EXPERIENCE AND REASON |
Bile Acid Pneumonia: A "New" Form of Neonatal Respiratory Distress Syndrome?
* From the Division of Neonatology, Catholic University of the Sacred Heart, Rome, Italy
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSDISCUSSIONREFERENCES |
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We describe 3 cases of neonatal respiratory distress syndrome (RDS) in near-term infants, born from mothers with severe intrahepatic cholestasis of pregnancy. Common pictures of the cases were: good indices of lung maturity in the amniotic fluid; severe RDS requiring mechanical ventilation; high serum bile acid (BA) levels in the early days of life; no meconium aspiration; negative cultures; and absence of indirect laboratory signs of infection. After the first case, we hypothesized that abnormally high BA levels could have reversed the action of phospholipase A2 in the lungs, causing a degradation of phosphatidylcholines to lysophosphatidylcholines and the consequent lack of surfactant activity, leading to the severe respiratory distress. Consequently, in cases 2 and 3, we gave intratracheal surfactant to the infants, which, although administered around the first 24 hours of life, showed to be helpful. Our experience suggests that a high level of attention in the management of newborn infants (even near-term infants) born from women with intrahepatic cholestasis of pregnancy is necessary to detect as soon as possible signs and symptoms of this "unexpected" RDS, which can assume a very severe clinical picture. In such instances, we recommend that the diagnosis of BA pneumonia be kept in mind and that exogenous surfactant be given as soon as possible, even in the presence of indices of normal lung maturity in the amniotic fluid. Finding high levels of BA and lysophosphatidylcholines in the bronchoalveolar lavage of affected infants would aid in support of the diagnosis.
Key Words: intrahepatic cholestasis of pregnancy • neonatal RDS • respiratory distress syndrome • surfactant • bile acid pneumonia
Abbreviations: ICP, intrahepatic cholestasis of pregnancy • BA, bile acid • RDS, respiratory distress syndrome • L/S, lecithin/sphingomyelin • BAL, bronchoalveolar lavage
Intrahepatic cholestasis of pregnancy (ICP) is a clinical syndrome of unknown pathophysiology, characterized by generalized pruritus and biochemical cholestasis, occurring late during pregnancy and persisting until delivery. ICP may seriously impair the placental clearance of fetal bile acid (BA), leading to a dangerous accumulation of these compounds within the fetus and the newborn. This syndrome has been associated with increased fetal distress, premature delivery, perinatal mortality, and morbidity. No adverse outcomes have been reported in the newborn, apart from 1 infant dead in the first hour after birth from asphyxia.1–5
We describe 3 cases of respiratory distress syndrome (RDS) in near-term newborn infants in which the most common etiologies were excluded and a causative role of BA was supposed, leading to the diagnosis of "BA pneumonia." Pathophysiology and treatment of this condition are discussed briefly.
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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Case 1
A male infant weighing 3230 g was delivered by elective cesarean section at 37 weeks’ gestation from a woman in which ICP was diagnosed at the 34th week of gestation. The lecithin/sphingomyelin (L/S) ratio in the amniotic fluid was >2:1, and the serum BA level in the mother was 14.8 µmol/L at the time of delivery. The infant had a good cardiorespiratory adaptation, and Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. During the first 3 hours of life, signs of respiratory distress appeared, and the infant required oxygen administration up to 50% to achieve a normal arterial oxygenation. Progressive worsening of the RDS and deterioration of general conditions occurred in the following 12 hours of life, leading to the application of nasal continuous positive airway pressure. Cultures were taken from blood, cerebrospinal fluid, and urine, and antibiotic treatment with amikacin and ampicillin was commenced immediately in the suspect of sepsis with pneumonia. Complete blood count revealed normal white cell and platelet levels. At 48 hours of life, the infant needed to be intubated because of severe blood gas impairment with carbon dioxide retention. Bronchoalveolar lavage (BAL) was performed, and a specimen was sent to the laboratory for culture. Mechanical ventilation was started with a respiratory rate of 60 per minute, a peak pressure of 30 cm H2O, a positive end-expiratory pressure of 4 cm H2O, and 100% oxygen concentration. Systemic hypotension required dopamine administration, whereas inhaled nitric-oxide therapy at 20 ppm was commenced in view of the severe pulmonary hypertension as demonstrated by echocardiography. The serum BA level in the infant was 120 µmol/L at this time. Figure 1 shows the radiograph appearance at the moment of the maximum respiratory support. At 72 hours, nitric-oxide concentration was raised to 25 ppm and the fraction of inspired oxygen was lowered to 0.25. The serum BA level was still high at 62 µmol/L. Cardiorespiratory function progressively improved during the subsequent 2 days, ventilatory support was reduced, and both dopamine and nitric-oxide treatment were stopped. At 6 days of age, the infant was extubated to room air and had a normal radiograph and echocardiography. All the cultures, including the arterial catheter tip and BAL, were negative, and the white blood cell levels were always in the normal range, as were the C-reactive protein levels.
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Case 2
A female infant weighing 3010 g was born at 36 weeks’ gestation by cesarean section performed in a woman with ICP initially diagnosed at the 32nd week of gestation. The L/S ratio in the amniotic fluid was >2:1, and the serum BA level in the mother was 15.8 µmol/L at the time of delivery. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. During the first 2 hours of life, the infant developed tachypnea, grunting, and retraction. On auscultation of the lungs there were rales and poor air entry, and a radiograph showed diffuse density of the lung fields similar to that of case 1. The oxygen requirement to maintain a satisfactory arterial PaO2 increased up to 75%. At 2 hours of life, the infant was intubated and mechanical ventilation was started with a respiratory rate of 40 per minute, a peak pressure of 25 cm H2O, a positive end-expiratory pressure of 2 cm H2O, and 75% oxygen concentration. Cultures were taken from blood, cerebrospinal fluid, urine, and BAL, and antibiotic treatment (amikacin and ampicillin) was commenced. On day 2, ventilatory support had to be increased, with a respiratory rate of 40 per minute, a peak pressure of 35 cm H2O, positive end-expiratory pressure of 2 cm H2O, and 100% oxygen concentration. Echocardiography did not show signs of pulmonary hypertension, and the serum BA level in the infant was 85 µmol/L. Surfactant (Curosurf, Chiesi Farmaceutici, Parma, Italy) was given intratracheally at the dosage of 100 mg/kg of body weight, causing a decrease of the oxygen requirement to 50%. A second dose of surfactant was administered 24 hours later and allowed a significant reduction of the ventilatory support (peak pressure lowered to 22 cm H2O, and fraction of inspired oxygen decreased to 0.25). At 4 days of age, the infant was extubated to room air after a normal radiograph. In this case, as in the previous one, all the cultures (blood, cerebrospinal fluid, urine, BAL, and arterial catheter tip) were negative. White blood cell and C-reactive protein levels were always in the normal range.
Case 3
A male infant weighing 3490 g was born by vaginal delivery at 37 weeks’ gestation from a woman in which ICP was diagnosed at the 36th week of gestation. The L/S ratio in the amniotic fluid was >2:1, and the serum BA level in the mother was 46.5 µmol/L at the time of delivery. Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. During the first 4 hours of life, signs of mild respiratory distress appeared, requiring oxygen administration up to 30% to achieve a normal arterial oxygenation. Progressive worsening of the RDS with carbon dioxide retention and deterioration of general conditions occurred, and the infant needed to be intubated at 24 hours of life. Sepsis with pneumonia was suspected, and thus cultures were taken from blood, urine, and BAL, and antibiotic treatment with amikacin and ampicillin was commenced. A complete blood count revealed normal white cell and platelet levels. Radiograph appearance was similar to that of previous cases. Mechanical ventilation was started with a respiratory rate of 60 per minute, a peak pressure of 20 cm H2O, a positive end-expiratory pressure of 2 cm H2O, and 100% oxygen concentration. The serum BA level in the infant was 68.5 µmol/L. Surfactant was given intratracheally at the dosage of 100 mg/kg of body weight, and dexamethasone was started to reduce the lung inflammation.
On day 3, respiratory conditions worsened, requiring very aggressive ventilatory support with a respiratory rate of 80 per minute, a peak pressure of 40 cm H2O, a positive end-expiratory pressure of 0 cm H2O, and 100% oxygen concentration. A second dose of surfactant (100 mg/kg) was administered, and inhaled nitric-oxide therapy at 40 ppm was commenced because of severe pulmonary hypertension diagnosed by echocardiography, with a consequent significant reduction of the ventilatory support. Cardiorespiratory function progressively improved during the subsequent 2 days, ventilatory support was reduced, nitric-oxide treatment was stopped, and the infant was extubated to room air and had a normal radiograph and echocardiography at the age of 5 days. In this case, as well as in the other 2, cultures and indirect signs of infection were always negative.
A comparison of the 3 cases is reported in Table 1.
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DISCUSSION |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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ICP is a clinical syndrome of unknown pathophysiology, characterized by generalized pruritus with or without jaundice and biochemical cholestasis, which begins in the latter half of pregnancy and resolves in the puerperium. It seems to have a geographical variation, occurring commonly in Scandinavia and Chile,6,7 occasionally in China and Australia,8,9 and rarely in other countries. This syndrome has been associated with increased fetal distress, premature delivery, and perinatal mortality and morbidity, but no adverse outcomes have been reported in the newborn, apart from 1 infant dead in the first hour after birth from asphyxia.1–3 Intensive fetal surveillance and a policy of induction at term or with a mature L/S ratio may reduce the stillbirth rate.
The fetus synthesizes large amounts of BA that cross the placenta in the fetus-to-mother direction, and the serum concentration of BA in the fetus is controlled by this placental transfer system.10 The usefulness of BA determination is limited by lack of data on normal values in children, especially neonates and preterm infants. Feldmann et al,11 using spectrofluorometry, reported high values of BA in 15 premature infants (19.6 ± 10.4 µmol/L). More recently, Polkowska et al12 measured BA concentration using an enzymatic-colorimetric test in 278 children from 1 day to 16 years of age and found higher concentrations in newborns (19.6 ± 5.2 µmol/L), compared with adults (5.1 ± 2.9 µmol/L). Moreover, ICP may seriously impair the placental clearance of fetal BA, leading to a dangerous accumulation of these compounds within the fetus and the newborn. Considering our 3 cases, BA levels in each infant were substantially higher than in the mother.
The effect of BA on the lung could be due to bile aspiration or the uptake from the circulation. Bile aspiration produces a severe chemical pneumonitis in a porcine lung model,13 and intratracheally injected BA has been shown to produce severe pulmonary edema in rabbits.14 Kaneko et al15 studied intratracheal instillation of taurocholic acid in rabbits and found microscopic findings of widespread atelectasis, pooling of eosinophilic substances in the intra-alveolar spaces, and formation of hyaline membrane. The authors speculated that surfactant activity was inhibited by BA, because when 10 rabbits were treated additionally with surfactant, their alveoli were found to be well aerated, had a uniform expansion pattern, and nearly intact alveolar epithelial lining. More recently, Hills et al16 performed BAL during necropsy on 12 infants (average age: 3.1 months) and found lower phospholipid and higher BA levels in 6 sudden infant death syndrome cases, suggesting an association of bile salt with surfactant, possibly mediated by the role of phospholipase A2. Phospholipase A2 plays an important role in the synthesis of surfactant in the lung, but in the gut this enzyme hydrolyzes long-chain phosphatidylcholines to their lysophosphatidylcholines, a reaction that is the reverse of what it induces in the lung. The direction in which the reaction proceeds is determined mainly by the bile/phospholipid ratio.
In our 3 cases of neonatal RDS, we made the diagnosis of BA pneumonia, because a causative role of BA was likely to be the main one. In fact, meconium aspiration syndrome was excluded on the basis of the absence of meconium staining of the amniotic fluid, the normal Apgar scores, and the radiograph appearance. "Classic" hyaline membrane disease was difficult to be diagnosed in near-term infants (gestational age: 36–37 weeks) with a good L/S ratio. Infective pneumonia was excluded by negative cultures and the absence of indirect laboratory signs of infection. We hypothesize that despite the mature pattern of the L/S ratio in the amniotic fluid, the presence of abnormally high BA levels could have reversed the action of phospholipase A2 in the alveoli of our infants, causing a degradation of phosphatidylcholines to lysophosphatidylcholines, the relative lack of surfactant activity, and the consequent RDS.
Our clinical approach to the first case did not consider this mechanism of action, but in the following 2 cases we gave surfactant to our infants, obtaining a complete resolution of the RDS 48 hours from the treatment. Unfortunately, high-performance liquid chromatography was not available in our unit, so we could not determine the lysophosphatidylcholines and BA content of BAL, and samples were only sent to the laboratory for cultures.
Current obstetrical management of women with ICP is based on intensive fetal surveillance and a policy of induction near term or with a mature L/S ratio to reduce the stillbirth rate. Such a strategy can produce an increased number of near-term newborn infants at risk to develop this "unexpected" RDS, which can assume a very severe clinical appearance. Our experience suggests that a high level of attention during the first hours of life in all newborn infants born from women with ICP is necessary to detect as soon as possible signs and symptoms of RDS. In cases of RDS, we recommend that the diagnosis of BA pneumonia be kept in mind and that exogenous surfactant be given as soon as possible, even in the presence of indices of normal lung maturity in the amniotic fluid. Finding high levels of BA and lysophosphatidylcholines in the BAL of affected infants would aid in support of the diagnosis.
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FOOTNOTES |
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Received for publication Jun 23, 2003; Accepted Oct 16, 2003.
Reprint requests to (E.Z.) Division of Neonatology, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Roma, Italy. E-mail: enrizecca{at}rm.unicatt.it
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics
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