Neonatal pneumonia

Neonatal pneumonia

Neonatal Pneumonia Jerome O. Klein, MD, and Elizabeth D. Barnett, MD Infectious pneumonias in the neonate can be acquired in utero, at the time of del...

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Neonatal Pneumonia Jerome O. Klein, MD, and Elizabeth D. Barnett, MD Infectious pneumonias in the neonate can be acquired in utero, at the time of delivery, in the nursery, or at home. The pneumonia may be part of a generalized disease or the major focus of disease. Signs of disease that should prompt consideration of specific causes include respiratory distress syndrome (group B Streptococcus), empyema, lung abscesses and pneumatoceles (Staphylococcus aureus), wheezing and signs of bronchiolitis (respiratory syncytial virus), and a whoop or staccato cough (Bordetella pertussis or Chlamydia trachomatis). We review current information about the microbiology, pathogenesis, clinical signs, diagnosis, and management of these and other pneumonias that affect the newborn infant. Optimal management of pneumonia in the neonate requires consideration of appropriate diagnostic techniques and presumptive therapy for the most likely cause of the disease.

Copyright 9 1998 by W.B. Saunders Company

nfectious pneumonias in the neonate can be classified into

Iof acquisition the following three categories based on the time and mode of infection: pneumonia acquired by the transplacental route as part of a generalized congenital disease, pneumonia acquired during delivery caused by organisms that colonize the birth canal, and pneumonia acquired after birth in the nursery or at home from human contacts or contaminated equipment. In addition, a noninfectious pneumonia with inflammatory reaction in the lung that is usually associated with fetal asphyxia may be diagnosed at autopsy. We discuss the microbiology and pathogenesis, clinical signs, diagnosis, and management of the infant who presents with pneumonia and the specific characteristics of organisms of importance, including group B Streptococcus, Staphylococcus aureus, genital mycoplasmas, Chlamydia trachomatis, respiratory synctial virus (RSV), and Mycobacterium tuberculosis.

Microbiology and Pathogenesis Pneumonia acquired by the transplacental route or during birth may be caused by the TORCH organisms (Toxoplasma gondii, rubella, cytomegalovirus, and herpes simplex virus), Treponema pallidum, Listeria mono~ytogenes, and rarely, Mycobacterium tuberculosis. The pneumonitis usually is part of a disseminated infection characterized by hepatosplenomegaly, lesions of the skin and mucous membranes, or meningoencephalitis. Features specific for the infection, such as chorioretinitis (rubella, T gondii), cataracts (rubella), vesicular skin lesions (herpes simplex), and swollen red hands and feet and dactylitis (Tpallidum), also may be present. From theBosto;zUniversi[ySchoolofMedicine,Boston,MA. Address correspondenceto Jerome O. Klein, MD, Department of Pediatrics, Boston Medical Center,Boston,MA 02118. Copyright9 19980y W.B. SaundersCompany 1045-1870/98/0903-000758.00/0 2 12

Organisms present in the maternal genital tract may be responsible for intrauterine pneumonia resulting from aspiration of infected amniotic fluid; these include genital mycoplasmas, C trachomatis, group B Streptococcus (GBS), and gramnegative enteric bacilli. In addition, invasive infection in the mother at the time of birth can result in transplacental hematogenous infection during or shortly before delivery. Organisms acquired in the nursery or at home include those caused by respiratory viruses (eg, RSV, adeno- or parainfluenza viruses), S aureus, and gram-negative enteric bacilli. Infections acquired in the nursery may be caused by droplets from the respiratory tracts of parents, nursery personnel, or other infants. Contaminated equipment or materials (eg, nebulization equipment, room humidifiers, and bathing solutions) have been implicated in common-source nursery outbreaks.

Clinical Manifestations The clinical manifestations of pneumonia in the neonate may be subtle and nonspecific at onset; specific signs of respiratory infection may not be evident until late in the course of the illness. Infants who acquire pneumonia during the birth process or postnatally may have signs of systemic illness, such as hyperor hypothermia, jaundice, hepatosplenomegaly, lethargy, irritability, anorexia, vomiting, abdominal distention, or fever. Signs of respiratory distress may be present at the onset of the illness or may develop later; these signs include tachypnea, dyspnea, grunting, coughing, flaring of the alae nasi, irregular respirations, cyanosis, costal and sternal retractions, rales, and decreased breath sounds. Infants with severe disease may have progression to apnea, shock, and respiratory failure. Signs of pleural effusion or empyema may be present in suppurative pneumonias caused by S aureus, groups A and B streptococci, and Escherichia coli and other gram-negative enteric bacilli. Important clues to the cause of respiratory distress may be obtained from maternal history and signs in the baby. Some of

Seminars in Pediatric Infectious Diseases, Vol 9, No 3 (Ju~), 1998: pp 212-216

Neonatal Pneumonia these features and the likely condition in the infant are listed in Tables 1 and 2. Disease manifestations in the lung may be associated with specific microbial agents. Respiratory distress syndrome may be caused by an infectious or noninfectious condition. These unique features of pneumonia and the associated organism are listed in Table 3.

Diagnosis Radiologic Diagnosis The chest radiograph of the infant with pneumonia may show varied presentations, including streaky densities, confluent opacities, and peribronchial thickening. Some patterns are associated with specific microorganisms (see Table 3). Pleural effusion, abscess cavities, and pneumatoceles are frequent in infants with staphylococcal infections, but they also may occur in pneumonia caused by group A Streptococcus, E coil, or Kleb~iellapneumoniae. Diffuse pulmonary granularity or air bronchograms similar to those observed in respiratory distress syndrome have been observed in infants with pneumonia related to GBS. Computed tomography with contrast is of benefit in localizing pulmonary lesions, such as lung abscess, and distinguishing abscess from empyema, pneumatoceles, or bronchopleural fistulas. Ultrasound may be used for prenatal diagnosis of pulmonary conditions such as diaphragmatic hernia or hydrothorax.

Microbiological Diagnosis The bacterial cause of pneumonia in young infants can be determined only by culture of material from a suppurative focus in the lower respiratory tree. Bacterial cultures of the throat and nasopharynx are not helpful and may be misleading because of the frequency of colonization with respiratory pathogens. Some infants have generalized infection, and cultures of blood or cerebrospinal fluid may yield the cause of the pneumonia. More invasive techniques may be required for the infant who is critically ill or unresponsive to initial therapy. Tracheal aspiration through a catheter may be valuable when performed by direct laryngoscopy, but the aspirate often is contaminated when the catheter is passed through the nose or mouth. Bronchoscopy can provide visual, cytological, and microbiological evidence of pneumonia and may be of therapeutic value in

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Table 2.

Clinical Signs Suggesting the Cause of Respiratory Distress in the Neonate

Sign Scaphoid abdomen Difficulty breathing with closed mouth Shift of apical pulse

Shrill cry Flaccidity Increased tone Frothy blood from larynx Choking after feedings

Disease Diaphragmatic hernia Choanal atresia Pneumothorax Situs inversus Hypoplastic lung CNS event (meningitis, hemorrhage) Pulmonary hemorrhage Tracheo-esophageal fistula

Abbreviation:CNS, central nervous system. removing mucopurulent secretions. If a pleural effusion is present and the bacterial diagnosis is not yet evident, thoracentesis should be performed. Lung biopsy may be appropriate when a tissue diagnosis is important. Aspiration of pulmonary exudate (lung puncture or lung tap) can provide direct, immediate, and unequivocal information about the causative agents of pneumonia.l Lung punctures in infants and young children were used frequently in the preantibiotic era, but they are unknown today to most pediatricians. The procedure should be considered in the case of the criticallyill infant for whom a specific causative diagnosis is important in guiding antimicrobial therapy.

Histological and Cytological Diagnosis Although bronchoscopic washings are of value for Gram stain and culture, material obtained by aspiration of stomach contents usually is not helpful in diagnosing the cause of pneumonia in the first 24 hours of life. The gastric contents, including material aspirated from the maternal birth canal, may suggest the identity of the microflora of the genital tract and also may show white blood cells present in areas of chorioamnionitis. After the first 24 hours, polyTnorphonuclear leukocytes are derived from swallowed bronchial secretions, and the Gram stain and smear may identify the presence of an inflammatory process and the likely organism.

Table 3.

Unique Features of Pneumonias in the Neonate

Feature Table 1. Clues to the Cause of Respiratory Distress in the Neonate: Information From the Maternal History

Probable Condition in Neonate Pneumonia

Hyaline membrane disease Tracheo-esophageal fistula Asphyxia in utero

Information From Maternal History Peripartum fever Prolonged duration of ruptured membranes Foul-smelling amniotic fluid Prematurity Diabetes Hydramnios Fetal tachy- or bradycardia Prolapsed cord

Hyaline membrane disease or respiratory distress syndrome Empyema Pneumatoceles Lung abscess Bronchiolitis Pneumonia alba (obliterative fibrosis of lung) Whoop or staccato cough

Microorganism GBS and Haemophilus injluenzae

Staphylococcus aureus Staphylococcus aureus Staphylococcus aureus KlebsieUapneumoniae RSV Treponemapallidum BordetelIapertussis Chlamydia trachomatis

Abbreviations:GBS, group B Streptococcus;RSV, respiratory syncytial virus.

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Choice of Antimicrobial Agents Because the bacteriology of pneumonia in the newborn infant is the same as that of sepsis, the guidelines for management are similar. Initial antimicrobial therapy should include a penicillin (penicillin G or ampicillin) or a penicillinase-resistant penicillin (if staphylococcal infection is a possibility) and an aminoglycoside or a third-generation cephalosporin. The initial therapy should be reevaluated when the results of cultures are available. If the maternal history or a prior history of conjunctivitis in the neonate or other clinical signs suggest that the pneumonia is caused by C trachomatis, oral erythromycin or sulfisoxazole should be initiated. Mycoplasma may be responsible for some cases of pneumonia in the newborn; if further data corroborate these organisms as important causes of neonatal pneumonia, physicians will need to reevaluate presumptive therapy with [3-1actam antibiotics and aminoglycosides alone; addition or substitution of a macrolide for ureaplasma or clindamycin for Mycoplasma hominis will need to be considered. The duration of therapy depends on the causative agent; pneumonia caused by gram-negative enteric bacilli or GBS is treated for 10 days; disease caused by S aureus requires 3 to 6 weeks of antimicrobial therapy according to the severity of the pneumonia and the initial response to therapy. When clinical and radiologic signs of hyaline membrane disease are present, infection caused by GBS or gram-negative organisms, including Haemophilus b~uenzae, may be present. Until techniques are developed that can distinguish infectious from noninfectious causes of respiratory distress syndrome, it is prudent to treat all infants who present with clinical and radiologic signs of the syndrome with antimicrobial agents.

GBS Pneumonia is a frequent focus of early-onset GBS sepsis and has been estimated to occur in 35 to 55 percent of cases; sepsis without a focus occurs in 25 to 40 percent; and meningitis occurs in 5 to 15 percent of early-onset sepsis. 2,a GBS frequently is found within the hyaline membranes. Invasion of alveolar pneumatocytes and capillary endothelial cells by GBS may result in exudation of plasma proteins into the alveoli, deposition of fibrin, and hyaline membrane formation.4 An alternative mechanism may be immune complex mediated injury to the lung associated with deposition of C3, IgG, and fibrin deposition in the lung) The pneumonia may be focal or extensive, lobular or bronchial, and involve one or many lobes. Interstial inflammatory exudate and progressive atelectasis may be prominent in patients surviving more than 20 hours. 4 Respiratory signs, including apnea, grunting, tachypnea, or cTanosis, occur in almost all infants with GBS pneumonia and some infants with early-onset disease without pneumonia. Radiologic signs of hyaline membrane disease are evident in more than one-half of the infants with GBS pulmonary disease. Signs that may distinguish GBS pneumonia with hyaline membranes from noninfectious respiratory distress syndrome include apnea and shock within the first 24 hours of life, 1 minute Apgar scores less than or equal to 5, cardiomegaly, pleural effusions, and rapid progression of the pulmonary disease. Unusual respiratory

manifestations of GBS infection include retropharyngeal abscess, tracheitis, epiglottitis, and empyema. GBS are uniformly susceptible to all penicillins and cephalosporins (with the exception of a few strains that are relatively resistant to cefoxitin). Although in vitro data indicate synergy of a [3-1aetam drug and an aminoglycoside (usually gentamicin), no human data corroborate the in vitro activity. Because presumptive therapy for neonatal pneumonia or sepsis includes a [3-1actam and an aminoglycoside, the potential synergistic value is available to most infants who are documented to have GBS disease.

S aureus S aureus was a major cause of disease (frequently epidemic) in newborn nurseries in the 1950s to 1970s. Many nurseries throughout the United States were contaminated with a virulent staphylococcal phage type 80/81. Manifestations of infection included skin diseases (bullous impetigo, scalded skin syndrome, recurrent furunculosis, and abscesses), sepsis, osteomyelitis, arthritis, adenitis, and pneumonia. For reasons that remain unclear, suppurative disease caused by S aureus now is less common in the United States and Western Europe. Shinefield6 has suggested that newborn nurseries experience waves of staphylococcal epidemics that occur in 20-year cycles; although nurseries never are free completely of sporadic or endemic infections, disease usually is confined to the skin and is not severe. Staphylococcal pneumonia may occur by contiguous spread from infection in the upper respiratory tract or may occur as a secondary site after staphylococcal bacteremia. The aspirated bacteria may form microabscesses in the alveoli, may rupture through the pleura and result in empyema, and may occlude terminal bronchioles and lead to formation ofpneumatoceles. The clinical course is characterized by rapid onset of tachypnea and dyspnea, often after a mild upper respiratory infection. The infant is acutely ill, and paralytic ileus leading to abdominal distention is frequent. After clinical improvement, residual pulmonary abnormalities, such as pneumatoceles, are frequent and may persist for months in an asymptomatic patient. If staphylococcal disease is suspected, a penicillinaseresistant penicillin should be substituted for ampicillin or added to the initial regimen until results of culture and the clinical course suggest the causative agent. If the nursery recently has experienced disease caused by S aureus resistant to the penicillinase-resistant penicillins, vancomycin, a drug of uniform efficacy, should be used.

Mycoplasmal Infections The genital mycoplasmas, including Ureaplasma urealyticum and Mhominis, are present in many sexually active adults: mycoplasmas were isolated from the cervix or urine of more than 80 percent of pregnant women; U urea~ticum was isolated from cultures of 79 percent of women; Mhominis from 48 percent; and both species from 41 percent. 7 In the neonate, genital mycoplasmas are a likely cause of some cases of pneumonia; case reports indicate the organisms also may be responsible for meningitis, pericarditis, adenitis, and soft tissue abscesses. No evidence implicates Mycoplasma pneumoniae as a cause of lower respiratory tract infections or other disease in the neonate.

Neonatal Pneumonia The newborn infant is colonized by genital mycoplasmas during delivery. Mycoplasmas can be isolated from various skin and mucosal sites in up to 60 percent of newborn infants during the first weeks of life. Although many infants are colonized with genital mycoplasmas, few develop disease; however, mycoplasmas have been recovered from blood, urine, cerebrospinal fluid, pericardial fluid, abscesses, and infected lymph nodes. The role of genital mycoplasmas in neonatal pulmonary disease has been controversial because of the frequency of recovery of these organisms from the upper respiratory tract. The diagnostic dilemma is no different from the case with older infants and children from whom expectorated sputum from the lower respiratory tree is unavailable. Cassell and colleagues 8 summarized the following findings that suggest that U urealyticure is a cause of pneumonia in the fetus and newborn infant:

1. U urea[yticum has been isolated in pure culture from lung tissue at autopsy 2. Inflammatory changes compatible with pneumonia were shown in the lungs 3. Organisms have been identified by immunofluorescenceand electron microscopy in areas of pulmonary inflammation 4. U urea~ticum in the absence of other microorganisms has been isolated from endotracheal aspirates at birth from infants with radiologically defined respiratory disease 5. U urea~ticum has been isolated from pleural fluid 6. U urealyticum can induce ciliostasis in human fetal tracheal organ cultures, can induce proinflammatory cytokine release in neonatal pulmonary fibroblasts, and induces a significant increase in interleukins 6 and 8. In addition to the data about the association of genital mycoplasmas with acute lower respiratory tract infections, case reports 9 and population studies l~ suggest that these organisms may be responsible for chronic pulmonary" disease in very low-birth-weight infants. Isolation of U urea~ticum from endotracheal aspirates of infants with birth weights under 1,250 g within the first 24 hours of birth was associated with increased risk of broncbopulmonarydysplasia.11,12 The genital mycoplasmas are not susceptible to the usual antibiotic regimens prescribed for newborn sepsis, which include a [3-1actam and aminoglycoside antibiotics. Tetracyclines, macrolides, chloramphenicol, and some quinolones are effective, but they are drugs that are either used infrequently or contraindicated in the neonate. The macrolides, including clarithromycinand azithromycin, have in vitro activity against U urealyticum but not Mhominis; clindamycinis effective against M hominis but not U urea[yticum; tetracyelines and chloramphenicol are active against both genital mycoplasmas. If data from future studies identify mycoplasmas as causes of acute and chronic pulmonary disease (particularly in low-birth weight infants), studies of safety and efficacy will be needed to identify the optimal regimen for treatment.

Chlamydiae The chlamydiae comprise a unique group of obligate intracellular bacteria. C traehomatis (serotypes D-K) is responsible for neonatal disease, includinginclusionconjunctivitis and pneumonia of the newborn. Chlamydia pneumoniae is associated with

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atypical pneumonia, but no data exist to suggest that it is an important pathogen in the neonate. As is true of other organisms prevalent in the maternal genital tract, C trachomatis colonizes the infant during the birth process. C trachomatis is the most common sexually transmitted pathogen. The prevalence of chlamydial infection of the cervix in pregnant women in the United States is between 2 and 13 percent. The infant born to the infected woman is at 60 to 70 percent risk of acquiring infection during passage through the birth canal; approximately 20 to 50 percent of exposed infants develop conjunctivitis, and 10 to 20 percent develop pneumonia.~3 The respiratory illness in neonates caused by C trachomatis is apparent between the 2nd and 1lth weeks of life. The infants usually are afebrile or have low-grade fever. Upper respiratory tract signs include congestion and obstruction of the nasal passages and signs of acute otitis media. A history of conjunctivitis is obtained in approximately about one-half of the cases of pneumonia. Common respiratory signs include tachypnea and a paroxysmal staccato cough, which may simulate the whooping cough of pertussis. Rales but not wheezes usually are heard on auscultation. The chest radiograph findings include hyperexpansion of the lungs and bilateral interstitial infiltrates. The macrolides and sulfonamides are effective against C trachomatis; [3-1actamantibiotics and aminoglycosides are ineffective. Erythromycin and sulfisoxazole shorten the clinical course of pneumonia and decrease nasopharyngeal carriage of C trachomatis. 14Oral, but not topical, treatment of neonatal conjunctivitis eliminates the organism from the respiratory tract and prevents subsequent pneumonia.

RSV Although RSV is frequent in young infants and in adults, no evidence shows that disease in the neonate occurs in utero or during delivery. Infection in infancy occurs by direct contact from fomites or droplet spread from another infected individual. RSV is responsible for the majority of hospitalized cases of viral pneumonia in infants younger than 1 month of life. Nosocomial outbreaks have occurred in newborn nurseries, affecting premature and ill term infants. In the child's first month of life, the infection may be asymptomatic or manifest itself by an afebrile mild upper respiratory illness or a febrile illness with signs of bronchiolitis or pneumonia. Less commonly, adenoviruses and parainfluenza viruses can cause similar patterns of respiratory disease. Specific diagnosis of RSV infection should be sought so that a decision about instituting ribavMn therapy can be made. Ribavirin treatment for RSV infections remains controversial, but the Committee on Infectious Diseases of the American Academy of Pediatrics recommends that infants at risk should be considered for ribavirin aerosol therapy; these include infants younger than 6 weeks of age who are at risk for severe RSV illness. RSV immune globulin has been approved for prevention of RSV disease in children younger than 2 years of age with bronchopulmonary dysplasia or who were premature (younger than 35 weeks gestation). 15

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Tuberculosis Tuberculosis in the neonate can be acquired in utero from the infected placenta via the umbilical vein or by inhalation or ingestion of infected amniotic fluid. Neonatal tuberculosis can be acquired by inhalation or ingestion of infected droplets, by ingestion of infected human milk, or by contamination of traumatized skin or mucous membranes. Although congenital and postnatally-acquired tuberculosis are relatively rare, infants are highly susceptible and mortality is high in untreated infants. Appropriate diagnostic tests need to be considered in the infant born to an infected mother or in circumstances for which exposure to tuberculosis is likely. The onset of signs of disease in infants with congenital infection may occur within the first weeks of life, whereas onset of postnatally-acquired infection usually is after the first month. Systemic signs of congenital or postnatally-acquired tuberculosis include fever, hepatomegaly or splenomegaly, poor appetite, weight loss, lethargy, and lymphadenopathy, in addition to respiratory signs. Diagnosis of tuberculosis in the neonate usually is suggested by active pulmonary disease in the mother or a relative. The yield of M tuberculosis from various specimens in children with perinatal tuberculosis was described by Hageman and colleaguesl6: liver and lymph node biopsy were most sensitive (100%); gastric aspirate yielded diagnostic material in 83 percent of 12 cases; tracheal aspirate, bone marrow and urine also were useful sources for the recovery of acid-fast bacilli. The management of neonates after exposure in utero, in the nursery, and to a mother with a positive skin test was reviewed by Teele and Smith. 17 Although disease in the neonate is uncommon and comparative studies are unavailable, the usual antituberculous regimens, including isoniazid, riampin, and pyrazinamide, should be considered for the neonate and young infant.

References 1. KleinJO: Diagnostic lung puncture in the pneumonias of infants and children. Pediatrics 44:486-488, 1969 2. Anthony BF, Okada DM: The emergence of group B streptococci in infections of the newborn infant. Ann Rev Med 28:355-359 3. Baker CJ, Edwards MS: Group B streptococcal infections: Perinatal

impact and prevention methods. Ann NY Acad Sci 549:193-202, 1988 4. Katzenstein A, Davis C, Braude A: Pulmonary changes in neonatal sepsis due to group B beta-hemolytic streptococcus: Relation to hyaline membrane disease.J Infect Dis 133:430-435, 1976 5. Pinnas JL, Strunk RC, Fenton LJ: Immunofluorescence in group B streptococcal infection and idiopathic respiratory distress syndrome. Pediatrics 63:557-561, 1979 6. Shinefield HR: Staphylococcal infections, in Remington JS, Klein JO (eds): Infectious Diseases of the Fetus and Newborn Infant, (ed 4). Philadelphia, PA, Saunders, 1995, pp 1105-1141 7. Braun P, KleinJO, Lee YH, et al: Methodologic investigations and prevalence of genital mycoplasmas in pregnancy. J Infect Dis 121:391-400, 1970 8. Cassell GH, Waites KB, Crouse DT: Mycoplasma infections, in RemingtonJS, KleinJO (eds): Infectious Diseases of the Fetus and Newborn Infant, (ed 4). Philadelphia, PA, Sannders, 1995, pp 631656 9. Sanchez PJ, Regan JA: Ureaplasma urea~ticum colonization and chronic lung disease in low birth weight infants. Pediatr Infect DisJ 8:542-546, 1988 10. Wang EL, Cassell GH, Sanchez O, et al: Ureaplasma urea~ticum and chronic lung disease of prematurity; Critical appraisal of the literature on causation. Clin Infect Dis 17:S112-S115, 1993, (suppl 1) 11. Cassell GH, Crouse DT, Waites KB, et al: Does Ureaplasma urea~ticum cause respiratory disease in newborns? Pediatr Infect Dis J 7:535-541, 1988 12. Wang EE, Frayha H, Watts J, et al: The role of Ureaplasma urea~ticum and other pathogens in the development of chronic lung disease of prematurity. Pediatr Infect DisJ 7:547-551, 1988 13. SchachterJ, Grossman M: Chlamydia, in RemingtonJS, KleinJO (eds): Infectious Diseases of the Newborn Infant, (ed 4). Philadelphia, PA, Saunders, 1995, pp 657-667 14. Beem MO, Saxon EM, Tipple M: Treatment of chlamydial pneumonia in infancy. Pediatrics 109:653-655, 1986 15. American Academy of Pediatrics: Respiratory syncytial virus, in Peter G (ed): 1997 Red Book: Report of the Committee on Infectious Diseases, (ed 24). Elk Grove Village, IL, American Academy of Pediatrics, 1997, pp 443-447 16. HagemanJ, Shulman S, Schreiber M, et al: Congenital tuberculosis: Critical reappraisal of clinical findings and diagnostic procedures. Pediatrics 66:980-984, 1980 17. Smith MHD, Teele DW: Tuberculosis, in RemingtonJS, KleinJO (eds): Infectious Diseases of the Fetus and Newborn Infant, (ed 4). Philadelphia, PA, Saunders, 1995, pp 1082-1084