Sociedade Portuguesa de Cuidados Intensivos guidelines for stress ulcer prophylaxis in the intensive care unit



# Introduction
Stress ulcer-related gastrointestinal bleeding is a potential complication of critical illness, for which the pathophysiology is complex. Systemic hemodynamic and local alterations result in gastric mucosal blood flow impairment with subsequent ischemic mucosal injury. However, the crucial factor for the development of ulceration and gastric bleeding is the high gastric intraluminal acidity, which is potentiated by fasting. [bib_ref] Pathophysiology of the upper gastrointestinal tract in the critically ill patient: rationale..., Fennerty [/bib_ref] This provides the rationale for the use of acid-suppressive drugs for pharmacological prophylaxis. [bib_ref] Prophylaxis against Upper Gastrointestinal Bleeding in Hospitalized Patients, Cook [/bib_ref] Endoscopically evident upper gastrointestinal lesions may be found in up to 90% of critically ill patients within 3 days of admission; [bib_ref] Prospective endoscopic study of stress erosions and ulcers in critically ill adult..., Eddleston [/bib_ref] less than 50% of patients will have occult bleeding (defined as guaiac-positive gastric aspirate or guaiac-positive stool) and approximately 5% [bib_ref] Stress-related mucosal damage. What to do or not to do, Goldin [/bib_ref] will have overt bleeding (defined as hematemesis, bloody gastric aspirate, melena, or hematochezia). However, this does not necessarily translate into clinically significant gastrointestinal bleeding (defined as overt bleeding in the presence of hypotension, tachycardia or orthostasis, a drop in hemoglobin of > 2g/dL, or the need for surgery), [bib_ref] Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses, Cook [/bib_ref] whose incidence seems to have decreased over the years. In studies published before 1999, the incidence of clinically significant gastrointestinal bleeding was between 2% and 6% in patients not receiving prophylaxis. [bib_ref] Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses, Cook [/bib_ref] However, in studies published since 2001, the incidence has been reported to range between 0.1% and 4% with or without prophylaxis, [bib_ref] Clinically significant gastrointestinal bleeding in critically ill patients with and without stressulcer..., Faisy [/bib_ref] which is related to better overall critical care, including the increased use of early enteral feeding. This, along with concerns related to the reported increasing frequency of infectious complications (nosocomial pneumonia and Clostridium difficile infections), [bib_ref] The risks of PPI therapy, Moayyedi [/bib_ref] has challenged the traditional cornerstone of pharmacological prophylaxis with agents that suppress gastric acid for stress ulcer prophylaxis. [bib_ref] Do we still need pharmacological stress ulcer prophylaxis at the ICU?, Buendgens [/bib_ref] This guideline from the Sociedade Portuguesa de Cuidados Intensivos aims to summarize current evidence and give clinical recommendations for the use of stress ulcer prophylaxis in the intensive care unit (ICU) to provide a standardized prescribing policy and avoid injudicious use.

# Methodology
A multidisciplinary task force was assembled. The task force comprised physicians (specialists in gastroenterology and intensive care medicine), nurses, pharmacists and economists with special interest and expertise in stress ulcer prophylaxis and/or evidence-based medicine. All members of the task force declared that no conflict of interest influenced the development of the guidelines.
Task force members participated in a discussion via e-mail, and six clinical questions were built for evidence evaluation. Each working member took charge of one clinical question and built search queries in the PICO (Participants, Interventions, Comparisons, and Outcomes) format. [bib_ref] GRADE guidelines: 2. Framing the question and deciding on important outcomes, Guyatt [/bib_ref] The availability of a Cochrane review [bib_ref] Interventions for preventing upper gastrointestinal bleeding in people admitted to intensive care..., Toews [/bib_ref] relevant to the clinical questions was confirmed by searching the Cochrane Database of Systematic Reviews. A further complementary literature search of PubMed  was performed. Trial data identified by the search strategies were considered to represent the best-quality evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system principles [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] was used to assess the quality of evidence from high to very low and to determine the strength of recommendations.
Finally, the task force determined the direction (for or against) and strength (strong or weak) of the recommendations using a two-round (self-administered questionnaire with no meetings among the participants) simple Delphi method. [bib_ref] Using and reporting the Delphi method for selecting healthcare quality indicators: a..., Boulkedid [/bib_ref] This was done according to the GRADE system and considered the following factors: evidence quality, certainty in the balance between advantages and disadvantages, certainty or similarity in values and preferences, and resource implications. Arriving at a consensus required an average level of agreement of  80%. When the agreement level was < 80%, further discussions and voting were conducted.
A strong recommendation was worded as "we recommend" and a weak recommendation as "we suggest".
The key recommendations were presented at the annual symposium of the Sociedade Portuguesa de Cuidados Intensivos in Oporto and discussed by the panel and audience members.

# Statements

# Statement 1
We recommend maintaining (or initiating) agents that suppress gastric acid (namely, proton-pump inhibitors) in patients with compelling indications for acid suppression. Strong recommendation, moderate quality of evidence.

## Rational
Several clinical situations require gastric acid suppression (namely, proton-pump inhibitors), and indications should be respected, both in the ambulatory and hospital (including intensive care) settings.
Patients with compelling indications include the following:
-Known peptic ulcer disease in the healing phase and maintenance phase in selected circumstances [> 50 years old; multiple comorbidities; persistent symptoms; NSAID-negative and Helicobacter pylori-negative ulcers; need to continue NSAID or failure to eradicate Helicobacter pylori; ulcers complicated at the outset; and giant (> 2cm), refractory or recurrent ulcers]. (15) -Treatment of Helicobacter pylori infection. [bib_ref] ACG Clinical Guideline: treatment of Helicobacter pylori infection, Chey [/bib_ref] -Zollinger-Ellison syndrome and other hypersecretory conditions. [bib_ref] ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms:..., Jensen [/bib_ref] -Gastroesophageal reflux disease and acid-related complications (i.e., erosive esophagitis or peptic stricture) [bib_ref] Guidelines for the diagnosis and management of gastroesophageal reflux disease, Katz [/bib_ref] and Barrett's esophagus.-Eosinophilic esophagitis. [bib_ref] Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for diagnosis and management..., Lucendo [/bib_ref] -Dual antiplatelet therapy or concomitant anticoagulant therapy.Other approved indications (which should be discussed on a case-by-case basis) include the following: -Uninvestigated dyspepsiaand epigastric pain syndrome.Approved indications may vary with specific acid suppressants, and therefore labeling indications should be considered.

# Statement 2
We recommend prophylaxis with agents that suppress gastric acid rather than no prophylaxis in patients who have one major risk factor or two minor risk factors for stress ulceration.
complications. This metanalysis has been criticized, and a number of large phase-III trials comparing pharmacological prophylaxis and placebos are under way. Their results and subsequent updated meta-analyses are expected to provide important, more relevant data on the balance between the benefits and harms of stress ulcer prophylaxis. [bib_ref] What's new with stress ulcer prophylaxis in the ICU?, Marker [/bib_ref] Importantly, the incidence of stress ulcer-related gastrointestinal bleeding is not equally shared across the spectrum of patients admitted to intensive care, and certain patients appear more at risk for bleeding.
A large multicenter prospective cohort study [bib_ref] Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care..., Cook [/bib_ref] identified coagulopathy (defined as a platelet count < 50,000/m 3 , an international normalized ratio greater than 1.5, or a partial thromboplastin time greater than 2 times the control value) and respiratory failure (defined as the need for mechanical ventilation for at least 48 hours) as major risk factors for clinically significant gastrointestinal bleeding. The robustness of these risk factors has been confirmed in at least one additional small observational study. [bib_ref] Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to..., Schuster [/bib_ref] Older studies have been criticized because clinical practice has undergone major changes [bib_ref] Do we still need pharmacological stress ulcer prophylaxis at the ICU?, Buendgens [/bib_ref] in the last 20 years, which have reduced the incidence of stress ulcer-related gastrointestinal bleeding. Moreover, in line with what was previously described, a recent exploratory randomized clinical trial [bib_ref] Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): randomized double-blind exploratory study, Selvanderan [/bib_ref] comparing pharmacologic prophylaxis (with proton-pump inhibitors) and a placebo in mechanically ventilated critically ill patients anticipated to receive enteral nutrition did not show any benefit (or harm) of acid suppression. Because this was a feasibility trial, no firm evidence could be inferred, and the final conclusion was that it is possible to administer pharmacologic prophylaxis promptly after commencing mechanical ventilation.
Patients with traumatic brain injury (Glasgow Coma Scale score  8), traumatic spinal cord injury, or burn injury (> 35% of the body surface area) have been routinely excluded from these studies because of a presumed high-risk of stress ulcer-related gastrointestinal bleeding most likely mediated through neurological pathways. [bib_ref] Gastrointestinal prophylaxis in neurocritical care, Schirmer [/bib_ref] Nevertheless, small randomized controlled trials [bib_ref] Effect of ranitidine on intragastric pH and stress-related upper gastrointestinal bleeding in..., Burgess [/bib_ref] [bib_ref] Impact of multiple risk factors and ranitidine prophylaxis on the development of..., Metz [/bib_ref] [bib_ref] Pneumonia and stress ulceration in severely injured patients. A prospective evaluation of..., Fabian [/bib_ref] with different acid suppression regimens have demonstrated significant protection from stress ulcer-related gastrointestinal bleeding in these high-risk populations.
Major risk factor: -Coagulopathy (defined as a platelet count < 50,000/m 3 , an International Normalized Ratio (INR) greater than 1.5, or a partial thromboplastin time greater than 2 times the control value).
-Respiratory failure (defined as the need for mechanical ventilation for at least 48 hours).
-Traumatic brain injury (Glasgow Coma Scale score 8), traumatic spinal cord injury, or burn injury (>35% of the body surface area).
-Sepsis (acute change in total Sequential Organ Failure Assessment -SOFA score  2 points consequent to infection).

## Minor risk factors:
-Acute or chronic renal failure (needing intermittent or continuous renal replacement therapy).
-Shock (defined as continuous infusion with vasopressors or inotropes, mean arterial blood pressure below 70mmHg or plasma lactate level equal to or greater than 4mmol/L).
-Chronic hepatic failure (defined as cirrhosis proven by biopsy, history of variceal bleeding or hepatic encephalopathy).
-Glucocorticoid therapy ( 250mg hydrocortisone equivalent per day).
-Multiple trauma with an injury severity score  16.

## Strong recommendation, low quality of evidence.

## Rational
Meta-analysis and systematic reviews [bib_ref] Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis, Marik [/bib_ref] [bib_ref] Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a..., Alhazzani [/bib_ref] have consistently shown that agents that suppress gastric acid (namely, histamine-2-receptor antagonists and/or protonpump inhibitors) are superior to placebos in reducing the risk of clinically significant gastrointestinal bleeding. However, a recent meta-analysis [bib_ref] Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a..., Huang [/bib_ref] suggested that in patients receiving enteral feeding, pharmacologic prophylaxis of stress ulcers is not beneficial, and combined interventions may even increase the risk of some infectious No study has been performed specifically for sepsis; however, stress ulcer prophylaxis has been an integral part of the care of septic patients and is recommended by current guidelines. [bib_ref] Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock, Rhodes [/bib_ref] This makes sense regarding the new sepsis definitions [bib_ref] The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), Singer [/bib_ref] in which the infection-related dysregulated host response has to be associated with a severe (life-threatening) organ dysfunction (identified as an acute change in total SOFA score  2 points), and thus includes multiple risk factors.
The evidence supporting other minor risk factors for stress ulcer-related gastrointestinal bleeding is weak as a result of a high risk of systematic and random errors. However, an increasing number of risk factors is associated with an increased risk of bleeding, [bib_ref] Antacid titration in the prevention of acute gastrointestinal bleeding: a controlled, randomized..., Hastings [/bib_ref] and international guidelines recommended stress ulcer prophylaxis for patients with two or more risk factors.In the original description of stress-ulcer bleeding, hypotension (alongside sepsis and respiratory failure) was associated with stress-related mucosal damage. [bib_ref] Respiratory failure, hypotension, sepsis, and jaundice. A clinical syndrome associated with lethal..., Skillman [/bib_ref] A recent inception cohort study identified the presence of three or more comorbidities (including glucocorticoid therapy), preexisting liver disease, renal failure (with use of renal replacement therapy), and coexisting or acute coagulopathy and higher SOFA-score, as significant risk factors for stress-ulcer bleeding after multivariate analysis. [bib_ref] Mller MH; SUP-ICU co-authors. Prevalence and outcome of gastrointestinal bleeding and use..., Krag [/bib_ref] In another large cohort study, [bib_ref] Risk factors for clinically important upper gastrointestinal bleeding in patients requiring mechanical..., Cook [/bib_ref] acute kidney injury (assessed by maximum serum creatinine level) was independently associated with an increased risk of gastrointestinal bleeding in patients mechanically ventilated for more than 48 hours. Additionally, a small prospective randomized trial [bib_ref] Pneumonia and stress ulceration in severely injured patients. A prospective evaluation of..., Fabian [/bib_ref] demonstrated independent significance for the injury severity score.

# Statement 3
We recommend the use of a proton-pump inhibitor when prophylaxis with agents that suppress gastric acid is indicated. Strong recommendation, low quality of evidence.

## Rational
The choice of the pharmacological prophylaxis agent should take into account factors related to effectiveness, adverse effects and cost.
Sucralfate, a mucosa-protective agent, alone has traditionally been considered inferior to histamine-2-receptor antagonists for stress ulcer prophylaxis. [bib_ref] A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal..., Cook [/bib_ref] While this has been challenged in a recent meta-analysis of randomized controlled trials, [bib_ref] Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically..., Huang [/bib_ref] the results have been criticized because of significant heterogeneity between studies, of which only three had clinically significant gastrointestinal bleeding as a reported outcome. [bib_ref] Stress ulcer prophylaxis in critically ill patients: review of the evidence, Alhazzani [/bib_ref] The efficacy of proton-pump inhibitors and histamine-2-receptor antagonists in preventing stress-ulcer bleeding in critically ill patients has been compared in several randomized control trials and meta-analyses. [bib_ref] Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a..., Alhazzani [/bib_ref] [bib_ref] Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in..., Alshamsi [/bib_ref] [bib_ref] Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis..., Alhazzani [/bib_ref] [bib_ref] Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding..., Barkun [/bib_ref] [bib_ref] The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists..., Lin [/bib_ref] [bib_ref] Proton pump inhibitors for the prevention of stress-related mucosal disease in criticallyill..., Pongprasobchai [/bib_ref] The most recent and complete meta-analyses of randomized controlled trials [bib_ref] Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a..., Alhazzani [/bib_ref] [bib_ref] Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in..., Alshamsi [/bib_ref] consistently demonstrated that proton-pump inhibitors were more effective than histamine-2-receptor antagonists at reducing clinically significant gastrointestinal bleeding, although this was not accompanied by a reduction in ICU mortality or length of stay. The robustness of these conclusions is limited by the trial methodologies, differences between lower and higher quality trials, sparse data and possible publication bias. An ongoing cluster-randomized crossover trial [Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG): study number 1415-01] is comparing proton-pump inhibitors and histamine-2-receptor antagonists, and the results are expected to provide more relevant data. [bib_ref] What's new with stress ulcer prophylaxis in the ICU?, Marker [/bib_ref] There are multiple pharmacoeconomic analyses [bib_ref] Cost-effectiveness analysis: stress ulcer bleeding prophylaxis with proton pump inhibitors, H2 receptor..., Barkun [/bib_ref] [bib_ref] Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer..., Maclaren [/bib_ref] [bib_ref] Cost-effectiveness of histamine2 receptor antagonists versus proton pump inhibitors for stress ulcer..., Hammond [/bib_ref] focused on the comparison between histamine-2receptor antagonists and proton pump inhibitors for the prophylaxis of stress ulcerrelated gastrointestinal bleeding. The results are contradictory, mainly due to the use of different clinical inputs, and there is no strong evidence regarding which is the most effective alternative. Data from the most recent meta-analysis of clinical trials indicate that proton pump inhibitors should be used. However, if one relies on a propensity score-matched observational cohort study, histamine-2-receptor antagonists are the preferred option. [bib_ref] Cost-effectiveness of histamine2 receptor antagonists versus proton pump inhibitors for stress ulcer..., Hammond [/bib_ref] The only clear conclusion is that, as the cost of prophylaxis is small when compared to the costs of complications, the most effective alternative will constitute a dominant alternative. [bib_ref] Cost-effectiveness of histamine2 receptor antagonists versus proton pump inhibitors for stress ulcer..., Hammond [/bib_ref] Although the quality of evidence is suboptimal, proton-pump inhibitors have been the preferred regimen in intensive care units across Europe, the United States and Canada. [bib_ref] Stress ulcer prophylaxis in the intensive care unit: an international survey of..., Krag [/bib_ref] [bib_ref] American-Canadian consortium for Intensive care Drug utilization I. Pharmacoepidemiology of stress ulcer..., Barletta [/bib_ref] It is acknowledged that the published literature on this issue derives from heterogeneous populations of critically ill patients who may differ from the populations at risk identified by the previous recommendation.
Additionally, the expected adverse effects of protonpump inhibitors are a concern and must be taken into account. A cohort study [bib_ref] Type of stress ulcer prophylaxis and risk of nosocomial pneumonia in cardiac..., Bateman [/bib_ref] provided evidence of an increase in pneumonia with proton-pump inhibitor use; however, this study was related only to cardiac surgery patients, and confidence intervals were wide. Small randomized trials [bib_ref] Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): randomized double-blind exploratory study, Selvanderan [/bib_ref] [bib_ref] D; Canadian Critical Care Trials Group. Withholding pantoprazole for stress ulcer prophylaxis..., Alhazzani [/bib_ref] and a case-control study showed an increased adjusted risk for Clostridium difficile infections during treatment with proton-pump inhibitors, but this was more related to the duration of exposure. [bib_ref] Proton pump inhibitors increase the risk for hospitalacquired Clostridium difficile infection in..., Barletta [/bib_ref] Ultimately, the desirable consequences of stress ulcer prophylaxis with proton-pump inhibitors are expected to outweigh the undesirable consequences among the population at risk.

# Statement 4
We make no recommendation regarding specific proton-pump inhibitor regimens.

## Rational
The ideal drug regimen should be effective in reducing the risk of ulceration, with a low potential for adverse effects and drug interactions and pharmacokinetic characteristics that facilitate its use in patients with organ dysfunction; it should also be cost-effective.
There is no direct comparison between different proton-pump inhibitor-based regimens (including drug, dosing, route of administration and galenic formulation), and heterogeneity across studies (comparing proton-pump inhibitors to other regimens) impairs the comparison of effects between the individual proton-pump inhibitor regimens tested to date. An a priori defined subgroup analysis of at least one meta-analysis suggests that the route of administration (enteral versus intravenous) and dosing (once versus twice a day) do not affect the results. [bib_ref] Stress ulcer prophylaxis in critically ill patients: review of the evidence, Alhazzani [/bib_ref] [bib_ref] Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis..., Alhazzani [/bib_ref] In relation to the route of administration, multiple factors (e.g., vasopressor use, altered gastric emptying and motility, feeding tube and nutrient interactions) may influence enteral absorption in critically ill patients, and the intravenous route is generally preferred. [bib_ref] Introduction to drug pharmacokinetics in the critically ill patient, Smith [/bib_ref] This is disputed by a study showing that, despite a lower bioavailability, enteral lansoprazole suppressed acid in intensive care unit patients better than the intravenous formulation. [bib_ref] Comparison of the enteral and intravenous lansoprazole pharmacodynamic responses in critically ill..., Olsen [/bib_ref] However, this has not been confirmed by further studies, and lansoprazole requires a complex and labor-intensive galenic formulation for feeding tube administration.
Due to its safety in (at least moderate) organ dysfunction, lower probability of drug-drug interactions, and available formulations, intravenous pantoprazole (40mg qd) may be a reasonable choice. [bib_ref] Science review: The use of proton pump inhibitors for gastric acid suppression..., Brett [/bib_ref] However, the definitive choice of the specific proton-pump inhibitor regimen should be based on individual patient and medical values, experience, product labeling, cost-benefit analyses, anticipated risks of drug-drug interactions and adverse effects.

# Statement 5
We suggest using histamine-2-receptor antagonists in patients with Clostridium difficile infection and indications for stress ulcer prophylaxis. Weak recommendation, very low quality of evidence.

## Rational
Accumulating evidence suggests that the use of agents that suppress gastric acid may increase the frequency of infectious complications. [bib_ref] The risks of PPI therapy, Moayyedi [/bib_ref] [bib_ref] Systematic review of the risk of enteric infection in patients taking acid..., Leonard [/bib_ref] The most recent and comprehensive meta-analysis [bib_ref] Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis, Kwok [/bib_ref] found that therapy with agents that suppress gastric acid was associated with a significant risk of Clostridium difficile infections but that the risk was lower for histamine-2-receptor antagonists than with proton-pump inhibitors.
In the critically ill population, the increased risk for Clostridium difficile infections is still controversial because meta-analysis is weak in detecting a modest increase in these events. [bib_ref] Prophylactic acid-suppressive therapy in hospitalized adults: indications, benefits, and infectious complications, Faust [/bib_ref] Nevertheless, the risk of Clostridium difficile infections remains higher in patients receiving proton-pump inhibitors compared with patients receiving histamine-2-receptor antagonists. [bib_ref] Histamine-2 receptor antagonists vs proton pump inhibitors on gastrointestinal tract hemorrhage and..., Maclaren [/bib_ref] Moreover, observational studies [bib_ref] Continuous Proton pump inhibitor therapy and the associated risk of recurrent Clostridium..., Mcdonald [/bib_ref] [bib_ref] Proton pump inhibitors and risk for recurrent Clostridium difficile infection, Linsky [/bib_ref] have shown that continued proton-pump inhibitor use during incident Clostridium difficile infections increases the risk of recurrence.
Based on available data and given the significant disease burden and mortality associated with Clostridium difficile infections, proton-pump inhibitors should be avoided, and histamine-2-receptor antagonists should be the preferred therapy when stress ulcer prophylaxis is indicated. [bib_ref] Prophylactic acid-suppressive therapy in hospitalized adults: indications, benefits, and infectious complications, Faust [/bib_ref] 

# Statement 6
We recommend stopping prophylaxis with agents that suppress gastric acid when risk factors are no longer present and the patient is receiving enteral nutrition. Strong recommendation, low quality of evidence.

## Rational
Acid suppressants are inappropriately continued in a large proportion of patients after the resolution of risk factors and even after intensive care unit or hospital discharge, thus extending the potential risks and costs associated with stress ulcer prophylaxis beyond the intensive care unit. [bib_ref] Inappropriate continuation of stress ulcer prophylaxis beyond the intensive care setting, Farley [/bib_ref] This is in agreement with studies that have concluded that 88.5% of stress ulcer prophylaxis in nonintensive care unit patients is inappropriate [bib_ref] Acid suppressive therapy for stress ulcer prophylaxis in noncritically ill patients, Hong [/bib_ref] and that a relatively restrictive stress ulcer prophylaxis program not only reduces inappropriate use without increasing the rates of hospital-related gastrointestinal bleeding but also results in an estimated annualized cost savings of more than US$ 200.000. [bib_ref] Impact of a clinical pharmacist stress ulcer prophylaxis management program on inappropriate..., Buckley [/bib_ref] As previously described, [bib_ref] Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a..., Huang [/bib_ref] there is some evidence to suggest that in patients receiving enteral feeding, pharmacologic stress ulcer prophylaxis is not beneficial, and combined interventions may even increase the risk of some infectious complications. However, the evidence is still insufficient to justify withholding stress ulcer prophylaxis from patients who are at high risk for gastrointestinal bleeding. It is sufficiently compelling to support the cessation of prophylaxis when risk factors are no longer present and the patient is receiving enteral nutrition.
Patients should thus be evaluated daily during multidisciplinary care rounds for the continued need for prophylaxis, and once the patient is receiving enteral nutrition and risk factors are no longer present, stress ulcer prophylaxis should be discontinued. This strategy will reduce the overuse and unnecessary continuation of agents that suppress gastric acid upon discharge and in the outpatient setting. [bib_ref] Magnitude and economic impact of inappropriate use of stress ulcer prophylaxis in..., Heidelbaugh [/bib_ref] As one of the more common indications for stress ulcer prophylaxis is mechanical ventilation, extubation is crucial to identify and possibly discontinue acid suppression therapy. [bib_ref] Prophylactic acid-suppressive therapy in hospitalized adults: indications, benefits, and infectious complications, Faust [/bib_ref] 

## General algorithm
The general algorithm for the prophylaxis of stress ulcer bleeding in the intensive care unit is presented in [fig_ref] Figure 1 -: Algorithm for prophylaxis of stress ulcer bleeding in the intensive care unit [/fig_ref]. Patients with compelling indications for acid suppression should have an acid-suppressive regimen in accordance with the indication (Statement 1). Then, the risk for bleeding should be considered in each patient; the use of stress ulcer prophylaxis is appropriate for those with high risk. Patients at low risk should not start (or discontinue if previously initiated) stress ulcer prophylaxis (Statement 2). When a stress ulcer prophylaxis is recommended, the use of a proton-pump inhibitor is indicated (Statement 3) with no specific recommended regimen (Statement 4). The exception is cases of Clostridium difficile infection, for which histamine-2-receptor antagonists are preferred (Statement 5). Once the patient is receiving enteral nutrition and risk factors are no longer present, stress ulcer prophylaxis should be discontinued (Statement 6). [fig_ref] Table 1 -: Comparison of the different available proton-pump inhibitor-and histamine-2-receptor antagonist-based regimens Continue [/fig_ref] compares the different available proton-pump inhibitor-and histamine-2-receptor antagonist-based regimens.
The authors suggest that the practices recommended in this guideline are continuously evaluated and monitored and that this guideline is updated as new evidence becomes available. O paciente critico corre risco de desenvolver ulceras de estresse do trato gastrintestinal. Antiacidos e antiulcerosos de diferentes classes sao frequentemente prescritos para reduzir a incidencia de hemorragia gastrintestinal clinicamente significativa associada a ulcera de estresse. No entanto, o uso indiscriminado deste tipo de profilaxia em todos os pacientes admitidos a unidades de terapia intensiva nao so nao se justifica, como tem potenciais efeitos adversos e implicacoes de custo. As presentes diretrizes da Sociedade Portuguesa de Cuidados Intensivos resume a evidencia atual e fornece seis afirmacoes clinicas e um algoritmo com o objetivo de fornecer uma politica padronizada para prescricao de profilaxia da ulcera estresse em unidades de terapia intensiva.

## Resumo
Descritores: Estresse psicologico; Ulcera peptica; Profilaxia; Unidades de terapia intensiva
[fig] Figure 1 -: Algorithm for prophylaxis of stress ulcer bleeding in the intensive care unit. * If Clostridium difficile infection and indications for stress ulcer prophylaxis favor histamine-2-receptor antagonists. INR -International Normalized Ratio; aPPT -activated partial thromboplastin time; SOFA -Sequential Organ Failure Assessment. [/fig]
[table] Table 1 -: Comparison of the different available proton-pump inhibitor-and histamine-2-receptor antagonist-based regimens Continue... No data on enteral administration; consider alternative drugs;  consider alternative drugs;  consider substitution by pantoprazole. NaCl -sodium chroride. Continuous perfusion: after a 50mg bolus (see above), dilute 150mg to 250cc of 0.9% NaCl or 5% dextrose in H 2 O in perfusion at 10.4cc/hour Grind tablets and reduce to powder, and disperse the content in 40mL of non-carbonated water ... continuation [/table]