Pneumonia in the critically ill hospitalized patient

DOI 10.1378/chest.97.1.170 1990;97;170-181Chest

M S Niederman, D E Craven, A M Fein and D E Schultz Pneumonia in the critically ill hospitalized patient.

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I

170 Pneumonia in Critically III Hospitalized Patient (Niederman et a!)

clinical conferencePneumonia in the Critically III Hospitalized PatientMichael S. Niedernian, M.D., FC.C.P;* Donald E. Craven, M.D.;t

Alan Al. Fein, M.D. , FC.G.P4 and Douglas F. Schultz, M.D.�

CASE PRESENTATION

Dr Douglas Schultz: A 59-year-old white man with a three-,nonth

history of systemic lupus erytheinatost,s and a history of insulin-

dependent diabetes mellitus was admitted to the hospital with a

three-day history offever to 38.8#{176}Cand dysuria. Evaluation revealed

a urinary tract infection with F coli and benign prostatic hypertro-

phy. One month later, the patient underwent transi,rethral resection

ofthe prostate. On the fourth postoperative da)� he developed fever

to 39.4#{176}C, shortness of breath, weakness, confusion, and reported

a slightly productive cough. His medications at the time included

prednisone, 10 mg dail); and NPII insulin, 20 units sulxs,taneosislv

daily.On initial examination, the patient was found to be mildly short

ofbreath with a respiratory rate of32, blood pressure of 120/76 mm1-1g. and a temperature of 39.3#{176}Crectall}: His on1y remarkal)le

physical findings were crackles ii� the posterior aspect of the right

lung in the upper two-thirds ofthe chest. The remainder ofhis lung

examination was unremarkable and flO new extrapulmonary findings

were noted.

Laboratory evaluation showed a white blood cell count of 8,600

with 85 percent po1�s and 10 percent bands. Blood glucose was 347

mg/(1l and arterial blood gases, while breathing room air, showed a

p11 of 7.4, Pco� 38 mm 11g. and Pu, of 56 mm 11g. A chest

radiograph (Fig 1) showed a right i,pper lobe infiltrate. Sputum was

evaluated b� Gram stain and showed copious white blood cells with

(;ram-negative rods. Sputum �md blood cultures were obtained.

The remainder of the lalxratory data was i,,iremarkahle.

The patient was treated with a presumptive diagnosis of �u)5(x’o-

mial Gram-negative pneumonia and therapy included intravenous

hydration, oxygen via a 40 Iwrcent Venti-mask, aH(l iI1traveIu)L�s

ceftazidime. lii addition, the patient received appropriate increases

in steroid therapy for stress, and insulin coverage for hyperglycemia.

Two days later, the patient was fom�nd to he more short of breath

and he was transferred to Winthrop-University hospitals intensive

care m�nit for further care. On arrival, the patient had a hhxxl

pressure of 70 palpable. Arterial blood gases, with the p�itieiit

breathing via 40 percent Venti-mask, showed a p11 of7.36, Pco� = 22

4Ditect�r Medical and Respiratory Intensive Care Unit, Pulmonary

and Critical Care Medicine Division, Winthrop-University Ilos-pital; Assistant Professor of Medicine, Health Science Center,State University of New York at Stony Brook.

tProfessor of Medicine and Microbiolog� Boston University Schoolof Medicine; Infectious Disease Division, Boston City Hospital,Boston.

lDirector, Pulmonary and Critical Care Medicine Division, Win-throp-University Hospital; Associate Professor ofMedicine, healthScience Center, State University of New York at Stony Brook.

§Fellow, Pulmonary and Critical Care Medicine, Winthrop-Univer-sity Hospital, Mineola, New York

Reprint requests: Dr. Nieder,nan, 222 Station Plaza North, Muwola,New York 11501

mm 11g. and Po2 = 42 mm Hg. At that time, his blood cultures from

the other hospital were reported to show two strains of Pseudomonas

aeruginosa. A repeat chest radiograph (Fig 2) showed diffuse

infiltration of the right lung and faint infiltration at the left base.The patient was then endotracheally intubated and placed on

mechanical ventilation. Antibiotic therapy was directed towards

Pseudonwnas aeruginoca with amikacin added to ceftazidime.

Bronchosecmpy was performed with a protected specimen brush and

the brush was cut into 1 ml of tryptic soy broth and cultured

quantitatively, revealing greater than 10� Pseudomonas aeruginosaper ml in pure culture.

The patient was treated with mechanical ventilation for a period

of three weeks. his therapy also included supplemental oxygen,

titrated to maintain oxygenation, and he had gradual improvement

in his oxygenation status and control of his respiratory infection.

After three weeks of mechanical ventilation, the patient was

successfully extubated. His course had been complicated by diar-

rhea, felt to be related to antibiotic therapy and tube feedings,

intermittent supraventricular tachycardia, tracheostomy for airway

care, and intermittent return of fresh blood from his nasogastric

tube, in spite of prophylaxis of intestinal bleeding with cimetidine.

At the time of discharge from the intensive care unit, the patient

was felt to have recovered from his pneumonia and all of his

antibiotics were discontinued. Sputum cultures continued to reveal

Pseudomonas aeruginosa, but no therapy was prescribed.

Approximately one week after discharge from the intensive care

L,nit, the patient again developed dyspnea, cough productive of

green sputum, and fever to 38.3#{176}C.A repeat chest radiograph (Fig

3) demonstrated persistent infiltrates in the right chest along with

FIGURE 1. Chest radiograph demonstrating right-sided pneumonia

developing postoperativel):



FIGURE 2. Progression of pneumonia to a radiographic pattern

consistent with ARDS.

FIGURE 3. A second episode of pneumonia developed, with

infiltration in the left lung.

CHEST I 97 I 1 I JANUARY, 1990 171

a new left perihilar infiltrate. Fiberoptic I)ronchosc()py with pro-

tected specimen brush was repeated and again Pseudonumas

aeruginosa was recovered in greater than 1&’ organisms per ml.

However, at this time, the organism demonstrated a different

sensitivity pattern than the original organism and appropriate

antibiotic therapy was initiated. In addition, bronchoscopy with

bronchoalveolar lavage demonstrated Pneurnocystis carinii on

Giemsa staining and therapy with trimethoprim-sulfamethoxizole

was added to anti-Pseudomonal antibiotics. The patient again

required mechanical ventilation, but after a two-week course of

antibiotics, the patient had defervescence and clearing of his chest

radiograph and was eventually weaned offthe ventilator to ultimately

he discharged from the hospital.

Dr. Michael S. Niederman: Dr. Fein, can you describe

how systemic sepsL� may be complicated by ARDS?

Dr. Alan ?%I. Fein: Our patient exemplifies the close

clinical relationship which ties severe infection to the

adult respiratory distress syndrome (ARDS). The pa-

tient, a 59-year-old man with systemic lupus erythe-

matosus and diabetes mellitus, who was receiving

corticosteroids, presented with Gram-negative pneu-

monia which was uncontrolled by the prescribed

antibiotics and he then developed septic ARDS . ARDS

may be conceptualized as the pulmonary component

ofa generalized inflammatory injury, especially to the

endothelium. When initiated by severe infection, it

often progresses to involve in a sequential fashion

other major organ systems, including kidneys, gastro-

intestinal tract and liver leading to a syndrome of

multisystem organ failure. ARDS may have both direct

and indirect causes which often overlap. Pneumonia

is the most common direct cause of the adult respira-

tory distress syndrome, particularly if it involves a

large enough segment of parenchyma to severely

impair the mechanical and gas exchange function of

the lung.’ While viral pneumonia typically involves

the lung parenchyma in a diffuse fashion, most other

classes of organisms, including bacteria (most corn-

monly), fungi and mycobacteria, also have this capa-

1 Pnetnnocystis carinii has emerged as a common

cause of severe hypoxic respiratory failure, usually in

patients with AIDS.2

Infection may also initiate ARDS indirectly by

activation of systemic inflammation.3 Bacteria, viruses,

fungi, or even traumatized tissue induce a similar

systemic response characterized by hypermetabolism

(even in the absence of blood stream invasion) and

subsequent multiorgan failure.�’5 The link between

this systemic response, organ failure and infection is

under complex and active investigation. Recent work

has emphasized the central role of lymphocyte/mac-

rophage-derived tumor necrosis factor (cachectin) and

interleukin-1, in modulating the response to sepsis.6

Other potential mediators in this chain are activated

neutrophils, complement and the various components

of the thrombotic system, which may directly injure

tissue and amplify inflammation.3

Dr. Niederman: It is possible to predict which septic

patients will develop ARDS?

Dr. Fein: ARDS usually follows onset of the septic

syndrome within 72 hours.5 While isolated bacteremia

carries a relatively low risk for progressive lung injury

(6-15 percent), when combined with shock and throm-

bocytopenia, the risk rises dramatically to 65 and 46

percent, respective1y.�’7 Additional insults, such as

hypertransfusion, aspiration or burns will increase the

likelihood of sepsis leading to ARDS to approximately

50 percent.

At the present time, clinical signs in patients at risk

are the best predictors of progressive lung injury.4 In

a recent analysis combining injury severity score (155),

individual risk factors and initial oxygenation, Pepe et

al� reported that ISS, numbers of transfusions, the

presence of the septic syndrome and initial oxygena-

new tion best predicted ARDS, in that order. Our owndata suggest that severity of presenting hypoxemia



172 Pneumonia in Critically III Hospitalized Patient (Niede,man et a!)

and metabolic acidosis are better predictors of pro-

gression to ARDS in septic patients than are any

measurements of mediators in serum.9

In many studies, the measurement ofplasma factors

to predict ARDS has been disappointing.4’5’9 While

various components of activated complement are ele-

vated in septic patients, none has been shown to

consistently predict progressive lung 1q12 Re-

cently, a prospective study by Langlois and Gawryl’3

demonstrated the terminal complement complex was

increased by an average of 100 percent in septic

patients who developed ARDS prior to the onset of

clinical lung injury. While interesting, these findings

await confirmation at other clinical centers. The neu-

trophil is also an important participant in the initial

phases of lung ry’4 Despite this, our own data

suggest that neither neutrophil turnover nor neutro-

phil chemoattractant activity can identify which septic

patients will develop ARDS.9

Dr. Niederman: How does sepsLs affect the outcome of

ARDS?

Dr. &in: Advances in the management of respiratory

failure have reduced the number of patients who

succumb to hypoxemia. Rather, deaths occurring 72

hours or more after the initial insult usually result

from uncontrolled pulmonary �4 Nosocomial

pneumonia is evident in more than 70 percent of

patients with ARDS.’5 Infection in a damaged lung

potentially influences the outcome by several mecha-

nisms. The additional septic burden further enhances

the release ofinflammatory mediators including tumor

necrosis factor (TNF) and interleukin-1, directly po-

tentiating organ damage and recruiting more neutro-

phils and macrophages to the lung. These effector

cells release proteases and oxidants which promote

colonization by micro-organisms and lead to disor-

dered repair of connective tissue matrix and fibrosis.

Among ARDS patients with infection, 67 percent died

compared to only 7 percent of non-infected patients

and those with nosocomial pneumonia may have an

even higher 14 Most infected patients have

failure ofother organ systems in addition to the lung.’6

It is interesting that following the recovery from

ARDS, our patient developed a second episode of

respiratory failure, with recovery ofboth Pseudomonas

aeruginosa and Pneumocystis carinii. Both of these

organisms are indicators of a markedly compromised

host. Host defense impairments are common in the

multiorgan failure syndrome and clearly influence

outcome.’7 In our patient these compounded the

already significant effects of systemic lupus erythe-

matosus, diabetes, and corticosteroid therapy. Proteo-

lytic enzymes, especially neutrophil elastase, are re-

leased into the alveolar lining fluid in ARDS.’8 In

addition to its effects on connective tissue matrix,

elastase may inhibit ciliary function, and degrade

immunoglobulin IgG and secretory IgA, thereby in-

hibiting bacterial clearance and phagocytosis.’7”9’�#{176}

Likewise, the formation of pulmonary edema fluid

may directly inhibit bacterial clearance by macro-

phages2’ and washout surfactant, which has antimicro-

bial activity.� While there is no mention in our patient

of liver dysfunction, this is a frequent accompaniment

of ARDS and multiorgan failure.ss Liver dysfunction

limits clearance of gut bacteria, endotoxin and circu-

lating inflammatory mediators such as TNF, thus

enhancing injury.tm latrogenic factors may also impair

host defenses. High inspired oxygen tensions used in

the patient’s treatment as well as cortiscosteroids,

impair the phagocytic function of macrophages and

neutrophils.2#{176}’�’m It is clear that failure of multiple

host defenses contributed to the second episode of

acute respiratory failure which he sustained.

Dr. Niederman: The patient being discussed today had

Gram-negative colonization of the tracheobronchial

tree and Gram-negative pneumonia, two findings that

are closely interrelated. In addition, the pathogenesis

of airway colonization is related to many of the host

impairments that our patient demonstrated. He had

two eposides of pneumonia, both acquired in the

hospital, and at the conclusion of the first episode, he

continued to grow Pseudomonas aeruginosa in his

lower airway, in the absence of clinical signs of

infection. This represented airway colonization which

had persisted after an initial pneumonic episode.

While still colonized with Pseudomonas aetvginosa,

he developed a second episode of pneumonia which

was due to both Pseudomonas aeruginosa and Pneu-

mocystis carinii. The features of interest in this case

are the relationship of airway colonization to the

subsequent occurrence of pneumonia, the mecha-

nisms that allow risk factors to lead to colonization of

the airway by Gram-negative bacteria, and reasons for

persistent lower airway colonization by Pseudomonas

aeruginosa.

Colonization ofboth the upper and lower respiratory

tract are frequently associated with the occurrence of

nosocomial pneumonia. Rates of Gram-negative cob-

nization of the oropharynx are directly related to the

severity of illness for a given patient. In a study by

Johanson and colleagues,� utilizing multiple cultures

of the oropharnyx, it was found that no more than 6

percent of normal individuals had oropharyngeal cob-

onization by Gram-negative bacteria. However, as

patients became progressively ill, the incidence of

Gram-negative colonization of the upper airway in-

creased, such that with multiple cultures, nearly three-

quarters of the sickest patients in the hospital were

colonized with enteric Gram-negative bacteria. The

relevance of this finding to the occurrence of pneu-

monia was shown in a follow-up study of213 intensive

care unit patients, 26 of whom developed nosocomial




Table 1-Risk Factorafor Gram-Negative AirwayColonization

Oropharynx Lower Respiratory Tract

Antibiotic therapy Antibiotic therapy

Azotemia* Chronic bronchitis

Coma Ciiary dysfunctionDiabetes Corticosteroid therapy

Hypotension Bronchiectasis

Advanced age Cystic fibrosis

Endotracheal intubation4 Endotracheal intubation4

Pre-existing lung disease Tracheostomy4

Smoking4 Malnutntion*

Surgery* Surgery*

Serious illness4 Acute lung injury

Malnutntion* Viral infection*

Gastric acid-neutralization SmokingGastric acid-neutralization

�ffisk factor has been shown to operate, at least in part, by altering

bacterial adherence.

pneumonia.� Among the patients with pneumonia, 22

of 26 had prior oropharyngeal colonization by Gram-

negative bacteria, indicating a high co-association

between upper airway colonization and the subse-

quent occurrence of parenchymal lung infection. The

reason for the close relationship between airway

colonization and pneumonia may be the result of two

factors. First, once the airway is colonized by Gram-

negative bacteria, these organisms are available for

aspiration into the tracheobronchial tree. In addition,

it is possible that patients who have become colonized

in the oropharynx have host impairments which pre-

dispose not only to upper airway colonization, but also

to lower airway colonization and subsequent pneu-

monia. Thus, colonization ofboth the upper and lower

respiratory tract can be viewed as a “marker” of a

seriously ill patient who has multiple impairments in

respiratory host defenses.

The patient discussed today has multiple risk factors

for both upper and lower airway colonization (Table

1). These included his serious degree of underlying

illness, recent surgery, the use of multiple antibiotics,

endotracheal intubation and tracheostomy, malnutri-

tion, the use of corticosteroids, recurrent hypotensive

episodes, and the use of histamine type-2 receptor

blocking agents for the prophylaxis of gastrointestinal

bleeding. Each of these factors increased the risk of

airway colonization through a variety of mechanisms.

Antibiotics can increase the risk of infection by

interfering with the normal flora in both the upper

and lower respiratory 17�� The normal upper

respiratory tract rarely harbors Gram-negative bacte-

ria and is usually colonized by Gram-positive organ-

isms, particularly anaerobes, which may “interfere”

with the growth of Gram-negative organisms. It has

been conceptualized that the normal flora ofthe upper

airway occupy bacterial binding sites in the oropha-

ryngeal muscosa and, thereby, block subsequent cob-

nization by Gram-negative bacteria. This type of

interference can be eliminated with the use of sys-

temic antibiotics. A similar mechanism may also appby

in the bower airway, although in most individuals the

lower airway does not have normal flora and is ster-

Endotracheal intubation can increase the risk of

upper and lower airway colonization and pneumonia.

Patients with tracheostomy have nearby a 70 percent

incidence ofnosocomial pneumonia and this is bargeby

related to two factors.3’ First, patients with tracheos-

tomy have the capacity for organisms to directly enter

the lower respiratory tract, thereby bypassing upper

airway defenses. In addition, the presence of a trach-

eostomy or an endotracheal tube may traumatize the

tracheobronchial mucosa and alter its integrity, making

it more susceptible to invasion and cobonization.�’�

Corticosteroids may predispose to colonization by

interfering with a variety of host defense mecha-

nisms.’7 Histamine type 2 (H2) bbockers similarly may

predispose to colonization by the mechanisms to be

discussed by Dr. Craven. In our own studies of

mechanically ventilated patients, it has been observed

that Pseudomonas species colonization of the bower

airway was more common in patients receiving H2-

blockers than in patients who did not receive this

therapy.�

The major pathogenetic mechanism that unifies

many of the risk factors for upper and bower airway

colonization involves the cell-cell interaction termed

bacterial adherence. At multiple mucosab sites

throughout the body, the binding of bacteria to the

epithelial surface has been demonstrated to be an

important mechanism that beads to colonization. In

the respiratory tract, bacterial adherencem has been

demonstrated to mediate Gram-negative colonization

of both the upper and the bower airway.�’ Many of

the risk factors for airway colonization have been

shown to act by enhancing the ability of respiratory

epithelial cells to bind bacteria, thereby albowing

bacteria to establish a foothold on the respiratory

mucosa (Table 1). Studies to date have demonstrated

that general surgery, renal failure, malnutrition and

cardiac bypass surgery all have the ability to make

oropharyngeab epithebiab cells express more binding

sites for Gram-negative bacteria.�

In studies by Johanson and cobleagnes,� it has been

demonstrated that patients whose bungs became cob-

onized after general surgery had a serial rise in the

ability of their buccal epithebial cells to bind bacteria.

Such a serial rise was not observed in patients who

did not develop colonization following general surgery.

The mechanism whereby serious illness and systemic

insult increase the number of binding sites on oral

epithelial cells has been evaluated by the same inves-

tigators. In these studies, it was shown that certain



174 Pneumonia ni CritiCally HI Hospftahzed Patient (Niederman et a!)

critically ill patients elaborate proteases in their sail-

vary secretions which have the capacity to digest

fibronectin from the cell surface.� Fibronectin ap-

pears to be a blocking glycoprotein which covers

epitheliab cell receptors for Gram-negative bacteria.

With the release of oral proteases, fibronectin is

removed from the buccal epithelial surface, thereby

exposing more epithelial receptors for subsequent

bacterial binding. It is yet unknown whether similar

mechanisms operate in the lower respiratory tract.

However, it has been shown that patients with trach-

eostomy, colonized by Pseudomonas aeruginosa, had

an overall higher degree of tracheal cell binding

capacity than did tracheostomized patients who were

not colonized by Pseudomonas aeruginosa.32 In addi-

tion, patients with the highest degree of tracheal cell

adherence tended to have the highest levels of neutro-

phil elastase in their tracheal secretions.�#{176} Thus, it is

possible that proteases in high concentrations, in some

manner mediated the increased adherence to tracheal

epithelial cells that was seen in patients colonized in

the lower airway by Pseudomonas species.

Malnutrition is one host factor that has been related

to both colonization and increases in adherence to

both oral and tracheal epithelial cebls.32,�,37 Higuchi

and colleagues37 demonstrated, in an animal model,

that with progressive declines in animal weight, there

was a serial rise in the ability ofbuccal epithelial cells

to bind bacteria. In addition, among tracheostomy

patients, those with the most severe nutritional im-

pairment tended to have the highest degree of tracheal

cell adherence.� In patients with endotracheal intu-

bation who were receiving mechanical ventilation, it

has also been shown that patients who were severely

malnourished had a greaterlikelihood to develop lower

respiratory tract colonization by Pseudomonas species

than intubated patients who were better nourished)”

In studies of bacterial adherence, there has been

the consistent observation, in normal individuals and

in critically ill patients, that tracheal cells have a

greater capacity to bind Pseudomonas aeruginosa than

do buccal epithelial cells)’�”#{176}”'’The clinical relevance

ofthese findings may relate to the occurrence of tissue

“tropisms,” or preferences, ofPseudomonas aeruginosa

in the human respiratory tract. In other words, if

Pseudornonas aeruginosa binds to tracheal cells more

avidly than it binds to buccal cells, then possibly

Pseudomonas aeruginosa would preferentially colonize

the lower airway rather than the upper airway, if the

organism has access to both sites simultaneously. Such

a situation does exist in patients with tracheostomy

and in patients with endotracheal intubation. In both

of these populations, colonization studies have dem-

onstrated that Pseudomonas species colonized the

bower airway more frequently and persistently than

the upper airway)”� The patient discussed today did

not have bacterial adherence directly measured. How-

ever, it is likely that many clinical factors did increase

his tracheal cell capacity to bind Pseudomonas aeru-

ginosa and, thereby, led to persistent lower airway

colonization by Pseudomonas aeruginosa. The persist-

ence of colonization by Pseudomonas aeruginosa in

such patient may be related to multiple factors. The

patient was severely malnourished and if malnutrition

increased tracheal cell binding capacity for bacteria,

then Pseudomonas colonization would persist until

the malnutrition was reversed. In addition, with

colonization, airway inflammation is present and neu-

trophils in inflammatory secretions can release ebas-

tase which can, in turn, interfere with the local

protective function of IgA and further predispose to

airway cobonization.2#{176} A vicious circle of colonization

begetting more colonization is quite likely in this

circumstance.

In addition to more frequent and more persistent

colonization of the lower airway rather than the

oropharynx, the other expression of tissue “tropisms”

in the human respiratory tract may be that the lower

airway becomes colonized by Pseudomonas species

independent of the upper airway. In mechanically

ventilated patients, Pseudomonas species, in contrast

to other Gram-negative bacteria, have the capacity to

colonize the lower airway without first colonizing the

upper airway)’� This finding of primary tracheobron-

chial colonization has been observed by several inves-

tigators. Schwartz et al’#{176}have reported that while

Enterobacteriaceae entered the trachea after initial

oropharyngeal colonization, other organisms such as

Pseudomonas species rarely were found in the upper

airway before colonizing the lower airway. Pingleton

et al”' have also observed that intubated patients may

have primary tracheal colonization by Gram-negative

bacteria.

At least three different factors influence the adher-

ence of bacteria to cells. These include host cell

variables, bacterial variables, and micro-environmen-

tab factors.”� Among host cell variables, the most

important factors include the site of cellular origin

and the type of host from which the cells are taken.

Another cellular variable that may be important is the

presence of cilia. Recently, it has been shown that

Pseudomona3 aeruginosa can bind directly to ciiary

structures.�

Bacterial variables are important because certain

organisms have the capacity to bind epithelial cells

while others do not. Specific features that enhance an

organism’s ability to bind to epithelial cells include

the presence or absence of a capsule, the type of

surface appendages present, and the nature of the

exoproducts released by the bacteria.”�’47’� Certain

Pseudomonas species do have the capacity to bind

epithelial cells directly via their pili, which may serve



CHEST I 97 1 1 1 JANUARY, 1990 175

as bacterial adhesions that attach directly to the

epithelial surface.”7

The micro-environment in which bacteria meet

epithelial cells Is also a determinant of adherence . For

example, the composition ofsputum, both its protease

and mucin components, can influence whether or not

bacteria bind epithelial cells. In addition, the pH of

the epitheliab surface may influence the ability of

bacteria to bind.”#{176}As mentioned previously, proteo-

bytic components of sputum may alter the bacterial

binding interaction.� Mucins in sputum can serve as

receptors for bacterial binding and thus have the

capacity to competitively inhibit bacterial binding if

they bind to bacteria, but not directly to cells. On the

other hand, if mucins attach directly the cellular

surface, then they may act as a receptor “bridge” for

bacteria and further increase the capacity of the

epithelium to bind baeteria.’� This may be particularly

important in patients who have impaired mucociliary

clearance where large quantities ofmucins may adhere

to the epithelial surface and, thereby, predispose to

colonization.

Based on our understanding ofbacterial adherence,

it may become possible in the future to devise

prophylactic strategies for airway colonization. As we

better understand the nature of bacterial adherence,

we may be abbe to develop vaccines with the use of

adhesins as antigens and, thereby, form local antibody

which can block bacterial binding. To the extent that

mucins serve as cellular receptors for bacteria, the

use of mucolytic or ciliokinetic agents may be helpful

in modifying the risk of infection. In addition, our

insight into bacterial adherence studies has shown

that primary colonization of the bower airway by

Pseudomonas aeruginosa is possible. Consideration of

this finding may be useful in the design of protocols

that employ prophylactic antibiotics. As Dr. Craven

will discuss, many protocols that are designed to

prevent nosocomial pneumonia involve sterilization of

the oropharynx and the gastrointestinal tract, under

the presumption that these are the only sources of

organisms that enter the lung. If Pseudomonas aeru-

ginosa can enter the tracheobronchial tree without

first colonizing elsewhere, then prevention of infection

by this organism may require the direct application of

antibiotics to the lower airway, and not just to the

oropharynx and gastrointestinal tract.

Dr. Neid.erman: Dr. Craven, can �pu discuss the scope

and causes ofthe problem ofnosocomial pneumonia?

Dr. Craven: Nosocomial pneumonia accounts for ap-

proximately 15 percent of hospital-acquired infec-

tions�#{176}and is the leading cause ofdeath from nosocom-

ial infection.5’ Rates of nosocomial pneumonia are

considerably higher in intensive care unit patients

compared to patients on hospital wards, and mechan-

ically ventilated patients have a risk ofpneumonia that

is several fold higher than nonventilated patients.3152so

Celis et al� examined 120 consecutive episodes of

nosocomial pneumonia and found intubation increased

the risk of nosocomial pneumonia approximately 7-

fold. Cross and Roup&’ found rates of pneumonia in

patients receiving mechanical ventilation via an en-

dotracheal tube were increased 10-fold compared to

patients with no respiratory therapy device.3’ In the

Study on the Efficacy ofNosocomiab Infection Control

(SENIC), only 1 percent of the patients were treated

with continuous ventilatory support, but the rate of

pneumonia was 21-fold higher than patients who were

not receiving mechanical ventilation)’�

Gram-negative bacilli, such as Escherichia coli,

Kkbsiella pneumoniae, and Pseudomonas aeruginosa

are the most common types of bacteria causing noso-

comial pneumonia. Staphylococcus aureu.s�, which can

be methicillin-sensitive or resistant, accounts for a

large portion of hospital-acquired pneumonia in

some hospitals. Nosocornial pneumonia due to Le-

gionella pneumophila has been reported in certain

geographic areas such as Pittsburgh, Burlington (Ver-

mont), and Los Angeles. These infections are usualby

associated with cooling-tower reservoirs or hospital

water which is heavily colonized with the organism.

Anaerobes have been cultured from approximately 30

percent of infected patients, but appear to be less

important than aerobic pathogens. Most nosocomiab

pneumonias are caused by more than one pathogen.

Fatality rates for patients with nosocomial pneu-

monia remain high in many series.� Nosocomial

pneumonia contributed to 60 percent of the fatal

nosocomial infections in a study of 200 consecutive

hospital deaths by Gross et al.�’ Stevens et alM reported

fatality rates of 50 percent for intensive care unit

patients with hospital-acquired pneumonia compared

to 3.5 percent of patients without pneumonia and

rates were higher for patients infected with Pseudo-

monas aeruginosa. In our study of 233 mechanicabby

ventilated patients, there was a 55 percent fatality rate

for patients with pneumonia compared to a rate of 25

percent for patients without pneumonia)’� These data

underscore the need for earlier recognition, treat-

ment, and prevention.

Dr. Niederinan: What are some of the risk factors for

nosocomial pneumonia?

Dr. Craven: Aspiration ofbacteria from the oropharynx

is the primary route of entry into the lung, and a

number of factors affect the type and number of

bacteria that colonize the oropharynx.�’� Most of us

aspirate bacteria into our lower airways daily, but

pneumonia does not devebop)’#{176} The development of

pneumonia is not only related to the numbers and

types ofbacteria that are aspirated, but also ability of

the lung’s mechanical, humorab, and cellular defenses

to contain and prevent infection.



176 Pneumonia in CritiCally iii HOspitaliZed Patient (Niede,’man at a!)

Table 2-Factors That May increase the Risk of Nosocomial

Pneumonia by Aliering Colonization, Increasing the Risk ofAspiration, or impairing Host Defenses

Host factors:

Age

Obesity

Coma

Underlying disease-(chronic lung disease, congestive heart failure,

diabetes mellitus, AIDS, systemic lupus, cancer, central nervous

system diseases, seizures, head trauma, uremia, malnutritionDrugs:

Heroin, cocaine, alcohol, sedatives, antibiotics, antacids, histamine

type-2 blockers, steroids, cytotoxic drugs

Invasive Devices:

Intubation, tracheostomy, mechanical ventilation, nasogastnc tube

Surgery:Head and neck, chest, abdomen

Risk factors that may increase the risk of nosocomial

pneumonia are summarized in Table 2. Host factors

such as age and underlying disease may either allow

more bacteria to enter the lung or impair removal of

bacteria by various pulmonary host defense mecha-

nisms. Drugs or medications may either alter con-

sciousness or promote infection by impairing removal

of pathogens from the lung. Invasive devices and

surgery increase the risk of aspiration or removal of

bacteria from the lung.

As mentioned, the use ofan endotracheal tube may

increase the risk of nosocomial pneumonia at least 6-

to 21-fold compared to nonintubated patients.31’�

The presence of the endotracheal tube impairs re-

moval of bacteria, allows leakage of pathogens around

the cuff, and causes local trauma and inflammation

(Table 3). The upper part of the tracheobronchial tree

contains heavily ciliated epithebium and mucus that

can trap and clear bacteria from the lung. The cilia

beat hundreds oftimes per minute, in unison, to move

mucus and bacteria out ofthe trachea. Colonization of

the tracheobronchial tree may decrease or alter this

Table 3-Effect ofintubation on OropharyngealCOlonization and the Ibthogenesis of Pneumonia

Endotracheal Tube:

-bypasses nasopharynx and mechanical trapping of particles-impairs normal temperature and humidity of air

-acts as a foreign body and produces local trauma

-impairs cillary clearance and natural removal of secretions

-impairs swallowing-changes mouth flora-cuffleaks contaminated secretions from the oropharynx

-nasotracheal tube may cause sinusitis

-allows organisms to directly reach the lung

Nasogastric Tube:

-foreign body that impairs swallowing

-causes stagnation oforopharyngeal secretions

-increases reflux through lower esophageal sphincter

-acts as a conduit for bacterial migration

�-: may increase risk of sinusitis

activity, and increase the number of pathogens to be

cleared by alveolar macrophages, polymorpho- nuclear

leukocytes, humoral antibodies (1gM, IgG, IgA), and

complement. In addition, the endotracheal tube can

impair swallowing, and alter the host’s diet and thus

his intestinal flora. The use of a nasogastric tube is

also a widely unappreciated risk factor for pneumo-

nia,u� that may increase the risk of nosocomial pneu-

monia by several different mechanisms (Table 3).

Dr. Niederman: Dr Craven, could �pu comment on the

role ofrespiratory therapy equipment in the pathogen-

esis of pneumonia?

Di� Craven: When a patient is mechanically ventilated,

the bower respiratory tract may become colonized

more readily with bacteria. In the 1960s, the Dallas

group reported that ventilators with contaminated

mainstream nebulizers could generate bacterial aero-

sobs that infiltrated the terminal bronchioles and

alveoli, resulting in a necrotizing Gram-negative pneu-

monia.�#{176}’6’Most ventibators now heat and humidify the

inspiratory phase gas with humidifiers that do not

generate significant bacterial aerosols.

While ventilators rarely infect patients, secretions

from patients are a common source of bacterial con-

tamination of the mechanical ventilator tubing and

condensate present in the tubing.t1� If the condensate

is inadvertenfly flushed back into the patient, pneu-

monia can result, because the patient receives a large

inocubum of bacteria in a volume of fluid which can

be inoculated directly into the lungs, thereby over-

whelming host defenses. Several devices have been

advocated to remove condensate from the circuit. One

of these devices, the heat moisture exchanger, elimi-

nates the condensate problem, but may not provide

optimal humidity to the patient.6”M

In-line medication nebulizers are a potential source

ofbacterial aerosols that may penetrate to the terminal

bronchioles and avoid host defenses. These devices

may become contaminated by reflux of condensate

from the tubing. Humidifying cascades appear to be

un unbikely risk factor for pneumonia and ventilator

circuit coIonization.� Humidifying cascades should be

filled with sterile water and because of the high

temperature in the cascade, bacterial growth of the

most nosocomiab pathogens is limited.

Dr. Niederman: Please explain how gastric colonization

may serve as a risk factor for pneumonia and discuss

how we could approach intestinal bleeding prophylaxis

so as to minimize pneumonia risk.

Dr. Craven: First, bet me briefly discuss the subject

of stress ulcer prophylaxis. In contrast to the 1970s,

when stress bleeding was a serious complication for

intensive care patients, the incidence in the 1980s

appears to be less frequent, perhaps because of

improvements in mechanical ventilation, nutritional

support, and early treatment ofshock. For this reason,




it is critical to carefully assess the needs of each

specific patient and the risk-benefit ratio of any pro-

phylactic agent.

Many critically ill patients receive prophylaxis

against stress bleeding with antacids which may neu-

tralize gastric acid or H2-blockers that block gastric

acid secretion.#{176}� Antacids and/or H2-blockers such

as cimetidine and ranitidine have been used for

prophylaxis against stress bleeding in critically ill

patients with variable effectiveness. The efficacy de-

pends on the criteria used to assess stress bleeding,

the doses administered, and the patient population

studied.� Antacids have been most effective in

studies where they were administered every 2 hours

to maintain gastric pH above 3#{149}5#{149}�,67 H2-blockers have

been most effective in earlier studies ofstress bleeding

prophybaxis, and for critical care patients who have a

moderate risk of bleeding.�’� When macroscopic

bleeding is used as the criterion for efficacy and when

combining results of all studies, antacids and H2-

blockers appear to have similar efficacy and appear

more effective than placebo.�

Prophylaxis against stress bleeding can also be

achieved with sucrose octasulfate which acts by a

different mechanism. In contrast to the potential

effects of antacids and H2-blockers on gastric pH,

sucrose octasulfate (sucralfate) activity is independent

ofhydrogen diffusion or neutralization.m70 In addition,

sucralfate has littbe buffering capacity and appears to

act by adhesion to the mucosa, altering gastric mucus,

increasing PGE2 in the gastriclumen, and by absorbing

pepsin. In studies reported to date, sucralfate appears

to provide protection against stress bleeding that is

similar to antacids and H2-blockers.�’7#{176} Although

suspensions ofsucralfate are only available in Europe,

a useable preparation for critically ill patients can be

made by putting the tablet in solution, making a

suspension, and then flushing it down the nasogastric

tube.7’ It is very important that the sucralfate tablet

not be crushed before adding the saline solution or

sterile water, and that the nasogastric tube be flushed

after the sucralfate is given, to avoid clogging the tube.

Let me now briefly discuss the role of nasogastric

tubes and gastric colonization in the pathogenesis of

oropharyngeal colonization and pneumonia. Gastric

colonization may be an important prerequisite for

retrograde colonization of the oropharynx and the

development of nosocomial pneumonia. The bacteri-

cidal activity of hydrochloric acid (pH-i) and gastric

secretions was first demonstrated in 1939 by Garrod.72

Normally, the stomach maintains near-sterility by its

acid pH. Changes in the gastric flora may occur in

patients with increased age,73 malnutrition,74 achbor-

hydria,�’76 or other gastrointestinal diseases.�

Reduced gastric acid in the intubated intensive care

unit patients may result from intrinsic disease of

gastric acid production or from the use of antacids or

histamine type 2-blockers which neutralize or block

gastric acid secretion. Correlation between levels of

bacteria in the gastric juice and treatment of patients

with peptic ulcer disease with cimetidine was reported

by Ruddebb et �

du Moulin et � described gastric overgrowth with

Gram-negative bacilli in mechanically ventilated pa-

tients and related these finding to increasing the gastric

pH . These observations have been corroborated by

other investigators.57’� The level ofgastnc overgrowth

noted in critically ill ventilated patients is a concern.

Some patients with high gastric pH had colonization

with Gram-negative bacilli that reached 100 million

organisms/mb. Colonization was usually considerably

lower when the pH was less than 3.5. Gastric over-

growth with aerobic Gram-negative bacilli was most

common,m’�’�’�#{176} but high numbers of Gram-positive

bacteria and fungi may occur as

Several investigators have studied the time se-

quence of cobonization)”�’57’79’�#{176} du Moulin et alas

showed that 52 of 58 post-surgical patients with

respiratory failure had gastric and/or tracheal coboni-

zation with Gram-negative bacilli and a clear sequence

of transmission could be demonstrated in 17 of 52

patients. In 11 (65 percent of the patients), gastrjc

colonization preceded tracheal colonization. In a sim-

ilar study, using pharyngeal and gastric specimens

from 40 medical and surgical patients, Goularte et al�

showed a clear sequence ofcobonization in ten patients

in whom four (40 percent) had gastric colonization

that preceded colonization of the pharynx. Daschner

et � reported retrograde colonization of the trachea

from the stomach in 32 percent of 142 patients who

were receiving stress ulcer prophylaxis and mechani-

cal ventilation. When a nasogastric tube is in place, it

may facilitate the transfer ofbacteria from a colonized

stomach to the oropharynx and organisms may then

be aspirated into the lung.

The possible robe of gastric colonization in the

pathogenesis of pneumonia was supported in our

prospective study of risk factors for pneumonia in

mechanically ventilated patients)’�’ Overall, 21 percent

of the 233 patients receiving mechanical ventilation

developed pneumonia. Pneumonia occurred in 38

percent of 18 patients who received antacids and

cimetidine, 36 percent of 48 patients who received

cimetidine alone, and in 18 percent of 135 patients

who received antacids alone. Although the numbers

ofpatients with pneumonia in each group were small,

H2-blockers with and without antacids were inde-

pendently associated with the development of pneu-

monia (p = .01).

In a study of 153 critical care patients receiving

antacids and/or cimetidine therapy, Donowitz et al�#{176}

showed that 59 percent of gastric cultures with a pH



178 Pneumonia in CritiCally III Hospitalized Patient (Niederman eta!)

of �4 were positive for Gram-negative bacilli. In

contrast, only 14 percent of gastric cultures at a pH

�4 were positive for these organisms (p <.001). As

gastric pH increased, the proportion of specimens

with Gram-negative bacilli rose, and those with normal

flora decreased.

A more recent report of nosocomial pneumonia in

mechanically ventilated patients receiving prophylaxis

against stress bleeding concluded that rates of pneu-

monia directly correlated with increasing gastric pH)’�

In patients whose gastric pH was <3.4, the rate of

pneumonia was 41 percent compared to a rate of 69

percent in patients who had a pH >5.0.

Tube feeding and aspiration is particularly common

in critically ilb patients. Enteral feeding and prepara-

tions have a pH range from 6.4 to 7.0. Pingbeton et

at” demonstrated gastric colonization in 100 percent

ofventilated patients receiving enteral feeding without

antacid or H2-blocker therapy, and 1 1 (63 percent)

subsequently developed nosocomial pneumonia.

Two recent randomized trials81,�3�� of mechanically

ventilated intensive care unit patients given stress

ulcer prophylaxis with sucralfate compared to conven-

tional agents, found lower rates of pneumonia in

patients given sucralfate. In Tryba’s study,8’ rates of

pneumonia were increased 3-fold for patients receiv-

ing antacids compared to those given sucralfate. In

the study by Driks et al,� 61 patients were randomized

to sucralfate and 69 patients to conventional therapy;

antacids (N = 39), H2-blockers (N = 17), and antacids

and H2-blockers (N = 13). Rates of pneumonia were

12 percent in the sucralfate group compared to 23

percent for patients treated with antacids and/or H2-

blockers. Of note, pneumonia occurred in only 1 of

the 17 patients who received an H2-blocker alone as

prophylaxis against stress bleeding. The low rate of

pneumonia in the H2-blocker alone group suggests

the need for additional randomized trials to assess risk

and benefit compared to sucralfate. The H2-blocker

group was comprised mostly of medical intensive care

unit patients who may be at less risk for pneumonia.

Driks et al82 also reported that qualitative and

quantitative gastric colonization with Gram-negative

bacilli was significantly bower in patients given sucral-

fate compared to patients given conventional therapy.

Laggener et al� also reported colonization was signif-

icantly lower in the patients who received sucralfate

compared to patients who were treated with raniti-

dine)’�’ Although the changes in gastric colonization

were most likely rebated to gastric pH, two recent

reports have suggested that sucralfate may have intrin-

sic bactericidal activity)’�’M

Dr. Niederman: In addition to careful attention to

gastrointestinal bleeding prophylaxis, how can pneu-

monia be prevented in patients at risk?

Dr. Craven: Another approach to the prevention of

pneumonia and other nosocomial infections has been

selective decontamination ofthe trachea, oropharynx,

and gastrointestinal tract with antobiotics. Stouten-

beek et ab”� applied polymyxin B, tobramycin, and

amphotericin B (PTA) paste four times daily in the

oropharnyx, along with the use of a solution of these

antibiotics given via the nasogastric tube to eliminate

colonization in the stomach and upper gastrointestinal

tract. Systemic cefotaxime was also administered for

variable periods to treat incubating infections. Using

this regimen, nosocomial infections were reduced

from 81 percent in 59 historic control subjects to 16

percent in 63 patients receiving the prophylactic

antibiotic regimen, and “respiratory tract infection”

was reduced from 59 percent in the control group

compared to 8 percent for patients receiving prophy-

laxis,

Unertb et al� administered a solution of polymyxin

B, gentamicin, and amphotericin B to the nose,

oropharynx, and stomach of 19 intubated patients who

were expected to receive more than six days of

mechanical ventilation and compared infection rates

to 20 control patients. Colonization of the oropharynxand trachea were significantly bower (p <.001) in the

group given antibiotic prophylaxis. Nine cases of

pneumonia were identified in the control group com-

pared to one case in the group given antibiotic

prophylaxis.

In a more recent study ofintensive care unit patients

by Ledingham et al,� selective decontamination with

a regimen similar to that of Stoutenbeek et al reduced

the number of respiratory infections 6-fold compared

to historic control subjects (18 vs 3). There was also a

significant reduction in the colonization rates with

aerobic Gram-negative bacilli in the oropharynx and

rectum of patients given prophylaxis compared to

historical controls.

Flaherty et al� randomized patients in a cardiac

intensive care unit to receive sucralfate compared

with selective decontamination of the oropharynx and

stomach with gentamicin, nystatin, and polymyxin; no

systemic third generation cephalosporin was included.

Overall, rates of infection were 27 percent in the

sucralfate group vs 12 percent in the selective decon-

tamination group. Overall, there were five eposides of

pneumonia in the sucralfate group compared to one

in the antibiotic prophylaxis group. Patients in the

sucralfate group had three Gram-negative pneumonias

compared to none in the antiobiotic group. Although

there were no significant differences in ICU stay or

fatality rates, antibiotic use was increased 3-fold in the

sucralfate group. Antibiotic resistance was not ob-

served, but the duration ofthe study was short.

With the exception of the study of Flaherty et al,m

most of the data on selective decontamination of the

oropharynx and gastrointestinal tract has been tried




in multiple trauma patients with results compared to

historic controls. Of note is the absence ofany change

in fatality rates despite the marked decrease in noso-

comial infections. In addition, it is not clear if selective

decontamination will be applicable to chronically ill

patients who may develop colonization with more

resistant nosocomial pathogens. Although the selection

of antibiotic-resistant organisms was not encountered

in these studies, more data collected over a longer

time period are needed to definitively assess the risks,

benefits, and cost effectiveness of antibiotic prophy-

laxis in the intensive care unit patient.

ACKNOWLEDGMENT: The authors thank Ms. Ellen Maye forsecretarial assistance in preparing this manuscript.

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DOI 10.1378/chest.97.1.170 1990;97; 170-181Chest

M S Niederman, D E Craven, A M Fein and D E SchultzPneumonia in the critically ill hospitalized patient.

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