1.gif (1892 bytes)

Case Reports

Indian Pediatrics 1999;36:307-310 

Adenosine Infusion in the Management of a Micropremi Neonate with Pulmonary Hypertension


Sanjay Patole
Jacinta Lee
John Whitehall

 

From the Department of Neonatology (NICU), Kirwan Hospital for Women, Thuringowa, QLD 4817, Australia.

Reprint requests: Dr. Sanjay Patole, Department of Neonatology (NICU), Kirwan Hospital for Women, Thuringowa, QLD 4817, Australia. Fax: 07 4773 0320

Manuscript Received: July 29, 1998; Initial review completed: August 21, 1998;
Revision Accepted: September 16, 1998


 

We report a micropremi neonate with severe persistent pulmonary hypertension of the newborn (PPHN), treated successfully with intravenous adenosine infusion after failure of maximal medical therapy excluding inhaled nitric oxide (INO).

Case Report

An Australian aboriginal woman (gravida 2, para 0, miscarrige 1), received two doses of dexamethasone prior to spontaneous preterm delivery at 22 weeks and 5 days gestation. The 605 gram male neonate had Apgar scores of four and two at one and five minutes, respec­tively and required ventilation from birth. Ventilatory support was however minimal by day three. A hemodynamically significant patent ductus arteriosus (PDA) was treated with Indomethacin.

Rising oxygen requirements (40 to 50%) and the appearance of interstitial infiltrates on the chest X-ray from day six preceded the occurrence of a right pneumothorax on day nine. Blood cultures subsequently grew Staphylo­coccus hemolyticns and epidermidis, treated with Vancomycin and Cefotaxime. A trial of high frequency oscillatory ventilation (HFOV) on day ten failed to improve the oxygenation (Pa02 = 35 to 40 mm Hg) despite a mean airway pressure (MAP) of 18 and in­spired oxygen concentration of 100%. Further deterioration led to conventional mechanical ventilation (CMV) with peak inspiratory pres­sure and positive end expiratory pressure of 34 and 5 cm H2O, respectively at a rate of 60 per minute with 100% oxygen. Hypotension warranted inotropes. Echocardiography revealed a structurally normal heart with closed PDA and right to left shunting across the foramen ovale diagnostic of PPHN. A pre-existing grade I intraventricular hemorrhage (IVH) made the use of non-specific vasodilators like Tolazoline inappropriate due to risk of hypotension aggravating the IVH. Additionally the nearest center for INO therapy was 6 hours away by air transport. Hence after discussions with the mother of the risks and benefits, it was decided to try intravenous adenosine. An infusion of adenosine (Adenocor, Sanofi-Winthrop, 6.mg/2ml) at 30 micrograms/kg/min via an umbilical venous catheter into the right atrium, had no effect. At 60 micrograms/kg/min, arterial oxygen saturations rose from 94 to 100% and the Pa02 increased from 54 to 139 mmHg (Fig. 1.). Repeat echocardiography revealed complete reversal of the right to left shunt across the foramen ovale. Sustained improvement in ventilation and oxygenation led to weaning of the adenosine infusion over the next 12 hours. No significant changes were noted in the heart rate and the systemic blood pressure during adenosine infusion. The platelet count and cranial ultrasound findings remained un­changed. Unfortunately, two days later, systemic candidiasis ensued, complicated by a right atrial fungal mass. Despite high doses of antifungal treatment, the infection progressed and the neonate died of complications on day twenty-three.

Fig. 1. Graph of PaO2 and oxygen Index (01) showing improved oxygenation and lower oI after adenosine infusion reflecting reduced MAP and Oxygen requirements.

Discussion

Adenosine, a purine nucleoside is shown to be an effective pulmonary vasodilator in animals with hypoxic PPHN and in clinical study(1-4). The vasodilatory effects are mediated by release of endgenous nitric oxide following an increase in cyclic AMP levels due to endothelial Az aderiosine receptor stimulation(5-7). Stimulation of K+ATP channels, leading to hyperpolarization of smooth muscle and decreased entry of calcium into vascular smooth muscle are additional mechanisms of vasodilation by adenosine in PPHN(8,9).

We report a rapid and sustained improvement in oxygenation following adenosine in­fusion in a micropremi neonate with PPHN. We have recently managed 6 consecutive neonates with PPHN with adenosine infusion after failure of maximal medical therapy [CMV, and HFOV, surfactant instillation, metabolic alkalinization and magnesium sulphate as avasodilator](10). A rise in arterial PO2 >20 mmHg occurred in 5 of the 6 cases within 30 minutes of adenosine infusion via a right atrial catheter at 30, 60 or a maximum of 90 micrograms/kg/min. Three of our cases have been preterm neonates with gestations of 26, 28 and 30 weeks, and birth weights of 805, 1125, 1030 grams, respectively. The 26 week neonate developed a right arterial fungal mass, complicated by renal candidiasis, on day thirty-eight. A right atriotomy for removal of the fungal mass was successful, but post-operatively she developed PPHN. At 30 micrograms/kg/min, PaO2 rose from 42 to 73 mmHg. Within six hours' the MAP and inspired oxygen concentration were able to be reduced from 26 to 10 cm H2O and from 100 to 35%, respectively. There were no specific complications of adenosine however the baby died forty-eight hours after atriotomy due to renal failure and hyperkalemia related to worsening renal candi­diasis. In the 28 week neonate with PPHN unresponsive to adenosine, intensive support was withdrawn soon after delivery. Prolonged rupture of membranes for 8 weeks had led to pulmonary hypoplasia and severe multiple arthrogryposis. The 30 week neonate was also born after prolonged rupture of membranes, complicated by oligohydramnios. X-rays sug­gested pulmonary hypoplasia and there was severe PPHN. In contrast to the preceding case, 30 micrograms/kg/min of adenosine in­fusion resulted in a rise of PaO2 from 28 to 60 to 159 mmHg. Sustained improvement in oxygenation led to survival and discharge home on day 5. The near 23 week neonate in this report is the fourth consecutive preterm neonate we have treated with adenosine for PPHN. He appears to be the first micropremi neonate in whom adneosine has ameliorated PPHN without side effects. Konduri et al. have reported a transient improvement in oxygenation in term neonates with PPHN(4). A positive response (rise in PaO2 >20 Torr) oc­curred in 4 of 9 neonates receiving adenosine infusion at 25 and a maximum of 50 micro­grams/kg/min compared with none of nine neonates receiving placebo. One neonate in each group died before Extracorporeal Mem­brane Oxygenation (ECMO) and 7 of 9 neo­nates in both groups eventually needed ECMO, showing that the final outcome was no different in both the groups. Side effects related to adenosine therapy (bradycardia, hypotension, prolonged bleeding time) did not occur.

The current cost of this experimental therapy however may be prohibitive in situa­tions where medical decisions are influenced by cost. For example the total cost of therapy for 2 to 3 days in an infant with PPHN (birthweight 3 kg) responding to a dose of 60 micrograms/kg/min will be approximately 24,000 to 36,000 Rupees in India. The calculation is based on the cost of the currently available preparation of adenosine in India (Sanofi-Torrent: 6 mg/2ml/vial, Rupees 275 per vial); Inhaled nitric oxide though consid­ered the gold standard for vasodilator therapy in PPHN is not cheap either. The current costs of a chemileuscence monitor and an E-type cylinder containing 3,000 litres of nitric oxide are $10,000 and $1,200 (Australian), respec­tively. A considerable amount of training and clinical experience in tertiary care of critically sick neonates is required before routine use of INO therapy could be recommended at such centers. In situations where financial resources and availability of trained manpower rule medical decisions, adenosine may still prove to be an attractive option in management of PPHN in neonates.

In conclusion, adenosine may be a therapeutic option in preterm neonates with PPHN. Availability, simplicity of use, rapid onset of action and an extremely short half-life may prove to be the advantages of adenosine over other vasodilators.

 

 References



1. Paidas CN, Dudgeon DL, Haller JA Jr, Clemens MG. Adenosine triphosphate: A potential therapy for hypoxic pulmonary hyper­tension. J Pediatr Surg 1988; 12: 1154-1160.

2. Konduri GG, Woodward LL. Selective pulmonary vasodilation by low-dose infusion of adeosine triphosphate in newborn lambs. J Pediatr 1991; 119: 94-102.

3. Konduri GG, Gervasio CT, Theodorou AA. Role of adenosine triphosphate and adenosine in oxygen-induced pulmonary vasodilation in fetal Iambs. Pediatr Res 1993; 33: 533-539.

4. KQnduri GG, Garcia DC, Kazzi NI, Shankaran S. Adenosine infusion improves oxygenation in term infants with respiratory failure. Pediatrics 1996; 97: 295-300.

5. Konduri GG, Theodorou AA. Nitro-L-arginine attenuates pulmonary vasodilation caused by adenosine in fetal Iambs. Pediatr Res 1992; 31: 62 (Abstract).

6. Konduri GG, Theodorou AA, Mukhopadhyay A, Deshmukh DR. Adenosine triphosphate and adenosine increase the pulmonary blood flow to Postnatal levels in fetal lambs. Pediatr Res 1992; 31: 451-457.

7. Silver PJ, Walus K, Disalvo J. Adenosine mediated relaxation and activation of cyclic AMP dependent protein kinase in Coronary arterial smQQth muscle. J PharmacoI Exp Ther 1984; 228: 342-347.

8. Chen G: Suzuki H. Endothelium-dependent hyperpolarization elicited by adenine Compounds in rabbit carotid artery. Am J Physiol 1991; 260: H1037-H1042.

9. Ramagopal MY, Mustafa S1. Effect of adenosine and its analog on calcium influx in coronary artery. A J Physiol 1988; 255: H1492- . J1498.

10. Patole S, Lee J, Buettner P, Whitehall J. Improved oxygenation following Adenosine infusion in persistent pulmonary hypertension of the newborn (PPHN). BioI Neon (Accepted for publication in March 1998).

Home

Past Issue

About IP

About IAP

Feedback

Links

 Author Info.

  Subscription