Stress Ulcer Prophylaxis in ICU

Dr Jose Chacko & Dr Swapnil Pawar

Stress-induced gastrointestinal ulcers are common among patients admitted to the intensive care unit (ICU). These ulcers impose significant morbidity and mortality, therefore, stress ulcer prophylaxis (SUP) is a common clinical practice among healthcare providers dealing with these critically-ill patients.  A survey of 58 ICUs in North America, mainly in university teaching hospitals, revealed that 84% of patients admitted to the ICUs received SUP, with proton pump inhibitors being the most commonly used agents. Whether SUP is effective and safe, or not, remains a topic of controversy. The data is still conflicting, and the provision of a simple answer is not feasible at the present time.
What is the pathophysiology of stress ulcers?
Stress ulcers are hypothesized to occur due to two main reasons: First, is impaired protective function of the gastric mucosa.  The stomach lining is formed by a mucous layer containing glycoprotein.  This layer acts as a physical barrier to the diffusion of hydrogen ions and traps bicarbonate. The gastric acid that comes into contact with the wall of the stomach is neutralized by bicarbonate. Reflux of bile salts, uremic toxins, etc, may lead to denudation of the gastric barrier. Furthermore, the synthesis of the decreased when there is poor gut perfusion caused by hypovolemia, shock, sepsis, or trauma.●The second mechanism of stress ulcer formation is due to the hypersecretion of acid. Gastrin-mediated stimulation of parietal cells may also cause increased secretion of acid.  This is particularly been demonstrated in patients with traumatic brain injury. However, this is a relatively less frequent mechanism in ICU patients; most critically ill patients have normal or reduced acid secretion. Critically ill patients is a unique population. In critically ill patients, activation of the sympathetic nervous system, increased catecholamine release and vasoconstriction, hypovolemia, decreased cardiac output, and release of proinflammatory cytokines result in splanchnic hypoperfusion[5]. Subsequently, this hypoperfusion leads to a number of deleterious effects including, ischemic damage to the gastric wall integrity, bicarbonate secretion, gastric hypomotility resulting in delayed emptying of acid, delayed mucosal healing, and reperfusion injury after the restoration of splanchnic circulation[5]. In addition, these effects make the gastric wall vulnerable to damage and ulceration by acid, even if it is within a “normal” pH range.

Why do we need stress ulcer prophylaxis in ICU patients?
Based on available evidence that suggests a reduced incidence of bleeding, stress ulcer prophylaxis (SUP) is generally administered to patients who may be at “high risk” of bleeding [32]. The question arises, as to what may constitute “high risk”. The general consensus, some of which is based entirely on expert opinion, is to consider the following as clinically “high risk: situations: 

• The presence of a bleeding diathesis based on platelet counts (< 50,000), INR (>1.5), and APTT values (> twice the control).  

• Mechanical ventilation for >48 hours is generally considered to be a risk factor; however, this is largely based on evidence from more than two decades ago, when early enteral nutrition. 
• within the first 24 h was not the standard of care among ventilated patients. 

• Previous history of ulceration or bleeding in the past year. 

• Patients with severe traumatic brain injury, spinal cord injury, or extensive burns are considered to be at high risk.

• Presence or suspicion of occult gastrointestinal bleeding.  

• Use of corticosteroid medication, especially in high doses. 

• Patients who are on non-steroidal anti-inflammatory or antiplatelet medication.

These recommendations are based on data from clinical trials that suggest a reduction in the incidence of upper GI bleed among these groups of patients with the use of SUP compared to those who are not administered prophylactic therapy. Most clinical trials have excluded patients with traumatic brain injury, spinal cord injuries, and extensive burns; however, clinical experience suggests that the risk of GI bleed may be high among these patients.  The endoscopic evaluation has revealed that more than 75% of critically ill patients develop gross gastric lesions within 72 h of admission to the intensive care unit (ICU), and almost 100% of them among extremely critical patients[2]. However, only a minority of these ulcerations bleed. Indeed, overt bleeding (manifested as bloody nasogastric aspirate, hematemesis, or melena), is reported in 20% of patients without stress ulcer prophylaxis (SUP), while < 5% develop clinically significant bleeding (CSB), defined as overt bleeding with transfusion, hemodynamic instability, and/or the need for intervention[2]. These lesions usually remain superficial and cause sub-epithelial hemorrhages[3]. The occurrence of significant bleeding usually indicates a breach of the submucosa. Acid suppressive therapies seemed to be reasonable options after showing efficacy in decreasing the rate of overt and clinically important bleeding

What are the different options available for stress ulcer prophylaxis?
Broadly, the options are 1. Proton pump inhibitors, 2. H2 receptor antagonists and 3. Sucralfate (not in common use). An enteral PPI is generally preferred in most critically ill patients who are considered at high risk of bleeding. The choice of PPI is based on randomized trials and meta-analyses that the superiority of PPIs compared to other agents. If the enteral route is not feasible, intravenous PPIs or H2 receptor antagonists may be used. There is no data that supports one PPI or H2 receptor antagonist over the other.  
What’s the evidence out there in either favour of or against the stress ulcer prophylaxis?
It has been hypothesized that stress ulcers may be more related to impaired mucosal blood flow and ischemia reperfusion-related injury; hence, in contrast to peptic ulceration, the evolution and propagation of such ulcers may be less related to gastric acidity. Changes in clinical practice, particularly with the increased emphasis on expeditious resuscitation and early commencement of enteral nutrition may have reduced the risk of stress ulceration and clinically important bleeding in the ICU. Perhaps we need to rethink and modify our approach with the use of acid suppressant medication in the light of more contemporaneous evidence.
Most of the current recommendations regarding stress ulcer prophylaxis are based on results from studies and risk factors identified several decades ago. Changes in clinical practice, particularly with the increased emphasis on expeditious resuscitation and early commencement of enteral nutrition may have reduced the risk of stress ulceration and clinically important bleeding in the ICU. Do we need to rethink and modify our approach with the use of acid suppressant medication in the light of more contemporaneous evidence? Particularly, does acid-suppression lead to harm? 
In a propensity-matched, cohort study of patients on mechanical ventilation for more than 24 hours of PPIs were associated with a significantly higher incidence of pneumonia and C. difficile infection compared to H₂ receptor antagonists (H₂RA). A recent meta-analysis of 23 observational also revealed a significantly high association of C. difficile infection with the use of PPIs. In a cohort study of 56,406 patients from Denmark, PPI use was associated with a significantly increased risk of cardiovascular death and readmission to hospital with myocardial infarction or stroke. There is also concern regarding thrombocytopenia in patients with upper gastrointestinal bleeding who are treated with continuous infusions of PPIs.
There is good evidence that early commencement of enteral nutrition is adequate stress ulcer prophylaxis in most critically ill patients. Two early randomized controlled studies compared PPIs with placebo in mechanically ventilated patients who were commenced on early enteral nutrition within the first 24–48 h. Both these studies did not reveal an increased incidence of upper GI bleed in the placebo arm. The SUP-ICU trial investigated the effects of intravenous pantoprazole in critically ill adult patients at high risk of gastrointestinal bleeding. There was no increase in 90 d mortality (the primary endpoint) in the control group. Clinically important bleeding was lower with pantoprazole compared to placebo (2.5 vs. 4%); the significance of this finding was not evaluated; there was no information on whether enteral nutrition had been established at baseline.
I agree..SUP-ICU study had several limitations, such as clinical (rather than endoscopic) diagnosis of stress ulcer, limited power to detect differences in the subgroup analyses, and more importantly, the study was powered to detect an absolute mortality reduction of 5%, which is quite high and generally implausible in critical patients[23]. Moreover, the incidence of clinically important bleeding in critically ill patients has been reported to be as low as 2.6% in a large multicenter prospective study, further confirming that absolute reduction of mortality of 5% is unreasonable.A recent Cochrane systematic review and meta-analysis that included 129 clinical studies, found that SUP interventions, compared to placebo or no intervention, in general, decreased the rate of clinically important bleeding, but did not have any effect in the risk of nosocomial pneumonia, all-cause mortality, length of ICU stay, or length of intubation[25]. It also concluded that PPIs were superior to H2 antagonists by decreasing CSB. You mentioned about feeding and ulcer prophylaxis. In a systematic review, Huang and associates analyzed if SUP provided any protections to patients receiving enteral feeding and found no statistically significant difference in the rate of gastrointestinal bleeding, mortality, C. difficile infection, length of ICU stay, and duration of mechanical ventilation[30]. Although the current level of evidence strongly suggests no improvement in all-cause mortality from SUP, some authors argued that cause-specific mortality reduction, rather than all-cause mortality reduction, should be considered when investigating preventive therapies[29]. this is because recent evidence-based improvements in critical care practice, such as optimal fluid resuscitation (improving splanchnic hypoperfusion)and early provision of enteral feeding, might have led to a substantial decrease in the rate of CSB, and questions the efficacy of SUP to further decrease the risk of GI bleeding. Therefore, we need a large scale clinical trial comparing cause-specific mortality and morbidity between a group with early enteral feeding plus SUP to controls with early enteral feeding alone will adequately address this clinical issue. In a nutshell, the current data is neither satisfactory to prove the efficacy of this preventive measure nor to deny it, and until further evidence becomes available, it is at the discretion of the healthcare provider whether to administer SUP to critical patients. But it may be safe to say that the routine use of stress ulcer prophylaxis may be unnecessary in patients who can be initiated on early enteral nutrition within the first 24–48 hours.

Summary – It may be safe to say that the routine use of stress ulcer prophylaxis may be unnecessary in patients who can be initiated on early enteral nutrition within the first 24–48 hours. However, for high-risk patients, PPI use should be considered on an individual basis. #personalisedmedicine

References: 

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