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

Pulmonary vasodilators
Increases in PVR after CPB are one of the pathophysiologic mechanisms believed to contribute to LCOS
development, and children with preoperative left-sided obstructive lesions and those with left to right
shunts are at higher risk of elevated PVR following bypass. Cardiopulmonary bypass causes inflammation
that inhibits nitric oxide production and increases the production of endothelin-1. Thus, inhaled nitric
oxide (iNO) and its precursors have been trialed to treat or prevent LCOS. Inhaled nitric oxide is a selective
pulmonary vasodilator with little effect on the systemic vasculature. Miller et al. performed a prospective,
[26]
double-blind RCT of iNO in 124 infants at risk for pulmonary hypertension (PH) and found that iNO
reduced indexed PVR, number of PH crises, and proportion of patients mechanically ventilated at 7 days. In
addition, a recent RCT of prophylactic iNO demonstrated a reduction in the incidence of LCOS and the
need for ECMO, most markedly seen in children < 2 years of age, and after highly complex surgeries .
[27]
Another pulmonary vasodilator, the aerosolized prostacyclin iloprost, and iNO were found to be
[28]
comparable in increasing cardiac output and decreasing pulmonary artery pressures . However, in a study
[29]
by Wong et al. reviewing the PHIS database, of 1678 surgeries performed on patients with known PH,
iNO was used only 11.6% of the time, and its use was associated with increased cost and LOS, with no
improvement in mortality. Citrulline, a precursor to nitric oxide, has also been trialed to reduce LCOS
[30]
incidence and improve outcomes but has not been shown to decrease PH episodes significantly . Other
inhaled agents such as sildenafil, milrinone, and prostaglandin have also been used for PH but less
frequently for LCOS. At this time, there is insufficient data to support the routine use of pulmonary
vasodilators such as iNO, as a Cochrane systematic review did not find differences in mortality or many
secondary outcomes with its use . However, to better investigate the utility of iNO to increase survival and
[31]
ventilator-free days after CPB, the multicenter, randomized, double-blind NITric trial is currently
underway .
[32]
ADJUNCTIVE THERAPIES FOR THE LOW CARDIAC OUTPUT SYNDROME
Corticosteroids
Cardiopulmonary bypass is known to cause an inflammatory cascade that is believed to contribute to LCOS
and postoperative morbidity. Hence, anti-inflammatory therapy with corticosteroids has been extensively
studied for those undergoing cardiac surgery requiring CPB [33,34] . In addition, several studies have
investigated the cellular mechanisms whereby corticosteroid supplementation may be beneficial [34,35] .
[36]
However, a recent meta-analysis of 17 RCTs and 848 pediatric patients by Li et al. in 2020 concluded that
children receiving corticosteroids did not have a reduction in all-cause mortality compared to controls.
They did have a significant reduction in vasoinotropic score but had no significant improvement in other
secondary outcomes such as ICU LOS, duration of mechanical ventilation, serum lactate, or incidence of
LCOS, among others. A recent two-center RCT also failed to show a significant overall benefit in a
mortality-morbidity composite index but did similarly demonstrate a reduction in vasoactive
[37]
requirements . However, despite the results of this recent meta-analysis and several RCTs, a survey of 188
PCICS members from 85 centers found that 94% of survey respondents reported that they sometimes or
always administer corticosteroids for patients with moderate or severe LCOS, with hydrocortisone being the
[38]
most commonly used agent . To better understand the utility of corticosteroids for children undergoing
cardiac surgery with CPB, the currently ongoing multicenter, placebo-controlled STRESS trial is
investigating the efficacy and safety of methylprednisolone administration and its association with major
outcomes, including mortality, morbidity, and ventilator time .
[39]

Thyroid hormone replacement
Another class of medication that has been trialed in the management of LCOS over the past few decades is
thyroid hormone replacement therapy. It has been shown that triiodothyronine (T3) levels decrease in
[40]
infants and children after CPB . Given the important role of thyroid hormone in metabolism, it was