In a 29-day-old premature infant with respiratory syncytial virus (RSV) pneumonia, we have shown an additive effect of high-frequency oscillatory ventilation (HFOV) and continuous inhalation of prostacyclin (iPGI2) with improvement of ventilation and oxygenation. The addition of continuous inhaled iPGI2 to HFOV was beneficial in the treatment of hypoxemic respiratory failure owing to RSV-associated pneumonia. The improvement in alveolar recruitment by increasing lung expansion by HFOV along with less ventilation-perfusion mismatch by iPGI2 appears to be responsible for the synergistic effect and favorable clinical outcome. We conclude that the combined therapy of HFOV and continuous inhaled iPGI2 may be considered in RSV-associated hypoxemic respiratory failure in pediatric patients.
- HFOV —
- high-frequency oscillatory ventilation
- iPGI2 —
- inhaled prostacyclin
- OI —
- oxygenation index
- PGI2 —
- inhaled prostacyclin
- RSV —
- respiratory syncytial virus
For those infants who proceed to respiratory failure, a variety of treatment modalities have been postulated, including high-frequency oscillatory ventilation (HFOV), permissive hypercapnia, liquid ventilation, aerosolized ribavirin, nitric oxide inhalation, and extracorporeal membrane oxygenation.4–8
Previous evidence suggested improvement in oxygenation in severe respiratory failure on mechanical ventilation in the pediatric age group.9 We report a case of a premature infant with RSV-associated hypoxemic respiratory failure who had no improvement on a conventional mechanical ventilator and significant improvement in ventilation along with oxygenation on continuous inhaled prostacyclin (iPGI2) along with HFOV.
A 29-day-old premature female infant born at 34 weeks’ gestation who was not requiring supplemental oxygen before admission, presented with cough, coryzae, tachypnea, and respiratory distress to the emergency department of one of our peripheral hospitals. The infant was transferred to the pediatric floor at Sparrow Hospital, Lansing, Michigan, for further management and was diagnosed with RSV bronchiolitis. The patient tested positive for RSV antigen in nasopharyngeal secretions. This patient had not received palivizumab, as she was not eligible for prophylaxis as per the American Academy of Pediatrics criteria for prophylaxis.10
On admission, the patient was found to have respiratory distress in the form of tachypnea, retractions, and nasal flaring. She was tachycardic and her oxygen saturations were 93% on room air. Chest radiograph showed bilateral fluffy infiltrates.
The respiratory condition of the patient deteriorated and she required a higher oxygen supplementation. The infant was transferred to the PICU on day 2 of admission.
The patient was placed on nasal continuous positive airway pressure of 6 cm Hg and was started on intravenous antibiotics. The infant’s condition continued to deteriorate and the patient was placed on conventional mechanical ventilation on day 4 of admission at initial settings of FiO2 of 0.6, intermittent mandatory ventilation of 60, peak inspiratory pressure of 22 cm H2O, and positive end-expiratory pressure of 6 cm H2O. The initial arterial blood gas showed hypercapnia with Pco2 of 107 Torr and hypoxia with Po2 of 38 Torr.
The patient was not eligible to receive aerosolized ribavirin as per our hospital pharmacy guidelines for the treatment of RSV-associated pneumonia. These guidelines were based on previous studies that demonstrated that aerosolized ribavirin administration during mechanical ventilation to previously healthy full-term or premature infants with RSV-associated respiratory failure was not associated with reduction of mortality rate or duration of mechanical ventilation.11,12
On conventional mechanical ventilation, there was no clinical improvement and ventilatory settings were increased. The patient developed hypotension on day 5 of admission and dopamine was started.
The patient was given packed red blood cells for anemia (hemoglobin of 9 g). Antibiotics were continued for pneumonia. Conventional mechanical ventilation was continued on high settings for 6 days but repeated arterial blood gases showed respiratory acidosis along with hypoxemia. The oxygenation index (OI) increased from 19.5 to 26.0. Chest radiograph on day 9 of admission was suggestive of right upper lobe consolidation with atelectasis and bilateral streaky infiltrates, as seen in Fig 1.
The patient was started on HFOV on day 10 of admission because there was no improvement in the clinical condition. Oxygenation was marginal with an oxygenation index of 26 on HFOV.
On day 11 of admission, after carefully evaluating the risk and benefit ratio, the patient was started on iPGI2 as a rescue treatment.
This patient was started on iPGI2 because the patient was not eligible for inhaled nitric oxide use as per our institution guidelines for inhaled nitric oxide use in full-term and near-term neonates with pulmonary hypertension. In addition, there have been reports of successful use of iPGI2 for pulmonary hypertension in newborns and children.13–15
Parental consent was obtained and the patient was started on continuous iPGI2 (Epoprosteno sodium, Flolan, GlaxoSmithKline, Research Triangle Park, NC) at 30 ng/kg/min via Aeroneb micropump nebulizer (Aerogen, Mountain View, CA). The justification for this approach was poor oxygenation with rising OI and presumed ventilation-perfusion mismatch typically seen in severe cases of RSV-associated pneumonia. In addition, echocardiography was done 5 days before starting iPGI2, which showed tricuspid regurgitation, right ventricle systolic pressure of 28 mm Hg with flow across tricuspid valve of 1.19 m/s, along with mild pericardial effusion, mild pleural effusion, and no evidence of right to left shunting or decreased cardiac contractility.
After starting iPGI2 (Flolan), there was an immediate improvement in ventilation with gradual fall in Pco2. Oxygenation started to improve after 16 hours of continuous use of iPGI2 and there was a gradual decrease in OI as seen in Table 1. The FiO2 requirements also decreased to 0.4 at 32 hours after starting iPGI2.
A repeat chest radiograph was done, which showed significant improvement in the form of better lung expansion and decreasing atelectasis, as seen in Fig 2.
The weaning of iPGI2 was started 5 days later on day 16 of admission by 10 ng/kg/min every 8 hours and iPGI2 was completely stopped in 24 hours. The total duration of iPGI2 was 6 days. The patient continued on HFOV, after discontinuation of iPGI2. A repeat echocardiogram was done 4 days after starting iPGI2 and showed no significant tricuspid regurgitation. The flow across the tricuspid valve was lower at 1.08 m/s. Treatment with iPGI2 may have positive effects on pulmonary vasculature, which resulted in the disappearance of the tricuspid regurgitation jet.
Six hours after discontinuation of iPGI2, the Pco2 started rising and was 86 Torr at 12 hours; the Po2 started falling and FiO2 was increased from 0.4 to 0.6.
Subsequently, there was further respiratory status deterioration and iPGI2 inhalation was restarted.
The iPGI2 was restarted at 30 ng/kg/min. Within 2 hours, there was a significant decrease in Pco2 and in 6 hours there was an increase in Po2 along with clinical improvement in respiratory status. FiO2 was decreased to 0.4 and inhaled iPGI2 was continued.
On day 20 of admission, the patient was weaned to conventional mechanical ventilation. Initial ventilatory settings were peak inspiratory pressure/positive end-expiratory pressure 27/8, intermittent mandatory ventilation 35 at FiO2 of 0.45.
The iPGI2 was continued at 30 ng/kg/min. While on conventional mechanical ventilator, iPGI2 was delivered by using the Mini-Heart Low-Flow Nebulizer (Westmed, Tucson, AZ) and gradually ventilator settings were weaned over next 3 days.
Weaning of iPGI2 was started again on day 23 of admission at the rate of 10 ng/kg/min every 8 hours and completely stopped in 24 hours on day 24 of admission. On day 25, the patient was weaned off the ventilator to a high-flow nasal cannula. The patient showed significant clinical improvement and was gradually weaned to room air over next 8 days by day 33 of admission. The total duration of hospital stay was 35 days.
Prostacyclin (PGI2) is an arachidonic acid metabolite formed by prostacyclin synthetase in the vascular endothelial cells, including pulmonary vascular endothelium. It mediates pulmonary vasodilatation by binding and activating adenylate cyclase and increases production of intracellular cyclic adenosine monophosphate, which leads to the relaxation of vascular smooth muscle cells. PGI2 is spontaneously hydrolyzed to the nonactive metabolite, 6-keto-prostaglanding-F1α, at physiologic pH in plasma with a half-life of 2 to 3 minutes and thereby limiting systemic effects when delivered as an inhalation drug. When infused directly into the pulmonary vasculature, PGI2 demonstrated remarkable pulmonary vasodilatation. Intravenously administered PGI2 acts as a potent, nonselective vasodilator with its effectiveness limited by systemic hypotension and increased ventilation-perfusion mismatch. When administered as an inhalation therapy, PGI2 has been shown to increase pulmonary selectivity in a number of animal models of pulmonary hypertension.16,17 The iPGI2 has no known toxic effect or metabolite. The typical adverse reactions to intravenous PGI2, such as facial flushing, headache, jaw pain, diarrhea, and dizziness, are transient in nature and have not been observed with inhaled therapy. Hypotension and tachycardia induced by intravenous PGI2 has not been demonstrated in various clinical studies with inhalation administration. Inhibition of platelet aggregation is another potential side effect of PGI2. No effect on platelet aggregation has been demonstrated with iPGI2 in animal studies.16,17 iPGI2 can improve oxygenation in a variety of diseases associated with hypoxemic respiratory failure in the neonatal period. This has been well documented in recent literature.13–15
Beyond the newborn period, the mechanism by which iPGI2 improves oxygenation is predominantly by improvement of the ventilation perfusion mismatch, and in cases of inhomogeneous pulmonary infiltrates like RSV pneumonia, this might be more important than the overall reduction in pulmonary vascular resistance.18,19
The patient in the current report responded well to iPGI2 at 30 ng/kg/min. This is in agreement with Dahlem et al,15 who showed in a randomized controlled trial of aerosolized PGI2 therapy in children with acute lung injury that aerosolized PGI2 at a dosage of 30 ng/kg/min improved oxygenation in children with acute lung injury.
The combination of these 2 therapies (HFOV and iPGI2) has never been previously described in any case report in the pediatric age group.
The response to iPGI2 was immediate, with initial improvement in effective ventilation (as evident by decrease in Pco2) and a gradual improvement in oxygenation.
Response or no response to iPGI2 might be directly related to the degree of lung expansion, with resultant decrease in ventilation-perfusion mismatch, which can be variable during the course of the underlying disease. HFOV has an additive effect for optimal lung expansion, which appears to be crucial for iPGI2 to reach substantial parts of the lung.18,19
In our patient, HFOV was used alone for a few hours, but during this period there was no improvement in oxygenation. We then started continuous iPGI2 as rescue treatment, which yielded the desired improvement in ventilation and oxygenation.
Also, when we tried weaning, initially there was a sudden increase in Pco2 along with fall in oxygenation, with subsequent improvement when iPGI2 was restarted with measurable improvement in ventilation and oxygenation.
In hypoxemic respiratory failure owing to RSV pneumonia, the combination of HFOV and iPGI2 may be considered. Increased lung expansion and alveolar recruitment appear to be responsible for a synergistic effect of the combined treatment. This clinical observation needs to be confirmed by a randomized controlled trial.
- Accepted March 8, 2012.
- Address correspondence to Said Omar, MD, Neonatology Division, Sparrow Hospital, 1215 East Michigan Ave, Lansing, MI 48912. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
- Shay DK,
- Holman RC,
- Roosevelt GE,
- Clarke MJ,
- Anderson LJ
- Groothuis JR,
- Simoes EA,
- Hemming VG,
- Respiratory Syncytial Virus Immune Globulin Study Group
- Khan JY,
- Kerr SJ,
- Tometzki A,
- et al
- ↵Committee of infectious disease. Policy statement-Modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics 2009;124;1694–1701
- Fathi A,
- Parsapour K,
- Rodarte A,
- Peterson B
- Copyright © 2012 by the American Academy of Pediatrics