Target population

There is individual variability among preterms regarding the behaviour of patent ductus arteriosus, and spontaneous closure can be achieved in most instances by proper metabolic and respiratory management.Reference Koch, Hensley, Roy, Brown, Ramaciotti and Rosenfeld ² However, there is a subgroup of cases that definitely requires medical intervention and benefit from early ductal closure. Lower birth weight and earlier gestational age (23–25 weeks), the presence of chorioamnionitis and sepsis, and the absence of antenatal exposure to steroids are risk factors that interfere with spontaneous closure, and such cases constitute our target population.Reference Koch, Hensley, Roy, Brown, Ramaciotti and Rosenfeld ² We hypothesise that our treatment modality would be successful in a selected group of cases.

Why not cyclooxygenase (COX) inhibitors?

There are two reasons against the use of COX inhibitors:

• ∙ High failure rate of COX inhibitors in extremely low birth weight infants

  Sodini et alReference Sodini, Baragatti, Barogi, Laubach and Coceani ³ have shown that indomethacin results in the enhancement of nitric oxide in the ductal tissue, which may oppose the constriction resulting from COX inhibition and interfere with ductal closure.

  In addition, prostaglandin E2 is a substance that prepares the ductus for closure at birth by promoting intimal cushion formation.Reference Ivey and Srivastava ⁴ Therefore, COX inhibition in preterms can result in interruption of intimal cushion development, and thus may exacerbate the problem.

• ∙ Known and unknown side effects of COX inhibitors

  Treatment with COX inhibitors is associated with various side effects including decreased cerebral blood flow, transient renal impairment, and spontaneous intestinal perforation.Reference Abdel-Hady, Nasef, Shabaan and Nour ⁵ The possible interference of ibuprofen with albumin–bilirubin binding in very low birth weight infants should also be taken into account.Reference Abdel-Hady, Nasef, Shabaan and Nour ⁵

Why local therapy?

The ductus arteriosus as a vessel constitutes a very minor part of the circulatory system, and thus giving systemic COX inhibitors to achieve vasoconstriction solely in the ductus arteriosus without considering the effects on the rest of the circulatory system, such as the arteries that supply blood to the heart, brain, kidneys, and gut, does not sound reasonable. We believe that we should treat patent ductus arteriosus locally, and create local rather than systemic vasoconstriction for ductal closure. In particular, maintaining stable cerebral blood flow is critical in extremely low birth weight infants. Anything that might produce fluctuations in cerebral blood flow would directly contribute to the pathogenesis of periventricular leukomalacia.Reference Volpe ⁶

Concerns about platelet-rich plasma

Sallmon et al have highlighted some studies linking bioactive molecules of platelet-rich plasma to some serious neonatal conditions. However, any agent – including oxygen, which is one of the most widely used therapeutic agents in neonatology – can be toxic when administered in supraphysiological doses.Reference Dennery ⁷ On the other hand, local increase in concentrations of molecules such as platelet-derived growth factor, transforming growth factor-β, and vascular endothelial growth factor is a physiological process that already occurs in healthy term infants.Reference Hamrick and Hansmann ⁸ In particular, vascular endothelial growth factor, in stimulating endothelial proliferation, is the key trigger of remodelling, which is not achieved in preterms because of the thin-walled ductus. We hypothesise that local application of appropriate doses of platelet-rich plasma will mimic the normal physiological process, producing physiological concentrations of these bioactive molecules, rather than causing any adverse effect. Although there is no way of knowing the correct dose of platelet-rich plasma for ductal closure without conducting animal studies, we again hypothesise that 3−5 ml of cord blood should be sufficient in a preterm baby, based on the doses used for musculoskeletal indications in adults.Reference Patel, Dhillon, Aggarwal, Marwaha and Jain ⁹ In addition, use of otologous platelet-rich plasma preparation is not an essential prerequisite for our hypothesis. Platelet-rich plasma may well be prepared from a healthy donor, which will avoid the problem of altered function brought up by Sallmon and colleagues.

About the technique

Concerns were also raised about whether the majority of the plasma dose would actually reach the ductal tissue or not. However, the flow velocity and pattern of the proximal descending aorta close to the ductal ampulla can be measured by functional echocardiography.Reference Shiraishi, Endo, Ichihashi, Kuramatsu and Yanagisawa ¹⁰ We believe that because orally administered ibuprofen can reach the ductal tissue, sufficient local concentrations of growth factors in the ductus arteriosus should also be achievable by this method.

Although umbilical arterial catheterisation is not a routine procedure for all preterms, it is not an extra procedure in this specific group of patients.Reference Shahid, Dutta, Symington and Shivananda ¹¹ Catheter-related complications can be minimised by strict adherence to guidelines for catheter care.Reference Suresh and Edwards ¹²

On platelets and ductus arteriosus

Sallmon and colleagues state that the clinical relevance of platelets in patent ductus arteriosus in humans is unclear; however, the crucial role of platelets in the permanent closure of the ductus has been shown histologically by Echtler et al.Reference Echtler, Stark and Lorenz ¹³ Moreover, Sallmon et alReference Sallmon, Weber and Huning ¹⁴ have previously stated that impaired platelet function rather than platelet number might be the main factor contributing to the failure of ductal closure. As there has been no clinical research investigating the role of platelet function on patent ductus arteriosus, clarification of this issue awaits the results of future studies.

We again thank Dr Sallmon and colleagues for their interest. They have raised several important points that support further investigation of this hypothesis.