Journal of Critical Care (2005) 20, 35-45
`
`El.SEVIER
`
`PTX-073
`
`Journal of
`Critical Care
`
`Pathophysiology and prophylaxis of stress ulcer in
`intensive care unit patients
`
`Neil Stollman Moa,*, David C. Metz MDb
`
`aDivision of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco,
`CA 94 J10, USA
`bDivision of Gastroenterology, Department of Medicine, University of Pennsylvania Health System, Philadelphia,
`PA 19104, USA
`
`Received 12 May 2004; revised 24 August 2004; accepted 12 October 2004
`
`Keywotds: •
`:PathoJ'>hY~ioloey; ·
`~rophylruds;0
`.Dicer
`
`••
`
`•
`
`Abstract Gastrointestinal complications frequently occur in patients admitted to the intensive care unit.
`Of these, ulceration and bleeding related to stress-related mucosa! disease (SRMD) can lengthen
`hospitalization and increase mortality. The purpose of this review is to discuss the many risk factors and
`underlying illnesses that have a role in the pathophysiology of SRMD and evaluate the evidence
`pertaining to SRMD prophylaxis in the intensive care unit population. Suppressing acid production is
`fundamental to preventing stress-related mucosa! ulceration and clinically important gastrointestinal
`bleeding. Traditional prophylactic options for SRMD in critically ill patients include antacids, sucralfate,
`histaminez-receptor antagonists (IhRAs ), and proton pump inhibitors. Many clinicians prescribe
`intermittent infusions of H2RAs for stress ulcer prophylaxis, a practice that has not been approved for
`this indication and may not provide the necessary degree or duration of acid suppression required to
`prevent stress ulcer-related bleeding. New data suggest that proton pump inhibitors suppress acid
`production more completely in critically ill patients, but more studies are required to assess their clinical
`effectiveness and safety for this indication. The prophylactic regimen chosen to prevent stress ulcer
`bleeding should take into account the risk factors and underlying disease state of individual patients to
`provide the best therapy to those most likely to benefit.
`© 2005 Elsevier Inc. All rights reserved.
`
`1. Introduction
`
`An estimated 4.4 million patients are admitted to
`intensive care units (ICUs) each year. Of these, about
`12%, or 500000 patients, die in the ICU [l]. Gastrointestinal
`(GI) complications (eg, gastric and intestinal motor dys-
`
`* Corresponding author. East Bay Center for Digestive Health,
`Oakland, CA 94609, USA. Tel.: +l 510 444 3297; fax: +l 510 444 6421.
`E-mail address: nstollman@medsfgh.ucsfedu (N. Stollman).
`
`0883-9441/$ - see front matter © 2005 Elsevier Inc. All rights reserved.
`doi: 10.1016/j.jcrc.2004.10.003
`
`function as well as stress-related mucosal disease [SRMD])
`frequently occur in these patients and adversely affect patient
`outcomes. Gastrointestinal motor dysfunction may predis(cid:173)
`pose patients to impaired enteral nutrition and pulmonary
`aspiration of gastric contents [2]. Stress-related mucosal
`damage-an acute erosive gastritis-occurs in many criti(cid:173)
`cally ill patients in ICUs and may develop within 24 hours of
`admission [3]. The incidence of clinically important GI
`bleeding, defined as overt bleeding complicated by hemo(cid:173)
`dynamic instability, decrease in hemoglobin, and/or need for
`
`(_,bh,L_
`I ,J
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`dlibit No.
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`2HARLENE FRIEDMAN
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`36
`
`blood transfusion, from SRMD in the ICU population was
`1.5% in a prospective study of2252 patients [4]. In addition,
`the morbidity associated with this type of severe ulceration
`and bleeding can increase the length of stay in the ICU by up
`to 8 days, and mortality is as much as 4-fold higher than it is
`in ICU patients without this complication [5].
`
`2. Pathophysiology and pathogenesis of SRMD
`
`Several factors have a role in the pathogenesis of SRMD,
`including gastric acid secretion, mucosal ischemia ( as a result
`of splanchnic hypoperfusion), and reflux of upper intestinal
`contents into the stomach (Fig. 1) [6,7]. Gastric hypoperfu(cid:173)
`sion leads to an imbalance between oxygen supply and
`demand that may induce mucosal damage. Moreover,
`reperfusion after prolonged hypoperfusion may itself result
`in nonocclusive mesenteric ischemia and mucosal damage.
`As a result of ischemia, there is also a reduced ability to
`neutralize hydrogen ions, which can contribute to cell death
`and ulceration. Protective processes such as mucous produc(cid:173)
`tion may also be impaired, further promoting SRMD [ 6,8]. In
`animal studies, Ritchie [6] showed that elevated gastric acid
`levels, bile salts, and ischemia must all be present for gastric
`lesions to form, whereas none of these factors alone or in
`combination with each other led to ulceration.
`In stress ulceration, homeostasis of the gastric mucosa is
`disrupted as are the cellular defense mechanisms that
`normally protect against a highly acidic gastric milieu.
`Cellular defense is primarily mediated by gastric prosta(cid:173)
`glandins, which, in animal models, have been shown to
`prevent ulcer formation and accelerate the healing process.
`This seems to occur partly because prostaglandins reduce
`acid secretion. More importantly, they have been shown to
`exert a direct cytoprotective effect against agents that kill
`
`N. Stollman, D.C. Metz
`
`mucosal cells on contact [9]. Thus, prevention of acid injury
`and stress ulceration might be achieved by therapies that
`reduce acid secretion or enhance protective mechanisms.
`The endoscopic signs of SRMD include multiple sub(cid:173)
`epithelial petechiae progressing to superficial erosions, and
`in some cases, discrete ulceration, particularly in the gastric
`fundus [8]. Microscopically, these lesions are characterized
`by focal loss of the superficial epithelium, coagulation
`necrosis of the mucosa, and hemorrhage [10]. These lesions
`do not usually perforate and tend to bleed from superficial
`mucosal capillaries [11]. Because of the diffused nature of
`the lesions, stress ulcers are not generally amenable to
`endoscopic therapy.
`
`2.1. Splanchnic hypoperfusion
`
`Critical illness that warrants admission to an ICU (eg,
`trauma, severe shock, bums, sepsis) can contribute to
`splanchnic hypoperfusion, which has a major role in the
`pathogenesis of SRMD. Significant decreases in visceral
`blood flow can occur even when systemic circulation is
`maintained, and conventional measures of systemic tissue
`oxygenation may not accurately reflect regional GI oxy(cid:173)
`genation [12,13]. Intramucosal pH, which can be measured
`using gastric tonometry, is a marker of the adequacy of
`oxygenation in the upper GI tract and is used in
`experimental settings to assess the magnitude of splanchnic
`ischemia [12].
`
`2.2. Underlying illness
`
`Critical illness is often characterized by hypotension and
`hypovolemia, which can directly contribute to gastric
`hypoperfusion. In addition, critically ill patients often
`exhibit inflammatory responses involving the release of
`cytokines that can also result in hypoperfusion [8].
`
`Crltlcal Illness
`
`lncret111C1d
`catecholFmln@11
`t
`~=== J, C11fdiall llYlpYI
`lnC!'HHd vnaooon11trl lion
`
`/
`~
`
`Hypllvlll@mia
`
`JilffiiflllllfflffllllllfY
`11yl@lti1u1 ffil@ll§@
`
`Splonehnle hypop@rfutlc:>n
`
`Reduced
`HC03
`secretion
`
`Reduced
`fflYOOilil
`blood flow
`
`Acute 1tro11 ulcer
`Fig. 1 Pathophysiology of stress ulcers. Adapted from Chest 2001;119:1222; Hosp Pract 1980;15:93.
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`Stress ulcer prophylaxis
`
`2.3. Mechanical ventilation
`
`Mechanical ventilation can influence systemic hemody(cid:173)
`namics, especially with potentially injurious ventilator
`strategies such as high tidal volumes or high positive end(cid:173)
`expiratory pressure (PEEP). High PEEP decreases venous
`return and reduces preload, which in tum may reduce cardiac
`output (CO) [14] and result in splanchnic hypoperfusion.
`PEEP promotes plasma-renin-angiotensin-aldosterone
`activity, as well as catecholamine release, which may also
`contribute to splanchnic hypoperfusion [8,15,16]-
`Mesenteric blood flow and CO were found to signifi(cid:173)
`cantly decrease with increasing levels of PEEP in rats
`randomized to PEEP vs control [15]- An inverse relationship
`between increasing plasma catecholamine levels and
`decreases in CO was observed in dogs treated with graded
`doses of PEEP [14]. Effects on the sympathetic nervous
`system have also been validated in human beings. In a study
`of 10 healthy males receiving continuous positive-pressure
`breathing, muscle sympathetic nerve activity rapidly
`increased, as did measurements of vasopressin and plasma
`renin activity as compared to control [17]- In addition,
`mechanical ventilation with large tidal volumes and high
`end-expiratory pressures have been shown in animals to
`promote release of pulmonary cytokines, which can enter the
`systemic circulation from the lungs, potentially causing
`splanchnic hypoperfusion [8, 18, 19]·
`Despite these data showing that PEEP can negatively
`influence blood flow, the effect of PEEP on GI bleeding in
`the ICU setting remains unknown.
`
`2.4. Medications used in the ICU
`
`Medications administered to patients in the ICU can have
`deleterious effects on GI function, especially when com(cid:173)
`pounded with the effects of mechanical ventilation. Opiates
`and sedatives, such as benzodiazepines, can decrease gut
`motility and impair venous return [20]. Other agents that
`may contribute to GI complications include vasopressors
`and antibiotics [2,8,21 l Theoretically, any drug resulting in
`hypotension, decreased heart rate, or CO can in tum reduce
`mesenteric blood flow and put a critically ill patient at risk
`of developing SRMD [15]-
`
`2.4.1. Helicobader pylori
`Helicobacter pylori has been implicated as the causative
`agent in the pathogenesis of chronic gastritis and peptic
`ulcer. Its relationship to stress ulceration and GI bleeding,
`however, is not well documented. The relatively few studies
`exploring this association yielded conflicting results. A
`prospective epidemiologic survey of critically ill patients in
`an ICU found a significantly higher rate of seropositivity for
`H pylori in the ICU group than in the control group (67% vs
`39%, P < .001) [3} The relationship between Hpylori status
`and GI bleeding was not significant, but there was a trend
`toward increasing seropositivity with increasing bleeding
`severity-from 50% seropositivity among patients with
`
`37
`
`occult bleeding to 100% seropositivity among those with
`clinically significant bleeding [3]. In a prospective cohort
`analysis, 50 consecutive patients admitted to the ICU
`requiring mechanical ventilation were screened for H pylori
`infection using the laser-assisted ratio analyzer urea breath
`test and underwent endoscopy to assess mucosal injury. Of
`the 29 patients who developed minor mucosal disease,
`34.5% were infected with H pylori. On the contrary, of the
`15 patients that presented with major mucosal disease, 80%
`were infected, supporting the theory that the severity of
`mucosal injury is correlated with H pylori infection [22].
`Yamamoto et al [23] inoculated a group of test animals
`with H pylori. After these, control animals were subjected to
`stress treatment; ulcer formation and bleeding occurred
`regardless of whether the animals were or were not infected
`with H pylori. However, after 30 minutes of treatment, the
`bleeding rate and index were significantly higher in the
`infected group than in the uninfected group ( P = .036 and
`P = .038, respectively). The ulcer index was also higher in
`the infected group. It was determined that H pylori infection
`lowers the threshold for gastric mucosal injuries in the early
`phase of stress exposure, but suppresses the formation of
`mucosal lesions in the late phase [23].
`In contrast, another study found no association between
`H pylori infection and GI bleeding. This study was
`conducted prospectively over I year in patients with and
`without evidence of GI bleeding admitted to the ICU after
`cardiac surgery. All patients received stress ulcer prophy(cid:173)
`laxis with ranitidine. Results showed that H pylori infection
`was not significantly more prevalent in patients with upper
`GI bleeding than in those without bleeding [24]. Only a
`limited association was found in another study. Among 874
`critically ill patients admitted to an ICU and followed for 6
`weeks, 76 (8.7%) developed stress gastritis [25]. Anti-H
`pylori immunoglobulin A was found to be an independent
`risk factor for stress gastritis, but not anti-H pylori
`immunoglobulin G, possibly suggesting that only a subset
`of individuals with chronic H pylori infection is at risk for
`stress gastritis [25].
`
`3. Complications associated with SRMD
`
`Mortality rates increase proportionately with the inci(cid:173)
`dence and severity of SRMD. In 2 prospective multicenter
`studies, Cook et al [4,5] found significant differences in
`mortality between clinically important GI bleeding and
`nonbleeding patients (Fig. 2). In these studies, patients who
`bled as a result of SRMD had mortality rates of 49% and
`46%. In contrast, mortality rates for nonbleeding patients
`were 9% and 21% (P < .001 and P < .0001, respectively)
`[ 4,5]- These findings are consistent with those of a study
`that evaluated the effectiveness of cimetidine in prevention
`and treatment of stress-induced GI lesions. In this study,
`mortality was significantly correlated with severity of GI
`mucosal injury: mortality rates were 57% in patients with
`
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`38
`
`50
`
`45
`40
`
`"o' 35
`a"
`-30
`
`-~ t! 25
`~ 20
`15
`
`10
`
`5
`
`• Bleeding
`D Non-bleeding
`
`*
`
`0-1-------
`
`Patients
`Fig. 2 Differences in mortality between bleeding (n = 33) and
`nonbleeding (n = 2219) patients. Asterisk indicates P < .001.
`Adapted from N Engl J Med 1994;330:377.
`
`endoscopically evident ulcers and/or bleeding and 24% in
`patients with nonhemorrhagic erosions or normal mucosa
`(P < .03) [26]. Because it is possible to identify patients
`who are at the greatest risk for bleeding, strategies should
`logically focus on the prevention of SRMD and bleeding,
`rather than on its treatment after the fact. Such an approach
`may minimize complications associated with SRMD and,
`ideally, improve outcomes.
`
`3.1. Impact of GI bleeding on ICU patients
`
`Clinically important GI bleeding may cause hemody(cid:173)
`namic instability or require red blood cell transfusions. The
`attendant risks of transfusion include infection and potential
`for immunosuppression, as well as possible blood-related
`incompatibilities [27]. As noted earlier, there is a potential
`for an increased length of stay in the ICU among patients
`with significant bleeding compared to nonbleeders, as well
`as a statistically significant increase in mortality.
`
`4. Risk factors for stress
`ulcer-related bleeding
`
`As noted, critically ill patients admitted to ICUs are at
`risk for developing stress ulceration and subsequent
`bleeding as a result of both underlying disease and
`therapeutic interventions. Prophylaxis against stress ulcers
`can significantly minimize bleeding, but such therapy may
`be costly and can have adverse effects. Therefore, it is
`important to identify risk factors that would substantiate the
`need for prophylaxis and target interventions to those at
`highest risk. A study involving more that 2200 patients
`admitted to ICUs (primarily postcardiovascular surgery)
`evaluated potential risk factors for stress ulcer-related
`bleeding [4]. Prophylactic therapy was withheld in all
`
`N. Stollman, D.C. Metz
`
`except 674 patients; these patients had received drugs that
`increased their risk of bleeding, had a history of peptic ulcer
`or gastritis, were undergoing high-risk surgery, or required
`prophylaxis for other reasons (eg, head injury, trauma) [4].
`The only independent risk factors for clinically important
`stress ulcer bleeding determined by the study were
`respiratory failure requiring more than 48 hours of
`mechanical ventilation (odds ratio, 15.6) and coagulopathy
`(odds ratio, 4.3) [4]. Among 847 patients who had one or
`both of these risk factors, 31 (3.7%) developed clinically
`important bleeding, whereas among 1405 patients who had
`neither risk factors, only 2 (0.1%) developed significant
`bleeding [4].
`Hastings et al [28] randomly assigned 100 patients at risk
`of developing stress ulcers and bleeding to receive antacid
`prophylaxis or no prophylaxis. An analysis of the patients
`reported 6 risk factors for acute GI bleeding: respiratory
`failure, extraabdominal sepsis, peritonitis, jaundice, renal
`failure, and hypotension. Notably, the frequency of bleeding
`increased with the number of risk factors present in both
`treated and untreated groups (Fig. 3) [28]. Results of this
`study demonstrated that there is a distinct association
`between acute GI ulceration and bleeding, and presence of
`risk factors [ 2 8].
`The predictive value of risk factors for GI bleeding was
`also validated in another study of patients with illnesses or
`conditions requiring admission to an ICU [29]. In this study,
`the risk factors considered included surgery, bums, major
`trauma, established liver or renal disease, respiratory failure
`requiring mechanical ventilation, sepsis, and hypotension
`
`• Prophylaxis
`O No Prophylaxis
`
`40
`
`35
`
`bO
`C:
`
`25
`
`l 30
`:e a,
`GI
`a:i
`0
`8
`C:
`GI
`"C ·o
`£
`
`20
`
`15
`
`10
`
`5
`
`0
`
`1 Risk
`Factor
`
`2 Risk
`Factors
`
`3 to 6 Risk
`Factors
`
`Fig. 3 The incidence of bleeding by number of risk factors in
`patients receiving and not receiving antacid prophylaxis. Asterisk
`indicates P < .01; dagger, P < .025; double dagger, P < .005.
`Adapted from N Engl J Med 1978;298:1041.
`
`PTX-073.0004
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`Stress ulcer prophylaxis
`
`39
`
`[29} The authors demonstrated that the probability for
`massive GI bleeding from stress ulceration increased as the
`number of risk factors rose and as the intramucosal pH fell,
`implying mucosal hypoperfusion. Gastrointestinal bleeding
`was, in fact, seen only in patients whose intramucosal pH
`had fallen below the lower limit of normality (7.24). Thus,
`the combination of risk factors and intramucosal pH were the
`best predictors of bleeding [29]- It is important to note that
`none of the risk factors discussed have been conclusively
`demonstrated to be the direct cause of stress ulcer-related
`bleeding; rather, they may be surrogate markers for severity
`of illness. All of the studies described strongly suggest that
`identifying risk factors can provide a valid predictive tool for
`GI bleeding that will allow clinicians to prescribe prophy(cid:173)
`lactic treatment to the patients most likely to benefit [ 4, 29].
`The risk factors associated with increased risk of stress
`ulcer-related bleeding are summarized in Table 1.
`
`5. Stress ulcer prophylaxis options
`
`Prevention of stress-related bleeding is clearly the most
`effective strategy for patients at risk for SRMD in the ICU.
`This can be accomplished by preventing gastric ischemia or
`acid injury. Although high acid concentrations are not the
`only factor that contributes to SRMD, controlling acid
`production in at-risk patients seems to be protective against
`bleeding episodes [9]- A metaanalysis of clinical trials by
`Cook et al [30] reported that various prophylactic therapies
`such as antacids, sucralfate, and histamine2 receptor
`antagonists (H2RAs) reduced the incidence of overt or
`clinically important bleeding compared to no prophylaxis.
`Thus, agents that protect gastric mucosa from acid, either by
`minimizing injury from produced acid or by inhibiting acid
`secretion, have an important role in the prevention of
`bleeding due to SRMD.
`
`5.1. Antacids
`
`Antacids work by directly buffering or neutralizing the
`acidic contents of the stomach. In the study already referred
`to above, Hastings et al [28] found that in critically ill
`
`.• .R~i'girat~~ iliil!lfe .· •·
`· Coagul<>patliy ·
`Hypotens1on •
`·.s~~is
`. ·
`.I:Iepaiie faqure
`0R.e1ial !failure
`,Surgeiy
`·Burns\.
`•,
`ijajor iraUITI~
`· .Adapted /:ti;o~ Gastro/;'11terdfogyil983;815:6B;,N Engl J Med. 1978;;
`~98:tl)4I; ~i\llngl.J:Meyt I99!J;330:377. .
`.
`
`patients at risk for GI ulceration and bleeding, the frequency
`of bleeding was significantly reduced when antacid therapy
`was titrated to keep the pH above 3.5. Results showed that
`2 patients (4%) in the antacid group bled compared with
`12 patients (25%) in the group receiving no prophylaxis
`(P < .005). However, the fact that these agents need to be
`given every 1 or 2 hours to achieve adequate acid neutral(cid:173)
`ization makes their use cumbersome. Moreover, adminis(cid:173)
`tration of high doses of antacids may increase the risks of
`aspiration pneumonia and toxicity related to cation accu(cid:173)
`mulation (particularly in patients with renal dysfunction).
`
`5.2. Sucralfate
`
`Sucralfate protects the gastric mucosa from acid by
`adhering to epithelial cells and forming a protective barrier,
`but has no acid-neutralizing activity. Used in prevention of
`SRMD, it has been shown to be more effective than no
`prophylaxis in decreasing overt bleeding, but no more
`effective than placebo, antacids, and H2RAs in reducing
`clinically important bleeding rates [27 ,30]. The interest in
`sucralfate increased after a clinical trial, and a metaanalysis
`reported a trend toward a lower incidence of pneumonia
`with sucralfate than with agents that suppress acid [30,31].
`However, a large randomized study of 1200 ICU patients
`reported no difference in the incidence of nosocomial
`pneumonia between patients receiving intravenous raniti(cid:173)
`dine 50 mg every 8 hours and those receiving sucralfate
`suspension 1 g via nasogastric tube every 6 hours. In the
`ranitidine group, 114 (19%) of 596 patients had ventilator(cid:173)
`associated pneumonia compared with 98 (16%) of 604
`patients in the sucralfate group. More importantly, clinically
`important GI bleeding was higher in the sucralfate group
`than in the ranitidine group, 3.8% and 1.7%, respectively
`(P = .02) [32].
`
`5.3. Hrreceptor blockade
`
`H2RAs inhibit histamine-stimulated acid secretion by
`blocking Hz-receptor sites of the parietal cell in a highly
`selective manner; they have little or no effect on histamine
`receptors not involved with gastric secretion [9]. H2RAs
`have been found to be significantly better than placebo,
`antacids, and sucralfate in reducing the incidence of
`clinically significant bleeding (Fig. 4) [32].
`
`5.3.1. Continuous infusion vs bolus injection
`Maintaining the pH between 3.5 and 4.5 is a surrogate
`endpoint accepted by many and should be the minimum
`goal of prophylactic therapy [ll]. Effective prophylaxis
`requires selection of not only the proper drug and dose, but
`the appropriate method of administration. A continuous
`intravenous infusion of cimetidine (50-100 mg/h) was
`evaluated in a double-blind placebo-controlled study to
`determine its effectiveness in preventing upper GI hemor(cid:173)
`rhage [33]. Results showed that intragastric pH (>4.0 in both
`groups at baseline) declined over time in the placebo group
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`40
`
`Number of
`Studies
`
`Clinically Important Bleeding*
`Odds Ratio (950/o Cl)
`
`10
`
`10
`
`4
`
`H2RA vs. placebo
`H2RA vs. antacids
`H2RA vs. sucralfate
`
`--I------
`
`0
`
`Reduced
`risk
`
`10
`
`Increased
`risk
`
`Fig. 4 The results of a metaanalysis on the efficacy of H2RAs in
`stress ulcer prophylaxis. Asterisk indicates overt bleeding accom(cid:173)
`panied by hemodynamic changes or a decrease in hemoglobin of
`2 g/dL requiring transfusion of2 units of blood within 24 hours or
`requiring surgery. Adapted from JAMA 1996;275:308.
`
`but not in the cimetidine group, and significantly less upper
`GI bleeding occurred in the cimetidine group (P = .009)
`[33). This study clearly indicated that prophylaxis with
`continuously infused cimetidine is a valuable approach for
`preventing GI hemorrhage in patients with risk factors ( eg,
`major surgery, trauma, burns, hypotension, sepsis, or organ
`failure) for stress-related mucosal bleeding [33).
`Although cimetidine given by continuous intravenous
`infusion is currently the only regimen approved by the US
`Food and Drug Administration for prevention of stress(cid:173)
`related mucosal bleeding, various Hi-receptor antagonists
`are often given by intermittent infusion for this indication in
`clinical practice [34). However, the ability of these agents,
`when given intermittently, to maintain the intragastric pH
`above 4.0 is questionable, given their relatively short half(cid:173)
`lives [35). One study compared bolus doses and continuous
`infusions of cimetidine in the maintenance of intragastric
`pH above 4.0 in critically ill patients with at least one major
`organ system failure or multiple traumas. Patients were
`randomized to receive cimetidine either in bolus doses
`(up to 300 mg IV every 6 hours) or by continuous intra(cid:173)
`venous infusion (up to 50 mg/h for 24 hours) [36). Most
`patients (87%) receiving continuous infusions maintained
`their intragastric pH above 4.0. There was a strong (92.9%
`positive) correlation between serum levels of cimetidine
`and intragastric pH above 4.0. Thus, cimetidine given by
`continuous infusion proved to be effective in maintaining
`pH above 4.0, thereby potentially preventing stress ulcer(cid:173)
`ation (Fig. 5) [36). It is important to note that although
`H2RAs dosed as a continuous infusion are more effective in
`raising gastric pH than H2RAs dosed intermittently, there
`are no comparative trials evaluating these dosing regimens
`on clinical outcomes. One can only surmise that more
`complete acid suppression leads to enhanced GI protection.
`
`5.3.2. Risk of nosocomial pneumonia
`In regard to the association of increased pH-as a
`consequence of H2RA administration for SRMD prophy-
`
`N. Stollman, D.C. Metz
`
`laxis-with potential for nosocomial pneumonia, Navab and
`Steingrub [37) reported that the results of several studies
`were conflicting. They concluded that other factors such as
`intragastric volume, severity of illness, bile reflux, and
`infection contributed to the development of pneumonia and
`that the pathogenesis of pneumonia is multifactorial [3 7). As
`noted earlier, a large, well-controlled, randomized trial failed
`to find a difference in the rate of nosocomial pneumonia
`when ranitidine was compared to sucralfate in critically
`ill patients [3 2].
`
`5.3.3. Limitations of H2RAs
`A significant limitation of H2RAs is the tendency for
`tolerance to occur within a relatively short interval after
`initiation of therapy. Two studies in healthy subjects
`demonstrated that the H2RA ranitidine rapidly lost anti(cid:173)
`secretory effect after the first day of administration [38,39).
`One study reported the development of tolerance despite
`dose escalations on days 2 and 3 [38). The other study found
`that continuous infusions of ranitidine were superior to
`intermittent injections only on day 1 of treatment [39). The
`latter observation may seem to contradict results of the
`previously cited study comparing continuously infused and
`bolus doses of cimetidine. However, that study did not
`extend beyond a 12-hour observation period; thus, the
`impact of tolerance was not detected [36).
`Some H2RAs interfere with cytochrome P450 metabo(cid:173)
`lizing enzymes, potentially leading to drug interactions.
`Cimetidine and, to a lesser extent, ranitidine inhibit P450
`enzymes, which may facilitate accumulation and possibly
`toxicity of coadministered drugs. In addition, H2RAs require
`dosing adjustments in the setting of renal dysfunction [40).
`Another clinical concern is thrombocytopenia that may be
`induced by H2RAs, but it remains a rare occurrence in the
`absence of another independent risk factor [ 41 l
`
`5.4. Proton pump inhibitors
`
`Gastric acid is produced and regulated by mechanisms
`within the parietal cell [ 42). Transport of H+ by the
`proton pump, H+,K+-ATPase, is the underlying mediator
`and final step in the regulation of acid secretion [43).
`Proton pump inhibitors (PPis) inactivate this enzyme and
`inhibit gastric acid secretion by specific inhibition of
`H+,K+-ATPase at the secretory surface of the parietal cell
`[43), regardless of whether the cell is stimulated by
`histamine, gastrin, or acetylcholine.
`The efficacy and utility of PPis have been established for
`several acid-related GI disorders, but they have not, as yet,
`been approved as prophylaxis for GI bleeding associated
`with stress ulceration. Small open-label trials have examined
`the use of oral PPis administered as extemporaneously
`compounded suspensions in patients at risk for stress ulcer.
`No clinically significant bleeding was reported in these
`trials, but drawing conclusions regarding efficacy is difficult
`because of several methodological limitations of these
`studies, such as the lack of a comparator arm and the small
`
`PTX-073.0006
`
`Page 6 of 11
`
`Patent Owner Ex. 2022
`Mylan v. Pozen
`IPR2017-01995
`
`

`

`Stress ulcer prophylaxis
`
`41
`
`300 mg bolus+ 37.5 mg/h
`infusion
`
`300mgbolus
`
`·1. '
`: ;: .. . .
`
`: : l, :
`:::::. :
`:::::
`
`2
`
`4
`
`8
`6
`Time (h)
`
`10
`
`12
`
`8.0
`
`t_ 6.0
`V ·c
`'Iii
`~
`
`4.0
`
`2.0
`
`:.r:
`
`0
`
`Fig. 5 The effect of intermittent and continuous infusion
`cimetidine on gastric pH. Asterisk indicates effect on representa(cid:173)
`tive patient. Adapted with permission from Gastroenterology
`l 985;89:532.
`
`number of patients. In the first open-label study by Lasky et
`al [ 44], 60 mechanically ventilated trauma patients with an
`additional risk factor for stress ulcer development received
`omeprazole suspension 40 mg given twice on the first day,
`approximately 6 hours apart, followed by 20 mg/d. Baseline
`pH (a secondary outcome in this study) was 3.3 for patients
`enrolled in this study, with a mean gastric pH increase to 6.7
`after administration of omeprazole [ 44]. The second
`prospective open-label study by Phillips et al [ 45] included
`patients admitted to a surgical ICU and to a burn unit
`requiring mechanical ventilation and with at least one
`additional risk factor for stress ulcer disease. Seventy-five
`eligible patients received omeprazole suspension 40 mg,
`followed by a second 40-mg dose 6 to 8 hours later, and
`thereafter 20 mg daily. Four hours postomeprazole admin(cid:173)
`istration, the gastric pH increased to 7.1. The mean pH was
`6.8 after starting therapy, up from an initial mean baseline
`pH of 3.5 (P < .001) [45]- No bleeding was reported in
`either of these trials, but the number of patients enrolled is
`likely insufficient to adequately assess an outcome of such
`low incidence [44,45]-
`Few clinical studies have compared a PPI with an H2RA
`for prophylaxis of GI bleeding in patients at risk for stress
`ulceration. Levy et al [ 46] compared omeprazole with
`ranitidine in patients with risk factors for stress ulcer-related
`bleeding. Sixty-seven patients were randomized to receive
`either ranitidine (n = 32), as a 50-mg bolus followed by a
`50-mg IV infusion every 8 hours, or omeprazole (n = 32), as
`
`a 40-mg capsule administered orally or nasogastrically once
`a day [46]. Results showed significantly more clinically
`significant bleeding in the ranitidine group than in the
`omeprazole group (31 % vs 6%, P < .05). In addition, fewer
`patients receiving omeprazole developed nosocomial pneu(cid:173)
`monia (3% vs 14%), although the difference between groups
`was not significant [46]. It should be noted, however, that
`despite randomization, the ranitidine-treated patients had
`more risk factors present at baseline than the omeprazole
`group (2.7 vs 1.9, P < .05) [46]. The fact that PPis are more
`potent pump inhibitors raises theoretical concerns that their
`more potent acid suppression may actually confer increased
`risk of ventilator-associated pneumonia, which is a more
`frequent and serious problem than stress ulcer bleeding.
`Additional randomized trials in stress ulcer patients have
`been published in abstract form only. One study compared
`omeprazole suspension administered nasogastrically with
`continuously infused ranitidine (150 or 200 mg/d) in
`58 patients with at least 2 risk factors for stress ulcer-related
`bleeding. Omeprazole was shown to be superior to ranitidine
`in efficacy, safety, and cost. Clinically significant GI
`ble