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.