Br. J. Surg. 1992, Vol. 79, September, 967-968
K. L. Campbell and A. C . De Beaux Department of Surgery, University of Aberdeen. Aberdeen, UK Correspondence to: Mr K. L. Campbell, Nutrition
Metabolism Laboratory, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 021 15, USA
Non-steroidal anti-inflammatory drugs and appendicitis in patients aged over 50 years In a retrospective study 84 patients aged 2 5 0 years undergoing emergency appendicectomy were matched for age and sex with 84 randomly selected emergency admissions as controls. Of the former, 31 (37 per cent) were taking non-steroidal anti-inflammatory drugs (NSAIDs)at admission, compared with nine ( I I per cent) of the controls (P < 0.01). In the study group a suppression of the white cell count was identijied on admission in those taking NSAIDs (mean 11.9 x lo9 I - l ) compared with those not (mean 14.8 x lo9 I-’) ( P = 0.007). This is the first reported association between appendicitis and NSAIDs. The relative risk bj?odds ratio was substantially increased at 6.5 (95 per cent confidence interval 2.1 -8.8). An NSAID-related impairment of host defences leading to failure in the resolution of inflammatory episodes may explain this association. It is further postulated that the suppression of the white cell response may be a marker of such an eflect.
The adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs ) on the upper gastrointestinal tract have been extensively studied. Attention has recently focused on the lower gastrointestinal tract and an association between NSAID therapy and complicated diverticular disease has been demonstrated’.’. This paper reports a retrospective casecontrol study of NSAID intake and appendicitis in patients aged 2 5 0 years.
Patients and methods Scottish Morbidity Return data were used to identify patients aged 2 50 years who had undergone appendicectomy in Aberdeen Royal Infirmary in the 4-year period between August 1984 and August 1988. The case notes were obtained and the clinical, operative and pathological findings extracted. Patients undergoing appendicectomy with no pathological evidence of acute appendicitis were excluded. Drug therapy on admission, initial white cell count, duration of hospital stay and mortality were recorded. Again from the morbidity return data, the unit number and date of birth of 2000 patients aged 2 50 years admitted to this hospital as emergencies between August 1984 and 1988 were obtained. The sex-matched patient nearest in date of birth to each study patient was selected as a control; the ages matched to within 4 years in each case. Again, case notes were scrutinized and drug therapy at the time of admission noted. The quality of the clinical records for both study and control groups was found to be consistent. Statistics were calculated using Oxstat I1 (Microsoft UK, Wokingham, UK) and CIA (Professor M. J . Gardner and The British Medical Association, London, UK).
Results Ninety-one patients were identified; for three the case records were not available, for two they were incomplete and for two, despite coding as appendicitis, histological analysis was not confirmatory. The age range in the remaining 84 patients was 50-91 (median 61) years. Of the 84 patients with appendicitis, 31 (37 per cent) were taking NSAIDs at the time of admission compared with nine ( 11 per cent) of the controls. The relative risk by odds ratio of being on NSAID therapy at the time of appendicectomy if aged 2 50 years was 6.5, with a 95 per cent confidence interval ( c i ) of 2.1-8.8 ( P < 0.01, McNemar’s test for paired nominal data). In the study group three (10 per cent) of the 31 patients taking NSAIDs died in hospital compared with one (2 per cent)
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Ltd
of the 53 non-takers. The relative risk of death in patients with appendicitis who were taking NSAIDs was 2.1, with a 95 per cent c.i. of 1.1-4.1 ( P = 0.14, Fisher’s exact test). There was no difference in mean length of stay between patients receiving NSAIDs (10.4 days) and those not (9.0 days) ( P = 0.24, Student’s t test). The extent of peritonitis was similar in both groups; 19 (61 per cent) of the 31 takers of NSAIDs had a ‘perforated’ appendix, as did 31 (58 per cent) of the 53 non-takers. Abscess was found in five (16 per cent) of the 31 takers and in seven (13 per cent) of the 53 non-takers. There was no difference in temperature on admission between the two groups although the mean white cell count on admission in the NSAID takers was significantly lower (11.9 x lo9 1-’) than in the non-takers (14% x lo9]-’). The 95 per cent c.i. of this difference was 04-4.9 x lo9 I-’ ( P = 0.007, Student’s t test).
Discussion This is the first report of an association between NSAIDs and acute appendicitis. Although it is retrospective, the importance of drug therapy to emergency management, the emergency status of cases and controls, and the involvement of the same pool of resident house officers have maximized the yield and consistency of the data. In contrast, potentially relevant data such as chronicity of drug intake cannot be directly assessed in this way; however, as in a similarly constructed study on diverticular disease’, information on indication was generally available in the case notes. The indications closely resemble those previously reported, with the majority of patients having evidence of a specific and chronic complaint (most commonly osteoarthrosis). Chronic ingestion of NSAIDs with their symptom-relieving properties is strongly implied. The findings bear comparison with those of two recent studies of colonic diverticular complications and NSAID use1-*. The relative risk of being on NSAID therapy in patients undergoing appendicectomy for appendicitis was 6.5 for patients aged 2 50 years. This is a higher risk than that found in the analogous study of colonic diverticular complications requiring surgery2 (odds ratio 4.0, 95 per cent c.i. 15-13.6). in a prospective study of colonic diverticular Wilson et d.’, complications, found that 31 of 92 patients (34 per cent) were taking NSAIDs compared with only 4 per cent in a general practice-based control group. The emergency hospital admissions used as controls in this
967
NSAlDs and appendicitis: K. L. Campbell and A. C. De Beaux
and the analogous study on diverticular disease give a much higher incidence of NSAID therapy ( 11 per cent in appendicitis controls and 18 per cent in diverticular disease controls). NSAID intake increases with advancing age'; the median age of the patients with appendicitis was 61 years and in the analogous patients with diverticular disease 7 1 years. This alone could account for the differing rates of NSAID consumption in these two control groups. Langman et d 3 in , their study of small and large bowel perforation and haemorrhage, quoted control NSAID intake in 9.3 per cent of hospital patients aged >40 years and 10 per cent of general practice patients aged >60 years. It is unlikely that the control intake in this study is an underestimate and it may be that the relative risk as assessed in the general population is even higher. In this study, as in the equivalent study of colonic diverticular disease, a minority of patients (13 and 15 per cent respectively) were taking NSAIDs for a systemic disorder such as rheumatoid disease. These cases were equally distributed between the study and control groups and if excluded do not alter the conclusions. It is worthy of note that all studies show a relative risk of adverse effects in the large intestine in association with NSAIDs which is in excess of that commonly quoted for upper gastrointestinal tract perforation or bleeding3s4. There was no difference in complication rate or duration of hospital stay between the two groups but the hospital mortality rate was higher in NSAID takers, with a relative risk of 2.1 (95 per cent c.i. 1.1-4.1). This association requires confirmation. In uitro white cell function, including bactericidal activity, can be significantly altered in patients taking NSAIDsSS6.The observation that the white cell response to insult in uiuo, as measured by the total white cell count, may be suppressed has not previously been made. Although there was no difference in the frequency of perforation or abscess formation between
968
takers and non-takers of NSAIDs, the white cell count was significantly suppressed in the former group. Catarrhal inflammation can occur in the appendix but may not lead to appendicectomy if resolution occurs. Impairment of the inflammatory response may influence the outcome of such episodes and so increase the frequency of appendicectomy. It is postulated that the high rate of NSAID ingestion among patients aged 2 50 years undergoing appendicectomy for appendicitis may be related to alteration in host defences. The suppression of white cell response and increased mortality rate in this study may be crude markers of this effect.
References 1. 2. 3. 4. 5.
6.
Wilson RG, Smith AN, Macintyre IMC. Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 1990; 77: 1103-4. Campbell KL, Steele RJC. Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a controlled study. Br J Surg 1991; 78: 190-1. Langman MJS, Morgan L, Worral A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforation and haemorrhage. BMJ 1985; 290: 347-9. Bartle WR, Gupta AK, Lazor J. Non-steroidal anti-inflammatory drugs and gastrointestinal bleeding: a case control study. Arch Intern Med 1986; 146: 2365-7. Northover BJ. Effect of indomethacin and related drugs on the calcium ion-dependent secretion of lysosomal and other enzymes by neutrophil polymorphonuclear leucocytes in uitro. Br J Pharmacol 1977; 59: 253-9. MacGregor RR. The effect of anti-inflammatory agents and inflammation on granulocyte adherence. Am J Med 1976; 61: 597-607.
Paper accepted 4 March 1992
Br. J. Surg.. Vol. 79, No. 9, September 1992
K. L. Campbell and A. C . De Beaux Department of Surgery, University of Aberdeen. Aberdeen, UK Correspondence to: Mr K. L. Campbell, Nutrition
Metabolism Laboratory, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 021 15, USA
Non-steroidal anti-inflammatory drugs and appendicitis in patients aged over 50 years In a retrospective study 84 patients aged 2 5 0 years undergoing emergency appendicectomy were matched for age and sex with 84 randomly selected emergency admissions as controls. Of the former, 31 (37 per cent) were taking non-steroidal anti-inflammatory drugs (NSAIDs)at admission, compared with nine ( I I per cent) of the controls (P < 0.01). In the study group a suppression of the white cell count was identijied on admission in those taking NSAIDs (mean 11.9 x lo9 I - l ) compared with those not (mean 14.8 x lo9 I-’) ( P = 0.007). This is the first reported association between appendicitis and NSAIDs. The relative risk bj?odds ratio was substantially increased at 6.5 (95 per cent confidence interval 2.1 -8.8). An NSAID-related impairment of host defences leading to failure in the resolution of inflammatory episodes may explain this association. It is further postulated that the suppression of the white cell response may be a marker of such an eflect.
The adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs ) on the upper gastrointestinal tract have been extensively studied. Attention has recently focused on the lower gastrointestinal tract and an association between NSAID therapy and complicated diverticular disease has been demonstrated’.’. This paper reports a retrospective casecontrol study of NSAID intake and appendicitis in patients aged 2 5 0 years.
Patients and methods Scottish Morbidity Return data were used to identify patients aged 2 50 years who had undergone appendicectomy in Aberdeen Royal Infirmary in the 4-year period between August 1984 and August 1988. The case notes were obtained and the clinical, operative and pathological findings extracted. Patients undergoing appendicectomy with no pathological evidence of acute appendicitis were excluded. Drug therapy on admission, initial white cell count, duration of hospital stay and mortality were recorded. Again from the morbidity return data, the unit number and date of birth of 2000 patients aged 2 50 years admitted to this hospital as emergencies between August 1984 and 1988 were obtained. The sex-matched patient nearest in date of birth to each study patient was selected as a control; the ages matched to within 4 years in each case. Again, case notes were scrutinized and drug therapy at the time of admission noted. The quality of the clinical records for both study and control groups was found to be consistent. Statistics were calculated using Oxstat I1 (Microsoft UK, Wokingham, UK) and CIA (Professor M. J . Gardner and The British Medical Association, London, UK).
Results Ninety-one patients were identified; for three the case records were not available, for two they were incomplete and for two, despite coding as appendicitis, histological analysis was not confirmatory. The age range in the remaining 84 patients was 50-91 (median 61) years. Of the 84 patients with appendicitis, 31 (37 per cent) were taking NSAIDs at the time of admission compared with nine ( 11 per cent) of the controls. The relative risk by odds ratio of being on NSAID therapy at the time of appendicectomy if aged 2 50 years was 6.5, with a 95 per cent confidence interval ( c i ) of 2.1-8.8 ( P < 0.01, McNemar’s test for paired nominal data). In the study group three (10 per cent) of the 31 patients taking NSAIDs died in hospital compared with one (2 per cent)
ooO7-1323/92/09096742
0 1992 Butterworth-Heinemann
Ltd
of the 53 non-takers. The relative risk of death in patients with appendicitis who were taking NSAIDs was 2.1, with a 95 per cent c.i. of 1.1-4.1 ( P = 0.14, Fisher’s exact test). There was no difference in mean length of stay between patients receiving NSAIDs (10.4 days) and those not (9.0 days) ( P = 0.24, Student’s t test). The extent of peritonitis was similar in both groups; 19 (61 per cent) of the 31 takers of NSAIDs had a ‘perforated’ appendix, as did 31 (58 per cent) of the 53 non-takers. Abscess was found in five (16 per cent) of the 31 takers and in seven (13 per cent) of the 53 non-takers. There was no difference in temperature on admission between the two groups although the mean white cell count on admission in the NSAID takers was significantly lower (11.9 x lo9 1-’) than in the non-takers (14% x lo9]-’). The 95 per cent c.i. of this difference was 04-4.9 x lo9 I-’ ( P = 0.007, Student’s t test).
Discussion This is the first report of an association between NSAIDs and acute appendicitis. Although it is retrospective, the importance of drug therapy to emergency management, the emergency status of cases and controls, and the involvement of the same pool of resident house officers have maximized the yield and consistency of the data. In contrast, potentially relevant data such as chronicity of drug intake cannot be directly assessed in this way; however, as in a similarly constructed study on diverticular disease’, information on indication was generally available in the case notes. The indications closely resemble those previously reported, with the majority of patients having evidence of a specific and chronic complaint (most commonly osteoarthrosis). Chronic ingestion of NSAIDs with their symptom-relieving properties is strongly implied. The findings bear comparison with those of two recent studies of colonic diverticular complications and NSAID use1-*. The relative risk of being on NSAID therapy in patients undergoing appendicectomy for appendicitis was 6.5 for patients aged 2 50 years. This is a higher risk than that found in the analogous study of colonic diverticular complications requiring surgery2 (odds ratio 4.0, 95 per cent c.i. 15-13.6). in a prospective study of colonic diverticular Wilson et d.’, complications, found that 31 of 92 patients (34 per cent) were taking NSAIDs compared with only 4 per cent in a general practice-based control group. The emergency hospital admissions used as controls in this
967
NSAlDs and appendicitis: K. L. Campbell and A. C. De Beaux
and the analogous study on diverticular disease give a much higher incidence of NSAID therapy ( 11 per cent in appendicitis controls and 18 per cent in diverticular disease controls). NSAID intake increases with advancing age'; the median age of the patients with appendicitis was 61 years and in the analogous patients with diverticular disease 7 1 years. This alone could account for the differing rates of NSAID consumption in these two control groups. Langman et d 3 in , their study of small and large bowel perforation and haemorrhage, quoted control NSAID intake in 9.3 per cent of hospital patients aged >40 years and 10 per cent of general practice patients aged >60 years. It is unlikely that the control intake in this study is an underestimate and it may be that the relative risk as assessed in the general population is even higher. In this study, as in the equivalent study of colonic diverticular disease, a minority of patients (13 and 15 per cent respectively) were taking NSAIDs for a systemic disorder such as rheumatoid disease. These cases were equally distributed between the study and control groups and if excluded do not alter the conclusions. It is worthy of note that all studies show a relative risk of adverse effects in the large intestine in association with NSAIDs which is in excess of that commonly quoted for upper gastrointestinal tract perforation or bleeding3s4. There was no difference in complication rate or duration of hospital stay between the two groups but the hospital mortality rate was higher in NSAID takers, with a relative risk of 2.1 (95 per cent c.i. 1.1-4.1). This association requires confirmation. In uitro white cell function, including bactericidal activity, can be significantly altered in patients taking NSAIDsSS6.The observation that the white cell response to insult in uiuo, as measured by the total white cell count, may be suppressed has not previously been made. Although there was no difference in the frequency of perforation or abscess formation between
968
takers and non-takers of NSAIDs, the white cell count was significantly suppressed in the former group. Catarrhal inflammation can occur in the appendix but may not lead to appendicectomy if resolution occurs. Impairment of the inflammatory response may influence the outcome of such episodes and so increase the frequency of appendicectomy. It is postulated that the high rate of NSAID ingestion among patients aged 2 50 years undergoing appendicectomy for appendicitis may be related to alteration in host defences. The suppression of white cell response and increased mortality rate in this study may be crude markers of this effect.
References 1. 2. 3. 4. 5.
6.
Wilson RG, Smith AN, Macintyre IMC. Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 1990; 77: 1103-4. Campbell KL, Steele RJC. Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a controlled study. Br J Surg 1991; 78: 190-1. Langman MJS, Morgan L, Worral A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforation and haemorrhage. BMJ 1985; 290: 347-9. Bartle WR, Gupta AK, Lazor J. Non-steroidal anti-inflammatory drugs and gastrointestinal bleeding: a case control study. Arch Intern Med 1986; 146: 2365-7. Northover BJ. Effect of indomethacin and related drugs on the calcium ion-dependent secretion of lysosomal and other enzymes by neutrophil polymorphonuclear leucocytes in uitro. Br J Pharmacol 1977; 59: 253-9. MacGregor RR. The effect of anti-inflammatory agents and inflammation on granulocyte adherence. Am J Med 1976; 61: 597-607.
Paper accepted 4 March 1992
Br. J. Surg.. Vol. 79, No. 9, September 1992
