287 The comparative efficacy of cimeti- dine and ranitidine in controlling gastric pH in critically ill Stewart Ross Reid MD, Charles Dugald Bayliff PHARMD patients The comparative efficacy of intravenous cimetidine and The use of cimetidine, a histamine-2 (H2) receptor ranitidine in controlling gastric pH in 100 intensive care antagonist, and antacids to increase gastric acid pH unit patients was assessed in a double blind, prospective, and reduce the risk of stress ulceration is well randomized study. The total number of gastric pH deter- documented.l-3 While some studies have shown minations and the number of pH determinations with pH antacids to be superior to cimetidine 4-5 others have less than five were recorded. Patients received either stated that cimetidine is equally efficacious. 1'3 cimetidine or ranitidine via continuous infusion, with Proponents of the use of cimetidine have cited dosage adjustments for patients with renal insufficiency. equal efficacy, convenience (versus hourly titration Antacids were administered each time the gastric pH was of antacid) and reduced incidence of adverse effects less than five. There was no difference overall in the when compared to high dose antacids as the reasons number of patients who had at least one gastric pH for its widespread use. L3 determination < pH 5. There was however, a larger pro- However, cimetidine is a less than ideal agent in portion of patients with >-10, >-15. >--20 and >-25 per the critically ill, especially because of central cent of gastric pH determination < pH 5 in the cimetidine nervous system toxicity and the potential for drug group than in the ranitidine group. This difference was interactions. 6-s Ranitidine, a recently released H2 statistically significant for >25 per cent. The drugs were receptor antagonist, may offer an advantage over well tolerated. Ranitidine was as effective as cimetidine cimetidine since it does not result in the same degree and possibly more so in controlling gastric pH. of neurological toxicity nor interfere with drug metabolism in therapeutic doses. 9 Ranitidine may also be effective when cimetidine has failed, j~ Based on these potential advantages, it seemed appropriate to compare intravenous cimetidine and intravenous ranitidine in the control of gastric pH. Key words GASTROINTESTINAL TRACT: gastric pH, cimetidine, Methods ranitidine; HISTAMINE-2 RECEPTOR ANTAGONISTS: From July 13, 1983 to January 7, 1984,100 patients cimetidine, ranitidine. admitted to the Surgical Intensive Care Unit (SICU) who underwent randomization within 12 hours of From the Departments of Anaesthesia and Pharmacy, admission to the unit were entered into the study, University of Toronto, Sunnybrook Medic',d Centre, providing no exclusion criteria were present. Speci- Toronto, Ontario. fic exclusion criteria were: known hypersensitivity Address correspondence to: Dr. S. R. Reid, Depart- to cimetidine or ranitidine; previous upper gastroin- ment of Anaesthesia, Sunnybrook Medical Centre, 2075 testinal surgery; previous history/evidence of pre- Bayview Avenue, Toronto, Ontario, Canada, M4N 3M5. existing peptic ulcer disease; severe liver disease; Supported in part by Glaxo Canada Limited. haemorrhagic diathesis; moderate pre-existing re- CAN ANAESTH SOC J 1986 / 33:3 / pp287-93 288 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL TABLE 1 Drug doses related to renal function continuous EKG monitoring and an assessment of the Glascow Coma Scale daily. The patients were Creatinine clearance Cimetidine dose Ranitidine dose continued in the study until one of the following > 1 ml/sec 1200 mg/day events occurred: 0.2- I. 0 ml/sec 900 mg/day 1 The patient received a full seven days of therapy. <0.2 ml/sec 600 mg/day 2 The patient was started on oral or nasogastric >0.2 rob'see 300 rag/day feedings. -<0.2 ml/sec 150 mg/day 3 The patient experienced a major gastrointestinal bleed defined as appreciable or continued appear- nal insufficiency (serum creatinine -> 260 ance of blood either fresh or altered blood in the mmol-L-l); prior use of an H2 receptor antagonist nasogastric secretions or melena stools asso- or antacids within 24 hours; age less than 12 years; ciated with a drop in haemoglobin of 20 g.L- ~or pregnant or nursing women; previous history of more. pyloric stenosis, oesophageal stricture, oesopha- 4 The patient developed an adverse effect of geal ring, scleroderma, hiatus hernia or atrophic significant magnitude to preclude continuation of gastritis; a body weight < 40 kg or > 90 kg. the study. Informed consent was obtained from the patient or 5 The patient expired. next of kin. The protocol was reviewed and ac- The number of pH readings < pH 5 and total cepted by the University and Hospital Research number of pH readings were recorded. Patients and Ethics Committees. were deemed eligible for analysis only if they Patients were randomly allocated, by selecting completed 36 hours in the study and had at least nine the next consecutive number box, to receive either gastric acid determinations. Differences between cimetidine 300 mg intravenously over 20 minutes means were analyzed by an unpaired t-test. Differ- followed by a continuous intravenous infusion of ences between proportions were measured by Chi 50 mg per hour (1200 mg daily) or ranitidine 50 mg square analysis. The level of p < 0.05 was con- intravenously over 20 minutes followed by a con- sidered significant. tinuous infusion of 12.5mg per hour (300mg daily). Syringes of the drug were prepared and Results boxes containing these drug kits (for first 24-hour Of the original 100 patients entered in the study 71 period) were stored in the SICU. These kits were (38 of the cimetidine group and 33 of the ranitidine prepared by the Department of Pharmacy with group) were included in the final analysis. The 17 neither the SICU staff nor the patient having patients not included for analysis in the ranitidine knowledge of which drug the kit contained. The group were excluded for the following reasons: nine Pharmacy Department was responsible for supply- improved and were transferred from the SICU in ing subsequent solutions of appropriate drug and less than 36 hours, three died within 36 hours, two any necessary dosage alterations. Patients with mild were started on tube feedings, two were excluded pre-existing renal insufficiency or who developed for an inadequate number of samples and one was renal insufficiency while on study received reduced excluded because of body weight < 40 kg. The 12 doses as indicated in Table I. patients in the cimetidine group not included for A nasogastric tube was inserted and gastric pH analysis were excluded for the following reasons: was measured every four hours using a commer- seven improved and were transferred in less than 36 cially available pH sensitive tape (Colourphast| hours, two died within 36 hours, one was excluded commencing at time 0. Thirty ml of antacid (Gelusil for an inadequate number of samples, one was Extra Strength| was administered via the nasogas- excluded because of body weight > 90 kg and one tric tube if the pH was less than five. Routine blood because of the drug infusion being inadvertently work including serum electrolytes, BUN and creati- turned off for a period of 12 hours. The demo- nine were measured daily. Liver function tests were graphic data are shown in Table II. The two groups done on the day of admission and the day of were comparable with respect to age, sex and hours discharge. Thyroid function tests were done on in the study. admission and one week later. All patients had When patients who failed to have gastric pH Reid and Bayliff: H 2 ANTAGONISTS AND CONTROL OF GASTRIC PH 289 TABLE II Demographicdata TABLE IV Outcomeof patients Cimetidine Ranitidine Cimetidine Ranitidine group group (n = 38) (n = 33) (n = 38) (n = 33) Mortality 7/38 (18.4%) 6/33 (18.2%) Age(years) 39.1-19.4 41.3• Evidenceof bleed 1/38 2/33 Sex (M/F) 24/14 19/14 Length of study time (hours) 81.8 -+ 36.1 91.7-+ 82.0 Primary diagnosis Vascular 3 6 group had microscopic bleeding. This difference Craniofacial surgery 4 4 between groups was not statistically significant. Trauma 11 8 After excluding the first aspirate obtained at time Closed head injury --- trauma 11 7 0, 27 of the 38 patients (71.1 per cent) receiving Neurosurgical/spinalcord trauma 5 5 Acute respiratory failure 1 1 eimetidine had a pH <5 on at least one occasion Sepsis 0 1 while 22 of 33 patients (66.7 per cent) receiving Other (myocardial infarction, 3 0 ranitidine had a pH <5 on at least one occasion seizures, CVA) (p = NS). There were a number of patients in both groups who were completely controlled with these agents. Subsequent analysis of the data and division controlled were placed in risk groups one through of the patients into groups based on the percentage five depending on the number of risk factors of gastric pH determinations of <5 revealed the present, there was no significant difference be- information summarized in the Figure. Poor control tween the groups (Table III) even though there were five patients in the cimetidine group with five risk factors but only one in the ranitidine 60 [•CimeUdlne group with five risk factors. There were no pa- tients who had more than five of the seven risk [] Ranltldine factors. The seven risk factors for stress ulcer- ation included sepsis, respiratory failure, major 50 operative procedures, renal failure, hypotension, -r multiple trauma, head injury and spinal cord injury. r Data were not specifically analyzed within each of 40 the risk groups because of the small numbers in each group. There was no statistical correlation between the number of risk factors and the inability to 30 control gastric pH (r = -0.038).