The association between severe physiologic stress and gastric ulcers is well established. About three fourths of patients with severe head trauma may develop some form of gastrointestinal (GI) bleeding, ranging from Hematest-positive nasogastric lavage to life-threatening hemorrhage. The pathophysiologic basis for ulceration of the proximal GI tract following severe head trauma is unclear, but disturbances in several important areas of gastric physiology have been implicated. Given the high morbidity and mortality associated with GI bleeding in head trauma patients, prophylactic acid suppression has become standard practice. The evidence supporting this practice in patients with neurologic injury, however, is limited. The optimal prophylactic agent has not been established, and there is evidence favoring both histamine₂ (H₂)-receptor antagonists and proton pump inhibitors (PPIs). The following case demonstrates an atypical presentation of an upper GI bleed in a patient with head trauma.

Case Presentation

An 84-year-old woman with a history of atrial flutter and cardiac valve replacement, for which she took warfarin sodium (Coumadin), presented to our emergency department complaining of recent-onset nausea and vomiting, which had been followed by a significant change in her mental status. Two weeks ago, she had been evaluated in another emergency department after being involved in a motor vehicle accident. Her only complaint had been back pain; she denied headache, dizziness, or visual changes. Computed tomography (CT) scans of the head, abdomen, and pelvis taken at that time were unremarkable. The next day, she fell at home but did not seek medical attention.

During this visit to the emergency department, her vital signs were stable. Physical examination findings, with the exception of the altered mental status, were unremarkable. Her family reported no melena, and she was guaiac-negative by digital rectal examination. Laboratory test results included a hemoglobin of 15.3 g/dL and hematocrit of 44.2%. Her international normalized ratio at admission was 4.9; it was corrected with plasma to 0.9. The patient was intubated in the emergency department for airway protection. A noncontrast head CT scan revealed a large right-sided intraventricular hemorrhage, with mass effect and right-sided subarachnoid, subdural, and cortical bleeds. CT scanning of the abdomen and pelvis was unremarkable, except for suggesting a possible bleeding source in the stomach. Subsequent nasogastric lavage yielded copious amounts of coffee-ground material, but no fresh blood. Repeat testing showed a hemoglobin level of 9.8 g/dL and hematocrit of 28.9%.

Esophagogastroduodenoscopy done later that day in the intensive care unit revealed an ulcer on the posterior side of the lesser curvature of the gastric body. Several areas of active bleeding within the ulcer were noted, including an area of spurting blood (Figure 1). Complete hemostasis was achieved with bipolar electrocautery (Figure 2). The patient's hemoglobin and hematocrit values stabilized, and no further signs of GI bleeding were noted during the admission.

Figure 1—Retroflexed view of bleeding ulcer (black arrows). The endoscope is obscured by pooling blood (white arrow).	Figure 2—The same ulcer after treatment with bipolar electrocautery (black arrows). The endoscope is now visible (white arrow).

Discussion

Stress ulcers
The association between severe physiologic stress and gastric ulcers is well established. Compared with chronic peptic ulcers, stress ulcers are generally more superficial, have less surrounding inflammation, and do not cause significant pain.¹ They tend to be located in acid-secreting areas (the gastric fundus and body). Although the vast majority are not clinically relevant, stress ulcers can present with significant hemorrhage or even perforation. Approximately 5% to 25% of critically ill patients will develop overt bleeding in the upper GI tract, as manifested by hematemesis, coffee-ground emesis or gastric aspirate, and melena or hematochezia.^2,3 Fewer than 2% of critically ill patients have clinically relevant bleeding, characterized by transfusion requirements or hemodynamic compromise.⁴

Well-established, independent risk factors for stress ulcer bleeding include mechanical ventilation for more than 48 hours and coagulopathy.⁴ Other risk factors are burns, renal and/or hepatic failure, hypotension, sepsis, major surgery, lack of enteral nutrition, and head trauma (Table).^3,4 The presence of multiple risk factors increases the likelihood of significant GI bleeding.⁵

GI bleeding and head trauma
Severe head trauma generally refers to a traumatic event leading to brain injury, as from a fall, assault, or a motor vehicle accident. It may also refer to spontaneous subdural hematoma and hemorrhagic or thromboembolic stroke. Gastric or duodenal ulcers resulting from head trauma are known as Cushing's ulcers, named for the neurosurgeon Harvey Cushing, who in 1932 reported a high number of GI erosions, ulcers, and perforations in his postoperative brain tumor patients. In contrast, ulcers in patients with severe burn injuries, another condition associated with significant physiologic stress, are known as Curling's ulcers.

Up to three fourths of patients with severe head trauma may develop some form of GI bleeding, ranging from Hematest-positive nasogastric lavage to life-threatening hemorrhage. About 40% of head trauma patients develop bleeding within 48 hours, and 17% may ultimately develop clinically significant bleeding⁶; the rate is significantly lower (around 3%) among the subclass of stroke patients.⁷ The most important independent risk factor for GI bleeding among all head trauma patients is the extent of the injury.⁶

Risk factors for GI bleeding in patients with cerebral infarction include older age, preexisting disability, and increased stroke severity.⁷ Risk factors for GI bleeding in patients with acute intracerebral hemorrhage include larger hematomas (>40 cc), sepsis, and a Glasgow Coma Scale score less than 6.⁸ It does not appear that Helicobacter pylori infection increases the risk of stress ulceration.9 Most GI bleeding occurs within the first 2 weeks of admission, but later development has been documented.^7,8 GI bleeding in head trauma patients is associated with increased mortality.⁴

Although the pathophysiologic basis for ulceration of the proximal GI tract after severe head trauma is unclear, disturbances in 3 important areas of gastric physiology have been implicated:

• Excessive stimulation of parietal cells, which may lead to the hypersecretion of acid
• Delayed gastric emptying, which has been observed in more than 60% of head trauma patients,¹⁰ and which results in gastric stasis and poor tolerance of enteral feeding (this would ordinarily have a protective effect on the gastric mucosa)
• Compromised gastric mucosa integrity caused by decreased blood flow, as blood is shunted from the mucosa to the submucosa, with resulting ischemia that leads to free-radical formation, decreased mucous production, and diminished acid-buffering capacity, ultimately allowing acid to diffuse back into the mucosa.¹

Prophylactic acid suppression
Given the high morbidity and mortality associated with GI bleeding in head trauma patients, prophylactic acid suppression has become standard practice. One study found that 90% of respondents at level 1 trauma centers prescribe stress ulcer prophylaxis in head trauma cases.¹¹ Whether this is appropriate is a matter of some debate.

No studies have directly evaluated clinical outcomes in head trauma patients. A 1997 review of prophylaxis in neurosurgical intensive care patients showed poor pH control with intravenous (IV) H₂-receptor antagonists in these patients.¹² A small study that looked at clinical outcomes found no difference in ulcer complications among patients who received prophylaxis with either sucralfate (Carafate) or an H₂-receptor antagonist compared with those who did not.¹³ Support for prophylaxis in head trauma patients comes from studies of all critically ill patients, including those with neurologic injury.

It is known that a gastric pH of less than 6 may contribute to bleeding. When clinically significant stress ulcer bleeding has been confirmed, aggressive acid suppression with an IV H₂-receptor antagonist has been shown to reduce the rates of rebleeding, surgery, and mortality.¹⁴ Although this would support the efficacy of prophylaxis in critically ill patients, some placebo-controlled studies have shown no reductions in initial bleeding with omeprazole (Prilosec), ranitidine (Zantac), or sucralfate.^15,16

Although the medications currently used for prophylaxis are generally considered safe, the risks of drug interactions and possible nosocomial pneumonia,¹⁶ along with the considerable costs, argue for a more focused approach. In addition, there is little doubt that the frequency of GI bleeding has decreased significantly in the past 30 years, but the reasons for the improvement have not been established. GI prophylaxis has become widespread, but changes in patient care, such as improved oxygenation and ventilation, better blood pressure management, and early antimicrobial use, have likely contributed to decreased rates of bleeding as well. The use of enteral feeding (by standard oral intake or by enteric tube feedings) has also been shown to significantly reduce the incidence of stress ulceration.¹⁷

Should prophylaxis be pursued, which medication to use is unsettled. Again, the support for various medications comes from studies of critically ill patients that included head trauma patients. A 1998 meta-analysis showed that ranitidine was superior to sucralfate in preventing upper GI bleeding in mechanically ventilated patients.¹⁸ PPIs, however, have superior pH control and healing efficacy for ulcers and erosive esophagitis when compared with H₂-receptor antagonists, such as ranitidine and cimetidine.¹⁹ But whether PPIs reduce the rate of significant upper GI bleeding in critically ill patients is not yet clear.

The most recent study comparing omeprazole (via orogastric or nasogastric tube) and IV cimetidine demonstrated a reduction in overall bleeding with omeprazole (3.9% versus 5.5% with cimetidine), but not in clinically significant bleeding (4.5% versus 6.8%, respectively, which is not a significant difference).²⁰ This was despite better pH control with omeprazole. This may explain why a recent survey of critical care physicians showed that 64% chose H₂-receptor antagonists as first-line therapy, followed by PPIs (23%) and sucralfate (12%).²¹

H₂-receptor antagonists are less expensive than PPIs, although oral PPIs were shown in one study to be more cost-effective for stress ulcer prophylaxis.²² IV PPIs are arguably the drug of choice when gut motility is impaired, which is common in head trauma patients. Several PPIs are now available, but there are insufficient data to support the use of one over another in critically ill patients.

Conclusion

People with head trauma of any type are at high risk for gastric and duodenal ulcers, even weeks after the traumatic event. Therefore, treating physicians must maintain a high index of suspicion for stress ulcers, even when there are no clinical signs. There are limited data supporting the widespread use of prophylactic acid suppression in all head trauma patients. Medications such as PPIs, H₂-receptor antagonists, and sucralfate should only be used after the type and number of risk factors have been carefully assessed. Prophylaxis is indicated in intubated or coagulopathic patients. Concomitant burns, renal and/or hepatic failure, hypotension, sepsis, major surgery, or lack of enteral nutrition would also support the use of prophylaxis.

If prophylaxis is used, there are no strong data to support the use of PPIs over other forms of acid suppression. PPIs do have a greater impact on gastric physiology, but data demonstrating their clinical superiority are lacking and do not necessarily justify the added costs. Interventions such as aggressive blood pressure management, sepsis treatment, or initiating enteral nutrition may be as important as acid suppression in the prevention of GI bleeding.

If bleeding does occur in head trauma patients, its association with increased mortality warrants aggressive treatment, endoscopically or even surgically, followed by the use of a continuous infusion of a PPI. In our patient, the bleeding was stopped, she was given a PPI infusion, and there was no evidence of recurrent bleeding.

References

1. Spechler SJ. Peptic ulcer disease and its complications. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger & Fordtran’s Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 7th ed. Philadelphia, Pa: W.B. Saunders: 2002:747-781.
2. Fennerty MB. Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale for the therapeutic benefits of acid suppression. Crit Care Med. 2002;30(suppl):S351-S355.
3. Martindale RG. Contemporary strategies for the prevention of stress-related mucosal bleeding. Am J Health Syst Pharm. 2005; 62(suppl 2):S11-S17.
4. Cook DJ, Fuller HD, Guyatt GH, et al, for the Canadian Critical Care Trials Group. Risk factors for gastrointestinal bleeding in critically ill patients. N Engl J Med. 1994;330:377-381.
5. Metz CA, Livingston DH, Smith JS, et al, for the Ranitidine Head Injury Study Group. Impact of multiple risk-factors and ranitidine prophylaxis on the development of stress-related upper gastrointestinal bleeding: a prospective, multicenter, double-blind, randomized trial. Crit Care Med. 1993;21:1844-1849.
6. Kamada T, Fusamoto H, Kawano S, et al. Gastrointestinal bleeding following head injury: a clinical study of 433 cases. J Trauma. 1977;17: 44–47.
7. Davenport RJ, Dennis MS, Warlow CP. Gastrointestinal hemorrhage after acute stroke. Stroke. 1996;27:421-424.
8. Misra U, Kalita J, Pandey S, et al. Predictors of gastrointestinal bleeding in acute intracerebral haemorrhage. J Neurol Sci. 2003;208: 25-29.
9. Svoboda P, Kantorova I, Scheer P, et al. Helicobacter pylori is not a risk factor for stress ulcer bleeding in polytraumatized patients. Hepatogastroenterology. 2004;51:476-480.
10. Nguyen NQ, Ng MP, Chapman M, et al. The impact of admission diagnosis on gastric emptying in critically ill patients. Crit Care. 2007; 11:R16.
11. Barletta JF, Erstad BL, Fortune JB. Stress ulcer prophylaxis in trauma patients. Crit Care. 2002;6:526-530.
12. Lu WY, Rhoney DH, Boling WB, et al. A review of stress ulcer prophylaxis in the neurosurgical intensive care unit. Neurosurgery. 1997; 41:416-425.
13. Carroll TA, Morris K, Rawluk D. Gastroprotection in neurosurgery: the practice in Great Britain. Br J Neurosurg. 1997;11:39-42.
14. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA. 1996;275:308-314.
15. Kantorova I, Svoboda P, Scheer P, et al. Stress ulcer prophylaxis in critically ill patients: a randomized controlled trial. Hepatogastroenterology. 2004;51:757-761.
16. Kallet RH, Quinn TE. The gastrointestinal tract and ventilator-associated pneumonia. Respir Care. 2005;50:910-921.
17. Cook D, Heyland D, Griffith L, et al, for the Canadian Critical Care Trials Group. Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical ventilation. Crit Care Med. 1999;27:2812-2817.
18. Cook D, Guyatt G, Marshall J, et al, for the Canadian Critical Care Trials Group. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med. 1998;338:791-797.
19. Robinson M. pH, healing and symptom relief with rabeprazole treatment in acid-related disorders. Aliment Pharmacol Ther. 2004; 20(suppl 6):30-37.
20. Conrad SA, Gabrielli A, Margolis B, et al. Randomized, double-blind comparison of immediate-release omeprazole oral suspension versus intravenous cimetidine for the prevention of upper gastrointestinal bleeding in critically ill patients. Crit Care Med. 2005;33:760-765.
21. Daley RJ, Rebuck JA, Welage LS, et al. Prevention of stress ulceration: current trends in critical care. Crit Care Med. 2004;32:2008-2013.
22. Schupp KN, Schrand LM, Mutnick AH. A cost-effectiveness analysis of stress ulcer prophylaxis. Ann Pharmacother. 2003;37:631-635.