EFFECTS OF DOXAPRAM ON POSTOPERATIVE PULMONARY COMPLICATIONS FOLLOWING THORACOTOMY

Br.J. Anaesth. (1980), 52, 81

EFFECTS OF DOXAPRAM ON POSTOPERATIVE PULMONARY COMPLICATIONS FOLLOWING THORACOTOMY P. S. SEBEL, E. J. KERSHAW AND W. S. RAO SUMMARY

An i.v. solution of 5% dextrose with doxapram 2 mg ml- 1 or 5% dextrose alone was administered to 53 patients following lateral thoracotomy. Estimations of arterial Pov Poo, and pH were made before operation, during infusion and 7 days after operation. Respiratory function tests were carried out before and 7 days after operation. There were no significant differences in arterial Pou Pco, and pH or in respiratory function tests between those who received doxapram and those who did not. In this study doxapram did not affect the frequency of postoperative pulmonary complications.

Doxapram hydrochloride is a respiratory stimulant which has an action both centrally and on the peripheral chemoreceptors (Kato and Buckley, 1964; Wang and Hirsch, 1973; Scott, Whitwam and Chakrabarti, 1977). The administration of doxapram has been shown to reduce respiratory complications and hypoxaemia in fit patients after abdominal surgery (Gupta and Dundee, 1974; Gawley, Dundee and Jones, 1975; Gawley et al., 1976; Downing et al., 1977). Lees and others (1976) suggested that reduction in hypoxaemia may be a result of a sparing effect on functional residual capacity (FRC). However, not all investigators agree that the drug is of value after surgery (Andersen and Krohg, 1976). We have investigated the effects of an infusion of doxapram on postoperative pulmonary complications and on arterial POJJ, Poo2 and pH in a group of patients with pre-existing lung disease undergoing lateral thoracotomy. PATIENTS AND METHODS

Fifty-three patients admitted to the same surgical unit for thoracotomy gave informed consent to investigation. Patients with severe hypertension (>112mmHg diastolic), severe coronary artery disease and those requiring repeat operation on the chest were excluded from the study. Before operation arterial blood was sampled from the femoral or radial artery into a heparinized P. S. SEBEL,* M.B., B.S., F.F.A.RX.S.I.J E. J. KERSHAW, M.B., B.S., F.F.A.R.C.S.; W . S. RAO, M.D., F.F.A.R.C.S., D.A.;

Brook Hospital, London, SE 18. •Present address: Department of Anaesthetics, Wilhelmina Gasthuis, Academisch Ziekenhuis bij de Universiteit van Amsterdam, le Helmersstraat 104, Amsterdam,Holland. 0007-0912/80/010081-04 $01.00

syringe with the patient breathing room air. The sample was analysed within 10 min for hydrogen ion activity ([H+]), P a ^ and P a ^ using a Corning pH/blood-gas 165 analyser previously calibrated using Corning buffer and calibration gas. Vital capacity (VC), the forced expiratory volume in 1 s (FEVj) and the peak expiratory flow rates (PEF) were measured using a Vitalograph dry spirometer. The carbon monoxide transfer factor corrected for alveolar volume (,KC0) was measured by the single breath method using a P. K. Morgan Respirometer. A chest x-ray was taken before operation. All patients were premedicated with papaveretum 10-20 mg and hyoscine 0.2-0.4 mg i.m. Anaesthesia was induced with a sleep dose of thiopentone. Following the administration of suxamethonium 100 mg, the trachea was intubated with an appropriate double-lumen tube. Ventilation was controlled throughout the operation with the aid of a nondepolarizing neuromuscular blocker and anaesthesia was maintained with a mixture of nitrous oxide in oxygen supplemented with fentanyl or phenoperidine. At the end of surgery, residual muscular paralysis was antagonized with neostigmine and atropine. TABLE I. Details of patients in the two groups

Doxapram Male Female Mean age (yr±SD) Operation Pneumonectomy Lobectomy No resection ± biopsy Pleurectomy

Control

21 3

25 4

59.2(11.09)

61.0(11.16)

11 7 4 2

9

8 8 4

© Macmillan Journals Ltd 1980

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TABLE I I . Arterial Pot, Pco, and acid-base data for the two groups. Mean values +SD. Range in parentheses. 1 = Before operation; 2 and 3 = 2 h and 7 days after operation Doxapram (n = 24) 2

1 [H+] (nmol litre"1) ^aco,(kPa) Pao,(kPa) Base excess 1 (mmol litre" )

TABLE

50.2 ±8.7

- 1 . 7 ±2.4 ( - 7 to +6.3)

- 3 . 1 ±3.94

3 38.0 ±3.7

6.0±1.15

4.8 ±0.63

13.0 ±4.08

9.8 ±1.74 + 0.1 ±2.8

1

2

40.5 ±4.58 (32-54) 4.9 ±0.63 (4.0-6.4) 10.6 ±1.99 (6.4-17.3)

49.2 ±6.4

-1.0±2.91 (-4.2 to +8)

3 38.0 ±2.7

5.9 ±0.86

4.7 ±0.52

14.8 ±4.39

9.6 ±1.54

- 4 . 2 ±2.38

- 0 . 7 ±3.17

111. Respiratory function tests, See also legend to by a Tekmar T51 infusion controller) for 6 h. Group table II two (29 patients) received the same quantity of 5% dextrose over t i e same period (table I). The two Doxapram Control 1

FEVj (litre) VC (litre) PEF (litres- 1 ) Kco

40.0 ±3.57 (38-44) 4.7 ±0.56 (3.9-5.6) 10.6 ±0.56 (6.3-15.2)

Control (n = 29)

3

1

2.7 ±1.23 1.8 ±0.75 2.6 ±0.91 (0.9-3.9) (1.2-3.5) 3.8 ±1.29 2.3 ±0.72 3.6 ±1.05 (2.3-5.8) (1.7-5.2)

3

1.8 ±0.68 2.4 ±0.7

6.6±2.36 4.9±2.1 6.7±1.98 5.1 ±1.43 (3.0-11.7) (4.0-10.6) 1.4±0.46 1.4±0.49 1.4±0.34 1.6±0.38 (0.3-2.2)

(0.8-2.0)

TABLE IV. Cough and spit

solutions were given in a double-bund manner. Each patient was given oxygen 4 litre min" 1 via a Hudson face-mask for 12 h. A sample of arterial blood was taken for estimation of arterial Po M Pco2 and [H+] 2 h after the start of the infusion. All patients received ampicillin and flucloxacillin for 5-7 days. They also received physiotherapy (breathing exercises) twice a day for 3 days after operation, and then daily. On the 7th day following operation, all the investigations carried out before operation were repeated. RESULTS

Before surgery there were no significant differences No/slight Cough and/or between the two groups in respect of arterial Pov cough purulent sputum % Pco a or [H+] or respiratory function. Before operation Two hours after operation, Pa Oj , PZQO, m& [H + ] Doxapram 4 21.0 were increased in both groups, but there were no 19 Control 27.2 6 22 significant differences between the groups. Neither was there any significant difference between the After operation Doxapram 4.5 groups at 7 days (table II). 22 Control 21.7 23 The respiratory function tests did not show any significant differences between the two groups TABLE V. Temperature data. See also legend to table II (table III). Taking production of purulent sputum or severe Temp. (°C): mean±SD cough, or both, as evidence of respiratory infection, Temperature 1 3 increase > 1 °C the doxapram group had a reduced frequency of infection although the difference between the groups Doxapram 36.4 ±0.57 36.5 ±0.37 2/21 was not statistically significant (table IV). Control 36.4 ±0.45 36.7 ±0.43 6/28 There was no significant difference in the number of patients who had an increase in temperature of After operation, patients were randomly allocated more than 1 °C (table V). The chest x-rays were reported by a radiologist to one of two groups. Group one (24 patients) received an infusion of doxapram 1000 mg in 500 ml who was unaware of the treatment group. He could 5% dextrose at the rate of 1 ml kg"1 h" 1 (controlled detect no differences between the two groups.

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83

Patients who underwent lobectomy showed some evidence of consolidation in the remaining lobe on the side of operation. Patients who underwent pneumonectomy, pleurectomy or who had no resection showed no evidence of collapse or consolidation that was not visible before operation. During the study, one patient experienced facial sweating which was the only side-effect attributable to the administration of doxapram.

expiratory reserve volume that this limited the possible beneficial effects of doxapram. We conclude that, although doxapram may reduce pulmonary complications after operation in fit patients, it has no effect on ventilation or postoperative respiratory complications in patients with lung disease undergoing thoracic surgery.

DISCUSSION

An infusion of doxapram 10 mg min" 1 for 30 min following operation has been shown to cause an increase in PaOt, and a decrease in P^cOt (Downing et al., 1977). Gawley and others (1976), using a dose of 2 mg min" 1 for 2 h found the increase in Pa Ol to be sustained until the 5th day after surgery. Lees and others (1976), who gave doxapram 250 mg over 2 h, found a significant increase in P a ^ only on the 1st day after operation and not subsequently. In this study,, doxapram was not effective as a pharmacological stimulus to breathing. It was used in a dose of 2 mg kg" 1 h" 1 for 6 h, which should have been long enough to outlast any residual respiratory depression from anaesthesia. This is the first study reporting the use of doxapram following surgery in patients with pre-existing lung disease, and in this group of patients it appeared to have had no effect on ventilation, as measured by Pa^ or The frequency of chest infections after abdominal surgery has been shown to be reduced by doxapram (Gupta and Dundee, 1974; Gawley, Dundee and Jones, 1975; Gawley et al., 1976). Although there was a reduced frequency of cough and spit in our study in patients receiving doxapram (4.5%) as compared with those not receiving doxapram (21.7%), the difference was not statistically significant Downing and others (1977) found that doxapram only reduced respiratory sequelae in patients not treated with antibiotics. All our patients received prophylactic antibiotic therapy and this may have contributed to the overall result. Lees and others (1976) have suggested that the effect of doxapram on hypoxaemia may be that of a sparing effect on FRC. FRC measurements would be impossible to interpret in patients in whom portions of lung had been removed, but we may speculate that the impaired lung function in our patients may have included such a large reduction in

ACKNOWLEDGEMENTS

We would like to thank A. H. Robins and Co. for supplies of doxapram and the infusion controller, the thoracic surgeons, staff of the respiratory laboratory and nurses at the Brook Hospital for their help and co-operation, Dr C. Penny for reporting the chest x-rays, Drs C. M. T. Gleave and J. G. Bovill for their help and encouragement and Mrs A. van Berkum for secretarial assistance. REFERENCES

Andersen, R., and Krohg, K. (1976). Postoperative analgesia combined with doxapram. Anaesthesia, 31, 114. Downing, J. W., Jeal, D. E., Allen, P. J., and Buley, R. (1977). I.v. doxapram hydrochloride and pulmonary complications after lower abdominal surgery. Br. J. Anaesth., 49, 473. 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. Jones, C. J. (1975). The role of doxapram in the reduction of pulmonary complications following surgery. Br. J. Anaesth., 47, 906. Gupta, P. K., and Dundee, J. W. (1974). Morphine combined with doxapram or naloxone. Anaesthesia, 29, 33. Kato, H., and Buckley, J. P. (1964). Possible sites of action of the respiratory stimulant effect of doxapram hydrochloride. J. Pharmacol. Exp. Ther., 144, 260. Lees, N. W., Howie, H. B., Mellon, A., McKee, A. H., and McDiarmid, A. I. (1976). The influence of doxapram on postoperative pulmonary function in patients undergoing upper abdominal surgery. Br. J. Anaesth., 48, 1197. Scott, R. M., Whitwam, J. G., and Chakrabarti, M. K. (1977). Evidence of a role for the peripheral chemoreceptors in the ventilatory response to doxapram in man. Br. J. Anaesth., 49, 227. Wang, S. C , and Hirsch, K. (1973). Doxapram. Lancet, 2, 1314. EFFETS DU DOXAPRAM SUR LES COMPLICATIONS PULMONAIRES POSTOPERATOIRES APRES UNE THORACECTOMIE RESUME

On a administre par voie intraveineuse a 53 malades une solution a 5% de dextrose et de doxapram a raison de 2 mg ml- 1 , ou a 5% de dextrose seule apres une thoracectomie laterale. On a precede a des estimations de la Po, arterielle, de la Pco, et du pH avant l'operation, pendant l'infusion et 7 jours apris ['intervention chirurgicale. On a effectud des tests sur la fonction respiratoire avant et

BRITISH JOURNAL OF ANAESTHESIA

84 7 jours apres l'opcration. II n'y a pas eu de differences importantes dans la Po a arterielle, la Pco, et le pH ou dans les tests de la fonction respiratoire, entre les malades qui avaient recu du doxapram et ceux auxquels on n'en avait pas administri. Dans cette etude, le doxapram n'a pas affectc la frequence des complications pulmonaires postoperatoires. WIRKUNGEN VON DOXAPRAM AUF POSTOPERATIVE PULMONARE ERSCHEINUNGEN NACH BRUSTWANDEROFFNUNG ZUSAMMENFASSUNG

Eine intravenos verabreichte Losung von 5% Dextrose mit 2 mg ml" 1 Doxapram, oder von 5% Dextrose allein erhielten 53 Patienten nach einer lateralen Brustwanderoffnung. Schatzungen des arteriellen Pov Pco, und pH wurden vor der Operation, wShrend der Infusion und 7 Tage nach der Operation gemacht. Respiratorische Funktionstests wurden vor und 7 Tage nach der Operation durchgefUhrt. Zwischen den Patienten, die Doxapram

erhielten, und den anderen Patienten gab es keine beachtlichen Unterschiede beim arteriellen fOj, Pco, und pH, und auch nicht bei den respiratorischen Funktionstests. In dieser Studio beeintrachtigte Doxapram die Haufigkeit postoperativer pulmonarer Komphkationen nicht. EFECTOS DEL DOXAPRAM SOBRE COMPLICACIONES PULMONARES A RAIZ DE TORACOTOMIA SUMAHIO

Se administni una soluci6n i.v. de 5% de dextrosa con 2 mg ml" 1 de doxapram o de 5% de dextrosa sola a 53 pacientes despues de una toracotomia lateral. Antes de la operad6n, se hicieron estimaciones del Po^ Pcot y del pH, as! como durante la infusi6n y 7 dlas despues de la operaci6n. Se lleveron a cabo pruebas de la funcion respiratoria antes de la operaci6n y 7 Hfn« deapues de la misma. No hubo diferencias significativas en el Pot, Pco, y pH ni tampoco en las pruebas de la funci6n respiratoria entre los que recibieron doxapram y los que no lo recibieron. En este estudio, el doxapram no afect6 la frecuencia de las comphcaciones puknonares postoperatorias.