seiecieD RepORis Longterm Favorable Effect of Oxygen Administration on a Patient with Primary Pulmonary Hypertension*
Table 1—Effect of Oxygen and Vasoactive Agents on Pulmonary Arterial Pressure and Systemic Blood Pressure in a Patient with Primary Pulmonary Hyperten sion
Pressure Condition and (mean) BP Kouto2 and Hg110/32(62)94/12(42)100/24(52)90/14(49)72/10(34)76/18(43)70/ mm Hg120/60125/45120/60110/50120/50115/60110/55110 mm TreatmentAwakoControlOxygenPhcntolamineAsleepControlOxygenPhenoxybenzamineOxyge
nasal10 L/min,
PA*2 rng, intra
Ytifcio Nagasaka M.D.; Hiroshi Akutsu M.D.; yong Sik Lee M.D.; S/iiro Ftijimoto M.D.; and Junji Chikamori M.D.
nasal10 L/min, po2mg, nasal+5 L/min,
A 17-year-old girl with primary pulmonary hypertension was treated with longterm administration of oxygen. Oxygen was delivered only at night for eight hours daily. Her clinical status has been improved for more than 17 months. Cardiac catheterization revealed almost 50 percent reduction of pulmonary vascular resistance. This is the first known report of successful treatment of pri mary pulmonary hypertension with oxygen administra tion.
*PA: pulmonary artery. **AT: angiotensin.
Primary pulmonary hypertension is a progressive dis ease of unknown cause. Regression of this disease is extremely rare and we could find only one case in which regression of this disease process was noted.1 In the following case of advanced primary pulmonary hyper tension, use of oxygen with oral phenoxybenzamine was found to be effective while monitoring the pulmonary arterial pressure. During the night, administration of oxygen with phenoxybenzamine was tried and after 17 months' follow-up, considerable beneficial effect has
hospital day without complications. A Swan-Ganz catheter was placed in the main pulmonary artery for 24 hours. Some vasodilating drugs and oxygen were administered and the response of pulmonary and systemic arterial pressure was recorded. The pulmonary arterial pressure while the patient was awake was considerably higher than when she was asleep, and hence, the effect of treatment was noted with each control pressure reading (Table 1). The combined use of phenoxybenzamine and oxygen resulted in maximal pul monary arterial pressure reduction.
rectal500 mg, ng/kg/min,intra PA*10 mg, intra PA*
Table 2—Pulmonary Arterial Pressure and Pulmonary Vascular Resistance during the Three Years of Observation in a Patient with Primary Pulmonary Hypertension
been observed.
CASE REPORT A 14-year-old girl was admitted to National Kinki-Chuo Hospital because of increasing dyspnea in July, 1976. She was well until age seven when she first noted dyspnea on exertion. She was diagnosed as having primary pulmonary hypertension in 1974, at the age of 12. Reserpine and phenoxybenzamine were prescribed without symptomatic re lief. In July, 1976, she noted increasing dyspnea with influ enza-like symptoms and was admitted to the hospital. Physical examination on admission revealed an obese girl who appeared acutely ill. Prominent pulmonary arterial thrust and pulmonic valve closure were felt. Atrial gallop sound and Graham-Steell murmur were heard. The lungs were clear. No peripheral edema, clubbing or cyanosis was found. Raynaud's phenomenon was not observed. Electrocar diogram revealed right axis deviation and right ventricular hypertrophy. X-ray film of the chest demonstrated an en larged right ventricle and main pulmonary artery. Pulmonary function studies were normal except for slightly decreased carbon monoxide diffusing capacity. Cardiac catheterization was performed on the seventh "From the National Kinki-Chuo Hospital, Sakai City, Japan. Reprint requests: Dr. Nagasaka, National Kinki-Chuo Hos pital, 1180 Nagasone, Sakai City, Osaka, Japan 591
CHEST,74: 3, SEPTEMBER, 1978
Phenoxybenza 4(28)92/16(52)102/22(56)82/16(42)Systemic po50mg mineIndomethaoinl-Sar-8-Ileu-At**-IIDipyridamolcPA*
Pressure dyne, sec, (mean) cm-61480 Hg145/65(100) mm
ofExaminationAug Date
mcntfNone
30, 1974 Aug 22, 1975 Reserpine 0.3 mg
110/50 (70) 1470
1380 Reserpine 0.3 mgPA* 132/66 (85)TPVR** Aug 6, 1976Treat +Phenoxybenzamine 25 mg
Sept 14, 1976 Reserpine +Phenoxy 25 mg +Oxygen 8 hours Mar 25, 1977
0.3 mg benzamine
83/20 (50)
710
92/28 (56)
690
2L/min, daily
same as the above
*PA, pulmonary artery. **TPVR, total pulmonary vascular resistance. •¿ (Treatment,administered for at least four weeks prior to the date of exermination.
FAVORABLE EFFECT OF0? IN PRIMARYPULMONARY HYPERTENSION299
During the night, administration of oxygen at a rate of 2 L per min was started in addition to previously prescribed phenoxybenzamine and reserpine. Two weeks later, her dyspnea on exertion subsided. Craham-Steell murmur disap peared and pulmonary arterial thrust became faint. Four weeks later, cardiac catheterization revealed almost 50 percent reduction of pulmonary vascular resistance. With more than 17 months of follow-up study, we believe continued oxygen administration at night proved very effective. Cardiac cathe terization performed seven months later confirmed these observations (Table 2).
DISCUSSION The effect of oxygen on pulmonary arterial pressure has been well documented in congenital heart diseases only for acute conditions.-"'1 On the other hand, Bishop1 reported longterm effects of oxygen administration on cor pulmonale associated with chronic bronchitis. He revealed that oxygen administration for more than 15 hours daily was effective, but when given for less than 12 hours daily, was not effective. In our patient, the clinical course has been observed for more than three years and the clinical observation with repeated cardiac catheteri zation proved that continued oxygen therapy was effec tive. Oxygen was administered at a rate of 2 L/rnin for only eight hours daily because of her daily activity, such as going to school, but its effect was as remarkable as Bishop's cases. We observed that oxygen administration depressed the pulmonary arterial pressure and additional phenoxy benzamine further reduced the pulmonary arterial pres sure (Table 1). Phenoxybenzamine is an alpha-adrenergic blocking agent and 25 mg was prescribed daily in four divided doses. Reserpine was also prescribed for a period of time at 0.3 mg daily, as a sympathetic blocking 80
SLEEPING
AWAKING
DROWSE
DRINKINGCOLDWATER
i i I I
40
FIGURE1. Effect of sympathetic stimulation on pulmonary arterial pressure in a patient with primary pulmonary hyper tension. Awaking, laughing and drinking cold water caused tachycardia and elevation of pulmonary arterial pressure. Recordings were obtained during 24 hours of monitoring on August 6,1976. 300 NAGASAKAETAL
agent. There was other evidence that would explain the effectiveness of our combination of treatment. We ob served that sympathetic stimulation caused tachycardia and increased pulmonary arterial pressure (Fig 1). In a recent experimental study, using lobar perfusion of cat lung, alpha-adrenergic blockade reduced the pulmonary vasoconstrictor effect of hypoxia.5 Some vasoactive substances, such as angiotensin-II6 and prostaglandins' were reported to mediate pulmo nary vasoconstrictor effect of hypoxia. Inhibitor of angio tensin-II (l-Sar-8-Ileu-Angiotensin-II) and the inhibitor of prostaglandin synthetase (indomethacin) were also tried in this case; however, no beneficial effect was observed. Many drugs have been tried for the treatment of primary pulmonary hypertension, but in most cases, their effects were reported to be temporary in nature.s>9 Shettigar et al'° reported that administration of sublingual isoproterenol was effective in improving exercise tolerance for over three years, although progression of the pulmonary hypertension was observed despite its effect. Bouldillon and Oakley1 reported that the regres sion of primary pulmonary hypertension was observed after anticoagulation therapy, but the cause of regression was not clarified. In our patient, we observed the im mediate effect of oxygen and phenoxybenzamine on primary pulmonary hypertension. Following prolonged treatment her pulmonary vascular resistance decreased and her clinical status improved for more than 17 months of our observation.
REFERENCES 1 Bouldillon PDV, Oakley CM: Regression of primary pulmonary hypertension. Br Heart J 38:264-270, 1976 2 Swan HJC, Burchell HB, Wood EH: Effect of oxygen on pulmonary vascular resistance in patients with pulmonary hypertension associated with atrial septal defect. Circula tion 20:66-73, 1959 3 Marshall HW, Swan HJC, Burchell HB, et al: Effect of breathing oxygen on pulmonary arterial pressure and pulmonary vascular resistance in patients with ventricular septal defect. Circulation 23:241-252, 1961 4 Bishop JM: Hypoxia and pulmonary hypertension in chronic bronchitis. Prog Resp Res 9:10-16, Basel, Karger, 1975 5 Porcclli RT, Viau A, Demeny M, et al: Relation between hypoxic pulmonary vasoconstriction, its humoral media tors and alpha-beta adrenergic receptors. Chest 71:249251, 1977 6 Berkov S: Hypoxic pulmonary vasoconstriction in the rat—the necessary role of angiotensin II. Circ Res 35:256261, 1974 7 Said SI, Yoshida T, Kitamura S, et al: Pulmonary alveolar hypoxia: Release of prostaglandins and other humoral mediators. Science 185:1181-1183, 1974 8 Shinnick JP, Cudkowicz L, Blanco G, et al: A problem in pulmonary hypertension, Part 1: the clinical course. Chest 65:69-75, 1974 9 Yu PN: Primary pulmonary hypertension: Report of six cases and review of literature. Ann Intern Med 49:11381161, 1958 10 Shettigar UR, Hultgren HN, Specter M, et al: Primary pulmonary hypertension—Favorable effect of isopro terenol. N Engl J Med 295: 1414-1415, 1976
CHEST,74: 3, SEPTEMBER, 1978
Table 1—Effect of Oxygen and Vasoactive Agents on Pulmonary Arterial Pressure and Systemic Blood Pressure in a Patient with Primary Pulmonary Hyperten sion
Pressure Condition and (mean) BP Kouto2 and Hg110/32(62)94/12(42)100/24(52)90/14(49)72/10(34)76/18(43)70/ mm Hg120/60125/45120/60110/50120/50115/60110/55110 mm TreatmentAwakoControlOxygenPhcntolamineAsleepControlOxygenPhenoxybenzamineOxyge
nasal10 L/min,
PA*2 rng, intra
Ytifcio Nagasaka M.D.; Hiroshi Akutsu M.D.; yong Sik Lee M.D.; S/iiro Ftijimoto M.D.; and Junji Chikamori M.D.
nasal10 L/min, po2mg, nasal+5 L/min,
A 17-year-old girl with primary pulmonary hypertension was treated with longterm administration of oxygen. Oxygen was delivered only at night for eight hours daily. Her clinical status has been improved for more than 17 months. Cardiac catheterization revealed almost 50 percent reduction of pulmonary vascular resistance. This is the first known report of successful treatment of pri mary pulmonary hypertension with oxygen administra tion.
*PA: pulmonary artery. **AT: angiotensin.
Primary pulmonary hypertension is a progressive dis ease of unknown cause. Regression of this disease is extremely rare and we could find only one case in which regression of this disease process was noted.1 In the following case of advanced primary pulmonary hyper tension, use of oxygen with oral phenoxybenzamine was found to be effective while monitoring the pulmonary arterial pressure. During the night, administration of oxygen with phenoxybenzamine was tried and after 17 months' follow-up, considerable beneficial effect has
hospital day without complications. A Swan-Ganz catheter was placed in the main pulmonary artery for 24 hours. Some vasodilating drugs and oxygen were administered and the response of pulmonary and systemic arterial pressure was recorded. The pulmonary arterial pressure while the patient was awake was considerably higher than when she was asleep, and hence, the effect of treatment was noted with each control pressure reading (Table 1). The combined use of phenoxybenzamine and oxygen resulted in maximal pul monary arterial pressure reduction.
rectal500 mg, ng/kg/min,intra PA*10 mg, intra PA*
Table 2—Pulmonary Arterial Pressure and Pulmonary Vascular Resistance during the Three Years of Observation in a Patient with Primary Pulmonary Hypertension
been observed.
CASE REPORT A 14-year-old girl was admitted to National Kinki-Chuo Hospital because of increasing dyspnea in July, 1976. She was well until age seven when she first noted dyspnea on exertion. She was diagnosed as having primary pulmonary hypertension in 1974, at the age of 12. Reserpine and phenoxybenzamine were prescribed without symptomatic re lief. In July, 1976, she noted increasing dyspnea with influ enza-like symptoms and was admitted to the hospital. Physical examination on admission revealed an obese girl who appeared acutely ill. Prominent pulmonary arterial thrust and pulmonic valve closure were felt. Atrial gallop sound and Graham-Steell murmur were heard. The lungs were clear. No peripheral edema, clubbing or cyanosis was found. Raynaud's phenomenon was not observed. Electrocar diogram revealed right axis deviation and right ventricular hypertrophy. X-ray film of the chest demonstrated an en larged right ventricle and main pulmonary artery. Pulmonary function studies were normal except for slightly decreased carbon monoxide diffusing capacity. Cardiac catheterization was performed on the seventh "From the National Kinki-Chuo Hospital, Sakai City, Japan. Reprint requests: Dr. Nagasaka, National Kinki-Chuo Hos pital, 1180 Nagasone, Sakai City, Osaka, Japan 591
CHEST,74: 3, SEPTEMBER, 1978
Phenoxybenza 4(28)92/16(52)102/22(56)82/16(42)Systemic po50mg mineIndomethaoinl-Sar-8-Ileu-At**-IIDipyridamolcPA*
Pressure dyne, sec, (mean) cm-61480 Hg145/65(100) mm
ofExaminationAug Date
mcntfNone
30, 1974 Aug 22, 1975 Reserpine 0.3 mg
110/50 (70) 1470
1380 Reserpine 0.3 mgPA* 132/66 (85)TPVR** Aug 6, 1976Treat +Phenoxybenzamine 25 mg
Sept 14, 1976 Reserpine +Phenoxy 25 mg +Oxygen 8 hours Mar 25, 1977
0.3 mg benzamine
83/20 (50)
710
92/28 (56)
690
2L/min, daily
same as the above
*PA, pulmonary artery. **TPVR, total pulmonary vascular resistance. •¿ (Treatment,administered for at least four weeks prior to the date of exermination.
FAVORABLE EFFECT OF0? IN PRIMARYPULMONARY HYPERTENSION299
During the night, administration of oxygen at a rate of 2 L per min was started in addition to previously prescribed phenoxybenzamine and reserpine. Two weeks later, her dyspnea on exertion subsided. Craham-Steell murmur disap peared and pulmonary arterial thrust became faint. Four weeks later, cardiac catheterization revealed almost 50 percent reduction of pulmonary vascular resistance. With more than 17 months of follow-up study, we believe continued oxygen administration at night proved very effective. Cardiac cathe terization performed seven months later confirmed these observations (Table 2).
DISCUSSION The effect of oxygen on pulmonary arterial pressure has been well documented in congenital heart diseases only for acute conditions.-"'1 On the other hand, Bishop1 reported longterm effects of oxygen administration on cor pulmonale associated with chronic bronchitis. He revealed that oxygen administration for more than 15 hours daily was effective, but when given for less than 12 hours daily, was not effective. In our patient, the clinical course has been observed for more than three years and the clinical observation with repeated cardiac catheteri zation proved that continued oxygen therapy was effec tive. Oxygen was administered at a rate of 2 L/rnin for only eight hours daily because of her daily activity, such as going to school, but its effect was as remarkable as Bishop's cases. We observed that oxygen administration depressed the pulmonary arterial pressure and additional phenoxy benzamine further reduced the pulmonary arterial pres sure (Table 1). Phenoxybenzamine is an alpha-adrenergic blocking agent and 25 mg was prescribed daily in four divided doses. Reserpine was also prescribed for a period of time at 0.3 mg daily, as a sympathetic blocking 80
SLEEPING
AWAKING
DROWSE
DRINKINGCOLDWATER
i i I I
40
FIGURE1. Effect of sympathetic stimulation on pulmonary arterial pressure in a patient with primary pulmonary hyper tension. Awaking, laughing and drinking cold water caused tachycardia and elevation of pulmonary arterial pressure. Recordings were obtained during 24 hours of monitoring on August 6,1976. 300 NAGASAKAETAL
agent. There was other evidence that would explain the effectiveness of our combination of treatment. We ob served that sympathetic stimulation caused tachycardia and increased pulmonary arterial pressure (Fig 1). In a recent experimental study, using lobar perfusion of cat lung, alpha-adrenergic blockade reduced the pulmonary vasoconstrictor effect of hypoxia.5 Some vasoactive substances, such as angiotensin-II6 and prostaglandins' were reported to mediate pulmo nary vasoconstrictor effect of hypoxia. Inhibitor of angio tensin-II (l-Sar-8-Ileu-Angiotensin-II) and the inhibitor of prostaglandin synthetase (indomethacin) were also tried in this case; however, no beneficial effect was observed. Many drugs have been tried for the treatment of primary pulmonary hypertension, but in most cases, their effects were reported to be temporary in nature.s>9 Shettigar et al'° reported that administration of sublingual isoproterenol was effective in improving exercise tolerance for over three years, although progression of the pulmonary hypertension was observed despite its effect. Bouldillon and Oakley1 reported that the regres sion of primary pulmonary hypertension was observed after anticoagulation therapy, but the cause of regression was not clarified. In our patient, we observed the im mediate effect of oxygen and phenoxybenzamine on primary pulmonary hypertension. Following prolonged treatment her pulmonary vascular resistance decreased and her clinical status improved for more than 17 months of our observation.
REFERENCES 1 Bouldillon PDV, Oakley CM: Regression of primary pulmonary hypertension. Br Heart J 38:264-270, 1976 2 Swan HJC, Burchell HB, Wood EH: Effect of oxygen on pulmonary vascular resistance in patients with pulmonary hypertension associated with atrial septal defect. Circula tion 20:66-73, 1959 3 Marshall HW, Swan HJC, Burchell HB, et al: Effect of breathing oxygen on pulmonary arterial pressure and pulmonary vascular resistance in patients with ventricular septal defect. Circulation 23:241-252, 1961 4 Bishop JM: Hypoxia and pulmonary hypertension in chronic bronchitis. Prog Resp Res 9:10-16, Basel, Karger, 1975 5 Porcclli RT, Viau A, Demeny M, et al: Relation between hypoxic pulmonary vasoconstriction, its humoral media tors and alpha-beta adrenergic receptors. Chest 71:249251, 1977 6 Berkov S: Hypoxic pulmonary vasoconstriction in the rat—the necessary role of angiotensin II. Circ Res 35:256261, 1974 7 Said SI, Yoshida T, Kitamura S, et al: Pulmonary alveolar hypoxia: Release of prostaglandins and other humoral mediators. Science 185:1181-1183, 1974 8 Shinnick JP, Cudkowicz L, Blanco G, et al: A problem in pulmonary hypertension, Part 1: the clinical course. Chest 65:69-75, 1974 9 Yu PN: Primary pulmonary hypertension: Report of six cases and review of literature. Ann Intern Med 49:11381161, 1958 10 Shettigar UR, Hultgren HN, Specter M, et al: Primary pulmonary hypertension—Favorable effect of isopro terenol. N Engl J Med 295: 1414-1415, 1976
CHEST,74: 3, SEPTEMBER, 1978
