Chapter 17. Prevention of Ventilator-Associated Pneumonia (continued)
Selective digestive tract decontamination (SDD) involves the use of non-absorbable antibiotics topically applied to the gastrointestinal tract in an effort to sterilize the oropharynx and stomach. The goal is to decrease the pathogenicity of aspirated secretions and thereby reduce the incidence of VAP.
Most studies have used a combination of topical polymixin, tobramycin or gentamicin, and amphotericin applied to the oropharynx (by hand) and the stomach (by nasogastric tube). About half of the studies also included a short (3-4 day) course of systemic intravenous antimicrobial therapy, most commonly ceftriaxone. In general, topical antibiotics were applied several times daily from the time of intubation until extubation (or shortly thereafter).
Opportunities for Impact
SDD is not widely used in the United States. The Centers for Disease Control and Prevention and the American Thoracic Society's guidelines published in the 1990s do not recommend its routine use. Given the frequency and morbidity of VAP, if the practice is beneficial substantial opportunity for patient safety enhancement exists.
There have been over 30 randomized controlled trials and seven meta-analyses of SDD (see Table 17.3.1). A representative meta-analysis identified 33 randomized trials of SDD using a structured search of the literature that met the authors' methodologic inclusion criteria: measurement of clinical outcomes (including VAP and mortality), inclusion of unselected patient populations, and mechanical ventilation in at least half of patients. As with several of the other meta-analyses, individual trials in this particular meta-analysis were grouped into those that used topical antibiotics only and those that used topical and systemic antibiotics. This meta-analysis was unique in that the investigators obtained individual patient data for the majority of patients (4343 (76%) of the 5727 patients involved).
All meta-analyses reported risk of VAP and mortality at hospital or ICU discharge. Individual study outcomes also included number of days intubated, length of ICU stay, duration of antibiotic therapy, time to onset of VAP, and cost. Several meta-analyses performed subgroup analysis to assess the importance of statistical methods (e.g., quality of randomization, blinding, VAP definition) and clinical factors (e.g., Acute Physiology and Chronic Health Evaluation (APACHE) score).
Evidence for Effectiveness of the Practice
All seven meta-analyses report substantial reduction in the risk of VAP with the use of SDD (see Table 17.3.1). Four of seven meta-analyses report a statistically significant reduction in mortality. Four of seven meta-analyses separately analyzed trials using topical antibiotics only and those using topical and systemic antibiotics. All four revealed a statistically significant mortality benefit with combined topical and systemic prophylaxis and no mortality benefit with topical prophylaxis alone. However, these four meta-analyses did reveal a significant decrease in VAP incidence in those given topical antibiotics only compared to the placebo group. Several of the meta-analyses included subgroup analyses to assess the benefit of SDD in patients categorized by type of illness (surgical, medical) and severity of illness (APACHE score), with conflicting results.
Potential for Harm
There were no significant adverse events reported in most trials, although allergic reactions to the antibiotic preparations have been uncommonly noted. The primary long-term concern with the widespread use of SDD is the development of antibiotic resistance. The data are unclear regarding the impact of SDD on the emergence of resistant organisms, and no study has demonstrated an impact of increased bacterial resistance on morbidity or mortality.
Costs and Implementation
The cost of implementing SDD appears minimal in most trials, but there have been no in depth reviews of the subject. Several trials have found that patients receiving SDD had lower total antibiotic costs. Overall hospital costs also may be lower, mediated through the decreased rate of VAP.
SDD is a very promising method of reducing VAP and ICU-related mortality. The data supporting a significant reduction in risk of VAP and short-term mortality with SDD using topical and short-term intravenous antibiotics are strong. SDD is a relatively non-invasive intervention and the additional financial cost is minimal. What remains to be determined is the long-term effect of SDD on antibiotic resistance patterns, and the impact of such effect on morbidity and mortality. Research into the impact of SDD on the emergence of antibiotic resistance should be strongly encouraged.
Table 17.3.1. Meta-analyses of selective digestive tract decontamination*
|Study Design||Pneumonia (95% CI)||Mortality (95% CI)|
|Nathens, 1999: 21 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections; dual analysis of medical and surgical patients|
Medical: OR 0.45 (0.33-0.62)
Surgical: OR 0.19 (0.15-0.26)
Overall: OR 0.91 (0.71-1.18)
Topical/IV: OR 0.75 (0.53-1.06)
Topical: OR 1.14 (0.77-1.68)
Overall: OR 0.70 (0.52-0.93)
Topical/IV: OR 0.60 (0.41-0.88)
Topical: OR 0.86 (0.51-1.45)
|D'Amico, 1998: 33 randomized controlled trials from of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections; dual analysis of topical and systemic antibiotics combined and topical antibiotics alone|
Overall: not reported
Topical/IV: OR 0.35 (0.29-0.41)
Topical: OR 0.56 (0.46-0.68)
Overall: OR 0.88 (0.78-0.98)
Topical/IV: OR 0.80 (0.69-0.93)
Topical: OR 1.01 (0.84-1.22)
|Hurley, 1995: 26 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections||Overall: OR 0.35 (0.30-0.42)||Overall: OR 0.86 (0.74-0.99)|
|Kollef, 1994: 16 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections||Overall: RD 0.145 (0.116-0.174)||Overall: RD 0.019 (-0.016-0.054)|
|Heyland, 1994: 25 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections; performed subgroup analyses|
Overall: RR 0.46 (0.39-0.56)
Topical/IV: RR 0.48 (0.39-0.60)
Topical: RR 0.43 (0.32-0.59)
Overall: RR 0.87 (0.79-0.97)
Topical/IV: RR 0.81 (0.71-0.95)
Topical: RR 1.00 (0.83-1.19)
|SDD Trialists' Collaborative Group, 1993: 22 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections; performed subgroup analyses|
Overall: OR 0.37 (0.31-0.43)
Topical/IV: OR 0.33 (0.27-0.40)
Topical: OR 0.43 (0.33-0.56)
Overall: OR 0.90 (0.79-1.04)
Topical/IV: OR 0.80 (0.67-0.97)
Topical: OR 1.07 (0.86-1.32)
|Vandenbroucke-Grauls, 1991: 6 randomized controlled trials of antibiotic prophylaxis used to decrease nosocomial respiratory tract infections||Overall: OR 0.12 (0.08-0.19)||Overall: OR 0.70 (0.45-1.09)|
* CI indicates confidence interval; RD, risk difference, RR, relative risk; and OR, odds ratio.
1. D'Amico R, Pifferi S, Leonetti C, Torri V, Tinazzi A, Liberati A. Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials. BMJ 1998;316:1275-1285.
2. Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus statement, American Thoracic Society, November 1995. Am J Respir Crit Care Med 1996;153:1711-1725.
3. CDC. Guidelines for prevention of nosocomial pneumonia. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1997;46:1-79.
4. Craven DE, Steger KA. Nosocomial pneumonia in mechanically ventilated adult patients: epidemiology and prevention in 1996. Semin Respir Infect 1996;11:32-53.
5. Hurley JC. Prophylaxis with enteral antibiotics in ventilated patients: selective decontamination or selective cross-infection? Antimicrob Agents Chemother 1995;39:941-947.
6. Nathens AB, Marshall JC. Selective decontamination of the digestive tract in surgical patients: a systematic review of the evidence. Arch Surg 1999;134:170-176.
7. Kollef MH. The role of selective digestive tract decontamination on mortality and respiratory tract infections. A meta-analysis. Chest 1994;105:1101-1108.
8. Heyland DK, Cook DJ, Jaeschke R, Griffith L, Lee HN, Guyatt GH. Selective decontamination of the digestive tract. An overview. Chest 1994;105:1221-1229.
9. Meta-analysis of randomised controlled trials of selective decontamination of the digestive tract. Selective Decontamination of the Digestive Tract Trialists' Collaborative Group. BMJ 1993;307:525-532.
10. Vandenbroucke-Grauls CM, Vandenbroucke JP. Effect of selective decontamination of the digestive tract on respiratory tract infections and mortality in the intensive care unit. Lancet 1991;338:859-862.
11. van Saene HK, Stoutenbeek CP, Hart CA. Selective decontamination of the digestive tract (SDD) in intensive care patients: a critical evaluation of the clinical, bacteriological and epidemiological benefits. J Hosp Infect 1991;18:261-277.
12. Ebner W, Kropec-Hubner A, Daschner FD. Bacterial resistance and overgrowth due to selective decontamination of the digestive tract. Eur J Clin Microbiol Infect Dis 2000;19:243-247.
13. Bartlett JG. Selective decontamination of the digestive tract and its effect on antimicrobial resistance. Crit Care Med 1995;23:613-615.
14. Quinio B, Albanese J, Bues-Charbit M, Viviand X, Martin C. Selective decontamination of the digestive tract in multiple trauma patients. A prospective double-blind, randomized, placebo-controlled study. Chest 1996;109:765-772.
15. Verwaest C, Verhaegen J, Ferdinande P, Schetz M, Van den Berghe G, Verbist L, et al. Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med 1997;25:63-71.
16. Sanchez Garcia M, Cambronero Galache JA, Lopez Diaz J, Cerda Cerda E, Rubio Blasco J, Gomez Aguinaga MA, et al. Effectiveness and cost of selective decontamination of the digestive tract in critically ill intubated patients. A randomized, double-blind, placebo-controlled, multicenter trial. Am J Respir Crit Care Med 1998;158:908-916.
17. Silvestri L, Mannucci F, van Saene HK. Selective decontamination of the digestive tract: a life saver. J Hosp Infect 2000;45:185-190.
Aspiration of gastric secretions may contribute to the development of VAP. It has been observed that gastric colonization by potentially pathogenic organisms increases with decreasing gastric acidity, leading to the hypothesis that pH-altering drugs may cause increased rates of VAP. H2-antagonist therapy, widely used in mechanically-ventilated patients for stress ulcer prophylaxis (see Chapter 34), significantly elevates gastric pH. Sucralfate, an alternative prophylactic agent that does not affect gastric pH, may allow less gastric colonization with potentially pathogenic organisms than H2-antagonists and therefore prevent some cases of VAP.
In general, 1 g of sucralfate suspension is given through a nasogastric tube every four to six hours. When H2-antagonists are used, their dosing and frequency vary. A representative study used 50 mg of ranitidine intravenously every eight hours, dose adjusted for creatinine clearance. Stress ulcer prophylaxis is usually started upon initiation of mechanical ventilation and continued until extubation (Chapter 34).
Opportunities for Impact
Stress ulcer prophylaxis is usually given to critically ill ventilated patients. A large cohort study of over 2000 critically ill patients suggests that the majority receive H2-antagonists (71.8%) followed by sucralfate (7.0%) and combination therapy (15.4%) or other single agents (omeprazole, antacids, prostaglandins). There is, therefore, significant opportunity for impact should sucralfate prove to lower rates of VAP and improve survival.
There have been over 20 randomized controlled trials of stress ulcer prophylaxis using sucralfate, H2-antagonists, and other therapies in critically ill patients. Seven meta-analyses have been published to date. The individual trials and meta-analyses have significant variation in methodology. In general, the individual trials randomized critically ill patients to sucralfate, H2-antagonists, other agents such as antacids and pirenzepine, or placebo. The majority of patients included in these studies required mechanical ventilation. Various drug-drug, drug-placebo combinations were compared, and the rates of VAP and mortality were recorded.
Most trials report development of VAP and mortality as primary endpoints. There is significant variation in the definition of VAP used in these trials. In the largest and most recent randomized trial, VAP was defined as a new radiographic infiltrate plus two of the following: temperature of >38.5�C or <35.0�C, leukocyte count >10,000/mm3 or <3000/mm3, purulent sputum, and isolation of pathogenic bacterial from an endotracheal aspirate. Mortality was reported at time of discharge from the ICU.
Evidence for Effectiveness of the Practice
The results of the seven meta-analyses and one recent large randomized controlled trial are inconclusive (see Table 17.4.1). The two largest meta-analyses to date suggest a decreased incidence of VAP with sucralfate compared to H2-antagonists, and one reports a statistically significant mortality benefit with sucralfate. A recent randomized controlled trial of 1200 ventilated patients reports no significant difference between the two therapies in terms of VAP or mortality.
Potential for Harm
Sucralfate therapy has been associated with a statistically significant increased risk of clinically important gastrointestinal bleeding when compared to H2-antagonists. Clinically important bleeding developed in 3.8% of patients receiving sucralfate compared with 1.7% of patients receiving H2-antagonists (relative risk for H2-antagonist = 0.44, 95% CI: 0.21-0.92). Gastrointestinal bleeding in critically ill patients has an attributable mortality of approximately 12.5%. While previous meta-analyses have suggested little difference in rates of gastrointestinal bleeding between the various prophylactic agents, these results from a large randomized trial are convincing. There are very few adverse effects from sucralfate therapy aside from constipation, rare nausea and vomiting and very rare bezoar formation and aluminum intoxication. Sucralfate administration has been associated with transmission of vancomycin resistant enterococcus, likely due to increased manipulation of patients' nasogastric tubes. Unlike parenteral H2-blockers, sucralfate mandates nasogastric tube placement in intubated patients. The drug can also lead to decreased absorption of other medications.
Costs and Implementation
Several studies have looked at the cost-effectiveness of stress ulcer prophylaxis. Based on decision analysis, the cost per episode of gastrointestinal bleeding averted in high-risk patients is several thousand dollars greater with H2-antagonists than with sucralfate. This cost difference remains significant even if H2-antagonists are assumed to be 50% more effective. There are no reliable data comparing overall costs from the actual clinical trials. The mean cost, largely driven by prolonged length of stay, is significantly higher for patients who bleed than for those who do not ($70,000 vs. $15-20,000), implying that in patients at high risk for GI bleeding (e.g., mechanically ventilated patients, those with a coagulopathy), stress ulcer prophylaxis may be cost-neutral or even cost-saving (see also Chapter 34). Implementation of sucralfate use would be largely an issue of staff education as administration is relatively uncomplicated.
The data supporting stress ulcer prophylaxis with sucralfate instead of H2-antagonists to prevent VAP are inconclusive, and the theoretical contribution of increased gastric colonization with potentially pathogenic organisms to the development of VAP is unproven. There are data both supporting and refuting a decreased incidence of VAP with sucralfate. Most investigators have found at least a trend toward decreased incidence of VAP with sucralfate, and larger studies are warranted. The greatest benefit from sucralfate may be the prevention of late-onset VAP in patients requiring long-term ventilation. Any increased risk of gastrointestinal bleeding with sucralfate therapy in these patients may be offset by the decreased risk of VAP. Until the data are more definitive, however, when stress ulcer prophylaxis is deemed appropriate (Chapter 34), the use of H2-blockers seems preferable to sucralfate because of the former's superiority in preventing clinically important gastrointestinal bleeding.
Table 17.4.1. Studies of stress ulcer prophylaxis
|Study Design||Design, Outcomes||Pneumonia* (95% CI)||Mortality* (95% CI)|
|Meta-analysis of randomized controlled trials comparing ranitidine with placebo, sucralfate with placebo and ranitidine with sucralfate for the prevention of pneumonia in critically ill patients. (Messori, 2000)||Level 1A,|
ranitidine vs. sucralfate: 1.35 (1.07-1.70)
ranitidine vs. placebo: 0.98 (0.56-1.72)
sucralfate vs. placebo: 2.21 (0.86-5.65)
|Multicenter randomized, blinded, placebo-controlled trial of sucralfate with ranitidine in 1200 critically ill mechanically ventilated patients. Endpoints were gastrointestinal bleeding, VAP and mortality. (Cook, 1998)||Level 1,|
|ranitidine vs. sucralfate: 1.18 (0.92-1.51)||ranitidine vs. sucralfate: 1.03 (0.84-1.26)|
|27 randomized trials of stress ulcer prophylaxis in critically ill patients. The majority of patients were mechanically ventilated. Endpoints were gastrointestinal bleeding, pneumonia and mortality. (Cook, 1996)||Level 1A,|
sucralfate vs. H2-antagonist: 0.77 (0.60-1.01)
H2-antagonist vs. placebo: 1.25 (0.78-2.00)
|sucralfate vs. H2-antagonist: 0.73 (0.54-0.97)|
|14 randomized trials of stress ulcer prophylaxis in critically ill patients. (Tryba, 1995)||Level 1A,|
|sucralfate vs. H2-antagonist/ antacid: 0.67 (p<0.05)||not reported|
|6 (outcome VAP) and 7 (outcome mortality) randomized trials of stress ulcer prophylaxis in critically ill patients. (Cook, 1995)||Level 1A,|
|sucralfate vs. H2-antagonist/ antacid: 0.50 (0.21-0.79)|
sucralfate vs. H2-antagonist: 0.71 (0.49-1.04)
sucralfate vs. antacid: 0.70 (0.52-0.94)
|14 randomized trials of stress ulcer prophylaxis in critically ill patients. Endpoints were gastrointestinal bleeding and pneumonia. (Tryba. 1991)||Level 1A,|
sucralfate vs. H2-antagonist: 0.50 (0.32-0.78)
sucralfate vs. antacid: 0.40 (0.24-0.69)
|sucralfate vs. H2-antagonist/ antacid: 0.81 (NA)|
|9 randomized trials of stress ulcer prophylaxis in critically ill patients. (Tryba, 1991)||Level 1A,|
|sucralfate vs. H2-antagonist/ antacid: 0.48 (p<0.05)||sucralfate vs. H2-antagonist/ antacid: 0.72 (p<0.05)|
|8 randomized trials of stress ulcer prophylaxis in critically ill patients studying the rate of pneumonia with different drug regimens. (Cook, 1991)||Level 1A,|
sucralfate vs. H2-antagonist/ antacid: 0.55 (0.28-1.06)
H2-antagonist/antacid vs. placebo: 0.42 (0.17-1.11)
* Point estimates reflect odds ratio or relative risk.
1. 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.
2. Tryba M. Prophylaxis of stress ulcer bleeding. A meta-analysis. J Clin Gastroenterol 1991;13: S44-55.
3. Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994;330:377-381.
4. Messori A, Trippoli S, Vaiani M, Gorini M, Corrado A. Bleeding and pneumonia in intensive care patients given ranitidine and sucralfate for prevention of stress ulcer: meta-analysis of randomised controlled trials. BMJ 2000;321:1103-1106.
5. Cook DJ, Laine LA, Guyatt GH, Raffin TA. Nosocomial pneumonia and the role of gastric pH. A meta-analysis. Chest 1991;100:7-13.
6. Cook DJ, Reeve BK, Guyatt GH, Heyland DK, Griffith LE, Buckingham L, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996;275:308-314.
7. Cook DJ. Stress ulcer prophylaxis: gastrointestinal bleeding and nosocomial pneumonia. Best evidence synthesis. Scand J Gastroenterol Suppl 1995;210:48-52.
8. Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998;338:791-797.
9. Tryba M. Sucralfate versus antacids or H2-antagonists for stress ulcer prophylaxis: a meta-analysis on efficacy and pneumonia rate. Crit Care Med 1991;19:942-949.
10. Tryba M, Cook DJ. Gastric alkalinization, pneumonia, and systemic infections: the controversy. Scand J Gastroenterol Suppl 1995;210:53-59.
11. McCarthy DM. Sucralfate. N Engl J Med 1991;325:1017-1025.
12. Slaughter S, Hayden MK, Nathan C, Hu TC, Rice T, Van Voorhis J, et al. A comparison of the effect of universal use of gloves and gowns with that of glove use alone on acquisition of vancomycin-resistant enterococci in a medical intensive care unit. Ann Intern Med 1996;125:448-456.
13. Ben-Menachem T, McCarthy BD, Fogel R, Schiffman RM, Patel RV, Zarowitz BJ, et al. Prophylaxis for stress-related gastrointestinal hemorrhage: a cost effectiveness analysis. Crit Care Med 1996;24:338-345.
14. Erstad BL, Camamo JM, Miller MJ, Webber AM, Fortune J. Impacting cost and appropriateness of stress ulcer prophylaxis at a university medical center. Crit Care Med 1997;25:1678-1684.
15. Prod'hom G, Leuenberger P, Koerfer J, Blum A, Chiolero R, Schaller MD, 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;120:653-662.
Final Comment to Chapter 17
Ventilator-associated pneumonia is common, costly, and morbid. This chapter confirms that there are several low-risk interventions that carry the potential to reduce the frequency of this complication. Further research will be needed to confirm the benefit of promising practices (e.g., semi-recumbency or continuous aspiration of subglottic secretions) or fully allay concerns regarding practices that have potential for harm (e.g., antibiotic resistance with selective decontamination).