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.