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ANNALS OF SURGERYVol. 218, No. 2,111-119© 1993 J. B. Lippincott Company

The Gastrointestinal TractThe "Undrained Abscess" of MultipleOrgan Failure

John C. Marshall, M.D., F.R.C.S.C., F.A.C.S.,*Nicolas V. Christou, M.D., Ph.D., F.R.C.S.C., F.A.C.S.,tand Jonathan L. Meakins, M.D., D.Sc., F.R.C.S.C., F.A.C.S.t

From the Departments of Surgery, University of Toronto, Toronto, Ontario,*and McGill University, Montreal, Quebec,t Canada

ObjectiveThis study determined the association between proximal gastrointestinal (GI) colonization and thedevelopment of intensive care unit (ICU)-acquired infection and multiple organ failure (MOF) ina population of critically ill surgical patients.

Summary Background DataICU-acquired infection in association with progressive organ system dysfunction is an importantcause of morbidity and mortality in critical surgical illness. Oropharyngeal and gastriccolonization with the characteristic infecting species is common, but its association with ICUmorbidity is poorly defined.

MethodsA prospective cohort study of 41 surgical ICU patients was undertaken. Specimens of gastricand upper small bowel fluid were obtained for quantitative culture; the severity of organdysfunction was quantitated by a numeric score.

ResultsOne or more episodes of ICU-acquired infection developed in 33 patients and involved at leastone organism concomitantly cultured from the upper GI tract in all but 3. The most commonorganisms causing ICU-acquired infection-Candida, Streptococcus faecalis, Pseudomonas,and coagulase-negative Staphylococci-were also the most common species colonizing theproximal GI tract. Gut colonization correlated with the development of invasive infection within 1week of culture for Pseudomonas (90% vs. 13% in noncolonized patients, p < 0.0001) orStaphylococcus epidermidis (80% vs. 6%, p < 0.0001); a weaker association was seen forcolonization with Candida. Infections associated with GI colonization included pneumonia (16patients), wound infection (12 patients), urinary tract infection (11 patients), recurrent (tertiary)peritonitis (1 1 patients), and bacteremia (10 patients). ICU mortality was greater for patientscolonized with Pseudomonas (70% vs. 26%, p = 0.03); organ dysfunction was most marked inpatients colonized with one or more of the following: Candida, Pseudomonas, or S. epidermidis.

ConclusionsThe upper GI tract is an important reservoir of the organisms causing ICU-acquired infection.Pathologic GI colonization is associated with the development of MOF in the critically ill surgicalpatient.

111

112 Marshall, Christou, and Meakins

Nosocomial infection acquired within the intensivecare unit (ICU) commonly complicates the course ofcrit-ical surgical illness. Infections develop during as many as

one third of all admissions to a surgical ICU,` and are

associated with increased mortality and a significant pro-longation of ICU stay.4

ICU-acquired infections differ clinically and epidemio-logically from the life-threatening surgical infections thatprecipitate ICU admission. An important factor in theirdevelopment is impairment oflocal host defenses by sur-

gery and the presence of invasive monitoring devices,3'5the use of broad spectrum antibiotics with disruption ofthe endogenous flora,5'6 and the prolonged absence ofenteral feeding.7 Moreover, they arise in the setting oftransient but profound abnormalities of intrinsic hostdefenses,8 and their prevalence is highest in patients withthe most marked degrees of organ dysfunction.9The microbiology of ICU-acquired infection is also

strikingly different from that ofcommunity-acquired in-fection. The most common isolates from episodes ofICU-acquired infection are endogenous organisms oflow intrinsic virulence including coagulase-negativeStaphylococci, Candida, and enterococci, in addition togram-negative aerobes with a predilection for the com-

promised host, in particular, Pseudomonas, Entero-bacter, and Acinetobacter.3 4'9"' l The reservoirs of theseorganisms are incompletely defined. Although infectiontransmission by ICU staff or other patients,'2 or by con-

taminated devices6 has been documented, most ICU-ac-quired infections are caused by the patient's own flora,after pathologic colonization of endogenous reservoirs.Earlier reports focused on the role of oropharyngeal co-

lonization in the pathogenesis ofnosocomial infection.'3More recently, it has been appreciated that the stomachand small bowel also become colonized with the organ-isms responsible for a significant number of nosocomialinfections in critically ill patients,'147 and it has beenhypothesized that the pathologic colonization of thegastrointestinal (GI) tract may be a critical prelude tothe development of the syndrome of multiple organ

failure (MOF). 18-20We previously reported that the most common causes

of nosocomial infection in patients with MOF-Staphy-lococcus epidermidis, Pseudomonas, and Candida-arealso the most frequent isolates from the upper GI tract ofcritically ill surgical ICU patients.9 The current report

Presented in part at the Surgical Forum, American College ofSurgeons,October 1987, and at the 33rd World Congress of Surgery, Sep-tember 1989, Toronto, Ontario, Canada.

Supported by grants from the Medical Research Council of Canadaand the Dalhousie Medical Research Foundation.

Address reprint requests to John Marshall, M.D., F.R.C.S.C., F.A.C.S.,Eaton North 9-234, Toronto General Hospital, 200 ElizabethStreet, Toronto, Ontario M5G 2C4, Canada.

extends those observations to assess the association ofproximal gut colonization with the development ofICU-acquired infection and MOF.

METHODS

Study Subjects

Forty-one patients admitted to the Surgical IntensiveCare Unit of the Royal Victoria Hospital, Montreal,Quebec, Canada, were studied. All patients had pre-ex-isting access to the upper GI tract through one or moreindwelling nasogastric or nasoenteral tubes, or a surgicalgastrostomy or jejunostomy, and were considered onclinical grounds to be at high risk for the development ofICU-acquired infections. The protocol was approved bythe Human Ethics Committee ofthe Royal Victoria Hos-pital, and informed consent was obtained from the pa-tient or a relative.

Definitions

Infection was diagnosed according to microbiologicand radiographic criteria as described previously.9 Thediagnosis ofpneumonia required the presence ofa heavygrowth ofan organism in two consecutive sputum speci-mens, in conjunction with purulent sputum and a chestroentgenogram revealing a new or changing pulmonaryinfiltrate. Urinary tract infection was defined as the pres-ence of an organism at a concentration of greater than105 colony-forming units (CFU) per milliliter of urine.Bacteremia was said to be present when an organism wasisolated from a single blood culture specimen, or in thecase of S. epidermidis, from two simultaneous speci-mens or a single specimen and an intravenous cathetertip. The diagnosis ofwound infection required the dem-onstration of organisms from a wound that drained pus,or the persistent presence of organisms in an openwound that failed to show formation of granulation tis-sue. The diagnosis of recurrent (tertiary) peritonitis wasbased on the isolation ofan organism from a specimen ofperitoneal fluid obtained at surgical laparotomy, zipperlaparostomy, or percutaneous catheter drainage.

Infections that were present at the time ofICU admis-sion or that developed subsequently as a direct conse-quence of a surgical procedure were termed primary in-fections. An infection was considered to be ICU-ac-quired if it developed at least 48 hours after ICUadmission and involved either a different anatomic siteor micro-organisms different from those cultured from aprimary infection.

Ann. Surg. * August 1993

Upper GI Flora and ICU-Acquired Infection 113

MOF Scores StatisticsThe severity of organ dysfunction over the course of

the ICU admission was quantitated using an organ fail-ure score as previously described.9 Abnormalities in thefunction of eight separate organ systems (respiratory,renal, hepatic, cardiovascular, neurologic, metabolic, he-matologic, and immunologic), each graded from 0 (min-imal or no dysfunction) to 2 (severe dysfunction), aresummed to produce the MOF score.

Quantitative Proximal GI CulturesUpper GI fluid for quantitative culture was obtained

from indwelling gastric and enteric tubes, a method pre-viously shown to yield reliable and reproducible resultswhen compared with results obtained by direct samplingat laparotomy.2' After discarding the initial 3 to 5 mL offluid in the tubing, between 5 and 15 mL ofGI fluid wereaspirated into a sterile syringe and immediately trans-ported to the laboratory for processing. The pH of analiquot ofeach specimen was determined using indicatorpapers, then serial tenfold dilutions in sterile saline wereperformed. One hundred microliters of each dilutionwas plated on selective media (blood agar and MacCon-key agar for aerobes, blood agar, and phenylethyl alcoholagar for anaerobes). Aerobic plates were incubated for 24hours at 37 C and anerobic plates for 48 hours at 37 C.Colonies were then enumerated and species were identi-fied using the API 20E system (API Laboratory Prod-ucts) for identification of gram-negatives and standardtechniques for gram-positives. Candida organisms wereidentified by growth on blood agar and morphology inwet preparation and were further divided into albicansand non-albicans species on the basis of germ tube for-mation after incubation for 2 hours in horse serum. Theculture technique permitted detection oforganisms pres-ent at a density of as low as 100 CFU/mL of sample; theupper limit of detection was 108 CFU/mL. Results areexpressed as log10 CFU/mL of GI fluid.

No. of patients 41Mean age (± SD) 64.5 ± 12.8 yrSex

Male 21Female 20

Admission APACHE II (± SD) 18.4 ± 7.3Infection

Primary 18/41 (44%)ICU-acquired 33/41 (81%)

Median length of stay 23 days (range, 1-219 days)MOF score (± SD) 7.8 ± 4.6ICU mortality 15/41 (36%)

Results are presented as the mean ± standard devia-tion. The Student's t test and one-way analysis of vari-ance were used to compare means of normally distrib-uted continuous data. Group frequencies were com-pared using the chi square statistic with Yates'continuity correction, or the Fisher exact test. Resultswere considered to be significant for values of p < 0.05.

RESULTSDemographic Data

Demographic data for the 41 patients enrolled into thestudy are summarized in Table 1. The ICU mortalityrate was 36.6% (15 patients); one or more episodes ofICU-acquired infection developed in 33 patients (80.5%of the study population).

Assessment of Culture TechniqueThe 83 samples obtained for quantitative culture

yielded a mean of 1.8 ± 1.1 different organisms per sam-ple (range, 0 to 5). Four specimens were sterile, whilebacterial concentrations exceeded the upper limit of de-tection (2 x 108 CFU/mL) in four cases. Aerobes or fa-cultative aerobes were the predominant isolates; strictanaerobes were isolated from only four specimens.

Simultaneous gastric (by gastrostomy) and jejunal (byfeedingjejunostomy) cultures were performed in two pa-tients. In both cases, cultures from the two separate sitesyielded similar results: five ofsix organisms isolated werepresent in both sites at a comparable concentration.Nine patients had two or more specimens taken over aperiod of more than 7 days. In 8 of 9 cases, at least 1organism initially present persisted for more than 1week, and of 19 organisms initially present in these 9patients, 10 were present in a subsequent specimentaken more than 1 week later.

Microbiology of Proximal GI ColonizationThe most common colonizing species are summarized

in Table 2. Candida, the enterococcus, S. epidermidis,and Pseudomonas were the most frequent isolates.

Patterns of proximal gut colonization were stronglyinfluenced by the pH of the specimen. Gram-negativeorganisms were only cultured when the pH was greaterthan 4, while viable Candida could be cultured fromgastric fluid at a pH as low as 1 (Fig. 1).

ICU-Acquired InfectionICU-acquired infection was a common complication,

developing during more than 80% of ICU admissions.

Vol. 218 - No. 2

114 Marshall, Christou, and Meakins

Peritonitis12

Empyema2

Bacteremia

Log10(CFU/mL ± SD)

Candida 19 4.3 ± 1.6Streptococcus faecalis 12 6.8 ± 0.8Pseudomonas 10 6.9 ± 1.1Staphylococcus epidermidis 10 5.7 ± 1.6Non group D Streptococci 7 6.9 ± 1.2Escherichia coli 7 6.2 ± 1.6Enterobacter 5 6.7 ± 1.4Serratia 5 6.5 ± 0.8Klebsiella 5 5.6 ± 1.7Staphylococcus aureus 5 5.6 ± 2.0Citrobacter 4 6.2 ± 1.1Bacteroides 3 7.0 ± 0.9

19

Pneumonia22

\ x.'..'-...'.'~..................Wound

17Urinary Tract

22Figure 2. Sites of ICU-acquired infection in the 34 patients who had atleast one episode of ICU-acquired infection. Numbers refer to the numberof patients having at least one episode of infection at the site indicated.

The sites of these infections are summarized in Figure 2and their microbiology is presented in Table 3. Mostpatients had infection at more than one site, often withmore than one organism at a given site monitored overtime; recurrent infection at a given site was common.The data on the prevalence of infections, therefore, re-flect the development of at least one episode ofinfectionat that site, while the microbiologic data indicate the iso-lation of the particular organism from at least one siteduring the ICU stay.

Correlation of Proximal GI Colonizationwith ICU-Acquired InfectionThe most common isolates from the upper GI tract of

the study population closely paralleled the most preva-

7.1

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lent isolates in cases ofICU-acquired infection. Ofthe 33patients with ICU-acquired infection, all but 3 had atleast 1 episode of infection with 1 or more organismspresent in the proximal GI tract. Because serial cultureswere not performed in a systematic fashion, it is not pos-sible to determine the temporal relationship of coloniza-tion to infection; colonization preceded, coincided with,and followed infection in approximately similar percent-ages of cases.

Patients whose upper GI tract was colonized withCandida, Pseudomonas, or S. epidermidis were signifi-cantly more likely to have one or more episodes of inva-sive infection with that organism over the course of theICU stay than patients who were not colonized. The asso-ciation was strongest for patients colonized with Pseudo-monas (9 of 10 colonized patients had one or more epi-sodes of Pseudomonas infection compared with 6 of 31patients not colonized, p = 0.0003), but it was also evi-dent for S. epidermidis (8 of 10 infections in colonizedpatients vs. 10 of 31 in patients not colonized, p = 0.02)and Candida (15 of 19 infections in colonized patientsvs. 9 of 22 in patients not colonized, p = 0.03, Yates'

0

*0

-II

Pseudomonas S. epidermidis Enterococcus Candida

Figure 1. The pH of upper GI fluid specimens that yielded Pseudomonaswas consistently above 4.0, while Candida could be grown from speci-mens with a pH as low as 1. Mean pH values of specimens growingCandida are significantly lower than those growing Pseudomonas (p <0.001).

pm>§ -148 U l Sej e. . . U ; .. . ........... =.........................~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ....:...

Organism No. of Patients

Candida 24Streptococcus faecalis 22Staphylococcus epidermidis 20Pseudomonas 16Escherichia coli 15Staphylococcus aureus 12Enterobacter 10Klebsiella, Serratia 7 each

OrganismNo. of

Patients Colonized

Mean pH

9

8

7

6pH 5

4

3

2

...

Ann. Surg. - August 1993

Upper Gl Flora and ICU-Acquired Infection

No. of Patients with InvasiveInfection with Same Organism*

No GIOrganism GI Colonization Colonization Pt

Pseudomonas 9/10 (90%) 4/31 (13%) <0.0001Staphylococcus

epidermidis 8/10 (80%) 2/31 (6%) <0.0001Candida 11/19 (58%) 8/22 (36%) NSStreptococcus faecalis 7/12 (58%) 8/29 (28%) NS

* Indicates the number of patients experencing invasive systemic infection within 1week of the time of positive GI culture whose upper GI tract was colonized (GIcolonization) or was not colonized (no GI colonization) with the organism in question.t Chi square test with Yates' continuity correction.

corrected chi square). No such correlation between gutcolonization and infection was found for the other com-mon causes of proximal GI colonization-S. faecalisand Escherichia coli.

Prolonged ICU stays were the rule for many of thepatients studied; therefore, we also analyzed the correla-tion of upper GI colonization with the development ofinvasive infection during a period of 1 week before andup to 1 week after the GI culture was performed. Whenthis was done, the association between gut colonizationand coincident invasive infection was even stronger forPseudomonas and S. epidermidis, but not for Candidaor S. faecalis (Table 4).

Site-Specific Infections with Upper GIOrganismsAs summarized in Table 5, of those patients having

ICU-acquired infections, colonization of the proximalGI tract with at least one of the responsible organismswas common, occurring in from 50% of patients withurinary tract infections to 92% of patients with tertiaryperitonitis. Representative clinical vignettes illustratetypical cases.

Pneumonia

One or more episodes of ICU-acquired pneumoniawith an organism isolated from the proximal GI tractoccurred in 16 patients; the mortality rate was 50%. Themicrobiology of these infections included the spectrumof organisms classically associated with ICU-acquiredpneumonia-Pseudomonas (6 patients), Serratia (3 pa-tients), Enterobacter (3 patients), and Staphylococcusaureus (3 patients).

A 69-year-old woman with chronic lung disease under-went an emergency sigmoid resection for a significant di-

verticular bleed. Gastric cultures performed within thefirst 24 hours of ICU admission grew Pseudomonas aeru-

ginosa. Pseudomonas pneumonia and bacteremia were

diagnosed 6 days later; she died 2 days later.

Wound Infection

Twelve patients had wound infections with an organ-

ism present in the upper GI tract; 7 patients ultimatelydied. The infecting organisms included Candida (five pa-tients), S. epidermidis (four patients), Pseudomonas(four patients), S. faecalis (four patients), and Serratia(two patients).

Urinary Tract Infection

Eleven patients had one or more episodes of urinarytract infection with an organism that was also present inthe upper GI tract. Candida was the most common iso-late, present in nine patients, while Pseudomonas was

the infecting organism in two patients; E. coli and S.faecalis were responsible for urinary tract infections inone patient each.

A 39-year-old woman sustained a cervical spine fractureand small bowel and colonic perforations in a motor vehi-cle accident. Gastric cultures taken 4 days after ICU ad-mission grew Candida. Urine cultures were persistentlypositive for Candida, although the organism was grown atno other site.

Recurrent (Tertiary) Peritonitis

Recurrent or tertiary peritonitis (defined as the persis-tence or recurrence of culture-positive intraperitonealinfection at least 72 hours after apparently adequate ther-apy for an episode of primary or secondary peritonitis)occurred in 11 patients, 8 of whom died. Four of thesepatients had direct communication between the upperGI tract and the peritoneal cavity as a result of either a

perforation (two patients) or an anastomotic leak (twopatients); in the remaining seven, the upper GI tract wasanatomically intact. The infecting species were S. faeca-lis (five patients), Pseudomonas (five patients), S. epider-midis (four patients), and Candida (two patients).

.. :: :: ::....:.

~~~~~~~~~~ ~ ~ ~ ~_....

No. of Patients No. of Colonized PatientsSite Infected Experiencing Infection

Pneumonia 22 16 (73%)Wound 17 12 (71%)Urinary tract 22 11 (50%)Tertiary peritonitis 12 11 (92%)Bacteremia 19 10 (53%)Empyema 2 1 (50%)

Vol. 218-No. 2

116 Marshall, Christou, and Meakins

A 69-year-old man underwent surgical exploration forinfected pancreatic necrosis; cultures grew Candida. Hewas managed with repeat laparostomies using a mesh andzipper approach. S. epidermnidis was isolated from boththe stomach and necrotic peripancreatic tissue 1 weekafter his initial procedure.

Bacteremia

Bacteremia or fungemia, the sine quia non of invasiveinfection, occurred with an organism from the upper GItract in ten patients (Table 5). Pseudornonas was isolatedin four patients, Candida in three, and S. epidermnidis, E.coli, and S. facca/is in one.

A 30-year-old man sustained multiple injuries includ-ing a pelvic fracture in a fall. Gastric cultures performed 3days later yielded a heavy growth of S. '/iwcalis. The sameorganism was isolated from the blood 4 days later, and atthe same time in insignificant numbers in the urine.

An additional patient had a primary infection in asso-ciation with proximal GI colonization:

A 54-year-old woman on home total parenteral nutri-tion (TPN) was admitted in septic shock. Blood culturesgrew Klebsiellai pneumoniae; the same organism wasgrown from her proximal jejunostomy effluent at a con-centration of 105 CFU/mL.

Empyema

Of two patients in whom empyemas were diagnosedduring the ICU stay, one patient had the same organismisolated from the upper GI tract:

A 35-year-old woman sustained traumatic hemiplegiain a fall from a height and underwent surgical stabilizationof the spine by an anterior approach. Jejunal cultures ob-tained 13 days after injury grew S. epidermidis: S. epider-midIs and S. tiecalis were cultured from the chest tubedrainage 3 days later.

Correlation of Proximal GI Colonizationwith ICU Mortality

ICU mortality rates for patients having GI coloniza-tion with Pseuidoinonas were significantly elevated overthose of patients who did not have colonization (70% vs.26(7X, p = 0.03, Yates' corrected chi square). ICU mortal-ity rates were also elevated for patients colonized with S.eIidcrlfelidis (60%) or the enterococcus (58%); however,the differences did not attain statistical significance.

Correlation of Proximal GI Colonizationwith MOF Scores

GI colonization with Candida, iye¾udoinonas, or S.epidc1rinidis was associated with the greatest degree oforgan dysfunction, while MOF scores for patients colon-ized with S. /Ieccalis were marginally lower (Fig. 3). The

14-1

12-

0

CoIL0

10-

8-

6-

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2-

0

T T T T

S. epidermidis Candida Pseudomonas S. fecalis

*

Others

Colonizing MicroorganismFigure 3. Organ failure (MOF) scores for patients colonized with Can-dida (19 patients), Pseudomonas (10 patients), S. epidermidis (10 pa-tients), or S. faecalis (12 patients) were significantly higher than the scoresfor the 7 patients who were not colonized with any of these 4 organisms (p

0.02, one-way analysis of variance). MOF scores were calculated aspreviously described.9 Results are mean ± SD.

seven patients in whom none of these organisms wasisolated from upper GI fluid had significantly lowerMOF scores (p = 0.02. one-way analysis of variance).

DISCUSSIONIn health, the stomach and proximal GI tract are ster-

ile, or sparsely populated with a relatively avirulent floraincluding Lactobaci/li and Strepto()co((i.21'22 As this andprevious studiesi4-7 demonstrate, critical illness is asso-ciated with significant proximal gut overgrowth with typ-ical ICU pathogens. Both descriptive and interventionalstudies suggest that this pathologic colonization contrib-utes significantly to the development of ICU-acquiredinfection.

In the current study, more than 90% of the 33 patientswith ICU-acquired infection had at least one episode ofinfection with an organism that was simultaneously pres-ent in the upper GI tract. Moreover, colonization witheither Pseuidomonas or S. epidermnidis was strongly asso-ciated with concomitant infection, while colonizationwith C'andida was significantly associated with invasivefungal infection at some time during the ICU admission.A purely descriptive study such as this cannot estab-

lish causality. It can be argued that gut colonization is aconsequence of infection and a manifestation of micro-bial dissemination from the initial focus of infection;however, this interpretation appears less tenable. Despitethe fact that GI cultures were performed at disparate andarbitrary timepoints while diagnostic cultures were per-formed regularly on the basis of clinical evidence of in-fection, gut colonization equally preceded, coincidedwith, and followed the development of invasive infec-

Ann. Surg. * August 1993

Upper GI Flora and ICU-Acquired Infection

tion. ICU-acquired infections rarely showed evidence ofwidespread dissemination with multiple positive sitesand bacteremia; indeed, bacteremias most commonlyappeared to arise as a result ofcontaminated intravascu-lar catheters. The interpretation that gut colonizationsets the stage for the development ofinvasive infection issupported by published reports demonstrating a reduc-tion in rates of ICU-acquired infection as a result of se-

lective decontamination of the digestive tract'6'23'24 or

the use of cytoprotective agents for stress ulcer prophy-laxis,25'26 although the efficacy of both of these strategieshas been questioned.27'28The relative sterility of the upper GI tract is main-

tained through the interaction ofa number ofinfluences,including gastric acidity,29 normal intestinal motility,30and, to a lesser extent, bile salts,3' IgA,32 and defensinsfrom Paneth cells.33 Enteral feeding is a potent stimulusto the activation of normal proximal gut antimicrobialdefenses, stimulating gastric acid release, bile flow, andsmall intestinal motility; cholecystokinin and secretinrelease, in turn, augment IgA production by the smallbowel mucosa.34 Critical illness is associated with pro-

found disruption of these normal defenses. Acid-reduc-ing measures to reduce the risk of stress ulceration resultin gastric gram-negative overgrowth,'4'15"17'25 a phenome-non clearly evident in the current study. Few of the pa-

tients in this report were fed enterally because of co-ex-

isting ileus; randomized trials have clearly demonstrateda reduction in rates of nosocomial infection when en-

teral nutrition is instituted early.7The indigenous GI flora exerts an important influence

in rendering the gut resistant to colonization with exoge-

nous pathogens; this phenomenon, attributable to theanerobic flora, has been termed "colonization resis-tance."35 Disruption of the normal flora by antibioticscan reduce colonization resistance, and in experimentalmodels has been shown to promote pathologic coloniza-tion by two of the most common isolates seen in thisstudy-Candida36 and Pseudomonas.37 Whether antibi-otic use affected patterns of colonization in the patientsreported here is impossible to determine because all but5 of the 41 patients had received broad spectrum antibi-otics before the performance of the quantitative GI cul-tures.

Subclinical aspiration of contaminated gastric secre-

tions causing nosocomial ICU-acquired pneumonia is awell-documented phenomenon,'4'25 believed by many tobe the most important cause ofpneumonia in the ICU.38Pneumonia with an organism simultaneously culturedfrom the upper GI tract was documented in 39% of thepatients in this study, the infecting species being thecommon isolates in cases ofICU-acquired pneumonia.38All ofour patients had indwelling access to the upper GItract, usually in the form of a nasogastric tube; subclini-cal aspiration in conjunction with nasogastric tubes has

been shown to be a risk factor for the development ofICU-acquired pneumonia.39

In addition to the 16 documented cases ofpneumonia,however, we also observed remote invasive infectionwith organisms colonizing the upper GI tract. Concomi-tant colonization ofan infected wound and the upper GItract in our 12 cases may simply reflect a process ofgener-alized epithelial colonization, unrelated to the develop-ment of systemic infection. Some of the cases of tertiaryperitonitis may have been secondary to bacterial passagethrough anatomic defects in the gut, although only 4 ofthe 11 patients with this complication had a macroscopiccommunication between the gut lumen and the perito-neal cavity. The organisms isolated from these cases-co-agulase-negative Staphylococci, Candida, Pseudomonas,and the enterococcus-are the organisms typically seenin recurrent or tertiary peritonitis.40 There were 11 caseseach of urinary tract infection and bacteremia (1 pri-mary) with organisms simultaneously present in the gut,suggesting that bacterial translocation may be a factor ofimportance in the pathogenesis of ICU-acquired infec-tion. The most common causes of gut colonization inthis study-Candida,4' Pseudomonas,42 S. epidermidis,and the enterococcus43-have all been shown in animalmodels to be capable oftranslocation across an anatomi-cally intact GI tract. Moreover, factors known to pro-mote translocation, including trauma, endotoxemia, par-enteral feeding, cholestasis, and use of broad spectrumantibiotics, are commonly present in the critically ill sur-gical patient."

It has been suggested that ICU-acquired infection is amanifestation of organ system dysfunction rather thanits cause,9'45 and studies of attributable mortality of no-socomial infection support this interpretation.46'47 Thus,the more pronounced degrees of organ dysfunction seenin patients colonized with Candida, Pseudomonas, or S.epidermidis may reflect the fact that these organismsmore readily colonize the sickest patients. Gram-nega-tive and fungal intestinal overgrowth alone has beenshown in animal models to induce changes in interme-diary metabolism48 and systemic immune responsive-ness49'50 characteristic of those developing in the criti-cally ill patient, and it is possible that the adverse se-quelae of gut colonization are less related to thedevelopment of invasive infection than to noninfectiousinfluences on systemic homeostasis.Whether the relationship between gut colonization

and systemic infection reflects cause and effect or simplyassociation, it is apparent that the microbial milieu ofthecritically ill patient is well-reflected in the patterns ofgutcolonization that evolve during the ICU stay. Moreover,whether ICU-acquired infection is a cause or a manifes-tation of morbidity, the strong correlation betweenpathologic proximal gut colonization, ICU-acquired in-fection, and the evolution of the clinical syndrome of

Vol. 218 - No. 2

118 Marshall, Christou, and Meakins

MOF justifies the conceptual characterization of the GItract as the "undrained abscess" of MOF. The clinicalchallenge, and the proofor refutation ofthe gut hypothe-sis, lies in finding an effective method of drainage.

Acknowledgments

The authors thank Dr. Ruth Horn for supervising the microbial cul-tures and specimen identification, Ms. Betty Giannias for performingthe quantitative bacterial cultures, Lise Laporte, RN, and Mary deSantis, RN, for collecting clinical data, and Ms. Elaine Caon for assist-ing with the preparation of the manuscript.

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