Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Should stress ulcer prophylaxis be abandoned for any ICU patient?
- Jean-Charles Preiser (9 November 2000)
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Ranitidine and Gastrointestinal Bleeding in ITU
- Tim Dexter, Stephen Drage (22 November 2000)
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Ranitidine Ineffective for SUP or Uncertain?
- Lee Ann Thayer (19 December 2000)
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Important negative results !
- Tony Rahman (4 January 2001)
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Jean-Charles Preiser, Clinical director ICU - Clinique Reine Fabiola, 73, avenue du Centenaire, B6061 Montignies-sur-Sambre, Belgium
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Sir, I read with a major interest the meta-analysis published by Messori and coworkers in the 4th November issue of BMJ (1). Even though the data presented clearly confirm the absence of usefulness of a systematic prevention of stress ulcer prophylaxis by H2-receptor antagonists or sucralfate, an important issue is left unanswered by this study and by the meta-analysis of Cook et al (2). Indeed, several critically ill patients receive stress ulcer prophylaxis for specific reasons including brain injury (trauma, surgery, hemorrhage), steroïd therapy or coagulation abnormalities. Does the available literature support the appropriateness of stress ulcer prophylaxis to these patients? In other words, should the intensivists keep the prescription of stress ulcer prophylaxis for selected subgroups of patients? If the available literature does not resolve this issue, should the further trials suggested by Messori et al stratify the groups according to the patients' condition? References 1. Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. Br Med J 2000;321:1103-1106. 2. Cook D, Reeve BK, Guyatt GH, Heyland DK, Griffith LE, Buckingham L et al. Stress ulcer prophylaxis in critically ill patients: resolving discordant meta-analyses. JAMA 1996;275:308-314. |
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Tim Dexter, Consultant/ Specialist Registrar in Anaesthetics Wycombe Hospital, Queen Alexandra Road, High Wycombe, Stephen Drage
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Sir - Intensive care has always been a difficult area for research. Firstly, patients are rarely able give informed consent, this places increased pressure on researchers and ethics committees to ensure patients are not exposed to risk, making placebo controlled trials difficult even when the standard treatment has no good evidence for effect. Secondly, the patient population is highly variable and often small in number making comparison and recruitment of sufficient numbers for statistical analysis difficult. This is born out by the meta-analysis by Messori et al(1) in the 4th November issue of the BMJ, where meta-analysis B assessing the effectiveness of sucralfate consisted of one paper! We also have problems with the outcome used in meta-analysis A, comparing ranitidine to placebo. In 4 out of 5 papers the outcome was acute, rapid blood loss as seen by melaena, red blood per nasogastric tube or haemo-dynamic changes. These are the signs of an acutely bleeding vessel within an ulcer, as is often seen in patients presenting to A&E with haematemesis. The usual pathology in ITU is entirely different, with the presence of multiple small ulcers, stress ulcers, causing continual, low grade blood loss, breakdown of mucosal defences and increased need for transfusion. Very few of these ulcers go on to erode gastric vessels and cause dramatic blood loss. However, between 75 and 100% of patients with critical illness develop these ulcers within 3 days of intensive care admission(2), even in the absence of low perfusion states. For these reasons we would dispute the implication from Messori’s paper that this occult blood loss is not “clinically important”. Interestingly, it was Burgess’s paper (3), the only one that stood a chance of assessing ranitidine’s effectiveness against this pathology, which suggested a benefit with ranitidine. The argument for stress ulcer prophylaxis has now moved on even from sucralfate with the renewed emphasis on early enteral feeding including low rate enteral feed instillation even in patients with high nasogastric aspirates and ileus (4). Finally, there is the issue of prevention of aspiration using pharmacological agents. Endotracheal intubation or tracheostomy are far from absolute guardians of the airway and leakage of material passed the balloon of the airway device is a real risk, both in ITU and anaesthesia. Ranitidine has been shown to reduce gastric acidity during high risk periods and its use should still be considered on ITU during airway manipulation. Overall, it is our practice to use stress ulcer prophylaxis on all patients on ITU, which agent will depend on the individual patient. We find it very difficult to criticise any of our colleagues’ choices in this contentious area. 1. Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ 2000; 321: 1103-6. 2. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106(4): 562-7. 3. Burgess P, Larson GM, Davidson P, Brown M, Metz CA. Effect of ranitidine on intragastric pH and stress related upper gastrointestinal bleeding in patients with severe head injury. Dig Dis Sci 1995; 40: 645- 50. 4. Pingleton SK, Hadzima SK. Enteral alimentation and gastrointestinal bleeding in mechanically ventilated patients. Crit Care Med 1983; 11(1):13-6. Tim Dexter Stephen Drage Wycombe Hospital, Wycombe HP11 2TT |
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Lee Ann Thayer, Clinical Specialist, Drug Utilization Yale-New Haven Hospital
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I think it is important to point out again the last line in the article. "Our main conclusion is that there are insufficient data on effectiveness to be able to conclude anything one way or the other." A drug information news letter reporting this article seemed somewhat misleading as stating Usual Medications Ineffective for patients in ICUs.. This study seems only to confirm what was already known. It is very uncertain what benefit if any the use of SUP with ranitidine or sucralfate provides. |
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Tony Rahman, SpR ICU St. Thomas's Hospital, London, UK
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The study by Messori et al. attempts by way of performing metanalyses, to assess or determine the effectiveness of either ranitidine or sucralfate in the prevention of stress ulceration. It also performs further metanalysis to assess these treatments and their risk of nosocomial pneumonia. Ranitidine and sucralfate are widely used to prevent stress ulceration. Ranitidine is a histamine-2 receptor antagonist and acts by regulation of HCL production at the parietal cells in the stomach. Sucralfate is an aluminium hydroxide sulphated sucrose complex which, coats the gastric surface, anion binding to positively charged proteins. This may prevent diffusion of hydrogen ions and also stimulates mucus and bicarbonate production and prostaglandin secretion. The metanalysis requires the search for randomised trials, this was performed by searching the key words (stress, pneumonia, ranitidine, sucralfate, randomised controlled trial/random) below in the following medical literature databases; Medline 1966-2000, Iowa-IDIS system, Drugdex. Each trial is assessed using a scoring system based on the testing of variables which is termed the “Methodological Quality”; This means that the selection of each appropriate randomised study is rated and given a score based on the following selection criteria; patient selection, patient characteristics, randomisation, blinding, definition of pneumonia and or bleeding. If the studies are examined rigorously there is marked variability in the methodological quality of the studies that have been chosen and it is clear from the data that the numbers in each of the randomised controls examined are very small. The paper aims to provide five separate meta-analyses: •A- ranitidine v’s placebo - rate of bleeding
Rate of bleeding
Incidence of nosocomial pneumonia
This paper has highlighted a very important point, that little that we do in terms of the use of prevention of stress ulceration is evidence based. There is no conclusive data from any one study or from this metanalysis, however, a natural conclusion suggests the need for a randomised controlled blinded study. Meta-analyses are dependant upon trials with large numbers of patients, few studies examined here have large numbers some have between 20-40 patients in each group. The trials themselves were not powered to demonstrate any significant difference between groups and if one examines these studies carefully the end points are very different. The accuracy of “methodological quality score” must also be questioned as many of the studies had disparate entry criteria, variable dosing of drugs, alternate routes of administration and differing criteria of bleeding and pneumonia. The most important factor, however, in terms of stress ulceration prevention or occurrence is that few of the studies take into account disease stratification and other factors such as; enteral/parenteral nutrition, presence of renal impairment and or failure, infection and disseminated intravascular coagulopathy and thrombocytopaenia. So in conclusion; Overview of trials of ranitidine and sucralfate against placebo shows poor effectiveness. From the single trial of sucralfate no conclusions can be drawn and trials of ranitidine show no difference compared to placebo. Metanalysis of the nosocomial pneumonia incidence reveals a significant result. However, this also must be interpreted with caution as this analysis contains a large subset of patients from one trial. |
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