Continuous Intravenous Infusion of Omeprazole in Elderly Patients with Peptic Ulcer Bleeding

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1 Continuous Intravenous Infusion of Omeprazole in Elderly Patients with Peptic Ulcer Bleeding Results of a Placebo-Controlled Multicenter Study G. HASSELGREN, T. LIND, L. LUNDELL, E. AADLAND, P. EFSKIND, A. FALK, A. HYLTANDER, c. SODERLUND, s. ERIKSSON & P. FERNSTROM Depts. of Surgery, Sahlgrenska University Hospital, and Dept. of Surgery, Ostra sjukhuset, Goteborg; Karnsjukhuset, Skovde; Sodersjukhuset, Stockholm; and Astra Hassle AB, Molndal; Sweden, and Depts. of Medicine, Aker sykehus, Oslo, and Sentralsykehuset, Fredrikstad, Norway Hasselgren G, Lind T, Lundell L, Aadland E, Efskind P, Falk A, Hyltander A, Soderlund C, Eriksson S, Fernstrom P. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand J Gastroenterol 1997;32:32%333. Background: Does profound acid inhibition by continuous infusion of omeprazole for 72 h reduce further bleeding in elderly patients with peptic ulcer bleeding (PUB)? Methods: Three hundred and thirty-three patients 260 years old with PUB were randomized to omeprazole (80 mgi8 mgih) or placebo as continuous infusion for 72 h. From day 4 to 21 all patients received 20 mg omeprazole orally once daily. Results: When evaluated on day 3, the primary variable overall outcome (based on an ordinal ranking scale; see Study variables) (P = 0.017) and the secondary variables, surgery (P = 0.003), degree (P = 0.004) and duration of bleeding (P = 0.003) all favored the omeprazole group. Blood transfusions, need for endoscopic treatment, and mortality were not statistically different. On follow-up, by day 21, the mortality in the group initially receiving intravenous omeprazole was 6.9%, while the intravenous placebo group showed an extremely low mortality, 0.6%. Conclusion: Three days infusion of omeprazole improved overall outcome and reduced need for intervention in PUB patients. Key words: Blood transfusion; elderly patients; endoscopic treatment; omeprazole; overall outcome; peptic ulcer bleeding; surgery Tore Lind, M.D., Ph.D., Dept. of Surgery, Karnsjukhuset, S Skovde, Sweden (fax: ( ) Peptic ulcer bleeding (PUB) is a serious and potentially lifethreatening condition. Even though endoscopic treatment has halved the rebleeding rate (1,2) and today constitutes the cornerstone of modern therapy, severe hemorrhage from peptic ulcerations continues to expose patients to a substantial risk. Therefore, there is still a clinical need for further therapeutic improvements. Intravenous H2-receptor antagonists (H2RAs) have seen widespread use in patients with upper gastrointestinal bleeding (UGIB). However, whereas a meta-analysis of published studies with H&4s in UGIB (3) showed trends towards reductions in rebleeding rate and need for surgery, it was concluded that the data were inadequate to establish the usefulness of these pharmacologic agents. This also seems to apply when H2RAs are given as a continuous infusion (4). Results from studies using intravenous injection of omeprazole in patients with UGIB have been inconsistent (56). The rationale for the use of acid-inhibitory drugs in PUB has been based on in vitro data showing that hemostatic mechanisms are highly ph-dependent and that coagulation and stable platelet aggregation do not occur at ph levels below 6 (7-9). Furthermore, pepsin exerts its maximal proteolytic effect at ph 2, gradually decreasing to negligible activity at ph above 5 (10, 11). It is therefore reasonable to assume that for an acid-inhibitory therapy to improve outcome in PUB, it must maintain an intragastric ph level of approximately 6 or above. Pharmacodynamic studies using various intravenous doses of H2RAs have shown that they cannot fulfill this criterion (12, 13). Omeprazole markedly reduces 24-h intragastric acidity (14), and a continuous intravenous infusion (80 mg as a bolus infusion over min, followed by 8 mg/h) can maintain intragastric ph at 6 (15, 16). Consequently, the following hypothesis was formulated: continuous intravenous infusion of omeprazole during a 3-day course in elderly patients with PUB will improve overall outcome when evaluated on day 3. PATIENTS AND METHODS Patients The patients were recruited from 20 centers in Sweden and

2 Omeprazole in Peptic Ulcer Bleeding centers in Norway. All patients admitted with melena or hematemesis (starting less than 48 h before admission) were endoscoped within 12 h of admission. Inclusion criteria were age 260 years, presence of a peptic ulcer in the stomach or duodenum at endoscopy classified as Forrest Ia (spurting arterial bleeding), Ib (oozing bleeding), IIa (visible vessel), or IIb (black base or clot) (17). Exclusion criteria were upper gastrointestinal malignancy; deficient hemostasis (that is, prothrombin <40% or platelet count <lo0 x lo9); severe renal, hepatic, or cardiac failure making study compliance questionable; ciinically significant abnormalities in the laboratory screen, or receipt of anticoagulation therapy within 5 days of admission. The study was performed in accordance with the Declaration of Helsinki and with the approval of local ethical committees and national health authorities. Written informed consent was obtained from all patients before inclusion. Methods The study was double-blind, randomized, and placebocontrolled in design. Included patients were randomized separately for each center and within blocks of two consecutive patients, Medical history and current medication were recorded, and at the index endoscopy, endoscopic treatment (for example, sclerotherapy or heater probe) was only allowed in patients with spurting ulcer bleeding (Forrest la). Patients received either 80 mg omeprazole or placebo (40 mg mannitol, identical to omeprazole in appearance and at this dose without known therapeutic effects). The study medication was administered over 20 to 30 min as a bolus infusion immediately followed by a continuous infusion of omeprazole, 8 mgh, or placebo, for 72 h. After the infusion period, all patients in both groups were given 20 mg oral omeprazole once daily until day 21. In the following text, however, the two treatment groups are referred to on the basis of the infused substance, omeprazole or placebo. All personnel involved in the study were unaware of treatment allocation. Patients were hospitalized and cared for in accordance with local practice, and decisions regarding clinical management were made by the local study physician. Antiulcer medication, tranexamic acid, and non-steroidal anti-inflammatory drugs were not permitted. Patients were fasted during the first 24 h, and use of a nasogastric tube was optional. Every 12 h during the infusion period the patients were evaluated by the study physician with regard to 1) number of blood units transfused, 2) occurrence (presence of blood in nasogastric tube, hematemesis, or blood per rectum) and 3) degree of bleeding during the preceding 12 h, classified as none, mild, or severe (defined as not affecting or affecting the hemodynamic stability of the patient), 4) need for intervention with surgery or endoscopic treatment, 5) blood pressure, heart rate, and laboratory variables, and, finally, 6) any adverse events (including questioning) were recorded. After detailed and comprehensive discussions by the principal investigators and trialists, it was recommended to transfuse blood if two of the following three criteria were fulfilled: 1) hemoglobin <lo0 s/l, 2) systolic blood pressure <lo0 mm Hg, 3) tachycardia >lo0 beats/min (that is, hemodynamically unstable). Endoscopic intervention or surgery was performed to control bleeding-that is, if a patient was hemodynamically unstable (see above) despite having received 4 units of blood over 24 h or more than 8 units since admission. Endoscopic treatment was always recommended before surgery if possible. Patients requiring endoscopic or surgical therapy reached a study end point, and study medication was withdrawn. Subsequent treatment was decided by the physician responsible. Blood transfused after this point was not included in the efficacy analyses, since they were considered less likely to be influenced by study medication. Furthermore, since bleeding before inclusion cannot be influenced by treatment, the number of blood units prescribed at randomization to compensate for pre-entry blood loss was not included in the analysis. A follow-up was performed on all patients on day 21 with regard to rebleeding during the oral treatment period, need for surgical or endoscopic treatment, and mortality. Study variables The efficacy of the infusion therapy was evaluated after day 3 (that is, 72 h). An ordinal scale variable was defined, to consider the overall outcome, as no other individual variable can accurately mirror all of the various outcomes that are possible. The primary variables were the number of blood transfusions given and the ordinal scale variable. The latter was created by using a 5-point scale ranking the outcome from worst to best as follows: 5) death, 4) surgery, 3) endoscopic treatment, 2) >3 units of blood transfused, 1) 0-3 units of blood transfused. Secondary variables were a) worst degree of bleeding over the 72 h (see above), b) duration of bleeding (number of 12-h periods with bleeding), c) need for surgery, d) need for endoscopic treatment, e) mortality, and f) treatment failure that was defined as death or need for surgery or endoscopic treatment during the 72-h infusion period. All study variables were defined before study start. Statistics The sample size was based on the test power requirements for the number of blood transfusions. The aim was to attain a test power of 80% and a risk of a type-1 error of < 5% (twosided test). With the assumptions that 1) the standard deviation (s) is the same for omeprazole and placebo and that the s for placebo is 1.2 times the placebo mean, and 2) that omeprazole reduces the need for blood transfusions by onethird, the total sample size was calculated to be 400 patients. The primary variables and other quantitative and ordinal variables were analyzed with a Wilcoxon rank sum test, whereas binary variables were evaluated with a chi-square

3 ~~ ~ 330 G. Hasselgren et al. test or Fisher s exact test if the assumptions required for a chisquare test were not satisfied. Confidence intervals (CI) for proportions and means were based on the standard normal approximation. P values are calculated using multiple logistic regression analyses. A subgroup analysis was performed on those patients who had an ongoing oozing bleeding when they entered the study (Forrest Ib). These patients represent an additional challenge to a pharmaceutical agent, as they require not only stabilization but also facilitation of coagulation. A multiple logistic regression analysis of mortality, surgery, and endoscopic treatment was also performed, to adjust for possible differences at base line which might otherwise distort the result. Before breaking the treatment code, all classifications and decisions on exclusion of data from the analysis were made and documented. Safety monitoring The study was conducted by a Steering Committee and an independent, external statistician was responsible for sequentially monitoring mortality. Only in the case of safety concerns was the Steering Committee to be informed. At the third of four planned analyses of mortality, when 333 patients had been randomized, a lower mortality was observed in the placebo group. An external expert group reviewed the data and recommended that the Steering Committee discontinue further inclusion of patients while a thorough investigation was performed. The Steering Committee decided later not to resume inclusion as the included number of patients was sufficient to detect a true effect on the primary variable blood transfusions of 37%, compared with the planned 33% if all 400 patients had been included. Adverse events observed, spontaneously reported, or reported in response to active questioning were recorded during the study. A serious adverse event was defined before study start as an adverse event that constitutes a definite hazard or handicap to the patient. RESULTS A total of 333 patients were randomized; 322 (159 omeprazole and 163 placebo) were included in the intention-to-treat analysis (4 patients received unknown study drug, 4 did not receive any study medication at all, and 3 did not fulfill inclusion criteria). Since there were only minor differences between the perprotocol and the intention-to-treat analyses, only results from the latter are given. Demographic and base-line characteristics of the patients (Tables I and 11) in the two groups were similar with the following exceptions: there were fewer patients with a hemoglobin level lower than 90g/l in the placebo group (29%) than in the omeprazole group (43%), and previous Table I. Base-line patient characteristics. Number of patients if not otherwise stated Age, years (mean (s)) Sex (ME) Smokers Patients in shock Mean systolic blood pressure mm Hg (4 Mean heart rate, beats/min (s) Mean hemoglobin, g/l (s) Patients with hemoglobin 590 gfl Patients with melena Patients with hematemesis Mean ulcer size at entry, mm (s) Forrest classification Ia t Ib IIa IIb Ulcer site (gastric/duodenal) Omeprazole, n = (8.2) 106* 53 90: (26.4) 90 (16.5) 99 (23.8) (7.4) :71 * One patient was 59 years old. t Twenty received initial endoscopic treatment. Placebo, n = (7.4) : (29.0) 89 (17.8) 105 (26.1) (7.6) :73 ulcer history was commoner in the placebo group (56%) than in the omeprazole group (45%). Eficacy variables The ranking scale variable showed a significant difference (P = 0.017) in favor of omeprazole after the infusion period. The other primary variable, the mean number (s) of transfused blood units up to day 3, showed no significant difference between the study groups: 1.4 (1.6), and 1.6 (2.3), respectively. (Mean values, not corrected for the pre-entry blood loss, differed little from the above values: omeprazole, 1.9; placebo, 2.1.) The results for the secondary variables are given in Table 111. Need for surgery (P=0.003), degree of bleeding (P = 0.004), duration of bleeding (P = 0.003), and treatment failure (P=0.0009) were reduced in those patients who received omeprazole infusion, whereas the difference with regard to endoscopic treatment only reached numerical Table 11. Medical history in the two treatment groups. Number of patients Medical history factor No history of peptic ulcer Cardiovascular disease Myocardial infarction Cerebrovascular accident Malignancy Congestive heart failure Intake of non-steroid anti-inflammatory drugs Omeprazole Placebo

4 Omeprazole in Peptic Ulcer Bleeding 331 Table 111. Secondary efficacy variables, day 3. Number of patients (%) Omeprazole Placebo Variable (n = 159) (n = 163) P value None Mild Severe Duration of bleeding (mean no. of 12-h periods) Endoscopic treatment Surgery Mortality Treatment failure 95 (65.0) 39 (26.7) 12 (8.2) (3.1) 4 (2.5) l(0.6) 9 (6.2) 74 (49.7) 49 (32.9) 0.004* 26 (17.4) (6.7) (9.8) l(0.6) > (18.1) Table V. Serious adverse events, days 1-21, by outcome at follow-up (day 21). Number of patients Omeprazole Placebo Type of event Fatal Non-fatal Fatal Non-fatal Myocardial infarction Cardiac failure Cerebrovascular accident Pulmonary embolus GI hemorrhage Cancer Miscellaneous Total no difference (P = 0.12). Mortality after the infusion period was identical in the treatment groups (1 versus 1). The subgroup analysis in patients with ongoing oozing bleeding (Forrest Ib) comprised 41 patients in each treatment arm. The ranking scale variable in this subgroup significantly favored omeprazole (P = 0.01), whereas other variables showed numerical, but not statistically significant, differences (surgery, 1 versus 7; endoscopic treatment, 0 versus 2; and mean number of blood transfusions, 1.4 versus 2.1, in omeprazole and placebo-treated groups, respectively). FOllOW-Up There was no difference in the number of severe rebleedings between the groups during the follow-up period, when all patients received 20 mg omeprazole orally once daily. The cumulative number of patients who required surgery showed a persistent significant difference in favor of initial omeprazole therapy, 7 versus 17 (P = 0.016), whereas the difference with regard to endoscopic treatment remained non-significant. Mortality in the group initially receiving placebo was 0.6% (1 patient), and in the group initially receiving omeprazole 6.9% (11 patients) (P = 0.012) (Table IV). These patients were thus classified as having a fatal serious adverse event. However, there were fewer patients with non-fatal serious adverse events in the omeprazole group (13 patients) than in the placebo group (18 patients). Serious adverse events were mainly cardiovascular (Table V). There was no visual disturbances in the omeprazole group, whereas one patient in the placebo group experienced impaired vision. Non-serious Table IV. Results of the safety follow-up (days 1-21). Number of patients (%) Omeprazole Placebo Variable (n = 159) (n = 163) P value Rebleeding* 5 (3.1) 4 (2.5) >0.20 Endoscopic treatment 11 (6.9) 13 (8.0) >0.20 Surgery 7 (4.4) 17 (10.4) Mortality 11 (6.9) l(0.6) * Days4-21. adverse events were generally mild and evenly distributed between the treatment groups. DISCUSSION The present study shows that, in elderly patients with PUB, infusion with omeprazole during 3 days reduces bleeding duration and intensity and the need for surgery and improves overall outcome. The primary variable, overall ranking of outcome, showed a significantly better result in patients given omeprazole infusion (P = 0.017). This composite variable was chosen because it has the potential advantage of circumventing the problem of counteracting effects between different efficacy variables used, since our patients were always ranked on the basis of the worst outcome. The other primary variable, number of blood transfusions, showed a numerical, but statistically insignificant, difference in favor of omeprazole. This lack of statistical significance can, among other factors, be due to the large interindividual variation in number of blood units transfused, making this variable susceptible to influence of extreme outliers. The commonly used efficacy variable rebleeding was not used because, although it enables comparisons between studies, it may often be misleading. The definition of rebleeding may be equivocal in both quantitative and qualitative terms between studies. Omeprazole was also effective in the subgroup of patients with oozing bleeding. These observations may indicate a hemostatic effect also in patients with ongoing bleeding by maintaining intragastric ph at a high level. In contrast to many previous studies with acid-reducing agents, the present study reports consistent effects on bleeding-related variables with omeprazole infusion. A most likely explanation of this is that omeprazole, unlike the H2W, can maintain intragastric ph at the required level (15,16). Furthermore, intravenous omeprazole has been shown to be free of tachyphylaxis, which has previously been observed with high-dose ranitidine and can occur already within a day after initiating treatment (18, 19).

5 332 G. Hasselgren et al. The mortality in both the omeprazole group and the placebo group was low, 0.6%, at the end of the 3-day infusion period. After the subsequent follow-up period, during which both groups received 20 mg omeprazole daily, the mortality remained extremely low (0.6%) in the group initially treated with placebo infusion, whereas in patients who initially had received omeprazole infusion the mortality rate was 6.9%, a figure within the expected range. Mortality figures after PUB reported in the literature differ depending on various factors, such as the length of follow-up after the index bleeding. Short-term mortality figures (within 3 days) are infrequently reported. Instead, mortality rates are often reported without specification of the length of the follow-up period. Consequently, fatal outcome for patients aged 60 years or over, as in the present study, varies from 6% to 29% (2&24). Our figure after 3 weeks in the omeprazole group is thus at the lower limit of this range despite the unusually long follow-up period, and the placebo mortality rate of 0.6% is unexpectedly low. The placebo figure is particularly difficult to explain since in a parallel study of similar design (Schaffalitzky de Muckadell and colleagues in this issue) the mortality figures for the omeprazole and placebo groups are 6.2% and 5.9%, respectively. There are only a few studies (25,26) in the literature in which intravenous infusion of omeprazole has been used in patients with PUB. No deaths were reported in any of these studies, but the number of included patients was very small. In the present study the number of non-fatal serious adverse events is higher in the placebo group (Table V>. If omeprazole had had any detrimental effect, it would be likely to also influence both non-fatal and fatal serious adverse events. Imbalances in risk factors at base line may be one factor contributing to the mortality difference. There were fewer patients with hemoglobin concentration lower than 90 g/1 in the placebo group (29%) than in the orneprazole group (43%). However, other conventionally reported risk factors such as high age, shock, and endoscopic stigmata were well balanced. There was, however, an imbalance between the groups with regard to patients who had previously experienced a peptic ulcer: 92 patients in the placebo group versus 72 in the omeprazole group. It has been reported that patients with a history of a previous ulcer have a lower mortality risk (27,28). This is in accordance with our results, in which 10 of the 158 patients without a history of peptic ulcer died, compared with only 2 of the 164 patients who had previously had a peptic ulcer. Despite these various considerations, chance influence is still a possible explanation of the placebo mortality and a phenomenon that, in fact, has provided an explanation of other unexpected findings (29,30). The finding that an absence of a history of previous ulcer seems to be a risk factor for death raises an interesting question. Can a PUB in a patient with no history of previous ulcer be an expression of a severe and rapid decline in health status due to, for example, progressive heart failure, silent myocardial infarctions, or malignancies, which ultimately will lead to death? Hence, stopping the PUB may only marginally prolong survival. This hypothesis fits with our finding that the deaths were uniformly distributed over the follow-up period, and, as in other studies (31), most deaths were due to cardiovascular complications. Conventionally accepted risk factors for an unfavorable outcome are high age, shock, rebleeding, and endoscopic stigmata. Perhaps factors other than these determine the long-term outcome in these patients. Important clinical questions thus remain to be clarified. What are the factors determining the mortality in these high-risk patients, provided hemorrhage is adequately controlled? Can cardiovascular preventive measures be taken to minimize this risk? Should special care be taken in patients without a history of previous ulcer? We conclude that marked, stable, and sustained acid inhibition with intravenous infusion of omeprazole improves overall outcome as assessed by a ranking scale when evaluated on day 3. Furthermore, it reduces the duration and intensity of bleeding and the need for active intervention in elderly patients with PUB. ACKNOWLEDGEMENTS This study was sponsored by Astra Hassle AB. The results have been presented in part at the Digestive Disease Week in San Diego 1995 (abstract in Gastroenterology 1995;108:4, A150). REFERENCES 1. Blum A, Stoltzing H, Bauerfeind P. 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6 Omeprazole in Peptic Ulcer Bleeding Piper D, Fenton B. ph stability and activity curves of pepsin with special reference to their clinical importance. Gut 1965;6: Berstad A. A modified hemoglobin substrate method for the estimation of pepsin in gastric juice. Scand J Gastroenterol 1970;5: Merki HS, Witzel L, Kaufman D. Continuous intravenous infusions of famotidine maintain high intragastric ph in duodenal ulcer. Gut 1988;29: Cederberg C, Thompson ABR, Kirdeikis P, Kristersson C. Effect of continuous intravenous infusion of omeprazole on 24- hour intragastric ph in fasting DU-patients: comparison to repeated bolus doses of omeprazole or ranitidine. Gastroenterology 1992;102:A Lind T, Moore M, Olbe L. Intravenous omeprazole: effect on 24-hour intragastric ph in duodenal ulcer patients. Digestion 1986;34: Nielsen J, Strijm M, FernstrBm P. Effect of continuous infusion of omeprazole and ranitidine on intragastric acidity [abstract]. Scand J Gastroenterol 1990;25 Suppl 176: Cederberg C, Bergstrand R. Continuous intravenous-infusion of omeprazole effectively controls intragastric ph even during pentagastrin challenge. The World Congress of Gastroenterology, Sydney, Australia Forrest JA, Finlayson ND, Shearman DJ. Endoscopy in gastrointestinal bleeding. Lancet 1974;2: Merki HS, Wilder-Smith C. Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing? Gastroenterology 1994;106: Kiilerich S, Rannem T, Elsborg L. Effect of intravenous omeprazole and ranitidine on twenty-four-hour intragastric ph in patients with a history of duodenal ulcer. Digestion 1995;56: Serrano De Actro A. Hemorragia digestiva superior en pacientes mayores de 60 anos. Rev Soc Venezol Gastroenterol 1993;47: Pimp1 W, Boeckl 0, Waclawiczek HW, Heinerman M. Estimation of the mortality rate of patients with severe gastroduodenal hemorrhage with the aid of a new scoring system. Endoscopy 1987;19: Branicki FJ, Boey.I, Fok PJ. Bleeding gastric ulcer: a prospective evaluation of rebleeding and mortality. Aust NZ J Surg 1989;59: Branicki FJ, Boey J, Fok PJ. Bleeding duodenal ulcer. A DrosDective evaluation of risk factors for rebleeding - and death. knisurg 1990;211: Wheatlev KE, Snvman JET. Brearlev S. Keiehlev MR, Dykes PW. Mhtality in patients with bleeding peptic ulcer when those aged 60 or over are operated on early. Br Med J 1990;301: Goletti 0, Sidoti F, Lippolis PV, De Negri F, Cavina E. Omeprazole versus ranitidine plus somatostatin in the treatment of severe gastroduodenal bleeding: a prospective, randomized, controlled trial. Ital J Gastroenterol 1994;26: Kohler B, Benz C, Maier M, Knobloch M, Riemann JF. Gastric 27 ph-monitoring in patients with acute ulcer bleeding under continuous intravenous therapy with omeprazole (om) or ranitidine (ran). Gastroenterology 1994;106:A 109. Silverstein FE, Gilbert DA, Tedesco FJ, Buenger NK, Persing J. The national ASGE survey on upper gastrointestinal bleeding. 11. Clinical prognostic factors. Gastrointest Endosc 1981;27: Branicki FJ, Coleman SY, Fok PJ. Bleeding peptic ulcer: a prospective evaluation of risk factors for rebleeding and mortality. World J Surg 1990;14:262-9; discussion The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330: Hennekens CH, Buring JE, Peto R. Antioxidant vitaminsbenefits not yet proved [editorial]. N Engl J Med 1994;330: 108CL Friedman LS, Martin P. The problem of gastrointestinal bleeding. Gastroenterol Clin North Am 1993;22: APPENDIX The study group consisted of: Steering Committee: Erling Aadland (Oslo), Lars Lundell (Goteborg), Tore Lind (Skovde), Sven Eriksson (Goteborg), Paula Fernstrom (Goteborg), and Goran Hasselgren (Goteborg). Principal investigators and centers: Sweden: R. Jansson, Boris lasarett; S. Back, Lanssjukhuset, GAvle; S. Sjostedt, Huddinge sjukhus; H.-0. Hdkansson, Lanssjukhuset, Kalmar; G. Persson, Lanssjukhuset, Ryhov; H. Forsell, Centrallasarettet, Karlskrona; U. Knutson. Norrkopings lasarett; B. Hallerback, Norra Alvsborgs lanssjukhus; C. Lindholmer, Sabbatsbergs sjukhus; L. Lundell, Sahlgrenska sjukhuset; T. Lind, Karnsjukhuset, Skovde; J.-0. Svensson, Sundsvalls sjukhus; C. Soderlund, Sodersjukhuset, Stockholm; B. SandzCn, Regionsjukhuset, Umei; C. Rudberg, Vaster& lasarett; B. G. Peterson, Vaxjo lasarett; G. Agren, Regionssjukhuset, Orebro; A. Falk, Ostra sjukhuset, Goteborg; G. Edlund, Ostersunds lasarett; J. Jarnhult, Hoglandssjukhuset, Eksjo. Norway: R. Pedersen, Diakonissehjemmets sykehus, Bergen; R. Breckan, Nordland sentralsykehus; P. Efskind, Sentralsykehuset for Bstfold; E. Aadland, Aker sykehus; J. H. Solhaug, Diakonhjemmets sykehus; H. Myrvold, Regionsykehuset i Trondheim; S. Ritland, Buskerud Centralsykehus; T. Schulz, Aust-Agder sentralsjukehus; U. Fjflsne, Innherred sykehus. Received 9 July 1996 Accepted 18 November 1996