Dear Editor,

We read with interest the article by Vanhaesebrouck S et al[1]. We support the author's aims to properly study the role of conservative management of PDA, but advise caution in accepting their conclusions from results of such a small study. In their introduction the authors refer to the known consequences of a left to right shunt when a PDA is clinically significant, including IVH, NEC and chronic lung disease. These significant clinical outcomes need to be properly assessed in an appropriately powered study prior to recommending changes in management. The authors also state that the aim of their study is to evaluate the need for prophylactic ibuprofen when infants are managed conservatively, in this study defined as mild fluid restriction and more PEEP. The study is not however designed to answer this question - rather it examines the role of conservative management versus any treatment of the PDA. In their 5 year retrospective study the authors describe their management of clinically diagnosed PDA. It is unclear as to whether any infants in their unit at this time received ibuprofen or indomethacin, either prophylactically or as treatment. If so the reported cohort would be a biased population sample. They have not explained either the physiological or theoretical rationale behind each of their strategies in closing the PDA. Restricting to a total daily fluid intake of 130 ml/kg in preterm neonates has the potential to cause significant electrolyte disturbances, oliguria and hyperbilirubinaemia, particularly in infants <1000gms. The duration of fluid restriction required and the occurrence of any adverse effects has not been reported. The PEEP of 4.5 cm of H2O used in the strategy is not really ¡§high¡¨ PEEP as PEEP settings of 6-10 cm of H2O are often used [2]. The 1 year prospective study includes only 30 babies of whom only 10 developed a ¡§haemodynamically important¡¨ PDA. These numbers are far too small to report on meaningful outcomes such as NEC, IVH and chronic lung disease or even the incidence of any adverse effects of fluid restriction. Again the authors should clarify if this cohort represents all ventilated infants < 30 weeks gestation admitted to their unit in this time period or a selected subgroup. Are the outcomes of non ventilated/CPAP babies < 30 weeks also available? In their 5 year retrospective study there was a 6% incidence of ductal ligation. As there is mounting evidence that ductal ligation itself may be harmful [3], avoiding early use of PG synthetase inhibitors which results in an increase in ductal ligation rates may not be optimal management. The prospective study again is too small to assess the effect of conservative management of PDA on ductal ligation rates. We strongly agree with the authors¡¦ conclusions that the best way to properly assess the role of prophylaxis or conservative management is to undertake a properly powered randomized controlled trial. We are presently undertaking such a trial using early echocardiography to target prophylactic treatment in infants with haemodynamically important PDA.

Rajeshwar Reddy Angiti, MD, DM

Martin Kluckow*, MBBS, FRACP, PhD

Department of Neonatology, Royal North Shore Hospital, St Leonards NSW 2065, Australia

Email: mkluckow@med.usyd.edu.au

*Corresponding author

Competing interests: None

References:

1) Vanhaesebrouck S, Zonnenberg I, Vandervoort P, Bruneel E, Van Hoestenberghe MR, Theyskens C, Conservative treatment for patent ductus arteriosus in the preterm.Arch Dis Child Fetal Neonatal Ed. 2007 ;92: F244 -7. Epub 2007 Jan 9.

2) Wiswell TE, Srinivasan P, Continuous Positive Airway Pressure, In Assisted Ventilation of the neonate, Goldsmith JP, Karotkin EH Eds Saunders, Philadelphia 2003, p 127.

3) Kabra NS, Schmidt B, Roberts RS, Doyle LW, Papile L, Fanaroff A, Neurosensory impairment after surgical closure of patent ductus arteriosus in extremely low birth weight infants: results from the Trial of Indomethacin Prophylaxis in Preterms; Trial of Indomethacin Prophylaxis in Preterms Investigators. J Pediatr. 2007;150:229-34, 234.e1.

Dear Editor,

We read with interest the recent article by Vanhaesebrouck S et al describing the conservative management of preterm infants with a patent ductus arteriosus (PDA). We would be interested in the duration of the fluid restriction and the impact on infant growth and kcal/kg/day. From our calculations, expressed human milk with the addition of human milk fortifier (e.g. Nutriprem: approx 85kcals plus 2.3g protein per 100ml) would provide approx 111kcals/kg plus 3.0g/kg protein. Low birth weight formula milk (e.g. Nutriprem 1: 80kcals plus 2.5g protein per 100mls) would provide approx 104kcals/kg plus 3.25g/kg protein. Such amounts appear to fall short of the estimated nutrient requirements for preterm infants, in particular for extremely low birth weight infants, especially if fluid restriction is prolonged beyond the first week(1). In addition, fluid restriction in the presence of a PDA may potentially worsen systemic blood flow distal to the PDA. In a prospective study carried out in our unit involving 33 preterm infants, we demonstrated the detrimental effect a PDA has on celiac artery blood flow3. In the presence of a PDA, celiac artery blood flow (CAF) fell from 30 to 20 mL/kg/min, and returned to 40 mL/kg/min following successful treatment. The decrease in flow occurred despite a rise in left ventricular output. No infants underwent fluid restriction during our study and the fall in CAF was attributed to the presence of a PDA. We therefore speculate that fluid restriction may potentially lead to a further drop in CAF and contribute further to hypoperfusion(2). We would be grateful for the authors’ response to these comments.

References:

1.‘Nutrition of the Preterm Infant Scientific Basis and Practical Guidelines, 2nd Edition. Edited by Reginald C Tsang, Ricardo Uauy, Berthold Koletzko and Stanley H Zlotkin. Publishers: Digital Educational Publishing, Inc. 2005.

2.EL-Khuffash A, Walsh K, Molloy EJ. Quantitative Assessment of the Degree of Ductal Steal Using Celiac Artery Blood Flow to Left Ventricular Output Ratio in Preterm Infants. Neonatology 2007 (in press).

Dear Editor,

An interesting aspect is that the combination of adjustment of ventilation and fluid restriction achieved an overall ductal closure rate of 100%. There is no evidence for any effect of differing ventilation modalities upon the incidence of PDA.

Both inspiratory time and positive end expiratory pressure (PEEP) can affect the mean airway pressure during mechanical ventilation. But mean airway pressure increased from an increase in PEEP will result in a decrease in the effect of inspiratory time on mean airway pressure.

It is not explained how this ventilatory strategy might have achieved such amazing ductal closure rate. This should be more elaborated.

Dear Editor,

I found this article interesting but found the data presented in Table 2 regarding complication rates to be confusing. An n value of 30 is given for the conservative treatment group. However only 10 babies were "treated" for their PDA, 20 babies did not have a PDA. Therefore is it correct to compare percentage rates with studies of babies who did have a PDA?

2% of this group had a grade 3 IVH - this is 0.6 babies. If only 1 baby had an IVH this figure would be 3.3%, are these percentages correct? Of course if all the complications were in the true treatment group (n=10) then the proportion would increase threefold. Clearly much larger numbers are needed.