Pulmonary hypertension is a group of pulmonary vascular diseases characterized by a progressive increase in pulmonary artery pressure and resistance, which eventually leads to right heart failure or even death [1]. Idiopathic pulmonary arterial hypertension (IPAH), a type of pulmonary hypertension without a history of pulmonary hypertension-related genetic mutations and clear risk factor exposure, has an unknown etiology and is one of the most common types of pulmonary hypertension in children.
The treatment of pulmonary arterial hypertension has gained significant progress in the last decade as research into its pathogenesis has intensified. In the treatment of IPAH, different drugs need to be selected according to the patient’s condition, and the acute pulmonary vasodilatation test is an important part in determining the treatment strategy. Currently, acute pulmonary vasodilatation tests are routinely performed in foreign countries for cases diagnosed with IPAH before selecting a treatment plan, but not many pediatric patients in China have undergone this test.
Clinical information
I. Subjects
From October 2009 to June 2011, pediatric patients with IPAH admitted to our department participated in the study. Inclusion criteria were: IPAH, age ≤14 years, and WHO cardiac function class II-III. Exclusion criteria were: pulmonary hypertension due to other factors, age >14 years.
The study protocol was approved by the Medical Ethics Committee of Shanghai Children’s Medical Center, and all children signed an informed consent form.
II. Methods
1. Right heart catheterization and acute pulmonary vasodilation test: The left or right femoral vein was punctured and a vascular sheath was placed under intravenous anesthesia or local anesthesia, and a 5F or 6F balloon float catheter was delivered, and right heart catheterization was routinely performed. Adenosine (Shenyang Everbright Pharmaceutical Co., Ltd.) at a starting dose of 50 µg/(kg?min), with increments of 25 µg/(kg?min) every 2 minutes until the end point of the trial was reached (see termination indications for details). During the drug trial, non-invasive or invasive methods were used to monitor arterial blood pressure in the body circulation in real time, while ECG monitoring was performed to observe changes in heart rate and heart rhythm. Pulmonary artery pressure and arterial pressure of the body circulation were recorded before the start of the test and before the end of the test, and blood samples from the pulmonary artery and descending aorta were taken for blood oxygen measurement and cardiac index was calculated according to the Fick method.
2. Indications for termination of the acute pulmonary vasodilatation test: In the acute pulmonary vasodilatation test, the test can be terminated if the following conditions occur: (1) The systolic pressure of the arteries in the body circulation decreases more than 30%. (2) Heart rate is less than 60 beats/min and hypotension in the body circulation. (3) The occurrence of intolerable adverse reactions. (4) Mean pulmonary arterial pressure (mPAP) decreases to positive criteria. (5) Vasodilator has been applied to a maximum dose of 250 µg/(kg?min).
3, positive criteria for acute pulmonary vasodilation test: The positive criteria for acute pulmonary vasodilation test are based on the criteria recommended by the European Society of Cardiology (ESC) and the American College of Chest Physicians (ACCP) [2-3]: a decrease in mPAP of more than 10 mm Hg and an absolute value of ≤40 mm Hg, and an increase or at least no change in cardiac output. Both of these criteria must be met for a patient to be diagnosed with a positive test result.
Results
I. Baseline data
Fifteen pediatric patients with IPAH were included in this study, 10 males and 5 females, aged 6 months to 14 years, with a median age of 6.3 years. mPAP was (67.1±15.9) mm Hg (1 mm Hg=0.133 kPa) and pulmonary capillary wedge pressure (PCWP) was (9.7). PCWP) was (9.7±2.9) mmHg, and pulmonary vascular resistance index (PVRI) was (17.9±7.5) Wood U?m2 (Table 1). All children had a WHO cardiac function classification of II to III.
Table 1 Baseline hemodynamic data of 15 pediatric IPAH patients
Example number
Sex
Age (years)
Mean pulmonary artery pressure
(mm Hg)
Mean right atrial pressure
(mm Hg)
Pulmonary capillary wedge pressure
(mm Hg)
Pulmonary vascular resistance index
(Wood U?m2)
01
Male
3.8
57
15
11
15.3
02
Female
0.5
51
8
10
9.1
03
Female
4.5
65
14
11
23.3
04
Female
12.0
68
5
9
19.2
05
Male
2.0
66
9
7
13.5
06
Male
7.8
86
11
14
19.2
07
Male
6.3
83
9
12
17.4
08
Male
2.5
49
7
11
7.5
09
Male
2.0
60
12
14
10.5
10
Male
8.4
66
8
11
10.9
11
Male
9.5
50
7
9
22.8
12
Male
8.3
101
14
9
28.8
13
Male
7.5
88
16
9
34.3
14
Female
5.3
50
13
6
21.3
15
Female
14.0
67
1
3
15.4
Mean±standard deviation
67.1±15.9
9.9±4.2
9.7±2.9
17.9±7.5
II. Acute pulmonary vasodilation test
According to the aforementioned positive judgment criteria, 3 out of 15 cases were positive reactions, and the remaining 12 cases were negative reactions, with a positivity rate of 20%. The hemodynamic data before and after drug administration are detailed in Table 2.
Table 2 Results of acute pulmonary vasodilation test in 15 pediatric IPAH patients
Case number
Before
After
Test
Result
Pulmonary artery pressure (mm Hg) [systolic/diastolic (mean)
Body circulation blood pressure (mm Hg) [systolic/diastolic (mean)
Cardiac index
[L/(min?m2)
Pulmonary artery pressure (mm Hg) [systolic/diastolic (mean)
Body Circulating Blood Pressure (mm Hg) [Systolic/Diastolic (Mean)
Cardiac index
[L/(min?m2)
1
70/48 (57)
82/59 (69)
3.0
70/48（53）
78/55 (64)
3.07
Negative
2
64/40 (51)
55/31 (40)
4.5
57/28 (42)
44/26 (34)
4.5
Negative
3
90/52 (65)
99/69 (82)
2.32
59/29 (39)
91/62 (80)
2.52
Positive
4
100/45 (68)
114/60 (83)
3.07
126/53 (84)
107/53 (76)
4.7
Negative
5
92/49 (66)
74/47 (59)
4.37
94/50 (68)
60/35 (47)
3.85
Negative
6
123/63 (86)
126/75 (98)
3.75
116/63 (84)
70/38 (52)
4.53
Negative
7
111/66 (83)
84/51 (64)
4.09
113/66 (84)
85/52 (66)
4.18
Negative
8
62/41 (49)
100/56 (77)
5.07
48/27 (39)
86/49 (67)
5.43
Positive
9
76/36 (60)
151/83 (113)
4.4
56/26 (41)
130/58 (88)
/
Negative
10
95/45 (66)
115/74 (91)
5.04
89/67 (75)
112/71 (87)
/
Negative
11
67/38 (50)
94/70 (81)
1.8
80/45 (59)
104/78 (89)
/
Negative
12
130/80 (101)
93/60 (70)
3.2
89/70 (78)
64/38 (47)
/
Negative
13
112/72 (88)
88/54 (67)
2.3
99/68 (81)
71/44 (55)
3.09
Negative
14
64/46 (50)
99/68 (76)
2.07
56/28 (39)
117/78 (96)
3.55
Positive
15
100/51 (67)
114/58 (82)
4.15
99/49 (71)
112/55 (80)
/
Negative
Note: Cardiac index was not measured after the test in some negative responders
III. Adverse reactions
The incidence of adverse reactions was 33.3% in 5 of 15 patients. 1 patient with local anesthesia experienced chest discomfort when the dose of adenosine was increased to 200µg/(kg?min), and the other 14 patients were all under general intravenous anesthesia. 3 patients experienced significant body circulation hypotension, 1 patient experienced high atrioventricular block and severe All of these adverse reactions disappeared rapidly after 30-60 s after stopping adenosine.
DISCUSSION
Oral calcium channel blockers (CCBs) are the traditional treatment for IPAH, but foreign studies have confirmed that only 10%-15% of adult cases with IPAH are sensitive to CCBs, and treatment with CCBs improves their quality of life and survival prognosis; most patients with IPAH are not sensitive to CCBs The majority of IPAH patients are insensitive to CCBs, do not benefit from long-term treatment with CCBs, and may even deteriorate in the short term. During right heart catheterization, short-acting vasodilators are applied to observe changes in the hemodynamics of the pulmonary circulation and to determine the responsiveness of small pulmonary arteries to vasodilators. This test method has become the most reliable internationally recognized test for screening patients sensitive to CCBs [4].
The diagnostic value of the acute pulmonary vasodilator test includes two aspects: first, it can be used to determine the prognosis of patients with pulmonary hypertension, and positive responders tend to have a better prognosis; second, it can guide the application of CCBs, and positive responders tend to have better results with oral CCBs. 2009 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) pulmonary hypertension expert consensus recommends [5] that an acute pulmonary vasodilator test is mandatory for all patients with IPAH who are likely to be on long-term CCBs, whereas an acute pulmonary vasodilator test is not required for patients with IPAH who are not likely to be on long-term CCBs, such as those with significant right heart failure or hemodynamic instability. All patients in this study had a WHO cardiac function class II to III. For patients with a WHO cardiac function class IV, acute pulmonary vasodilation testing is not recommended because such patients are not candidates for CCBs.
The ideal vasodilator for this test should be selective for the pulmonary circulation and have a rapid onset and short duration of action. The most commonly used drugs abroad are inhaled nitric oxide (iNO), intravenous epoprostenol and intravenous adenosine, but in China only intravenous adenosine is available. Adenosine is a purine nucleoside substance that acts directly on the A2 adenosine receptor on the smooth muscle cell membrane of the blood vessel wall, which activates adenylate cyclase and increases intracellular cyclic adenosine monophosphate (cAMP) to exert its vasodilating effect. Adenosine has a very short half-life of 5-10 s, so it must be administered by central vein or directly by pulmonary artery to effectively exert its pulmonary vasodilating effect. Adenosine is quickly metabolized after passing through the pulmonary circulation, and the concentration entering the arteries of the body circulation is very low. The most common adverse effects of intravenous adenosine infusion include facial flushing, headache, sweating, palpitations, chest pain, hypotension, shortness of breath, etc. If the infusion rate is too fast, atrioventricular block or even cardiac arrest can be induced. In a case study reported by Jing et al [6] in a group of mainly adult patients, the incidence of adverse reactions in a group of acute pulmonary vasodilatation tests using adenosine reached 47.3%, with palpitations and shortness of breath being the most common, with an incidence of 36.5%. In this group of cases, one case of local anesthesia developed chest discomfort when the dose of adenosine was increased to 200 µg/(kg?min), and the other 14 cases were all under general intravenous anesthesia, among which three cases developed significant body circulation hypotension, and one case developed high atrioventricular block and severe bradycardia, all of which disappeared rapidly 30-60 s after stopping adenosine. The incidence of adverse reactions in this group was 33.3%, which was lower than that in adult cases, probably because most of the children were under general anesthesia, and it was impossible to have conscious symptoms such as headache, palpitation, chest pain and shortness of breath under general anesthesia. However, the incidence of hypotension in the body circulation was higher in this group than in adult patients. Because adenosine is rapidly metabolized in the body and has a short half-life, the adverse effects will disappear within a short period of time after stopping the drug, and its safety is still high as long as the changes in heart rate and blood pressure are closely monitored.
The criteria for a positive acute pulmonary vasodilation test are still controversial. In the past, the most commonly used criteria for a positive test were a greater than 20% decrease in mPAP and pulmonary vascular resistance (PVR) and an increase or at least no change in cardiac output after the test [7]. The most recent positive criteria recommended by ESC and ACCP are a decrease in mPAP of more than 10 mm Hg and an absolute value of ≤40 mm Hg, and an increase or at least unchanged cardiac output. Both criteria must be met to diagnose a patient as having a positive test result. This criterion is highly specific for determining the effectiveness of treatment with CCBs, but somewhat less sensitive, meaning that it may miss a small number of patients for whom long-term CCBs are effective, but reliably exclude those who are not suitable for long-term CCBs, thus providing maximum safety. In patients with a basal mPAP below 40 mm Hg, there are no relevant positive criteria due to the limited data on acute pulmonary vasodilatation tests performed in this group of patients.
The pathology, pathophysiology and pathogenesis of pulmonary hypertension in children are similar to those of adult patients. However, the lungs and pulmonary vasculature are still developing during childhood, and their pathological changes and pulmonary vascular reactivity may also be different from those of adult patients.Barst et al [8] earlier reported that 31 of 74 pediatric patients with IPAH had a positive acute pulmonary vasodilatation test, with a positive rate of 40%, which was significantly higher than that of adult patients. In this study, it was also found that the younger the age at diagnosis, the higher the positive rate of acute pulmonary vasodilatation test, but the criteria used in this study were the previous positive criteria; the current study concluded [2] that the positive rate of acute pulmonary vasodilatation test in pediatric IPAH patients is close to that of adult patients, with 10% to 15% or even lower of those with positive acute vascular response, and in a report by Haworth et al [9], only 4 out of 54 pediatric IPAH patients had positive acute pulmonary vasodilatation test. positive, with a positive rate of only 7.4%. In the present study, acute pulmonary vasodilatation tests were performed in 15 patients with IPAH, and three of them were positive, with a positive rate of 20%, which is slightly higher than that of adult patients, but the sample size of this study is small and needs to be further increased.
IPAH is one of the most common types of pulmonary hypertension in children, and the acute pulmonary vasodilatation test is a key part of the standardized diagnosis and treatment of patients with IPAH, and is an important guide for the development of scientific treatment plans. If CCBs are applied blindly for IPAH based on experience, it may have serious consequences. Although right heart catheterization and acute pulmonary vasodilatation tests for IPAH have become routine diagnostic tools abroad, there are few reports of standardized right heart catheterization for IPAH in children in China, especially in acute pulmonary vasodilatation tests, and there are no reports of relevant studies in children in China. It may not be uncommon to apply CCBs blindly without acute pulmonary vasodilatation tests [10]. It is imperative to promote right heart catheterization and acute pulmonary vasodilatation tests in domestic pediatric IPAH patients, which will help improve the diagnosis and treatment of pulmonary hypertension in children in China.