Discussion
The mechanisms of action and targets of pulmonary vasodilators differ from agent to agent, and hence, various therapeutic variants can be used depending on specific product availability and experience of a given center.
Magnesium sulfate is a natural blocker of calcium channels, one of the most common agents administered to patients with PPHN. Despite multiple documented good experiences with magnesium sulfate, a meta-analysis of clinical trials published in 2007 did not provide enough evidence to recommend the administration of this agent in patients with PPHN [11]. However, the results of further studies seem to be promising [12]. Aside from vasodilation, magnesium sulfate has also a strong sedative effect when administered at higher doses, and hence, additional sedation is not needed or can be limited. Although none of the patients included in this case series responded adequately to the magnesium sulfate therapy, this agent has been successfully used in other patients treated at our center. Another important argument for the use of magnesium sulfate is the lack of significant side effects as long as the concentration of magnesium is maintained within the recommended range; the side effects were also not observed in any of the patients included in this series.
Milrinone is a phosphodiesterase 3 (PDE3) inhibitor. This agent is frequently used at cardiology departments because of its inotropic and vasodilatory effects. Its vasodilating effect in pulmonary vessels was first documented in an experimental study of ovine fetuses [7]. Milrinone was also shown to produce beneficial effects when combined with inhaled nitric oxide in neonates who did not respond adequately to iNO monotherapy [8-10]. Milrinone can be particularly useful in patients in whom PPHN coexists with left ventricular dysfunction [13].
According to literature, potential adverse effects of Milrinone therapy include increased risk of IVH and hypotension [14]. While electroencephalography showed no cerebral abnormalities in cases 1 and 2 included in our series, a massive bilateral PVHI was observed in case 3. However, this complication should not be linked solely to the use of milrinone and seemed to be primarily related to extreme prematurity of the patient, resultant multiorgan failure and dysfunction of regulatory mechanisms.
In cases 1 and 3, a decrease in mean arterial pressure was observed after milrinone administration. Mean arterial pressure normalized after the milrinone dose has been tapered down to 0.25 µg/kg/min, still sufficient to maintain the therapeutic effect. While administration of pressor amines was not required in case 1, combination therapy with dobutamine and dopamine had to be given in case 3, given extreme prematurity of the patient, cardiorespiratory failure, and a slight a decrease in systemic blood pressure. In case 2, administration of dobutamine, later combined with dopamine, was required due to disorders of systemic blood pressure that emerged during the administration of 20% MgSO4, before the introduction of milrinone.
Noticeably, an early attempt to withdraw milrinone in cases 1 and 2 was reflected by the worsening of the general condition of the patients and their echocardiographic parameters. This might justify prolonged administration of the agent, perhaps longer than the 35 hours recommended by the manufacturer [15], even despite an evident therapeutic effect. While our patients showed good tolerance to prolonged milrinone therapy, this issue requires further verification.
In all hereby presented cases, the administration of milrinone was associated with a favorable clinical effect, namely a regression of clinical manifestations of PPHN and related echocardiographic anomalies.
To summarize, milrinone can be an effective treatment option in PPHN and may constitute an alternative for the recommended, albeit not always available or contraindicated therapies. Importantly, we did not observe an evident unfavorable relationship between the drug tolerance and its dose and treatment duration; furthermore, none of our patients showed signs of clinically significant hypotension. Milrinone seems to have a similar effect on fluctuations of systemic blood pressure as 20% MgSO4, and its therapeutic effect is similar or stronger than in the case of the latter agent.