Stress-Related Mucosal Disease: Risk Factors and Prophylactic

ABSTRACT

Background: The term stress-related mucosal disease (SRMD) represents a continuum of conditions rangingfrom stress-related injury (superficial mucosal damage) to stress ulcers (focal deep mucosal damage). Caused bymucosal ischemia, SRMD is most commonly seen in critically ill patients in the intensive care unit (ICU).Prophylaxis of stress ulcers may reduce major bleeding but has not yet been shown to improve survival.

Objectives: This article reviews currently available agents for the prophylaxis of SRMD and discusses theiruses and potential adverse effects.

Methods: Relevant articles in the English-language literature were identified through a MEDLINE search(1968–2003) using the key words stress-related mucosal disease, stress-related injury, ulcer, prophylaxis, intensive careunit, and upper gastrointestinal bleeding.

Results: The most widely used drugs for stress-related injury are the intravenous histamine2–receptor antag-onists. These drugs raise gastric pH but are associated with the development of tolerance and possible drug inter-actions and neurologic manifestations. Sucralfate, which can be administered by the nasogastric route, can pro-tect the gastric mucosa without raising pH, but may decrease the absorption of concomitantly administered oralmedications. The prostaglandin misoprostol has not been shown to be of benefit in the prophylaxis of SRMD.Antacids lower the risk of gastrointestinal bleeding, but large volumes of antacids are required and treatment islabor intensive. Proton pump inhibitors (PPIs) are the most potent acid-suppressive pharmacologic agents avail-able. Esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole substantially raise gastric pH forup to 24 hours after a single dose. The availability of an intravenous formulation of pantoprazole may helpimprove the treatment of SRMD in ICU patients, particularly those receiving mechanical ventilation. Tolerancedoes not develop, and few adverse effects have been reported.

Conclusions: Recent studies of PPIs have shown promising results in high-risk patients, making this class ofdrugs an option for the prophylaxis of SRMD. (Clin Ther. 2004;26:197–213) Copyright © 2004 ExcerptaMedica, Inc.

Key words: ulcer, prophylaxis, gastric mucosa, intensive care unit, enzyme inhibitors.

CLINICAL THERAPEUTICS®/VOL. 26, NO. 2, 2004

Copyright © 2004 Excerpta Medica, Inc. 197

Accepted for publication November 19, 2003.Printed in the USA. Reproduction in whole or part is not permitted. 0149-2918/04/$19.00

Stress-Related Mucosal Disease: Risk Factors and Prophylactic Therapy

Mitchell J. Spirt, MD

Division of Gastroenterology, Department of Medicine, UCLA School of Medicine, Los Angeles, California

INTRODUCTIONThe association between severe physiologic stress andgastrointestinal (GI) ulceration is well established.1,2

The pathogenesis of stress-related mucosal disease(SRMD) has not been described completely, but thereis strong evidence that hypoperfusion of the upper GItract is the major cause.1–4 Aggressive management ofthe underlying disease is the most important factor inthe prevention of stress ulceration.1,5,6 Improvingunderstanding and classification of the different typesof stress injury will facilitate communication and aidin the diagnosis, prognosis, and therapeutic manage-ment of SRMD. Elucidating the mechanism of injurywill help develop interventions that may lead to areduction in mortality.

Various medications are currently used to reducethe incidence of stress-related GI bleeding. This arti-cle reviews currently available agents for the prophy-laxis of SRMD and discusses their uses and potentialadverse effects. Relevant English-language publica-tions were identified through a search of MEDLINE(1968–2003) using the terms stress-related mucosaldisease, stress-related injury, ulcer, prophylaxis, intensivecare unit, and upper gastrointestinal bleeding.

STRESS-RELATED MUCOSAL DISEASETerminology

The terminology of SRMD is often confusing, withstress ulcer, stress gastritis, stress erosions, and stress

lesions used interchangeably. However, there areimportant differences between these entities. For clar-ity, this review distinguishes between stress-relatedinjury (SRI) and stress ulcers, which lie along thecontinuum of manifestations of SRMD. As illustratedin Figure 1, SRI involves superficial mucosal damage(primarily erosions), whereas stress ulcers involvefocal deep mucosal damage and carry a high risk forbleeding. Both SRI and stress ulcers are found inphysiologically stressed patients, particularly thoserequiring mechanical ventilation.1,2,7

PathogenesisThe gastric mucosa is exposed to a very low intralu-

minal pH. Under normal physiologic conditions, theintegrity of this tissue depends on a balance betweenaggressive factors (ie, gastric acid secretion, enzymesecretion, infection) and countervailing mucosaldefense mechanisms.3,5 Studies in animal models haveshown that mucosal defense is intimately related toadequate microcirculation through tissues of the upperGI tract.8 This circulation provides nutrients andremoves waste products, particularly oxygen free radi-cals. In a rat model, Itoh and Guth8 found that oxygen-derived free radicals, particularly O2

–, appear to playan important role in the formation of gastric lesionsproduced by ischemia plus hydrochloric acid.

In another study in rats, Yasue and Guth9 foundthat even without intragastric hydrochloric acid, sys-

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Figure 1. Endoscopic photographs of mucosal lesions: (A) stress-related injury and (B) stress ulcer.

A B

temic ischemia followed by retransfusion of shedblood caused histologic mucosal injury in the corpusand antrum. They also found that a limited period ofischemia alone (systemic hypotension for 20 minuteswithout retransfusion) resulted in no more histologiclesions than occurred in controls not subjected tohemorrhage. These investigators reported that alonger period of ischemia caused more lesions andthat reperfusion (retransfusion) was a critical factor inlesion development. In a canine model, Chung et al10

found that local ischemia and congestion precededthe development of gross mucosal ulcerations.

These studies point to a multifactorial etiology forstress ulcers in which the breakdown of mucosaldefenses—usually by ischemia and reperfusion—allows aggressive physiologic processes, particularlygastric acid secretion, to produce injury and ulceration.

LocationSRMD is typically seen in the acid-producing areas

of the stomach (ie, the corpus and fundus),3,11 unlikeoutpatient peptic ulcers, which are more common inthe antrum or duodenal bulb.12 In rabbits and rats,Menguy and Masters11 found that with respect to themaintenance of energy metabolism, the antralmucosa tolerated the partial ischemia of hemorrhagicshock and the complete ischemia of total severance ofthe gastric vascular connections far better than didthe corpus mucosa. Leung et al13 reported that gastriclesions began to appear when blood pressure fell to33% of baseline during hemorrhagic shock in rats. Atblood pressures 80% below baseline, a mean (SD) of26.8% (4.5) of the total corpus area developedlesions, compared with 5.3% (1.4) of the antral area(P < 0.05, both regions vs control animals). With rareexceptions, corpus mucosal lesions were larger thanantral mucosal lesions at all levels of hypotension.

It is believed that low-grade mucosal ischemiaoccurs during sepsis and multiple organ failurebecause of changes in blood volume and redistribu-tion of blood flow.5,14 In a study in critically ill, nor-motensive, septic, ventilated patients, Spirt et al4

used endoscopic reflectance spectrophotometry tomeasure blood flow as an index of hemoglobin satu-ration and oxygen concentration. Control values werederived from patients undergoing routine endoscopyfor the evaluation of symptoms of gastroesophagealreflux disease. The septic intensive care unit (ICU)

patients had a 50% to 60% reduction in upper GImucosal blood flow compared with controls.

MortalitySRMD differs from outpatient peptic ulcer disease

in many respects, including the location and numberof lesions, risk factors, pathophysiology, prognosis,recurrence, management, and therapy.3,12 One studyreported a mortality rate of 46% in critically illpatients with GI bleeding, compared with 21% inpatients without bleeding (P < 0.001).15 Several stud-ies have confirmed this high mortality rate.16,17

However, the SRMD lesions remit when the patientrecovers and, in a healthy host, do not recur.

Risk FactorsA multicenter study in 2252 patients reported that

the 2 strongest risk factors for stress-related GI bleed-ing were respiratory failure (odds ratio [OR], 15.6)and coagulopathy (OR, 4.3).16 The risk increaseswith increasing number of days of mechanical venti-lation and length of ICU stay.7 Other factors confer-ring high risk for both SRI and stress ulcers includerecent major surgery, major trauma, severe burns,head trauma, hepatic or renal disease at admission,sepsis, and hypotension.6,16,18–23

Stress-Related InjuryThe results of most studies indicate that 75% to

100% of patients in the ICU have abnormalities of thegastric mucosa within hours after admission2,18,22–24

and that samples of gastric juice test positive for bloodin 35% to 100% of critically ill patients.25,26 However,occult blood in the gastric juice does not predictimpending hemorrhage.25 The mucosal changes ofSRI mainly involve small erosions (Figure 2) that donot usually lead to hemodynamically significant GIbleeding. When bleeding does occur in patients withSRI, there is usually a concomitant coagulopathy.16

Clinically apparent bleeding occurs in ~20% ofpatients,27 whereas hemodynamically significantbleeding probably occurs in <5% of patients.28

Erosions associated with SRI are not caused byhyperacidity, as affected patients have normal orslightly decreased gastric acid volume. If massivebleeding does occur, it is usually from a discrete stressulcer rather than from diffuse SRI.3,5,28 These lesionstend to be superficial, and perforation is distinctly

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uncommon, compared with an incidence of 1% to2% in patients with gastric and duodenal ulcers.

Stress UlcersStress ulcers differ from routine peptic ulcers. Peptic

ulcer disease is relatively manageable; patients usuallypresent with abdominal pain and epigastric discom-fort and can receive treatment on an outpatient basis.A minority (≈10%) of outpatients with peptic ulcerdisease develop complications (eg, bleeding, obstruc-tion, perforation) requiring hospitalization.29 Stressulcers (Figure 2), on the other hand, cause GI bleed-ing and are usually not associated with abdominalpain.2 Clinical bleeding often occurs between thethird and seventh days after ICU admission.

In a 1987 review, Zuckerman and Shuman17 reportedthat ICU patients with stress ulcer bleeding had a mor-tality rate of 50% to 77%, compared with 9% to 22% inICU patients without bleeding. In contrast to patientswith SRI, patients with stress ulcers are at increased riskfor hemodynamically significant GI hemorrhage,although this is rarely the cause of death.2 Death is usu-ally the result of multiple organ failure and is probablyrelated to hypoperfusion of the entire gut, promoting thetranslocation of bacteria and endotoxin.1,4 Althoughstress-related ulcers are a recognizable sign of this low-perfusion state,5 the prophylaxis of stress ulcers has notbeen shown to improve survival, even in the few trials inwhich the incidence of major bleeding appeared to havebeen favorably decreased.30–33

PROPHYLAXIS OF STRESS ULCERSThe incidence of significant stress-related bleedinghas decreased dramatically over the past severalyears, probably as a result of advances in the moni-toring and support of critically ill patients, includingoptimization of hemodynamic status, tissue oxygena-tion, and treatment of sepsis.3,21,34 Nevertheless, thevarying definitions of bleeding used in clinical stud-ies tend to obscure the true incidence of stress-related bleeding. Criteria have ranged from guaiac-positive stool and guaiac-positive nasogastric aspirateto frank hematemesis, a drop in blood pressure, andthe need for blood transfusion. The prevalence ofacute stress-related GI bleeding is 1.5% to 6% in crit-ically ill patients not receiving prophylaxis.16,35 Thestrongest predictors of bleeding in ICU patients arerespiratory failure requiring prolonged mechanicalventilation and coagulopathy.16,36

Taking the radical viewpoint, one might questionwhether there is a need for prophylaxis of stress-relatedGI bleeding, as bleeding from such lesions is usuallynot the cause of death and therapy has not beendemonstrated to reduce mortality.21 There is consid-erable disagreement on this matter, but the consensusis that patients at very high risk for stress-relatedbleeding should receive prophylaxis (Table I3,16,37,38),and this is the standard of care in most ICUs.21

Moreover, a recent evidence-based review of clinicaltrials supported the use of prophylactic acid suppres-sion in critically ill patients with coagulopathy or

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Stress-Related Injury

Mucosa

Submucosa Muscle Exudate

Stress Ulcer

Inflammator Edema

Figure 2. Mechanism and depth of tissue injury in (A) stress-related injury and (B) stress ulcer. Adapted with permission.28

A B

undergoing prolonged mechanical ventilation.39 Theavailable evidence-based data do not support the useof any specific drug class over another for the pro-phylaxis of stress ulcer bleeding.39 Following is a dis-cussion of the available agents and information perti-nent to their use.

Histamine2–Receptor AntagonistsA variety of histamine2–receptor antagonists

(H2RAs) can be used for the prophylaxis of stressulcer bleeding in the ICU. The available H2RAs arenot equally potent in blocking the actions of hista-mine on parietal cells. Cimetidine is the least potent,ranitidine and nizatidine are more potent, and famo-tidine is the most potent. Cimetidine, however, is theonly H2RA with US Food and Drug Administrationapproval for the prevention of upper GI bleeding inthe ICU. There are other differences between thesemedications and the methods of administering themthat are discussed later in this article. AlthoughH2RAs can effectively protect against SRI,24,40 they areonly moderately effective in the prophylaxis of truestress ulcers. In their 1999 therapeutic guidelines onstress ulcer prophylaxis,21 the American Society ofHealth-System Pharmacists noted that the results of

clinical trials of the efficacy of H2RAs in the preven-tion of stress ulcers fluctuate widely and provide noclear consensus (Table II27,32,33,41–46).

Routes of AdministrationIntermittent bolus administration and continuous

infusion are the main modes of intravenous adminis-tration. Continuous infusion of H2RAs is superior tointermittent bolus administration in maintaining gas-tric pH at levels >4.12,47 However, no studies havedemonstrated improved safety, more effective pro-phylaxis of ulcers, faster healing of existing ulcers, ora lower rebleeding rate with either method.21 Becausesome drug-related adverse effects associated withH2RAs are thought to result from high serum drugconcentrations,1 maintaining steady blood concentra-tions within the therapeutic range may reduce thepotential for these adverse effects.48 Continuous infu-sion avoids the peaks and troughs associated withbolus administration.12

Oral therapy is also an option with H2RAs. Thefindings of a small study in 18 patients suggested thatenteral administration of ranitidine 150 or 300 mgevery 12 hours led to effective absorption of drugfrom the upper GI tract.49 With both doses, serumconcentrations remained within or exceeded the thera-peutic range after 12 hours in nearly 80% of ICUpatients with clinically important risk factors forSRMD. Regardless of the route of administration ordosing interval, daily doses should be reduced inpatients with renal insufficiency.50

One major concern that requires further research isthe development of tolerance to H2RAs, which hasbeen reported to develop in the ICU within 42 hoursafter intravenous administration by both repeatedbolus and continuous infusion.41,51 The resultingreduction in the antisecretory effect of H2RAs is notexplained by altered pharmacokinetics.52

CimetidineCimetidine has been marketed in the United States

for >25 years and has a well-established safety profile.Drug interactions, which occur more frequently thanwith other H2RAs, are the major concern with itsuse.1,53 Thrombocytopenia has also been associatedwith cimetidine use.54 Because it can cause neurolog-ic manifestations and drug interactions, cimetidineshould be used with caution in the ICU. A list of

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Table I. Factors associated with a high risk for stress-related bleeding.

Very high riskProlonged mechanical ventilation*

Coagulopathy*

High riskSepsis†

Renal failure†

Hepatic failure†

Hypotension†

Trauma†

Severe burns†

Neurologic trauma†

Myocardial infarction†

Neurologic surgery†

Multiple organ failure†

Ileus‡

High-dose corticosteroids§

*Cook et al.16

†Beejay and Wolfe.3‡Crill and Hak.37

§MacLaren et al.38

drugs known to interact with cimetidine is providedin Table III.55–58

RanitidineRanitidine has 5 to 12 times greater antisecretory

potency than cimetidine. However, there is no evi-dence of its superiority to cimetidine for the pre-vention of SRMD, and a meta-analysis of random-ized studies indicated that ranitidine was no moreeffective than placebo in the prevention of GI bleed-ing in the ICU.59 Ranitidine is usually well tolerat-

ed; however, it can cause adverse central nervoussystem reactions, including agitation and restless-ness, in ICU patients given the usual doses.48

Ranitidine is known to interact with warfarin.60

Patients with impaired renal function may experi-ence lethargy, confusion, somnolence, and disorien-tation with ranitidine.48

FamotidineFamotidine is the most potent H2RA available in

the United States.55 It is ≈8 to 10 times more

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Table II. Prophylaxis for gastrointestinal bleeding due to stress-related mucosal disease in controlled trials in high-riskpatients.

Study/Treatments No. of Patients Bleeding Rate, % P

Martin et al41

H2RA (cimetidine) 65 14 <0.05Placebo 66 33

Zinner et al27

H2RA (cimetidine) 100 14 NS vs no treatmentAntacid 100 5 <0.005 vs no treatmentNo treatment 100 20

Weigelt et al42

H2RA (cimetidine) 61 5 NAAntacid 16 0 NA

Kingsley43

H2RA (cimetidine) 124 4.8 NAAntacid 125 8.8 NA

Ben-Menachem et al44

H2RA (cimetidine) 100 5 NS vs placeboSucralfate 100 5 NS vs placeboPlacebo 100 6

Cook et al33

H2RA (ranitidine) 596 1.7Sucralfate 604 3.8 0.02 vs H2RA

Levy et al45

H2RA (ranitidine) 35 31PPI (omeprazole) 32 6 <0.05 vs H2RA

Azevedo et al46

H2RA (ranitidine) 38 10.5Sucralfate 32 9.3PPI (omeprazole) 38 0 NS vs H2RA and

sucralfate

Hastings et al32

Antacid 51 4 <0.05Placebo 49 25

H2RA = histamine2–receptor antagonist; NA = not available; PPI = proton pump inhibitor.

potent than ranitidine. A lower volume of adminis-tration (10 mL/d) is required with famotidine com-pared with cimetidine and ranitidine (60–80 mL/d).This characteristic may be particularly useful inpatients with congestive heart failure or those requir-ing fluid restriction. Twice-daily dosing (20 mg q12h)maintains the pH above 4 for most of the day,61

and higher doses (50 mg q24h) can maintain pH atthis level for 24 hours.62 Drug interactions appearto be minimal with famotidine. Rare cases ofthrombocytopenia have occurred,63 and there arereports of central nervous system reactions with itsuse.64 In controlled trials of famotidine, no druginteractions were observed with agents metabo-lized by the cytochrome P450 (CYP) enzyme sys-tem, including warfarin, theophylline, phenytoin,and diazepam.63

Proton Pump InhibitorsFive proton pump inhibitors (PPIs) are available in

the United States: omeprazole, esomeprazole, lanso-prazole, rabeprazole, and pantoprazole.3,65 The mostpotent antisecretory agents available, these prodrugsblock the final pathway for acid secretion by irre-versibly inhibiting H+,K+–adenosine triphosphatase

(ATPase, the proton pump) in gastric parietal cells.3

PPIs are capable of elevating or maintaining intragas-tric pH above 6.66,67 Studies have demonstrated thatalthough an intragastric pH >4 may be adequate forpreventing stress ulceration, a pH >6 may be neces-sary to maintain clotting in patients at risk forrebleeding of a peptic ulcer.68

PPIs are well tolerated and appear promising for the prophylaxis of SRMD, although the results ofonly 2 randomized clinical trials have been reported(Table II).45,46 One of these trials, which involved 67patients, showed a significant reduction in bleedingwith omeprazole compared with ranitidine (2/32[6.3%] vs 11/35 [31.4%], respectively; P < 0.05),45

but this study was limited by a higher number of riskfactors per patient in the H2RA group and a higherrate of clinical bleeding than is generally reported inthe literature. In the second trial, which involved 108ICU patients,46 the rate of upper GI hemorrhage was10.5% in the ranitidine group, compared with 0% inthe omeprazole group (P = NS).

OmeprazoleOmeprazole was the first PPI approved in the United

States. A single morning dose of omeprazole in healthyindividuals maintains intragastric pH at ≥5 for up to 24 hours.69 After 15 to 24 hours, acid begins to returnto the stomach, and omeprazole is cleared within 72 hours.70 The drug is given orally; no intravenousform is available in the United States. An early studyusing various doses of omeprazole reported that singleintravenous doses of 10 to 80 mg produced dose-dependent and long-lasting inhibition of pentagastrin-stimulated gastric acid secretion.71 Omeprazole 40 mgIV given once daily significantly reduced intragastricpH after 5 days of treatment, although it was not suffi-cient to maintain intragastric pH above 4 in all patientsduring the first day of treatment.72 During the first 72 hours of treatment, a continuous infusion of omepra-zole maintained pH above 4 for ≈95% of the time, withthe maximal effect occurring between 3 and 5 days.70,73

In 2 prospective studies in 75 mechanically venti-lated patients66 and 60 trauma patients,67 omeprazolesuspension administered by nasogastric tube safelyprevented clinically significant GI bleeding and main-tained gastric pH at favorable levels. No cases of clin-ically important upper GI bleeding were observed.Although intravenous omeprazole was reported to

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Table III. Drug–drug interactions with cimetidine.55–58

Coadministered cimetidine interferes with elimination of:N-acetylprocainamideProcainamide

Coadministered cimetidine interferes with absorption of:Calcium channel blockersChlordiazepoxideDiazepamFentanylLidocaineMeperidineMetronidazoleMidazolamNifedipinePhenytoinPropafenonePropranololQuinidineTheophyllineTriazolamTricyclic antidepressantsWarfarin

prevent gastric acid stimulation by parenteral nutri-tion with amino acids, it failed to maintain intra-gastric pH above 4.74 Development of tolerance toomeprazole does not appear to occur.75

Although efficacy and safety studies are currentlyunder way, oral omeprazole is not approved for theprophylaxis of stress ulcers. Omeprazole is known to interact with certain drugs. For example, it canprolong the elimination of diazepam, warfarin, andphenytoin, which are metabolized by oxidation in the liver.69 Interactions have also been reported withcertain drugs metabolized by the CYP system, such as cyclosporine (Table IV53,56).69,76,77

EsomeprazoleEsomeprazole, the S-isomer of omeprazole,65 is the

most recently approved PPI in the United States. It ismetabolized in the liver and may interfere withCYP2C19, the major metabolizing enzyme of the CYPsystem.65,78 No significant drug interactions betweenesomeprazole and phenytoin, warfarin, quinidine,clarithromycin, or amoxicillin have been demonstrat-ed in clinical studies.65,79 Coadministration ofesomeprazole and diazepam (a CYP2C19 substrate)resulted in a 45% decrease in the clearance ofdiazepam.65 Esomeprazole is well tolerated. The mostcommon adverse events associated with its use arediarrhea (4.3%), headache (3.8%), and abdominalpain (3.8%).65,78

LansoprazoleLansoprazole was the second PPI to become avail-

able in the United States. It is well tolerated, and itsadverse effects are similar to those of other PPIs.80

The most commonly occurring adverse effects areheadache and diarrhea.80–82

RabeprazoleRabeprazole was the third PPI to become available.

It has a rapid onset of H+,K+-ATPase inhibition.83

Like pantoprazole, rabeprazole has a minimal effecton the CYP enzyme system and has shown no poten-tial for significant drug interactions.84

PantoprazolePantoprazole was the fourth PPI approved in the

United States. It has the lowest potential for druginteractions of the PPIs. There is some evidence that

pantoprazole may have pharmacologic propertiesleading to longer duration of antisecretory efficacy.85

PPIs inhibit acid production by binding to specificcysteine residues within the proton-transfer domainof actively secreting pumps.83 Whereas lansopra-zole, omeprazole, and rabeprazole interact withonly 1 of the 2 available residues at a time, pan-toprazole appears to covalently modify both.86

Furthermore, lansoprazole, omeprazole, and rabe-prazole are capable of binding other cysteines on theproton pump that are unrelated to acid suppression,which may dilute the level of drug available forinteraction with active enzymes and possibly con-tribute to unwanted systemic effects.83 Its uniquebinding characteristics may explain pantoprazole’sextended inhibitory action. Among the PPIs, panto-prazole has the lowest pH of activation and thehighest stability under moderately acidic condi-tions.85,87 Consequently, pantoprazole is predictedto have high gastric selectivity and a low likelihoodof interacting with ion pumps in cell types otherthan the parietal cell.

The fact that pantoprazole has no known druginteractions, probably because of its low affinity forCYP enzymes,88–90 makes it the most specific of thePPIs. This feature, in addition to its high potency andthe availability of an intravenous form, makes it wellsuited for the prophylaxis of SRMD in the ICU.

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Table IV. Drug–drug interactions with omeprazole andsucralfate.53,56

Coadministered omeprazole interferes with elimination of:CyclosporineDiazepamPhenytoinWarfarin

Coadministered sucralfate interferes with absorption of:CimetidineDigoxinFluoroquinolone antibioticsKetoconazoleL-thyroxinePhenytoinQuinidineRanitidineTetracyclineTheophylline

Intravenous AdministrationThe great majority of patients at risk for SRMD are

found in the ICU. Many of these critically ill patientsrequire mechanical ventilation; have acute gastro-paresis, ileus, or both; and cannot tolerate oral ornasogastric administration of medications. Therefore,their care may be improved by the use of intravenousforms of treatment for the prophylaxis of SRI or stressulcers. In addition, because PPIs work at the cellularlevel, intravenous administration may provide themost efficient and rapid path for these drugs to reachtheir targets. The intravenous form of pantoprazole isequipotent to the oral form in suppressing acid secre-tion in critically ill patients.91 Inhibition of gastric acidsecretion is dose dependent, and a dosage of 80 mg/dsuppresses acid secretion by >90%.92 The availabilityof an intravenous formulation of pantoprazole willallow comparison of the prophylactic efficacy andsafety of this PPI with H2RAs in critically ill patients.93

Other TreatmentsSucralfate

Sucralfate consists of a core of sucrose moleculessurrounded by aluminum hydroxide sulfate salts. Itdoes not inhibit acid secretion or neutralize gastricacid; rather, it coats the gastric mucosa and forms athin protective layer between the mucosa and the gas-tric acid in the lumen.26,94 Another mechanism ofaction may be the stimulation of mucosal defensesthat trigger the release of prostaglandin E2, which iscytoprotective.95,96 Sucralfate has comparable efficacyto antacids in the healing of ulcers.95 A meta-analysisof the efficacy of sucralfate compared with that ofH2RAs (9 studies) and antacids (8 studies) for theprophylaxis of stress ulcers indicated that sucralfatewas at least as effective as the other agents.97

Sucralfate is not a systemic drug and therefore hasadvantages over some other agents in that it does notinteract with other drugs in the bloodstream. A majordrawback to the use of sucralfate is that it maydecrease the absorption of other concomitantlyadministered oral medications such as cimetidine andranitidine (Table IV).94 Therefore, sucralfate shouldbe administered separately from these other drugs;administering the other medication 2 hours beforesucralfate may eliminate drug interactions.94

Aluminum toxicity has occurred in patients withchronic renal failure given sucralfate.94 Toxic eleva-

tions in plasma aluminum levels have been reportedin critically ill patients requiring continuous veno-venous hemofiltration who were receiving sucralfatefor the prophylaxis of stress ulceration.98 A liquidform of sucralfate is available that can be adminis-tered via nasogastric tube.

ProstaglandinsThe only commercially available prostaglandin for

the prophylaxis of GI ulcers is misoprostol, a syn-thetic prostaglandin E1 analogue. This medicationprotects the mucosa and diminishes gastric acidsecretion.99 Very few studies have evaluatedprostaglandin analogues for the prophylaxis of stress-related bleeding in the ICU. One study comparingmisoprostol with antacid titration found no differencebetween treatment groups in lesion scores atendoscopy based on a standard scale or in the inci-dence of serious adverse effects.99 The rate of diarrheawas >22% in both groups, considerably higher thanthat seen with other prophylactic agents for stressulcers.

Somatostatin AnaloguesSomatostatin exerts a powerful tonic inhibitory

effect on acid secretion. There is a local feedbackmechanism by which intraluminal acid stimulatessomatostatin, which in turn attenuates acid secre-tion.100 Somatostatin is the main inhibitor of gastrinin vivo. There are no clinical data evaluating somato-statin analogues for the prophylaxis of SRMD.Therefore, they cannot be recommended for the pro-phylaxis of stress ulcers.

AntacidsAntacids work by neutralizing gastric acid and

inactivating the proteolytic activity of pepsin. Bothactions are achieved at a pH of 5. With frequent dos-ing and pH monitoring, both of which are laborintensive, antacids can maintain a luminal pH ≥3.5.32

A randomized study in ICU patients found that 2 of51 patients (4%) receiving antacid prophylaxis and12 of 49 patients (25%) not receiving antacid pro-phylaxis had stress-related bleeding.32 Patients withrenal failure or hypotension were at particular risk forbleeding. More deaths occurred in patients receivingantacid prophylaxis than in those who were notreceiving such prophylaxis (11 vs 7, respectively).

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Care should be taken when raising the pH of thestomach and concomitantly increasing gastric volumethrough frequent dosing via nasogastric tube. Thiscombination may increase the number of pathogenicflora,101 and the large volumes may increase the riskof aspiration.

Antibiotics for Helicobacter pylori EradicationThe role of Helicobacter pylori in SRMD is contro-

versial.102 A prospective study included serologicanalysis of samples from all consecutive patients overa 1-year period who showed significant upper GIbleeding (defined as hematemesis, melena, or grosslybloody nasogastric aspirate) after cardiac surgery.103

Patients with no evidence of GI hemorrhage after car-diac surgery were chosen as controls. H pylori was notfound to be a risk factor for upper GI bleeding,whereas patients who required prolonged mechanicalventilation were at high risk.

Antibiotic treatment of H pylori infection in theICU setting can be associated with such severe conse-quences as selection for resistant organisms, acquisi-tion of methicillin-resistant Staphylococcus aureus,promotion of ventilator-associated pneumonia,104

and induction of Clostridium difficile colitis.105

Therefore, use of antibiotics for the eradication of H pylori in the acute setting is strongly discourageduntil there is further evidence that the benefit of earlytreatment outweighs the risks.

Continuous Nasogastric FeedingEnteral feeding is widely used in the prevention of

SRMD and is the standard of care in burn units,although its efficacy has not been well established inclinical studies.38 Nonetheless, early enteral nutritionhas been effective in preventing stress ulceration ofthe upper GI tract in severely burned patients.106 Themechanism behind this protective effect is unclear,although because most enteral feeding solutions havea high pH, the constant neutralization of gastric acid-ity has been proposed. The available evidence doesnot support this hypothesis, however. A more likelymechanism is that enteral feeding increases mucosalblood flow, as demonstrated in patients with chronicmesenteric ischemia.107

Care should be taken when choosing prophylacticdrug therapies to be administered with continuousenteral nutrition. Gastric feeding has been shown to

reduce the effectiveness of sucralfate, whereas coad-ministration of enteral nutrition and ranitidine for theprophylaxis of stress ulcers has been associated withreduced bleeding rates.108,109

PROPHYLAXIS OF STRESS ULCERS ANDNOSOCOMIAL PNEUMONIAOne concern with the prophylaxis of stress ulcers isthe reported risk of nosocomial pneumonia,110 whichis the most common infection in mechanically venti-lated patients.111 This complication was thought tobe related to increased gastric pH followed by aspira-tion. Preserving gastric acidity with acidified enteralfeeding solutions has reduced gastric colonization incritically ill patients.112 Alternatively, development ofnosocomial pneumonia could be related to incom-plete suppression of acid volume. Antacids andH2RAs have been associated with increased gastriccolonization, primarily by gram-negative organisms,at gastric pH values >4.101,113,114 Gram-negative bacteria do not grow well in the stomach when the pH is <3.5.115

Several early studies suggested that gastric colo-nization might be less frequent and less severe whenventilated patients were given sucralfate rather thanantacids or H2RAs.116–119 It was thought that not rais-ing the gastric pH might reduce the incidence ofnosocomial pneumonia, as aspiration of organismsfrom the stomach is a major route to the pulmonarytree.120,121 In one of the earliest studies, whichinvolved 130 mechanically ventilated patients,122

nosocomial pneumonia occurred in twice as manypatients receiving antacids, an H2RA, or both com-pared with those receiving sucralfate only (95% CI,0.89–4.58; P = NS). On stratification by single med-ication use, however, receipt of antacids alone wasassociated with a 23.0% incidence of pneumonia,compared with 5.9% with H2RAs alone (lower thanthe 11.5% incidence in the sucralfate group). Theincidence of pneumonia was 46.2% in patients whoreceived both antacids and H2RAs. It is unclearwhether this increase in the incidence of pneumoniawas the result of acid suppression or of increasedgastric volume from frequent antacid administration.The mortality rate was 1.6 times higher in the groupsthat received antacids or H2RAs compared with thegroup that received sucralfate (95% CI, 0.99–2.5; P = NS). A more recent study in children receiving

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ranitidine or sucralfate found that sucralfate did notsignificantly decrease the incidence of ventilator-associated pneumonia compared with ranitidine(7.5% vs 11.1%, respectively) or compared with noprophylaxis.123

In contrast, a meta-analysis of studies in adults foundthat the risk of nosocomial pneumonia was significant-ly increased in critically ill patients who received raniti-dine compared with sucralfate (P = 0.012).59 Anothermeta-analysis found that pneumonia occurred signifi-cantly less frequently in patients given sucralfate com-pared with H2RAs in 5 studies (typical OR, 0.498; 95%CI, 0.316–0.783) or antacids in 4 studies (typical OR,0.402; 95% CI, 0.235–0.687).97 A later randomizedcontrolled trial involving 244 patients reported thatsucralfate reduced the risk for developing late-onsetpneumonia (after 4 days) compared with an antacidand ranitidine (5%, 16%, and 21%, respectively; P =0.022) by maintaining a significantly lower median gas-tric pH (P < 0.001) and significantly reducing gastricbacterial colonization (P = 0.015).124

In a study comparing omeprazole and ranitidinefor stress ulcer prophylaxis,45,125,126 14% of patientsreceiving ranitidine developed nosocomial pneumo-nia, compared with 3% of patients receiving omepra-zole; this difference was not statistically significant.The largest trial to date was a 4-year, prospective, ran-domized trial conducted at 16 Canadian ICUs (N =1200).33 Clinically important bleeding occurred in1.7% of patients receiving intravenous ranitidine,compared with 3.8% of patients receiving sucralfateorally or by nasogastric tube (relative risk = 0.44;95% CI, 0.21–0.92; P = 0.02). There was no signifi-cant difference in the rates of ventilator-associatedpneumonia (19.1% vs 16.2%, respectively).

The prophylaxis of stress ulcers in patients receiv-ing mechanical ventilation remains controversialbecause of the apparent potential for promoting air-way colonization. More study is needed to clarify therates of pneumonia and effectiveness of prophylaxis.In addition, methods of improving host defensemechanisms should be studied to determine whetherventilator-associated pneumonia can be prevented.127

ADVERSE-EFFECT PROFILESHistamine2–Receptor Antagonists

All H2RAs are capable of crossing the blood–brainbarrier and can be associated with neuropsychiatric

symptoms such as agitation, confusion, lethargy, anddisorientation.56 They also block H2 receptors onleukocytes, inhibiting histamine-induced immune func-tions (eg, cytokine production) and interfering withimmunosurveillance.128,129 Their anti-inflammatoryproperties may be related in some way to the increasein GI bacterial colonization associated with the use ofH2RAs. Most adverse effects of H2RAs are dose depen-dent. As mentioned previously, drug interactions occurwith some H2RAs, with the notable exception of famo-tidine. Therefore, use of famotidine may be preferablein patients receiving concomitant medications.63 Up to30% of patients treated with high-dose intravenous ran-itidine had increases in serum aminotransferase levels,but only 10% were affected in this way at lowerdoses.130 Adverse effects are more pronounced in thepresence of renal insufficiency.

Proton Pump InhibitorsOf the available PPIs, omeprazole has the highest

drug-interaction potential (Table IV). All 5 PPIs sig-nificantly raise the pH of the gastric fluid, which canalter the chemistry, absorption, or pH-dependentrelease of oral medications.84 There is no evidencethat this leads to clinically significant consequences.

The interaction of PPIs with the CYP enzyme fam-ily is a potential source of adverse drug interactions.Omeprazole and, to a much lesser extent, lansopra-zole have been shown to induce the activity of CYPenzymes, which could affect the metabolism of othercompounds (eg, caffeine, theophylline, carbama-zepine, warfarin, phenytoin, diazepam, mephenytoin,cyclosporine, bismuth, methotrexate, ketocona-zole).82,131 Of the 5 PPIs, pantoprazole and rabepra-zole have the lowest potential to induce CYP enzymesand therefore have a relatively lower risk for adverseeffects.84

SucralfateSucralfate can decrease the absorption of certain

medications when they are coadministered (Table IV).Other adverse effects of sucralfate include constipationand GI or esophageal bezoar formation.21 However,the incidence of these adverse effects is low (<2%).

ProstaglandinsUse of the synthetic prostaglandin E1 analogue

misoprostol is associated with diarrhea even at mod-

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erate doses and has induced a flare of colitis inpatients with inflammatory bowel disease.132

Prostaglandins cause diarrhea in nearly one third ofpatients, limiting their clinical usefulness.99

AntacidsAntacids are associated with electrolyte abnormal-

ities32 and changes in bowel motility.42 Magnesium-containing preparations create a predisposition todiarrhea and cannot be given to patients with renalinsufficiency, whereas use of aluminum/calcium-containing preparations leads to constipation.56

Prolonged use of antacids may cause alkalosis.42,54,56

CONCLUSIONSImproving GI mucosal hemodynamics by aggressivetreatment of the underlying disease is of paramountimportance in the treatment of SRMD. Removal ofmucosal irritants such as gastric acid is also crucial.An ideal agent would be easily administered, haveminimal potential for drug interactions and adverseeffects, and be available in an intravenous form.

Prostaglandins and somatostatin have no provenbenefit in the prophylaxis of SRMD and cannot berecommended. Their use is associated with diarrhea.Use of somatostatin analogues can lead to electrolyteabnormalities and thyroid dysfunction. The use ofantacids is labor intensive, and the large volumesinvolved may increase the risk of aspiration. Therecan be clinically significant electrolyte abnormalities,diarrhea, and constipation with the use of theseagents, and prolonged use may cause alkalosis. Nostudy has demonstrated a greater benefit withantacids compared with H2RAs or PPIs. H2RAs do notcompletely suppress acid secretion, have the poten-tial for the development of tolerance, and can haveadverse effects; consequently, they are not idealagents for the prophylaxis of stress ulcers. Antibiotictreatment of H pylori infection in the ICU setting can be associated with such severe consequences asselection for resistant organisms, acquisition ofmethicillin-resistant S aureus, promotion of ventilator-associated pneumonia, and induction of C difficile colitis.

The PPIs are the most potent of the availableagents. Their efficacy and low incidence of adverseeffects or drug interactions make them attractive can-didates for the prophylaxis of SRMD, and preliminarystudies have shown promise in this area. One of the

primary factors limiting this application has been thelack of a PPI that could be administered intravenous-ly, although an intravenous formulation of pantopra-zole is now available.

ACKNOWLEDGMENTThis review was supported by Wyeth Pharmaceuticals,Philadelphia, Pennsylvania.

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Address correspondence to: Mitchell J. Spirt, MD, 2080 Century Park East, Suite 1106, Los Angeles, CA 90067.E-mail: [email protected]

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Stress-Related Mucosal Disease: Risk Factors and Prophylactic