Scand J T h o r Cardiovasc Surg 25: 73-76. 1991
ANTIBIOTIC PROPHYLAXIS IN NON-CARDIAC THORACIC SURGERY A Double-blind Study of' Penicillin u s , Cefiiroxime
Mark Krasnik,] J e n s Thiis' a n d Niels Frimodt-Mglle? From the 'Department of Cardiothoracic, Surgery, County Hospital, Gentofte, und the 'Department of Clinical Microbiology, County Hospital, Herlev. University of Copenhagen, Denmark
Scand Cardiovasc J Downloaded from informahealthcare.com by University of Newcastle on 01/09/15 For personal use only.
(Accepted for publication May 16, 1990)
Abstract. Patients referred for elective pulmonary surgery were enrolled in a prospective, randomized, double-blind study comparing the prophylactic efficacy of four-dose regimens of penicillin-(; 5 million I U and cefuroxime 1.5 g, the first dose given immediately preoperatively. The treatment groups were comparable preoperatively with regard to all tested demographic factors. No significant intergroup difference was found concerning postoperative empyema, wound infection, septicaemia, pneumonia or fever of unknown origin, or any other complication or parameter tested in connection with pulmonary surgery. No side effects were observed, and no effects on the patients normal bacterial flora. Penicillin is recommended as prophylaxis in this type of surgery.
Key words: antibiotic prophylaxis, non-cardiac thoracic surgery, penicillin, cefuroxime, double-blind study.
The major postoperative infections in non-cardiac thoracic surgery are e m p y e m a , pneumonia and wound sepsis, any of which may be further cornplicated by septicaemia. These infections cause increased morbidity, leading to prolonged hospital stay a n d more extensive use of antibiotics, a n d may even be fatal (3, 6, 7, 9-1 1). E a r l y studies indicated that peroperative antibiotic administration helps to prevent postoperative e m p y e m a (4), though this ha s not b een proven in prospective, double-blind, placebo-controlled trials. More importantly, the surgical technique has improved, e.g. with efficient closure of t h e bronchial s t u m p after pulmonary resection. Several later studies showed t h a t peroperative antibiotic prophylaxis can significantly reduce the incidence of postoperative wound infections as compared with placebo (3, 6, 7, 9-11). T h e s e infections are mainly staphylococcal. The value o f antibiotic prophylaxis in preventing postoperative pneumonia is doubtful, however. Haernophilus influenzae a p p e a r s t o be a major pathogen in these infections, but pneumococci, Staphylococcus aureus or Enterobacteriaeceae can
also play a role (3, 6). Some earlier results indicated that cephalosporins, but not penicillin-G, may have some effect in preventing pneumonia (3, 7, 9). In o r d er t o test if a cephalosporin with good in vitro activity against both staphylococci an d H . influenzae could be superior t o penicillin-(; in preventing postoperative infections in non-cardiac thoracic surgery, w e conducted a prospective, controlled, double-blind trial comparing four-dose regimens of t h ese agents as prophylaxis in su ch surgery.
MATERIAL AND METHODS The double-blind, randomized, controlled, prospective study was conducted at the Department of Thoracic Surgery, Gentofte Hospital from February to November 1988. The patients had been referred for elective thoracotomy, possibly with pulmonary resection. Eligible patients were older than 18 years, had no allergy to penicillin or cephalosporins, had not received antibiotics within 3 days before the operation, and gave informed consent to inclusion in the study. Reasons for exclusion of enrolled patients were finding of a suppurative process in the chest at operation, cancellation of scheduled operation or omission of one or more doses of the antibiotic under study. The prophylactic regimen consisted of four doses of penicillin-(? (Leo), 5 million lU, or four doses of cefuroxime (ZinaceP, Glaxo) 1.5 g, both drugs intravenously. The first dose was administered immediately before surgery and the other three doses at 8-hour intervals thereafter. The antibiotics, of identical appearance, were supplied in precoded, randomly numbered packets, and each patient enrolled in the study was assigned one packet. Immediately before operation the skin of the surgical field was disinfected with a solution containing euflavine 0.1 %, hibitane 5 % and ethanol 96%. Pleural drainage was standard for all thoracotomies except pneumonectomy. Regular chest physiotherapy was given postoperatively in all cases, and continuous positive airway pressure was used. Patients were clinically assessed by the thoracic surgical team at least twice daily after the operation. Chest roentgenograms were routinely obtained daily for the first 7 postoperative days, and also shortly before discharge. Additional films were taken whenever indicat%and J Thor Cardiova.!c.25
74
M . Krasnik et al.
Table I. Postoperative infections in antibiotic groupsn
Scand Cardiovasc J Downloaded from informahealthcare.com by University of Newcastle on 01/09/15 For personal use only.
Antibiotic prophylaxis with Penicillin ( ~ 4 8 )
Cefuroxime (n=46)
Postoperative infections
no.
%
no.
%
P
Empyema Pneumonia Septicaemia Wound infection Fever of unknown origin No. of patients with infection(s)
1 13 1 3 2 17
2(-2%-6%) 27 (14%-40%) 2(-2%-6%) 6(-1%-13%) 4(-2%-10%) 35 (22 % 4 8 %)
1
2 (-2%6%) 17 ( 6 7 ~ 2 8 % ) 2 (-2%-6%) 4 (-2%-10%)
>0.05' >0.05 >0.05 >0.05 >0.05 >0.05
8
1 2 10
22 (10%-34%)
Figures in brackets denote 95% confidence limits. not significant.
'p>0.05
ed by change in clinical condition. An allergic reaction to the drugs was considered if an urticaria1 rash, laryngeal oedema or other anaphylactic reaction appeared during or immediately after antibiotic medication. The observation period for the study incorporated the whole hospital stay, usually 10 days. Any further relevant information provided during the 3-month follow-up at the outpatient clinic was also recorded. The effectiveness of prophylaxis was measured by the incidence of postoperative infections, duration of postoperative hospital stay and non-prophylactic use of antibiotics postoperatively. The criteria for infectious complications were as follows. Empyema: recovery of pus from the pleural space, with or without positive culture. Pneumonia: clinical signs, with rectal temperature >38"C. and chest roentgenogram showing signs of new densities for which no other cause could be found; positive sputum culture was not required for the diagnosis. Wound infection: erythema, induration, tenderness and suppuration of the wound. Septicaemia: at least one positive blood culture with bacteria not considered contaminants, such as Staphylococcus epidermidis, and clinical signs of sepsis, including rectal temperature >38.5"C. Fever of unknown origin: rectal temperature >38.5"C for unknown reason for at least 3 days. Urinary tract infection was not included in evaluation of the prophylactic regimen. All evaluations were made before the code was broken at the end of the study. The trial was conducted in accordance with the 1975 Helsinki Declaration and approved by the Danish National Health Service (Sundhedsstyrelsen) as well as by the local ethical committee. Statistical analysis. The objective of the trial was to obtain a 20% reduction in the incidence of postoperative pneumonia from the 35% previously found in penicillintreated patients at the same hospital (3). Incorporating a significance level of 5 % and accepting a 20% type I1 error, the estimated necessary size of each treatment group was approximately 40 patients (2). With an estirnated drop-out rate of lo%, the study was designed to continue until a: least 90 patients had been included. Scand J Thor Cardiovasc 25
For intergroup comparisons by means of discrete variables, Fisher's exact test or the chi-square test was used, depending on the size of the study population. Comparison of continuous variables was made with the MannWhitney test. Two-tailed tests were used and p
ANTIBIOTIC PROPHYLAXIS IN NON-CARDIAC THORACIC SURGERY A Double-blind Study of' Penicillin u s , Cefiiroxime
Mark Krasnik,] J e n s Thiis' a n d Niels Frimodt-Mglle? From the 'Department of Cardiothoracic, Surgery, County Hospital, Gentofte, und the 'Department of Clinical Microbiology, County Hospital, Herlev. University of Copenhagen, Denmark
Scand Cardiovasc J Downloaded from informahealthcare.com by University of Newcastle on 01/09/15 For personal use only.
(Accepted for publication May 16, 1990)
Abstract. Patients referred for elective pulmonary surgery were enrolled in a prospective, randomized, double-blind study comparing the prophylactic efficacy of four-dose regimens of penicillin-(; 5 million I U and cefuroxime 1.5 g, the first dose given immediately preoperatively. The treatment groups were comparable preoperatively with regard to all tested demographic factors. No significant intergroup difference was found concerning postoperative empyema, wound infection, septicaemia, pneumonia or fever of unknown origin, or any other complication or parameter tested in connection with pulmonary surgery. No side effects were observed, and no effects on the patients normal bacterial flora. Penicillin is recommended as prophylaxis in this type of surgery.
Key words: antibiotic prophylaxis, non-cardiac thoracic surgery, penicillin, cefuroxime, double-blind study.
The major postoperative infections in non-cardiac thoracic surgery are e m p y e m a , pneumonia and wound sepsis, any of which may be further cornplicated by septicaemia. These infections cause increased morbidity, leading to prolonged hospital stay a n d more extensive use of antibiotics, a n d may even be fatal (3, 6, 7, 9-1 1). E a r l y studies indicated that peroperative antibiotic administration helps to prevent postoperative e m p y e m a (4), though this ha s not b een proven in prospective, double-blind, placebo-controlled trials. More importantly, the surgical technique has improved, e.g. with efficient closure of t h e bronchial s t u m p after pulmonary resection. Several later studies showed t h a t peroperative antibiotic prophylaxis can significantly reduce the incidence of postoperative wound infections as compared with placebo (3, 6, 7, 9-11). T h e s e infections are mainly staphylococcal. The value o f antibiotic prophylaxis in preventing postoperative pneumonia is doubtful, however. Haernophilus influenzae a p p e a r s t o be a major pathogen in these infections, but pneumococci, Staphylococcus aureus or Enterobacteriaeceae can
also play a role (3, 6). Some earlier results indicated that cephalosporins, but not penicillin-G, may have some effect in preventing pneumonia (3, 7, 9). In o r d er t o test if a cephalosporin with good in vitro activity against both staphylococci an d H . influenzae could be superior t o penicillin-(; in preventing postoperative infections in non-cardiac thoracic surgery, w e conducted a prospective, controlled, double-blind trial comparing four-dose regimens of t h ese agents as prophylaxis in su ch surgery.
MATERIAL AND METHODS The double-blind, randomized, controlled, prospective study was conducted at the Department of Thoracic Surgery, Gentofte Hospital from February to November 1988. The patients had been referred for elective thoracotomy, possibly with pulmonary resection. Eligible patients were older than 18 years, had no allergy to penicillin or cephalosporins, had not received antibiotics within 3 days before the operation, and gave informed consent to inclusion in the study. Reasons for exclusion of enrolled patients were finding of a suppurative process in the chest at operation, cancellation of scheduled operation or omission of one or more doses of the antibiotic under study. The prophylactic regimen consisted of four doses of penicillin-(? (Leo), 5 million lU, or four doses of cefuroxime (ZinaceP, Glaxo) 1.5 g, both drugs intravenously. The first dose was administered immediately before surgery and the other three doses at 8-hour intervals thereafter. The antibiotics, of identical appearance, were supplied in precoded, randomly numbered packets, and each patient enrolled in the study was assigned one packet. Immediately before operation the skin of the surgical field was disinfected with a solution containing euflavine 0.1 %, hibitane 5 % and ethanol 96%. Pleural drainage was standard for all thoracotomies except pneumonectomy. Regular chest physiotherapy was given postoperatively in all cases, and continuous positive airway pressure was used. Patients were clinically assessed by the thoracic surgical team at least twice daily after the operation. Chest roentgenograms were routinely obtained daily for the first 7 postoperative days, and also shortly before discharge. Additional films were taken whenever indicat%and J Thor Cardiova.!c.25
74
M . Krasnik et al.
Table I. Postoperative infections in antibiotic groupsn
Scand Cardiovasc J Downloaded from informahealthcare.com by University of Newcastle on 01/09/15 For personal use only.
Antibiotic prophylaxis with Penicillin ( ~ 4 8 )
Cefuroxime (n=46)
Postoperative infections
no.
%
no.
%
P
Empyema Pneumonia Septicaemia Wound infection Fever of unknown origin No. of patients with infection(s)
1 13 1 3 2 17
2(-2%-6%) 27 (14%-40%) 2(-2%-6%) 6(-1%-13%) 4(-2%-10%) 35 (22 % 4 8 %)
1
2 (-2%6%) 17 ( 6 7 ~ 2 8 % ) 2 (-2%-6%) 4 (-2%-10%)
>0.05' >0.05 >0.05 >0.05 >0.05 >0.05
8
1 2 10
22 (10%-34%)
Figures in brackets denote 95% confidence limits. not significant.
'p>0.05
ed by change in clinical condition. An allergic reaction to the drugs was considered if an urticaria1 rash, laryngeal oedema or other anaphylactic reaction appeared during or immediately after antibiotic medication. The observation period for the study incorporated the whole hospital stay, usually 10 days. Any further relevant information provided during the 3-month follow-up at the outpatient clinic was also recorded. The effectiveness of prophylaxis was measured by the incidence of postoperative infections, duration of postoperative hospital stay and non-prophylactic use of antibiotics postoperatively. The criteria for infectious complications were as follows. Empyema: recovery of pus from the pleural space, with or without positive culture. Pneumonia: clinical signs, with rectal temperature >38"C. and chest roentgenogram showing signs of new densities for which no other cause could be found; positive sputum culture was not required for the diagnosis. Wound infection: erythema, induration, tenderness and suppuration of the wound. Septicaemia: at least one positive blood culture with bacteria not considered contaminants, such as Staphylococcus epidermidis, and clinical signs of sepsis, including rectal temperature >38.5"C. Fever of unknown origin: rectal temperature >38.5"C for unknown reason for at least 3 days. Urinary tract infection was not included in evaluation of the prophylactic regimen. All evaluations were made before the code was broken at the end of the study. The trial was conducted in accordance with the 1975 Helsinki Declaration and approved by the Danish National Health Service (Sundhedsstyrelsen) as well as by the local ethical committee. Statistical analysis. The objective of the trial was to obtain a 20% reduction in the incidence of postoperative pneumonia from the 35% previously found in penicillintreated patients at the same hospital (3). Incorporating a significance level of 5 % and accepting a 20% type I1 error, the estimated necessary size of each treatment group was approximately 40 patients (2). With an estirnated drop-out rate of lo%, the study was designed to continue until a: least 90 patients had been included. Scand J Thor Cardiovasc 25
For intergroup comparisons by means of discrete variables, Fisher's exact test or the chi-square test was used, depending on the size of the study population. Comparison of continuous variables was made with the MannWhitney test. Two-tailed tests were used and p
