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Acid Suppression in the Perioperative Setting

Brooks D. Cash, MD, FACP

Posted: 11/9/2005

Introduction
Concerns surrounding acid-related perioperative complications are most commonly focused on the risk of pulmonary aspiration
of gastric contents and the development of stress-related mucosal disease (SRMD). Aspiration is an uncommon event, with an
incidence of about 3 episodes for every 10,000 general anesthetic administrations.[1] Aspiration-related complications such as
pneumonitis, adult respiratory distress syndrome, and laryngeal complications remain important causes of perioperative
morbidity and mortality and represent major medical-legal concerns. Gastrointestinal bleeding from SRMD is a relatively
common clinical problem in at-risk patients in the critical care setting that is also associated with significant morbidity and
mortality.[2] Because of the multiplicity of patient- and procedural-related variables, summary risk estimates quantifying the
incidence of SRMD and its complications in the perioperative period are not available. Perhaps the best estimates of SRMD
incidence come from the critical care setting in which clinically important bleeding due to SRMD occurs in 0.5% to 4% of
patients (many of them postoperative) and results in mortality rates more than 5 times that of nonbleeding controls.[3]

This column reviews the risk factors associated with both of these perioperative complications and also explores the clinical
evidence supporting the use of medications that block gastric acid secretion as a means to reduce the frequency of aspiration
and SRMD.

Acid-Related Pulmonary Complications

Aspiration has been defined as "inhalation of material into the airway below the level of the true vocal cords."[4] The most
common clinical scenarios arising from aspiration include symptomatic aspiration (coughing, choking, shortness of breath,
respiratory distress), aspiration pneumonitis (a noninfectious acute inflammatory reaction characterized by infiltrate[s] on chest
radiograph), and aspiration pneumonia (a parenchymal inflammatory reaction to aspirated material mediated by an infectious
agent). The effects of aspiration are multiple and are thought to be attributable to the acid, chemical, particulate, and
microbiological composition, as well as the volume, of aspirate. Critical threshold values for the volume and pH of gastric fluid
that are thought to place patients at increased risk for aspiration have been established at 0.4 mL/kg and a pH < 2.5.[5] More
recent estimates have redefined these values as 1 mL/kg and a pH < 1.[6] It is important to realize, however, that these values
are extrapolated from animal studies, and thus their application to humans is unproven.

Acid exposure has both immediate and delayed effects. First, direct toxicity results in the loss of ciliated and nonciliated cells.
Later, an inflammatory cascade results in the release of multiple cytokines. These cytokines promote the upregulation of cell
adhesion molecules as well as the production of thromboxanes and free-radical oxygen species, which in turn lead to alveolar
damage and increasing hypoxia.[7,8] Aspiration of particulates, if large enough, can result in direct airway obstruction, but a more
worrisome consequence of particulate aspiration is the possibility of polymicrobial pneumonia.

Risk Factors for Aspiration in the Perioperative Setting

A number of redundant mechanisms protect the airway from exposure to gastric contents; these include the upper and lower
esophageal sphincters, the esophagoglottal closure reflex, and esophageal peristalsis. All of these mechanisms are
compromised with the induction of general anesthesia and unconsciousness, placing patients at greater risk for aspiration.
Groups of patients who are believed to be at an increased risk for pulmonary aspiration include those with increased acid
production (peptic ulcer disease, esophagitis), increased intragastric pressure (pregnancy, obesity, bowel obstruction, recent
food ingestion), impaired gastric or intestinal motility (diabetes, chronic renal insufficiency), structural disorders that reduce
esophageal clearance (hiatal hernia), neuromuscular disease (cerebrovascular accidents), and those with a depressed
sensorium. Other factors that have been linked to an increased risk for aspiration include advanced age and the use of
nasogastric tubes that, by bridging the esophagus, may actually impair the protection of the upper and lower esophageal
sphincters.

Prevention of Aspiration
The American Society of Anesthesia (ASA) has established recommendations for the prevention of aspiration in the
perioperative setting. These recommendations include a 2-hour period of fasting for clear liquids and 6 hours of fasting after a
light meal. Pharmacologic therapy with gastrointestinal stimulants, gastric acid secretion blockers (histamine-2-receptor
antagonists [H2RAs] or proton-pump inhibitors [PPIs]), antacids, antiemetics, or anticholinergic agents in patients with no
apparent increased risk for aspiration is not currently recommended by the ASA.[9] Escolano and colleagues[10] demonstrated
that the preoperative administration of ranitidine results in a gastric pH > 2.5 and a significant reduction in gastric volume within
60 minutes of a 150-mg oral dose. Nishina and colleagues[11] demonstrated similar findings after the administration of
ranitidine, lansoprazole, or rabeprazole, either alone or in combination preoperatively, compared with placebo. Memis and
colleagues[12] directly compared the effects of intravenous placebo vs 40 mg of pantoprazole vs 50 mg of ranitidine on gastric
volume and pH in 90 ASA status I-II patients administered 1 hour before elective surgeries. Both the PPI and H2RA groups had
significantly increased intragastric pH values and diminished gastric volumes compared with placebo. Unfortunately, none of
these studies, nor others that have demonstrated similar clinical effects of other acid secretion blocking agents, have been of
sufficient power to show that these agents conclusively diminish the risk for aspiration in patients undergoing surgery with
general anesthesia. Current recommendations call for these agents to be used primarily in patients who are at increased risk for
aspiration.[13] Superiority of either class of acid-suppressing medication (H2RA or PPI) has also not been definitively proven,
although the majority of evidence supports the preoperative administration of H2RAs in most patients, with the reservation of
PPI therapy for patients on chronic acid suppression who may have developed some degree of tolerance to such chronic acid
suppression.

Stress-Related Mucosal Disease

The etiology of SRMD, like aspiration damage, is multifactorial and complex. Patients with head injury or burns represent those
at highest risk, likely due to gastric acid secretion resulting from vagal stimulation. Other critically ill patients appear to develop
SRMD as a result of diminished mucosal defenses and hypoperfusion.[14] Although subject to significant disparity, prospective
clinical trials have estimated that clinically important bleeding occurs in 3% to 6% of ICU patients with the most common risk
factors (ie, those patients on prolonged mechanical ventilation, those with persistent hypotension, or patients with
coagulopathy).[3,15] Multiple trials that have examined acid suppression with H2RAs or PPIs for reducing the incidence of
SRMD-related bleeding have yielded discordant results, likely due to significant differences in study methodology, including
patient populations, antisecretory agents and doses used, and definitions of the clinical endpoints studied.[16-24]

The largest randomized controlled trial performed to date involved 1200 mechanically ventilated patients and determined that
ranitidine was significantly more effective than sucralfate in reducing clinically important SRMD-related bleeding (odds ratio
[OR]: 0.44; 95% confidence interval [CI]: 0.21-0.92).[17] However, this trial had a number of limitations -- the most notable being
that most patients classified as having clinically important bleeding did not have a source identified, which therefore does not
permit absolute conclusions about prophylaxis to be drawn. When faced with such a situation, it may be helpful to look to an
overview article, such as a meta-analysis or systematic review, to provide a comprehensive review of the data and, in the case of
a meta-analysis, a summary numerical estimate of treatment effect. There have been several meta-analyses for SRMD bleeding
prophylaxis and most have demonstrated that acid suppression with antacids or H2RAs does appear to result in lower rates of
clinically important bleeding.[25-27] In one of these analyses, Cook and colleagues[25] examined 57 trials involving more than
7200 ICU patients and found that antacids were associated with a trend towards lower rates of overt and clinically important
bleeding compared with no therapy (OR: 0.66; 95% CI: 0.37-1.17; and OR: 0.35; 95% CI: 0.09-1.41, respectively), and that H2RAs
were significantly better than no therapy for reducing overt bleeding (OR: 0.58; 95% CI: 0.42-0.79) and reducing clinically
important bleeding (OR: 0.44; 95% CI: 0.22-0.88), and also had superiority over antacids for overt bleeding (OR: 0.56; 95% CI:
0.37-0.84).

However, important limitations of this analysis by Cook and colleagues include the lack of differentiation between the various
H2RAs with respect to agent, dose, or route of administration. In an effort to clarify this, Messori and colleagues[26] reported a
series of meta-analyses on published trials of individual H2RAs and concluded that ranitidine was not associated with lower
rates of SRMD-related bleeding, whereas cimetidine (the only H2RA approved for this indication) did appear to be more effective
than placebo (OR: 0.37; 95% CI: 0.23-0.60). It should be noted that neither of these meta-analyses included the 1200-patient
randomized controlled trial discussed above. Additionally, there have been no direct comparative trials of individual H2RAs for
this indication; thus, conclusions regarding individual/relative superiority are not possible on the basis of existing data.

If we accept that acid suppression with H2RAs is effective in reducing SRMD-related bleeding in high-risk patients, then the
logical question that arises is whether PPIs are more effective. There are several reasons why PPIs may be preferable to H2RAs.
PPIs have been repeatedly proven to result in a greater degree of acid inhibition for a longer period of time than H2RAs.
Tolerance to H2RAs, with either bolus dosing or continuous infusion, has been well documented, and H2RAs have been
associated with both thrombocytopenia and potentially important drug interactions. It is unlikely, however, that these concerns
would carry much weight in the realm of the routine perioperative setting where the administration of antisecretory agents
would be short-lived and the use of a rapidly-acting agent, such as an H2RA, may be preferable to the slower-onset PPIs.
However, in patients with significant comorbidities who may be expected to have a more prolonged or complicated perioperative
hospital course, these considerations may be more important.

Multiple studies have examined the effects of PPIs in reducing SRMD-related bleeding, but all have been small and many
measured intermediate endpoints.[28] Some studies have been observational with PPI therapy alone, whereas others have
compared PPI therapy with placebo or H2RA therapy. Conclusions that can be garnered from a review of this literature are that
the acid suppression achieved with PPI therapy is more effective than that achieved with H2RAs, and that the clinical benefit of
PPIs for reducing SRMD-related bleeding appears to be at least similar to that achieved with H2RAs. Most recently, Laine and
colleagues[29] reported the results of a randomized trial involving 359 patients administered bolus nasogastric tube dosing of
omeprazole suspension compared with continuous-infusion cimetidine in a noninferiority study. Omeprazole suspension
maintained gastric pH > 4, 86% of the time compared with 70.7% of the time for cimetidine (P < .005), and was associated with
similar rates of "clinically significant bleeding" (3.9% vs 5.5%) and pneumonia (7.9% vs 6.1%).

The weight of evidence regarding acid suppression for prophylaxis of SRMD-related bleeding supports its use in selected, high-
risk patients, and this is reflected in current guidelines.[30] The exact degree of protection conferred remains unclear, but a
reasonable estimate is that prophylaxis with acid-suppressing agents such as H2RAs and PPIs in patients at the greatest risk
for SRMD results in approximately 50% less clinically important bleeding than no prophylaxis at all. Therefore, if the risk of
SRMD-related bleeding is 5% in a high-risk population, the number-needed-to-treat (NNT) to prevent 1 episode of clinically
important bleeding would be 40 patients (absolute risk reduction: 0.05-0.025 = 0.025; NNT: 1.0/0.025 = 40). The optimal agent,
dose, duration, and route of administration remains unclear, but current trends indicate increasing awareness and use of acid
suppression in this population, with H2RAs representing first-line agents and PPIs gaining use.[31]

Conclusions
In the perioperative setting, the acid-mediated complications of aspiration and SRMD are serious events that are associated with
significant increases in morbidity and mortality. Although the pathogenesis of both processes is complex and multifactorial, it is
clear that gastric acid plays an important, if not primary, role. Agents that block acid secretion, such as H2RAs and PPIs, have
been proven to reliably increase intragastric pH and decrease gastric volume preoperatively. Outcomes data regarding the
effectiveness of antisecretory agents for the prevention of aspiration or SRMD are generally lacking, but preliminary data
suggest that these medications are beneficial in selected, high-risk patients. The optimal agents, doses, routes of
administration, and pH goals required to prevent these events also remain unproven. Current best evidence supports the
selective use of H2RAs for both aspiration and SRMD prophylaxis in high-risk patients. Prophylaxis with antisecretory agents is
currently not recommended for patients who cannot be classified as high risk. For patients who may be expected to have a more
complicated postoperative course with longer exposure to risk factors for aspiration and SRMD, the longer-acting PPIs with their
superior antisecretory and safety profile, and lack of tachyphylaxis, may be the preferred approach, although more studies in this
setting are warranted.
References

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