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Sahulee et al. Vessel Plus 2022;6:5 https://dx.doi.org/10.20517/2574-1209.2021.94 Page 5 of 10

demonstrated that the levosimendan group had improvements in cardiac output and cardiac index.
However, inotropic score, lactate levels, and ICU LOS were unchanged between groups. Using post-
[17]
operative lactate as a surrogate marker of cardiac output, Momeni et al. describe equal efficacy of
milrinone and levosimendan in a cohort of 41 children following cardiac surgery; however, because of the
high cost and lack of Food and Drug Association approval, levosimendan is not at this time widely used for
[14]
the management of LCOS in the United States .
Milrinone has been studied extensively in children after surgery requiring CPB. Milrinone inhibits
phosphodiesterase type 3 leading to an increasing concentration of intracellular cAMP, resulting in
increased myocardial contractility. It also accelerates the removal of calcium from the cytosol, allowing
more time for myocardial relaxation, thus its lusitropic effect. In addition, its effect on cGMP in the
peripheral and coronary smooth muscle cells leads to smooth muscle vasodilation. These simultaneous
changes improve myocardial performance without increasing myocardial oxygen demand, and thus
milrinone has many advantageous properties. Many studies have reported the positive hemodynamic effects
of milrinone in children after cardiac surgery. Most importantly, in the double-blind, placebo-controlled
[11]
RCT PRIMACORP study, Hoffman et al. demonstrated that high dose milrinone significantly reduced
LCOS incidence without increases in adverse events. Since that landmark study, milrinone has become a
widely used pharmacologic agent to prevent and treat LCOS in children. However, a 2015 Cochrane review
concluded there was insufficient evidence of the effectiveness of prophylactic milrinone in preventing death
or LCOS in children undergoing surgery for congenital heart disease . Nonetheless, in a recent Pediatric
[18]
Cardiac Intensive Care Society (PCICS) provider survey, 97% of respondents stated their center routinely
uses milrinone to prevent or treat LCOS after CPB .
[14]

Systemic vasodilators
The purpose of using systemic vasodilators in managing LCOS is to increase stroke volume, cardiac output,
and delivery of oxygen to the tissues while decreasing myocardial oxygen demand. Several medications in
this class have been trialed in the treatment of LCOS, including systemic nitric oxide donors, natriuretic
peptides, and α-antagonists. Sodium nitroprusside releases nitric oxide from vascular endothelial cells
leading to systemic vasodilation. Appelbaum et al. first described the use of nitroprusside after cardiac
[19]
surgery and found a 17% increase in cardiac index. Similarly, the nitro-vasodilator nitroglycerine activates
cGMP leading to vasodilation of the systemic arterioles and venules. However, due to its preferential effects
on the venodilatory properties, it has been found to be less effective in vasodilation compared to
[20]
nitroprusside . The selective calcium channel blocker nicardipine has also been found to be safe and
effective when treating postoperative systemic hypertension, even in children < 6 months of age .
[21]
Nesiritide, a recombinant form of brain natriuretic peptide, induces smooth muscle relaxation and mitigates
the effect of vasopression, leading to vasodilation and promoting diuresis. Although initial adult studies of
nesiritide use were associated with improved outcomes after cardiac surgery, subsequent more robust
studies and a pooled analysis of RCTs failed to do so [22-24] . Phenoxybenzamine has also been used to block
α-1 and α-2 receptors, relax the smooth muscle of systemic vasculature and increase cardiac output.
Tweddell et al. demonstrated an association between improved mortality and the use of
[25]
phenoxybenzamine in infants with hypoplastic left heart syndrome after stage 1 palliation, thought to be
attributed to reduced SVR, reduced fluctuation in systemic venous and arterial saturation, and improved
balance of pulmonary to systemic ratio and delivery of oxygen. However, according to an international
survey by Roeleveld and de Klerk , pure systemic vasodilators are not often used as first-line therapy for
[14]
LCOS, except for patients with single ventricle circulation, where nitroprusside is the most commonly used
agent.