|Year : 2008 | Volume
| Issue : 2 | Page : 179-184
Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis
Smita Prakash1, Anutam Rai2, Anoop Raj Gogia3, Sunil Prakash4
1 Senior Specialist, Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India
2 Senior Resident, Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India
3 Senior Specialist & Head of Department, Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India
4 Senior Physician, Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjang Hospital, New Delhi, India
|Date of Acceptance||15-Feb-2010|
|Date of Web Publication||19-Mar-2010|
C - 17 HUDCO Place, New Delhi- 110049
Source of Support: None, Conflict of Interest: None
This study was conducted to evaluate the incidence of early- and late-onset nosocomial pneumonia, gastric colonization, and gastrointestinal bleeding in 50 orotracheally intubated, mechanically ventilated patients treated with sucralfate or ranitidine for stress ulcer prophylaxis in the intensive care unit.
Patients received either iv ranitidine (50 mg every 6h) in Ranitidine group or nasogastric sucralfate suspension (1 g every 6h) in Sucralfate group.
The overall incidence of pneumonia and incidence of early-onset pneumonia was comparable between the two groups (p > 0.05). Late- onset pneumonia was observed in 10 (23.8%) patients in the Ranitidine group and 2 (4.8%) patients in the Sucralfate group (P= 0.001). The mean gastric pH (6.04 ± 1.34 and 3.64 ± 1.55, respectively; P= 0.001)), rate of gastric colonization (92% and 16%, respectively; P=0.000), and gastric source of pneumonia (10 patients and 1 patient, respectively; P= 0.017) was higher in the Ranitidine group as compared to the Sucralfate group. Mortality and gastrointestinal bleeding were comparable between groups.
We concluded that stress ulcer prophylaxis with ranitidine increases the risk for late- onset pneumonia in mechanically ventilated critically ill patients by favoring gastric colonization by gram- negative bacilli compared with sucralfate. In patients receiving mechanical ventilation, the use of sucralfate may be preferable to H 2 blockers.
Keywords: Nosocomial pneumonia; Stress ulcer; Sucralfate;Ranitidine; Tracheal intubation; Mechanical ventilation
|How to cite this article:|
Prakash S, Rai A, Gogia AR, Prakash S. Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis. Indian J Anaesth 2008;52:179-84
|How to cite this URL:|
Prakash S, Rai A, Gogia AR, Prakash S. Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Ranitidine or Sucralfate as Stress Ulcer Prophylaxis. Indian J Anaesth [serial online] 2008 [cited 2019 Aug 18];52:179-84. Available from: http://www.ijaweb.org/text.asp?2008/52/2/179/60618
| Introduction|| |
Mechanically ventilated patients in the intensive care unit (ICU) are at a four to 21 times higher risk of stress ulceration compared with those patients in ICUs who do not receive mechanical ventilation  .The mortality associated with bleeding from stress ulceration has been reported to be 64% compared with 9% in those without stress ulceration  . Hence, stress ulcer prophylaxis is an integral part of the treatment protocol for mechanically ventilated patients.
Antacids, the first agents employed for stress ulcer prophylaxis, have been widely displaced by histamine 2 - receptor blockers (H 2 blockers) and sucralfate due to the excessive demand on nursing time resulting from frequent dosing and gastric pH testing  . H 2 blockers, such as ranitidine, block the secretion of gastric acid. Sucralfate causes ulcer healing by binding to proteins at the ulcer base, forming a protective coating over it. There are conflicting data on the effect of H 2 blockers and sucralfate on the development of nosocomial pneumonia. Studies have suggested that agents that raise the gastric pH may promote proliferation of bacteria in the stomach, particularly gram- negative bacilli, which may originate in the duodenum ,,,, . Passive esophageal reflux and micro aspiration of the gastric contents along the tracheal tube might lead to colonization of the trachea, and then, to pneumonia ,,,,10],, . Sucralfate does not alter gastric pH; its use could possibly lead to decreased occurrence of nosocomial pneumonia compared with H 2 blocker therapy.
Our study was proposed to evaluate the incidence of nosocomial pneumonia, gastric colonization, and clinically significant gastrointestinal bleeding in fifty orotracheally intubated, mechanically ventilated patients treated with sucralfate or ranitidine for stress ulcer prophylaxis in the intensive care unit.
| Methods|| |
The study protocol was approved by the institutional ethics committee, and informed consent was obtained from the patients or, if this was not possible because of the clinical condition, from a relative of the family. Patients admitted to the adult ICU who were receiving mechanical ventilation for at least 24 hours, had a nasogastric tube in place, and had an expected ICU stay of at least 3 days were included in the study. Patients were excluded from the study if they were anticipated to require mechanical ventilation for less than 24 hours, had received antacids, H 2 blockers or sucralfate within the previous 48 hours, had active gastrointestinal bleed, had evidence of infiltrates on the chest radiograph at the time of admission, were on steroids, had undergone gastric or esophageal surgery, or were pregnant.
Patients were randomly assigned to prophylaxis with either ranitidine 50mg administered intravenously every 6 hours (Ranitidine group) or sucralfate administered as 1gm of suspension diluted in 20 ml sterile water through a nasogastric tube every 6 hours (Sucralfate group). The nasogastric tube was flushed with 10 ml sterile water and clamped for 30 minutes after instillation. Randomization was done using a computer generated random number table.
For all eligible patients, demographic profile, physical signs, laboratory tests, and medications were recorded prospectively. However, only patients eventually intubated for more than 24 hours were followed and included in the final analysis. The following investigations were performed within 24 hours of admission to the ICU: complete blood count with differential, serum electrolytes, chest radiography, gastric aspirate pH, gastric aspirate culture, and tracheal aspirate culture. Glasgow Coma and Acute Physiology and Chronic Health Evaluation (APACHE II) scoring systems were used to assess the severity of the acute illness. 
Patients were followed up for a period of 7 days with daily chest radiograph, complete blood count with differential, serum electrolytes, and gastric pH measurements. Chest radiographs were interpreted by a radiologist who had no knowledge of the patients' treatment group after randomization. Gastric aspirate pH was measured once daily, starting from before institution of stress ulcer prophylaxis, by pH indicator strips (pH range, 2 - 10; Merck).Gastric pH values were determined before the tube feedings were begun. Gastric aspirate cultures were obtained on days 3, 5, and 7. Blood cultures and a tracheal aspirate for Gram's stain, culture and sensitivity were obtained if the patient's temperature > 38 o C, total leucocyte count >10,000/mm 3 , or appearance of fresh infiltrates on the chest radiograph. Tracheal aspirates were obtained by bronchoalveolar lavage.
Criteria for diagnosis of pneumonia were derived from those of Thomason et al.  Pneumonia was defined as an infiltrate on chest X-ray plus three of the following criteria: (1) leucocytosis >10,000 cells/mm 3 , (2) pathogenic bacteria on a tracheal or blood culture, (3) Gram's stain of tracheal aspirate showing moderate to heavy bacteria or polymorphs-neutrophils >25/HPF, (4) temperature >38 o C. Using the criteria of Langer and colleagues,  early-onset and late-onset pneumonia were diagnosed if they occurred during the first 4 days of or 4 days after the initiation of mechanical ventilation, respectively. Patients observed for more than four days were evaluated for the development of late-onset pneumonia.
Gastric colonization was defined by the isolation of the same organism from the gastric aspirate culture on at least two occasions. Gastric source of pneumonia was defined as cases where pneumonia developed after gastric colonization, with the same organism being isolated from both tracheal and gastric aspirates. 
Significant upper gastrointestinal bleeding was considered to be present in the event of haematemesis, malaena, haematochezia, or fresh blood per nasogastric tube, which did not clear after lavage with 500ml sterile saline.
Statistical analysis was performed with student's ttest for continuous variables and chi-square analysis for discrete variables. A P value of <0.05 was considered significant.
SPSS software (version 10.0; SPSS Inc., Chicago, IL, USA) was used for statistical analysis.
| Results|| |
Fifty patients were evaluated- 25 patients in each treatment group. There were no significant differences between the groups with respect to age, sex, distribution of underlying diseases, the severity of illness, prophylactic antibiotic therapy, and gastric pH at admission [Table 1].
Pneumonia developed in 25 (50%) of the 50 study patients - 15 (60%) in the Ranitidine group and 10 (40%) in the Sucralfate group. The difference in the overall incidence of nosocomial pneumonia was not statistically significant between the two groups (P = 0.258) [Table 2].
The incidence of early-onset pneumonia was 20% in the Ranitidine group and 32% in the Sucralfate group. This difference was not statistically significant (P= 0.098).
Seven patients were extubated and one patient died before four days of observation and could not be analysed for the development of late onset pneumonia. Of the 42 patients observed for more than four days, late- onset pneumonia was diagnosed in 10 patients (23.8%) in the Ranitidine group and in 2 patients (4.8%) in the Sucralfate group; P= 0.001 [Table 2]. The mean gastric pH at admission in the Ranitidine group (2.68 ± 1.07) and the Sucralfate group (3.04 ± 1.40) were comparable; P= 0.312. The mean gastric pH after administration of the study drugs in the Ranitidine group (6.04 ± 1.34) was significantly higher compared with that in the Sucralfate group (3.64 ± 1.55); P= 0.001.
The mean gastric pH in patients who developed pneumonia (5.48 ± 1.96) was significantly higher as compared to the gastric pH in patients who did not develop pneumonia (4.20 ± 1.58); P = 0.014.
Twenty seven of the 50 patients in the study population developed gastric colonization. 92% (23 of 25 patients) of patients in the Ranitidine group exhibited gastric colonization compared with 16% (4 of 25 patients) of patients in the Sucralfate group; P= 0.000 [Table 3].
The mean gastric pH in patients exhibiting gastric colonization was 5.78 ± 1.63, which is significantly higher than that observed in patients without gastric colonization (3.74 ± 1.54) (P = 0.006). Of the 25 patients who developed nosocomial pneumonia, 18 (72%) had gastric colonization by gram- negative bacilli, while 7 (28%) did not exhibit gastric colonization. This difference was statistically significant; P= 0.023.
Bacterial isolates from gastric and tracheal aspirate cultures are shown in [Table 4] and [Table 5].
Of the 25 patients who developed pneumonia, 11 (44%) patients fulfilled the criteria for gastric source of pneumonia, that is, gastric colonization preceded pneumonia and the same organisms were isolated from the tracheal and the gastric aspirates. Of the 11 patients, 10 patients belonged to the Ranitidine group and one patient to the Sucralfate group. The difference was statistically significant; P = 0.017 [Table 3].
Significant upper GI bleeding developed in one patient belonging to the Ranitidine group. Blood transfusion was not required.
There were 8 (16%) deaths in the study population; 5 (20%) in the Ranitidine group and 3 (12%) in the Sucralfate group. The mortality rate among patients in the two groups was not statistically significant (P = 0.461). Of the 8 patients who died, 6 patients had pneumonia. The mortality rate in patients with and without pneumonia in the two groups was not significantly different; P = 1.000.
| Discussion|| |
Patients receiving mechanical ventilation are at an increased risk for the development of pneumonia ,,. The presence of the tracheal tube (impairs coughing, impedes pulmonary clearance mechanisms, allows leakage of oropharyngeal secretions in the tracheobronchial tree)  , supine position for long periods  , presence of a nasogastric tube (renders the lower esophageal sphincter incompetent, may act as a conduit for bacteria to ascend from the stomach to the pharynx)  , and enteral feeding (raises gastric pH)  are some of the factors that are implicated in the development of nosocomial pneumonia.
The overall incidence of nosocomial pneumonia in our study was 50%, which is comparable to that reported in previous studies by Salata et al (41%)  and Kerver et al (67%)  . Lower incidence rates ranging from 13% to 22% have been reported by others ,,, .
The incidence of pneumonia over the 7day  period was not significantly different between the Ranitidine group and the Sucralfate group. These results are consistent with the findings of Thomason et al  and Prod'hom et al  . Driks et al  found a significantly lower incidence of pneumonia for sucralfate (11.5%) as compared to the antacid-H 2 blocker combination (23.2%) but when the three groups were considered separately, there was no significant difference in the incidence of pneumonia between the H 2 blocker group and Sucralfate group.
The difference in the incidence of early- onset pneumonia between the Ranitidine group and the Sucralfate group was not statistically significant. These findings are consistent with the observations of previous workers. , Prod'hom et al  reported an incidence of early-onset pneumonia in 10 per cent of patients in the Ranitidine group and 8 per cent of patients in the Sucralfate group. The etiology of early- onset pneumonia is postulated to be different from that of late- onset pneumonia.  In early- onset pneumonia, the spectrum of bacteria mostly includes oropharyngeal species thought to have been introduced in the trachea before, or at the time of intubation. , Therefore, early- onset pneumonia is unlikely to depend much on the gastric pH modifications induced by therapy with the various anti-stress ulcer medications. 
The incidence of late-onset pneumonia in the Ranitidine group (23.8 %) was significantly higher compared to that in the Sucralfate group (4.8 %) in our study. This is similar to that reported by Prod'hom et al  - 5% and 21% for Sucralfate and Ranitidine group, respectively. Thomason et al  also found a trend towards decreased incidence of late- onset pneumonia (5% in Sucralfate group and 15% in Ranitidine group), but their results fell just short of being statistically significant. The reason for increase in the incidence of late- onset pneumonia in the ranitidine group can be retrograde colonization by gramnegative bacilli from the stomach. Prod'hom et al  postulate that the higher rate of late-onset pneumonia observed in patients treated with antacid or Ranitidine are most likely a result of the gastric pH elevation induced by these agents. Pneumonia that develops after a few days of intubation is most frequently associated with gram-negative bacilli , . This was established by our study where 96% of organisms isolated from tracheal aspirates were gram- negative bacilli.
Mean gastric pH was found to be significantly higher in patients receiving ranitidine as compared to those receiving Sucralfate. Studies have correlated high levels of gastric pH with logarithmic increases in the concentrations of gram-negative bacilli in the gastric aspirates, and demonstrated the development of retrograde colonization from the stomach to the pharynx and the trachea , . In the present study, the mean gastric pH in patients with gastric colonization was significantly higher than the gastric pH in patients without gastric colonization. Low gastric pH inhibits the growth of bacteria, so raising the gastric pH increases the number of organisms in the stomach. Prod'hom et al  demonstrated a 48% gastric colonization rate for patients with gastric pH = 4 as compared with 28% in those with pH < 4.
The incidence of pneumonia in patients having gastric colonization (72%) was significantly higher than that in patients without gastric colonization (28%) in our study. In addition, the number of patients fulfilling criteria for gastric source of pneumonia was greater in the Ranitidine group (40%) as compared to the Sucralfate group (4%). Similar results were reported by Driks et al  who found a significantly higher proportion of patients exhibiting gastric source of pneumonia in patients with gastric pH= 4 than those with gastric pH< 4. Thomason et al  observed a higher gastric to tracheal colonization in patients who developed pneumonia.
There were no significant differences in the mortality rates and incidence of significant upper gastrointestinal bleeding between the two study groups. None of the previous studies , registered any significant difference in upper gastrointestinal bleeding between patients receiving either H 2 blockers or sucralfate. Driks et al  reported a higher mortality in the group of patients receiving H 2 blocker-antacid combination. The mortality rate in our study is similar to that reported by Prod'hom et al. 
In conclusion, the overall incidence of nosocomial pneumonia during the study period was not significantly different between the two groups of mechanically ventilated patients receiving ranitidine or sucralfate for stress ulcer prophylaxis. However, late onset pneumonia occurred more frequently in patients receiving ranitidine as compared to those receiving sucralfate. Forty four per cent of patients who developed pneumonia had gastric source of pneumonia, which supports the role of retrograde colonization in the causation of nosocomial pneumonia. The mean gastric pH, rate of gastric colonization, and gastric source of pneumonia was higher in the ranitidine group as compared to the sucralfate group. Sucralfate was as effective as ranitidine in preventing clinically significant stress-ulcer bleeding. Our results suggest that agents like H 2 blockers that elevate gastric pH, increase the risk of late-onset pneumonia in patients receiving mechanical ventilation by favoring gastric colonization by gram- negative bacilli. In patients receiving mechanical ventilation, the use of sucralfate, which preserves the natural acid barrier against bacterial overgrowth, may be preferable to H 2 blockers.
| References|| |
|1.||Cook DJ, Laine LA, Guyatt GH, Raffin TA. Nosocomial pneumonia and the role of gastric pH: a meta- analysis. Chest 1991; 100: 7-13. [PUBMED] [FULLTEXT] |
|2.||Cook DJ, Witt LG, Cook RJ, Guyatt GH. Stress ulcer prophylaxis in the critically ill: a meta- analysis. Am J Med 1991; 91: 519-527. [PUBMED] |
|3.||Fabian TC, Boucher BA, Croce MA, et al. Pneumonia and stress ulceration in severely injured patients: A prospective evaluation of the effects of stress ulcer prophylaxis. Arch Surg 1993; 128: 185-192. [PUBMED] |
|4.||du Moulin GC, Paterson DG, Hedley-Whyte J, Lisbon A. Aspiration of gastric bacteria in antacid- treated patients: a frequent cause of postoperative colonization of the airway. Lancet 1982; 1: 242-245. [PUBMED] |
|5.||Donowitz LG, Page MC, Mileur BL, Guenthner SH. Alteration of normal gastric flora in critical care patients receiving antacid and cimetidine therapy. Infect control 1986; 7: 23- 26. [PUBMED] |
|6.||Daschner F, Kappstein I, Engels I, et al. Stress ulcer prophylaxis and ventilation pneumonia: prevention by anti-bacterial cytoprotective agents? Infect Control Hosp Epidemiol 1988; 9: 59-65. [PUBMED] |
|7.||Ruddell WS, Axon AT, Findlay JM, Bartholomew B, Hill MJ. Effect of cimetidine on the gastric bacterial flora. Lancet 1980; 1: 672- 674. |
|8.||Inglis TJ, Sherratt MJ, Sproat LJ, Gibson JS, Hawkey PM. Gastroduodenal dysfunction and bacterial colonization of the ventilated lung. Lancet 1993; 341: 911- 913. |
|9.||Atherton ST, White DJ. Stomach as source of bacteria colonizing respiratory tract during artificial ventilation. Lancet 1978; 2:968- 969. [PUBMED] [FULLTEXT] |
|10.||Garvey BM, McCambley JA, Tuxen DV. Effects of gastric alkalization on bacterial colonization in critically ill patients. Crit Care Med 1989; 17: 211- 216. [PUBMED] |
|11.||Simms HH, DeMaria E, McDonald L, et al. Role of gastric colonization in the development of pneumonia in critically ill trauma patients: results of a prospective randomized trial. J Trauma 1991; 31: 531- 537. [PUBMED] |
|12.||Tryba M. The gastropulmonary route of infection- fact or fiction. Am J Med 1991; 91: 135-146. |
|13.||Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med 1985; 13: 818- 829. [PUBMED] |
|14.||Thomason MH, Payseur ES, Hakenewerth AM, et al. Nosocomial pneumonia in ventilated trauma patients during stress ulcer prophylaxis with sucralfate, antacid, and ranitidine. J Trauma 1996; 41: 503-508. [PUBMED] [FULLTEXT] |
|15.||Langer M, Cigada M, Mandelli M, Mosconi P, Tognoni G. Early- onset pneumonia: a multi-center study in intensive care units. Intensive Care Med 1987; 13: 342- 346. [PUBMED] |
|16.||Craven DE, Kunches LM, Lichtenberg DA, et al. Risk factors for pneumonia and fatality in patients receiving continuous mechanical ventilation. Am Rev Respir Dis 1986; 133: 792-796. [PUBMED] |
|17.||Cross AS, Roup B. Role of respiratory assistance devices in endemic nosocomial pneumonia. Am J Med 1981; 70: 681- 685. [PUBMED] [FULLTEXT] |
|18.||Craven DE, Driks MR. Pneumonia in the intubated patient. Semin Respir Infect 1987; 2: 20-33. [PUBMED] |
|19.||Spray SB, Zuidema GD, Cameron Hl. Aspiration pneumonia: incidence of aspiration with endotracheal tubes. Am J Surg 1976; 131: 701- 703. |
|20.||Pingleton SK, Hinthorn DR, Liu C. Enteral nutrition in patients receiving mechanical ventilation: multiple sources of tracheal colonization include the stomach. Am J Med 1986; 80: 827- 832. [PUBMED] [FULLTEXT] |
|21.||Salata RA, Lederman MM, Schaes DM, Jacobs MR, Eckstein E, Tweardy D, et al. Diagnosis of nosocomial pneumonia in intubated, intensive care unit patients. Am Rev Respir Dis 1987; 135: 426-32. |
|22.||Kerver ALH, Rommes JH, Mevisen-Verhage EAE, et al. Colonization and infection in surgical intensive care patients: a prospective study. Intensive Care Med 1987; 13: 347- 351. |
|23.||Pickworth KK, Falcone RE, Hoogeboom JE, Santanello DO. Occurrence of nosocomial pneumonia in mechanically ventilated trauma patients: Crit Care Med 1993; 21: 1856-1862. |
|24.||Driks RM, Craven DE, Celli BR, et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histamine type 2 blockers: the role of gastric colonization. N Engl J Med 1987; 317: 1376- 1382. |
|25.||Bonten MJ, Gaillard CA, van der Geest S, et al. The role of intragastric acidity and stress ulcer prophylaxis on colonization and infection in mechanically ventilated patients. Am J Respir Crit Care Med 1995; 152: 1825- 1834. [PUBMED] |
|26.||Prod'hom G, Leuenberger P, Koerfer J, et al. Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer: a randomized controlled trial. Ann Intern Med. 1994; 20: 653-662. |
|27.||Pugin J, Auckenthaler R, Lew DP, Suter PM. Oropharyngeal decontamination decreases incidence of ventilator- associated pneumonia: a randomized, placebo- controlled, double- blind clinical trial. JAMA 1991; 265: 2704- 2710. [PUBMED] |
|28.||Goularte TA, Lichtenberg DA, Craven DE. Gastric colonization in patients receiving antacids and mechanical ventilation: a mechanism for pharyngeal colonization. Am J Infect control 1986; 14: 88. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]