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Three Part Question

In [severe PPH of the newborn] is [nebulised tolazoline an option when intravenous tolazoline] has [failed to produce an improvement in oxygenation]?

Clinical Scenario

You are working as a pharmacist supporting a tertiary neonatal unit. A 36/40 gestation infant is transferred from another hospital. The infant had been born by normal vaginal delivery and collapsed on the postnatal ward at 3 hours of age. The child is hypoxic despite high pressures and 100% oxygen. The diagnosis of persistent pulmonary hypertension (PPH) is suggested; intravenous tolazaline had been tried without significant improvement. Nebulised tolazaline is mentioned, and you are asked to find out more.

Search Strategy

Secondary sources and Primary Sources searched.
• Secondary Sources
Medicines for children: information on intravenous tolazoline but not on nebulised.
Guy's formulary: no information.
LTH neonatal formulary: no information.
Northern neonatal network formulary: intratracheal instillation experimental, when formulary written.
• Primary Sources
Medline: "tolazoline" AND "nebulised/nebuliser/vapourisers/aerosols/inhalation" (two relevant studies)

Search Outcome

In total 3 papers were found.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Welch JC et al, 1995,	One infant	Retrospective case report (level 4)	Increased oxygen saturation and concomitant rise in systemic BP. Resolution of metabolic acidosis		Tolazoline is acid in solution with pH of 4. Direct administration of an acid solution to the lungs may cause some alveolar injury
Parida SK et al, 1997,	12 neonates	Case series (level 3b)	Improved oxygenation, particularly sick preterm infants	Significant increase (p<0.005) in the mean levels of oxygen saturation and the arterial oxygen tension	Endotracheal route is preferred because it is devoid of significant side effects (e.g. hypotension and flushing)
Meadow W et al, 1998,	23 piglets	Bench research (level 5)	Did not reduce pulmonary artery pressure significantly but did lower systemic arterial pressure		Cautious extrapolation of these findings to selected clinical conditions in human infants may be warranted

Comment(s)

There is no good quality study addressing the use of nebulised tolazoline in PPH, and none addressing the use after intravenous tolazoline has failed. The only study that has been conducted to date was a case series of only 12 infants. It is difficult to attach significance to a treatment group so small. The study concluded that the endotracheal route is preferred because it is devoid of significant side effects (for example, hypotension and flushing), but it is worth noting that tolazoline is acid in solution and may cause some alveolar injury. The case report concluded that in their case the endotracheal use of tolazoline was life saving and warrants further clinical trials.

Clinical Bottom Line

Nebulised tolazaline may be effective, but no data reliably compare it to the intravenous route or other drugs.

References

1. Welch JC, Bridson JM, Gibbs JL. Endotracheal tolazoline for severe persistent pulmonary hypertension of the newborn. Br Heart J 1995;73(1):99–100.
2. Parida SK, Baker S, Kuhn R, et al. Endotracheal tolazoline administration in neonates with persistent pulmonary hypertension. J Perinatol 1997;17(6):461–4.
3. Meadow W, Rudinsky B, Bell A, et al. Effects of nebulized nitroprusside on pulmonary and systemic hemodynamics during pulmonary hypertension in piglets. Pediatr Res 1998;44(2):181–6.