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Colon perforation with acute peritonitis after taking clindamycin and diclofenac following wisdom tooth removal
ARTICLE IN PRESS Journal of Cranio-Maxillofacial Surgery (2004) 32, 330–334 r 2004 European Association for Cranio-Maxillofacial Surgery doi:10.1016/j.jcms.2004.05.007, available online at http://www.sciencedirect.com
Colon perforation with acute peritonitis after taking clindamycin and diclofenac following wisdom tooth removal Juergen ERVENS1, Leif SCHIFFMANN2, Gerd BERGER2, Bodo HOFFMEISTER1 1
Department of Maxillofacial and Facial Plastic Surgery (Chairman: Prof. Dr. Dr. B. Hoffmeister); Department of General Surgery I (Chairman: Prof. Dr. H.-J. Buhr), Charite´—Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany 2
SUMMARY. Introduction: Non-steroidal anti-inflammatory drugs have a high analgesic and anti-inflammatory effect and are widely taken for acute and chronic pain. Especially following long-term use, they may cause gastrointestinal side effects such as mucosal ulceration, perforation and strictures in the small and large bowel. Patient: A 16-year-old female developed colonic perforation and purulent peritonitis after wisdom tooth removal and short-term intake of non-steroidal anti-inflammatory drugs. Discussion: Non-steroidal antiinflammatory drugs may exert their deleterious effects on the lower gastrointestinal tract through both local and systemic actions. Systemic effects are caused by the inhibition of cyclooxygenase and reduction of protective prostaglandins. The local damage of the intestinal mucosa in the distal bowel segments seems to be caused by sustained release formulation with a high enterohepatic circulation. The latter may act time and again on the intestinal mucosa through metabolites secreted in the gallbladder. Concomitant intake of clindamycin may have favoured this acute complication. Conclusion: Intestinal perforation after short-term intake of non-steroidal anti-inflammatory drugs is very rare. However, it is life-threatening and illustrates the need for careful prescribing at as low an effective dose and as short a time as possible, especially when combining different drugs. Paracetamol only has a weak effect on cyclooxygenase and continues to be a possible alternative for postoperative dental pain with a favourable benefit-risk ratio. It is the drug of choice for children, adolescents and patients with an increased risk of non-steroidal anti-inflammatory drug-induced gastro-enteropathy. r 2004 European Association for Cranio-Maxillofacial Surgery
Keywords: NSAID; Gastro-enteropathy; Colon perforation; Tooth removal
In this paper, the unusual finding of a transverse colon perforation with ulcerated peritonitis is reported in an otherwise healthy 16-year-old female with short-term simultaneous oral intake of diclofenac and clindamycin after surgical removal of all four wisdom teeth.
INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs and are commonly applied in the treatment of rheumatic diseases as well as for acute and chronic pain (Bjarnason et al., 1993; Blum et al. 1998; Haas, 2002). Although NSAIDs have excellent analgesic, antiinflammatory and antipyretic effects, they also have undesirable side effects, including acute and chronic renal dysfunction, NSAID-induced asthma, and especially gastrointestinal ulceration, bleeding and related complications (Bjarnason et al., 1993; Ribeiro et al., 1998; Stichtenoth and Froehlich, 2001; Schiemann and Kellner, 2002; Sikes et al., 2002). NSAID enteropathy is often not detected until the occurrence of small and large bowel ulceration, intestinal strictures or perforations (Holt et al., 1993; Byrne et al., 2002). Furthermore, NSAIDs are responsible for two-thirds of all drug-related deaths in patients with chronic polyarthritis, more specifically an estimated 2200 deaths in Germany annually (Blum et al., 1998).
CASE REPORT The 16-year-old female presented with severe, persistent abdominal pain to the emergency room of the University Hospital Benjamin Franklin. Acute pain had started 12 h earlier, increased continuously in intensity and was accompanied by watery (but not bloody) stool after 6 h. The patient reported the surgical removal of all four wisdom teeth 12 days earlier as well as postoperative analgesics and antibiotics: diclofenac (2 75 mg/d/orally for 5 days) and clindamycin (3 300 mg/d/orally for 10 days). She had no history of previous abdominal operations, chronic inflammatory bowel disease or other diseases. 330
ARTICLE IN PRESS Colon perforation with acute peritonitis 331
Clinical findings On initial presentation, the patient presented in poor condition, blood pressure was 110/80 mmHg, pulse rate 130/min, rectal temperature 40 1C. Examination revealed a markedly distended abdomen with a taut abdominal wall and guarding, especially in the epigastric region. McBurney’s and Lanz’s pressure points were unremarkable, but bowel sounds were absent. Investigation showed: haemoglobin 9.4 g/dl, leukocytes 11900/ml, thrombocytes 376/nl, CRP 240 mg/ l, lactate 3.3 mmol/l, creatinine 66 mmol/l, GPT (ASAT) 5 U/l, GOT (ALAT) 5 U/l, Quick 51%, PTT 44 s. A lateral plain radiograph of the abdomen showed free abdominal air, individual gas/liquid levels and mesogastric loops (Fig. 1).
Fig. 2 – Sixteen year-old female. Sharply delimited intestinal perforation in the transverse colon with extraluminal fibrin layers following purulent peritonitis.
Therapy and course Laparoptomy was performed for progressive pain and the presence of radiologically free abdominal air, indicating viscus perforation. Extreme ulcerative peritonitis extending from the diaphragm to the pelvis was found. Assuming a perforated ulcer, the stomach and duodenum were initially inspected after thorough lavage, but proved to be normal even after staining with methylene blue. All intestinal loops were covered by fibrin with no evidence of perforation. Only inspection of the colon disclosed a perforation of the transverse colon which appeared punched out (Fig. 2). Two similar lesions, which did not perforate the intestinal mucosa, were found nearby. Although the remaining intestinal mucosa was macroscopically free of inflammation and macroscopically normal, several biopsies were taken to exclude chronic inflammatory bowel disease. Separate smears from the intestinal lumen were obtained for microbiological examination to exclude a possible intestinal infection with Clostridium difficile.
Fig. 1 – Sixteen year-old female. Preoperative left lateral plain radiograph of the abdomen. Arrows indicate the free abdominal gas.
Fig. 3 – Sixteen year-old female. Postoperative findings after explantation of the perforation site and creation of a double-lumen transverse colostomy.
Antibiotic therapy with piperazillin (3 4 g/d/i.v.), tazobactam (3 0.5 g/d/i.v.) and gentamycin (1 320 mg/i.v. according to levels) was initiated intraoperatively. The perforation site was exteriorized to the abdominal wall with creation of a doublelumen colostomy, since postoperative primary anastomosis of the transverse colon seemed to involve too high a risk of postoperative complication due to the pronounced ulcerative peritonitis (Fig. 3). Histological examination, conventional and immunohistochemical staining of the biopsies from the intestinal wall revealed signs of localized non-specific inflammation without any signs of chronic inflammatory bowel disease such as Crohn’s disease, any malignancy, endometriosis or infection with acidresistant rods or fungi. Microbiological stool diagnostics to detect possible infection with Clostridium difficile was negative in both the culture and toxin assay. Ten weeks later, the transverse colostomy was closed without complication once the patient had recovered from peritonitis (Fig. 4).
ARTICLE IN PRESS 332 Journal of Cranio-Maxillofacial Surgery
Fig. 4 – Sixteen year-old female. Postoperative findings after repositioning the transverse artificial anus.
DISCUSSION The typical undesirable side effects of NSAIDs are caused by the inhibition of cyclooxygenase (COX), a membrane-bound key enzyme which exists in two isoforms and synthesizes prostaglandins from arachidonic acid (Brune et al., 2000; Kehrer et al., 2000; Brsyne et al., 2002). Serious side effects of NSAIDs are more frequent than hitherto suspected. The clinically most important undesirable effect of NSAID therapy is gastrointestinal ulcer and its complications, observed in about 15% of the cases (Blum et al., 1998). The frequency of complications is clearly dosedependent, the effect being systemic. The risk of undesirable side effects is greater the longer the drugs are taken (Bjarnason et al., 2003; Holt et al., 1993; Brsyne et al., 2002; Sikes et al., 2002). Gastrointestinal side effects of NSAID therapy restrict their application in children and adolescents (Fuehrer, 1999). A perforation in the upper gastrointestinal tract, i.e. the stomach or duodenum, was initially assumed here because of short-term NSAID intake. Surprisingly, the perforation was found in the transverse colon. NSAID-induced small bowel strictures were first described by Lang et al. (1988). Since then, there have been a number of publications on the occurrence of mucosal ulceration, perforation and intest-
inal strictures in the small and large bowel after longterm NSAID intake (Huber et al., 1991; Halter et al., 1993; Robinson et al., 1995; Hooker et al., 1996; Abrahamian et al., 1998; Eis et al., 1998; Gopal and Katon, 1999; Weinstock et al., 1999). NSAIDs may exert their deleterious effects on the distal bowel segments through both local and systemic actions. The direct toxic damage to the intestinal mucosa seem to be caused in particular by sustained release formulation of NSAIDs, and the effect of metabolites secreted in the gallbladder from NSAIDs with a high enterohepatic circulation (e.g. diclofenac). NSAIDs and their metabolites can thus reach the distal bowel segments, damage the intestinal mucosa and cause ulceration with complications, as well as increased intestinal permeability with loss of albumin (Halter et al., 1993; Ribeiro et al., 1998; Seitz and Boelsterli, 1998; Schiemann and Kellner, 2002). Remarkably in this patient the time between drug intake and intestinal perforation was short, which distinguishes this from other cases reported in the literature. Here, the combination of diclofenac und clindamycin, both drugs with biliary secretion and high enterohepatic circulation, may have aggravated local damage to the distal intestinal mucosa and magnified the complications (Ribeiro et al., 1998; Seitz and Boelsterli, 1998). Moreover, the patient’s young age may have been a possible predisposing factor that cannot be entirely ruled out (Fuehrer, 1999). Perforation of the intestinal wall as a consequence of chronic inflammatory bowel disease (e.g. Crohn’s disease) was considered in the differential diagnosis (Bjarnason et al., 1993). Intraoperative inspection of the intestinal wall and conventional histological and immunohistochemical assessment of the biopsy samples yielded no signs of inflammatory bowel disease. Instead, the histological examination revealed a localized, non-specific inflammation at the perforation site, supporting the assumption that the intestinal perforation was caused by NSAID-induced local inflammation of the mucosa (Byrne et al., 2002). Pseudomembranous enterocolitis, as described after the intake of clindamycin, was excluded. Some microbiological testing of intraoperative stool samples yielded no Clostridium difficile by culture or toxin assay. A new approach to avoid typical NSAIDs side effects has been found after the discovery of another COX isoform and the development of specific COX-2 inhibitors (Fu et al., 1990). Erosions, ulceration and gastrointestinal perforations have in the meantime been described for all drugs with preferential COX-2 inhibition (Brune et al., 2000). COX-2 inhibitors are also being used in dental pain therapy, and clinical studies have proved their suitability, but a clear superiority of COX-2 inhibitors in postoperative dental pain therapy has not yet been shown (Bakshi et al., 1994; Malmstrom et al., 1999; Seymour et al., 2000; Chang et al., 2002; Hyllested et al., 2002; Jeske, 2002; Seymour et al., 2003).
ARTICLE IN PRESS Colon perforation with acute peritonitis 333
In contrast to NSAIDs, the aniline derivative paracetamol has only a weak effect on COX-1 and none on COX-2. This concur with the fact that paracetamol has a weak anti-inflammatory effect and no influence on thrombocytes (Brune et al., 2000; Stichtenoth and Froehlich, 2001). Nevertheless, controlled prospective clinical studies have shown that when compared with NSAIDs, therapeutically adequate concentrations of paracetamol administered after surgery also have a sufficiently high analgesic effect (Mattews et al., 1984; Coulthard et al., 2001; Hyllested et al., 2002; Bjørnsson et al., 2003; Seymour et al., 2003). Thus, ibuprofen (4 600 mg/d/orally) administered after surgical removal of wisdom teeth showed no clinical advantage over paracetamol (4 1000 mg/d/orally) with regard to reducing postoperative swelling and pain (Bjørnsson et al., 2003). With a favourable benefit–risk ratio, paracetamol is a good alternative to NSAIDs in postoperative pain therapy after dental surgery and is the drug of choice for children, adolescents and patients at increased risk of NSAID-induced gastro-enteropathy (Fuehrer, 1999; Nguyen et al., 1999; Hyllested et al., 2002; Jeske, 2002; Ong and Seymour, 2003). NSAID-induced intestinal perforation must be assumed in this case as the most likely cause after evaluating all findings and with no detection of chronic inflammatory bowel disease or clindamycininduced pseudomembranous enterocolitis. This assumption is supported by conventional and immunohistochemical findings of localized non-specific inflammation of the perforation site, and no evidence of Clostridium difficile in the culture and toxin assay from the microbiological stool examination. The combination of diclofenac and clindamycin, which both have biliary secretion and high enterohepatic circulation, may have favoured development of this complication. Although it is difficult to be absolutely certain.
CONCLUSION Intestinal perforation after short-term intake of nonsteroidal anti-inflammatory drugs is very rare. However, it is a life-threatening complication and illustrates the necessity for careful prescribing at as low an effective dose and for as short a time as possible, especially when combining different drugs. The local damage of the distal bowel mucosa seems to be caused by sustained release formulation and high enterohepatic circulation, which may act time and again on the intestinal mucosa. Compared with nonsteroidal anti-inflammatory drugs, paracetamol has only a weak effect on cyclooxygenase but in therapeutically adequate concentrations also has a sufficiently high analgesic effect. With a favourable benefit–risk ratio, paracetamol is a good alternative in postoperative and/or dental pain therapy and is the drug of choice for children, adolescents and patients with an increased risk.
References Abrahamian GA, Polhamus CD, Muskat P, Karulf RE: Diaphragm like strictures of the ileum associated with NSAID use: a rare complication. South Med J 91: 395–397, 1998 Bakshi R, Frenkel G, Dietlein G, Meurer-Witt B, Schneider B, Sinterhauf U: A placebo-controlled comparative evaluation of diclofenac dispersible versus ibuprofen in postoperative pain after third molar surgery. J Clin Pharmacol 34: 225–230, 1994 Bjarnason I, Hayllar J, MacPherson AJ, Russell AS: Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 104: 1832–1847, 1993 Bjørnsson GA, Haanæs HR, Skoglund LA: A randomized, doubleblind crossover trial of paracetamol 1000 mg four times daily vs ibuprofen 600 mg: effect on swelling and other postoperative events after third molar surgery. Br J Clin Pharmacol 55: 405–412, 2003 Blum AL, Bolten WW, Labenz J, Stolte M, Ro¨sch W: Therapie und Pra¨vention des ASS- und NSAR-Ulkus. Dtsch A¨rztebl 95: 348–354, 1998 Brune K, Kalden J, Zacher J, Zeilhofer HU: Selektive Inhibitoren der Zyklooxygenase 2. Evolution oder Revolution? Dtsch A¨rztebl 97: A1818–1825, 2000 Byrne MF, McGuiness J, Smyth CM, Manning DS, Sheehan KM, Bohra SG, Patchett E, Murray FE: Nonsteroidal antiinflammatory drug-induced diaphragms and ulceration in the colon. Eur J Gastroenterol Hepatol 14: 1265–1269, 2002 Chang DJ, Desjardins PJ, Chen E, Polis AB, McAvoy M, Mockoviak SH, Geba GP: Comparison of the analgesic efficacy of refecoxib and enteric-coated diclofenac sodium in the treatment of postoperative dental pain: a randomized placebocontrolled clinical trial. Clin Ther 24: 490–503, 2002 Coulthard P, Hill CM, Frame JW, Ridge BD, Bacon TH: Pain control with paracetamol from a sustained release formulation and a standard release formulation after third molar surgery: a randomised controlled trial. Br Dent J 191: 319–324, 2001 Eis MJ, Watkins BM, Philip A, Welling RE: Nonsteroidal-induced benign strictures of the colon: a case report and review of the literature. Am J Gastroenterol 93: 120–121, 1998 Fu JY, Masferrer JL, Seibert K, Raz A, Needelmann P: The induction and suppression of prostaglandin H2 synthase (Cyclooxygenase) in human monocytes. J Biol Chem 265: 16737–16740, 1990 Fuehrer M: Besondere Aspekte der Schmerztherapie im Kindesalter. Internist 40: 183–189, 1999 Gopal DV, Katon RM: Endoscopic balloon dilation of multiple NSAID-induced colonic strictures: case report and review of literature on NSAID-related colopathy. Gastrointest Endosc 50: 120–123, 1999 Haas DA: An update on analgesics for the management of actue postoperative dental pain. J Can Dent Assoc 68: 476–482, 2002 Halter F, Weber B, Huber T, Eigenmann F, Frey MP, Ruchti C: Diaphragm disease of the ascending colon Association with sustained-release diclofenac. J Clin Gastroenterol 16: 74–80, 1993 Holt S, Rigoglioso V, Sidhu M, Irshad M, Howden CW, Mainero M: Nonsteroidal antiinflammatory drugs and lower gastrointestinal bleeding. Dig Dis Sci 38: 1619–1623, 1993 Hooker GD, Gregor JC, Ponich TP, McLarty TD: Diaphragm-like strictures of the right colon induced by indomethacin suppositories: evidence of a systemic effect. Gastrointest Endosc 44: 199–202, 1996 Huber T, Ruchti C, Halter F: Nonsteroidal antiinflammatory druginduced colonic strictures: a case report. Gastroenterology 100: 1119–1122, 1991 Hyllested M, Jones S, Pedersen JL: Kehlet: Comparative effect of paracetamol NSAIDs or their combination in postoperative pain management: a qualitative review. Br J Anaesth 88: 199–214, 2002 Jeske AH: Selecting new drugs for pain control, evidence-based decisions or clinical impressions. J Am Dent Assoc 144: 1052–1056, 2002 Kehrer G, Bosseckert H, Koppe P, Will U, Zinsser E: Unusual negative side effects of non-steroidal anti-inflammatory drugs in the proximal colon. Z Gastroenterol 38: 499–503, 2000
ARTICLE IN PRESS 334 Journal of Cranio-Maxillofacial Surgery Lang J, Price AB, Levi AJ: Diaphragm disease: the pathology of NSAID-induced disease of the small bowel. J Clin Pathol 41: 516–626, 1988 Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Desjardins PJ: Comparison of refecoxib and celecoxib two cyclooxygenase-2 inhibitors in postoperative dental pain: a randomized, placeboand active-comparator-controlled clinical trial. Clin Ther 21: 1653–1663, 1999 Mattews RW, Scully CM, Levers BG: The efficacy of diclofenac sodium (Voltarol) with and without paracetamol in the control of post-surgical dental pain. Br Dent J 157: 357–359, 1984 Nguyen AM, Graham DY, Gage T, Griffiths GR: Nonsteroidal anti-inflammatory drug use in dentistry: gastrointestinal implications. Gen Dent 47: 590–596, 1999 Ong KS, Seymour RA: Maximizing the safety of nonsteroidal antiinflammatory drugs use for postoperative dental pain: an evidence-based approach. Anaesth Prog 50: 62–74, 2003 Ribeiro A, Wolfsen H, Wolfe JT, Loeb DS: Colonic stictures induced by nonsteroidal anti-inflammatory drugs. South Med J 91: 568–572, 1998 Robinson MHE, Wheatley T, Leach IA: Nonsteroidal antiinflammatory drug-induced colonic stricture. An unusual cause of large bowel obstruction and perforation. Dig Dis Sci 40: 315–319, 1995 Schiemann U, Kellner H: Gastrointestinale Nebenwirkungen der Therapie rheumatischer Erkrankungen. Z Gastroenterol 40: 937–943, 2002 Seitz S, Boelsterli UA: Diclofenac acyl glucuronide, a mayor biliary metabolite, is directly involved in small intestinal injury in rats. Gastroenterology 115: 1476–1482, 1998 Seymour RA, Moore U, Hawkesford J, Coulthard P, JacksonLeech D, Thomas D, Hill M, Combs ML, Renton T, McGurk
M: An investigation into the efficacy of intravenous diclofenac in post-operative dental pain. Eur J Clin Pharmacol 56: 447–452, 2000 Seymour RA, Hawkesford J, Sykes J, Stillings M, Hill M: An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J 194: 153–157, 2003 Sikes DH, Agrawal NM, Zhao WW, Kent JD, Recker DP, Verburg KM: Incidence of gastroduodenal ulcers associated with valecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis. Eur J Gastroenterol Hepatol 14: 1101–1111, 2002 Stichtenoth DO, Froehlich JC: Therapie mit pra¨ferenziellen und spezifischen COX-2-Inhibitoren. Internist 42: 421–426, 2001 Weinstock LB, Hammoud Z, Brandwin L: Nonsteroidal antiinflammatory drug-induced colonic stricture and ulceration treated with balloon dilatation and prednison. Gastrointest Endosc 50: 564–566, 1999
Dr. med. Dr. med. dent. Juergen ERVENS Department of Maxillofacial & Facial Plastic Surgery Charite´—Universita¨tsmedizin Berlin Campus Benjamin Franklin Hindenburgdamm 30 D-12200 Berlin, Germany Tel.:+49 30 8445 2474 Fax:+49 30 8445 4458. E-mail: [email protected] Paper Received 22 September 2003 Accepted 13 May 2004
Colon perforation with acute peritonitis after taking clindamycin and diclofenac following wisdom tooth removal Juergen ERVENS1, Leif SCHIFFMANN2, Gerd BERGER2, Bodo HOFFMEISTER1 1
Department of Maxillofacial and Facial Plastic Surgery (Chairman: Prof. Dr. Dr. B. Hoffmeister); Department of General Surgery I (Chairman: Prof. Dr. H.-J. Buhr), Charite´—Universita¨tsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany 2
SUMMARY. Introduction: Non-steroidal anti-inflammatory drugs have a high analgesic and anti-inflammatory effect and are widely taken for acute and chronic pain. Especially following long-term use, they may cause gastrointestinal side effects such as mucosal ulceration, perforation and strictures in the small and large bowel. Patient: A 16-year-old female developed colonic perforation and purulent peritonitis after wisdom tooth removal and short-term intake of non-steroidal anti-inflammatory drugs. Discussion: Non-steroidal antiinflammatory drugs may exert their deleterious effects on the lower gastrointestinal tract through both local and systemic actions. Systemic effects are caused by the inhibition of cyclooxygenase and reduction of protective prostaglandins. The local damage of the intestinal mucosa in the distal bowel segments seems to be caused by sustained release formulation with a high enterohepatic circulation. The latter may act time and again on the intestinal mucosa through metabolites secreted in the gallbladder. Concomitant intake of clindamycin may have favoured this acute complication. Conclusion: Intestinal perforation after short-term intake of non-steroidal anti-inflammatory drugs is very rare. However, it is life-threatening and illustrates the need for careful prescribing at as low an effective dose and as short a time as possible, especially when combining different drugs. Paracetamol only has a weak effect on cyclooxygenase and continues to be a possible alternative for postoperative dental pain with a favourable benefit-risk ratio. It is the drug of choice for children, adolescents and patients with an increased risk of non-steroidal anti-inflammatory drug-induced gastro-enteropathy. r 2004 European Association for Cranio-Maxillofacial Surgery
Keywords: NSAID; Gastro-enteropathy; Colon perforation; Tooth removal
In this paper, the unusual finding of a transverse colon perforation with ulcerated peritonitis is reported in an otherwise healthy 16-year-old female with short-term simultaneous oral intake of diclofenac and clindamycin after surgical removal of all four wisdom teeth.
INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs and are commonly applied in the treatment of rheumatic diseases as well as for acute and chronic pain (Bjarnason et al., 1993; Blum et al. 1998; Haas, 2002). Although NSAIDs have excellent analgesic, antiinflammatory and antipyretic effects, they also have undesirable side effects, including acute and chronic renal dysfunction, NSAID-induced asthma, and especially gastrointestinal ulceration, bleeding and related complications (Bjarnason et al., 1993; Ribeiro et al., 1998; Stichtenoth and Froehlich, 2001; Schiemann and Kellner, 2002; Sikes et al., 2002). NSAID enteropathy is often not detected until the occurrence of small and large bowel ulceration, intestinal strictures or perforations (Holt et al., 1993; Byrne et al., 2002). Furthermore, NSAIDs are responsible for two-thirds of all drug-related deaths in patients with chronic polyarthritis, more specifically an estimated 2200 deaths in Germany annually (Blum et al., 1998).
CASE REPORT The 16-year-old female presented with severe, persistent abdominal pain to the emergency room of the University Hospital Benjamin Franklin. Acute pain had started 12 h earlier, increased continuously in intensity and was accompanied by watery (but not bloody) stool after 6 h. The patient reported the surgical removal of all four wisdom teeth 12 days earlier as well as postoperative analgesics and antibiotics: diclofenac (2 75 mg/d/orally for 5 days) and clindamycin (3 300 mg/d/orally for 10 days). She had no history of previous abdominal operations, chronic inflammatory bowel disease or other diseases. 330
ARTICLE IN PRESS Colon perforation with acute peritonitis 331
Clinical findings On initial presentation, the patient presented in poor condition, blood pressure was 110/80 mmHg, pulse rate 130/min, rectal temperature 40 1C. Examination revealed a markedly distended abdomen with a taut abdominal wall and guarding, especially in the epigastric region. McBurney’s and Lanz’s pressure points were unremarkable, but bowel sounds were absent. Investigation showed: haemoglobin 9.4 g/dl, leukocytes 11900/ml, thrombocytes 376/nl, CRP 240 mg/ l, lactate 3.3 mmol/l, creatinine 66 mmol/l, GPT (ASAT) 5 U/l, GOT (ALAT) 5 U/l, Quick 51%, PTT 44 s. A lateral plain radiograph of the abdomen showed free abdominal air, individual gas/liquid levels and mesogastric loops (Fig. 1).
Fig. 2 – Sixteen year-old female. Sharply delimited intestinal perforation in the transverse colon with extraluminal fibrin layers following purulent peritonitis.
Therapy and course Laparoptomy was performed for progressive pain and the presence of radiologically free abdominal air, indicating viscus perforation. Extreme ulcerative peritonitis extending from the diaphragm to the pelvis was found. Assuming a perforated ulcer, the stomach and duodenum were initially inspected after thorough lavage, but proved to be normal even after staining with methylene blue. All intestinal loops were covered by fibrin with no evidence of perforation. Only inspection of the colon disclosed a perforation of the transverse colon which appeared punched out (Fig. 2). Two similar lesions, which did not perforate the intestinal mucosa, were found nearby. Although the remaining intestinal mucosa was macroscopically free of inflammation and macroscopically normal, several biopsies were taken to exclude chronic inflammatory bowel disease. Separate smears from the intestinal lumen were obtained for microbiological examination to exclude a possible intestinal infection with Clostridium difficile.
Fig. 1 – Sixteen year-old female. Preoperative left lateral plain radiograph of the abdomen. Arrows indicate the free abdominal gas.
Fig. 3 – Sixteen year-old female. Postoperative findings after explantation of the perforation site and creation of a double-lumen transverse colostomy.
Antibiotic therapy with piperazillin (3 4 g/d/i.v.), tazobactam (3 0.5 g/d/i.v.) and gentamycin (1 320 mg/i.v. according to levels) was initiated intraoperatively. The perforation site was exteriorized to the abdominal wall with creation of a doublelumen colostomy, since postoperative primary anastomosis of the transverse colon seemed to involve too high a risk of postoperative complication due to the pronounced ulcerative peritonitis (Fig. 3). Histological examination, conventional and immunohistochemical staining of the biopsies from the intestinal wall revealed signs of localized non-specific inflammation without any signs of chronic inflammatory bowel disease such as Crohn’s disease, any malignancy, endometriosis or infection with acidresistant rods or fungi. Microbiological stool diagnostics to detect possible infection with Clostridium difficile was negative in both the culture and toxin assay. Ten weeks later, the transverse colostomy was closed without complication once the patient had recovered from peritonitis (Fig. 4).
ARTICLE IN PRESS 332 Journal of Cranio-Maxillofacial Surgery
Fig. 4 – Sixteen year-old female. Postoperative findings after repositioning the transverse artificial anus.
DISCUSSION The typical undesirable side effects of NSAIDs are caused by the inhibition of cyclooxygenase (COX), a membrane-bound key enzyme which exists in two isoforms and synthesizes prostaglandins from arachidonic acid (Brune et al., 2000; Kehrer et al., 2000; Brsyne et al., 2002). Serious side effects of NSAIDs are more frequent than hitherto suspected. The clinically most important undesirable effect of NSAID therapy is gastrointestinal ulcer and its complications, observed in about 15% of the cases (Blum et al., 1998). The frequency of complications is clearly dosedependent, the effect being systemic. The risk of undesirable side effects is greater the longer the drugs are taken (Bjarnason et al., 2003; Holt et al., 1993; Brsyne et al., 2002; Sikes et al., 2002). Gastrointestinal side effects of NSAID therapy restrict their application in children and adolescents (Fuehrer, 1999). A perforation in the upper gastrointestinal tract, i.e. the stomach or duodenum, was initially assumed here because of short-term NSAID intake. Surprisingly, the perforation was found in the transverse colon. NSAID-induced small bowel strictures were first described by Lang et al. (1988). Since then, there have been a number of publications on the occurrence of mucosal ulceration, perforation and intest-
inal strictures in the small and large bowel after longterm NSAID intake (Huber et al., 1991; Halter et al., 1993; Robinson et al., 1995; Hooker et al., 1996; Abrahamian et al., 1998; Eis et al., 1998; Gopal and Katon, 1999; Weinstock et al., 1999). NSAIDs may exert their deleterious effects on the distal bowel segments through both local and systemic actions. The direct toxic damage to the intestinal mucosa seem to be caused in particular by sustained release formulation of NSAIDs, and the effect of metabolites secreted in the gallbladder from NSAIDs with a high enterohepatic circulation (e.g. diclofenac). NSAIDs and their metabolites can thus reach the distal bowel segments, damage the intestinal mucosa and cause ulceration with complications, as well as increased intestinal permeability with loss of albumin (Halter et al., 1993; Ribeiro et al., 1998; Seitz and Boelsterli, 1998; Schiemann and Kellner, 2002). Remarkably in this patient the time between drug intake and intestinal perforation was short, which distinguishes this from other cases reported in the literature. Here, the combination of diclofenac und clindamycin, both drugs with biliary secretion and high enterohepatic circulation, may have aggravated local damage to the distal intestinal mucosa and magnified the complications (Ribeiro et al., 1998; Seitz and Boelsterli, 1998). Moreover, the patient’s young age may have been a possible predisposing factor that cannot be entirely ruled out (Fuehrer, 1999). Perforation of the intestinal wall as a consequence of chronic inflammatory bowel disease (e.g. Crohn’s disease) was considered in the differential diagnosis (Bjarnason et al., 1993). Intraoperative inspection of the intestinal wall and conventional histological and immunohistochemical assessment of the biopsy samples yielded no signs of inflammatory bowel disease. Instead, the histological examination revealed a localized, non-specific inflammation at the perforation site, supporting the assumption that the intestinal perforation was caused by NSAID-induced local inflammation of the mucosa (Byrne et al., 2002). Pseudomembranous enterocolitis, as described after the intake of clindamycin, was excluded. Some microbiological testing of intraoperative stool samples yielded no Clostridium difficile by culture or toxin assay. A new approach to avoid typical NSAIDs side effects has been found after the discovery of another COX isoform and the development of specific COX-2 inhibitors (Fu et al., 1990). Erosions, ulceration and gastrointestinal perforations have in the meantime been described for all drugs with preferential COX-2 inhibition (Brune et al., 2000). COX-2 inhibitors are also being used in dental pain therapy, and clinical studies have proved their suitability, but a clear superiority of COX-2 inhibitors in postoperative dental pain therapy has not yet been shown (Bakshi et al., 1994; Malmstrom et al., 1999; Seymour et al., 2000; Chang et al., 2002; Hyllested et al., 2002; Jeske, 2002; Seymour et al., 2003).
ARTICLE IN PRESS Colon perforation with acute peritonitis 333
In contrast to NSAIDs, the aniline derivative paracetamol has only a weak effect on COX-1 and none on COX-2. This concur with the fact that paracetamol has a weak anti-inflammatory effect and no influence on thrombocytes (Brune et al., 2000; Stichtenoth and Froehlich, 2001). Nevertheless, controlled prospective clinical studies have shown that when compared with NSAIDs, therapeutically adequate concentrations of paracetamol administered after surgery also have a sufficiently high analgesic effect (Mattews et al., 1984; Coulthard et al., 2001; Hyllested et al., 2002; Bjørnsson et al., 2003; Seymour et al., 2003). Thus, ibuprofen (4 600 mg/d/orally) administered after surgical removal of wisdom teeth showed no clinical advantage over paracetamol (4 1000 mg/d/orally) with regard to reducing postoperative swelling and pain (Bjørnsson et al., 2003). With a favourable benefit–risk ratio, paracetamol is a good alternative to NSAIDs in postoperative pain therapy after dental surgery and is the drug of choice for children, adolescents and patients at increased risk of NSAID-induced gastro-enteropathy (Fuehrer, 1999; Nguyen et al., 1999; Hyllested et al., 2002; Jeske, 2002; Ong and Seymour, 2003). NSAID-induced intestinal perforation must be assumed in this case as the most likely cause after evaluating all findings and with no detection of chronic inflammatory bowel disease or clindamycininduced pseudomembranous enterocolitis. This assumption is supported by conventional and immunohistochemical findings of localized non-specific inflammation of the perforation site, and no evidence of Clostridium difficile in the culture and toxin assay from the microbiological stool examination. The combination of diclofenac and clindamycin, which both have biliary secretion and high enterohepatic circulation, may have favoured development of this complication. Although it is difficult to be absolutely certain.
CONCLUSION Intestinal perforation after short-term intake of nonsteroidal anti-inflammatory drugs is very rare. However, it is a life-threatening complication and illustrates the necessity for careful prescribing at as low an effective dose and for as short a time as possible, especially when combining different drugs. The local damage of the distal bowel mucosa seems to be caused by sustained release formulation and high enterohepatic circulation, which may act time and again on the intestinal mucosa. Compared with nonsteroidal anti-inflammatory drugs, paracetamol has only a weak effect on cyclooxygenase but in therapeutically adequate concentrations also has a sufficiently high analgesic effect. With a favourable benefit–risk ratio, paracetamol is a good alternative in postoperative and/or dental pain therapy and is the drug of choice for children, adolescents and patients with an increased risk.
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Dr. med. Dr. med. dent. Juergen ERVENS Department of Maxillofacial & Facial Plastic Surgery Charite´—Universita¨tsmedizin Berlin Campus Benjamin Franklin Hindenburgdamm 30 D-12200 Berlin, Germany Tel.:+49 30 8445 2474 Fax:+49 30 8445 4458. E-mail: [email protected] Paper Received 22 September 2003 Accepted 13 May 2004