapram dans une solution de dextrose a 5%—par opposition a une perfusion de dextrose a 5% sans additif—sur des patients recuperant d'une intervention chirurgicale a la partie superieure de l'abdomen est associee a une reduction du degre d'hypoxemie apres l'operation. Cela peut etre du a un effet d'epargne sur la capacite fonctionnelle residuelle.
DER EINFLUSS VON DOXAPRAM AUF DIE POSTOPERATIVE LUNGENFUNKTION BEI PATIENTEN, DIE SICH UNTERLEIBSOPERATIONEN UNTERZIEHEN ZUSAMMENFASSUNG
Eine Infusion von 250 mg Doxapram in Dextrose, verglichen mit 5% Dextrose allein, bei Patienten nach Operationen im oberen Unterleib wird in Zusammenhang gebracht mit einer Verringerung des Ausmasses der Hypoxamie nach der Operation. Dies konnte das Resultat einer geringfugigen Wirkung auf die funktionelle Residualkapazitat sein. LA INFLUENCIA DE DOXAPRAM SOBRE LA FUNCION PULMONAR POSTOPERATORIA EN PACIENTES SOMETIDOS A CIRUGIA ABDOMINAL ALTA SUMARIO
Una infusion de doxapram 250 mg en 5% dextrosa, comparada con dextrosa 5% sola en pacientes recuperandose de cirurgia abominal alta, es asociada con una reduction en el grado de hipoxemia tras la operation. Ello pudiera ser resultado de un efecto economizante sobre la capacidad residual funcional.
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
Gupta, P. K., and Dundee, J. W. (1974). The effect of an infusion of doxapram on morphine analgesia. Anaesthesia, 29,40. Kato, H., and Buckley, J. P. (1964). Possible sites of action of the respiratory stimulatory effect of doxapram hydrochloride. J. Pharmacol. Exp. Ther., 144, 260. Meneely, G. R., and Kultreider. N. L. (1949). The volume of the lung determined by helium dilution. Description of the method and comparison with other procedures. J. Clin. Invest., 28, 129. Menin, R. G., and Boba, B. (1966). E.e.g. effect of doxapram hydrochloride in humans. Ada Anaesthesiol. Scand., (Suppl.) 23, 36. Severinghaus, J. W. (1966). Blood-gas calculator. J. Appl. Physiol., 21, 1108. Spence, A. A., and Smith, G. (1971). Post-operative analgesia and lung function: a comparison of morphine with epidural block. Br. J. Anaesth., 43, 144. Stephen, C. R., and Talton, I. (1964). Investigation of doxapram as a post-anesthetic respiratory stimulant. Anesth. Analg. (Cleve.), 43, 628. Wang, S. C , and Hirsch, K. (1973). Doxapram. Lancet, 1, 753. Winnie, A. P., Gladisch, J. T., Angel, J. J., Ramamurthy, S.j and Collins, V. J. (1971). Chemical respirogenesis. I I : Reversal of post-operative hypoxemia with the "Pharmacologic Sigh". Anesth. Analg. (Cleve.), 50, 1043.
THE INFLUENCE OF DOXAPRAM ON POSTOPERATIVE PULMONARY FUNCTION IN PATIENTS UNDERGOING UPPER ABDOMINAL SURGERY N. W. LEES, H. B. HOWIE, A. MELLON, A. H. MCKEE AND I. A MCDIARMID SUMMARY
An infusion of doxapram 250 mg in dextrose 5% compared with dextrose 5% alone in patients recovering from upper abdominal surgery was associated with a reduction in the degree of hypoxaemia after operation. This may be the result of a sparing effect on the functional residual capacity.
METHODS
Forty patients admitted to the same surgical unit and undergoing elective upper abdominal surgery for vagotomy and pyloroplasty (23) or cholecystectomy (17) gave consent to the investigations and the administration of doxapram (table I). Patients who were obese or suffered from cardiac or respiratory disease were excluded. They were allocated randomly to one of two groups. Group I received doxapram 250 mg in 500 ml of dextrose 5% in water i.v. during the first 2 h after operation. Group II received the same amount of dextrose 5% without doxapram over the same period. All the patients were anaesthetized using the same technique comprising sodium thiopentone 5 mg/kg and suxamethonium 1 mg/kg. The N. W. LEES, F.F.A.R.C.S.; HELEN B. HOWIE, F.F.A.R.C.S.; ANNE MELLON, F.F.A.R.C.S.; A. H. MCKEE, F.F.A.R.C.S.;
I. A. MCDIARMID, F.F.A.R.C.S.; Departments of Anaesthesia,
Victoria Infirmary, Stobhill General Hospital, and Western Infirmary, Glasgow.
patients were ventilated with 66% nitrous oxide in oxygen and neuromuscular blockade was obtained with pancuronium 0.1 mg/kg. This was antagonized at the end of operation with atropine 1.2 mg and neostigmine 2.5 mg. Up to 10 mg of morphine i.v. was given during the operation. After operation, the inspired oxygen concentration was enriched by administering 3 litre of oxygen via an Edinburgh face mask for 4-6 h. During the first 2 days after operation, all patients received morphine 10 mg i.m. for analgesia every 4 h (Alexander, Parikh and Spence, 1973). Each patient had supervision of breathing exercises once per day by a physiotherapist. TABLE I. Sex and age of the patients in the two groups Operation Group I Cholecystectomy Vagotomy and drainage Group II Cholecystectomy Vagotomy and drainage
Male Female
Mean age (yr + SEM)
3
5
46.4 ±5.16
5 4
6 5
41.6 + 2.06 43.5 + 4.39
7
5
41.7±3.32
Lung function was measured with the patient in a semi-recumbent position on the day before operation and on the 1st, 2nd and 5th days after operation. The first set of measurements was made 24 h after operation. In some patients, a full set of measurements was not obtained. A sample of blood was taken percutaneously from the radial artery for the measurement of PaOs, Pa c o , and pH using standard Radiometer electrodes. All measurements were made with the patients breathing room air. A correction factor of 1.065 was applied to the measurement of PaOi to allow for the difference in the response of the Po 2 electrode to blood and the gas with which it had been calibrated. When appropriate, the samples were corrected for temperature using a Severinghaus slide rule (Severinghaus, 1966).
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
Although many factors are known to influence the severity of hypoxaemia in patients recovering from surgery, the aetiology of the condition is not understood. Alexander and others (1973) have suggested that it is associated with collapse or narrowing of dependent small airways resulting from a reduction in functional residual capacity (FRC). It would seem reasonable to propose that mechanisms which increase the tidal volume might reduce the degree of postoperative hypoxaemia (Winnie et al., 1971). Doxapram is a respiratory stimulant which acts both centrally (Kato and Buckley, 1964) and peripherally (Wang and Hirsch, 1973). We have investigated the effect of an infusion of doxapram on arterial oxygenation in the period following surgery. Patients undergoing upper abdominal surgery were studied, since hypoxaemia after this type of operation is both severe (Diament and Palmer, 1967) and protracted (Spence and Smith, 1971).
1198
BRITISH JOURNAL OF ANAESTHESIA
RESULTS
After operation, the arterial Po2 was reduced significantly when compared with the values before surgery in both groups. However, the mean reduction in arterial Po 2 was greater in the control group (group II) than in the doxapram group (group I) on each day after operation (table II). The difference on the 1st day after operation is statistically significant (P < 0.01). Although there was no significant difference in arterial Pco2 between the two groups on any day, in group II there was a small but significant increase in Pa C02 on the 1st and 2nd days after operation compared with the preoperative value (P< 0.02). No such increase occurred in group II (table III). There was no significant difference in the pH values between or within the two groups on any of the days. In group I, the reduction in tidal volume and FRC after operation was less than in the control group. Table IV shows the changes in tidal volume. On the 1st day after operation, the mean control value was 0.47 litre and that of the doxapram group was 0.57 litre. This difference is statistically significant (P< 0.025). A similar pattern of changes was observed in the changes in FRC which are calculated as a percentage reduction compared with the values before surgery (table V). The control group showed a greater percentage reduction in FRC on the 1st and 2nd days after operation. The 2nd day difference is highly significant (P<0.001). The percentage change in CV showed a similar pattern (table VI). In each of the days following surgery, the percentage reduction in CV was less
TABLE II. Mean arterial Po2 (mm Hg) values (and SEM) before and after operation in the control (n = 19) and doxapram (n = 21) groups Day after operation Before operation
Group Control Doxapram
91.6 (2.22) 91.4 (1.98)
1
2
5
69.18* (2.74) 79.6* (2.26)
72.6 (2.85) 76.6 (2.53)
83.0 (3.14) 89.2 (2.53)
* Significant difference between the two groups (P < 0.01). TABLE III. Mean arterial Pco2 (mm Hg) (and SEM) before and after operation Day after operation Before operation
Group Control (n = 19) Doxapram (n = 21)
34.3 (0.90) 36.1 (0.60)
1
2
5
37.5* (0.89) 37.5 (0.99)
38.2* (0.94) 37.1 (0.82)
35.1 (0.90) 36.0 (0.97)
* Significant difference from mean value before operation in the same group (P < 0.05). TABLE IV. Mean tidal volume (litre) (and SEM) before and after operation Day after operation
Group
operation
Control
1
2
5
(0.01)
0.47* (0.03)
0.54 (0.06)
0.56 (0.04)
19
17
16
19
0.62 (0.03)
0.57* (0.03)
0.57 (0.03)
0.59 (0.03)
21
20
18
21
0.7 n:
Doxapram n:
* Significant difference between the two groups (P< 0.025). TABLE V. FRC values before operation (litre) and after operation (expressed as % of measurements before operation). (Means and SEM) Day after operation
Group
operation
Control
3.2
(0.18) n:
Doxapram n:
1
2
5
77.7 (6.42)
76.1* (5.01)
94.2 (5.73) 19 91.0 (4.14) 21
19
17
16
2.85 (0.127)
82.7 (4.36)
94.9* (5.17)
21
20
18
* The difference between the two groups is highly significant on the second day (P< 0.001).
Downloaded from http://bja.oxfordjournals.org/ at University of York on July 20, 2015
The functional residual capacity (FRC) was measured using the closed-circuit helium equilibration technique of Meneely and Kultreider (1949). A Jaeger Spirotest I closed-circuit spirometer was charged with 21% oxygen and 79% helium. Oxygen was added to the circuit via a solenoid valve for the replacement of losses as a result of the patient's metabolic consumption. The concentration of helium was measured using a helium analyser (P. K. Morgan Ltd, Rochester, Kent). Following measurement of FRC, the vital capacity (VC) and its subdivisions were measured using the Spirotest. The closing volume (CV), which is that volume during an expiration following a maximal inspiration at which the dependent airways begin to close, was measured using the xenon-133 method of Dollfuss, Milic-Emili and Bates (1967). These techniques, as used in our laboratory, have been described in detail elsewhere (Alexander et al., 1973).
DOXAPRAM AND LUNG FUNCTION AFTER SURGERY TABLE V I . Closing volume measurements before operation (litre) and after operation {expressed as % of measurements before operation). Means and SEM Day after operation
Group Control n:
Doxapram n:
operation
1
2
5
2.80 (0.19)
85.7 (7.21)
84.0 (7.36)
89.8 (7.83)
19
17
16
19
2.88 (0.19)
87.9 (9.03)
96.2 (9.88)
96.6 (7.14)
21
16
16
21
Differences do not reach statistical significance.
DISCUSSION
Our results suggest that the administration of doxapram 250 mg by infusion over 2 h has a beneficial effect on hypoxaemia after operation as measured by changes in Pa.Ol at 24 h. In association with this, the tidal volume and functional residual capacity are reduced less than would be expected. PaCOa changes in the control group, although statistically significant, probably do not represent significant hypoventilation, since all the Pa C02 values are low. This may represent mild hyperventilation as a result of anxiety. These results are in agreement with those of Winnie and his colleagues (1971) who found an improvement in the PaOa values after intermittent doxapram administration i.v. However, Dobkin, Boyles and Po-Giok (1967) found no difference at 24 h between two groups of patients, one of which received doxapram 300 mg over 2 h. These differences may result from dissimilar anaesthetic techniques. Dobkin's patients were ventilated with up to 1.5% methoxyflurane in a mixture of nitrous oxide in oxygen, whereas the patients in our series were ventilated with nitrous oxide in oxygen and received up to 10 mg of morphine i.v. Doxapram is metabolized very rapidly when given i.v. The effect of a single i.v. dose lasts for 8-10 min (Stephen and Talton, 1964) and blood concentrations decrease rapidly by up to 66% in the 1st hour (Bruce et al., 1965). Because it is metabolized rapidly, it is unlikely that the drug continues to act as a respiratory stimulant 24 h later, and our measured Pa C02 values (table III) tend to support this. Winnie and colleagues
(1971) suggested that the induced hyperventilation reduced atelectasis. Gupta and Dundee (1974) showed that doxapram reduced the respiratory depressant effect of morphine without antagonizing the analgesia, enabling the patients to cough and breathe more deeply. Gawley and others (1976) found that the administration of doxapram 1.5-2.0 mg/kg as an infusion after operation reduced the frequency of cough and expectoration of sputum. The relative sparing effect on FRC and CV associated with doxapram may be the mechanism by which doxapram reduces hypoxaemia after operation, although undoubtedly there are other factors in the aetiology of hypoxaemia following surgery, which doxapram does not influence. The absence of side-effects is in keeping with other studies which showed the absence of cardiac arrythmia (Dobkin, Boyles and Po-Giok Su, 1967) and e.e.g. changes (Menin and Boba, 1966). Stephen reported one patient who exhibited athetoid movement. In all three series, a small increase in arterial pressure and heart rate in association with doxapram was noted.
ACKNOWLEDGEMENTS
This work was supported by a grant from the Secretary of State for Scotland. We are grateful to our surgical and nursing colleagues for their co-operation. We wish to thank Dr A. A. Spence for his help and encouragement, Mrs Martha MacLeod for secretarial help and Miss Sylvia O'Grady for technical assistance.
REFERENCES
Alexander, J. I., Parikh, R. K., and Spence, A. A. (1973). Post-operative analgesia and lung function. A comparison of narcotic analgesia regimen. Br. J. Anaesth., 45, 396. Spence, A. A., Parikh, R. K., and Stuart, B. (1973). The role of airway closure in post-operative hypoxaemia. Br. J. Anaesth., 45, 34. Bruce, R. B., Pitts, J. E., Pinchbeck, F., and Newman, J. (1965). Excretion, distribution and metabolism of doxapram hydrochloride. J. Med. Chem., 8, 157. Diament, A. L., and Palmer, K. N. V. (1967). Venous/ arterial pulmonary shunting as the principal cause of post-operative hypoxaemia. Lancet, 1, 15. Dobkin, A. B., Boyles, P. H., and Po-Giok, Su J. (1967). Comparison of ethamivan and doxapram in the management of post-anesthetic respiratory depression. Anesth. Analg. (Cleve.), 46, 449. Dollfuss, R. E., Milic-Emili, J., and Bates, D. V. (1967). Regional ventilation of the lung studies with boluses of 133
Xenon. Respir. Physiol., 2, 234.
Gawley, T. H., Dundee, J. W., Gupta, P. K., and Jones, C. J. (1976). Role of doxapram in reducing pulmonary complications after major surgery. Br. Med. J., 1, 122.
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than in the control group. However, these differences did not reach statistical significance. During this study, no side-effects occurred which could be associated with the administration of doxapram.
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INFLUENCE DU DOXAPRAM SUR LA FONCTION PULMONAIRE POSTOPERATOIRE DE PATIENTS AYANT SUBI UNE INTERVENTION CHIRURGICALE A LA PARTIE SUPERIEURE DE L'ABDOMEN RESUME
La perfusion de 250 mg de doxapram dans une solution de dextrose a 5%—par opposition a une perfusion de dextrose a 5% sans additif—sur des patients recuperant d'une intervention chirurgicale a la partie superieure de l'abdomen est associee a une reduction du degre d'hypoxemie apres l'operation. Cela peut etre du a un effet d'epargne sur la capacite fonctionnelle residuelle.
DER EINFLUSS VON DOXAPRAM AUF DIE POSTOPERATIVE LUNGENFUNKTION BEI PATIENTEN, DIE SICH UNTERLEIBSOPERATIONEN UNTERZIEHEN ZUSAMMENFASSUNG
Eine Infusion von 250 mg Doxapram in Dextrose, verglichen mit 5% Dextrose allein, bei Patienten nach Operationen im oberen Unterleib wird in Zusammenhang gebracht mit einer Verringerung des Ausmasses der Hypoxamie nach der Operation. Dies konnte das Resultat einer geringfugigen Wirkung auf die funktionelle Residualkapazitat sein. LA INFLUENCIA DE DOXAPRAM SOBRE LA FUNCION PULMONAR POSTOPERATORIA EN PACIENTES SOMETIDOS A CIRUGIA ABDOMINAL ALTA SUMARIO
Una infusion de doxapram 250 mg en 5% dextrosa, comparada con dextrosa 5% sola en pacientes recuperandose de cirurgia abominal alta, es asociada con una reduction en el grado de hipoxemia tras la operation. Ello pudiera ser resultado de un efecto economizante sobre la capacidad residual funcional.
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Gupta, P. K., and Dundee, J. W. (1974). The effect of an infusion of doxapram on morphine analgesia. Anaesthesia, 29,40. Kato, H., and Buckley, J. P. (1964). Possible sites of action of the respiratory stimulatory effect of doxapram hydrochloride. J. Pharmacol. Exp. Ther., 144, 260. Meneely, G. R., and Kultreider. N. L. (1949). The volume of the lung determined by helium dilution. Description of the method and comparison with other procedures. J. Clin. Invest., 28, 129. Menin, R. G., and Boba, B. (1966). E.e.g. effect of doxapram hydrochloride in humans. Ada Anaesthesiol. Scand., (Suppl.) 23, 36. Severinghaus, J. W. (1966). Blood-gas calculator. J. Appl. Physiol., 21, 1108. Spence, A. A., and Smith, G. (1971). Post-operative analgesia and lung function: a comparison of morphine with epidural block. Br. J. Anaesth., 43, 144. Stephen, C. R., and Talton, I. (1964). Investigation of doxapram as a post-anesthetic respiratory stimulant. Anesth. Analg. (Cleve.), 43, 628. Wang, S. C , and Hirsch, K. (1973). Doxapram. Lancet, 1, 753. Winnie, A. P., Gladisch, J. T., Angel, J. J., Ramamurthy, S.j and Collins, V. J. (1971). Chemical respirogenesis. I I : Reversal of post-operative hypoxemia with the "Pharmacologic Sigh". Anesth. Analg. (Cleve.), 50, 1043.