Patients With Idiopathic Pulmonary Health And Social Care Essay

INTRODUCTION

Pulmonary vascular tone is maintained by the action of vasoprotective

compounds including nitric oxide (NO) (1).NO can be synthesized endogenously

in the body via L-arginine and NOS-independent mechanism from the anion nitrite (NO2-) (2, 3).Nitric oxide (NO) causes cyclic guanosine monophosphate-mediated vasodilatation of the pulmonary vasculature. Endogenous NO is also produced from the metabolism of citrulline; an amino acid generated by the urea cycle (4). NO is critical for normal development of the pulmonary vasculature and loss of this vasodilator factor and subsequent endothelial dysfunction is proposed as one of the possible explanations for development of pulmonary hypertension (1).

From a clinical standpoint, pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD).Its presence is associated with shorter survival and worse clinical outcome. In a setting of COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. Recent investigations have demonstrated endothelial dysfunction and changes in the expression of endothelial-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease(5). Pulmonary vascular involvement from congenital heart disease like Eisenmeger syndrome is another important category of patients with PAH. In this congenital disease pulmonary vascular involvement follows a period in which pulmonary resistance is low and pulmonary blood flow is high (6, 7, 8).Finally, idiopathic pulmonary hypertension (IPAH) is the third category of these patients. IPAH has unknown etiology and is characterized by progressive obliteration of small and medium size pulmonary arteries; elevation in pulmonary arterial pressure, and an increase in pulmonary vascular resistance. Presence of these pathologies eventually leads to right heart failure and death (9).

Due to vasodilatory properties of the NO, one of the therapeutic approaches for IPAH is oral use of nitric oxide precursors (10). Efficacy of L-arginine is well-documented in the current literature but there is paucity of data with regard to L-citrulline- malate. Hence, this study will evaluate therapeutic efficacy of L-citrulline- malate in two categories of patients with pulmonary arterial hypertension (IPAH, and Eisenmeger syndrome). This randomized clinical trial utilizes 6-minute walk an indicator of functional improvement of the patients, PAP (pulmonary arterial hypertension), the quality of life and level of plasma pro-BNP (brain natriuretic peptide) in these patients.

METHODES

Patient selection

Patients with pulmonary arterial hypertension (idiopathic, occurring after surgical

repair of congenital systemic-to-pulmonary shunts that had been performed at least five years previously or not repaired at all) were included in this study.

Pulmonary hypertension has been defined as an increase in mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest as assessed by right heart catheterization(RHC) (11,12).

Pulmonary pressures were also estimated by Doppler echocardiography with the following diagnostic criteria: (1) significant tricuspid regurgitation (2) enlarged or hypertrophied right ventricle without evidence of pulmonary stenosis, or (3) intra ventricular septal flattening (13, 14). Ethics committee for human research of Shahid Beheshti University of Medical Sciences has reviewed and accepted the entire study protocol. A written informed consent was obtained from all patients. Our study protocol required all patients to continue their conventional therapy. The study protocol was registered in clinicaltrial.gov and the identifier number is NCT01683981.

Exclusion criteria of this study were: all patients more than 70 years old, patients with a six-minute walking distance of less than 100 meters (m), active pulmonary or extra pulmonary infection, serious coronaropathy and/ or ventricular dysfunction, significant renal illness and/or hepatitis, detected immunosuppressive illnesses, carrier of known neoplasias, pregnancy, lack of family support, psychosocial problems, drug or alcohol abuse, and noncompliance with established medical protocol.

Outcome measures

The primary measure of efficacy was the change in exercise capacity, as measured by the total distance walked in six minutes, from baseline to week 2. Other measures of efficacy were the changes in mean pulmonary-artery pressure, also the change in the frequency of admission, change in the quality of life. Quality of life measures were assessed according to SF-36 questioner. Adverse events were monitored throughout the study period.

Study protocol

Twenty five patients were prospectively enrolled in this randomized, clinical trial, before and after study at pulmonary arterial hypertension (PAH) clinic in National Research Institute of Tuberculosis and Lung Disease (NRITLD) between August and October of 2012.This study recruited 20 patients (4males and 16females) with IPAH and a functional class II or III according to the diagnostic criteria defined by ESC. This study also included 5 patients (3 males and 2 females) with Eisenmenger Syndrome with no complex congenital heart disease. All patients underwent an echocardiography as part of the initial diagnostic work up even if they had been diagnosed as pulmonary hypertension. Furthermore, a 6-minute walk test and a pro-BNP level were taken. L-Citrulline was administered as a 100 mg/mL (10%) solution with distilled water as a suspending agent. Patients were followed for 2 weeks after given 1gr of L-citrulline-malate by the 6-minute walk test, pro-BNP level and echocardiographic index like PAP.

Statistical analysis

Interval variables are presented as mean±SD. For the nominal variables frequency and percentage were reported. The first and third end points, the six minute walking test and the frequency of admission were evaluated with the use of a stratified Wilcoxon’s rank-sum test. The secondary end point (mean pulmonary-arterial pressure) was evaluated with the use of an independent T-Test. And the other end points, the quality of life were evaluated with a Chi-squared cross-tabulation. Statistical significance was defined as a p-value lower than 0.05. All data were analyzed SPSS version 17 for Windows.

Results

A total of 25 patients were randomly assigned to receive L-citrulline malate in dose of 1 gram divided 3 times a day for two weeks.

Baseline characteristics

Baseline characteristics of the patients were similar among all 25 patients. Pulmonary arterial hypertension was the most frequent diagnosis between them, 20 (80%) of all patients were idiopathic pulmonary arterial hypertension and 5 (20%) of them were Eisenmenger syndrome. Seventeen patients (74%) of the total 23 that were entered into this study were female and 8 of those (26%) were male. The mean age of them was 31.29.27. The youngest participant was 18 years old and the oldest one was 51.Two of the total patients were excluded from the study due to the drug adverse events.

Exercise Capacity

Distance walked in six minutes was increased after receiving L-citrulline malate as compared with before receiving it at two weeks. The difference between mean distance walked in six minutes before and after receiving L-citrulline malate was significant (P-value=0.005). There was no significant difference between male and female in distance walk in six minutes before receiving L-citrulline malate and after receiving it (P-Value=0.34). Also the effect of age on difference between mean distance walk before and after receiving L-citrulline malate was not significant (P-Value=0.08).

Pulmonary Arterial Pressure

Mean pulmonary-artery pressure before receiving L-citrulline malate compared with after receiving it was significantly higher (P-value=0.01).

Quality of Life

In all dimensions score of participants after receiving L-citrulline malate was higher than before receiving it or they were equal (table 1) .There was a significant difference between mean Physical functioning(P-Value=0.02), energy-fatigue(P-Value<0.001), emotional well being(P-Value=0.02), pain(P-value=0.02) and general health(P-Value=0.004). No patient changed in limit due to physical health, limit due to emotional health and social functioning.

Pro-BNP

Comparing pro-BNP before with after receiving L-citrulline malate, it was higher after receiving L-citrulline malate but the difference was not significant (P-Value=0.9).

Table-1

Mean Before receiving L-citrulline malate (S.D)

Mean After receiving L-citrulline malate (S.D)

Walking distance at 6 min — m

351.6(116.4)

395.7(136.5)

Pulmonary-artery pressure — mm Hg

83.34(22.4)

79.1(22.2)

SF36

Physical functioning

61.5(11.3)

64.3(12.3)

Limit due to physical health

95.7(14.4)

95.7(14.4)

Limit due to emotional health

97.1(9.5)

97.1(9.5)

Energy-fatigue

54.8(16.8)

60.2(16.2)

Emotional well being

65.1(7.8)

66.1(8.2)

Social functioning

87.5(0)

87.5(0)

Pain

89.0(15.9)

91.2(14.7)

General health

60.0(12.4)

61.9(13.8)

Pro-BNP

339.7(247.4)

342.1(206.3)

Table-2

Mean Difference Before receiving L-citrulline malate – After receiving L-citrulline malate (CI)

P-Value

Walking distance at 6 min

-44.1(-73.2 to -15.1)

0.005

Pulmonary-artery pressure

4.2(1.0 to 7.4)

0.01

SF36

Physical functioning

-2.8(-5.1 to -0.58)

0.02

Limit due to physical health

Not changed

-

Limit due to emotional health

Not changed

-

Energy-fatigue

-5.4(-7.9 to -3.0)

<0.001

Emotional well being

-0.95(-1.8 to -0.1)

0.02

Social functioning

Not changed

-

Pain

-2.2(-4.0 to -0.4)

0.02

General health

-2.0(-3.2 to -0.7)

0.004

Pro-BNP

-2.4(-76.8 to -72.0)

0.9

Safety

Most adverse events were mild to moderate in intensity for all participants; adverse events that were considered in the present study were edema in terminal limbs; urine frequency; increased cough and heart burn in tow patients.

Discussion

In this randomized, clinical trial, before and after study, L-citrulline malate significantly improved exercise capacity, as assessed according to the six-minute walking test, in patients with pulmonary arterial hypertension, whether it was idiopathic or congenital systemic-to-pulmonary shunts. The study was not designed to assess mortality. The six-minute walking test is an independent predictor of death in patients with idiopathic pulmonary arterial hypertension (15) and has been used as the primary end point in most clinical trials involving patients with pulmonary arterial hypertension. (16) The treatment-related increase in walking distance of 44m observed in this study is similar to the increases observed with the use of oral bosentan (44 m) (17) and is higher than the increase seen with the use of subcutaneous treprostinil (16 m) (18) and inhaled iloprost (36 m), (19) and is less than intravenous epoprostenol (47 m), (20) and with the use of oral sildenafil citrate (45 to 50 m) .(21) All patients in this present study had pulmonary arterial hypertension of WHO class II or III, representing a less sick population than other studies. In those trials, the sickest patients (those with pulmonary arterial hypertension of WHO class III or IV) had the greatest improvement in the six-minute walking distance. Previous studies have shown that short-term administration of L-arginine can improve endothelial dysfunction, which is related to reduce exercise capacity in patients with congestive heart failure (22, 23).

Thus, it is also possible that the increase in exercise capacity with L-citrulline malate regard to L-arginine may be partly attributable to improvement in endothelium dependent peripheral vasodilation in patients with pulmonary hypertension. Abnormalities in endogenous vasodilator substances such as NO have been proposed as important in the development of pulmonary hypertension (24-26). Recently, the biologic actions of L-arginine, the precursor of NO, have been examined in a variety of cardiovascular diseases (22, 27-29). However, the therapeutic potential of orally administered L-citrulline malate in patients with pulmonary hypertension remains unknown.

The consequence of the oral supplementation of L-citrulline malate was significant decreases in mean pulmonary arterial pressure and was similar to those observed with intravenous epoprostenol (20) and oral bosentan (17) in smaller studies.These results suggest that L-citrulline malate may cause pulmonary vasodilation at least partly via a NO-mediated mechanism.

L-citrulline malate also significantly improved the quality of life in these patients. Physical functioning, energy-fatigue, emotional well being, pain and general health were improved in this present study. No patient changed in limit due to physical health, limit due to emotional health and social functioning. This study also demonstrated no reduction in pro-BNP plasma level of these patients, but one-week supplementation of L-arginine tended to decrease plasma ANP and BNP, potential markers of right ventricular dysfunction (30, 31). With the dose of L-citrulline malate, most adverse events were of mild to moderate severity, and there were no clinically significant changes in laboratory variables. Complex delivery systems, significant side effects, or both, are associated with intravenous epoprostenol (e.g., catheter-related infections, sepsis, and pump malfunctions), (20) subcutaneous treprostinil (infusion-site pain), (18) inhaled iloprost (multiple daily inhalations), (19) and oral bosentan (abnormalities of hepatic function). (17)

Limitation of this study

Conclusion

Short-term oral administration of L-citrulline malate modestly decreased pulmonary arterial hypertension and improved exercise capacity, and quality of life without serious adverse effects in patients with pulmonary arterial hypertension (IPAH, Eisenmenger syndrome).