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Abstract and Introduction

Authors and Disclosures

Reveiz, Ludovic MD, MSc; Guerrero-Lozano, Rafael MD; Camacho, Angela MD; Yara,

Lina MD; Mosquera, Paola Andrea Psi, MSc

Research Institute (LR, PAM), Grupo de Evaluacin de Tecnologas, and the Department ofPediatrics (RG-L, AC, LY), National University of Colombia, Bogot, Colombia.

Abstract

Objective: To identify and evaluate the quality of evidence supporting prophylactic use oftreatments for stress ulcers and upper gastrointestinal bleeding. Stress ulcers, erosions ofthe stomach and duodenum, and upper gastrointestinal bleeding are well-knowncomplications of critical illness in children admitted to the pediatric intensive care unit.Data sources: Studies were identified from the Cochrane Central Register of ControlledTrials, PUBMED; LILACS; Scirus. We also scanned bibliographies of relevant studies.Study Selection: This systematic review of randomized controlled trials assessed the effectsof drugs for stress-related ulcers, gastritis, and upper gastrointestinal bleeding in criticallyill children admitted to the pediatric intensive care unit.Data extraction and synthesis: Two reviewers independently extracted the relevant data.Most randomized controlled trials were judged as having unclear risk of bias. When poolingtwo randomized controlled trials, treatment was significantly more effective in preventingupper gastrointestinal bleeding (macroscopic or important bleeding) compared with notreatment (two studies = 300 participants; relative risk, 0.41; 95% confidence interval,0.19 0.91; I 2 = 12%). Meta-analysis of two studies found no significant difference in deathrates among groups (two randomized controlled trials = 132 participants; relative risk,1.39; 95% confidence interval, 0.70 2.79; I 2 = 4%). The rate of pneumonia was notsignificantly different when comparing treatment and no treatment in one study. Whencomparing ranitidine with no treatment, significant differences were found in theproportion of mechanically ventilated children with normal gastric mucosal endoscopicfindings by histologic specimens (one randomized controlled trial = 48 participants;relative risk, 3.53; 95% confidence interval, 1.34 9.29). No significant differences werefound when comparing different drugs (omeprazole, ranitidine, sucralfate, famotidine,amalgate), doses, or regimens for main outcomes (deaths, endoscopic findings of erosion orulcers, upper gastrointestinal bleeding, or pneumonia).Conclusions: Although pooled data of two studies suggested that critically ill pediatricpatients may benefit from receiving prophylactic treatment to prevent uppergastrointestinal bleeding, we found that high-quality evidence to guide clinical practice isstill limited.

Introduction


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Stress ulcers of the stomach and duodenum as well as upper gastrointestinal (UGI)bleeding are well-known complications of critical illness in children admitted to a pediatricintensive care unit (ICU). The prevalence of stress ulceration in critically ill adults andchildren may vary depending on the severity of the illness and methods used for diagnosis.A cohort of 1006 consecutive admissions enrolled in a pediatric ICU reported that 10.2% of

pediatric participants had UGI bleeding and 1.6% had clinically significant UGI bleeding .[1]

Clinically important UGI bleeding has an important attributable morbidity and mortality inadults, associated with a significant risk of death (relative risk [RR], 4.1; 95% confidenceinterval [CI], 2.6 6.5) and an excess length of ICU stay of approximately 4 to 8 days .[2] Clinically important UGI bleeding is defined as macroscopic bleeding that results inhemodynamic instability and the need for red blood cell transfusion and may lead tocomplications, such as gastrointestinal perforations and surgery .[3,4]

Prophylaxis against stress ulcers has been recommended for the prevention of UGIbleeding in critically ill adults patients. A systematic review published more than onedecade ago found that prophylaxis with histamine2-receptor antagonists decreases the

occurrence of overt gastrointestinal bleeding (odds ratio [OR], 0.58; 95% CI, 0.42 0.79)and clinically important bleeding (OR, 0.44; 95% CI, 0.22 0.88) .[5] Another study foundthat, among critically ill adult patients requiring mechanical ventilation, those receivingranitidine had a significantly lower rate of clinically important gastrointestinal bleedingthan those treated with sucralfate and no significant differences were found in the rates ofventilator-associated pneumonia, the duration of the stay in the ICU, or mortality .[6] However, a more recent integrative study found that ranitidine was ineffective in theprevention of UGI bleeding in patients in intensive care compared with placebo (OR, 0.72;95% CI, 0.30 1.70) and might increase the risk of pneumonia when compared withsucralfate (OR, 1.35; 95% CI, 1.07 1.70) and that studies on sucralfate do not provideconclusive positive results .[7] A guideline on stress ulcer prophylaxis published in 2006recommended pharmacologic intervention in adults admitted to the ICU who havecoagulopathy, require mechanical ventilation for>48 hrs, have a history of gastrointestinalulceration or bleeding within 1 yr before admission, or have at least two of the followingrisk factors: sepsis, ICU stay of>1 wk, occult bleeding lasting 6 day s, and use of>250 mg ofhydrocortisone or the equivalent .[8] Unfortunately, there is still conflicting evidenceconcerning prophylaxis for stress ulcers in children and we did not find any systematicreview on this topic.

The aims of the systematic review presented here are to assess the best evidence on theeffects of interventions for stress ulcer in children, to identify gaps in the literature, and tosuggest further clinical investigation.

Methods

Literature Search

Relevant randomized controlled trials (RCTs) were identified from the Cochrane CentralRegister of Controlled Trials ( The Cochrane Library 2008, Issue 3), (1966 to June 2008),LILACS (1982 to June 2008), and Scirus (June 2008). A search strategy to locate studies on


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stress ulcer, UGI in children was structured and adapted according to each electronicdatabase (Appendix A). The International Clinical Trials Registry Platform search portal(http://www.who.int/trialsearch/Default.aspx ), the metaRegister of controlled trials(http://www.controlled-trials.com ) and http://clinicaltrials.gov/ were searched forongoing trials. Eligible RCTs were included regardless of the language of publication. We

also scanned bibliographies of relevant studies for possible references to additional RCTs.

Study Selection

Two authors independently decided which trials fit the inclusion criteria. Anydisagreements were resolved by discussion between the reviewers, with referral to a thirdauthor if necessary. Only RCTs of interventions for stress ulcer in hospitalized children(studies that included participants aged


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and the strength of recommendations by two reviewers. A systematic approach for gradingthe strength of management recommendations can minimize bias and aid interpretation ofclinical practice guidelines. This system takes into account study design, study quality,consistency, and directness in judging the quality of evidence for each importantoutcome .[10]

Definitions and Outcomes

The main outcomes considered were death; presence of ulcers, gastritis, or UGI bleeding;bleeding that requires transfusion; bleeding associated with hemodynamic instability;gastrointestinal perforations; and pneumonia. In addition, endoscopic findings categorizedaccording to the severity of UGI tract lesions were also considered primary outcome. Weanticipated that diverse classifications could have been used by trialists. Other outcomeswere: delayed gastric emptying; bacteremia during the follow-up; mean patient's gastricaspirates pH during 24-hr monitoring, pediatric ICU stay; duration of mechanicalventilation hematologic test; cultures of gastric and tracheal secretion, gastric and tracheal

colonization; and complicated postoperative course. We only included data on adverseevents from RCTs; no further searches for other types of studies were done .[11]

Statistical Analysis

Statistical analyses were done with Review Manager version 5.0 (Cochrane Collaboration)software. The results expressed as RR and 95% CI for dichotomous primary outcomes werecalculated by the Mantel-Haenszel fixed-effects model. Weighted mean difference with 95%CI was used for continuous outcomes. For the pooled analysis, we calculated the I 2 statistic,which describes the percentage of total variation across studies caused by heterogeneity .[9] Low, moderate, and high levels of heterogeneity approximately correspond to I 2 values of

25%, 50%, and 75%, respectively.

Results

Description of Studies

A total of 294 citations were identified from the diverse sources of information. Of the 74potentially RCTs screened, we excluded 52 references because they were guidelines,observational studies, or case series reports. We identified 22 studies assessing the effectsof different therapeutic interventions for stress ulcers in children (Fig. 1). However, weexcluded 13 studies because they were nonrandomized or noncontrolled or focused onpharmacokinetics of drugs .[12 24] One study in Hungarian is pending for evaluation .[25] Intotal, we included and analyzed eight RCTs evaluating the effects of drugs for preventingstress ulcers in children .[26 33] The main characteristics of the eight included studies aredetailed in Table 1 . Table 1 : We could not assess publication bias (e.g., funnel plot or Eggerregression test) because we found less than nine RCTs and we could not pool outcomes formore than three studies.


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Effects of Interventions

Treatment versus No Treatment We found four studies that evaluated a number ofmedications (cimetidine, almagate, ranitidine, sucralfate, and omeprazole) vs. no treatmentor placebo for different outcomes; data were not available in all RCTs for each

outcome .[26,28,30,33]

When pooling two RCTs (Fig. 2), "treatment" (which included almagate, ranitidine,sucralfate, and omeprazole) was significantly more effective in preventing UGI bleeding(macroscopic or important bleeding) compared with "no treatment" (two studies = 300participants; RR, 0.41; 95% CI, 0.19 0.91; I 2 = 12%) .[28,30] However, no significantdifference was found when pooling both studies of treatment vs. no treatment with anadditional RCT comparing treatment vs. placebo (three studies = 340 participants; RR,0.69; 95% CI, 0.41 1.17; I 2 = 63%) .[26,28,30] In addition, meta-analysis of two studies [30,33] found no significant difference in death rates among groups (two RCTs = 132 participants;RR, 1.39; 95% CI, 0.70 2.79; I 2 = 4%). The rate of pneumonia was not significantly different

when comparing treatment and no treatment in one study .[30] Summary of relevantfindings for primary outcomes of RCTs included in the review are detailed in Table 3 .

Meta-analysis of prophylaxis for preventing upper gastrointestinal bleeding (macroscopicor important bleeding) compared with no treatment. M-H , Mantel-Haenszel; CI , confidenceinterval; df , degrees of freedom.

Ranitidine

One RCT [33] in mechanically ventilated preterm and full-term newborns treated in aneonatal ICU showed that rates of normal gastric mucosal endoscopic findings by visual

inspection (one RCT = 48 participants; RR, 3.04; 95% CI, 1.30 7.12) and histologicspecimens (one RCT = 48 participants; RR, 3.53; 95% CI, 1.34 9.29) were significantlyhigher in the ranitidine group compared with no treatment groups. However, no significantdifferences among groups were found in the rates of patients with erosions or ulceration,gastrointestinal problems (bleeding from the gastrointestinal tract and/or vomiting ordelayed gastric emptying), positive bacterial cultures from the biopsy specimens, and therisk for later suspected or proven bacteremia during the follow-up. An RCT of children whoneeded mechanical ventilation on admission [30] showed no significant difference between


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groups in macroscopic bleeding, pneumonia occurrence, duration of mechanical ventilation(days) and pediatric ICU stay (days). Another RCT of children admitted to a pediatric ICU( [28] ) did not show statistical difference in the rates of patients with important UGIhemorrhage among groups. A significant difference favoring ranitidine was found in thepercentage of children with mean pH of>4 during>50% of study time compared with no

treatment (one RCT = 70 participants; RR, 8.67; 95% CI, 2.89 26.02).

Amalgate

An RCT[28] showed a significant difference favoring amalgate in the percentage of patients'gastric aspirates with mean pH of>4 during>50% of study time (one RCT = 70 participants;RR, 11.00; 95% CI, 3.72 32.56). No significant difference was found among groupsregarding the rates of patients with important UGI hemorrhage.

Sucralfate

In one RCT ,[28] a trend favoring sucralfate was found in the percentage of patients' gastricaspirates with mean pH of>4 during>50% of study time (one RCT = 70 participants; RR,3.33; 95% CI, 1.00 11.09). However, no significant difference between groups was foundfor other outcomes, such as rate of patients with important UGI hemorrhage. AnotherRCT[30] did not report significant difference among groups in rates of macroscopic bleeding,pneumonia, and deaths as well as in the duration of mechanical ventilation and pediatricICU stay.

Omeprazole

In one RCT ,[28] omeprazole was not superior to no treatment in groups in rates of

macroscopic bleeding, pneumonia, deaths, and in the duration of mechanical ventilationand pediatric ICU stay.

Cimetidine

In one RCT ,[26] cimetidine was not superior to placebo in rates of UGI bleeding.

Drug vs. Any Other Active Compound

We found seven studies comparing diverse drugs, doses, and regimen .[27 32] Most studiesdid not report outcomes, such as mortality, rates of UGI bleeding, and pneumonia.

Pirenzepine vs. Famotidine

No significant differences were found between groups in one RCT of children whounderwent corrective or palliative surgery for congenital heart disease concerning rates ofpneumonia and organism cultured from the stomach and from tracheal secretion .[32]

Ranitidine vs. Sucralfate


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One RCT ( [28] ) showed that ranitidine had a significant effect in the rate of patients' gastricaspirates with mean pH of>4 during>50% compared with sucralfate (one RCT = 70participants; RR, 2.60; 95% CI, 1.49 4.55). However, no significant differences were foundin the rates of patients with important UGI hemorrhage ( [28] ) and macroscopic bleeding,death and pneumonia, and in the duration of mechanical ventilation and pediatric ICU

stay .[29]

Ranitidine vs. Amalgate

Ranitidine was significantly superior to amalgate in the rate of patients' gastric aspirateswith mean pH of>4 during>50% of study time (one RCT = 70 participants; RR, 0.79; 95%CI, 0.64 0.97). No significant differences were found between groups in the rates ofpatients with important UGI hemorrhage and gastrointestinal symptoms, such as nausea,vomiting, or diarrhea .[28]

Amalgate vs. Sucralfate

One RCT ( [28] ) showed that amalgate had a significant effect in the rate of patients' gastricaspirates with mean pH of>4 during>50% compared with sucralfate (one RCT = 70participants; RR, 3.30; 95% CI, 1.94 5.61). No significant differences were found betweengroups in the rates of patients with important UGI hemorrhage and gastrointestinalsymptoms, such as nausea, vomiting, or diarrhea .[28]

Ranitidine vs. Famotidine

No significant differences were found between groups in one RCT ( [31] ) of critically illpediatric patients in the rate of patients' gastric aspirates with mean pH of>4 during>80%

of study time.

Other Comparisons

No significant differences were found between groups in one RCT ( [30] ) of patients whoneeded mechanical ventilation on admission concerning rates of macroscopic bleeding,deaths, pneumonia, and the duration of mechanical ventilation and pediatric ICU stay whencomparing omeprazole vs. ranitidine and omeprazol vs. sucralfate.

Ranitidine versus Ranitidine at Different Doses and Regimen

One RCT ( [27] ) showed that intravenous ranitidine at 2 mg/kg and 4 mg/kg had a significanteffect in the rate of patients' gastric aspirates with mean pH of>4 during>80% of study timecompared with ranitidine by nasogastric tube (one RCT = 20 participants; RR, 0.25; 95% CI,0.07 0.90 and RR, 0.25; 95% CI, 0.07 0.90, respectively). Another RCT did not findsignificant difference in patients' gastric aspirates pH when comparing bolus dosing andcontinuous infusion dosing of 4 mg/kg per day of intravenous ranitidine .[29]

Discussion


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The RCTs included in this review have assessed a broad range of treatments that resultedin limited opportunities to describe and pool useful data. Studies available for analysis area highly heterogeneous group, with different drugs being used and different methods forassessing their efficacy (e.g., some used endoscopy on all patients, others simply monitorednasogastric output for bleeding). Furthermore, because the majority of RCTs had an

unclear risk of bias, small sample size, and did not reported relevant outcomes, it wasdifficult to conclude whether one treatment was more beneficial than the comparator mostof the time. Most RCTs focused on secondary outcomes, such as gastric pH control. Inaddition, methods used for diagnosis of UGI bleeding greatly varied across studies and wecould not integrate data for most comparisons.

Pooled data of two studies suggested that pediatric patients may benefit from receivingprophylactic treatment for preventing UGI bleeding. There was reasonable evidence thatranitidine is better than "no treatment" in mechanically ventilated preterm and full-termnewborns treated in a neonatal ICU in improving rates of normal gastric mucosalendoscopic findings by visual inspection and histologic specimens .[33] In addition,

ranitidine, sucralfate, and amalgate were also better than no treatment in improving ratesof patients' gastric aspirates with mean pH of>4 during>50% of study time .[28] However,we found no evidence to support that prophylaxis medication is better than "no treatment"to decrease the rates of ulcers or erosion or deaths. Furthermore, no evidence was found tosupport that prophylaxis decreases the duration of mechanical ventilation or pediatric ICUstay. On the other hand, we did not find significant increase in the rates of pneumonia oradverse event. Finally, intravenous ranitidine was superior to ranitidine by nasogastrictube in improving rates of patients with mean pH of>4 during>80% of study time.

A meta-analysis evaluating the effect of stress ulcer prophylaxis on gastrointestinalbleeding, pneumonia, and mortality in critically ill adult patients demonstrates thatprophylaxis with histamine2-receptor antagonists decreases the occurrence of overtgastrointestinal bleeding (OR, 0.58; 95% CI, 0.42 0.79) and clinically important bleeding(OR, 0.44; 95% CI, 0.22 0.88). Authors also reported a trend toward an increased risk ofpneumonia associated with histamine2-receptor antagonists as compared with noprophylaxis (OR, 1.25; 95% CI, 0.78 2.00). However, sucralfate was associated with a lowerprevalence of nosocomial pneumonia and reduced mortality rate when compared withantacids and histamine2-receptor antagonists .[5] An additional RCT found that ranitidinehad a significantly lower rate of clinically important UGI bleeding than sucralfate in 1200critically ill adult patients requiring mechanical ventilation. Authors also reported nosignificant differences in the rates of ventilator-associated pneumonia, the duration of thestay in the ICU, or mortality .[6]

A number of risk factors associated with stress ulcers, gastritis, and gastrointestinalbleeding in severelly ill pediatric patients have been described in observational studies(Table 4 ).[1,34 40] A cohort study found that respiratory failure, coagulopathy, and aPediatric Risk of Mortality Score of 10 were independent risk factors for clinicallysignificant upper GI bleeding, using multivariate analysis. Based on those findings, authorsrecommended that prophylaxis to prevent UGI bleeding may be limited to patients whopresent with at least two risk factors .[1]


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We have produced an updated coverage of RCTs of prophylactic treatments for stressulcers in children by summarizing the best available data. Although pooled data of twostudies suggested that critically ill pediatric patients may benefit from receivingprophylactic treatment for preventing UGI bleeding, the overall quality of the evidence islow, leading to a weak recommendation (using GRADE approach) .[10] Although limited

evidence is available, some of the drugs studied (histamine2 receptor antagonists,sucralfate, amalgate) have been replaced in clinical use by proton pump inhibitors.However, only one study including patients treated with omeprazole was found .[30] Weneed more evidence demonstrating the effectiveness and safety of different prophylacticdrugs and improved design and reporting of RCTs. We should also investigate the use ofproton pump inhibitors in children.

References

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intensive care unit stay of clinically important gastrointestinal bleeding in criticallyill patients. Crit Care 2001; 5:368 375

3. Erstad BL, Barletta JF, Jacobi J, et al: Survey of stress ulcer prophylaxis. Crit Care 1999; 3:145 149

4. Cook DJ, Fuller HD, Guyatt GH, et al: Risk factors for gastrointestinal bleeding incritically ill patients. N Engl J Med 1994; 330:377 381

5. Cook DJ, Reeve BK, Guyatt GH, et al: Stress ulcer prophylaxis in critically ill patients:Resolving discordant meta-analyses. JAMA 1996; 275:308 314

6. Cook DJ, Guyatt GH, Marshall J, et al: A comparison of sucralfate and ranitidine forprevention of upper gastrointestinal bleeding in patients requiring mechanicalventilation. N Engl J Med 1998; 338:791 797

7. Messori A, Trippoli S, Vaiani M, et al: Bleeding and pneumonia in intensive carepatients given ranitidine and sucralfate for prevention of stress ulcer: Meta-analysisof randomised controlled trials. BMJ 2000; 321:1103 1106

8. Spirt MJ, Stanley S: Update on stress ulcer prophylaxis in critically ill patients. CritCare Nurse 2006; 26:18 28

9. Higgins JPT, Green S (Eds). Cochrane Handbook for Systematic Reviews ofInterventions Version 5.0.0 [Updated February 2008]. The Cochrane Collaboration,2008. Available at: http://www.cochrane-handbook.org. Accessed November 23,2009

10. Guyatt GH, Oxman AD, Vist G, et al: Rating quality of evidence and strength ofrecommendations GRADE: An emerging consensus on rating quality of evidence andstrength of recommendations. BMJ 2008; 336:924 926

11. Golder S, McIntosh HM, Duffy S, et al: Developing efficient search strategies toidentify reports of adverse effects in MEDLINE and EMBASE. Health Info Libr J 2006;23:3 12

12. Agarwal AK, Saili A, Pandey KK, et al: Role of cimetidine in prevention and treatmentof stress induced gastric bleeding in neonates. Indian Pediatr 1990; 27:465 469


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