Br. J. Surg. Vol. 65 (1978) 101-105
Gallstone disease presenting as septicaemic shock R . G. F A B E R , S. Z. IBRAHIM. D. M. THOMAS, G. P. J. BEYNON A N D L. P. LE QUESNE* SUMMARY
Three patients are described who were admitted to hospital with septicaemic shock due to gallstones, but in none of whom had the presence of gallstones been diagnosed previously. All 3 had positive blood cultures, Clostridium welchii being isolated in one patient (in another patient this organism was isolated from the bile). Two patients had renal failure requiring dialysis. All 3 patients survived. The management of this serious presentation of gallstones, hitherto poorly described in British literature, is discussed. T H Eassociation between gallstones and biliary tract infection has been recognized for many years (Rogers, 1903). In a bacteriological study of 50 consecutive cholecystectomy specimens nearly 50 years ago, organisms were cultured from the fluid contents of the gallbladder in 34 cases and from the wall of the gallbladder in 36 cases (Gordon-Taylor and Whitby, 1930). More recently, septic complications, including septicaemia, developing after removal of stones from the common bile duct have become well recognized (Thomas et al., 1971) and it is now appreciated that the bile is infected in about 75 per cent of patients with stones in the common duct (Scott, 1971). However, it is not so clearly recognized that gallstone disease may present as septicaemic shock in patients not previously diagnosed as having gallstones. Three examples of this serious complication of gallstones are presented here. Case reports Case 1 : Mr. B. L., aged 62, was admitted to the medical wards as an emergency on 1 March 1976 complaining of upper abdominal pain, nausea, vomiting and jaundice. His illness had started 5 days previously with moderate upper abdominal pain which was intermittent in nature, but with a constant ache. Two days later his urine had become dark and he had developed jaundice. About 2 weeks before the onset of his illness he had had a transient episode of severe upper abdominal pain. Diabetes had been diagnosed in 1961 and remained well controlled with phenformin. In 1971 he underwent transurethral resection of the prostate, which was followed by an episode of deep venous thrombosis and a pulmonary embolus. In 1973 he suffered a myocardial infarct followed by a further pulmonary embolus. On examination he was grossly obese, extremely drowsy and deeply jaundiced. His temperature was 38.2 "C, pulse 120/min, respiratory rate 27/min and blood pressure 120/80 mmHg, and there was tenderness in the right hypochondrium. Full haematological and biochemical (Vickers's profile) blood screening investigations were performed, and the following results were of note: haemoglobin 14.7 g/dl; WBC 21 x 10g/l; bilirubin 212 pmol/l; alkaline phosphatase 195 i.u./l; aspartate aminotransferase (AST) 150 i.u./l; urea 6.6 mmol/l; blood sugar 8.0 mmol/l; arterial Po, 46 mmHg; Pco, 27 mmHg; p H 7.74. A provisional diagnosis of obstructive jaundice due to gallstones with ascending cholangitis was made, and blood cultures were taken. Septrin was started and to combat incipient hepatic failure he was given neomycin by mouth, put on a high carbohydrate oral intake containing no protein and was given intravenous fluids. Over the next 24 h, despite a fluid intake of 5 1, he only passed 250 ml of urine, and his blood urea rose to 27,7 mmolll.
The patient was transferred to the intensive therapy unit and was seen in consultation by the surgical and gastroenterological teams. At this time the diagnosis was still thought to be ascending cholangitis secondary to obstructive jaundice, and the advisability of early operation was discussed; it was considered that he was too ill for operation (see below) and conservative treatment was continued. Over the next 12 h he received a further 5 1 of intravenous crystaloid solution and intravenous frusemide, but his urine output remained low and his blood urea rose to 40 mmol/l; peritoneal dialysis was therefore started. At this time his bilirubin was 500 pmol/l, alkaline phosphatase 324 i.u./l, AST 35 i.u./l and albumin 25 g/l. The initial blood culture was reported as growing Klebsiella spp. and Escherichia coli and so gentamicin was started. Dialysis was continued for 8 days, during which time his urine output slowly improved and his blood urea fell to 12 mmol/l. However, he remained mentally confused and uncommunicative and developed an hepatic 'flap'; his bilirubin was 423 pmol/l, alkaline phosphatase 250 i.u./l and AST 37 i.u./l. In view of this and his failure to improve, the possibility that his condition was due not to ascending chloecystitis but rather to an acute fulminating hepatitis was considered. In order to resolve this problem, endoscopic retrograde cholangiography (ERCP) was performed o n 10 March. A large filling defect in the common bile duct with a dilated biliary tree proximal to the obstruction was demonstrated (Fig. I). Operation was performed the same day through Kocher's incision. A large stone was found lying partly in the gallbladder and partly in the common bile duct, having ulcerated through from Hartmann's pouch into the latter (Fig.2). This calculus was removed and a T tube was placed in the common bile duct through this fistula. The bile was purulent and on culture grew KIebsieZIu spp. The deep layers of the wound were closed leaving open the skin and subcutaneous tissue. Following operation the patient's clinical condition improved dramatically, and over the next 2 weeks renal and hepatic function slowly returned to normal. However, on 26 and 31 March he passed two melaena stools which necessitated an 1I-unit blood transfusion. Upper gastrointestinal endoscopy was performed on 31 March and a large superficial duodenal ulcer, containing fresh blood clot, was seen. Cimetidine (200 mg t.i.d. and 400 mg nocte) was administered orally and n o further bleeding occurred. By 8 April he was well with normal liver function tests. The wound had healed satisfactorily, but blood urea remained 11 mmol/l. T tube cholangiography showed no calculi in the common bile duct so the T tube was removed and the fistulous tract healed promptly. The patient left hospital o n 10 April and thereafter made a steady recovery. By 26 April his blood urea was normal, but the creatinine clearance was only 46 ml/min. Gastroduodenoscopy was repeated twice over the next 2 months and on the second occasion the duodenal ulcer was seen to have healed and the cimetidine was stopped. On review in June 1977, he reported a recurrence of epigastric pain. Further endoscopy revealed that the duodenal ulcer had recurred, but renewed treatment with cimetidine gave relief of symptoms. Case 2: Mrs S . B., aged 81, was admitted to the medical wards as an emergency on 11 August 1976 with a history of nausea, epigastric pain and feeling generally unwell for 24 h. She had had two loose bowel actions before admission. On examination she was mildly jaundiced, her temperature was 38.5 "C, pulse 90/min, respiratory rate 2l/min and blood pressure 180/90 mmHg. There was tenderness, but no guarding, in the epigastrium and right hypochondrium.
* Department of Surgical Studies, Th e Middlesex Hospital and Medical School, London.
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Fig. 1. Case 1. Endoscopic retrograde cholangiography. The
common hepatic duct is grossly dilated by a single calculus. A faint outline of the collapsed common bile duct, distal to the stone can be seen.
v\
CHD
gallstone
Fig. 2. Case 1. Findings at operation. Obstruction of the common hepatic duct by a solitary stone, which had eroded through Hartmann's pouch. C HD Common hepatic duct; CBD, common bile duct.
Full haematological and biochemical screening was performed and the following investigations noted: haemoglobin 11.2 g/dl; WBC 14.3 x 10s/l; bilirubin 78 p n o l / l ; alkaline phosphatase 132 i.u./l; AST 63 i.u./l; urea 5.2 mmol/l; exchangeable glucose 6.2 mmol/l. A diagnosis of probable gallstones causing obstructive jaundice was made. A blood culture was taken and a course of ampicillin started. The next day she had a rigor, her temperature rose to 40 "C, pulse to 150/min and her blood pressure fell to 80/50 mmHg. Another blood culture was taken, she was treated with intravenous fluids and oxygen, and gentamicin was added to the ampicillin; her condition rapidly improved over the next few hours. The first blood culture grew Klebsiellu spp. and Escherichia coli, both resistant to ampicillin but sensitive to gentamicin, while the second blood culture grew KIebsielIa spp. only. Over the next few days serum bilirubin, alkaline phosphatase and AST all returned to normal values. A double-dose oral cholecystogram was performed o n 24 August and no opacification of the gallbladder was seen, but a dilated and partially obstructed common bile duct was outlined. Th e patient was seen in consultation by the surgical team on 4 September and laparotomy was perfomed on 6 September via a Kocher's incision. A very small fihrosed gallbladder full of stones was found and further calculi were palpated in the common bile duct; the latter were confirmed on operative cholangiography. Cholecystectomy and exploration of the bile duct were performed and the common bile duct was cleared of stones and biliary sludge; the choledochotomy incision was converted into a choledochoduodenostomy without T tube drainage. The wound was closed, leaving open the skin and subcutaneous tissue. Bile from the common bile duct was cultured and grew E. coli, Streptococcus faecalis and CIostridium welchii. The postoperative course was complicated first by right lower lobe pneumonia and secondly by a leak from the choledochoduodenal anastomosis. The former responded to physiotherapy, ampicillin and flucloxacillin and the latter to wound drainage and intravenous feeding. Following this she made a slow, but uneventful recovery. The open wound was treated with daily dressings and healed by second intention with minimal inflammation. On outpatient review after 3 months she was well with normal biochemical blood values and a hairline abdominal scar. Case 3 : Mrs J. C., aged 64, was admitted as an emergency on 7 August 1976 directly from the casualty department to the intensive therapy unit under the care of the physicians. She was extremely ill and unable to give a history of her condition. On examination she was grossly obese, drowsy and incoherent, not jaundiced but centrally cyanosed; her temperature was 40 "C, pulse 140/min, blood pressure 170/90 mmHg and respiratory rate 35/min. There were coarse crepitations at the right base of the chest and the abdomen was generally soft with definite right upper quadrant tenderness. A history was later obtained from a relative. The patient had developed right-sided abdominal pain 5 days previously and had vomited o n several occasions. Twenty-four hours before admission she had become confused and disorientated. In the past she had had recurrent attacks of right hypochondria1 pain which she attributed to gallstones, but for which she had never attended hospital. In 1973 she had been admitted to the Middlesex Hospital with bronchopneumonia. Full haematological and biochemical screening were performed and the following investigations noted: haemoglobin 13.1 g/dl; WBC 6 . 2 lOs/l; ~ bilirubin 34 pmol/l; alkaline phosphatase 53 i.u./l; urea 8.8 mmol/l; amylase 160 units/l; exchangeable glucose 4.5 mmol/l; arterial Po, 42 mmHg; Pco? 29 mmHg; p H 7.52. A diagnosis of septicaemia secondary to right lower lobe pneumonia or empyema of the gallbladder was made. A blood culture was taken and she was initially treated with intravenous fluids, oxygen and broad spectrum antibiotic cover, consisting of penicillin, ampicillin and gentamicin. Despite this treatment her condition further deteriorated, she developed hypotension and anuria and there was n o change in the arterial gas figures. Her WBC rose to 20 x 10e/l and alkaline phosphatase to 153 i.u./l, but serum amlyase remained normal (200 units/l).
Gallstone disease Twelve hours after admission an endotracheal tube was passed and positive pressure ventilation started. The next day she was seen in consultation by the surgical team and septicaemia secondary to empyema of the gallbIadder was considered the most likely diagnosis; however, she was considered to be too ill to withstand laparotomy (see below) and conservative management was continued. Over the next 3 days, despite an apparently adequate fluid intake, her urine output remained sparse and her blood urea rose to 31.5 mmol/l and creatinine clearance fell to 5 ml/min; peritoneal dialysis was started. The initial blood cultures grew Closfridium wefchii and Escherichiu coli, both sensitive to gentamicin, which was continued and the ampicillin stopped. The patient responded slowly but well to this treatment and after 2 weeks was transferred from the intensive therapy unit to the main ward; however, within 1 2 h she had another episode of septicaemic shock. On this occasion she responded rapidly to intravenous fluid replacement and the reintroduction of antibiotics; E. cofi was again grown from repeat blood culture, but n o C. welchii on this occasion. Operation was performed on 31 August through a transverse subcostal incision. An empyema of the gallbladder was found, but a n operative cholangiogram showed a normal biliary tree with no calculi in the common bile duct and rapid flow into the duodenum. The pancreas was apparently normal with no evidence of previous acute o r chronic inflammation. Cholecystectomy was performed and the deep layers of the wound were closed leaving open the skin and subcutaneous tissue. Culture of the pus from the gallbladder grew E. coli, Proteus spp. and Bacteroides spp. Postoperatively, despite mechanical ventilation for the first 24 h, she developed bilateral lower lobe collapse and a urinary tract infection; both responded well to treatment. By the time of discharge her blood urea was 2.8 mmol/l and creatinine clearance 60 ml/min. The open wound was treated with daily dressings and healed by second intention. At the latest outpatient review 9 months after the operation, she was well with normal biochemical blood values and a hairline abdominal scar.
Discussion The first description of patients with gallstones presenting with rigors and jaundice appeared in the British Medical Journal more than 70 years ago (Rogers, 1903). The syndrome of acute obstructive suppurative cholangitis, characterized by a diagnostic pentad of abdominal pain, fever, jaundice, mental confusion and shock, was first clearly described by Reynolds and Dargan (1958), who emphasized that the aetiological factor is infected bile under pressure. The condition occurs mainly in the elderly and has a mortality of over 60 per cent (Dow and Lindenauer, 1969). Despite this syndrome being well described in American publications, apart from a discussion at the Royal Society of Medicine (Williams and Dawson, 1969), a Medlars offline computer search has failed to find another reference in the British literature. The present communication has been prompted by the admission, during a 6-month period, of 3 patients presenting with septicaemia secondary to previously undiagnosed gallstones; their case histories illustrate well the main difficultiesin the diagnosis and treatment of this difficult condition. All 3 patients presented the diagnostic pentad, with variants, of acute obstructive suppurative cholangitis : abdominal pain was present in two and the third comatose patient had guarding in the right upper quadrant of the abdomen; all had a fever; all had mental confusion-one being admitted in coma and another lapsing into coma; all developed hypotensive shock; 1 patient was jaundiced on admission and the other 2 developed jaundice shortly afterwards. Two of the patients developed acute renal
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failure, a well-recognized and serious complication of this condition (Bismuth et aI., 1975). There are two points of difference between the 3 patients reported in this paper and those of the American series. First, the one common factor that stands out in the histories of these patients is that in none of them had a diagnosis of cholelithiasis been made before their admission to hospital. Furthermore, and in retrospect, only 1 of the 3 patients admitted to previous episodes of abdominal pain before the onset of the presenting illness. This is in contrast to American reports in which the majority of patients had had previous biliary disease or previous biliary surgery (Dow and Lindenauer, 1969; Hinchey and Couper, 1969; Saharia and Cameron, 1976). Secondly, only 2 of our patients had calculi in the common bile duct, while the third patient had a narrow common duct, demonstrably free of calculi on operative cholangiogram, but an obstructed cystic duct. A11 the American papers on this subject (Reynolds and Dargan, 1958; Glen and Moody, 1961; Dow and Lindenauer, 1969; Hinchey and Couper, 1969; Saharia and Cameron, 1976) emphasize that the clinical picture of abdominal pain, fever, jaundice, mental confusion and shock is produced by complete obstruction of the common bile duct by calculi, strictures or carcinoma in the presence of severe infection, resulting in acute suppurative cholangitis ;our patient, however, illustrates the fact that an indistinguishable condition can be caused by obstruction to the cystic duct. Organisms were cultured from the blood and the bile of all our patients. I n Cases 1 and 3, 2 organisms were found in the blood, while only 1 organism was found in Case 2. On the other hand, only 1 organism was cultured from the bile of both Case 2 and Case 3. This discrepancy is hardly surprising, as on the one hand only the virulent organisms will be expected to pass from the biliary tract into the blood, and on the other hand antibiotics had been given to all patients after culturing the blood but before culturing the bile. Of particular interest was the recovery of Clostridium welchii from the blood of one patient and the bile of another. Despite Gordon-Taylor and Whitby (1930, 1932) finding C. welchii in 16 out of the 100 gallbladders that they studied, reports of biliary tract infection with this organism are extremely rare. Pyrtek and Bartus (1962), Bennett and Healey (19631, Dow and Lindenauer (1969) and Clancy and O’Brian (1975) each report a single case of C. welchii septicaemia secondary to biliary tract infection; 2 of these 4 patients died before operation. This organism can also rarely cause infective complications after biliary tract surgery; Pyrtek and Bartus (1962) described 2 fatal cases of septicaemia, while ElliottSmith and Ellis (1957) reported a patient who developed gas gangrene after cholecystectomy and survived. The management of patients with acute obstructive suppurative cholangitis gives rise to considerable difficulties. Of prime importance is the establishment of the diagnosis, which is that much more difficult if there is n o history of previous biliary disease, as was the case in the patients reported here. Glen and Moody (1961) emphasized that the condition must be suspected when any combination of the diagnostic pentad was present and that often one or other of the signs or symptoms did not develop until late in the
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progress of the disease. They particularly emphasized first, that severe jaundice is often absent, as was initially the situation in our Cases 2 and 3, and secondly, that there may be considerable difficulty in differentiating the condition from severe acute hepatitis. This was certainly the problem in Case 1, and it was only finally resolved by ERCP. With the increasing availability of this examination and grey scale ultrasound, it is now possible to determine, with a high degree of accuracy and with minimum disturbance to the patient, whether or not the duct is obstructed. These techniques may well prove to be of great value in differentiating between acute hepatic necrosis and acute obstructive suppurative cholangitis, and could with advantage have been used at an early stage in our patients. Once the diagnosis has been established, the emphasis in the management of these patients has recently slightly changed. In 1958 Reynolds and Dargan stated that the presence of fever, jaundice and right upper quadrant pain is an indication for urgent operation, and that operation becomes mandatory if either mental confusion or shock supersede. The only one of their patients treated conservatively died, while 3 out of 4 patients having urgent operation survived. Hinchey and Couper (1969) operated on 6 out of 8 patients in shock who failed to respond to emergency resuscitation and 4 of these 6 survived; 2 patients in whom conservative measures were continued died before being considered fit for operation. On the other hand, of their 11 patients who improved with emergency resuscitation, only 3 remained well enough to await planned operation, while 8 again deteriorated and required emergency surgery from which 4 died. However, in the reports by the authors mentioned above, neither the risk of the jaundiced patient developing renal failure, nor the treatment of the patient with established renal failure, was considered. Williams and Dawson (1969) recommended that, in order to prevent acute renal failure, it was first necessary to maintain an adequate circulating volume and high flow of dilute urine with adequate transfusion and diuretics, and also to give massive doses of antibiotics. Emergency operation could then be undertaken if there was no improvement in the patient’s condition over the next 24-36 h. Bismuth et al. (1975) reported on 3 patients with acute renal failure complicating acute suppurative cholangitis who were operated upon as an emergency; all 3 died. In the light of this experience they managed their next 15 patients fist by treating the shock by resuscitation and antibiotics, secondly by performing dialysis and finally by operating when the patient’s general condition was, at least to some extent, stabilized; 12 of 15 patients so managed survived. There is no doubt that the essential step in the management of these patients is drainage of the common duct; the rapid improvement shown by Case 1 after operation in the presence of renal and hepatic failure emphasizes this point. The case histories reported illustrate the difficulties in making the decision to operate in a desperately ill patient, and in retrospect this decision was unduly delayed in our patients . Based upon our own and reported experience with this condition, our present conclusion is that, once the diagnosis of acute suppurative cholangitis has been
made, the immediate treatment should be to institute resuscitative treatment based on restoration of the circulatory state by adequate, prompt administration of intravenous fluids and of the appropriate antibiotics: as an adjunct to the latter, prompt blood culture is essential. If there is no response to this treatment, urgent drainage of the biliary tree is indicated as the only hope of saving life. If the condition is further complicated by renal failure, dialysis should be performed to control the failure before operation is undertaken, but this should not be unduly delayed. Similarly, if the patient responds well to the initial resuscitative treatment, surgical relief of the obstruction should follow promptly. The dangers of delay are well illustrated by Case 3 , who developed a second attack of septicaemia. Hitherto, the only method of obtaining drainage of the biliary tract has been by open operation, a procedure which carries a considerable mortality in this condition. However there are now two alternative methods for decompressing the biliary tree. First, the successful use of percutaneous transhepatic cholangial drainage in the emergency management of patients with ascending suppurative cholangitis has already been reported (Takada et al., 1974, 1976). Secondly, endoscopic sphincterotomy (Cotton et al., 1976) may also be of value when obstruction is due to impacted stones at the lower end of the common bile duct. Both these procedures have obvious attractions in these seriously ill patients and should carry a lower mortality than emergency operation. One final point of interest in the management of these cases is that in none of our patients was the skin or subcutaneous tissue sutured at operation because of the very high risk of wound infection. All wounds healed by second intention, without septic complications, resulting in very satisfactory scars. Acknowledgements For permission to report these case histories we are grateful to Dr J . D. N. Nabarro, Dr 5. Wedgewood and D r P. A. J. Ball, under whose care these patients were initially admitted to the Middlesex Hospital. We are also indebted to D r J. D . H. Slater, who was responsible for the dialysis, and the many other members of staff who collaborated in the care of these desperately ill patients. We also thank Messrs Smith, Kline & French for the gift of cimetidine used in the treatment of Cuse 1.
References and HEALEY P, I. M. (1963) Spherocytic hemolytic anaemia and acute cholangitis caused by Clostridium welchii. N . Engl. J. Med. 268, 1070-1072. BISMUTH H., KUNTZIGER H. and CORLETTE M. B. (1975) Cholangitis with acute renal failure: priorities in therapeutics. Ann. Surg. 181, 880-887. CLANCY M. I. and O’BRIAN s. (1975) Fatal Clostridium welchii septicaemia following acute cholecystitis. Br. J. Surg. 62, 5 18-51 9. COTTON P. B., CHAPMAN M., WHITESIDE c. G . et al. (1976) Duodenoscopic papillotomy and gallstone removal. Br. J . Surg. 63, 709-714. DOW R. w. and LINDENAUER s. M. (1969) Acute obstructive suppurative cholangitis. Ann. Surg. 169, 272-276. ELLIOTT-SMITH M. and ELLIS H. (1957) Clostridium welchii infection following cholecystectomy. Lancet 2 , 723. GLEN F. and MOODY F. G. (1961) Acute obstructive suppurative cholangitis. Surg. Gynecol. Obstct. 113, 265-273. GORDON-TAYLOR G. and WHITBY L. E. H. (1930) A bacteriological study of fifty cases of cholecystectomy with special reference to anaerobic infections. Br. J. Surg. 18, 78-83. BENNETT J. M.
Gallstone disease and WHITBY L. E. H. (1932) The incidence of anaerobic infections in the gall-bladder. Br. J. Surg. 19, 61 9-621. HINCHEY E. J . and COUPER c. E. (1969) Acute obstructive suppurative cholangitis. Am. J . Surg. 117,62-68. PYRTEK L. J. and BARTUS s. H. (1962) Clostridiurrt welrhii infection complicating biliary tract surgery. N. Engl. J. Med. 266,689-693. REYNOLDS B. M. and DARGAN E. L. (1958) Acute obstructive cholangitis. Ann. Surg. 150,299-303. ROGERS L. (1903) Biliary abscesses of the liver: with operation. Br. Med. J . 2, 706-707. SAHARIA P. c. and CAMERON J. L. (1976) Clinical management of acute cholangitis. Surg. Gynecol. Obsret. 142, 369-372. SCOTT A. J. (1971) Bacteria and diseases of the biliary tract. Gut 12. 487-492. CORDON-TAYLOR G.
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s. et al. (1976) Percutaneous transhepatic cholangial drainage: direct approach under fluoroscopic control. J. Surg. Oncol. 8, 83-97. TAKADA T., HANYU F., MIKOSHIBA u. et al. (1974) Severe cholangitis causing numerous cyst-like hepatic abscesses. Inr. Surg. 59, 180-182. THOMAS c. C. jun., NICHOLSON C. P. and OWEN J . (1971) Effectiveness of choledochoduodenostomy and transduodenal sphincterotomy in the treatment of benign obstruction of the common duct. Ann. Surg. 173, 845-846. WILLIAMS R. and DAWSON J. L. (1969) The management of ascending cholangitis. Proc. R . Soc. Med. 62, 243-245. TAKADA T., HANYU F., KOBAYSHI
Paper accepted 17.8.1977.
Gallstone disease presenting as septicaemic shock R . G. F A B E R , S. Z. IBRAHIM. D. M. THOMAS, G. P. J. BEYNON A N D L. P. LE QUESNE* SUMMARY
Three patients are described who were admitted to hospital with septicaemic shock due to gallstones, but in none of whom had the presence of gallstones been diagnosed previously. All 3 had positive blood cultures, Clostridium welchii being isolated in one patient (in another patient this organism was isolated from the bile). Two patients had renal failure requiring dialysis. All 3 patients survived. The management of this serious presentation of gallstones, hitherto poorly described in British literature, is discussed. T H Eassociation between gallstones and biliary tract infection has been recognized for many years (Rogers, 1903). In a bacteriological study of 50 consecutive cholecystectomy specimens nearly 50 years ago, organisms were cultured from the fluid contents of the gallbladder in 34 cases and from the wall of the gallbladder in 36 cases (Gordon-Taylor and Whitby, 1930). More recently, septic complications, including septicaemia, developing after removal of stones from the common bile duct have become well recognized (Thomas et al., 1971) and it is now appreciated that the bile is infected in about 75 per cent of patients with stones in the common duct (Scott, 1971). However, it is not so clearly recognized that gallstone disease may present as septicaemic shock in patients not previously diagnosed as having gallstones. Three examples of this serious complication of gallstones are presented here. Case reports Case 1 : Mr. B. L., aged 62, was admitted to the medical wards as an emergency on 1 March 1976 complaining of upper abdominal pain, nausea, vomiting and jaundice. His illness had started 5 days previously with moderate upper abdominal pain which was intermittent in nature, but with a constant ache. Two days later his urine had become dark and he had developed jaundice. About 2 weeks before the onset of his illness he had had a transient episode of severe upper abdominal pain. Diabetes had been diagnosed in 1961 and remained well controlled with phenformin. In 1971 he underwent transurethral resection of the prostate, which was followed by an episode of deep venous thrombosis and a pulmonary embolus. In 1973 he suffered a myocardial infarct followed by a further pulmonary embolus. On examination he was grossly obese, extremely drowsy and deeply jaundiced. His temperature was 38.2 "C, pulse 120/min, respiratory rate 27/min and blood pressure 120/80 mmHg, and there was tenderness in the right hypochondrium. Full haematological and biochemical (Vickers's profile) blood screening investigations were performed, and the following results were of note: haemoglobin 14.7 g/dl; WBC 21 x 10g/l; bilirubin 212 pmol/l; alkaline phosphatase 195 i.u./l; aspartate aminotransferase (AST) 150 i.u./l; urea 6.6 mmol/l; blood sugar 8.0 mmol/l; arterial Po, 46 mmHg; Pco, 27 mmHg; p H 7.74. A provisional diagnosis of obstructive jaundice due to gallstones with ascending cholangitis was made, and blood cultures were taken. Septrin was started and to combat incipient hepatic failure he was given neomycin by mouth, put on a high carbohydrate oral intake containing no protein and was given intravenous fluids. Over the next 24 h, despite a fluid intake of 5 1, he only passed 250 ml of urine, and his blood urea rose to 27,7 mmolll.
The patient was transferred to the intensive therapy unit and was seen in consultation by the surgical and gastroenterological teams. At this time the diagnosis was still thought to be ascending cholangitis secondary to obstructive jaundice, and the advisability of early operation was discussed; it was considered that he was too ill for operation (see below) and conservative treatment was continued. Over the next 12 h he received a further 5 1 of intravenous crystaloid solution and intravenous frusemide, but his urine output remained low and his blood urea rose to 40 mmol/l; peritoneal dialysis was therefore started. At this time his bilirubin was 500 pmol/l, alkaline phosphatase 324 i.u./l, AST 35 i.u./l and albumin 25 g/l. The initial blood culture was reported as growing Klebsiella spp. and Escherichia coli and so gentamicin was started. Dialysis was continued for 8 days, during which time his urine output slowly improved and his blood urea fell to 12 mmol/l. However, he remained mentally confused and uncommunicative and developed an hepatic 'flap'; his bilirubin was 423 pmol/l, alkaline phosphatase 250 i.u./l and AST 37 i.u./l. In view of this and his failure to improve, the possibility that his condition was due not to ascending chloecystitis but rather to an acute fulminating hepatitis was considered. In order to resolve this problem, endoscopic retrograde cholangiography (ERCP) was performed o n 10 March. A large filling defect in the common bile duct with a dilated biliary tree proximal to the obstruction was demonstrated (Fig. I). Operation was performed the same day through Kocher's incision. A large stone was found lying partly in the gallbladder and partly in the common bile duct, having ulcerated through from Hartmann's pouch into the latter (Fig.2). This calculus was removed and a T tube was placed in the common bile duct through this fistula. The bile was purulent and on culture grew KIebsieZIu spp. The deep layers of the wound were closed leaving open the skin and subcutaneous tissue. Following operation the patient's clinical condition improved dramatically, and over the next 2 weeks renal and hepatic function slowly returned to normal. However, on 26 and 31 March he passed two melaena stools which necessitated an 1I-unit blood transfusion. Upper gastrointestinal endoscopy was performed on 31 March and a large superficial duodenal ulcer, containing fresh blood clot, was seen. Cimetidine (200 mg t.i.d. and 400 mg nocte) was administered orally and n o further bleeding occurred. By 8 April he was well with normal liver function tests. The wound had healed satisfactorily, but blood urea remained 11 mmol/l. T tube cholangiography showed no calculi in the common bile duct so the T tube was removed and the fistulous tract healed promptly. The patient left hospital o n 10 April and thereafter made a steady recovery. By 26 April his blood urea was normal, but the creatinine clearance was only 46 ml/min. Gastroduodenoscopy was repeated twice over the next 2 months and on the second occasion the duodenal ulcer was seen to have healed and the cimetidine was stopped. On review in June 1977, he reported a recurrence of epigastric pain. Further endoscopy revealed that the duodenal ulcer had recurred, but renewed treatment with cimetidine gave relief of symptoms. Case 2: Mrs S . B., aged 81, was admitted to the medical wards as an emergency on 11 August 1976 with a history of nausea, epigastric pain and feeling generally unwell for 24 h. She had had two loose bowel actions before admission. On examination she was mildly jaundiced, her temperature was 38.5 "C, pulse 90/min, respiratory rate 2l/min and blood pressure 180/90 mmHg. There was tenderness, but no guarding, in the epigastrium and right hypochondrium.
* Department of Surgical Studies, Th e Middlesex Hospital and Medical School, London.
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Fig. 1. Case 1. Endoscopic retrograde cholangiography. The
common hepatic duct is grossly dilated by a single calculus. A faint outline of the collapsed common bile duct, distal to the stone can be seen.
v\
CHD
gallstone
Fig. 2. Case 1. Findings at operation. Obstruction of the common hepatic duct by a solitary stone, which had eroded through Hartmann's pouch. C HD Common hepatic duct; CBD, common bile duct.
Full haematological and biochemical screening was performed and the following investigations noted: haemoglobin 11.2 g/dl; WBC 14.3 x 10s/l; bilirubin 78 p n o l / l ; alkaline phosphatase 132 i.u./l; AST 63 i.u./l; urea 5.2 mmol/l; exchangeable glucose 6.2 mmol/l. A diagnosis of probable gallstones causing obstructive jaundice was made. A blood culture was taken and a course of ampicillin started. The next day she had a rigor, her temperature rose to 40 "C, pulse to 150/min and her blood pressure fell to 80/50 mmHg. Another blood culture was taken, she was treated with intravenous fluids and oxygen, and gentamicin was added to the ampicillin; her condition rapidly improved over the next few hours. The first blood culture grew Klebsiellu spp. and Escherichia coli, both resistant to ampicillin but sensitive to gentamicin, while the second blood culture grew KIebsielIa spp. only. Over the next few days serum bilirubin, alkaline phosphatase and AST all returned to normal values. A double-dose oral cholecystogram was performed o n 24 August and no opacification of the gallbladder was seen, but a dilated and partially obstructed common bile duct was outlined. Th e patient was seen in consultation by the surgical team on 4 September and laparotomy was perfomed on 6 September via a Kocher's incision. A very small fihrosed gallbladder full of stones was found and further calculi were palpated in the common bile duct; the latter were confirmed on operative cholangiography. Cholecystectomy and exploration of the bile duct were performed and the common bile duct was cleared of stones and biliary sludge; the choledochotomy incision was converted into a choledochoduodenostomy without T tube drainage. The wound was closed, leaving open the skin and subcutaneous tissue. Bile from the common bile duct was cultured and grew E. coli, Streptococcus faecalis and CIostridium welchii. The postoperative course was complicated first by right lower lobe pneumonia and secondly by a leak from the choledochoduodenal anastomosis. The former responded to physiotherapy, ampicillin and flucloxacillin and the latter to wound drainage and intravenous feeding. Following this she made a slow, but uneventful recovery. The open wound was treated with daily dressings and healed by second intention with minimal inflammation. On outpatient review after 3 months she was well with normal biochemical blood values and a hairline abdominal scar. Case 3 : Mrs J. C., aged 64, was admitted as an emergency on 7 August 1976 directly from the casualty department to the intensive therapy unit under the care of the physicians. She was extremely ill and unable to give a history of her condition. On examination she was grossly obese, drowsy and incoherent, not jaundiced but centrally cyanosed; her temperature was 40 "C, pulse 140/min, blood pressure 170/90 mmHg and respiratory rate 35/min. There were coarse crepitations at the right base of the chest and the abdomen was generally soft with definite right upper quadrant tenderness. A history was later obtained from a relative. The patient had developed right-sided abdominal pain 5 days previously and had vomited o n several occasions. Twenty-four hours before admission she had become confused and disorientated. In the past she had had recurrent attacks of right hypochondria1 pain which she attributed to gallstones, but for which she had never attended hospital. In 1973 she had been admitted to the Middlesex Hospital with bronchopneumonia. Full haematological and biochemical screening were performed and the following investigations noted: haemoglobin 13.1 g/dl; WBC 6 . 2 lOs/l; ~ bilirubin 34 pmol/l; alkaline phosphatase 53 i.u./l; urea 8.8 mmol/l; amylase 160 units/l; exchangeable glucose 4.5 mmol/l; arterial Po, 42 mmHg; Pco? 29 mmHg; p H 7.52. A diagnosis of septicaemia secondary to right lower lobe pneumonia or empyema of the gallbladder was made. A blood culture was taken and she was initially treated with intravenous fluids, oxygen and broad spectrum antibiotic cover, consisting of penicillin, ampicillin and gentamicin. Despite this treatment her condition further deteriorated, she developed hypotension and anuria and there was n o change in the arterial gas figures. Her WBC rose to 20 x 10e/l and alkaline phosphatase to 153 i.u./l, but serum amlyase remained normal (200 units/l).
Gallstone disease Twelve hours after admission an endotracheal tube was passed and positive pressure ventilation started. The next day she was seen in consultation by the surgical team and septicaemia secondary to empyema of the gallbIadder was considered the most likely diagnosis; however, she was considered to be too ill to withstand laparotomy (see below) and conservative management was continued. Over the next 3 days, despite an apparently adequate fluid intake, her urine output remained sparse and her blood urea rose to 31.5 mmol/l and creatinine clearance fell to 5 ml/min; peritoneal dialysis was started. The initial blood cultures grew Closfridium wefchii and Escherichiu coli, both sensitive to gentamicin, which was continued and the ampicillin stopped. The patient responded slowly but well to this treatment and after 2 weeks was transferred from the intensive therapy unit to the main ward; however, within 1 2 h she had another episode of septicaemic shock. On this occasion she responded rapidly to intravenous fluid replacement and the reintroduction of antibiotics; E. cofi was again grown from repeat blood culture, but n o C. welchii on this occasion. Operation was performed on 31 August through a transverse subcostal incision. An empyema of the gallbladder was found, but a n operative cholangiogram showed a normal biliary tree with no calculi in the common bile duct and rapid flow into the duodenum. The pancreas was apparently normal with no evidence of previous acute o r chronic inflammation. Cholecystectomy was performed and the deep layers of the wound were closed leaving open the skin and subcutaneous tissue. Culture of the pus from the gallbladder grew E. coli, Proteus spp. and Bacteroides spp. Postoperatively, despite mechanical ventilation for the first 24 h, she developed bilateral lower lobe collapse and a urinary tract infection; both responded well to treatment. By the time of discharge her blood urea was 2.8 mmol/l and creatinine clearance 60 ml/min. The open wound was treated with daily dressings and healed by second intention. At the latest outpatient review 9 months after the operation, she was well with normal biochemical blood values and a hairline abdominal scar.
Discussion The first description of patients with gallstones presenting with rigors and jaundice appeared in the British Medical Journal more than 70 years ago (Rogers, 1903). The syndrome of acute obstructive suppurative cholangitis, characterized by a diagnostic pentad of abdominal pain, fever, jaundice, mental confusion and shock, was first clearly described by Reynolds and Dargan (1958), who emphasized that the aetiological factor is infected bile under pressure. The condition occurs mainly in the elderly and has a mortality of over 60 per cent (Dow and Lindenauer, 1969). Despite this syndrome being well described in American publications, apart from a discussion at the Royal Society of Medicine (Williams and Dawson, 1969), a Medlars offline computer search has failed to find another reference in the British literature. The present communication has been prompted by the admission, during a 6-month period, of 3 patients presenting with septicaemia secondary to previously undiagnosed gallstones; their case histories illustrate well the main difficultiesin the diagnosis and treatment of this difficult condition. All 3 patients presented the diagnostic pentad, with variants, of acute obstructive suppurative cholangitis : abdominal pain was present in two and the third comatose patient had guarding in the right upper quadrant of the abdomen; all had a fever; all had mental confusion-one being admitted in coma and another lapsing into coma; all developed hypotensive shock; 1 patient was jaundiced on admission and the other 2 developed jaundice shortly afterwards. Two of the patients developed acute renal
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failure, a well-recognized and serious complication of this condition (Bismuth et aI., 1975). There are two points of difference between the 3 patients reported in this paper and those of the American series. First, the one common factor that stands out in the histories of these patients is that in none of them had a diagnosis of cholelithiasis been made before their admission to hospital. Furthermore, and in retrospect, only 1 of the 3 patients admitted to previous episodes of abdominal pain before the onset of the presenting illness. This is in contrast to American reports in which the majority of patients had had previous biliary disease or previous biliary surgery (Dow and Lindenauer, 1969; Hinchey and Couper, 1969; Saharia and Cameron, 1976). Secondly, only 2 of our patients had calculi in the common bile duct, while the third patient had a narrow common duct, demonstrably free of calculi on operative cholangiogram, but an obstructed cystic duct. A11 the American papers on this subject (Reynolds and Dargan, 1958; Glen and Moody, 1961; Dow and Lindenauer, 1969; Hinchey and Couper, 1969; Saharia and Cameron, 1976) emphasize that the clinical picture of abdominal pain, fever, jaundice, mental confusion and shock is produced by complete obstruction of the common bile duct by calculi, strictures or carcinoma in the presence of severe infection, resulting in acute suppurative cholangitis ;our patient, however, illustrates the fact that an indistinguishable condition can be caused by obstruction to the cystic duct. Organisms were cultured from the blood and the bile of all our patients. I n Cases 1 and 3, 2 organisms were found in the blood, while only 1 organism was found in Case 2. On the other hand, only 1 organism was cultured from the bile of both Case 2 and Case 3. This discrepancy is hardly surprising, as on the one hand only the virulent organisms will be expected to pass from the biliary tract into the blood, and on the other hand antibiotics had been given to all patients after culturing the blood but before culturing the bile. Of particular interest was the recovery of Clostridium welchii from the blood of one patient and the bile of another. Despite Gordon-Taylor and Whitby (1930, 1932) finding C. welchii in 16 out of the 100 gallbladders that they studied, reports of biliary tract infection with this organism are extremely rare. Pyrtek and Bartus (1962), Bennett and Healey (19631, Dow and Lindenauer (1969) and Clancy and O’Brian (1975) each report a single case of C. welchii septicaemia secondary to biliary tract infection; 2 of these 4 patients died before operation. This organism can also rarely cause infective complications after biliary tract surgery; Pyrtek and Bartus (1962) described 2 fatal cases of septicaemia, while ElliottSmith and Ellis (1957) reported a patient who developed gas gangrene after cholecystectomy and survived. The management of patients with acute obstructive suppurative cholangitis gives rise to considerable difficulties. Of prime importance is the establishment of the diagnosis, which is that much more difficult if there is n o history of previous biliary disease, as was the case in the patients reported here. Glen and Moody (1961) emphasized that the condition must be suspected when any combination of the diagnostic pentad was present and that often one or other of the signs or symptoms did not develop until late in the
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progress of the disease. They particularly emphasized first, that severe jaundice is often absent, as was initially the situation in our Cases 2 and 3, and secondly, that there may be considerable difficulty in differentiating the condition from severe acute hepatitis. This was certainly the problem in Case 1, and it was only finally resolved by ERCP. With the increasing availability of this examination and grey scale ultrasound, it is now possible to determine, with a high degree of accuracy and with minimum disturbance to the patient, whether or not the duct is obstructed. These techniques may well prove to be of great value in differentiating between acute hepatic necrosis and acute obstructive suppurative cholangitis, and could with advantage have been used at an early stage in our patients. Once the diagnosis has been established, the emphasis in the management of these patients has recently slightly changed. In 1958 Reynolds and Dargan stated that the presence of fever, jaundice and right upper quadrant pain is an indication for urgent operation, and that operation becomes mandatory if either mental confusion or shock supersede. The only one of their patients treated conservatively died, while 3 out of 4 patients having urgent operation survived. Hinchey and Couper (1969) operated on 6 out of 8 patients in shock who failed to respond to emergency resuscitation and 4 of these 6 survived; 2 patients in whom conservative measures were continued died before being considered fit for operation. On the other hand, of their 11 patients who improved with emergency resuscitation, only 3 remained well enough to await planned operation, while 8 again deteriorated and required emergency surgery from which 4 died. However, in the reports by the authors mentioned above, neither the risk of the jaundiced patient developing renal failure, nor the treatment of the patient with established renal failure, was considered. Williams and Dawson (1969) recommended that, in order to prevent acute renal failure, it was first necessary to maintain an adequate circulating volume and high flow of dilute urine with adequate transfusion and diuretics, and also to give massive doses of antibiotics. Emergency operation could then be undertaken if there was no improvement in the patient’s condition over the next 24-36 h. Bismuth et al. (1975) reported on 3 patients with acute renal failure complicating acute suppurative cholangitis who were operated upon as an emergency; all 3 died. In the light of this experience they managed their next 15 patients fist by treating the shock by resuscitation and antibiotics, secondly by performing dialysis and finally by operating when the patient’s general condition was, at least to some extent, stabilized; 12 of 15 patients so managed survived. There is no doubt that the essential step in the management of these patients is drainage of the common duct; the rapid improvement shown by Case 1 after operation in the presence of renal and hepatic failure emphasizes this point. The case histories reported illustrate the difficulties in making the decision to operate in a desperately ill patient, and in retrospect this decision was unduly delayed in our patients . Based upon our own and reported experience with this condition, our present conclusion is that, once the diagnosis of acute suppurative cholangitis has been
made, the immediate treatment should be to institute resuscitative treatment based on restoration of the circulatory state by adequate, prompt administration of intravenous fluids and of the appropriate antibiotics: as an adjunct to the latter, prompt blood culture is essential. If there is no response to this treatment, urgent drainage of the biliary tree is indicated as the only hope of saving life. If the condition is further complicated by renal failure, dialysis should be performed to control the failure before operation is undertaken, but this should not be unduly delayed. Similarly, if the patient responds well to the initial resuscitative treatment, surgical relief of the obstruction should follow promptly. The dangers of delay are well illustrated by Case 3 , who developed a second attack of septicaemia. Hitherto, the only method of obtaining drainage of the biliary tract has been by open operation, a procedure which carries a considerable mortality in this condition. However there are now two alternative methods for decompressing the biliary tree. First, the successful use of percutaneous transhepatic cholangial drainage in the emergency management of patients with ascending suppurative cholangitis has already been reported (Takada et al., 1974, 1976). Secondly, endoscopic sphincterotomy (Cotton et al., 1976) may also be of value when obstruction is due to impacted stones at the lower end of the common bile duct. Both these procedures have obvious attractions in these seriously ill patients and should carry a lower mortality than emergency operation. One final point of interest in the management of these cases is that in none of our patients was the skin or subcutaneous tissue sutured at operation because of the very high risk of wound infection. All wounds healed by second intention, without septic complications, resulting in very satisfactory scars. Acknowledgements For permission to report these case histories we are grateful to Dr J . D. N. Nabarro, Dr 5. Wedgewood and D r P. A. J. Ball, under whose care these patients were initially admitted to the Middlesex Hospital. We are also indebted to D r J. D . H. Slater, who was responsible for the dialysis, and the many other members of staff who collaborated in the care of these desperately ill patients. We also thank Messrs Smith, Kline & French for the gift of cimetidine used in the treatment of Cuse 1.
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Gallstone disease and WHITBY L. E. H. (1932) The incidence of anaerobic infections in the gall-bladder. Br. J. Surg. 19, 61 9-621. HINCHEY E. J . and COUPER c. E. (1969) Acute obstructive suppurative cholangitis. Am. J . Surg. 117,62-68. PYRTEK L. J. and BARTUS s. H. (1962) Clostridiurrt welrhii infection complicating biliary tract surgery. N. Engl. J. Med. 266,689-693. REYNOLDS B. M. and DARGAN E. L. (1958) Acute obstructive cholangitis. Ann. Surg. 150,299-303. ROGERS L. (1903) Biliary abscesses of the liver: with operation. Br. Med. J . 2, 706-707. SAHARIA P. c. and CAMERON J. L. (1976) Clinical management of acute cholangitis. Surg. Gynecol. Obsret. 142, 369-372. SCOTT A. J. (1971) Bacteria and diseases of the biliary tract. Gut 12. 487-492. CORDON-TAYLOR G.
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s. et al. (1976) Percutaneous transhepatic cholangial drainage: direct approach under fluoroscopic control. J. Surg. Oncol. 8, 83-97. TAKADA T., HANYU F., MIKOSHIBA u. et al. (1974) Severe cholangitis causing numerous cyst-like hepatic abscesses. Inr. Surg. 59, 180-182. THOMAS c. C. jun., NICHOLSON C. P. and OWEN J . (1971) Effectiveness of choledochoduodenostomy and transduodenal sphincterotomy in the treatment of benign obstruction of the common duct. Ann. Surg. 173, 845-846. WILLIAMS R. and DAWSON J. L. (1969) The management of ascending cholangitis. Proc. R . Soc. Med. 62, 243-245. TAKADA T., HANYU F., KOBAYSHI
Paper accepted 17.8.1977.
