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  In addition to immunologic mechanisms, physical (motility), chemical (gastric acidity), and microbiologic (normal colonizing flora) factors normally protect the gastrointestinal tract against infection.

  
  
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  Esophagitis, most commonly caused by Candida albicans or herpes simplex virus, may be underrecognized among patients in the intensive care unit.

  
  
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  Infection with Helicobacter pylori may play a role in the pathogenesis of gastric stress ulceration among critically ill patients.

  
  
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  The epidemiology and microbiology of diarrheal illness is significantly different among patients in the critical care unit than is observed in the community setting. Most infectious diarrhea is hospital acquired and is usually attributable to Clostridium difficile.

  
  
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  A systematic approach to the critically ill patient with diarrhea includes consideration of pathogens that cause noninflammatory, inflammatory, and hemorrhagic diarrhea. Thorough history taking supplements laboratory data in the diagnosis of these patients.

  
  
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  C difficile infection is the single most common cause of gastrointestinal infection among patients in the intensive care unit. The spectrum of disease induced by C difficile infection is broad. Timely diagnosis and treatment is critical both for the management of the infected patient and to prevent the spread of infection through the unit.

While rarely severe enough to warrant admission to the intensive care unit, gastrointestinal infections account for substantial morbidity and mortality among critically ill patients. Because of severe comorbid disease, impaired immune defenses, and the invasive interventions to which they are subjected, patients in the ICU are especially susceptible to hospital-acquired GI infection. Nevertheless, despite the frequency with which these infections occur, the morbidity and mortality that they cause, and the costs they incur, GI infections can go undetected and untreated in the ICU. While trying to manage patients with deteriorating cardiac function, marginal ventilatory performance, and life-threatening metabolic abnormalities, clinicians in the ICU may fail to recognize the important early signs of GI infection.

Any discussion of GI infections among critically ill patients must begin with a consideration of the host defenses that normally protect the alimentary tract. As such, the first section of this chapter is devoted to a description of the unique nonimmunologic mechanisms normally active in the GI tract. Particular consideration is given to the means by which these defenses may be compromised in patients in the ICU. Following this introduction, the clinical manifestations of infection affecting each segment of the GI tract are discussed (Table 76-1). In addition to describing the microbiology associated with each syndrome, a rational diagnostic and therapeutic approach is offered, based on the most up-to-date experience reported in the medical literature. The chapter concludes with an expanded discussion of the unique clinical challenges presented by the patient in the ICU with Clostridium difficile infection.

MOTILITY

GI motility, in addition to its central role in normal digestion, is one of the principal host defenses against infection. By continuously flushing the lumen of the GI tract, normal motility prevents the accumulation of infectious organisms and the virulent toxins associated with disease. When bacteria are permitted to collect and reproduce unchecked, such as in blind bowel loops rendered devoid of normal motility by surgical interventions, infection can ensue. Causes of abnormal GI motility can be multifactorial in a critically ill patient and may include drugs (notably narcotics and catecholamines), electrolyte abnormalities, hypoglycemia, shock, or abdominal surgery. The consequences of abnormal GI motility such as poor nutrition, esophagitis, increased risk of aspiration, and ventilator-associated pneumonia can all prolong intensive care unit stays and increase mortality.¹

GASTRIC ACIDITY

Gastric acidity provides a unique chemical barrier to the establishment of upper GI colonization and infection. In the highly acidic environment of the stomach, few pathogens are able to survive, much less thrive. However, the gastric pH of patients in the ICU is often much higher, providing an environment that is more hospitable to bacteria. More importantly, ingested microbes can pass into the lower GI tract. Once again, pharmacologic interventions are primarily responsible for this disruption of normal protective physiology. The attenuation of gastric acidity is deliberate, an effort to lessen the likelihood of stress-induced gastritis and resultant GI hemorrhage. Medications such as histamine (H₂)-receptor blockers and proton-pump inhibitors are commonly employed for this practice in both medical and surgical ICUs.

NORMAL COLONIZING FLORA

While not intuitively obvious as a component of host defense against infection, the normal colonizing flora of the GI tract provides as much protection as any physical or chemical barrier. Together, the host and normal GI flora comprise a delicate and varied ecology into which the introduction of new and potentially virulent flora is not favored. The bacteria that populate the GI tract are varied, depending on the anatomic segment under consideration. The mouth normally contains a mixed population of gram-positive, gram-negative, and anaerobic bacteria. In the esophagus, the population is less diverse. As already noted, the acidic environment of the stomach is distinctly inhospitable to the establishment of bacterial colonization. However, one organism, discussed in detail later, has been found to be of profound clinical relevance. Because of its ability to survive in the acidic stomach, Helicobacter pylori plays a critical role in the pathogenesis of peptic ulcer disease. In contrast to the case of the stomach, the lower GI tract plays host to substantial microbiologic diversity. An enormous range of gram-negative, gram-positive, and anaerobic flora populates the intestines, especially the colon. Specific constituents include enterococci and Bacteroides species, as well as members of the family Enterobacteriaceae.

Disturbance of the dynamic between host and bacterial colonizers, such as occurs after exposure to broad-spectrum antimicrobial agents, predisposes patients to GI infection, most notably colitis caused by Clostridium difficile. While this association is well recognized, the factors that govern this phenomenon are still not completely understood. It is not known if the normal flora compete with infecting pathogens for nutrients or substrates, occupy limited mucosal binding sites, or somehow otherwise alter the microenvironment in a way that reduces the likelihood of colonization. Regardless of the actual mechanism, an interesting therapeutic corollary can be inferred from the relationship between the normal host and GI colonizers. Deliberate intestinal colonization with probiotics such as Saccharomyces cerevisiae may offer a means by which to preclude the onset of health care–associated infection or to attenuate the effects of these infections once established.²

The esophagus may be easily overlooked as a site of infection in patients hospitalized in the ICU. These patients may be unable to verbalize or otherwise express to caregivers the subjective complaints that indicate the presence of infection. To make matters worse, mechanical instrumentation commonly employed in the ICU, including endotracheal, nasogastric, and orogastric intubation, may limit the clinician’s ability to thoroughly examine the patient for signs of upper GI infection. Moreover, even when characteristic physical findings of infection are visualized, they may be incorrectly attributed to mechanical irritation or inflammation associated with such devices. When the opportunity to diagnose upper GI infection is missed, directed therapy may be withheld and infection allowed to proceed unchecked.

CLINICAL PRESENTATION

Nearly 20% of ICU patients who underwent upper endoscopy in one study were incidentally noted to have esophagitis.³ These patients typically experience dysphagia with or without odynophagia. The pain of esophagitis is described as retrosternal and is typically exacerbated by the recumbent position. In the alert, awake, and communicative patient, these hallmark complaints are easily called to the attention of caregivers. However, as was already noted, the intubated and sedated patient in the ICU may not be able to express these complaints. Fever is an unreliable clinical finding in the patient with esophagitis. Regardless of the causative organism, fewer than one-third of all patients with esophagitis will experience an elevation in temperature.⁴

MICROBIOLOGY

Among hospitalized patients, esophagitis is most often caused by Candida albicans. While C albicans remains the yeast species most frequently associated with esophagitis, an increasing proportion of cases have been linked to non-albicans Candida species, including C tropicalis, C parapsilosis, C krusei, and C glabrata.⁵ This changing epidemiology has been attributed to the increasingly common use of empiric and prophylactic therapy with triazole antifungal agents such as fluconazole, to which many non-albicans Candida species are resistant. Awareness of this epidemiologic phenomenon needs to be incorporated into the approach to therapy for such patients.

Herpes simplex virus (HSV) is another frequent cause of esophagitis and is the most common serious viral infection of the upper GI tract among patients in the ICU. For the most part, HSV-1 is more likely to cause esophagitis than is HSV-2, which is more typically associated with genital infections. Less frequently, other viruses, including cytomegalovirus (CMV), can cause esophageal ulceration. For patients with CMV disease, lesions may extend throughout the length of the GI tract.

DIAGNOSIS

Thorough physical examination is not only essential to the diagnosis of esophagitis, but may offer preliminary clues as to the causative pathogen. Both yeast and viral pathogens infecting the esophagus can produce telltale lesions in the oral cavity, where they will be easily detected on routine physical examination. Although present in fewer than one-third of all patients with HSV esophagitis, oral or labial herpetic ulcers should not be missed in the physical examination of the critically ill patient with unexplained fever.⁶ Similarly, an adherent white coating to the lateral aspects of the tongue, which when scraped away reveals patches of inflammation, should point to Candida albicans as the cause of a suspected case of esophagitis. Despite the utility of such findings, it is equally important to recognize that esophagitis most often occurs in the absence of such clues. Nevertheless, to miss these clinical findings, when present, is to miss a critical opportunity for early diagnosis and intervention.

Upper GI endoscopy can be a useful tool to confirm the pathologic and microbiologic diagnosis of esophagitis. Unfortunately, even when visualized through the endoscope, the lesions of Candida and HSV esophagitis may appear quite similar. Even the large shallow ulcers typical of CMV esophagitis may be mimicked by Candida or HSV. Because of this lack of discriminatory power, it is advisable to proceed to confirmatory biopsy. Brush specimens alone can be inadequate, especially as Candida species can be isolated as colonizers of the upper GI tract in up to 20% of asymptomatic individuals.⁷ Once obtained, tissue should be sent for viral and fungal culture as well as for histopathologic examination to confirm tissue invasion.

THERAPY

Under most circumstances, directed therapy for esophagitis should be withheld until the causative organism has been identified. However, for critically ill patients with suspected esophagitis in whom endoscopy is not practical and microbiologic diagnosis is not feasible, it is appropriate to treat empirically for C albicans, based on the prevalence of this entity in this population. For esophagitis when C albicans is known or suspected to be the cause, the most effective treatment is fluconazole given intravenously at a dose of 100 to 200 mg per day for 14 to 21 days. Itraconazole and the newer agents, voriconazole and posaconazole, can be used as alternatives to fluconazole. Studies have shown similar success rates of cure for echinocandins in comparison to fluconazole but higher rates of relapse among those patients receiving echinocandins. Because of higher cost and higher relapse rates, echinocandins should not be the first choice in the absence of detecting fluconazole-resistant pathogens or persistent infection. For those infected with Candida species resistant to fluconazole, or for patients with persistent infection despite first-line therapy, echinocandins or amphotericin B can be used as salvage therapy.^8,9

For HSV esophagitis, the antiviral agent with which there is the most clinical and published experience is acyclovir. Most patients in the ICU will require parenteral therapy—5 mg/kg intravenously every 8 hours for 7 to 14 days. If the virus is resistant to acyclovir, intravenous foscarnet can be substituted.

While the stomach is not typically considered an important site of infection among hospitalized patients, the association between Helicobacter pylori infection and gastric stress ulceration suggests another means by which GI pathogens may take a toll among critically ill patients. The etiologic relationship between the presence of Helicobacter pylori and ulcerative disease of the upper GI tract, and particularly the duodenum and stomach, has been firmly established. Importantly, treatment of H pylori infection with combinations of antimicrobial agents and inhibitors of gastric acidity will eradicate H pylori infection, and in so doing promote the resolution of peptic ulcer disease.¹⁰ Antibiotics employed for this purpose are active against H pylori and include macrolides, metronidazole, and β-lactam agents. Acid suppressive agents given concurrently include sucralfate, H₂-receptor blockers, and proton-pump inhibitors.¹¹

Given these findings and a growing clinical experience with this strategy, it is not surprising that a link between H pylori infection and the stress-induced gastritis that affects patients in the ICU has been proposed. Thus far, the results concerning this possible association remain inconclusive. In a prospective, single-institution study of patients admitted to a medical/surgical ICU, half of all patients were positive for H pylori by urea breath test. After adjusting for other risk factors, H pylori infection was the only clinical factor significantly associated with subsequent major mucosal injury.¹² However, the same investigators observed that the prevalence of H pylori infection among ICU patients declined to 8% by the third day of admission, and to 0% by 1 week, owing to intercurrent antibiotic exposure.¹³ In another study by Robert and others, 1776 intensive care unit patients were screened for H pylori by stool antigen testing and only 6.3% of patients were found to be positive. Of these patients who tested positive for H pylori the authors did not find any additional risk of gastrointestinal bleeding.¹⁴ Based on these conflicting results, there does not seem to be a role for routine screening for H pylori in all intensive care unit patients.

Diarrhea, the principal manifestation of intestinal infection among the critically ill, affects approximately one-third of all patients admitted to the ICU.¹⁵ Patients in the ICU with diarrhea are especially vulnerable to the clinical sequelae of infection. For the critically ill patient, the dehydration that frequently accompanies severe diarrhea strains a circulatory capacity already limited by impaired cardiac contractility and septic hemodynamics. Such individuals are at high risk for further systemic deterioration, often culminating in multisystem organ failure. In addition to life-threatening volume loss, diarrhea in the critically ill patient can precipitate metabolic derangements including electrolyte imbalances and acidosis, further exacerbating the potential for cardiac rhythm irritability. Finally, uncontrolled diarrhea in a severely ill immobile patient can predispose to compromise of the protective barrier of the skin. As such, the patient is rendered vulnerable to further infectious complications. Considering these dire clinical consequences, the prompt detection, microbiologic diagnosis, and treatment of infectious diarrhea must be a high priority for clinicians in the ICU.

The epidemiology of diarrheal illness among patients in the ICU is substantially different from that seen among less severely ill patients in the community. Such differences render most of the schemes used to classify diarrhea in other settings somewhat less useful to the evaluation of the critically ill patient. Infectious diarrhea acquired in the outpatient setting is rarely sufficiently severe to warrant admission to the ICU. Therefore, infectious diarrhea among patients in the ICU is most often acquired in the hospital. As a result, the spectrum of clinical disease and associated pathogens for the patient in the ICU tends to be less diverse than that encountered in the community. In fact, the majority of all cases of infectious diarrhea diagnosed in the ICU can be attributed to a single pathogen, Clostridium difficile. For many of these patients, the differential diagnosis consists largely of noninfectious entities, such as diarrhea induced by hyperosmolar enteral feeding solutions.¹⁶ Norovirus and related viral pathogens, the most common causes of endemic and epidemic diarrhea in the outpatient setting, are rarely identified as the cause of diarrhea in critically ill patients. Similarly, while outbreaks of food-borne gastroenteritis have been reported among hospitalized patients,¹⁷ in the absence of an identified cluster, the workup of the ICU patient with diarrhea usually need not include consideration of these pathogens.

However, it is in recognition of the relative infrequency with which the clinician in the ICU will encounter diarrhea that is not hospital acquired that a review of these less familiar presentations is actually warranted. While the distinctions between these syndromes are somewhat arbitrary, and there is considerable overlap between them, it is imperative that the clinician caring for critically ill patients at least be able to recognize these syndromes. In the sections that follow, inflammatory, noninflammatory, and hemorrhagic diarrheas are considered separately. Each is discussed with respect to the most common clinical presentations and pathogens that could be expected in the ICU (Table 76-2). A general approach to the diagnosis and treatment of diarrhea among patients in the ICU follows. The chapter concludes with an in-depth discussion of diarrhea caused by C difficile—an organism whose central role as a cause of diarrhea among patients in the ICU has already been noted.

NONINFLAMMATORY DIARRHEA

In general, the noninflammatory diarrheal syndromes are characterized by the production of large volumes of watery stool devoid of gross blood or inflammatory cells. By definition, stool examination for fecal leukocytes in such patients will be negative. The typical presentation and pathophysiology of noninflammatory diarrhea are best exemplified by infection with Vibrio cholerae. While this gram-negative bacillus is the most prevalent cause of dehydrating diarrhea throughout the world, it is rarely encountered as a pathogen causing serious disease in the developed world. That said, the metabolic sequelae of cholera are capable of generating systemic illness sufficiently severe as to require ICU admission in a returning traveler.

The diarrhea of cholera is secretory in nature. Having established itself in the lumen of the bowel, V cholerae releases an extracellular protein that binds to the membrane of intestinal epithelial cells. The enterotoxin induces an increase in intracellular cyclic adenosine monophosphate (cAMP). The high concentration of cAMP induces an increase in chloride secretion and a decrease in sodium absorption, producing the massive fluid and electrolyte loss characteristic of cholera.¹⁸

While the diarrhea experienced by the patient infected with V cholerae is characteristic of the other noninflammatory diarrheal infections, the severity of disease is unique to cholera. Diarrhea is voluminous, often described as “rice water” stool and patients can lose more than 1L of fluid every hour. Affected patients are at high risk for life-threatening dehydration. Vital signs will reveal tachycardia and hypotension. The metabolic abnormalities can precipitate severe acidosis. To compensate, the patient may become tachypneic. Skin evaluation in these individuals reveals decreased turgor. The mucous membranes, including conjunctivae, appear dry. In extreme cases, the patient’s eyes will appear sunken, producing a characteristic facies. If fluids are not replaced promptly and in sufficient quantity, the infection will be fatal. The mainstay of therapy is rapid fluid replacement. Severely dehydrated patients may require replacement of 10% of their bodyweight within a 2 to 4-hour period. The timely use of antibiotic treatment, usually with a fluoroquinolone, doxycycline, or azithromycin, is generally recommended.¹⁹

While V cholerae

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