Brit. 3. Dis. Chest (1975) 69, 195
EFFECT OF BROMHEXINE ON THE INCIDENCE OF POSTOPERATIVE BRONCHOPNEUMONIA AFTER UPPER ABDOMINAL SURGERY S. A. HARGRAVE, K. N. V. PALMER
AND
E. J. B.
MAKIN
Department of Medicine, University of Aberdeen, and Boehringer Ingelheim Limited, Bracknell, Berks BROMHEXINE, a synthetic derivative of vasicine, has been claimed to reduce the viscosity of bronchial secretion and to increase its volume in animals (Engelhorn & Puschmann I 963 ; Boyd & Sheppard 1966)) and the same has been claimed for bronchitic patients (Hamilton et al. 1970). We report here the result of using this drug with physiotherapy after upper abdominal surgery in an attempt to reduce the incidence of postoperative bronchopneumonia, particularly in high-risk patients. Patients
and Methods
Seventy patients (5 I males and I g females), mean age 4g * 3 years (range 29-7 I), who were admitted for elective upper abdominal surgery, were admitted to the trial. No patient had been taking bromhexine before admission and no female patient was pregnant. All patients had a clinical examination, spirometry and chest radiograph, before the operation and were then allocated at random to either treatment or control groups. There was no significant difference between treated and control groups in respect of age, weight, sex distribution or spirometry. The treatment group were given 8 mg bromhexine in 4 ml of diluent by intramuscular injection postoperatively, until oral therapy could be started at a dose of 16 mg three times daily, which was continued until the fifth postoperative day. Because of the large volume of each injection after the operation, it was not considered ethical to give placebo injections to the control group, since patients could have received injections for up to 5 days. However, the observer who was responsible for the pre- and postoperative examination of the patients, the radiologist who reported the chest radiographs and the clinician who decided whether the patient had developed postoperative bronchopneumonia were unaware whether the patient had received bromhexine. Patients were examined daily after the operation for 5 days and chest radiographs were taken at daily intervals for this period. All patients received routine chest physiotherapy. Table I shows the distribution of the patients between the treated and control groups, the numbers of males and females and (Received for publication April 1975)
HARGRAVE
196 TABLE
I.
DISTRIBUTION
OF
PATIENTS TYPE OF
BY TREATMENT OPERATION
GROUP,
Treated No. of patients Mean age (years) Males Gastric Biliary Females Gastric Biliary
TABLE
and
range
surgery tract surgery
2.
AGE,
OF SEX
HIGH-RISK AND TYPE
range
AL.
SEX
AND
Total 70
25
21
;A
i 4
4 ‘3 8 5
5 ‘9
PATIENTS OF OPERATION
Treated No. of patients Mean age (years) and Males Gastric surgery Biliary tract surgery Females Gastric surgery Biliary tract surgery
38 48 (30-66) 25
2
DISTRIBUTION
AGE,
Control
50 ($71)
surgery tract surgery
ET
52 (ii-71) ‘5 ‘4
BY
TREATMENT
Control
48 &?-SI) II 10
I 2 I
; 2
I
2
I2
7
GROUP,
Total 32 26 24 i
3 3
whether they had gastric or biliary tract surgery. It can be seen that there was no difference between the groups in any of these respects. The patients were further subdivided into a high-risk group, that is to say, those who smoked more than IO cigarettes per day, who admitted to a productive cough during the month preceding the operation and in whom the forced expiratory volume in I second as a percentage of the forced vital capacity was less than 70. There were 17 high-risk patients in the treated and 15 in the control group; the treated high-risk group were slightly older and heavier than the controls but these differences did not reach statistical significance, nor was there a statistical difference in mean preoperative spirometry. In other respects the two groups appeared similar (Table 2). Results The incidence of postoperative bronchopneumonia (that is to say, the presence of mucopurulent or purulent sputum, fever greater than 38.5 “C and a significant radiological abnormality during the first 5 postoperative days, which was not present on the preoperative film) was 2 I of 70 (3 I %). The incidence in the bromhexine treated group was 8 of 32 (25%) and 13 of 38 (34%) in the control group, but this difference in favour of bromhexine does not reach statistical significance.
BROMHEXINE TABLE
3.
AND INCIDENCE
All patients Postoperative
POSTOPERATIVE
BRONCHOPNEUMONIA
OF
BRONCHOPNEUMONIA PATIENTS
POSTOPERATIVE AND IN HIGH-RISK
‘97 IN
ALL
PATIENTS
Treated
Control
Total
32 8
38 ‘3*
21
‘7 t
‘5 9t 7
32 ‘5 ‘3
0
2
bronchopneumonia
High-risk patients Postoperative bronchopneumonia Males Females
70
2
* not significant t Pco.05
In the high-risk group, 6 of 17 of the treated patients developed postoperative bronchopneumonia, compared with g of 15 of the control group. None of the treated patients had lobar collapse and consolidation radiologically, but this was present in 3 of g of the control patients. These results are summarized in Table 3. Discussion The incidence of postoperative bronchopneumonia after upper abdominal surgery in this series (3 I %) is similar to that reported by others (Palmer 1955 ; Wightman I 968). The importance of pre-existing chronic bronchopulmonary disease, especially chronic bronchitis, as a factor in the development of postoperative bronchopneumonia is well recognized. Stein et al. (1962) found that 70% of patients with minimal bronchitis and even minor abnormalities in pulmonary function tests developed this complication after abdominal surgery, but this occurred in only 3% of patients with normal chests and normal pulmonary function tests. These figures are very similar to those seen in our control group of 15 high-risk patients, that is to say, those with some degree of bronchitis and abnormal spirometry, 60% of whom developed postoperative bronchopneumonia. Since our rate of postoperative bronchopneumonia and the incidence in the high risk control group was comparable to those in other published series, and since all the patients received similar postoperative care, including physiotherapy, it is reasonable to ask whether the reduction in the incidence of postoperative bronchopneumonia in the high-risk group treated with bromhexine was due to the effect of the drug. Anv mucolytic action of the drug making the bronchial secretion thinner might decrease sputum retention by making the elimination of secretions more effective, by expectoration, the mucociliary clearance mechanism and physiotherapy. Thomson et al. ( r 974) have shown that bromhexine increases the depth of penetration and rate of mucociliary clearance of inhaled radioactive particles in patients with chronic bronchitis. From the present study it appears reasonable to ask whether bromhexine and physiotherapy might reduce the incidence of postoperative bronchopneumonia in high-risk cases and whether it might also reduce the severity of this complication.
HARGRAVE
198
ET
AL.
Summary The incidence of postoperative bronchopneumonia in 70 patients undergoing upper abdominal surgery who received intramuscular and oral bromhexine after operation for 5 days was 25% (8 of 32), compared with 34% (13 of 38) in a control group, but this difference in favour of bromhexine does not reach statistical significance. All patients had postoperative physiotherapy. However, in a high-risk group (patients who smoked more than IO cigarettes a day, who admitted to a productive cough before the operation and in whom the forced expiratory volume as a percentage of the forced vital capacity was less than 70) the incidence of postoperative bronchopneumonia in those who had bromhexine was 6 of I 7 compared with g of I 5 in the controls. Thus bromhexine for the prevention and treatment of postoperative bronchopneumonia in high-risk patients after upper abdominal surgery deserves further study. ACKNOWLEDGEMENTS
Our thanks are due to Professor David Kerridge for statistical Aberdeen Teaching Hospitals who allowed us to examine their reported the chest radiographs; and to Boehringer Ingleheim
advice; patients; Ltd for
to the surgeons of the to Dr S. S. Amar who supplying the drug.
REFERENCES
BOYD, E. M. & SHEPPARD, P. (1966) On the expectorant activity of Bisolvon. Arks int. Phnrmacodyn. Thb. 163, 284. ENGELHORN, R. & PUSCHMANN, S. (1968) The pharmacological investigation of a substance with mucolytic properties. Arzneimittel-Forsch., 13, 474. HAMILTON, W. F. D., PALMER, K. N. V. & GENT, M. (1970) The expectorant action of Bromhexine in chronic obstructive bronchitis. Br. med. J., 3, 260. PALMER, K. N. V. (1955) Postoperative pulmonary complications. Postgrad. med. J., 31, 25. STEIN, M. KOOTA, G. M., SIMON, M. & FRANK, H. A. (1962) Pulmonary evaluation of surgical patients. 3. Am. med. Ass., r81, 765. THOMSON, M. L., PAVIA, D., GREGG, I. & STARK, J. E. (1974) Bromhexine and mucociliary clearance in chronic bronchitis. Br. 3. Dis. Chest, 68, 21. WIGHTMAN, J. A. K. (1968) A prospective survey of the incidence of postoperative pulmonary complications. Br. 3. Surg., 55, 86.
EFFECT OF BROMHEXINE ON THE INCIDENCE OF POSTOPERATIVE BRONCHOPNEUMONIA AFTER UPPER ABDOMINAL SURGERY S. A. HARGRAVE, K. N. V. PALMER
AND
E. J. B.
MAKIN
Department of Medicine, University of Aberdeen, and Boehringer Ingelheim Limited, Bracknell, Berks BROMHEXINE, a synthetic derivative of vasicine, has been claimed to reduce the viscosity of bronchial secretion and to increase its volume in animals (Engelhorn & Puschmann I 963 ; Boyd & Sheppard 1966)) and the same has been claimed for bronchitic patients (Hamilton et al. 1970). We report here the result of using this drug with physiotherapy after upper abdominal surgery in an attempt to reduce the incidence of postoperative bronchopneumonia, particularly in high-risk patients. Patients
and Methods
Seventy patients (5 I males and I g females), mean age 4g * 3 years (range 29-7 I), who were admitted for elective upper abdominal surgery, were admitted to the trial. No patient had been taking bromhexine before admission and no female patient was pregnant. All patients had a clinical examination, spirometry and chest radiograph, before the operation and were then allocated at random to either treatment or control groups. There was no significant difference between treated and control groups in respect of age, weight, sex distribution or spirometry. The treatment group were given 8 mg bromhexine in 4 ml of diluent by intramuscular injection postoperatively, until oral therapy could be started at a dose of 16 mg three times daily, which was continued until the fifth postoperative day. Because of the large volume of each injection after the operation, it was not considered ethical to give placebo injections to the control group, since patients could have received injections for up to 5 days. However, the observer who was responsible for the pre- and postoperative examination of the patients, the radiologist who reported the chest radiographs and the clinician who decided whether the patient had developed postoperative bronchopneumonia were unaware whether the patient had received bromhexine. Patients were examined daily after the operation for 5 days and chest radiographs were taken at daily intervals for this period. All patients received routine chest physiotherapy. Table I shows the distribution of the patients between the treated and control groups, the numbers of males and females and (Received for publication April 1975)
HARGRAVE
196 TABLE
I.
DISTRIBUTION
OF
PATIENTS TYPE OF
BY TREATMENT OPERATION
GROUP,
Treated No. of patients Mean age (years) Males Gastric Biliary Females Gastric Biliary
TABLE
and
range
surgery tract surgery
2.
AGE,
OF SEX
HIGH-RISK AND TYPE
range
AL.
SEX
AND
Total 70
25
21
;A
i 4
4 ‘3 8 5
5 ‘9
PATIENTS OF OPERATION
Treated No. of patients Mean age (years) and Males Gastric surgery Biliary tract surgery Females Gastric surgery Biliary tract surgery
38 48 (30-66) 25
2
DISTRIBUTION
AGE,
Control
50 ($71)
surgery tract surgery
ET
52 (ii-71) ‘5 ‘4
BY
TREATMENT
Control
48 &?-SI) II 10
I 2 I
; 2
I
2
I2
7
GROUP,
Total 32 26 24 i
3 3
whether they had gastric or biliary tract surgery. It can be seen that there was no difference between the groups in any of these respects. The patients were further subdivided into a high-risk group, that is to say, those who smoked more than IO cigarettes per day, who admitted to a productive cough during the month preceding the operation and in whom the forced expiratory volume in I second as a percentage of the forced vital capacity was less than 70. There were 17 high-risk patients in the treated and 15 in the control group; the treated high-risk group were slightly older and heavier than the controls but these differences did not reach statistical significance, nor was there a statistical difference in mean preoperative spirometry. In other respects the two groups appeared similar (Table 2). Results The incidence of postoperative bronchopneumonia (that is to say, the presence of mucopurulent or purulent sputum, fever greater than 38.5 “C and a significant radiological abnormality during the first 5 postoperative days, which was not present on the preoperative film) was 2 I of 70 (3 I %). The incidence in the bromhexine treated group was 8 of 32 (25%) and 13 of 38 (34%) in the control group, but this difference in favour of bromhexine does not reach statistical significance.
BROMHEXINE TABLE
3.
AND INCIDENCE
All patients Postoperative
POSTOPERATIVE
BRONCHOPNEUMONIA
OF
BRONCHOPNEUMONIA PATIENTS
POSTOPERATIVE AND IN HIGH-RISK
‘97 IN
ALL
PATIENTS
Treated
Control
Total
32 8
38 ‘3*
21
‘7 t
‘5 9t 7
32 ‘5 ‘3
0
2
bronchopneumonia
High-risk patients Postoperative bronchopneumonia Males Females
70
2
* not significant t Pco.05
In the high-risk group, 6 of 17 of the treated patients developed postoperative bronchopneumonia, compared with g of 15 of the control group. None of the treated patients had lobar collapse and consolidation radiologically, but this was present in 3 of g of the control patients. These results are summarized in Table 3. Discussion The incidence of postoperative bronchopneumonia after upper abdominal surgery in this series (3 I %) is similar to that reported by others (Palmer 1955 ; Wightman I 968). The importance of pre-existing chronic bronchopulmonary disease, especially chronic bronchitis, as a factor in the development of postoperative bronchopneumonia is well recognized. Stein et al. (1962) found that 70% of patients with minimal bronchitis and even minor abnormalities in pulmonary function tests developed this complication after abdominal surgery, but this occurred in only 3% of patients with normal chests and normal pulmonary function tests. These figures are very similar to those seen in our control group of 15 high-risk patients, that is to say, those with some degree of bronchitis and abnormal spirometry, 60% of whom developed postoperative bronchopneumonia. Since our rate of postoperative bronchopneumonia and the incidence in the high risk control group was comparable to those in other published series, and since all the patients received similar postoperative care, including physiotherapy, it is reasonable to ask whether the reduction in the incidence of postoperative bronchopneumonia in the high-risk group treated with bromhexine was due to the effect of the drug. Anv mucolytic action of the drug making the bronchial secretion thinner might decrease sputum retention by making the elimination of secretions more effective, by expectoration, the mucociliary clearance mechanism and physiotherapy. Thomson et al. ( r 974) have shown that bromhexine increases the depth of penetration and rate of mucociliary clearance of inhaled radioactive particles in patients with chronic bronchitis. From the present study it appears reasonable to ask whether bromhexine and physiotherapy might reduce the incidence of postoperative bronchopneumonia in high-risk cases and whether it might also reduce the severity of this complication.
HARGRAVE
198
ET
AL.
Summary The incidence of postoperative bronchopneumonia in 70 patients undergoing upper abdominal surgery who received intramuscular and oral bromhexine after operation for 5 days was 25% (8 of 32), compared with 34% (13 of 38) in a control group, but this difference in favour of bromhexine does not reach statistical significance. All patients had postoperative physiotherapy. However, in a high-risk group (patients who smoked more than IO cigarettes a day, who admitted to a productive cough before the operation and in whom the forced expiratory volume as a percentage of the forced vital capacity was less than 70) the incidence of postoperative bronchopneumonia in those who had bromhexine was 6 of I 7 compared with g of I 5 in the controls. Thus bromhexine for the prevention and treatment of postoperative bronchopneumonia in high-risk patients after upper abdominal surgery deserves further study. ACKNOWLEDGEMENTS
Our thanks are due to Professor David Kerridge for statistical Aberdeen Teaching Hospitals who allowed us to examine their reported the chest radiographs; and to Boehringer Ingleheim
advice; patients; Ltd for
to the surgeons of the to Dr S. S. Amar who supplying the drug.
REFERENCES
BOYD, E. M. & SHEPPARD, P. (1966) On the expectorant activity of Bisolvon. Arks int. Phnrmacodyn. Thb. 163, 284. ENGELHORN, R. & PUSCHMANN, S. (1968) The pharmacological investigation of a substance with mucolytic properties. Arzneimittel-Forsch., 13, 474. HAMILTON, W. F. D., PALMER, K. N. V. & GENT, M. (1970) The expectorant action of Bromhexine in chronic obstructive bronchitis. Br. med. J., 3, 260. PALMER, K. N. V. (1955) Postoperative pulmonary complications. Postgrad. med. J., 31, 25. STEIN, M. KOOTA, G. M., SIMON, M. & FRANK, H. A. (1962) Pulmonary evaluation of surgical patients. 3. Am. med. Ass., r81, 765. THOMSON, M. L., PAVIA, D., GREGG, I. & STARK, J. E. (1974) Bromhexine and mucociliary clearance in chronic bronchitis. Br. 3. Dis. Chest, 68, 21. WIGHTMAN, J. A. K. (1968) A prospective survey of the incidence of postoperative pulmonary complications. Br. 3. Surg., 55, 86.
