Improving respiratory outcomes after pediatric cardiac surgery:
new uses for nitric oxide.
Congenital heart surgery is performed on tens of thousands of neonates
and infants every year. Most of them are extubated within 3 days of
surgery. However, 20% of these children remain intubated after 72 hours
and 10% are still intubated after 7 days.1,2Prolonged intubation can lead to ventilator acquired pneumonia,
barotrauma, subglottic stenosis, and increased cost. Furthermore, while
the mean intensive care unit (ICU) length of stay (LOS) for a neonate
after cardiac surgery is 9 days, and 6 days for an
infant,3 9% will stay in the ICU for greater than 14
days.3 These outliers can have a disproportionate
impact on hospital finances. Pasquali in 2014 found that 2 additional
days in the ICU after ventricular septal defect (VSD) repair was
associated with an increased cost of $10,661, and those staying 1 week
beyond the median incurred an extra $100,000 in
costs.4 Effective treatment or prevention of prolonged
mechanical ventilation in post cardiac surgical infants is beneficial
for both the patient and society. The study presented by Huang et
al5 in this issue shows the advantage of combining 2
complementary treatments in post-cardiac surgical patients with
respiratory failure.
Pagowska-Klimek in 2010 showed a tripling of mean ICU LOS in pediatric
cardiac surgical patients with pulmonary hypertension
(PHTN).3 PHTN also increases the risk of prolonged
post-operative mechanical ventilation (>7 days)
3-fold.1 Infants with left to right shunts, such as
VSD and atrioventricular canal, have increased pulmonary blood flow
(PBF) and often elevated pulmonary arterial pressure, which predisposes
them to develop PHTN.6 When these patients undergo
cardiopulmonary bypass (CPB), afterwards they can have increased
pulmonary vascular reactivity7 which leads to repeated
episodes of acute elevation in pulmonary vascular resistance (PVR). This
increase in right ventricle afterload worsens any ongoing right heart
failure, leading to significant morbidity and delays weaning from the
ventilator.6 Causes for this reactivity are theorized
to include endothelial dysfunction from systemic inflammation triggered
by the CPB machine as well as ischemic lung reperfusion
injury.8 Even in the absence of pre-existing pulmonary
hypertension, those with single ventricle physiology and passive PBF are
particularly sensitive to changes in PVR and may benefit from pulmonary
vasodilation8.
Optimizing pulmonary blood flow after congenital heart surgery is
desirable, particularly in the subset of patients who have hypoxic
respiratory failure requiring prolonged ventilation. Milrinone is
commonly used for this purpose, but with 2 important caveats. First, it
also causes systemic vasodilation, potentially leading to
hypotension.8 Second, as an intravenous agent, its
efficacy depends on its ability to reach the pulmonary vessels. In the
setting of certain right to left shunts a portion of the milrinone
bypasses the lungs completely.8
Inhaled nitric oxide (iNO) has been used for more than 20 years as a
pulmonary vasodilator in both cardiac6 and
non-cardiac9 settings. It has the advantage of being
delivered directly to the alveoli without reliance on regional PBF.
Because it is administered as a gas, it preferentially vasodilates lung
regions that are well aerated, which improves ventilation/perfusion
matching and leads to improved oxygenation.10 After
leaving the lungs, iNO is inactivated by reacting with hemoglobin,
resulting in minimal systemic vasodilation.6 Avoiding
rebound PHTN while withdrawing from iNO remains a
concern.8
Mercier in 1998 demonstrated that although iNO improved the oxygenation
index (OI) in neonates with non-cardiac hypoxic respiratory failure, the
efficacy varied with the underlying pathology. For example, persistent
pulmonary hypertension of the newborn responded very well to iNO, but
those infants with congenital diaphragmatic hernia saw much less
benefit.11 Survival could be predicted by response to
iNO after 30 minutes of exposure.11 Dowell in 2017
retrospectively studied children (average age 3) with acute respiratory
distress syndrome (ARDS) in the absence of cardiac disease who received
iNO and found that while not all patients responded to iNO with an
improved oxygenation index (OI), those that did had few ventilator days
(10 days vs 16) but no change in mortality.9
Miller in 2000 used iNO prophylactically in cardiac surgical infants who
had lesions associated with increased PBF and pre-op PHTN. Treated
patients had lower PVR and had significantly fewer PHTN crisis events
after surgery (4 vs 7).6 They also achieved extubation
criteria sooner, but had unchanged ICU LOS.6 Cai in
2008 combined iNO with milrinone in post-op fenestrated Fontan patients
with elevated PVR and found that combining iNO with milrinone had an
additive effect in reducing the transpulmonary
gradient.8 Villarreal in 2020 published a
meta-analysis showing that children who receive iNO after CPB had
decreased pulmonary artery pressure and decreased duration of mechanical
ventilation as well as ICU-LOS. There was no impact on hospital
LOS.7
Wong in 2019 retrospectively reviewed 40,000 pediatric cardiac surgical
admissions and found that 1.8% of admissions received iNO despite
having no diagnosed PHTN.12 These patients had higher
mortality and increased hospital LOS. Of the admissions with PHTN, 12%
received iNO, and these had no significant reduction in hospital LOS or
mortality.12 Gupta in 2019 examined 100,000 post
cardiac surgical admissions, and found that of the 15% who received
iNO, only 25% of these patients had diagnosed PHTN. Centers with lower
volume used iNO more frequently, but nonetheless had higher
mortality.13 Indiscriminate use of iNO is therefore
not associated with improved outcomes.
Besides nitric oxide, infants with hypoxic respiratory failure are
treated with high frequency oscillatory ventilation (HFOV). This
modality improves oxygenation by optimizing alveolar
recruitment.14 Bojan in 2011 showed that post cardiac
surgical infants with hypoxic respiratory failure who were treated with
HFOV had shorter duration of ventilation and shorter ICU LOS compared to
a matched cohort managed with conventional ventilation
only.14 Wang and Li in 2013 studied 64 pediatric
patients with ARDS following cardiac surgery who were treated with HFOV.
They found a significant reduction in oxygenation index (13.4 vs 9.8)
with no significant change in mean arterial pressure or central venous
pressure after 24hrs on HFOV.15 Unfortunately, this
was accompanied by a 34% incidence of pneumothorax.15
Combining HFOV with iNO to treat hypoxic respiratory failure has been
studied in non-cardiac surgical infants. The purported benefit lies from
recruitment of alveoli by the HFOV, resulting in better delivery of iNO
to the pulmonary vasculature.16 Dobyns in 2002 studied
108 patients with an oxygenation index (OI) >15 receiving
either HFOV or conventional ventilation (unblinded). They received
either iNO or placebo gas. She found that the PaO2/FiO2 ratio (P/F
ratio) and OI improved with both iNO and HFOV given separately but saw
the most improvement when combined.16 Kang in 2013
examined outcomes in non-cardiac surgical neonates with an oxygenation
index>25 who received either HFOV alone or HFOV + iNO. The
neonates receiving combination therapy had shorter ventilation time and
less early mortality (8% vs 23%).10.
This combination of therapies has not been well studied in post- cardiac
pediatric surgical patients until now.
Huang et al (2021) in this issue present a retrospective study of
post-cardiac surgical pediatric patients with hypoxemic respiratory
failure (P/F ratio < 300 or OI >8) at a single
hospital who had failed conventional ventilation.5 All
the children had PHTN confirmed by echocardiography pre and post CPB.
They had simple left to right shunts (atrial septal defect, VSD, or
patent ductus arteriosus) with good surgical repair and acceptable
hemodynamic parameters. All the children received intravenous milrinone.
39 patients were treated with HFOV alone and 24 received combined HFOV
and iNO. When given, the iNO, was discontinued after 2-3 days. They
found that the OI improved in both groups but combining iNO with HFOV
resulted in lower OI at 48 hours (7.1 vs 6.1). The P/F ratio was also
higher in the combination group (243 vs 215). Besides oxygenation
indices, the experimental group had a shorter duration of mechanical
ventilation (5.6 vs 7 days) and shorter ICU-LOS (9.9 vs 12.8 days). The
hospital LOS was not affected, and the complication rate was not
significantly different between the groups. 5
Limitations to the general applicability of this study are the fact that
it is retrospective, excludes single ventricle physiology, and includes
a large fraction (45%) of patients who did not undergo CPB. The use of
iNO was subject to physician discretion, which introduces the potential
for selection bias. The effect of treatment on the right ventricle was
not specifically reported. This is unfortunate because the impact of
combined therapy on right ventricular function may have had a greater
impact on ICU LOS and duration of ventilation than the improvement in
oxygenation indices.
Nonetheless, this study advances our knowledge of effective management
of hypoxic respiratory failure after pediatric cardiac surgery. Further
work in this field should include a prospective randomized trial to
ascertain if the reduction in duration in ventilation and ICU LOS
persists when use of iNO is randomized and blinded. One would also want
to study the optimal duration of iNO therapy. This study discontinued
the iNO after 3 days, yet the patients were on average extubated after 5
to 7 days. Use of iNO is complicated by the fact that it must be weaned
slowly to prevent rebound PHTN, making the timing of discontinuation
important.6 The benefit of combined iNO + HFOV to
post-cardiac surgical patients with single ventricle physiology without
PHTN also remains to be examined.
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