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GASTROENTEROLOGY 2005;128:600–606

echanisms of Gastroesophageal Reflux in Critically Illechanically Ventilated Patients

ARRY NIND,* WEI–HAO CHEN,* RICHARD PROTHEROE,‡ KATSUHIKO IWAKIRI,*OBERT FRASER,§ ROBERT YOUNG,‡ MARIANNE CHAPMAN,‡ NAM NGUYEN,* DANIEL SIFRIM,�

ACHAEL RIGDA,* and RICHARD H. HOLLOWAY*Department of Gastroenterology, Hepatology and General Medicine, ‡Department of Anaesthesia and Intensive Care, and §Universityepartment of Medicine, Royal Adelaide Hospital, Adelaide, South Australia; and �Center for Gastroenterological Research, Katholieke

niversity, Leuven, Belgium

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ackground & Aims: Gastroesophageal reflux is a majorroblem in mechanically ventilated patients and may

ead to pulmonary aspiration and erosive esophagitis.ransient lower esophageal sphincter relaxations arehe most common mechanism underlying reflux in non-entilated patients. The mechanisms that underlie refluxn critically ill ventilated patients have not been studied.he aim of this study was to determine the mechanismsnderlying gastroesophageal reflux in mechanically ven-ilated patients in the intensive care unit. Methods: In 15echanically ventilated intensive care unit patients,

sophageal motility, pH, and intraluminal impedance11/15 patients) were recorded for 1 hour before and 5ours during continuous nasogastric feeding. Results:asal lower esophageal sphincter pressure was uniformly

ow (2.2 � 0.4 mm Hg). The median (interquartile range)cid exposure (pH <4) was 39.4% (0%–100%) fasting and2% (7.5%–94.2%) fed. Acid reflux occurred in 10 patients,ut slow drifts in esophageal pH were also an importantontributor to acid exposure. If esophageal pH decreasedo pH <4, it tended to remain so for prolonged periods. Aotal of 46 acid reflux events were identified. Most (55%)ccurred because of absent lower esophageal sphincterressure alone; 45% occurred during straining or coughing.onclusions: Gastroesophageal reflux in mechanically ven-ilated patients is predominantly due to very low or absentower esophageal sphincter pressure, often with a super-mposed cough or strain. These data suggest that mea-ures that increase basal LES pressure may be useful torevent reflux in ventilated patients.

astroesophageal reflux is a major problem in criticallyill patients in the intensive care unit (ICU). Reflux has

een incriminated as an important cause of nosocomialneumonia.1–3 Reflux esophagitis is also a common findingn critically ill patients, has been reported to be present in5%–30% of ICU patients undergoing upper gastrointes-inal endoscopy, and is the most common cause of upper

astrointestinal bleeding.4,5

The mechanisms that underlie gastroesophageal refluxn ventilated patients, however, have not been character-zed. In awake patients with reflux disease, the majorechanism of reflux is transient lower esophageal sphinc-

er relaxation (TLESR), although absent basal lowersophageal sphincter (LES) pressure is an importantechanism in a substantial minority of patients, partic-

larly those with hiatus hernias.6,7 Straining, associatedith increased abdominal pressure or deep inspiration, iscontributory factor in 20%–30% of reflux episodes.7,8

In mechanically ventilated patients in the ICU, the physi-logical environment differs substantially from that in thewake subject. Esophageal function may be influenced by aariety of potentially confounding factors.9 Anesthesia andedation inhibit the triggering of TLESRs,10 and this would bexpected to decrease the rate of reflux events. However, basalES pressure may be decreased through the effects of sepsis11,12

nd shock,13 thereby potentially increasing the likelihood ofeflux. Mechanical ventilation substantially alters the pres-ure profile across the gastroesophageal junction and affectssophageal motility. The mechanisms that underlie refluxn these patients are therefore likely to differ substantiallyrom those in awake or asleep patients with reflux disease.he aim of this study, therefore, was to investigate theechanisms of gastroesophageal reflux in mechanically ven-

ilated patients in the intensive care setting.

Methods

Patients

We studied 15 mechanically ventilated patients (12en; median age, 55 years; range, 23–77 years) admitted to aixed medical and surgical ICU. The clinical details of the

Abbreviations used in this paper: ICU, intensive care unit; LES, lowersophageal sphincter; TLESR, transient lower esophageal sphincterelaxation.

© 2005 by the American Gastroenterological Association0016-5085/05/$30.00

doi:10.1053/j.gastro.2004.12.034

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March 2005 REFLUX IN ICU PATIENTS 601

atients are summarized in Table 1. Patients were eligible fornrollment if they had been admitted to the ICU 2–14 daysreviously and were tolerating nasogastric feeding. Patientsere excluded if they had undergone previous gastric or esoph-

geal surgery, had a documented history of gastroesophagealeflux disease or esophageal varices, had active gastrointestinalleeding, or had been taking histamine H2 receptor blockersithin 2 days or proton pump inhibitors within 3 days before

he study. The protocol was approved by the Research Ethicsommittee of the Royal Adelaide Hospital, and written in-

ormed consent was obtained from the next of kin.

Recording Techniques

Patients underwent concurrent esophageal manom-try, pH monitoring, and measurement of intraluminallectrical impedance. Esophageal manometry was performedith a 3.5-mm-outer-diameter multilumen-perfused man-metric assembly. LES pressure was recorded with a sleeveensor. A side-hole 1 cm beyond the distal margin of theleeve recorded gastric pressure, side-holes at 3-cm intervalstarting at the proximal margin of the sleeve recordedsophageal body activity, and a side-hole in the pharynxecorded swallowing. The sleeve and gastric side-hole wereerfused with distilled water at 0.3 mL/min, and the esoph-

able 1. Demographic Details of the Patients

Subject Age SexICUdays Diagnosis Ventilatio

1 77 F 6 Gallstone pancreatitisARDS

PEEP

2 62 M 7 Septic shockSecondary pneumonia

PEEP

3 74 M 5 Subarachnoid andintracranial hemorrhage

PEEP

4 76 F 4 Ruptured abdominal aorticaneurysm

SIMV/PEE

5 39 M 5 Burns SIMV/PEE

6 67 M 6 Pneumonia-ARDS SIMV/PEE

7 65 M 8 Burns SIMV/PEE8 45 M 9 Organophosphate

poisoningPS

9 50 M 9 VF arrest, Myocardialinfarction

PS

Acute renal failure10 23 M 12 Traumatic intracranial

hemorrhageSIMV

11 56 M 8 Exacerbation of COPD PS12 38 F 3 Subarachnoid hemorrhage SIMV13 55 M 11 Strychnine poisoning PS14 26 M 4 Pneumonia-ARDS SIMV

15 36 M 6 Hemopneumothorax SIMV/PEE

EEP, positive end-expiration pressure; SIMV, spontaneous intermittistress syndrome; COPD, chronic obstructive pulmonary disease.

geal side-holes were perfused at 0.15 mL/min by a capillary a

nfusion pump (Dentsleeve, Wayville, SA, Australia). Theharyngeal side-hole was perfused with air at 16 mL/min.he manometric assembly also incorporated a central lumen

or the delivery of liquid nasogastric feed.To detect possible weak acidic reflux during continuous intra-

astric feeding, intraluminal electrical impedance was measuredn 11 of the 15 patients by using a separate 2.1-mm assemblySandhill Scientific, Highlands Ranch, CO) that incorporated 6airs of ring electrodes, each 4 mm long and spaced 2 cm apart.he electrode pairs were set at 3-cm intervals that corresponded to

he position of the esophageal manometric side-holes. The tip ofhe impedance assembly was tied to the tip of the manometricssembly to maintain the relative positions of the manometric andmpedance recording sites.

Esophageal pH was recorded by using an antimony pHlectrode positioned 5 cm above the upper border of theanometrically defined LES. The manometric, impedance, and

H signals were recorded and stored by a computerized data-cquisition system (Insight; Sandhill) for subsequent reviewnd analysis.

Protocol

Patients were studied after a 4-hour fast. The recording

Induction Sedation Other meds Prokinetic agents

entanyl/midazolam

Fentanyl/midazolam

Salbutamol/metoprolol

None

Propofol Salbutamol/epinephrine

None

Morphine/midazolom/propofol

Salbutamol/ipratropium

Erythromycin

Morphine/midazolam

Norepinephrine None

Salbutamol/ipratropium/norepinephrine

Metoclopramide

Morphine/midazolam

Salbutamol/norepinephrine

Propofol Salbutamol Noneropofol Salbutamol/

ipratropium pNone

ropofol Amiodarone Metoclopramide

Morphine/midazolam

Metoclopramide

ropofolropofol Noneropofol None

Morphine/midazolam

Salbutamol/ipratropium

Metoclopramide

ropofol Salbutamol/ipratropium

andatory ventilation; PS, pressure support; ARDS, adult respiratory

n

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ssemblies were introduced through the nose under topical

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602 NIND ET AL GASTROENTEROLOGY Vol. 128, No. 3

asal anesthesia. When necessary, a single small dose of propo-ol (140–400 mg), fentanyl (50 mg), or midazolam (1 mg) wasdministered immediately before intubation. The assembliesere positioned such that the sleeve sensor straddled the LES.plain chest radiograph was taken to check the position of the

ssemblies before enteral feeding was started. Recordings wereade for 1 hour with the patients fasting. A standard liquid

eed (Ensure; Abbott Laboratories, Columbus, Ohio) was thenelivered into the stomach through the central lumen of theanometric assembly in a bolus of 100 mL followed by an

nfusion of 50 mL/h for 5 hours.During the recordings, a detailed record was kept of any

rugs, such as sedatives, opiates, or inotropic agents, that theatient was given; the position of the patient; and interven-ions such as suction of the endotracheal tube. Nine patientseceived sedation with propofol (n � 2) or midazolam andorphine or fentanyl (n � 7); 5 patients received inotropic

gents (epinephrine, n � 1; norepinephrine, n � 4); and 9atients received bronchodilators (salbutamol, ipratropium, oroth).

Data Analysis

LES pressure was measured at end-expiration and rel-tive to end-expiratory intragastric pressure. Basal LOS pres-ure was measured as a 1-minute visual mean every 30 min-tes, and mean values were calculated for the 1-hourreprandial and 5-hour postprandial periods.Esophageal pH recordings were analyzed to determine the

umber of reflux episodes and the duration that esophageal pHas �4. Acid reflux episodes were defined as a decrease in

sophageal pH to �4 for at least 4 seconds or, if basalsophageal pH was already �4, as a further decrease in pH oft least 1 pH unit. Instances in which esophageal pH driftedownward to �4 over several minutes were classified as pHrifts; these were included in the analysis of the duration ofsophageal acid exposure but were not scored as reflux epi-odes. Acid clearance time for individual reflux episodes waseasured from the time that pH decreased to �4 to the time

t which esophageal pH increased to �4.The impedance recording was also analyzed for the occur-

ence of liquid reflux episodes. Liquid reflux was defined as aequentially orally progressing decrease in impedance to40% of the baseline value starting distally at the most distal

ecording segment and propagating retrogradely to at least theext 2 more proximal measuring segments.14 Weakly acidiceflux was defined as impedance evidence of liquid reflux notccompanied by a pH decrease to �4.15

The time of onset of the decrease in esophageal pH or theecrease in impedance in the most distal recording segmentas used as the reference time for the analysis of the motor

vents associated with reflux. For each reflux episode, theechanism of reflux was determined from the patterns of LES

ressure and esophageal body activity and their relationship towallowing and abdominal straining.8,16 These mechanismsere classified as TLESR, swallow-induced reflux (including

ultiple swallow), absent basal LOS pressure, straining, and b

oninterpretable when pressures were obscured by movement-nduced artifacts. TLESRs were defined according to criteriaublished previously.17 LES relaxations that lasted more than5 seconds and that were associated with a swallow within 5econds before or 2 seconds after the onset of an LES relaxationere also included as TLESRs.18,19 Additionally, because basalES pressure was very low or undetectable in all patients, theES pressure recording at the time of reflux was also examinedor inhibition of the crural diaphragm and a prominent after-ontraction of the LES: these have been described as commonccurrences with TLESRs.20,21

Results

Gastroesophageal Reflux

Basal esophageal pH tended to range between 3.5nd 5 throughout the recording period. Esophageal acidxposure was recorded in 12 of the 15 patients; esopha-eal pH in 3 patients did not decrease to �4. Esophagealcid exposure varied widely. In patients in whom esoph-geal pH decreased to �4, postprandial acid exposureime ranged from 5% to 100% (median, 32%; interquar-ile range, 7.5%–94%; Figure 1). Preprandial acid expo-ure (median, 39%; interquartile range, 0%–100%) wasimilar to postprandial acid exposure. Impedance moni-oring in 11 patients detected 25 reflux episodes, 12 ofhich were also detected by a decrease in pH.A total of 46 acid reflux episodes were recorded (me-

ian, 2; interquartile range, 0–3.5 per patient). Thereas substantial heterogeneity, and the number per pa-

ient ranged between 0 and 8 (Figure 2). The mediancid clearance time after reflux events was 143 secondsinterquartile range, 28–747 seconds). For episodes inhich both acid and volume clearance could be compared

igure 1. Esophageal acid exposure. Each dot represents data for anndividual patient. The horizontal bars indicate median values.

y using combined pH and impedance monitoring, acid

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March 2005 REFLUX IN ICU PATIENTS 603

learance times (median, 148 seconds; interquartileange, 9.5–1156 seconds) were similar to those for vol-me clearance (median, 60 seconds; interquartile range,4.7–62 seconds).Not all of the acid exposure was the result of reflux

vents. A total of 42 slow downward drifts in esophagealH to �4 were detected in 11 patients; in 2 patientshey were the sole mechanism responsible for the esoph-geal acid exposure. Drifts in pH were associated withore prolonged periods of acid exposure (median, 1055

econds; interquartile range, 365–3600 seconds) thanere reflux episodes (median, 143 seconds; interquartile

ange, 28–747 seconds) and contributed a greater pro-ortion of the acid exposure than did acid reflux episodespreprandial: 100% [25%–100%] vs 0 [0%–75%] ofcid exposure; postprandial: 56% [21%–99%] vs 44%1.5%–79%] by reflux episodes).

Motor Events Associated With RefluxEpisodes

Two patterns of esophageal motor events weredentified with the onset of reflux episodes: absent basalES pressure (Figure 3) and straining, usually associatedith coughing provoked by suction of the endotracheal

ube (Figure 4). Most reflux episodes (55%) were associ-ted with absent basal LES pressure. The remaining 45%ere associated with coughing and straining in the set-

ing of low basal pressure (�5 mm Hg). TLESRs were

igure 2. Number of reflux episodes for the entire recording period.ach dot represents data for an individual patient. The horizontal bars

ndicate the median value.

ot identified in any patient. e

Esophageal Motility

Basal LES pressure was uniformly low, to theoint of being almost undetectable, in all patients. Theean basal pressure was 2.2 � 0.4 mm Hg (mean �

EM) during fasting and 2.2 � 0.4 mm Hg duringeeding, and it ranged from 0 to 5 mm Hg. Swallowingas uncommon, and swallow-induced LES relaxation wasot evident in any patient.

igure 3. Example of a spontaneous reflux event, as evidenced by aecrease in esophageal pH and in intraluminal impedance, that oc-urred during a period of absent basal lower esophageal sphincterLES) pressure. The reflux event was followed by a simultaneoussophageal pressure wave response.

igure 4. Example of a cough-induced reflux provoked by suctioningf the endotracheal tube. LES, lower esophageal sphincter; Esoph,

sophagus; Stom, stomach.

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604 NIND ET AL GASTROENTEROLOGY Vol. 128, No. 3

Esophageal body contractions were infrequent, andotor activity was characterized by long periods of qui-

scence. A total of 1397 motor events were recordedmedian, 78; interquartile range, 40–155 per patient).f these, 441 (32%) were triggered by swallowing. Most

94%) responses were nonperistaltic and characterized byither nontransmitted (34%) or simultaneous (60%)ressure waves. Only 80 (6%) responses were propagated.

Discussion

Gastroesophageal reflux is an important cause ofignificant morbidity in critically ill patients in intensiveare. However, relatively little is known about the pat-erns and severity of reflux in such patients. This is therst study to investigate the mechanisms of reflux inechanically ventilated patients in an ICU. We detected

igh levels of acid exposure in most of these patients,rimarily as a result of gradual drifts of esophageal pH,ut also after infrequent but poorly cleared acid refluxpisodes. Most reflux episodes occurred apparently spon-aneously in the setting of absent basal LES pressure, butsubstantial minority occurred during episodes of strain-

ng. This pattern differs markedly from that seen inwake subjects and has implications for antireflux ther-py in critically ill patients in intensive care.

The prevalence of gastroesophageal reflux in untreatedCU patients has not been reported previously. In thistudy, acid reflux occurred in 60% of untreated patients.oreover, substantial acid exposure can also occur be-

ause of slow downward drifts in pH. Reflux esophagitisas been reported to be present in at least 25% of ICUatients undergoing endoscopy.4,5 However, not all pa-ients with gastroesophageal reflux have esophagitis, andhis figure is likely to underestimate the actual preva-ence of reflux. Wilmer et al22 reported pathologic bileeflux in 12 of 25 ventilated ICU patients receiving aciduppression with ranitidine. Our finding that impedanceeasurements detected weakly acidic reflux events ap-

roximately 55% of the time compared with combinedH and impedance recordings is in agreement with thosef Wilmer. Because reflux has been incriminated in theathogenesis of other significant complications of inten-ive care, such as nosocomial pneumonia,1–3 these find-ngs are worthy of further study.

A strength of our study was the incorporation ofultiple intraluminal impedance measurements. Al-

hough our patients were not receiving acid-suppressiveherapy during the study, continuous intragastric feed-ng may buffer gastric acid. Esophageal impedance mon-toring is now regarded as the most sensitive method for

he detection of reflux episodes, particularly weakly e

cidic or nonacid reflux,14,15,23,24 and was included in theecording methods of 11 patients. We detected 25 refluxpisodes by this technique, 13 of which were not asso-iated with a detectable decrease in esophageal pH.gents such as histamine H2 receptor antagonists that

ncrease intragastric pH have been shown to increase thencidence of gram-negative bacilli in gastric aspirates, asell as tracheal aspirates from patients with pneumonia.3

eflux of relatively nonacid gastric contents during treat-ent with acid suppressants may be an important con-

ributor to this process. Further studies are needed toetermine the prevalence of weak acid reflux in venti-ated patients receiving acid suppressants. Impedanceetected 86% of acid reflux episodes. This is a smallerroportion than the 95%–98% that has been publishedreviously.15 The reason why fewer reflux events wereetected by impedance than by pH measurement is notlear. Some reflux acid events are missed by impedanceeasurement, possibly because the volume of refluxate is

oo small to alter intraluminal impedance.24 Also, theensitivity of impedance to detect liquid reflux is im-aired in the presence of low basal impedance values15:his was the case in some instances. In most patients,here were prolonged periods, up to �30 minutes, wherempedance values were very high and in the range nor-ally seen with gas. These could be cleared transiently

y esophageal motor activity, suggesting that the valuesere due to intraluminal content rather than equipmentalfunction. The reasons for accumulation of gas in the

sophagus are not known but may relate to clearanceailure because of the paucity of esophageal motor activ-ty.

The mechanisms that underlie reflux episodes in me-hanically ventilated critically ill patients differ substan-ially from those in nonventilated patients. The majorechanism of reflux in healthy subjects and most pa-

ients with reflux disease is TLESR. Absent basal LESressure, however, is the predominant mechanism in aubstantial minority of patients with reflux disease, par-icularly those with severe esophagitis,16 large hiatusernias,7 or both. In contrast, all of the reflux episodes inhe ICU patients occurred during periods of low tobsent basal LES pressure. Two thirds of the refluxpisodes occurred apparently spontaneously when LESressure was absent. However, straining, mostly associ-ted with coughing induced by suction of the endotra-heal tube, was an important factor in the remainder. NoLESRs were observed in any of the recordings, probablyecause TLESRs are largely suppressed during sleep25,26

r anesthesia10 and because basal LES pressure was tooow for much of the time to allow detection of these

vents. TLESRs are associated with inhibition of the

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March 2005 REFLUX IN ICU PATIENTS 605

rural diaphragm20 and can be identified when basal LESressure is low by detection of diaphragmatic inhibi-ion.27 We did not specifically record the activity of therural diaphragm either with a reverse-perfused sleeveensor28 or by electromyography.29 It is possible, how-ver, to detect the mechanical effects of the crural dia-hragm on pressure at the gastroesophageal junction bysing a standard-perfused sleeve sensor. The LES pressureecording did not show the usual rhythmic pressurencreases associated with crural diaphragm contractionuring inspiration, presumably because the patients wereeceiving mechanical ventilation, and, even on carefulnspection of the LES pressure tracing, we could notdentify any transient changes in the pressure recordingsssociated with apparently spontaneous reflux episodes.

Relatively few actual reflux events were recorded, andhe major contributor to the extraordinarily prolongederiods of esophageal acid exposure in the patients wasmpaired acid clearance. In some patients, 1 reflux epi-ode or pH drift was sufficient to acidify the esophagusor the remainder of the study. Acid clearance is a 2-steprocess: volume clearance by esophageal peristalsis fol-owed by chemical neutralization by swallowed salivaryicarbonate.30 Both of these elements are likely to beeverely impaired in ventilated patients. First, as haseen reported previously,31 esophageal motility wasarkedly impaired. Second, salivary secretion is dimin-

shed by sleep.32 Furthermore, the finding that imped-nce clearance was similar to that measured by esopha-eal pH also supports the notion that impairment ofolume clearance is a major contributor to impaired acidlearance in critically ill patients.

A significant contributor to esophageal acid exposureas a slow drift in esophageal pH. The mechanismnderlying these drifts is unclear. Under conditions ofow to absent basal LES pressure, the recording assemblyay act as a wick. The available data on this issue,

owever, are conflicting, and it would seem that whereaspH catheter across the LES may impair acid clearance

nd thereby prolong acid exposure, it does not increasehe number of reflux episodes.33 Consideration of therofile of pH change suggests that these most likelyepresent a combination of inadequate acid clearancessociated with background variations in esophageal pH.irst, basal esophageal pH tended to vary within a nar-ow pH range (3.5–5) and often hovered at approxi-ately 4.5. In contrast to awake subjects, patients in the

CU who are sedated do not have regular swallow-in-uced clearance events and are likely to have relativelyittle salivary secretion. In such circumstances, the factorshat exist normally to maintain esophageal pH at ap-

roximately 5–6 are inoperative. Second, some events

ere characterized by a relatively abrupt increase in pHo approximately 4–4.5, followed by a slow drift down-ard. This pattern is compatible with only transient

ncreases of esophageal pH, with a subsequent drift backo basal levels.

A notable feature of esophageal motor activity in ouratients was the low or absent basal LES pressurehroughout the recording period and the paucity ofsophageal body activity. There are no previous reports ofES pressure in critically ill mechanically ventilatedatients. A number of factors may contribute to lowasal LES pressure in such patients. Most of the patientsere receiving adrenergic agonists for either circulatory

upport or as bronchodilators, and many were also re-eiving opiates as sedation for their ventilation. Theselasses of drug are known to decrease basal pressure.34–38

n addition, hypotension13 and sepsis associated withndotoxemia11,12 may also contribute in some patients.

The findings of this study may have important impli-ations for antireflux therapy in mechanically ventilatedatients in intensive care. Currently, treatment is basedargely on the use of acid-suppressive agents. However,oncern has been expressed that such agents may increasehe risk for nosocomial pneumonia by facilitating therowth of bacteria within the stomach.3 The finding thatost reflux episodes occur because of either absent LES

ressure or the overcoming of low basal pressure bytraining suggests that agents that increase basal LESressure might be useful in this setting. This approachas not proven particularly successful in awake patients,ossibly because of the greater importance of TLESRs asreflux mechanism and the likelihood that, even if basalES pressure is increased, reflux will still occur because ofLESRs. In ICU patients, however, TLESRs are likely toe suppressed by sedation and are therefore unlikely tomerge as a reflux mechanism even if basal LES pressures increased pharmacologically. This approach, however,emains to be tested.

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3. Driks M, Craven D, Celli B, Manning M, Burke R, Garvin G,Kunches L, Farber H, Wedel S, McCabe W. Nosocomial pneumo-nia in intubated patients given sucralfate as compared with ant-acids or histamine type 2 blockers. N Engl J Med 1987;317:1376–1382.

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Received June 26, 2004. Accepted December 9, 2004.Address correspondence to: Richard H. Holloway, MD, Department

f Gastroenterology, Hepatology and General Medicine, Royal Ad-laide Hospital, North Terrace, Adelaide, SA, 5000, Australia. e-mail:

hollowa@mail.rah.sa.gov.au; fax: (61) 8-8222-5885.