Stress Ulcer Prophylaxis Introduction

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Stress Ulcer Prophylaxis Introduction

  1. 1. Stress Ulcer Prophylaxis Introduction The development of “stress” ulceration in the upper gastrointestinal (GI) tract has been part of critical care folklore since the beginning. In 1842 Curling described a series of severe duodenal ulceration associated with burns; in 1832 Cushing reported ulcer disease associated with surgery and trauma. In the early years of intensive care, a strong association between severity of illness and the incidence of GI bleeds was established. Patients who had major bleeds had a high mortality rate, and, consequently, prophylaxis against this complication has become a central issue in ICU care. The objective of this tutorial is to give you an idea of the incidence, causes and risks associated with stress ulceration. We will also address the potential complications associated with prophylaxis. Learning Objectives To learn about the causes of stress ulceration To evaluate the incidence and cost effectiveness of prophylaxis, To explore the literature, addressing which agent is most effective at prophylaxis. To determine the complications associated with ulcer prophylaxis, Stress Ulcer Proph Stress Ulceration What is it? Why is it important?
  2. 2. Stress ulceration is a gastrointestinal mucosal injury related to critical illness. There is a relationship between GI bleeding and severity of disease. Likewise there is a strong relationship between bleeding and mortality Stress ulceration is a gastrointestinal mucosal injury related to critical illness. The ulceration may vary from diffuse superficial injuries to deep hemorrhaging ulcerations. There is a relationship between severity of disease and incidence of ulceration (1) The development of stress ulceration is not related to a history of peptic ulcer disease or Helicobacter infection. The cause, as we will see below, is multifactorial, and related to hypoperfusion and loss of host defenses. The development of clinically significant gastrointestinal ulceration can be devastating to the critically ill patient, representing, as it does, loss of physiological reserve and causing acute hypovolemia and end organ injury. The mortality rate associated with such bleeds is astonishingly high: varying between 48.5% (2) and 87.5% (3). Like all complications of critical illness, poor patient outcome following gastrointestinal bleeding may reflect underlying severity of illness, rather than importance of the disease process itself. A GI bleed may be a marker of the patient’s condition, rather like a low serum albumin. As the mortality rate for patients admitted to intensive care units is diminishing, so too is the incidence of life threatening gastrointestinal bleeds. Stress Ulceration What causes it? Ulceration is caused by ischemic injury to the gastric mucosa, loss of cytoprotectants and assault by gastric acid. The mucosa is injured and cannot repair itself sufficiently well to ward off aggressive factors
  3. 3. present in the gut lumen: these aggressors include gastric acid, bile and digestive enzymes. Mucosal blood flow is diminished, and there is an imbalance of demand for and supply of oxygen. The result is reduced production of cytoprotectant factors, such as prostaglandins, mucosal atrophy and increased permealility, loss of reparative capacity and loss of ability to neutralize acid (hydrogen ions). The mucosa is compromised by ischemia and attacked (mostly) by acid. It is injured, and, due to the presence of acid, cannot repair itself (hostile environment). The use of external agents to neutralize acid resolves this problem. Stress Ulceration Risk Factors The major risk factors are respiratory failure, coagulopathy, sepsis, hypotension and hepatic and renal failure. This has been extensively studied: based on the two studies by Cooke’s group (2;4) , we know that patients with respiratory failure and with coagulopathy have significantly higher incidences of bleeding than other patients. The other major risk factors were sepsis, liver failure, hypotension and renal failure. Overall, we know that there is a good relationship between severity of illness (as determined by, for example, Apache II scores) and incidence of ulceration. Moreover, the longer a patient is in ICU, the more likely they
  4. 4. are to have a GI bleed (5). Patients who are likely to have a number of these risk factors – burns patients for example (ventilated, hypotensive, coagulopathic), are more likely to have ulceration and bleeding. Stress Ulceration What is the Incidence? The incidence of stress ulceration is diminishing, probably reflecting better care before and during intensive care admission. In the 1970s and 80s, meta analyses have put the incidence of overt bleeding to be approximately 15% (6). The prevalence appears to be diminishing. Work by Cooke and colleagues ascribed the risk of overt bleeding to be 4.4% and clinically significant bleeding to be 1.5% (2)The incidence of clinically significant bleeding appears to be dependent on severity of illness and the type of patient population studied. For example, in Perioperative cardiac surgery patients the risk is approximately 0.4% (7). In stroke patients (who were not mechanically ventilated) the risk is 0.1% (8). There is a strong relationship between duration of mechanical ventilation, duration of intensive care stay, and incidence of ulceration: patients without coagulopathy and mechanical ventilation had an incidence of bleeding of 0.1% in the earlier Cooke study (2). Again, duration of care and mechanical ventilation represent markers of severity of illness rather than direct causes of ulceration. Stress Ulceration Treatment Ranitidine and sucralfate are the most effective agents. Ranitidine is associated with a lower incidence of clinically significant bleeding, sucralfate with a lower incidence of pneumonia. The prevention of stress ulceration has focused on reducing the quantity of luminal acid, using H2 receptor antagonists or antacids. The overall
  5. 5. objective of such therapy is to increase the pH of the stomach above 3.5. Multiple studies have compared H2 antagonists to sucralfate, a cytoprotectant agent, given as a gel which turns into a foam and coats the stomach on contact with acid. A large randomized controlled trial by Cooke and colleagues (4), remains the best source of data available. In this study, which compared the H2 antagonist ranitidine to sucralfate, the incidence of clinically important GI bleeding was 1.7% in the ranitidine group, compared with 3.8% in the sucralfate group (p=0.02). In absolute terms this represented 10 bleeds in 596 patients receiving ranitidine, and 23 bleeds in 604 patients receiving sucralfate; a very low overall incidence of bleeding. Interesting, a series of meta-analyses by Messori (9)failed to demonstrate a difference between both ranitidine and sucralfate as compared with placebo. There is little data available with regard to other anti-acid therapy, such as proton pump inhibitors, in the intensive care setting. Stress Ulceration Treatment Strategy Patients who do not have one of the six major risk factors do not require treatment. Patients in shock, sepsis, respiratory, hepatic or renal failure, or who have a coagulopathy, who are admitted to intensive care, should all be given stress ulcer prophylaxis. The agent of choice currently is probably ranitidine, based on best current evidence (although sucralfate remains a useful alternative). Patients involved in trauma probably also require prophylaxis, due to their propensity to develop the above problems. There is no evidence that prophylaxis of other patients, particularly chronic (non pulmonary) medical and perioperative surgical patients warrant the expense of prophylaxis. Stress Ulceration Treatment Complications Nosocomial pneumonia is the main
  6. 6. complication of ulcer prophylaxis treatment. Nosocomial pneumonia is common in critically ill patients, and remains the leading cause of death. It has been established that the use of anti-acid therapy promotes gastric colonization with pathogenic bacteria, and that aspiration of these bacteria may cause nosocomial pneumonia (10). The use, therefore, of ranitidine or proton pump inhibitors would be expected to be associated with a higher incidence of GI bleeds, and sucralfate would not. In the Cooke paper (4) there was a 19.1% incidence of nosocomial pneumonia in the ranitidine group compared with 16.2% in the sucralfate group – this was not statistically significant. In the Messori meta analysis (9), ranitidine significantly increased the rate of nosocomial pneumonia over sucralfate. Conversely, neither agent increased the nosocomial infection rate in meta analyses against placebo. The other side effects of these agents should not be forgotten: ranitidine can cause all kinds of mental status changes, particularly in elderly patients, and has been reported to cause arthralgia and other musculoskeletal pain. There is some evidence that giving H2 antagonists as a continuous infusion has greater efficacy (in terms of keeping gastric pH >3.5) than as intermittent boluses (11). Interestingly, in the Cooke study (4), randitidine was given as a bolus - 50mg every eight hours and gastric pH was not measured (as this would have unblinded the study). There have been no quality cost effectiveness analyses on stress ulcer prophylaxis to date. Stress Ulceration Key Points & References 1. Stress ulceration is a gastrointestinal mucosal injury related to critical illness. 2. There is a relationship between GI
  7. 7. bleeding and severity of disease. 3. Likewise there is a strong relationship between bleeding and mortality. 4. Ulceration is caused by ischemic injury to the gastric mucosa, loss of cytoprotectants and assault by gastric acid. 5. The major risk factors are respiratory failure, coagulopathy, sepsis, hypotension and hepatic and renal failure. 6. The incidence of stress ulceration is diminishing, probably reflecting better care before and during intensive care admission. 7. Ranitidine and sucralfate are the most effective agents. Ranitidine is associated with a lower incidence of clinically significant bleeding, sucralfate with a lower incidence of pneumonia. 8. Nosocomial pneumonia is the main complication of ulcer prophylaxis treatment. 9. Patients who do not have one of the six major risk factors do not require treatment. References (1) Pruitt BA, Jr., Foley FD, Moncrief JA. Curling's ulcer: a clinical-pathology study of 323 cases. Ann Surg 1970; 172(4):523-539. (2) Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994; 330(6):377-381. (3) Skillman JJ, Bushnell LS, Goldman H, Silen W. Respiratory failure, hypotension, sepsis, and jaundice. A clinical syndrome associated with lethal hemorrhage from acute stress ulceration of the stomach. Am J Surg 1969; 117(4):523-530. (4) Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R et al. A comparison of
  8. 8. sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998; 338(12):791-797. (5) Schuster DP, Rowley H, Feinstein S, McGue MK, Zuckerman GR. Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984; 76(4):623-630. (6) Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106(4):562-567. (7) Rosen HR, Vlahakes GJ, Rattner DW. Fulminant peptic ulcer disease in cardiac surgical patients: pathogenesis, prevention, and management. Crit Care Med 1992; 20(3):354-359. (8) Wijdicks EF, Fulgham JR, Batts KP. Gastrointestinal bleeding in stroke. Stroke 1994; 25(11):2146-2148. (9) 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(7269):1103-1106. (10) Cook DJ, Walter SD, Cook RJ, Griffith LE, Guyatt GH, Leasa D et al. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med 1998; 129(6):433-440. (11) Heiselman DE, Hulisz DT, Fricker R, Bredle DL, Black LD. Randomized comparison of gastric pH control with intermittent and continuous intravenous infusion of famotidine in ICU patients. Am J Gastroenterol 1995; 90(2):277-279.

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