All you need to read in the other general journalsBMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b2196 (Published 01 June 2009) Cite this as: BMJ 2009;338:b2196
All rapid responses
In the large, hospital-based pharmacoepidemiologic prospective cohort
of all patients admitted to a large, urban, academic medical center in
Boston acid-suppressive medication use was associated with 30% increased
odds of hospital-acquired pneumonia [4.9% vs 2%odds ratio, 2.6; 95%
confidence interval, 2.3-2.8]. In subset analyses, statistically
significant risk was demonstrated only for proton-pump inhibitor use (1).
Patients studied were at least 18 years of age; and hospitalized for 3 or
more days were eligible for inclusion. Admissions with time spent in the
intensive care unit were excluded.
These results suggest that nosocomial pneumonias developing in ward
patients might not be the product of the aspiration of gastric contents
that have lost their capacity to secrete acid and prevent bacterial
overgrowth, as Professor Fernando Martins do Vale and others suppose.
"Selective decontamination of the digestive tract notably reduces
mortality in critically ill surgical patients [R, 0.7; 95% CI, 0.52-
0.93],while critically ill medical patients derive no such benefit[OR,
0.91; 95%CI, 0.71-1.18]" (2). This implies that infections in surgical
patients aremore likely to have an endogenous source in the gut than
Why should there be a difference? Because surgical patients are more
likely than medical patients to have developed transient episodes of gut
mucosal ischaemia during their hospital stay (3)? If so translocation is
more likely to be a cause of nosocomial pneumonias in surgical ICU
patients than in medical ICU patients unless there is another cause for
translocation in medical patients. What might that be?
"Omeprazole in concentrations obtained during intravenous
administration may inhibit the function of PMNs in vitro" (4) and has
beenimplicated in the pathogenesis of colitis both in association with and
without C difficile (5). In human tumour cells, for example, omeprazole
inhibits vacuolar V-H+-ATPase activity and increases both extracellular
pHand the pH of lysosomal organelles. Lysosomal acidosis in needed for
effective bacterial killing.
The clinical importance of translocation from the colon is
illustrated by the dramatic reduction in mortality from fulminant amoebic
colitis achieved simply by a diverting ileostomy and colonic lavage (6).
Thus omeprazole would seem to have the potential to cause infections by
two means, translocation and impairment in immune function. It should be
added that gut mucosal ischaemia is known to be accompanied by impairment
opf immune function be it a direct or indirect effect.
What then of the many other medications that might damage
gastrointestinal mucosa, impair immune function, and/or impair oxidative
phopshorylation. Candidate offenders include omeprazole, all narcotics,
cardiac drugs, NSAIDS and antibiotics. Given the prevalence of
polypharmacy particularly in medical patients, and the theoretical
potential for additive effects demonstrated by the Polypill(7), the
possibility that the prevalence of hospital acquired infections might be
largely if not solely due to incomplete resuscitation and/or polypharmacy
needs to be seriously considered. If so monitoring infections, such as
MSRA and C difficile, is unlikely to be of much if any value in managing
patients or in improving outcome.
Making reporting of healthcare associated infections mandatory will
not do much good on its own. What would seem to be needed is universal
monitoring of gut or possibly sublingual intramucosal pH and of the
prescription of the candidate medications, listed above drugs, and the
combinations in which they are being administered in conjunction with
clinically significant measures of outcome. Infections per se would seem
to be of secondary or even tertiary importance.
1. Shoshana J. Herzig, MD; Michael D. Howell, MD, MPH; Long H. Ngo,
PhD; Edward R. Marcantonio, MD, SM. Acid-Suppressive Medication Use and
the Risk for Hospital-Acquired Pneumonia. JAMA. 2009;301(20):2120-2128.
2. Avery B. Nathens, MD, PhD, FRCSC; John C. Marshall, MD, FRCSC.
Selective Decontamination of the Digestive Tract in Surgical Patients. A
Systematic Review of the Evidence. Arch Surg. 1999;134:170-176.
3. FIDDIAN-GREEN, RICHARD G. Associations between intramucosal
acidosis in the gut and organ failure. Critical Care Medicine. 21(2)
Supplement:S103, February 1993.
4. JH Wandall. Effects of omeprazole on neutrophil chemotaxis, super
oxide production, degranulation, and translocation of cytochrome b-
5. Clostridium difficile colitis: A marker for ischemic colitis?
Richard Fiddian-Green. CMAJ • November 23, 2004; 171 (11).
6. SINGH Bhugwan (1) ; MOODLEY Jaynathan (1) ; RAMDIAL Pratistadevi
K. Fulminant amoebic colitis: A favorable outcome. International surgery.
2001, vol. 86, no2, pp. 77-81.
7. B.Franklin, J.Kahn, N.Gordon, R.Bonow. A cardioprotective
“polypill”? Independent and additive benefits of lifestyle modification.
The American Journal of Cardiology, Volume 94, Issue 2, Pages 162-166
Tonometric patents issued in my name
Competing interests: No competing interests
In a large hospital-based pharmacoepidemiologic cohort study, Herzig
et al. referred that use of acid-suppressive medication (ASM) was
associated with 30% increased odds of hospital-acquired pneumonia in
nonventilated patients. The association was significant for proton-pump
inhibitor (PPI). It was not excluded a small increased risk associated
with Histamine2 receptor antagonists.
Herzig et al. refer that the increased risk of pneumonia with ASM has been
attributed to a modification of the upper gastrointestinal/respiratory
flora, in the setting of a less acidic gastric medium. This hypothesis is
in agreement with the observed stronger association between ASM and
aspiration pneumonia, than with non-aspiration pneumonia. Alternative
explanation referred by the Authors may be the impairment of white blood
cell function associated with PPI therapy[2,3,4].
Analyzing patient’s baseline characteristics, we can see significant
differences in comorbidities between patients exposed and unexposed to
ASM: chronic pulmonary disease (6.205 vs. 2.865 respectively), diabetes
(6.562 vs. 3.486 respectively). These (and others) comorbidities probably
have contributed to biased results, with increased incidence of pneumonia
on ASM group. Among comorbidities differences, “peptic ulcer/reflux”
deserves special attention not only by the much greater number of patients
with this pathology in ASM group (7.678 with ASM vs. 874 without ASM), but
also because of a possible causal relationship.
As reflux of gastric contents into the pharynx, may induce recurrent
pulmonary aspiration and cause or aggravate chronic bronchitis, asthma,
pulmonary fibrosis, chronic obstructive pulmonary disease, or
pneumonia, it seems likely that the much greater number of patients
with “peptic ulcer/reflux” in the ASM group may have biased the results.
In the ASM group, the observed greater incidence of pneumonia, may be a
consequence of the more frequent silent reflux (without acid irritation -
but not sterile) in the ASM group, and not the result of PPI medication.
The smaller risk of pneumonia with H2 blockers (less effective on acid
suppression), may have resulted not only from inadequate power to detect
statistical significance of this smaller subgroup, but also may be related
with the antiseptic effect of a lower pH, or a cough defense against an
I agree with the Authors of this observational study, that a randomized
controlled trial (that produce more homogeneous groups) would be helpful
to better evaluate the association between ASM and pneumonia, which may
have causal or casual relationship.
1. Herzig SJ, Howell MD, Ngo LH; Marcantonio ER. Acid-Suppressive
Medication Use and the Risk for Hospital-Acquired Pneumonia. JAMA.
2. Scaringi L, Cornacchione P, Fettucciari K; et al. Activity
inhibition of cytolytic lymphocytes by omeprazole. Scand J Immunol.
3. Capodicasa E, De Bellis F, Pelli MA. Effect of lansoprazole on
human leukocyte function. Immunopharmacol Immunotoxicol. 1999;21(2):357-
4. Zedtwitz-Liebenstein K, Wenisch C, Patruta S, Parschalk B, Daxbock
F, Graninger W. Omeprazole treatment diminishes intra- and extracellular
neutrophil reactive oxygen production and bactericidal activity. Crit Care
5. Goyal Raj K, "Chapter 286. Diseases of the Esophagus" (Chapter).
Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL,
Loscalzo J: Harrison's Principles of Internal Medicine, 17th Edition:
Competing interests: No competing interests