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Jia B et al / Acta Pharmacol Sin 2002 Oct; 23 Supplement: 74-77
· 74 ·
 2002, Acta Pharmacologica Sinica
ISSN 1671-4083
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
http://www.ChinaPhar.com
Inhalation of nitric oxide in congenital heart defects
associated with pulmonary hypertension1
JIA Bing2, MI Ya-Ping, CHEN Zhang-Gen, HUI Wei, YE Ming, SUN Bo
Cardiovascular Center, Children’s Hospital of Fudan University, Shanghai 200032, China
KEY WORDS nitric oxide; pulmonary hypertension; congenital heart defects
ABSTRACT
AIM: To assess efficacy of inhaled nitric oxide (iNO) in postoperative cases of congenital heart defects who
developed critical pulmonary hypertension and had no response to conventional pulmonary vasodilator. METHODS:
From January 1997 to May 2002, 37 patients, age ranging 14 days to 14 years and body weight 3.1 to 32 kg, were
enrolled in the iNO therapy. Indication for iNO: ratio of pulmonary to systemic systolic arterial pressure (Pp/Ps)>
0.5, ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2)<150 mmHg, and conventional
pulmonary vasodilator failure. Initial iNO was started at 20×10-6 vol/vol (ppm), adjusted according to blood gas and
hemodynamic changes, maximal at 45 ppm, and maintained at 5-15 ppm. RESULTS: In 36 patients during iNO, Pp
decreased from (58.5±14.7) to (44.8±13.9) mmHg (P<0.01) without significant change in Ps (77.2±18.0 vs
78.2±13.5, P>0.05), whereas PaO2/FiO2 increased from 106.6±36.8 to 176.5±66.0 (P<0.01). Thirty four patients
discharged at (5.5±5.4) d (range 2-18 d) and 3 died. Inhaled nitrogen dioxide was less than 1 ppm and methemoglobin less than 2 %. No hemorrhage and other adverse effects were observed. CONCLUSION: iNO improved
pulmonary hemodynamics and blood oxygenation in postoperative critical pulmonary hypertension without adverse
effects.
INTRODUCTION
Pulmonary hypertension (PH) is a major complication of congenital heart defects (CHD) with left to
right shunt, such as ventricular septal defect (VSD),
atrioventricular septal defect (AVSD), total anomalous
pulmonary venous connection (TAPVC), and other
disorders. It is one of the most significant cause of
death after corrective procedures. Pulmonary hypertensive crisis (PHTC) usually results from uncontrolled
PH, which is characterized by an acute rise of pulmo1
Supported by Shanghai Bureau of Health (Grant No 97BR023,
99ZYI 001).
2
Correspondence JIA Bing. Fax 86-21-6443-8992.
E-mail [email protected]
nary vascular resistance initiating a cycle of right ventricular failure and poor cardiac output [1].
Despite traditional interventions, including intraventricular administered vasodilators, hyperoxic
hyperventilation, induced alkalosis, and inotropic
support, the morbidity and mortality associated with
PHTC remain unacceptably high. There is pulmonary
endothelial dysfunction in patients with PH, and endogenous production of nitric oxide (NO) by the pulmonary circulation is further impaired after open heart surgery[2]. Inhaled NO (iNO) is a selective pulmonary vasodilator therapy that acts directly on pulmonary vascular smooth muscle without causing adverse effects
on systemic hemodynamics[3]. In this study, we analyzed the effect of iNO in children with CHD associ-
Jia B et al / Acta Pharmacol Sin 2002 Oct; 23 Supplement: 74-77
ated with left to right shunt and pulmonary hypertension immediately after surgical procedures.
MATERIALS AND METHODS
Patient profile and protocol of iNO The study
protocol was approved by the scientific committee of
Children’s Hospital, and informed consent was obtained
from parents. Patients with CHD associated with left
to right shunt and PH underdone surgical procedures
were eligible for enrollment if their pulmonary systolic
arterial pressure (Pp) was 50 % or more of the systemic systolic arterial pressure (Ps) when they were
successfully weaned from cardiopulmonary bypass. All
patients were sedated and paralyzed, and mechanically
ventilated with hyperoxic hyperventilation to maintain
PaCO2 25-30 mmHg and pH 7.45-7.55, Inotropic agents
(Dopamine 5-10 µg⋅kg-1⋅min-1, dobutamine 5-10 µg⋅
kg-1⋅min-1) and vasodilators (sodium nitroprusside 1-3
µg⋅kg-1⋅min-1, prostaglandin (PGE1, 2-10 µg⋅kg-1⋅min-1)
were intravenously given. iNO was administered by
Servo 300A ventilator (Solna, Siemens-Elema AB,
Sweden). Concentration of iNO was started at 20×
10-6 vol/vol (parts per million in relative volumes, ppm),
and adjusted according to the changes of Pp and blood
gas. If Pp decreased, concentration of iNO was maintained or gradually turned down; otherwise concentration of iNO turned up, stepwise at 5 ppm increment,
but not exceed 45 ppm.
Hemodynamic measurement A pulmonary arterial catheter was placed in the left ventricle after the
operation in all the patients to monitor Pp and give vasodilator directly to pulmonary circulation. Heart rate
(HR), Ps, left and right atrial pressure (RAP), electrocardiogram (EKG), transcutaneous pulse oxygen saturation (SpO2), and end tidal carbon dioxide concentration (PetCO2) were continuously monitored. Baseline
hemodynamics and blood gas measurements were performed when patients were clinically stable after admission to the intensive care unit (ICU) from the operation room. In this study, we adopted the definition of
PHTC as an acute episode of suprasystemic Pp associated with a decrease in Sp[4].
Statistical analysis All data are expressed as
means±SD. Serial hemodynamic and blood gas measurements were compared using a paired t test. Significance of the differences of results were determined
if P<0.05.
RESULTS
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From January 1997 to May 2002, iNO was used
in 37 patients after cardiac surgery (18 male, 19 female).
The median age was 40.1 months (range, 14 days to 14
years) and the median body weight was 11.2 kg (range,
3.1 to 32 kg). The diagnoses are listed in Tab 1. PH
was identified by echocardiography in all patients, and
cardiovascular hemodynamic status evaluated at catheter lab was performed in 20 patients. The ratio of
pulmonary to systemic blood flow varied from 1.1 to
Tab 1. Patient diagnoses.
Diagnoses
Ventricular septal defect
Interrupted aortic arch or coarctation of
the aorta with ventricular septal defect
Atrioventricular septal defect
Total anomalous pulmonary venous return
d-TGA with ventricular septal defect
Truncus arteriosus
Double outlet right ventricle
Atrial septal defect
n
17
3
4
7
3
1
1
1
3.9. Pp/Ps varied from 0.7 to 1.0 and pulmonary vascular resistance (PVR) from 5.7 to 20.2 wood unit.
Corrective procedures were performed in all but
1 patient who had interrupted aortic arch and VSD followed by aortaplasty without closing VSD. Three patients with d-TGA and VSD were treated with arterial
switch operation and VSD closure. Cold crystalloid
cardioplegia solution was used in the first 15 cases and
cold blood cardioplegia was given in the late 22 cases
for myocardial protection. Conventional ultrafiltration
was performed in 12 cases during cardiopulmonary
bypass and modified ultrafiltration was performed in 9
cases immediately after cardiopulmonary bypass (CPB).
Peritoneal dialysis was engaged in 3 neonates. CPB
time varied from 52 to 206 min (mean 72.3 min±31.2
min) and the aortic cross clamp time was from 25 to
123 min (mean 50.1 min±22.8 min).
iNO started in the operating room in 3 cases as
Pp/Ps was >1 and CPB was unable to reverse the critical
situation despite inotropic agents and vasodilators were
applied. Thirty-seven cases started iNO at ICU, in which
Pp/Ps was 0.77 and PaO2/FiO2 106.6 mmHg after failure of conventional therapies. PHTC occurred in 7 cases
and iNO was started at 20 ppm. In 5 cases the maximal iNO was 45 ppm. The average of maximal iNO
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Jia B et al / Acta Pharmacol Sin 2002 Oct; 23 Supplement: 74-77
was (33.6±10.9) ppm. INO was reduced when clinical condition, Pp and oxygenation were improved. iNO
was weaned at 5 ppm or less if the patient had been
stable for more than 6 h in most cases. The duration of
iNO was from 5 h to 6 d (mean 28.2 h±11.3 h). No
rebound of Pp was observed. After weaning, patients
were extubated (intubation time, 11 h to 11 d, mean
38.2 h±18.7 h).
Inhalation of NO was considered effective if Pp
decreased more than 10 mmHg within 60 min of iNO.
In 36 patients (97.3 %), Pp decreased from (58.5±
14.7) to (44.8±13.9) mmHg (P<0.01) without significant change in Ps (Fig 1), whereas PaO2/FiO2 increased
from (106.6±36.8) to (176.5±66.0) mmHg (P<0.01,
Fig 2). HR, left atrial pressure and central venous pressure did not change (Tab 2). In 2 cases Pp didn’t decrease but PaO2/FiO2 increased significantly. 34 patients discharged from ICU at 5.5 days (range 2 to 18
d) and 3 died. The cause of death was severe infection
Fig 2. Dynamic change of PaO 2/FiO 2 during inhaled nitric
oxide. n=37. Mean±SD.
in 1 and respiratory failure in 2 cases. Nitrogen dioxide
concentration was (0.10±0.09) ppm (range 0.01 to
0.98 ppm). The methemoglobin concentration was
1.12 %±0.28 % (range 0.65 % to 1.92 %). No other
adverse effects were observed.
DISCUSSION
PH in children with CHD remains an important
cause of postoperative morbidity and mortality. PH crisis occurs in the patients with high preoperative PVR
and it results in very high mortality due to various
reasons. First, pulmonary endothelia function is decreased with advanced stages of pulmonary vascular
disease. Chammas and colleagues[5] demonstrated that
flow induced pulmonary vasodilation was reversed by
inhibition of NO synthase (NOS). Zangwill and colleagues[6] found that Pp and PVR increased with the
increasing of pulmonary blood flow only after competitive blockade of NOS was given. These studies
Fig 1. Dynamic changes in pulmonary systolic arterial pressure (Pp) and systemic systolic arterial pressure (Ps) during
treatment with inhaled nitric oxide. n=37. Mean±SD.
Tab 2. Hemodynamic and blood gas measurements. n=37. Means±SD. bP<0.05 vs baseline.
Baseline
Pp (mmHg)
Ps (mmHg)
Pp/Ps
PaO2 (mmHg)
FiO 2
PaO 2/FiO 2
PaO2 (mmHg)
HR (bpm)
LAP (mmHg)
CVP (mmHg)
56.8±16.1
77.7±17.6
0.7±0.2
95.4±32.9
0.9±0.1
106.5±36.8
35.5±5.3
131.5±30.4
12.4±5.6
11.5±2.6
1h
4h
44.8±13.9 b
78.2±13.5
0.6±0.2 b
111.6±32.2
0.7±0.1
176.5±66.0 b
35.6±7.4
128.6±29.6
12.5±5.8
11.1±3.0
41.7±14.5 b
87.0±16.0
0.5±0.2 b
120.2±35.3 b
0.6±0.1
218.4±78.8 b
36.7±7.3
125.7±27.3
12.1±5.2
11.3±3.6
12 h
39.3±14.3 b
87.0±15.0
0.5±0.2 b
116.7±33.9
0.5±0.2
242.6±96.2 b
34.7±8.3
128.2±19.4
12.1±5.4
12.3±3.5
24 h
48 h
38.8±14.3 b
85.5±14.9 b
0.5±0.2 b
112.1±31.1
0.5±0.2
251.7±94.6 b
37.4±6.1
129.8±23.0
11.9±6.1
12.0±2.8
37.6±15.1 b
85.4±4.2
0.5±0.2 b
113.4±10.2
0.4±0.1
283.5±25.3 b
36.4±7.2
130.4±25.9
11.5±5.3
11.7±4.7
Jia B et al / Acta Pharmacol Sin 2002 Oct; 23 Supplement: 74-77
suggest importance of blood flow induced vasodilation
mediated by NO. Giaid and associates[7] demonstrated
that patients with PH associated with CHD had decreased
immunohistochemical staining for endothelial NOS in
lung biopsy specimens. This implies decreased production of endogenous NO and dysfunction of pulmonary endothelia. Therefore it is rationale to consider
the use of iNO to control postoperative pH.
Our study showed that Pp decreased and oxygenation improved significantly, and immediately in most
cases, after iNO, in comparison to baseline measurements. In 3 cases, we initiated iNO in operating room
before weaning from CPB which resulted in acute reduction of Pp. We consider it of clinical beneficial for
some special cases under such circumstances. It has
been reported that early administration of iNO at operating room may reduce the need for extracorporeal life
support in children with critical postoperative PH [8], and
our experience support this note.
The morbidity and mortality of this group were
less than those of our previous report[9]. Although iNO
has not been approved as a routine method for postoperative PH crisis, recent study by prospective, randomized, controlled trial[10] evaluated the efficacy and adverse effects systematically. Our clinical experience
demonstrated that iNO was an effective and safe therapy
for the treatment of postoperative PH crisis after surgical reparation for CHD and it warrants our further study
on that track to identify its impact on the duration of
neuromuscular blockade, ventilation support strategy,
duration of intubation, inotropic support for PHTC.
ACKNOWLEDGEMENT Authors thank Dr Yong LU
for technical assistance, and Mrs Feng-Fei XU for measurement of methemoglobin.
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5
吸入一氧化氮治疗先天性心脏病术后肺动脉高压１
贾　兵 ２ ， 宓亚平，陈张根，惠　慰， 叶　明， 孙　波
（复旦大学附属儿科医院心血管中心 上海 ２０００３２，
中国）
关键词　一氧化氮；　肺动脉高压；　先天性心脏病；　手
术
目的 评价吸入一氧化氮（ＮＯ）在先天性心脏病术后
严重肺动脉高压及危象中的治疗效果． 方法
１９９７．１－２００２．５ 有 ３７ 例先心病患者术后予以吸入ＮＯ
治疗 年龄 １４ 天 －１４ 岁 体重 ３．１　ｋｇ－３２　ｋｇ．　治
疗指征 肺 体动脉收缩压之比（Ｐ ｐ ／Ｐ ｓ ）＞０．５ 氧
合指数（ＰａＯ２／ＦｉＯ２）＜１５０　ｍｍＨｇ 传统降肺动脉压治
疗方法无效．　初始吸入浓度为 ２０　ｐｐｍ 根据血气及
血流动力学情况进一步调整 不超过 ４５　ｐｐｍ 同时
监测 ＮＯ２ 浓度 高铁血红蛋白含量等．　结果 ３６ 例
吸入ＮＯ治疗后肺动脉压力明显下降（５８．５ １４．７至
４４．８ １３．９　ｍｍＨｇ Ｐ＜０．０１） 体动脉压力无明显
变化（７７．２ １８．０ 至 ７８．２ １３．５　ｍｍＨｇ） ＰａＯ ２／
ＦｉＯ２ 明显改善（１０６．６ ３６．８至１７６．５ ６６．０　ｍｍＨｇ
Ｐ＜０．００１） 监测 ＮＯ２ 浓度＜１　ｐｐｍ 高铁血红蛋白浓
度＜２　％．　未发现明显出血及其它不良反应．　结论
吸入ＮＯ治疗先心病术后严重肺高压及危象可以安全
有效地降低肺动脉压力 改善肺氧合情况．