PDA ligation controversies

Well, that was another excellent joint neonatal-Pediatric surgery conference at WCHOB. The subject was PDA and the discussion included basic PDA physiology, morbidity, treatment strategies, post ligation syndrome, and most importantly looked at the evidence (or lack of) supporting the need for PDA ligation.

The discussion began with the general principles of PDA physiology, including the normal role of prostaglandins produced by the placenta and the high intraluminal blood pressure in the ductus (secondary to high pulmonary vascular resistance) in keeping the ductus patent in utero. Normal term delivery reverses these factors and results in closure of the ductus initially by smooth muscle constriction then then anatomic remodeling.

The clinical consequences of a PDA are a result of the left to right shunt, and subsequent change in blood flow to vital organs with subsequent metabolic acidosis, increased risk of IVH and NEC secondary to diastolic steal, and pulmonary vascular disease due to continuous dilation of pulmonary vessels during diastole.

The main strategy for prophylaxis and treatment is the administration of Indomethacin, and when that fails, surgical ligation.

The first issue that comes up is the evidence for the need for the prophylaxis and treatment of PDA.

The literature supports the benefit of the prophylactic use of indomethacin for it's effectiveness of PDA closure, decrease the need for surgical ligation, decrease in the incidence and severity of pulmonary hemorrhage, and decrease in incidence of grade 3 and 4 IVH.

Indomethacin, however, is not innocuous. It can cause a transient change in renal function, increases the risk of GI perforation when administered simultaneously with steroids. It was not found to have any neurodevelopemental effects.

So why should a PDA be treated? A study looking at infants <1500 g showed an 8 fold increase in mortality in the presence of a PDA.

When it came to the subject of surgical ligation of PDA, the data was much less convincing and somewhat troubling. Studies not only shed doubt on the proposed rapid improvement of cardiovascular parameters (Raval et al. J Ped Surg 2007.42(1):69), some actually showed that surgical ligation may be associated with an increased risk of BPD, severe ROP, and neurosensory impairment in ELBW infants (Kabra et al. J Peds 2007;150:229).

Finally, the subject of post ligation cardiac dysfunction was addressed. This results from ligation of the PDA, which results in a sudden switch from volume to pressure overload on the heart which was, as a baseline, subjected to impaired coronary perfusion (form diastolic steal with a PDA), and preexisting pulmonary edema and cardiac failure. Post ligation cardiac dysfunction presents with severe hypotension, failure of oxygenation, and myocardial dysfunction. The hemodynamic profile shifts from pre ligation state of a high preload/low after load and myocardial ischemia from decreased diastolic perfusion, to post ligation state of a sudden increase in after load, decreased LV end diastolic volume, and decreased LV output.

Importantly, the extent of post ligation dysfunction depends on pre ligation hemodynamic, with some authors supporting the prophylactic use of milrinone when the pre ligation LV output is < 200 ml/kg/minute.

As to the management of post ligation cardiac dysfunction, the strategy is to use inotropes that do not increase after load (Milrinone/dobutamine), optimize oxygen carrying capacity, and fluid management.

The upshot on PDA interventions was that prophylactic ligation does not improve outcome, indomethacin prophylaxis decreases IVH and need for PDA ligation, indomethacin prophylaxis does not improve neurodevelopemental outcome in survivors, earlier Indomethacin treatment is associated with higher rates of DA closure. As to the ideal timing of medical or operative closure, that remains to be clarified.

With the current available data, many questions remain unanswered:

can we identify infants whose ductus will close spontaneously?
can we reduce the number of doses of indomethacin without compromising outcome?