A Review of Stress Ulcer Prophylaxis in the Neurosurgical Intensive Care Unit

ISSN 0148-396X

Accession 00006123-199708000-00017

Author(s)

Lu William Y MD Rhoney Denise H PharmD Boling Warren B MD Johnson John D MD Smith

Terry C MD

Issue Volume 41(2) August 1997 pp 416-426

Publication

Type [Topic Review]

Publisher Copyright copy by the Congress of Neurological Surgeons

Institution(s)

Central Florida Neurosurgical Associates (WYL) Orlando Florida Department of Pharmacy (DHR)

Detroit Receiving Hospital Detroit Michigan Division of Neurosurgery (WBB JDJ TCS) University

of Kentucky Medical Center Lexington Kentucky

Received August 20 1996 Accepted February 14 1997

Reprint requests William Y Lu MD Central Florida Neurosurgical Associates 328 E Spruce

Street Orlando FL 32804

Keywords Critical care Gastrointestinal bleeding Neurosurgery Stress ulcer

Outline

Abstract

PATHOPHYSIOLOGY

o Destructive factors

o Protective factors

CLINICAL RISK FACTORS

o Brain injury

o Spinal cord injury

o Animal experiments

STRESS ULCER PROPHYLAXIS THERAPY

o Antacids

o Histamine receptor antagonists

o Sucralfate

RELATED ISSUES

o Enteral nutrition

o Steroids

o Nosocomial pneumonia

o Gastric monitoring

o Surgery

CONCLUSION

REFERENCES

COMMENTS

Abstract^

STRESS ULCERS OCCUR frequently in intensive care unit patients who have intracranial disease After major

physiological stress endoscopic evidence of mucosal lesions of the gastrointestinal tract appears within 24

hours of injury 17 of these erosions progress to clinically significant bleeding Gastrointestinal hemorrhage

has been associated with mortality rates of up to 50 The pathogenesis of stress ulcers may not be completely

understood but gastric acid and pepsin appear to play significant roles Antacids H2 antagonists and

sucralfate are effective prophylactic agents in the medicalsurgical intensive care unit Appropriate therapy

for neurosurgical patients remains unclear however This review summarizes the current literature regarding

the pathogenesis and therapy of stress ulcers in neurosurgical patients

Stress ulcers occur frequently in intensive care unit (ICU) patients who have intracranial disease After major

physiological stress such as brain injury endoscopic evidence of mucosal lesions can appear within 24 hours

and 17 of these erosions can progress to clinically significant bleeding (56) Gastrointestinal (GI) hemorrhage

has been associated with mortality rates of up to 50 (102 105 120 122) Harvey Cushing reported 11 cases of

either GI ulceration perforation or hemorrhagic erosion in his postoperative brain tumor patients (24)

Subsequently all GI lesions associated with intracranial disease have borne his name Cushings ulcers

Studies with their focus on neurosurgical patients suggest that stress ulcer prophylaxis is warranted (1 5 11

13 33 34 41 43 45 47 55 56 58 66 68 71 73 99 112 128 130 142 143 145 148) This type of

preventive therapy has traditionally been directed toward neutralization of GI luminal acid several studies

have pointed toward a hypersecretion of gastric acid as the source of ulcerations (5 24 36 55 93 143)

Recent debate concerning the risk of nosocomial pneumonia associated with acid-neutralizing therapy has led

to the evaluation of sucralfate in stress ulceration because it does not affect gastric pH (30 32 57)

The literature dealing with stress ulcer prophylaxis is vast and conflicting This review will describe the

pathophysiology of stress-related mucosal lesions define some of the risk factors for bleeding and summarize

the studies concerning stress ulceration in neurosurgical patients It also seeks to evaluate the efficacy of

prophylactic therapy in neurosurgical patients as well as address related issues such as enteral nutrition

corticosteroid therapy and nosocomial pneumonia

PATHOPHYSIOLOGY^

The pathogenesis of stress ulcers is not completely understood but studies have indicated that the origin may

be multifactorial There is probably an imbalance between protective and destructive factors Major

destructive factors include acid pepsin and bile Protective factors include adequate mucosal blood flow the

mucus-bicarbonate layer epithelial cell renewal and prostaglandins all part of a normally functioning GI

mucosal barrier (88 144)

Destructive factors^

The presence of luminal acid is essential for the development stress ulcerations (62 63 85 89) An

overproduction of gastric acid is more likely to occur in patients with intracranial disease Acid and pepsin

hypersecretion peak by 3 to 5 days after central nervous system (CNS) injury (55 74) Several proteolytic

enzymes within pepsin may add to the destruction of GI mucosa already damaged by excess acid The reflux of

bile salts which is commonly found in critically ill patients is thought to disrupt the gastric mucosal barrier

and enhance mucosal injury (15 88 114 125 126)

Protective factors^

The first-line defense against GI injury is the thin layer of mucus that is adherent to the superficial mucosa

This gel-like substance is composed of bicarbonate which depends on normal gastric acid secretion and a

glycoprotein matrix which serves as a physical barrier to the influx of pepsin and hydrogen ions This mucous

layer can be disrupted by ischemic insults to the underlying mucosa the result being a change in mucosal

permeability Subsequently an unrestricted influx of hydrogen ions is permitted which can lead to direct

destruction of the gastric mucosa (16 42) Other factors that can lead to the breakdown of the mucus

glycoproteins are fasting states and corticosteroid use (115)

A variety of stressors can cause a reduction in gastric mucosal blood flow with resultant mucosal ischemia

This leads to a depletion of mucosal adenosine triphosphate energy stores which disrupts the production of

the alkaline mucus layer This permits the damaging back-diffusion of hydrogen ions The severity of mucosal

injury has been correlated with the magnitude of ischemia and intramural acidosis (37) The buildup of free

radical by-products of anaerobic metabolism can promote lipid peroxidation and membrane damage within the

mucosal cells (98 110)

Mucosal protection is also provided by the ability of the surface epithelial cells of the gastric mucosa to quickly

replenish normal cell turnover During periods of stress the gastric mucosa has a decreased rate of cellular

proliferation and deoxyribonucleic acid synthesis Fasting also decreases ribonucleic acid and protein synthesis

in the gastric epithelium Nutritional support or the use of trophic agents such as pentagastrin growth

hormone and epidermal growth factor may provide the catalysts for mucosal repair and regrowth (134)

Prostaglandins have a variety of actions within the gastric mucosa that may contribute to mucosal protection

These include the stimulation of mucus and bicarbonate secretion by gastric and duodenal mucosa as well as

increasing the gastric mucosal blood flow Prostaglandins also protect the mucosa from agents such as aspirin

alcohol and nonsteroidal anti-inflammatory agents High concentrations of prostaglandin E2 and prostaglandin

I2 are normally present in the gastric mucosa The role of exogenously administering prostaglandins for the

prevention of stress-related mucosal damage in the clinical setting has yet to be determined (88)

In summary the following sequence of events can occur among trauma patients It begins with an initial

episode of hypotension that induces GI mucosal ischemia Energy stores in the form of adenosine triphosphate

are rapidly depleted hampering the neutralization of back-diffusing hydrogen ions and disrupting the

production of the alkaline mucus layer The formation of mucosal erosions and frank hemorrhage can then

occur as a result of this breakdown of the gastric mucosal barrier (15 16 42 49 62 64 84 126 127)

CLINICAL RISK FACTORS^

A number of risk factors that may influence the development of GI bleeding in critically ill patients have been

reported In addition to CNS lesions these include the following burns of gt 25 body surface area respiratory

failure hypotension sepsis jaundice peritonitis coagulopathy renal failure and hepatic failure (19 24 26

49 78-80 88 107 120 126 150) The accumulation of risk factors seems to increase the risk of bleeding (13

49 87) Stress ulcer bleeding in patients with head trauma correlates with the severity of injury regardless of

the presence of other risk factors (56)

Brain injury^

A neurogenic basis for stress ulcerations was first proposed by Carl Rokitansky in 1841 Premortem ulcerations

of the GI system were found in newborns with intracranial tumors in children and adults with CNS disease and

in patients in cachectic states Harvey Cushing further elaborated on the subject in his classic work of 1932 He

reported 11 cases of either GI ulceration perforation or hemorrhagic erosion in postoperative tumor patients

He thought that these lesions arose from the actions of the parasympathetic centers of the hypothalamus with

their connections to vagal nuclei in the medulla Lesions occurring anywhere along this pathway would

interrupt normal inhibitory mechanisms causing unopposed parasympathetic stimulation This led to abnormal

amounts of acid secretion and consequently to gastric erosions Responsible insults included traumatic

injuries infectious diseases (especially of the basal brain) and tumors with an emphasis on cerebellar lesions

(24) Cushings hypothesis was corroborated by laboratory experiments that sought to destroy or stimulate

various hypothalamic areas (3 24 36) French et al (38) further demonstrated that an imbalance of

autonomic function originating in the hypothalamus predisposed patients to gastrointestinal ulcerations

Norton et al(92) showed that in vitro direct pressure stimulation of the vagal nuclei resulted in gastric acid

hypersecretion Lewis (73) wrote of the increased frequency of gastroduodenal ulceration and hemorrhage in

her review of childhood intracranial diseases She also postulated that the pathological basis was vagal

hyperactivity The success of vagotomy and pyloroplasty in preventing the recurrence of bleeding or ulceration

supported her theory

Clinical and autopsy studies have indicated the probable existence of Cushings ulcers in neurosurgical patients

An autopsy review of patients dying of CNS diseases revealed an incidence of hemorrhagic ulcers (125) that

was double that found in patients succumbing to non-neurological diseases (58) Gastric hypersecretion of

pepsin and acid does occur in neurosurgical patients (11-13 42 112) Severe head injury and Glasgow Coma

Scale scores of lt 9 can lead to gastric acid hypersecretion and hemorrhage rates exceeding 17 (5 45 47 50

55 56 68 87 93 143) Bleeding may be more likely to occur during the first 2 weeks of hospitalization (11

68) Other relevant risk factors include the following syndrome of inappropriate secretion of antidiuretic

hormone respiratory failure age of gt60 years CNS infection gastric pH value of lt4 and hypotension (11-13

50) As the number of risk factors increases the cumulative risk of bleeding also rises significantly (13 87)

High mortality rates can occur with GI complications up to one-third of patients can succumb as a direct result

(13) Herein lies the basis for the use of prophylactic measures in neurosurgical patients Conflicting reports on

the efficacy of various preventative medications have emerged however (11 13 47 68 87 112)

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

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7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

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hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

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11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

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controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

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STRESS ULCER PROPHYLAXIS THERAPY

o Antacids

o Histamine receptor antagonists

o Sucralfate

RELATED ISSUES

o Enteral nutrition

o Steroids

o Nosocomial pneumonia

o Gastric monitoring

o Surgery

CONCLUSION

REFERENCES

COMMENTS

Abstract^

STRESS ULCERS OCCUR frequently in intensive care unit patients who have intracranial disease After major

physiological stress endoscopic evidence of mucosal lesions of the gastrointestinal tract appears within 24

hours of injury 17 of these erosions progress to clinically significant bleeding Gastrointestinal hemorrhage

has been associated with mortality rates of up to 50 The pathogenesis of stress ulcers may not be completely

understood but gastric acid and pepsin appear to play significant roles Antacids H2 antagonists and

sucralfate are effective prophylactic agents in the medicalsurgical intensive care unit Appropriate therapy

for neurosurgical patients remains unclear however This review summarizes the current literature regarding

the pathogenesis and therapy of stress ulcers in neurosurgical patients

Stress ulcers occur frequently in intensive care unit (ICU) patients who have intracranial disease After major

physiological stress such as brain injury endoscopic evidence of mucosal lesions can appear within 24 hours

and 17 of these erosions can progress to clinically significant bleeding (56) Gastrointestinal (GI) hemorrhage

has been associated with mortality rates of up to 50 (102 105 120 122) Harvey Cushing reported 11 cases of

either GI ulceration perforation or hemorrhagic erosion in his postoperative brain tumor patients (24)

Subsequently all GI lesions associated with intracranial disease have borne his name Cushings ulcers

Studies with their focus on neurosurgical patients suggest that stress ulcer prophylaxis is warranted (1 5 11

13 33 34 41 43 45 47 55 56 58 66 68 71 73 99 112 128 130 142 143 145 148) This type of

preventive therapy has traditionally been directed toward neutralization of GI luminal acid several studies

have pointed toward a hypersecretion of gastric acid as the source of ulcerations (5 24 36 55 93 143)

Recent debate concerning the risk of nosocomial pneumonia associated with acid-neutralizing therapy has led

to the evaluation of sucralfate in stress ulceration because it does not affect gastric pH (30 32 57)

The literature dealing with stress ulcer prophylaxis is vast and conflicting This review will describe the

pathophysiology of stress-related mucosal lesions define some of the risk factors for bleeding and summarize

the studies concerning stress ulceration in neurosurgical patients It also seeks to evaluate the efficacy of

prophylactic therapy in neurosurgical patients as well as address related issues such as enteral nutrition

corticosteroid therapy and nosocomial pneumonia

PATHOPHYSIOLOGY^

The pathogenesis of stress ulcers is not completely understood but studies have indicated that the origin may

be multifactorial There is probably an imbalance between protective and destructive factors Major

destructive factors include acid pepsin and bile Protective factors include adequate mucosal blood flow the

mucus-bicarbonate layer epithelial cell renewal and prostaglandins all part of a normally functioning GI

mucosal barrier (88 144)

Destructive factors^

The presence of luminal acid is essential for the development stress ulcerations (62 63 85 89) An

overproduction of gastric acid is more likely to occur in patients with intracranial disease Acid and pepsin

hypersecretion peak by 3 to 5 days after central nervous system (CNS) injury (55 74) Several proteolytic

enzymes within pepsin may add to the destruction of GI mucosa already damaged by excess acid The reflux of

bile salts which is commonly found in critically ill patients is thought to disrupt the gastric mucosal barrier

and enhance mucosal injury (15 88 114 125 126)

Protective factors^

The first-line defense against GI injury is the thin layer of mucus that is adherent to the superficial mucosa

This gel-like substance is composed of bicarbonate which depends on normal gastric acid secretion and a

glycoprotein matrix which serves as a physical barrier to the influx of pepsin and hydrogen ions This mucous

layer can be disrupted by ischemic insults to the underlying mucosa the result being a change in mucosal

permeability Subsequently an unrestricted influx of hydrogen ions is permitted which can lead to direct

destruction of the gastric mucosa (16 42) Other factors that can lead to the breakdown of the mucus

glycoproteins are fasting states and corticosteroid use (115)

A variety of stressors can cause a reduction in gastric mucosal blood flow with resultant mucosal ischemia

This leads to a depletion of mucosal adenosine triphosphate energy stores which disrupts the production of

the alkaline mucus layer This permits the damaging back-diffusion of hydrogen ions The severity of mucosal

injury has been correlated with the magnitude of ischemia and intramural acidosis (37) The buildup of free

radical by-products of anaerobic metabolism can promote lipid peroxidation and membrane damage within the

mucosal cells (98 110)

Mucosal protection is also provided by the ability of the surface epithelial cells of the gastric mucosa to quickly

replenish normal cell turnover During periods of stress the gastric mucosa has a decreased rate of cellular

proliferation and deoxyribonucleic acid synthesis Fasting also decreases ribonucleic acid and protein synthesis

in the gastric epithelium Nutritional support or the use of trophic agents such as pentagastrin growth

hormone and epidermal growth factor may provide the catalysts for mucosal repair and regrowth (134)

Prostaglandins have a variety of actions within the gastric mucosa that may contribute to mucosal protection

These include the stimulation of mucus and bicarbonate secretion by gastric and duodenal mucosa as well as

increasing the gastric mucosal blood flow Prostaglandins also protect the mucosa from agents such as aspirin

alcohol and nonsteroidal anti-inflammatory agents High concentrations of prostaglandin E2 and prostaglandin

I2 are normally present in the gastric mucosa The role of exogenously administering prostaglandins for the

prevention of stress-related mucosal damage in the clinical setting has yet to be determined (88)

In summary the following sequence of events can occur among trauma patients It begins with an initial

episode of hypotension that induces GI mucosal ischemia Energy stores in the form of adenosine triphosphate

are rapidly depleted hampering the neutralization of back-diffusing hydrogen ions and disrupting the

production of the alkaline mucus layer The formation of mucosal erosions and frank hemorrhage can then

occur as a result of this breakdown of the gastric mucosal barrier (15 16 42 49 62 64 84 126 127)

CLINICAL RISK FACTORS^

A number of risk factors that may influence the development of GI bleeding in critically ill patients have been

reported In addition to CNS lesions these include the following burns of gt 25 body surface area respiratory

failure hypotension sepsis jaundice peritonitis coagulopathy renal failure and hepatic failure (19 24 26

49 78-80 88 107 120 126 150) The accumulation of risk factors seems to increase the risk of bleeding (13

49 87) Stress ulcer bleeding in patients with head trauma correlates with the severity of injury regardless of

the presence of other risk factors (56)

Brain injury^

A neurogenic basis for stress ulcerations was first proposed by Carl Rokitansky in 1841 Premortem ulcerations

of the GI system were found in newborns with intracranial tumors in children and adults with CNS disease and

in patients in cachectic states Harvey Cushing further elaborated on the subject in his classic work of 1932 He

reported 11 cases of either GI ulceration perforation or hemorrhagic erosion in postoperative tumor patients

He thought that these lesions arose from the actions of the parasympathetic centers of the hypothalamus with

their connections to vagal nuclei in the medulla Lesions occurring anywhere along this pathway would

interrupt normal inhibitory mechanisms causing unopposed parasympathetic stimulation This led to abnormal

amounts of acid secretion and consequently to gastric erosions Responsible insults included traumatic

injuries infectious diseases (especially of the basal brain) and tumors with an emphasis on cerebellar lesions

(24) Cushings hypothesis was corroborated by laboratory experiments that sought to destroy or stimulate

various hypothalamic areas (3 24 36) French et al (38) further demonstrated that an imbalance of

autonomic function originating in the hypothalamus predisposed patients to gastrointestinal ulcerations

Norton et al(92) showed that in vitro direct pressure stimulation of the vagal nuclei resulted in gastric acid

hypersecretion Lewis (73) wrote of the increased frequency of gastroduodenal ulceration and hemorrhage in

her review of childhood intracranial diseases She also postulated that the pathological basis was vagal

hyperactivity The success of vagotomy and pyloroplasty in preventing the recurrence of bleeding or ulceration

supported her theory

Clinical and autopsy studies have indicated the probable existence of Cushings ulcers in neurosurgical patients

An autopsy review of patients dying of CNS diseases revealed an incidence of hemorrhagic ulcers (125) that

was double that found in patients succumbing to non-neurological diseases (58) Gastric hypersecretion of

pepsin and acid does occur in neurosurgical patients (11-13 42 112) Severe head injury and Glasgow Coma

Scale scores of lt 9 can lead to gastric acid hypersecretion and hemorrhage rates exceeding 17 (5 45 47 50

55 56 68 87 93 143) Bleeding may be more likely to occur during the first 2 weeks of hospitalization (11

68) Other relevant risk factors include the following syndrome of inappropriate secretion of antidiuretic

hormone respiratory failure age of gt60 years CNS infection gastric pH value of lt4 and hypotension (11-13

50) As the number of risk factors increases the cumulative risk of bleeding also rises significantly (13 87)

High mortality rates can occur with GI complications up to one-third of patients can succumb as a direct result

(13) Herein lies the basis for the use of prophylactic measures in neurosurgical patients Conflicting reports on

the efficacy of various preventative medications have emerged however (11 13 47 68 87 112)

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

Studies with their focus on neurosurgical patients suggest that stress ulcer prophylaxis is warranted (1 5 11

13 33 34 41 43 45 47 55 56 58 66 68 71 73 99 112 128 130 142 143 145 148) This type of

preventive therapy has traditionally been directed toward neutralization of GI luminal acid several studies

have pointed toward a hypersecretion of gastric acid as the source of ulcerations (5 24 36 55 93 143)

Recent debate concerning the risk of nosocomial pneumonia associated with acid-neutralizing therapy has led

to the evaluation of sucralfate in stress ulceration because it does not affect gastric pH (30 32 57)

The literature dealing with stress ulcer prophylaxis is vast and conflicting This review will describe the

pathophysiology of stress-related mucosal lesions define some of the risk factors for bleeding and summarize

the studies concerning stress ulceration in neurosurgical patients It also seeks to evaluate the efficacy of

prophylactic therapy in neurosurgical patients as well as address related issues such as enteral nutrition

corticosteroid therapy and nosocomial pneumonia

PATHOPHYSIOLOGY^

The pathogenesis of stress ulcers is not completely understood but studies have indicated that the origin may

be multifactorial There is probably an imbalance between protective and destructive factors Major

destructive factors include acid pepsin and bile Protective factors include adequate mucosal blood flow the

mucus-bicarbonate layer epithelial cell renewal and prostaglandins all part of a normally functioning GI

mucosal barrier (88 144)

Destructive factors^

The presence of luminal acid is essential for the development stress ulcerations (62 63 85 89) An

overproduction of gastric acid is more likely to occur in patients with intracranial disease Acid and pepsin

hypersecretion peak by 3 to 5 days after central nervous system (CNS) injury (55 74) Several proteolytic

enzymes within pepsin may add to the destruction of GI mucosa already damaged by excess acid The reflux of

bile salts which is commonly found in critically ill patients is thought to disrupt the gastric mucosal barrier

and enhance mucosal injury (15 88 114 125 126)

Protective factors^

The first-line defense against GI injury is the thin layer of mucus that is adherent to the superficial mucosa

This gel-like substance is composed of bicarbonate which depends on normal gastric acid secretion and a

glycoprotein matrix which serves as a physical barrier to the influx of pepsin and hydrogen ions This mucous

layer can be disrupted by ischemic insults to the underlying mucosa the result being a change in mucosal

permeability Subsequently an unrestricted influx of hydrogen ions is permitted which can lead to direct

destruction of the gastric mucosa (16 42) Other factors that can lead to the breakdown of the mucus

glycoproteins are fasting states and corticosteroid use (115)

A variety of stressors can cause a reduction in gastric mucosal blood flow with resultant mucosal ischemia

This leads to a depletion of mucosal adenosine triphosphate energy stores which disrupts the production of

the alkaline mucus layer This permits the damaging back-diffusion of hydrogen ions The severity of mucosal

injury has been correlated with the magnitude of ischemia and intramural acidosis (37) The buildup of free

radical by-products of anaerobic metabolism can promote lipid peroxidation and membrane damage within the

mucosal cells (98 110)

Mucosal protection is also provided by the ability of the surface epithelial cells of the gastric mucosa to quickly

replenish normal cell turnover During periods of stress the gastric mucosa has a decreased rate of cellular

proliferation and deoxyribonucleic acid synthesis Fasting also decreases ribonucleic acid and protein synthesis

in the gastric epithelium Nutritional support or the use of trophic agents such as pentagastrin growth

hormone and epidermal growth factor may provide the catalysts for mucosal repair and regrowth (134)

Prostaglandins have a variety of actions within the gastric mucosa that may contribute to mucosal protection

These include the stimulation of mucus and bicarbonate secretion by gastric and duodenal mucosa as well as

increasing the gastric mucosal blood flow Prostaglandins also protect the mucosa from agents such as aspirin

alcohol and nonsteroidal anti-inflammatory agents High concentrations of prostaglandin E2 and prostaglandin

I2 are normally present in the gastric mucosa The role of exogenously administering prostaglandins for the

prevention of stress-related mucosal damage in the clinical setting has yet to be determined (88)

In summary the following sequence of events can occur among trauma patients It begins with an initial

episode of hypotension that induces GI mucosal ischemia Energy stores in the form of adenosine triphosphate

are rapidly depleted hampering the neutralization of back-diffusing hydrogen ions and disrupting the

production of the alkaline mucus layer The formation of mucosal erosions and frank hemorrhage can then

occur as a result of this breakdown of the gastric mucosal barrier (15 16 42 49 62 64 84 126 127)

CLINICAL RISK FACTORS^

A number of risk factors that may influence the development of GI bleeding in critically ill patients have been

reported In addition to CNS lesions these include the following burns of gt 25 body surface area respiratory

failure hypotension sepsis jaundice peritonitis coagulopathy renal failure and hepatic failure (19 24 26

49 78-80 88 107 120 126 150) The accumulation of risk factors seems to increase the risk of bleeding (13

49 87) Stress ulcer bleeding in patients with head trauma correlates with the severity of injury regardless of

the presence of other risk factors (56)

Brain injury^

A neurogenic basis for stress ulcerations was first proposed by Carl Rokitansky in 1841 Premortem ulcerations

of the GI system were found in newborns with intracranial tumors in children and adults with CNS disease and

in patients in cachectic states Harvey Cushing further elaborated on the subject in his classic work of 1932 He

reported 11 cases of either GI ulceration perforation or hemorrhagic erosion in postoperative tumor patients

He thought that these lesions arose from the actions of the parasympathetic centers of the hypothalamus with

their connections to vagal nuclei in the medulla Lesions occurring anywhere along this pathway would

interrupt normal inhibitory mechanisms causing unopposed parasympathetic stimulation This led to abnormal

amounts of acid secretion and consequently to gastric erosions Responsible insults included traumatic

injuries infectious diseases (especially of the basal brain) and tumors with an emphasis on cerebellar lesions

(24) Cushings hypothesis was corroborated by laboratory experiments that sought to destroy or stimulate

various hypothalamic areas (3 24 36) French et al (38) further demonstrated that an imbalance of

autonomic function originating in the hypothalamus predisposed patients to gastrointestinal ulcerations

Norton et al(92) showed that in vitro direct pressure stimulation of the vagal nuclei resulted in gastric acid

hypersecretion Lewis (73) wrote of the increased frequency of gastroduodenal ulceration and hemorrhage in

her review of childhood intracranial diseases She also postulated that the pathological basis was vagal

hyperactivity The success of vagotomy and pyloroplasty in preventing the recurrence of bleeding or ulceration

supported her theory

Clinical and autopsy studies have indicated the probable existence of Cushings ulcers in neurosurgical patients

An autopsy review of patients dying of CNS diseases revealed an incidence of hemorrhagic ulcers (125) that

was double that found in patients succumbing to non-neurological diseases (58) Gastric hypersecretion of

pepsin and acid does occur in neurosurgical patients (11-13 42 112) Severe head injury and Glasgow Coma

Scale scores of lt 9 can lead to gastric acid hypersecretion and hemorrhage rates exceeding 17 (5 45 47 50

55 56 68 87 93 143) Bleeding may be more likely to occur during the first 2 weeks of hospitalization (11

68) Other relevant risk factors include the following syndrome of inappropriate secretion of antidiuretic

hormone respiratory failure age of gt60 years CNS infection gastric pH value of lt4 and hypotension (11-13

50) As the number of risk factors increases the cumulative risk of bleeding also rises significantly (13 87)

High mortality rates can occur with GI complications up to one-third of patients can succumb as a direct result

(13) Herein lies the basis for the use of prophylactic measures in neurosurgical patients Conflicting reports on

the efficacy of various preventative medications have emerged however (11 13 47 68 87 112)

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

permeability Subsequently an unrestricted influx of hydrogen ions is permitted which can lead to direct

destruction of the gastric mucosa (16 42) Other factors that can lead to the breakdown of the mucus

glycoproteins are fasting states and corticosteroid use (115)

A variety of stressors can cause a reduction in gastric mucosal blood flow with resultant mucosal ischemia

This leads to a depletion of mucosal adenosine triphosphate energy stores which disrupts the production of

the alkaline mucus layer This permits the damaging back-diffusion of hydrogen ions The severity of mucosal

injury has been correlated with the magnitude of ischemia and intramural acidosis (37) The buildup of free

radical by-products of anaerobic metabolism can promote lipid peroxidation and membrane damage within the

mucosal cells (98 110)

Mucosal protection is also provided by the ability of the surface epithelial cells of the gastric mucosa to quickly

replenish normal cell turnover During periods of stress the gastric mucosa has a decreased rate of cellular

proliferation and deoxyribonucleic acid synthesis Fasting also decreases ribonucleic acid and protein synthesis

in the gastric epithelium Nutritional support or the use of trophic agents such as pentagastrin growth

hormone and epidermal growth factor may provide the catalysts for mucosal repair and regrowth (134)

Prostaglandins have a variety of actions within the gastric mucosa that may contribute to mucosal protection

These include the stimulation of mucus and bicarbonate secretion by gastric and duodenal mucosa as well as

increasing the gastric mucosal blood flow Prostaglandins also protect the mucosa from agents such as aspirin

alcohol and nonsteroidal anti-inflammatory agents High concentrations of prostaglandin E2 and prostaglandin

I2 are normally present in the gastric mucosa The role of exogenously administering prostaglandins for the

prevention of stress-related mucosal damage in the clinical setting has yet to be determined (88)

In summary the following sequence of events can occur among trauma patients It begins with an initial

episode of hypotension that induces GI mucosal ischemia Energy stores in the form of adenosine triphosphate

are rapidly depleted hampering the neutralization of back-diffusing hydrogen ions and disrupting the

production of the alkaline mucus layer The formation of mucosal erosions and frank hemorrhage can then

occur as a result of this breakdown of the gastric mucosal barrier (15 16 42 49 62 64 84 126 127)

CLINICAL RISK FACTORS^

A number of risk factors that may influence the development of GI bleeding in critically ill patients have been

reported In addition to CNS lesions these include the following burns of gt 25 body surface area respiratory

failure hypotension sepsis jaundice peritonitis coagulopathy renal failure and hepatic failure (19 24 26

49 78-80 88 107 120 126 150) The accumulation of risk factors seems to increase the risk of bleeding (13

49 87) Stress ulcer bleeding in patients with head trauma correlates with the severity of injury regardless of

the presence of other risk factors (56)

Brain injury^

A neurogenic basis for stress ulcerations was first proposed by Carl Rokitansky in 1841 Premortem ulcerations

of the GI system were found in newborns with intracranial tumors in children and adults with CNS disease and

in patients in cachectic states Harvey Cushing further elaborated on the subject in his classic work of 1932 He

reported 11 cases of either GI ulceration perforation or hemorrhagic erosion in postoperative tumor patients

He thought that these lesions arose from the actions of the parasympathetic centers of the hypothalamus with

their connections to vagal nuclei in the medulla Lesions occurring anywhere along this pathway would

interrupt normal inhibitory mechanisms causing unopposed parasympathetic stimulation This led to abnormal

amounts of acid secretion and consequently to gastric erosions Responsible insults included traumatic

injuries infectious diseases (especially of the basal brain) and tumors with an emphasis on cerebellar lesions

(24) Cushings hypothesis was corroborated by laboratory experiments that sought to destroy or stimulate

various hypothalamic areas (3 24 36) French et al (38) further demonstrated that an imbalance of

autonomic function originating in the hypothalamus predisposed patients to gastrointestinal ulcerations

Norton et al(92) showed that in vitro direct pressure stimulation of the vagal nuclei resulted in gastric acid

hypersecretion Lewis (73) wrote of the increased frequency of gastroduodenal ulceration and hemorrhage in

her review of childhood intracranial diseases She also postulated that the pathological basis was vagal

hyperactivity The success of vagotomy and pyloroplasty in preventing the recurrence of bleeding or ulceration

supported her theory

Clinical and autopsy studies have indicated the probable existence of Cushings ulcers in neurosurgical patients

An autopsy review of patients dying of CNS diseases revealed an incidence of hemorrhagic ulcers (125) that

was double that found in patients succumbing to non-neurological diseases (58) Gastric hypersecretion of

pepsin and acid does occur in neurosurgical patients (11-13 42 112) Severe head injury and Glasgow Coma

Scale scores of lt 9 can lead to gastric acid hypersecretion and hemorrhage rates exceeding 17 (5 45 47 50

55 56 68 87 93 143) Bleeding may be more likely to occur during the first 2 weeks of hospitalization (11

68) Other relevant risk factors include the following syndrome of inappropriate secretion of antidiuretic

hormone respiratory failure age of gt60 years CNS infection gastric pH value of lt4 and hypotension (11-13

50) As the number of risk factors increases the cumulative risk of bleeding also rises significantly (13 87)

High mortality rates can occur with GI complications up to one-third of patients can succumb as a direct result

(13) Herein lies the basis for the use of prophylactic measures in neurosurgical patients Conflicting reports on

the efficacy of various preventative medications have emerged however (11 13 47 68 87 112)

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

49 87) Stress ulcer bleeding in patients with head trauma correlates with the severity of injury regardless of

the presence of other risk factors (56)

Brain injury^

A neurogenic basis for stress ulcerations was first proposed by Carl Rokitansky in 1841 Premortem ulcerations

of the GI system were found in newborns with intracranial tumors in children and adults with CNS disease and

in patients in cachectic states Harvey Cushing further elaborated on the subject in his classic work of 1932 He

reported 11 cases of either GI ulceration perforation or hemorrhagic erosion in postoperative tumor patients

He thought that these lesions arose from the actions of the parasympathetic centers of the hypothalamus with

their connections to vagal nuclei in the medulla Lesions occurring anywhere along this pathway would

interrupt normal inhibitory mechanisms causing unopposed parasympathetic stimulation This led to abnormal

amounts of acid secretion and consequently to gastric erosions Responsible insults included traumatic

injuries infectious diseases (especially of the basal brain) and tumors with an emphasis on cerebellar lesions

(24) Cushings hypothesis was corroborated by laboratory experiments that sought to destroy or stimulate

various hypothalamic areas (3 24 36) French et al (38) further demonstrated that an imbalance of

autonomic function originating in the hypothalamus predisposed patients to gastrointestinal ulcerations

Norton et al(92) showed that in vitro direct pressure stimulation of the vagal nuclei resulted in gastric acid

hypersecretion Lewis (73) wrote of the increased frequency of gastroduodenal ulceration and hemorrhage in

her review of childhood intracranial diseases She also postulated that the pathological basis was vagal

hyperactivity The success of vagotomy and pyloroplasty in preventing the recurrence of bleeding or ulceration

supported her theory

Clinical and autopsy studies have indicated the probable existence of Cushings ulcers in neurosurgical patients

An autopsy review of patients dying of CNS diseases revealed an incidence of hemorrhagic ulcers (125) that

was double that found in patients succumbing to non-neurological diseases (58) Gastric hypersecretion of

pepsin and acid does occur in neurosurgical patients (11-13 42 112) Severe head injury and Glasgow Coma

Scale scores of lt 9 can lead to gastric acid hypersecretion and hemorrhage rates exceeding 17 (5 45 47 50

55 56 68 87 93 143) Bleeding may be more likely to occur during the first 2 weeks of hospitalization (11

68) Other relevant risk factors include the following syndrome of inappropriate secretion of antidiuretic

hormone respiratory failure age of gt60 years CNS infection gastric pH value of lt4 and hypotension (11-13

50) As the number of risk factors increases the cumulative risk of bleeding also rises significantly (13 87)

High mortality rates can occur with GI complications up to one-third of patients can succumb as a direct result

(13) Herein lies the basis for the use of prophylactic measures in neurosurgical patients Conflicting reports on

the efficacy of various preventative medications have emerged however (11 13 47 68 87 112)

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

GI bleeding may also occur in ischemic stroke patients and may be exacerbated by the use of antithrombotic

drugs The frequency of significant GI hemorrhage is low and does not usually contribute to increased

morbidity or mortality in the majority of patients (27 76 146) A reduction (from 65 to 6) in the frequency of

bleeding in patients with a Glasgow Coma Scale score of lt=10 has been reported in those who received

prophylactic cimetidine (76)

Spinal cord injury^

The incidence of GI ulceration or hemorrhage in spinal cord injury has ranged from 2 to 20 (34 43 65 66

142) A neurogenic basis for this association involving a persistence of vagal activity in the absence of

sympathetic outflow has been espoused by many (1 65 66 71 130 142) Those patients with cervical cord

injuries seem especially prone to developing GI complications compared with lesions at other levels (65 71

130 142) Again bleeding usually occurs during the acute phase of injury(within the first 4 wk) and peaks at 4

to 10 days postinjury (43 71 142) Other authors have not reported this increase in GI complications with

spinal cord injuries they implicate a multifactorial pathogenesis (33 66 71) Similarly the appropriate

prophylactic agent to use in this setting is unknown (148)

Animal experiments^

Recent experiments have refocused attention on the influence of the brain on gastric pathophysiology Animal

restraint and cold-stress models have been developed that accurately reproduce gastric ulcerations (41)

Bilateral lesions of the amygdala have ameliorated the degree of stress-induced gastric lesions bilateral

hippocampal lesions can aggravate these types of injuries (51) The CNS effects of various neuropeptides on

gastric acid secretion have also been studied Thyroid-releasing hormone receptors are abundant near the

preganglionic neurons of the vagus nerve of the dorsal motor nucleus An intracisternal injection of thyroid-

releasing hormone can cause the hypersecretion of gastric acid and antibodies to thyroid-releasing hormone

receptors can attenuate this gastric response (133) Corticotropin-releasing factor may be a protective

component of the stress response because its release in the hypothalamus will decrease gastric acid secretion

and increase duodenal bicarbonate production (46) The gastric protective effects neurotensin beta-

endorphin and neuropeptide Y also seem to be mediated by adrenergic systems using dopamine and

norepinephrine (52 60 70 97)

STRESS ULCER PROPHYLAXIS THERAPY^

The optimal method for the prophylaxis of GI complications for neurosurgical patients is a subject of debate

Which one of the available agents is best What dosing schedules are optimal for maximum benefit What are

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

the side effects of these therapies Most studies on the efficacy of prophylaxis have involved surgical and

medical ICU patients Cautious extrapolation of these results to the neurosurgical population may be

appropriate

Antacids^

Antacids have been the mainstay of preventive therapy As previously discussed gastric acid plays an integral

role in the formation of ulcers during stressful conditions Raising the intragastric pH to 35 has been shown to

decrease the incidence of bleeding (12 48) Attaining levels above 45 inactivates pepsin and pH values of 5

and higher neutralize 999 of the acid (8) Antacids elevate pH quickly for a sustained period of time

Magnesium hydroxide is more effective in achieving this goal than aluminum or aluminum-magnesium mixtures

(91) Increases in dosing and frequency are needed in many cases to produce pH elevation in critically ill

patients However when these compounds are given in large doses side effects may result These include

diarrhea or constipation electrolyte abnormalities hypophosphatemia (secondary to their phosphate-binding

properties) and metabolic alkalosis (91) The primary route of excretion for magnesium and aluminum may

also be compromised in renal failure Aluminum encephalopathy does not result from increased antacid intake

(138)

Clinical studies have confirmed the superiority of titrated antacid therapy over untreated control groups in

preventing the GI complications in critically ill patients McAlhany et al (81) effectively neutralized gastric

acid and reduced the incidence of hemorrhage and perforation in patients with burns of gt 35 body surface

area Hastings et al (48) demonstrated that antacid titration of gastric pH values above 35 could effectively

reduce the incidence of clinical GI bleeding Meta-analyses of many different clinical studies have also borne

out the efficacy of antacid therapy (21 67 122 141)

Histamine receptor antagonists^

Histamine receptor antagonists (cimetidine ranitidine and famotidine) have also been used as prophylactic

agents against GI bleeding The reversible inhibition of parietal cell histamine Type 2 receptors reduces acid

secretion Stimulation of acid production by pentagastrin pepsin and food are all suppressed by H2 blockade

in a dose-related fashion (113) The effects of bolus dosing in the case of cimetidine or ranitidine are

demonstrable within 30 minutes and keep pH elevated for 3 to 4 hours (95) Continuous infusion regimens are

more likely to abolish the peaks and troughs of gastric pH that are seen with intermittent dosing schedules

This achieves a more precise degree of pH control avoiding the potentially adverse effects of gastric alkalinity

(23 40) Renal excretion is the primary route of elimination of these agents although hepatic dysfunction may

also alter the pharmacokinetics of these drugs (95)

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

A number of studies have documented the ability of histamine antagonists to decrease GI bleeding in critical

care patients compared with placebo or untreated groups (13 21 67 72 102 122) Whether these agents are

more effective than antacids for prophylaxis is controversial H2 blockers are at least equal to the preventive

action of antacids (67 106 122 141) With an increased severity of illness and risk factors antacids seem to

hold a slight advantage but these studies were performed mainly with intermittent dosing regimens of H2

blockers (80 107 141 149) It has been shown that continuous infusion protocols control pH better and when

used in such a fashion they can be superior to control treatments antacids or intermittent H2 blockade (23

59 75 78 90 101 109 117 123 136)

Reports of neurosurgical patients are few In a recent study CNS injury predicted the poor control of gastric

pH in patients receiving continuous infusion ranitidine (41) Rapp et al(108) reported a failure of continuous

infusion ranitidine (625-1875 mghr) in maintaining gastric pH gt 4 in 12 ICU patients with head injuries We

recently evaluated the effectiveness of continuous infusion cimetidine (50-150 mghr) in controlling

intragastric pH in 12 patients with head injuries We found results similar to the above studies (unpublished

data)

CNS toxicity with cimetidine occurs in a dose-related fashion in less than 3 of patients (61 119) Liver andor

renal dysfunction and advanced age are risk factors for the development of this complication Both cimetidine

and ranitidine cross the blood-brain barrier Serum trough levels of gt125 microgml may be associated with the

milder CNS side effects of restlessness confusion disorientation agitation and visual hallucinations Levels of

gt20 microgml may infrequently produce muscular twitching seizures unresponsiveness and apnea A reduction

in dose or use of other agents in patients with these risk factors avoids unwanted changes in mental status (28

61 119 138)

Other major side effects of H2 antagonists include the inhibition of the cytochrome P450 enzyme system

interference with antibiotic activity hypotension and thrombocytopenia Altered hepatic metabolism occurs

mainly with cimetidine (138) Important drugs that are affected include theophylline phenytoin and warfarin

this necessitates the appropriate monitoring of their use Rapid bolus administration may cause hypotension

which can be avoided with slower infusion rates (54 95) Unexplained thrombocytopenia has been reported

with the concurrent use of cimetidine and phenytoin (147) We have also observed 12 cases(unpublished data)

Sucralfate^

Sucralfate consists of a complex of sucrose sulfates and aluminum hydroxide Its protective effect is exerted

through its mucosal strengthening action Sucralfate binds to normal and defective gastric mucosa increasing

the viscosity and mucin content of the gastric mucus as well as its hydrophobic characteristics (129)

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

Experimentally it has been shown to increase mucosal blood flow in a dose-dependent manner (14) A myriad

of other beneficial effects have been reported also including inhibition of peptic digestion stimulation of

prostaglandin protection of the mucosal proliferative zone and facilitation of mucosal regeneration and

healing Bactericidal properties and phosphate binding properties have also been described (139) These all

make sucralfate an attractive choice for use in the prevention of Cushings ulcers

Recently Eddleston et al (32) compared the frequency of acute stress ulceration in 60 ICU patients treated

with either sucralfate (1 gm every 6 h) or ranitidine (50 mg intravenously every 6 h) At admission the

frequency of gastric lesions was 135 After 4 days of therapy the rate had increased to 18 in patients

receiving sucralfate and 36 in patients receiving ranitidine This study included 19 patients with CNS injuries

The investigators recommended the adoption of sucralfate for routine prophylaxis against stress-related gastric

mucosal damage (32) In two meta-analyses sucralfate was found to be as effective as antacids but

significantly more efficacious than H2 antagonists in the prevention of clinical bleeding (140 141)

No major adverse effects of sucralfate have been reported but aluminum retention in patients with renal

failure may occur This has not been causally linked with aluminum encephalopathy however (139) Simply

dissolving the sucralfate tablet in water before administration eliminates the potential for sorbitol

accumulation with slurry formulations Decreased bioavailability has been reported with a concurrent oral

administration of a number of drugs (eg quinolone and tetracycline antibiotics theophylline compounds

phenytoin antacids digoxin and amitriptyline) No perceived reduction in the absorption of these medications

is seen if they are given at least 2 hours before sucralfate The interaction with histamine antagonists does not

seem to be clinically significant (82)

RELATED ISSUES^

Enteral nutrition^

It has been suggested that enteral nutrition plays a role in protection from stress ulceration The exact

mechanism is unclear but two explanations have been postulated Dilutional alkalinization may occur when

the feeding tube is located within the stomach Secondly the maintenance of an adequate nutritional state

provides a positive nitrogen balance which is important for normal reparative functions of the gastric mucosa

A fasting state can result in the disruption of gastric protective factors The evidence in the literature is

somewhat conflicting Kuric et al (66) retrospectively showed that enteral nutrition was associated with a

significantly lower incidence of ulceration in patients with spinal cord injuries Cannon et al (9) did not report

any differences in GI bleeding in patients who received enteral alimentation A potential concern of gastric

flora colonizing the trachea and causing nosocomial pneumonia has been raised (104) Further study is

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

necessary to establish the significance of enteral nutrition as a protective factor against stress-induced GI

hemorrhage

Steroids^

Steroids may exert their deleterious effects on the GI tract by the gastric inhibition of mucus secretion

epithelial proliferation and prostaglandin biosynthesis (4 25 29) Currently steroid use in the neurosurgical

ICU is limited mainly to patients with brain tumors or spinal cord injuries The results of three meta-analyses

revealed a very low incidence of steroid-induced GI complications (17 18 86) The consensus states that the

duration of steroid therapy of gt 3 weeks and dosing regimens of gt 400 to 1000 mgday of prednisone (or 10 mg

4 times a day of dexamethasone) increase the incidence of toxic effects (17 86 121 145) Even high doses of

up to 100 mgday of intravenously administered Decadron for short periods of time (lt3 weeks) have minimal

side effects (6 7 44 94 96 99 128)

Marshall et al (77) reported an increased risk for GI complications in patients with a history of peptic ulcer

disease who undergo steroid therapy Other conditions such as renal or hepatic dysfunction and

hypoalbuminemia (possibly associated with inadequate nutrition) may cause increased amounts of unbound

steroid with potentially adverse effects (29 145) The concurrent use of steroids and ulcerogenic medications

such as aspirin or nonsteroidal anti-inflammatory agents may increase the risk for the development of ulcers

(10 22 29 39) Patients with connective tissue disorders especially rheumatoid arthritis often fall into this

category Ulcers that develop because of steroid therapy are no more likely to perforate or hemorrhage than

controls (135) Decreasing the dosage or discontinuing the steroid dose should reverse symptoms when they

occur Patients receiving chronic steroid therapy should receive GI prophylaxis Those receiving short-term

steroid therapy probably do not need preventive measures unless risk factors are present

Nosocomial pneumonia^

A body of evidence has accumulated concerning the increased incidence of nosocomial pneumonia with the use

of pH-altering stress ulcer prophylaxis Bacteria originating in the oropharynx and stomach may play important

roles (111 118) When the pH of gastric secretions is kept consistently above 40 bacterial colonization of the

stomach contents rises in a logarithmic manner (2 20 31 53) The concentrations of bacteria may increase by

up to 10000 times with up to 30 of these pathogens later colonizing the respiratory tract Radioactively

labeled technetium studies have demonstrated that 40 of intubated patients aspirate gastric contents despite

their heads being elevated This confirms previous reports of aspiration despite inflated endotracheal tube

cuffs (131) Colonization of the respiratory tract develops into pneumonia in up to 60 with gram negative and

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

20 with gram positive organisms The exact mechanism in the development of nosocomial pneumonia is still

unclear (111 137)

Comparative studies of the rates of nosocomial pneumonia using the three preventive drug regimens yield

conflicting results One confounding variable may be the lack of universal criteria for diagnosing nosocomial

pneumonia Several clinical studies have shown an increased risk for pneumonia with pH-alkalinizing therapies

(30 32 57) Driks et al (30) suggested that sucralfate decreased the incidence of pneumonia when compared

with antacids but not to H2 blockers Two separate meta-analyses have also shown lower rates of pneumonia

with sucralfate (21 141) Individual studies have not confirmed this benefit (35 78 103) Fabian et al (35) did

not report a direct association between pH alkalinization and pneumonia but a multivariate analysis revealed

the following Glasgow Coma Score Injury Severity Score spinal cord injury shock and head injury as risk

factors for pneumonia development The association of pneumonia with pH-altering therapy has not been

firmly established Further large-scale trials will be necessary before a definitive answer is found

Gastric monitoring^

The standard methods for assessing the efficacy of GI prophylaxis include sampling for intragastric pH and

detecting for the presence of occult bleeding These parameters may be intrinsically flawed Layne et al(69)

found that acid adversely affected the sensitivity of Gastroccult (Smith Kline San Jose CA) results and

required neutralization before interpretation Commercial antacids may help neutralize gastric acid but they

interfered significantly with the detection of blood Rosenthal et al (116) confirmed that a dark-blue result on

Gastroccult testing was the only accurate predictor of blood in low pH conditions (116) The Hematest and Bili-

Labstix(Bayer Corp Elkhart IN) were too sensitive because only a few red blood cells were enough for a

positive result Meiners et al(83) found gastric luminal pH samples overestimated the mucosal pH when

obtained during an antacid administration Measurements of luminal and mucosal pH taken during parenteral

cimetidine therapy correlated well however Based on these reports monitoring for clinical bleeding seems to

be a more effective parameter than the detection of occult bleeding which may be too sensitive or may be

altered by antacid therapy Indicator paper should continue to be used for measurements of pH but interpreted

cautiously when used concurrently with antacid therapy (83)

Surgery^

When prophylaxis has failed and GI bleeding occurs there are a series of steps that may be instituted in an

attempt to control the hemorrhage Iced saline lavage is commonly used as a first step controlling 80 of

bleeding episodes (74) Other reviews have also reported that bleeding stops spontaneously with these

conservative measures in the majority of cases (100 132) Some reports have espoused the use of titrated

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

antacids to keep gastric pH greater than 70 in these critically ill patients Intravenously administered

vasopressin should probably only be used as a temporizing measure because of its damaging ischemic effects on

the gastric mucosa (125) Pharmacological therapy has otherwise been ineffective in stopping the hemorrhage

(100) Arteriographic embolization is hazardous with gastric and splenic necrosis being potential side effects

(125)

Endoscopic intervention has been evaluated in the management of acute GI bleeding In a recent review of this

type of therapy several facts have emerged No statistically significant benefits with regard to outcome were

garnered Lesions were usually not amenable to thermal coagulation Its unproven cost-effectiveness a 3 to 5

complication rate and better results when intervention was delayed until rebleeding occurs make this

intervention controversial Some valid reasons for endoscopy do exist however Hemodynamically significant

rapid bleeding demands urgent endoscopy for the identification of active bleeding sources These lesions and

any nonbleeding vessels or clots originating from ulcer craters that are visualized should undergo thermal

intervention leaving other lesions alone until rebleeding occurs Age of gt 60 years major associated diseases

inpatients with GI hemorrhage and rebleeding episodes are included in the National Institutes of Health

criteria for endoscopic hemostatic intervention (100 132)

When all measures have failed surgical intervention is indicated The majority of opinions favors vagotomy

with pyloroplasty and ligation of bleeding points (74 88 125) Partial gastrectomy with its increased mortality

risk is used only if there is diffuse bleeding or other associated critical illnesses (74 88)

CONCLUSION^

A central theory linking the brain and upper GI tract emerges from a review of the available literature

Intracranial diseases especially those that have a significant impact on the diencephalon and brain stem may

cause a disinhibition of the medullary vagal system This leads to the hypersecretion of gastric acid and pepsin

Simultaneously stress-induced alterations in neuropeptide levels within the brain may also indirectly affect GI

functioning At the mucosal level these dual actions may cause an imbalance between destructive and

protective mechanisms ultimately leading to erosions and hemorrhage

Several clinically relevant risk factors for the formation of stress-related mucosal damage have been reported

Diencephalic and brain stem injuries are more likely to be associated with the presence of erosions or

ulcerations in the GI tract These insults may result from severe head injuries (Glasgow Coma Scale score of lt

9) infection tumors or hemorrhagic events Cervical spinal cord injuries may also be a predisposing factor

along with others such as hypotension ventilator dependence renal or hepatic dysfunction and

thrombocytopenia An additive effect is seen with an increasing number of risk factors

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

Antacids H2 antagonists and sucralfate are all effective prophylactic agents for stress-related mucosal

damage in the medicalsurgical ICU Antacids given in doses titrated to intragastric pH values have been

proven to be superior to placebos yet their administration is time-consuming Continuous infusion cimetidine

is superior to intermittent H2 blockade antacids and sucralfate in the control of gastric pH but it is

ineffective in the context of severe CNS injury The incidence of pneumonia seems to increase with the use of

pH-altering therapy Hence the bactericidal properties and subsequent role in the prevention of nosocomial

pneumonia as well as its proven superiority to H2 blockers make the use of sucralfate very attractive

Routine prophylaxis with steroid use is not warranted except when certain risk factors are present a prior

history of peptic ulcer disease concurrent use with aspirin or nonsteroidal anti-inflammatory drugs renal or

hepatic dysfunction and malnourished states Only patients who were administered steroids for gt 3 weeks and

daily doses of dexamethasone (gt 40 mgd) seem to be at increased risk for GI side effects

Stress ulcer prevention plays an important role in the aggressive critical care of neurosurgical patients Certain

inferences from studies conducted in medical and surgical ICUs are applicable The proven superiority of

sucralfate and titrated antacids to H2 blockers in the prevention of GI erosions and hemorrhage exists Titrated

infusion of H2 blockers has been used unsuccessfully in the manipulation of gastric pH in head-injured patients

Whereas antacid use has certain drawbacks sucralfate may be able to diminish the incidence of nosocomial

pneumonia In theory these data would support the initial use of sucralfate in neurosurgical patients

Surveillance for overt clinical bleeding rather than occult hemorrhage seems to be a more efficient use of

resources with prompt endoscopic evaluation of clinical bleeding At this point either the further stepwise

addition of antacids and H2 blockers or aggressive surgical intervention should reduce the consequences of this

type of GI hemorrhage

REFERENCES^

1 Albert TJ Levine MJ Balderston RA Cotler JM Gastrointestinal complications in spinal cord injury Spine

16[Suppl 10]S522-S525 1991 [Context Link]

2 Atherton ST White DJ Stomach as source of bacteria colonising respiratory tract during artificial

ventilation Lancet 1968-969 1978 [Context Link]

3 Beattie J The relation of the tuber cinereum to gastric and cardiac functions A preliminary note Can Med

Assoc J 26278 1932 [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

4 Black HE The effects of steroids upon the gastrointestinal tract Toxicol Pathol 16213-222 1988

Bibliographic Links [Context Link]

5 Bowen JC Fleming WH Thompson JC Increased gastrin release following penetrating central nervous

system injury Surgery 75720-724 1974 Bibliographic Links [Context Link]

6 Bracken MB Shepard MJ Collina WF Holford TR Young W Baskin DS Eisenberg HM Flamm E Leo-Summers

L Maroon J Marshall LF Perot PL Piepmeier J Sonntag VKH Wagner FC Wilberger JE Winn HR A

randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal cord injury

Results of the Second National Acute Spinal Cord Injury Study N Engl J Med 3221405-1411 1990 Bibliographic

Links [Context Link]

7 Braughler JM Hall ED Current application of high dose steroid therapy for CNS injury A pharmacologic

perspective J Neurosurg 62806-810 1985 [Context Link]

8 Bruegge WFV Peura DA Stress-related mucosal damage Review of drug therapy J Clin Gastroenterol

12[Suppl 2]S35-S40 1990 [Context Link]

9 Cannon LA Heiselman DE Gardner WG Jones J Prophylaxis of acute stress-related gastrointestinal

hemorrhage in critically ill patients Arch Intern Med 1472101-2106 1987 Bibliographic Links [Context Link]

10 Caruso I Porro GB Gastroscopic evaluation of anti-inflammatory agents BMJ 28075-78 1980 [Context

Link]

11 Chan K Mann KS Failure of cimetidine prophylaxis in neurosurgery Aust N Z J Surg 59133-136 1989

Bibliographic Links [Context Link]

12 Chan K Lai ECS Tuen H Ngan JHK Mok F Fan Y Fung C Yu W Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

13 Chan K Mann KS Lai ECS Ngan J Tuen H Tue C Factors influencing the development of gastrointestinal

complications after neurosurgery Results of multivariate analysis Neurosurgery 25378-382 1989 Ovid Full

Text Bibliographic Links [Context Link]

14 Chen BW Hiu WM Lam SK Cho CH Teng MM Luk CT Effect of sucralfate on gastric mucosal blood flow in

rats Gut 301544-1551 1989 Bibliographic Links [Context Link]

15 Cheung LY Gastric mucosal blood flow Its measurement and importance in mucosal defense mechanisms

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20 Cook DJ Laine LA Guyatt GH Raffin TA Nosocomial pneumonia and the role of gastric pH A meta-

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21 Cook D Witt LG Cook R Guyatt GH Stress ulcer prophylaxis in the critically ill A meta-analysis Am J Med

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26 Czaja AJ McAlhany JC Pruitt BA Acute gastroduodenal disease after thermal injury An endoscopic

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28 Dimand RJ Use of H2-receptor antagonists in children Ann Pharmacother 24[Suppl 11]S42-S46 1990

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29 Domschke S Domschke W Gastroduodenal damage due to drugs alcohol and smoking Clin Gastroenterol

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30 Driks MR Craven DE Celli BR Manning M Burke RA Garvin GM Kunches LM Farber HW Wedel SA

McCabe WR Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or

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40 Gedeit RG Weigle CGM Havens PL Werlin SL Control and variability of gastric pH in critically ill children

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41 Glavin GB Role of the central nervous system in stress ulcers Compr Ther 173-5 1991 [Context Link]

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to severe head trauma Neurosurgery 12175-178 1983 Ovid Full Text [Context Link]

46 Gunion MW Tache Y Brain sites where bombesin and corticotropin-releasing factor influence gastric

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COMMENTS^

Gastrointestinal stress ulcerations are of special importance to neurosurgical patients who are particularly

prone to this complication In this exhaustive review Lu et al detail the salient pathogenic features of stress

ulcers and review the various therapies available for prophylaxis As the authors point out the incidence of

gastrointestinal bleeding can be reduced (but not eliminated) by careful attention to these treatment

parameters

Marc R Mayberg

Seattle Washington

Lu et al provide a valuable review of the pathophysiology of stress ulceration and an initial approximation of

treatment schemes As the authors clearly stress these schemes have centered on the neutralization of

hypersecretion of gastric acid Sucralfate H2 antagonist(especially when given as an infusion) and antacids all

are effective at least in some studies in the prevention of gastrointestinal hemorrhage

Unfortunately the only prospective randomized double-blind study of which I am aware in neurosurgical

patients is that by Chan et al(1) To truly provide relevant information in our neurosurgical patients these are

the subjects that must be studied The pathophysiology as suggested by the authors is indeed different

Clearly common factors still exist such as gastric ischemia The historical use of dehydration therapy in the

context of neurosurgical traumatic and nontraumatic disease has probably contributed to hypoperfusion of the

gastric mucosa as well as of the brain itself Maintenance of adequate tissue perfusion of all organs could be

expected to improve the overall medical status of the patients including gastrointestinal integrity

I do have a question about the recommendation for ice saline lavage Most gastroenterologists seem to have

abandoned this technique as potentially contributing to further ischemia of the gastric mucosa Similarly our

more current gastroenterological input to this problem has suggested that lavage of the stomach actually

dislodges clots and may well contribute to bleeding I notice that their Reference 74 dates back to 1971

Also the aggressive use of interventional radiology both for the identification of bleeding points and

embolization is somewhat abbreviated and under-represented in this review If expert interventional radiology

is available good results in terms of hemorrhage control can be achieved quickly and safely in a large number

of patients Similarly although intravenously administered vasopressin is mentioned in the article the

potential for directed intra-arterial vasopressin infusion in the control of hemorrhage is not mentioned but

may be useful

Endoscopy is more useful than the authors imply in that it can clearly help in identifying the patient with

generalized erosive gastritis and those who are bleeding from erosions actually induced by nasogastric tubes

(the majority of patients in some studies) and in actually making a diagnosis of gastrointestinal hemorrhage in

patients who are hemodynamically unstable or who have progressive anemia as the result of an unsuspected

duodenal ulcer without regurgitation of blood into the gastric contents

It is also worthwhile to emphasize again that the use of steroids per se in the majority of patients is not

associated with an increased risk of gastrointestinal hemorrhage and does not justify the addition of other

drugs which in fact do have their own complications Because each of the treatment modalities has its own

side effects or difficulties it indeed would be worthwhile to pursue randomized prospective studies of

effective prophylaxis in identified groups of patients at high risk who have neurosurgical diseases

The assumption that these patients are similar to the general surgical and general medical intensive care unit

population is perhaps the best that we can make at the moment but is probably not going to prove the case for

the majority of our patients Given the economic considerations of prolonged stay in the intensive care unit

and mortality and morbidity brought about by hypotension as the result of bleeding etc these studies would

be very worthwhile to pursue

Michael J Rosner

Birmingham Alabama

1 Chan K-H Lai ECS Tuen H Ngan JHK Mok F Fan Y-W Fung C-F Yu W-C Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

This is a thoughtful and well-prepared review of stress ulcer prophylaxis The reader will be especially served

by reviewing the conclusions in which the clinical risk factors for stress-related mucosal damage and the

advantages and disadvantages of various prophylactic agents are well reviewed Particularly instructive is the

conclusion regarding the concurrent use of routine prophylaxis with steroids the authors conclude that this is

warranted only when other risk factors are present or when patients have been receiving steroids for a long

time or in a high-dose regimen

Christopher M Loftus

Iowa City Iowa

The authors provide a comprehensive review of the issue of stress ulcer prophylaxis in critically ill

neurosurgical patients Diencephalic and brain stem injuries with subsequent disinhibition of the medullary

vagal system predisposing to gastric hypersecretion is not a new concept With modern validation of this

principle the wealth of epidemiological information cited by the authors provides compelling evidence that

neurosurgeons should offer routine prophylaxis in the majority of intensive care unit patients The authors also

make a substantial argument that agents such as sucralfate may provide optimal protection without increasing

the risk of nosocomial pneumonia

Their comment about the use of routine gastrointestinal prophylaxis in patients receiving steroids however is

controversial The authors state that unless risk factors are present such as a prior history of ulcer disease

concurrent use of aspirin renal or hepatic disease or malnourished states patients do not require prophylaxis

unless steroid use is prolonged or the doses are extremely high This recommendation goes against practice

patterns in the majority of areas with which I am familiar

and mortality and morbidity brought about by hypotension as the result of bleeding etc these studies would

be very worthwhile to pursue

Michael J Rosner

Birmingham Alabama

1 Chan K-H Lai ECS Tuen H Ngan JHK Mok F Fan Y-W Fung C-F Yu W-C Prospective double-blind placebo-

controlled randomized trial on the use of ranitidine in preventing postoperative gastroduodenal complications

in high-risk neurosurgical patients J Neurosurg 82413-417 1995 Bibliographic Links [Context Link]

This is a thoughtful and well-prepared review of stress ulcer prophylaxis The reader will be especially served

by reviewing the conclusions in which the clinical risk factors for stress-related mucosal damage and the

advantages and disadvantages of various prophylactic agents are well reviewed Particularly instructive is the

conclusion regarding the concurrent use of routine prophylaxis with steroids the authors conclude that this is

warranted only when other risk factors are present or when patients have been receiving steroids for a long

time or in a high-dose regimen

Christopher M Loftus

Iowa City Iowa

The authors provide a comprehensive review of the issue of stress ulcer prophylaxis in critically ill

neurosurgical patients Diencephalic and brain stem injuries with subsequent disinhibition of the medullary

vagal system predisposing to gastric hypersecretion is not a new concept With modern validation of this

principle the wealth of epidemiological information cited by the authors provides compelling evidence that

neurosurgeons should offer routine prophylaxis in the majority of intensive care unit patients The authors also

make a substantial argument that agents such as sucralfate may provide optimal protection without increasing

the risk of nosocomial pneumonia

Their comment about the use of routine gastrointestinal prophylaxis in patients receiving steroids however is

controversial The authors state that unless risk factors are present such as a prior history of ulcer disease

concurrent use of aspirin renal or hepatic disease or malnourished states patients do not require prophylaxis

unless steroid use is prolonged or the doses are extremely high This recommendation goes against practice

patterns in the majority of areas with which I am familiar

It seems to me that some form of prophylaxis during steroid therapy provides a reasonably low risk and

potentially cost-effective strategy when contrasted with the severity of potential gastrointestinal hemorrhage

Nevertheless this review should provide a ready resource to practitioners as they consider which agents to

employ in various clinical circumstances

H Hunt Batjer

Chicago Illinois

Key words Critical care Gastrointestinal bleeding Neurosurgery Stress ulcer

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