Science review: The use of proton pump inhibitors for gastric acid suppression in critical illness

Stress-related mucosal damage (SRMD) is an erosive gastritis of unclear pathophysiology, which can occur rapidly after a severe insult such as trauma, surgery, sepsis or burns. SRMD is apparent in 75–100% of critically ill patients within 24 hours of admission to an intensive care unit (ICU) [1, 2]. Clinically important bleeding, defined as macroscopic bleeding resulting in hemodynamic instability or the need for red blood cell transfusion, occurs as a result of SRMD in about 3.5% of ICU patients who are mechanically ventilated for 48 hours or more [3]. Along with mechanical ventilation, risk factors for clinically important bleeding from SRMD include coagulopathy, shock, severe burns, a history of gastrointestinal (GI) ulceration, and multiple organ failure [4, 5]. Bleeding is associated with a 20–30% increase in absolute risk of mortality, and with an increase of 1–4 in relative risk [3]. In addition, it increases the demand on limited blood stocks and extends the length of ICU stay by about 4–8 days [3], thereby adding to overall management costs.

To avert these consequences, prophylaxis has been recommended for all ICU patients at high risk of SRMD [4, 5]. Stress ulcer prophylaxis is included in the care bundle for critically ill patients on mechanical ventilation recommended by the Institute for Healthcare Improvement and adopted by the National Health Service Modernization agency in the UK [6]. The Surviving Sepsis Campaign, an international initiative founded by the European Society of Intensive Care Medicine, the Society of Critical Care Medicine and the International Sepsis Forum, has also recommended that prophylaxis be a part of critical care [7]. Specific risk factors for SRMD include: mechanical ventilation (more than 48 hours), coagulopathy, neurosurgery, any kind of shock, respiratory failure, sepsis, polytrauma, tetraplegia, severe burns (more than 30%) and multiple organ failure [4, 5]. Patients in the ICU with a history of gastric or duodenal ulceration, or with liver cirrhosis or acute renal failure, may also benefit from prophylactic measures [4, 5].

Although there was once concern that prophylaxis for SRMD by means of gastric alkalinisation might independently increase the risk of nosocomial pneumonia, this seems to have been unfounded. No significant difference in the rate of pneumonia was seen among 1200 patients randomised to treatment with intravenous (IV) ranitidine (19.1%) or intragastric sucralfate (16.2%), the latter having little effect on gastric pH [8]. In practice, the risk of ventilator-associated pneumonia can be reduced in any event through the adoption of the fundamental measures included in the recommended care bundle, such as elevating the head of the patient's bed to 30° or higher [6].

Few clinical trials have investigated the use of a proton pump inhibitor (PPI) in the prophylaxis of stress ulcer in critically ill patients. In the absence of robust data allowing a systematic review, the points made in this paper are based on a narrative review of the literature concerning the pharmacology of the PPIs and their use in other indications. Literature searches were undertaken on PubMed Medline, using broad terms such as 'stress ulcer' 'critically ill', 'intensive care', 'gastric acid', 'proton pump inhibitor' and 'histamine antagonist', as well as specific drug names, to identify relevant, peer-reviewed papers. Manual searching was conducted within the reference lists of the primary papers identified, and among relevant conference abstracts.

The pharmacokinetic characteristics of a drug are particularly important in prescribing in critical care, because of the prevalence of organ dysfunction. In a prospective study to assess the incidence of organ dysfunction or failure among 1449 patients admitted to 40 ICUs, it was found that 40% had at least some degree of renal impairment, and 19% had some degree of hepatic impairment [9]. Among ICU patients with sepsis (one of the patient groups most at risk for SRMD), these proportions were even higher, with 60% of 1643 patients found to have renal impairment and 73% hepatic impairment [10]. However, it is possible that even these figures might not accurately reflect the high prevalence of renal and hepatic dysfunction among the ICU population. Thus, a pharmacokinetic profile that obviates the need for dose adjustment in patients with renal or hepatic dysfunction is an important characteristic for a drug used routinely in critical care. Also important is the potential for drug interactions, and this is dealt with below.

Prophylaxis for SRMD essentially involves either protecting the gastric mucosa or increasing the intragastric pH. The principal means of directly protecting the gastric mucosa is the use of sucralfate. Although the potential protective effect of enteral nutrition on the gastric mucosa means that it should be considered as an adjunct to pharmacological prophylaxis in appropriate cases, there is currently no evidence that enteral nutrition alone is sufficient to reduce the risk of stress-related bleeding [11].

Traditionally, the options for elevating intragastric pH have been antacids and histamine H2 receptor antagonists (H₂RAs) [5]. An early study in ICU patients demonstrated that maintaining the gastric pH above 3.5 significantly reduced the risk of upper gastrointestinal (GI) bleeding [12]. It is now generally accepted that the aim of acid suppression in the prophylaxis of SRMD is to maintain gastric pH above 4, a value at which there is a significant decrease in back-diffusible hydrogen ions and inactivation of pepsin [5]. The time taken to elevate pH is also important, because increasing the percentage of time at which pH is greater than 4 is associated with a lower incidence of lesions and subsequent haemorrhagic complications [13].

Sucralfate, the antacids, and the H₂RAs have each been shown to be effective in reducing the risk of overt and clinically significant bleeding compared with placebo [5, 14]. H₂RAs are currently the most widely used agents [15].

PPIs, such as esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole, are the most effective agents for suppressing gastric acidity; the superior efficacy of a PPI over an H₂RA has been demonstrated in patients with pepticulcer disease, gastroesophageal reflux disease, GI damage caused by non-steroidal anti-inflammatory drugs, and Zollinger–Ellison syndrome [51–58]. In general GI practice, PPIs are now considered the drug of choice in the management of most acid-related GI disorders [1]. No tachyphylactic phenomena have been reported in patients taking PPIs [13, 28], resulting in more predictable and sustained pH control than with H₂RAs [14, 29]. Adverse effects from PPIs are uncommon, but can include headaches, diarrhoea, nausea, constipation and pruritis [59–61].

The possibility of achieving a more profound and sustained acid suppression provides a rationale for the use of the PPIs in preference to H₂RAs in prophylaxis for SRMD, although few studies have evaluated PPIs specifically for stress ulcer prophylaxis. However, most such studies have demonstrated clearly that enteral or IV administration of a PPI elevates intragastric pH and maintains a pH of at least 4 [62–72]. Furthermore, comparative studies have shown PPIs to be more effective than H₂RAs for elevating intragastric pH [13, 28, 65, 66], and two have shown enteral omeprazole to be more effective than ranitidine in reducing the risk of SRMD-associated bleeding [64, 69].

As the most effective antisecretory agents, PPIs undoubtedly have the potential to benefit ICU patients at risk for SRMD. However, further clinical studies in the ICU setting are required to confirm this expectation. The link between the superior acid-suppressive efficacy of the PPIs and a reduced risk of SRMD versus H₂RAs has been demonstrated in only a limited number of clinical trials, and this evidence base needs to be extended. As far as their cost effectiveness is concerned, PPIs might be expected to offer potential cost savings compared with no treatment or treatment with traditional agents, through reducing the incidence of stress-related bleeding, costs associated with red cell transfusions and avoiding the consequent extension of ICU stay. In addition, both the option of continuous infusion of IV formulations and the lack of any need for pH monitoring with the PPIs have the potential to save costs associated with nursing time. However, it must be emphasised that the pharmacoeconomic data to confirm these potential benefits are not currently available, and given the cost differential between intravenous formulations of PPIs and H2RAs, studies to define the overall cost effectiveness of PPIs in critical care should be a further avenue of future research.

In a clinical situation in which most patients may have renal and/or hepatic dysfunction and require multiple drug treatment, differences between PPIs in terms of pharmacokinetics and the potential for drug interactions may be of significant importance. Pantoprazole can be used without dose adjustment in patients with organ dysfunction and has a low potential for drug interactions, and therefore among the currently available agents it may have advantages in stress ulcer prophylaxis for certain patient groups in the ICU setting.