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Editor—We were disappointed to hear that a doctor in India has been criticised for treating pulmonary hypertension in three neonates (so called blue babies) with the phosphodiesterase type 5 inhibitor sildenafil (Viagra), a drug not licensed for this purpose.1
Many drugs are widely and appropriately used outside their product licence.2 Such prescribing practice is common in adult medicine, but is particularly prevalent in paediatrics because companies rarely undertake the work necessary to gain a licence for children. The decision to prescribe outwith a drug's licence should be supported by evidence of safety and potential benefit and, when possible, by a reasonable body of supporting professional opinion.
Of course, controlled clinical trials should be performed when possible to evaluate new treatments for specific indications. But these data are not always available, and then clinicians must make difficult decisions as to whether other information, such as efficacy and safety in other groups of patients, justifies unlicensed drug use. Subsequently, case reports should be published, facilitating scientific debate and informing the design of clinical trials.
Evidence is growing that sildenafil acts as a vasodilator in the pulmonary circulation and is effective in lowering pulmonary artery pressure in pulmonary arterial hypertension. This effect has been shown in adults with pulmonary hypertension and healthy volunteers with pulmonary hypertension induced by hypoxia.3,4 Intravenous sildenafil also normalised pulmonary artery pressure in an animal model of neonatal pulmonary hypertension.5
The evidence currently available is not sufficient generally to recommend the use of sildenafil in neonates with pulmonary hypertension. Assuming, however, that sildenafil was used as a last resort, after standard treatment, we believe that there are sufficient data to support the actions of this doctor. Perhaps the publicity that has arisen about this action will encourage further clinical research into the potential of inhibiting phosphodiesterase type 5 as a treatment for neonatal pulmonary hypertension, which may ultimately result in wider benefit to patients.
References
1.Kumar S. Indian doctor in protest after using Viagra to save “blue babies.”. BMJ. 2002;325:181. doi: 10.1136/bmj.325.7357.181. . (27 July.) [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Prescribing unlicensed drugs or using drugs for unlicensed indications. Drug Ther Bull. 1992;30:97–99. [PubMed] [Google Scholar]
3.Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation. 2002;105:2398–2403. doi: 10.1161/01.cir.0000016641.12984.dc. [DOI] [PubMed] [Google Scholar]
4.Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation. 2001;104:424–428. doi: 10.1161/hc2901.093117. [DOI] [PubMed] [Google Scholar]
5.Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. Am J Respir Crit Care Med. 2002;165:1098–1102. doi: 10.1164/ajrccm.165.8.2107097. [DOI] [PubMed] [Google Scholar]
BMJ. 2002 Nov 16;325(7373):1174.
Ethics, conscience, and science have to be balanced against limited resources
Editor—The unlicensed use of sildenafil (Viagra) by an Indian doctor to save “blue babies” has recently been the topic of a heated debate.1-1 Before passing any judgment it is important to note that most neonatal nurseries in the developing countries cannot afford either to document or to treat persistent pulmonary hypertension in newborn infants by the currently accepted standards. Access to pulse oximetry and cardiac echocardiography is difficult, and very few units are equipped for ventilation and surfactant therapy.1-2 Transfer to regional centres is almost impossible given the lack of neonatal transport services.
Advocating a theory of failure of conventional management before resorting to experimental treatments after informed consent is easy. It must, however, not be forgotten that the worldwide use of hyperventilation, muscle paralysis, bicarbonate infusion, and non-specific vasodilators such as magnesium sulphate, prostacycline, glyceryl trinitrate, and sodium nitroprusside in the conventional management of persistent pulmonary hypertension in newborn infants is not based on evidence from any randomised controlled trials.1-3 The use of the most popular non-specific pulmonary vasodilator tolazoline has also been serendipitous, stemming from the original case report of persistence of the fetal circulation in 1969 rather than from controlled studies of its efficacy, kinetics, or safety.
The current expensive gold standard—using specific pulmonary vasodilator treatment and inhaled nitric oxide—is unlikely to be available or affordable in developing countries in the near future.1-3 Moreover, nitric oxide has also not proved to be the single magic bullet for persistent pulmonary hypertension in newborn infants. Nearly 20-30% of cases do not respond to nitric oxide, especially those with severe parenchymal lung disease (as in meconium aspiration and pneumonia) or pulmonary hypoplasia (as in congenital diaphragmatic hernia).1-3 The recent addition of adenosine, pentoxifylline, and dipyridamole as possible therapeutic options for persistent pulmonary hypertension in newborn infants is also based on case reports or series rather than randomised controlled trials.
Given the lack of resources, a conscientious doctor in a developing country may unsurprisingly resort to an experimental but potentially promising treatment in a desperate attempt to save a blue baby with possible persistent pulmonary hypertension when conventional treatments have failed.1-4,1-5 The issue of defining appropriate conventional treatments for persistent pulmonary hypertension in newborn infants in developing countries is extremely complex.
References
1-1.Kumar S. Indian doctor in protest after using Viagra to save “blue babies.”. BMJ. 2002;325:181. doi: 10.1136/bmj.325.7357.181. . (27 July.) [DOI] [PMC free article] [PubMed] [Google Scholar]
1-2.Paul VK. Newborn care in India: a promising beginning but a long way to go. Semin Neonatol. 1999;4:141–149. [Google Scholar]
1-3.Macrae DJ. Drug therapy in PPHN. Semin Neonatol. 1997;2:49–58. [Google Scholar]
