Does endotracheal instilled prostacyclin (epoprostenol) improve
          oxygenation in preterm infants with persistent pulmonary hypertension?
          Four preterm infants were studied. Prostacyclin (50 ng x kg(-1)) was
          injected as an endotracheal bolus. In two patients the prostacyclin bolus
          was repeated and in one patient prostacyclin was administered
          continuously. Oxygenation was evaluated through the oxygenation index and
          the ratio of arterial oxygen tension to the fraction of inspired oxygen.
          The mean arterial blood pressure was used to evaluate systemic
          circulation. The oxygenation index (+/-SD) decreased significantly from 39
          (+/-13.3) to 7 (+/-2.5) and the ratio of arterial oxygen tension to the
          fraction of inspired oxygen (+/-SD) increased significantly from 47
          (+/-13) to 218 (+/-67), most likely related to a reduction of the
          pulmonary vascular resistance with a reversal of the extrapulmonary
          shunting at the ductus arteriosus and atrial level. The blood pressure did
          not change. All effects were reversed on drug withdrawal. Repeated or
          continuous endotracheal administration of prostacyclin in three children
          demonstrated a sustained response without tachyphylaxis, and without overt
          side-effects. Endotracheal instillation of prostacyclin resulted in an
          improved oxygenation without systemic vascular repercussions in four
          preterm infants with persistent pulmonary hypertension. Repeated or
          continuous administration showed a sustained response and no overt
          side-effects were noticed

Anker, J.N. (John) van den

Jaegere, A. (Anne) de

Erasmus University Digital Repository

Eur Respir J 1998; 12: 932–934DOI: 10.1183/09031936.98.12040932Printed in UK - all rights reservedCopyright ©ERS Journals Ltd 1998European Respiratory JournalISSN 0903 - 1936Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonary hypertensionA.P.M.C. De Jaegere, J.N. van den AnkeraaPersistent pulmonary hypertension (PPH) is a clinicalsyndrome, characterized by a sustained elevation of thepulmonary vascular resistance with a right-to-left shunt ac-ross the ductus arteriosus and/or the foramen ovale, caus-ing severe hypoxaemia. Although generally associated withdiseases of term newborns PPH has been increasingly de-scribed in preterm infants as well [1]. Inhaled nitric oxide(iNO) has been described as an effective selective pulmo-nary vasodilator improving oxygenation in newborns inclu-ding preterm infants. However, concern over iNO relatesto its potential toxicity and to difficulties in developingsafe and effective delivery systems. Intravenous prostacy-clin (epoprostenol) is a potent vasodilator in PPH [2].Nevertheless, its effect on systemic vasculature and onpulmonary vessels of nonventilated areas limits its clinicalapplication. Recently, aerosolized prostacyclin has beenreported both in clinical and experimental settings to be aselective pulmonary vasodilator without side-effects onthe systemic vasculature [3–5]. No human data on topicalepoprostenol-related toxicity are available. In an animalstudy no signs of acute pulmonary toxicity were shownfrom prostacyclin inhalation [6]. We here describe theeffect of endotracheal instillation of prostacyclin on oxy-genation and haemodynamics in four preterm infants withsevere pulmonary hypertension.Patients and methods The patients' underlying diseases were hyaline mem-brane disease (patients 1–3) and septicaemia caused byEscherichia coli (patient 4). Demographic data are listed intable 1. All patients had an arterial oxygen tension (Pa,O2)/fraction of inspired oxygen (FI,O2) ratio <70 despite opti-mum ventilator settings during at least 6 h. Oxygenationwas monitored using pre- and postductal transcutaneouspulse oximetry and a pre- and/or postductal indwellingarterial catheter. The variables measured and calculatedwere the Pa,O2/FI,O2, the oxygenation index (OI; ((FI,O2 ×mean airway pressure)/ Pa,O2) × 100) and mean systemicarterial blood pressure (MAP). Patients were only enrolledafter informed consent was obtained from the parents. Inall infants the presumptive diagnosis of persistent pulmo-nary hypertension was confirmed with air-contrast echo-cardiography showing a right-to-left shunt across the ductusarteriosus and/or the foramen ovale. The epoprostenol, dis-solved in glycine buffer (Flolan®, GlaxoWellcome B.V.,Zeist, the Netherlands), was diluted with saline (NaCl 0.9%)to a concentration of 50 ng·mL-1. The pH of this solutionwas 10.3. This epoprostenol solution of 50 ng·mL-1 wasinstilled as a bolus of 1 mL·kg-1 endotracheally through acatheter reaching the distal end of the endotracheal tube.Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonaryhypertension. A.P.M.C. De Jaegere, J.N. van den Anker. ©ERS Journals Ltd 1998.ABSTRACT: Does endotracheal instilled prostacyclin (epoprostenol) improve oxy-genation in preterm infants with persistent pulmonary hypertension?Four preterm infants were studied. Prostacyclin  (50 ng·kg-1) was injected as anendotracheal bolus. In two patients the prostacyclin bolus was repeated and in onepatient prostacyclin was administered continuously. Oxygenation was evaluated thro-ugh the oxygenation index and the ratio of arterial oxygen tension to the fraction ofinspired oxygen. The mean arterial blood pressure was used to evaluate systemic cir-culation. The oxygenation index (±SD) decreased significantly from 39 (±13.3) to 7 (±2.5) andthe ratio of arterial oxygen tension to the fraction of inspired oxygen (±SD) increasedsignificantly from 47 (±13) to 218 (±67), most likely related to a reduction of the pul-monary vascular resistance with a reversal of the extrapulmonary shunting at theductus arteriosus and atrial level. The blood pressure did not change. All effects werereversed on drug withdrawal. Repeated or continuous endotracheal administrationof prostacyclin in three children demonstrated a sustained response without tachyph-ylaxis, and without overt side-effects. Endotracheal instillation of prostacyclin resulted in an improved oxygenationwithout systemic vascular repercussions in four preterm infants with persistent pul-monary hypertension. Repeated or continuous administration showed a sustained re-sponse and no overt side-effects were noticed.Eur Respir J 1998; 12: 932–934.Dept of Pediatrics, Division of Neonatol-ogy, Erasmus University and UniversityHospital Rotterdam/Sophia Children's Hos-pital, Rotterdam, The Netherlands.Correspondence: A.P.M.C. De JaegereDepartment of PediatricsSophia Children's HospitalDr. Molewaterplein 603015 GJ RotterdamThe NetherlandsFax: 31 10 4636811Keywords: Endotrachealpersistent pulmonary hypertensionpreterm infantsprostacyclinReceived: November 15 1997Accepted after revision May 12 1998ENDOTRACHEAL PROSTACYCLIN IN PRETERM INFANTS  933Epoprostenol was administered within 1–2 h after extra-pulmonal shunting was established with echocardiogram.In two children the endotracheal instillation of prostacyc-lin was repeated three times. In a third child, continuousendotracheal administration of 1 mL·kg-1·h-1 epoprostenolsolution was given for a period of 12 h. Registration ofventilator settings, blood gases and circulatory parameterswas carried out just before, 10 min after, and at 30 minintervals after administration of prostacyclin.Results We studied the effects of endotracheal instilled prosta-cyclin in four infants with persistent pulmonary hyperten-sion. The administration of 50 ng·kg-1 prostacyclin as anendotracheal bolus injection decreased the oxygenationindex (±SD) from 39 (±13.3) to 7 (±2.5) (fig. 1b) and in-creased the ratio of Pa,O2 to FI,O2 from 47 (±13.0) to 218(±66.6) (fig. 1a). Improvement of oxygenation is mostlikely related to the reduction of the pulmonary vascularresistance and reversal of the extrapulmonary shuntingat the ductal and atrial level. The mean systemic arterialblood pressure did not change after prostacyclin instil-lation (fig. 1c). The endotracheal instillation procedurewas well tolerated and no adverse cardiocirculatory eventsoccurred. Effects on oxygenation were reversed on drugwithdrawal. Repeated or continuous endotracheal admin-istration of prostacyclin in three infants demonstrated asustained response without tachyphylaxis and without overtside-effects.Discussion PPH in term and preterm infants is a complex disordercharacterized by an altered vasoreactivity with a markedpulmonary hypertension leading to a right-to-left shuntingof blood across the patent ductus arteriosus and foramenovale. Mechanisms for the vascular tone dysregulation areincompletely understood. However, a dysbalance of endo-genous vasodilators (such as prostacyclin or endothelium-derived NO) and vasoconstrictors (such as thromboxaneA2) play a role in this process [7]. In recent years iNO hasbeen shown to improve oxygenation through a selectivepulmonary vasodilation without repercussion on the sys-temic vasculature. Two recent prospective controlled trialsdemonstrated a reduced incidence of the invasive extracor-poreal membrane oxygenation therapy in term newbornssuffering PPH, however, without improvement of morbid-ity and mortality rates [8, 9]. Although major concernexists regarding potential toxicities of NO and its metabo-lites, no evidence of immediate toxic effect was found inthese studies. PELIOWSKI et al. [10] demonstrated an im-prove-ment in oxygenation with inhaled nitric oxide in eight pre-term infants. For the preterm infant differentconsiderations and concerns exist regarding toxicity ofNO and its metabolites [11]. Until now no data of pro-spective controlled trials in this population have beenavailable. Important considerations compared with termnewborns are maturational differences in haemoglobin,coagulation, free radical scavenging systems and sur-factant metabolism.Another difficulty in general with iNO is related to a safeand reliable delivery system [12, 13]. Intravenous prosta-cyclin is a potent, dose-dependent vasodilator. However,vasodilation is nonselective, resulting in both systemichypotension and an increase of ventilation/perfusion mis-match in nonventilated areas. Thus, intravenous prostacy-clin and inhaled NO are potent pulmonary vasodilators,but each with limitations in clinical application. There-Table 1.  –  Patient characteristicsPatientNo.Gestational ageweeksBirth weightg Disease123430.927.126.733.78457458952300HMDHMDHMDE. coli sepsisHMD: hyaline membrane disease; E. coli: Escherichia coli.300250200150100500Pa,O2/FI,O2  mmHga)6050403020100b)Oxygenation index01020304050c)MAP  mmHgBefore AfterFig. 1.  –  a) the arterial oxygen tension (Pa,O2)/inspiratory oxygen frac-tion (FI,O2) ratio, b) the oxygenation index and c) the mean arterialblood pressure are all shown before and after endotracheal instillationof a bolus of 50 ng·kg-1 epoprostenol. Data are presented as mean andSD.934 A.P.M.C. DE JAEGERE, J.N. VAN DEN ANKERfore, WALMRATH et al. [4] studied the effect of prostacyclinaerosol (17–50 ng·kg-1·min-1) on the lung vasculature inhumans. They showed pulmonary vasodilation in threeadults with acute respiratory distress syndrome, togetherwith reduced shunt-flow and improved arterial oxygena-tion, suggesting that the endotracheal route of prostacyclinap-plication probably allows targeting of prostanoid activ-ity to lung vessels in well-ventilated areas. BINDL et al. [3]and ZWISSLER et al. [14] investigated the effect of endotra-cheal prostacyclin in three term newborns with PPH [2]and congenital heart disease [1], respectively. They alsofound an improvement in oxygenation without repercus-sions on the systemic circulation. Our data indicate that, in preterm infants who sufferfrom hyaline membrane disease or sepsis with persistentpulmonary hypertension, endotracheal instillation of 50ng·kg-1 prostacyclin resulted in a significant improvementof arterial oxygenation by reversal of the extrapulmonalshunting. Repeated endotracheal instillation of 50 ng·kg-1prostacyclin showed sustained responses. Even continu-ous administration of 50 ng·kg-1·h-1 during 12 consecutivehours demonstrated a sustained response without anysign of tachyphylaxis. No negative systemic vascular effectswere noticed with this dosage. It is not known whethera higher dosage would result in systemic effects due toresorption of the epoprostenol. For stability reasons epo-prostenol is prepared in a glycine buffer (pH 10.5). There-fore, concerns can be raised regarding topical applicationof a highly alkaline solution within the airways of preterminfants. An animal study showed no acute toxicity ofendotracheal administered prostacyclin in healthy lambs[6]. However, no data exist on the toxicity of topical epo-prostenol in preterm infants and further randomized studiesshould be performed to investigate differences in toxicitiesat different strategies using prostacyclin therapy. ZOBEL et al.[5] compared inhaled nitric oxide and inhaled prostacyclinas selective pulmonary vasodilators in piglets. They dem-onstrated an improvement in oxygenation mainly due toimproved mismatch of pulmonary perfusion and ven-tila-tion. In contrast to NO, measurement of the inspired con-centration is unnecessary. However, concern exists re-garding the deposition of aerolized or instilled medica-tion. The exact dose and mode of administration has to beinvestigated in further studies. The use of surfactant as apotential carrier of prostacyclin might prove to be a usefulalternative in the treatment of pulmonary hypertension inpreterm newborns with hyaline membrane disease andpulmonary hypertension.References1. Walther FJ, Benders MJ, Leighton JO. Persistent pulmo-nary hypertension in premature neonates with severe res-piratory distress syndrome. Pediatrics 1992; 90: 899–904.2. Higenbottam T. The place of prostacyclin in the clinicalmanagement of primary pulmonary hypertension. AmRev Respir Dis 1987; 136: 782–785.3. Bindl L, Fahnenstich H, Peukert U. Aerosolised prostacy-clin for pulmonary hypertension in neonates. Arch DisChild Fetal Neonatal Ed 1994; 71: F214–216.4. Walmrath D, Schneider T, Pilch J, Grimminger F, SeegerW. Aerosolised prostacyclin in adult respiratory distresssyndrome. Lancet 1993; 342: 961–962.5. Zobel G, Dacar D, Rodl S, Friehs I. Inhaled nitric oxideversus inhaled prostacyclin and intravenous versus inhaledprostacyclin in acute respiratory failure with pulmonaryhypertension in piglets. Pediatr Res 1995; 38: 198–204.6. Habler O, Kleen M, Zwissler B, et al. Inhalation of pros-tacyclin (PGI2) for 8 hours does not produce signs ofacute pulmonary toxicity in healthy lambs. Intens CareMed 1996; 22: 426–433.7. Kinsella JP, Abman SH. Recent developments in thepathophysiology and treatment of persistent pulmonaryhypertension of the newborn. J Pediatr 1995; 126: 853–864.8. Roberts JD Jr, Fineman JR, Morin FC III, et al. Inhalednitric oxide and persistent pulmonary hypertension of thenewborn. The Inhaled Nitric Oxide Study Group. N EnglJ Med 1997; 336: 605–610.9. Anonymous. Inhaled nitric oxide in full-term and nearlyfull-term infants with hypoxic respiratory failure. TheNeonatal Inhaled Nitric Oxide Study Group. N Engl JMed 1997; 336: 597–604.10. Peliowski A, Finer NN, Etches PC, Tierney AJ, RyanAR. Inhaled nitric oxide for premature infants after pro-longed rupture of membranes. J Pediatr 1995; 126: 450–453.11. Skimming JW, Bender KA, Hutchison AA, DrummondWH. Nitric oxide inhalation in infants with respiratorydistress syndrome. J Pediatr 1997; 130: 225–230.12. De Jaegere APMC, Jacobs F, Laheij NDG, van den AnkerJN. Variation of inhaled nitric oxide concentration withthe use of a continuous flow ventilator. Crit Care Med1997; 25: 995–1002.13. Dellinger PR. Inhaled nitric oxide: can we deliver? Inten-sive Care Med 1997; 23: 933–935.14. Zwissler B, Rank N, Jaenicke U, et al. Selective pulmo-nary vasodilation by inhaled prostacyclin in a newbornwith congenital heart disease and cardiopulmonary by-pass. Anesthesiology 1995; 82: 1512–1516.

Endotracheal instillation of prostacyclin in preterm infants with persistent pulmonary hypertension

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