intravenous bolus versus continuous infusion of famotidine

Intravenous bolus versuscontinuous infusion of famotidineor ranitidine on 24 h intragastric

acidity in fasting healthy volunteersABR THOMSON MD PHD FRCPC FACP FRS FACC, P KIRDEIKIS RN, D WASARAB-ROLLAND,

L ZUK RN, B PINCHBECK PHD

REDUCTION OF INTRAGASTRIC

acidity with intravenousH2-receptor antagonists has been usedfor the prevention of stress-related gas-tric mucosal injury in intensive careunit patients and for the preventionand treatment of upper gastrointestinalbleeding. It is generally thought thatintragastric acidity has to be continu-ously reduced to a level correspondingto an intragastric pH of 4 or greater(1-3). The use of continuous infusionof H2-receptor antagonists in criticallyill patients has been reviewed (4). In-travenous cimetidine controls pH overa 24 h period when given in a dose of900 mg/day (37.5 mg/h) (5,6). Ostroand co-workers (7) have suggested thatcontinuous infusion of cimetidine at37.5 mg/h after a loading dose of 300mg is superior to repeated 300 mg bo-luses every 6 h. Ranitidine injections of150 mg/day or 6.25 mg/h leads to a 24 hmedian intragastric pH of 6.3 in duode-nal ulcer patients (8). No loading doseof ranitidine is needed for rapid onset(9,10). Siepler and colleagues (4) re-ported comparable effects on intragas-tric pH of continuous intravenousinfusion of famotidine 1.7 mg/h (40mg/day), ranitidine 8.3 mg/h (200mg/day) and cimetidine 50 mg/h (1200mg/day). Hannon et al (5) used anautomatic computerized pump tomaintain a constant intragastric pHabove 6.0, and demonstrated that

CLINICAL GASTROENTEROLOGY

ABR THOMSON, P KIRDEIKIS, D WASARAB-ROLLAND, L ZUK, B PINCH-BECK. Intravenous bolus versus continuous infusion of famotidine or raniti-dine on 24 h intragastric acidity in fasting healthy volunteers. Can JGastroenterol 1995;9(1):47-50. Infusions of H2-receptor antagonists may beclinically indicated to maintain intragastric pH above 4 to reduce acute gastricmucosal lesions or to treat patients with bleeding peptic ulcers. Eight fastinghealthy volunteers were randomly assigned to receive ranitidine infusion alone(150 mg/day), ranitidine infusion plus 50 mg bolus injection of ranitidine (totalof 200 mg/day), famotidine infusion alone (40 mg/day) or famotidine infusionplus 40 mg bolus injection of famotidine (total of 80 mg/day). Gastric fluid con-tents were aspirated for 24 h and collected as half-hourly samples in which pHmeasurements were made. Measures analyzed were mean and median pH, per-centage pH at or below 3, 4 or 5 for the 24 h period, daytime, evening and night-time. The data for each of the variables were analyzed as a Latin square crossoverdesign of variance therapy; base pH before treatment administration in eachcrossover phase was employed as the covariant. Significant differential treatmentmeans were tested by Newman-Keul’s multiple range test at the 5% level of sig-nificance. The mean and median evening pH were higher after famotidine thanafter ranitidine infusion, but all other pH readings were similar when using thesedoses. The addition of an initial loading bolus of 50 mg ranitidine to the raniti-dine infusion did not result in any added differences in pH, whereas the additionof an initial loading bolus of 40 mg famotidine to the famotidine infusion resultedin a higher 24 h median pH, as well as a lower percentage of pH values of 4 or be-low, 16.6% versus 28.5%, P<0.05. However, the loading doses of ranitidine andfamotidine were not equivalent in potency, and studies are needed to comparethe potency of equivalent doses of ranitidine and famotidine when given by bolusplus infusion. Also the clinical relevance of these findings needs to be exploredfurther in the type of individuals potentially requiring intravenous H2-receptorantagonists. (Pour résumé, voir page 48)

Key Words: Acid suppression, H2-receptor antagonists

Nutrition and Metabolism Research Group, Department of Medicine, Division ofGastroenterology and Clinical Investigation Unit, University of Alberta, Walter MackenzieHealth Sciences Centre, Edmonton, Alberta

Correspondence and reprints: Dr ABR Thomson, 519 Robert Newton Research Building,University of Alberta, Edmonton, Alberta T6C 2C2. Telephone (403) 492-6490, Fax (403)492-7964

Received for publication March 15, 1994. Accepted July 21, 1994

CAN J GASTROENTEROL VOL 9 NO 1 JANUARY/FEBRUARY 1995 47

mean famotidine use in normal volun-teers was greater with a 12 h bolus fol-lowed by infusion compared withinfusion of famotidine alone, and sur-prisingly onset of action was not appar-ently faster. The efficacy of continuousinfusion versus bolus injection fol-lowed by continuous infusions was notdetermined. The purpose of this studywas to test the hypothesis that famoti-dine and ranitidine given by an initialbolus followed by a continuous infusionof drug is superior to initial infusionalone to maintain intragastric acidityabove pH 4.0.

VOLUNTEERS AND METHODSEight healthy volunteers, four fe-

males and four males, ranging in agefrom 22 to 36 years (mean 28.5) wererecruited for the study. They were

healthy at the pretreatment evaluationand gave written informed consent toparticipate in the study. The exclusioncriteria included pregnancy, plannedpregnancy or lactation; active ulcera-tion and/or peptic ulcer symptoms thatrequired continuous medical treat-ment; treatment with antisecretorydrugs or regular antacid treatment dur-ing the week preceding the study start;pyloric stenosis; history of gastric sur-gery, excluding simple closure or a per-foration; chronic alcoholism, drugabuse or other conditions associatedwith poor volunteer compliance; car-diovascular disease or other conditionsthat might have compromised the vol-unteer’s tolerance to parenteral fluidloading; and any other significant dis-ease that might have placed the volun-

teer at risk or interfere with the studyprocedures.

The study was conducted accordingto the ‘Declaration of Helsinki’ as re-vised in Tokyo, Japan, 1975. Reviewand approval of the study by the insti-tutional review committee of the Uni-versity of Alberta was obtained beforethe start of the study. Before entry intothe study each volunteer underwent aclinical examination including medi-cal history, physical examination and alaboratory screen. Blood and urinesamples for a laboratory screen weretaken at the pre-entry examination andfollow-up. The variables measured in-cluded hemoglobin concentration, redblood cell, white blood cell and plateletcount, aspartate aminotransferase, glu-tamic pyruvic transaminase, alkalinephosphatase, sodium, potassium, cal-cium, creatinine, total bilirubin, andglucose and albumin concentrations.

The volunteers refrained from ex-cessive alcohol consumption duringthe study. The volunteers took no alco-hol for the day before each 24 h aciditytest. Before each experiment day thevolunteers were instructed to have themain evening meal no later than 20:00and, if desired, a light evening snack nolater than 22:00, after which fastingtook place. No antacids were allowedfrom 08:00 on the day before study.Study design: Each of the eight volun-teers took part in four 24 h experiments,separated by at least seven days. In eachexperiment ranitidine or famotidinewas given in random order by intrave-nous bolus plus infusion, or by infusionwithout bolus.

For the primed or ‘bolus’ infusions,50 mg of ranitidine or 40 mg of famoti-dine, in 2 mL, was mixed with 98 mL of2/3+1/3 glucose/saline intravenous so-lution. Each dose was given over 10mins (600 mL/h) at 08:00 only. Afteran initial dose of ranitidine 50 mg or fa-motidine 40 mg, the drug was adminis-tered by continuous infusion using anIVAC 570 pump at a rate of 6.25 mg/hranitidine (ie, 150 mg/day) or 1.7 mg/hfamotidine (ie, 40 mg/day), in 2/3+1/3given intravenously at a rate of 100 mL/h. For the nonprimed infusions, the in-fusion of famotidine or ranitidine wassimilar to the primed infusion, but was

Bolus intraveineux versus perfusion continue de famotidine oude ranitidine et acidité intragastrique sur 24 heures chez desvolontaires sains à jeun

RÉSUMÉ : Des perfusions d’anti-H2 peuvent être cliniquement indiquées afinde maintenir un pH intragastrique supérieur à 4 et atténuer ainsi les lésions aiguësde la muqueuse gastrique ou pour traiter les patients qui souffrent d’ulcères gastro-duodénaux hémorragiques. Huit volontaires sains à jeun ont été assignés auhasard à une perfusion de ranitidine seule (150 mg/jour), une perfusion de raniti-dine plus injection en bolus de 50 mg de ranitidine (pour un total de200 mg/jour), une perfusion de famotidine seule (40 mg/jour) ou une perfusion defamotidine plus injection en bolus de 40 mg de famotidine (pour un total de80 mg/jour). Le liquide gastrique a été aspiré au cours d’une période de 24 heureset recueilli sous forme d’échantillons aux demi-heures sur lesquels des mesures dupH ont été faites. Les mesures analysées étaient le pH moyen et médian, le pour-centage des pH égaux ou inférieurs à 3, 4 ou 5 au cours de la période de 24 heures,durant le jour, le soir et la nuit. Les données pour chacune des variables ont étéanalysées selon un modèle croisé en carré latin. Le pH de départ, avant l’adminis-tration du traitement, dans chaque phase croisée a été employé comme covari-able. Les moyennes différentielles significatives des traitements ont été testées aumoyen de l’épreuve à variables multiples de Newman-Keul, avec un degré deportée de 5 %. La moyenne et la médiane du pH du soir ont été plus élevées aprèsla perfusion de famotidine qu’après la perfusion de ranitidine, mais toutes lesautres lectures de pH étaient semblables avec ces doses. L’ajout d’un bolus decharge initial de 50 mg de ranitidine à la perfusion de ranitidine n’a pas provoquéde différence de pH, alors que l’ajout d’un bolus de charge initial de 40 mg de fa-motidine à la perfusion de famotidine a donné lieu à une médiane du pH sur24 heures plus élevée, de même qu’à un pourcentage plus faible des valeurs de pHde 4 ou moins, 16,6 % contre 28,5 %, P<0,05. Toutefois, les doses de charge deranitidine et de famotidine n’étaient pas équivalentes en terme de puissance.D’autres études sont nécessaires en vue de comparer la puissance de doses équiva-lentes de ranitidine et de famotidine lorsqu’elles sont administrées en bolus et enperfusion. La pertinence clinique de ces analyses doit encore être étudiée chez lessujets qui pourraient nécessiter l’administration d’anti-H2 par voie in-traveineuse.

48 CAN J GASTROENTEROL VOL 9 NO 1 JANUARY/FEBRUARY 1995

THOMSON et al

not preceded by a bolus injection ofranitidine or famotidine. The totaldaily doses were: ranitidine infusion,150 mg/day; ranitidine bolus plus infu-sion, 200 mg/day; famotidine infusion,40 mg/day; famotidine bolus plus infu-sion, 80 mg/day.Twenty-four hour intragastric acid-ity: In the morning of each experimentday, having fasted overnight, the vol-unteer came to the clinical investiga-tion unit. An indwelling cannula wasinserted in a forearm vein for infusion offamotidine or ranitidine. A 12 or 14 Fnasogastric tube was passed and posi-tioned in the most distal part of thestomach. The position was checked bythe water recovery technique; 5 mLsamples of gastric juice were aspirated5 mins before the beginning of thestudy, half-hourly between 00:00-14:00and hourly between 14:00-24:00. Thesubjects’ fluid load was maintained byhourly recording of input/output andregular blood pressure measurement.During the experiment no food was al-lowed. The volunteers were allowed torinse their mouths with tap water, butwere instructed not to swallow any. A2/3+1/3 glucose/normal saline solution(100 mL/h) was given as an intravenousdrip to maintain patient hydration. Thevolunteers were monitored for signs ofpossible adverse effects from the par-enteral fluid load. The following spe-cific safety assessments were done:blood pressure at 6 h intervals; and ac-

curate fluid intake and output record-ings through the 24 h experiment. Ineach gastric sample pH was recorded tothe nearest 0.01 unit, using a combinedglass and reference electrode and a pHmeter (Corning 3AG 500 M/A). Theelectrode was calibrated with standardbuffer solutions of pH 2.01, 4.03 and7.00. The calibration was checked atthe beginning and at the end of the 24 htest. During the 24 h experiment thevolunteers were encouraged to stay inbed. The volunteers stayed in the labo-ratory until about 09:00.Statistical design: The study design is aLatin square crossover with multiplemeasurements at each phase of thecrossover. Each of the eight healthyvolunteers was randomly assigned tothe treatment sequence, and the orderof the treatments in each sequence wasdictated by the Latin square. The meas-ures analyzed were mean and medianpH, and percentage pH less than 3.0,4.0 or 5.0 for each of: the 24 h day, andthe day (08:00-20:00), evening(20:00-24:00) and night (24:00-08:00)periods.

The data for each of the variableswere analyzed as a Latin square cross-over design analysis of covariance. Thebase pH, before treatment administra-tion in each crossover phase, was em-ployed as the covariate. An unrotatedprinciple components analysis was alsoapplied to the analysis variables to de-termine whether an underlying struc-

ture could be found for the variables.Significant differences among treat-ment means were tested by Newman-Keul’s multiple range test at the 5%level of significance.

The treatment means for base pHwere not found to be significantly dif-ferent. For most measures, significantdifferences for the healthy volunteerswere found, indicating that eight per-sons formed a minimum sample. Sig-nificant differences among treatmentswere found for 24 h, evening and nightmedian pH; for evening percentage pHless than 3, and for 24 h and eveningpercentage pH less than 4.0. The ef-fects due to the Latin square designwere not significant for any of the vari-ables. With the exception of eveningmean pH, the covariate effects werealso nonsignificant. The principlecomponents analysis revealed thatthere were two primary componentswithin the data. The first componentwas highly correlated with the 24 hmeasures and the mean pH measuresfor all periods for these data. The vari-ables of the evening period are also ofimportance, as was earlier indicated inthe analysis of covariance. The secondcomponent suggests that there is a re-sidual factor which weakly correlatesthe variables of the day and night peri-ods and which is not being estimated bythe first component.

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