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The continuing challenge of early mortality in acute pancreatitis

Several years ago, a retrospective audit of death from acute pancreatitis in Scotland between 1984 and 1995 reported that the mortality rate had changed little overall compared with that noted in a previous audit, and that 50–60 per cent of deaths occurred within the first week of illness1. These deaths were usually a consequence of multiple organ dysfunction syndrome (MODS) and as many as 80 per cent of early deaths occurred within 72 h of admission. It is probable that few of these patients were transferred out of the admitting hospital. Two recent multicentre randomized clinical trials have failed to demonstrate improved mortality with the use of either octreotide or lexipafant2,3. Both drugs had shown promise in preclinical and phase II clinical trials but, as with previous studies of this disease, the early results were not reproduced in the definitive phase III trials. If further progress is to be made, there needs to be a better understanding of the natural history of this complex illness to identify where improvements in care are likely to result in a reduction in mortality rate. Despite claims that early deaths are now a rarity since improvements in critical care4, it is clear from the results of the multicentre trials that in reality many patients continue to die within the first 1–2 weeks after admission. In the largest UK study of acute pancreatitis to date, 283 patients with predicted severe acute pancreatitis were randomized to receive the platelet-activating antagonist lexipafant, or placebo5. Of the 35 deaths, 13 occurred within the first week of illness. Similarly, a multicentre randomized trial of octreotide in 302 patients with severe acute pancreatitis, which included patients recruited from units in Switzerland and Germany where early deaths are said to be rare, reported that almost 40 per cent of deaths occurred within 2 weeks of admission3. Following the UK lexipafant study5, which suggested a possible benefit of lexipafant in the subgroup of patients treated within 48 h of symptom onset, a major international study recruited a total of 1518 patients from centres in the USA and Europe. Patients with predicted severe acute pancreatitis were randomized to placebo or one of two doses of lexipafant. Entry was restricted to patients within 48 h of symptom onset and death was the primary endpoint. Although the study demonstrated no effect on survival or complication rate with lexipafant treatment at either dose, it represents a large database of information regarding the natural history of the disease. One hundred and thirty-one patients died of whom 64 (48·9 per cent) succumbed within 7 days of admission, providing what must be considered definitive evidence that early death from MODS remains a major contributory factor to overall mortality from acute pancreatitis. Further support for the crucial role of early MODS in determining outcome from acute pancreatitis comes from a study of 121 patients with acute pancreatitis in Glasgow6. In keeping with the above results, 46 per cent of patients died within the first week of illness, and all had MODS. Furthermore, five of seven patients who died at a later stage had MODS within the first week, suggesting that early MODS is not only responsible for the significant number of deaths within the first week, but also defines those patients most at risk of death from later septic complications related to pancreatic necrosis. Similar findings have been reported by the Ulm group7. In the continuing absence of specific therapy, patients with acute pancreatitis complicated by MODS represent a formidable clinical challenge. Often the challenge is to avoid futile or counterproductive intervention in the face of pressure from intensivists or patients’ relatives. It is now clear that surgical intervention within 2 weeks of symptom onset is associated with a prohibitive mortality rate. Later intervention should be restricted to patients with proven infected pancreatic necrosis, but the mortality rate remains high with any form of surgical intervention in those with continuing MODS. Recent efforts to improve outcome in this group have focused on minimally invasive approaches and there are even reports of successful non-operative management with percutaneous drainage and antibiotics. Whether these measures can reduce the mortality rate among patients with infected pancreatic necrosis and MODS is not yet clear; further studies are awaited. International and UK guidelines8,9 suggest that patients with severe acute pancreatitis should be managed within specialist units, but when such facilities do not exist it will continue to be the responsibility of all clinicians to understand the disease and its management. Even within specialist