819
hypertension. Lancet 1991; 338: 1173-74. C, Fratacci MD, Wain JC, et al. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038-47. Roberts JD Jr, Chen TY, Wain J, et al. Inhaled nitric oxide is a selective pulmonary vasodilator of the hypoxic newborn lamb. Am Rev Respir Dis 1992; 145: A208. Clutton-Brock J. Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth
6. Frostell
7.
8.
1967; 39: 388-92. ADDRESSES Departments of Anesthesia (J. D Roberts, Jr, MD, D. M. Polaner, MD, Prof W. M. Zapol, MD) and Pediatrics (P. Lang, MD), Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Correspondence to Dr Jesse D Roberts Jr.
Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn
Figure-Change of preductal (0) and postductal (D) oxygen saturation (Sp02) in infants with PPHN before and during inhalation of 80 ppm NO at
F;02 09. from breathing F010
without NO. Inhalation tp < 05 value differs of 80 ppm NO increased preductal and postductal Sp02 in patients with Each point represents one hypoxaemic respiratory failure (p 40) or acute deterioration with PaOz < 40 mm Hg (5 33 kPa) despite full medical treatment. The study was approved by the institutional review board of the Children’s Hospital and by the United States Food and Drug Administration under a sponsor/investigator investigational new drug exemption. Parents gave informed consent. The study protocol specified that brief NO exposures (< 4 h) should be assessed in the first patients, with extension to 24 h in subsequent patients if there were no important side-effects. Immediately before NO treatment, echocardiographic measurements were made and post-ductal arterial blood was drawn for determination of pH, blood gas tensions, and methaemoglobin saturation. The NO gas (Airco) contained 450 ppm NO with less than 1 % contamination by other
820
TABLE [-I NDICES OF OXYGENATION AT BASELINE AND DURING FIRST 30 MIN OF NO IN 9 PATIENTS
Results are mean (SE) PaÛ2 in kPa; PaCÛ2 in kPa; ajA02= arterial/alveolar oxygen ratio; 01 =oxygenation mdex; BP=mean blood pressure (mm Hg)
oxides of nitrogen. It was introduced into the afferent limb of the ventilator circuit via an adaptor fitted within 25 cm of the endotracheal tube, thus mixing with the fixed flow rate of circuit gas. The resulting concentrations of inhaled NO were verified on-line by chemiluminescence. NO at 10 and 20 ppm was sequentially administered for 15 min periods with arterial blood gas tensions and methaemoglobin measured at each dose. During the extended treatment protocol, arterial blood gases, methaemoglobin levels, and systemic arterial blood pressure were recorded at baseline, 15 min, 30 min, 60 min, 90 min, 4 h, 12 h, and 24 h. Mean birthweight of the infants was 3295 g (range 2540-4610) and mean gestational age was 39 weeks (range 35-42). 4 had idiopathic PPHN; 5 had meconium aspiration syndrome and/or sepsis. 6 patients had PaOz less than 49
kPa immediately before NO treatment. The first 3 were treated with NO for less than 4 h, followed by ECMO. The next 6 were treated for 24 h and did not require ECMO. TableI shows patient indices for the first 30 min of NO at concentrations of 10 and 20 ppm. The oxygen index fell by 66% over the first 30 min without a fall in systemic arterial blood pressure. Oxygenation improved progressively with 20 ppm NO over the first study period of 4 h. In 6 patients treated with low dose NO (6 ppm), the improvement in oxygenation was sustained (table n and figure). None of the patients had a sustained rise in methaemoglobin to > 1 5%. Systemic arterial blood pressure was stable over the entire period of NO inhalation. These 6 patients subsequently recovered without the need for ECMO, were weaned from ventilator and supplemental oxygen therapy within the first month of life, and showed no evidence of chronic lung disease. Recently recognised as the endothelium-derived relaxing factor (EDRF), NO directly stimulates cyclic GMP in vascular smooth muscle, causing relaxation.5,6 Enhanced EDRF/NO activity has been shown to contribute to the normal decline in pulmonary vascular resistance at birth, and it is possible that decreased production of endogenous NO contributes to the failure of postnatal pulmonary vascular adaptation.’ When administered by inhalation, NO diffuses to vascular smooth muscle from the alveolar side. Avid binding of NO by haemoglobin decreases its availability for causing systemic vasodilatation, allowing for selective pulmonary vasodilatation.6 In our study a selective lowering of pulmonary vascular resistance decreased rightto-left shunting and thus increased pulmonary blood flow and oxygenation. Since NO is administered by inhalation, it will most effectively dilate pulmonary blood vessels that are TABLE II-INDICES OF OXYGENATION WITH LONG-TERM NO IN 6 PATIENTS
TIME (hours) arterial/alveolar oxygen tension ratio changes (a/A02) for 6 patients over 24 h of NO inhalation. in
Serial
associated with the best ventilated
lung units, enhancing ventilation-perfusion matching. This study was designed to investigate the haemodynamic effects of inhaled NO within "non-toxic" concentrations. We have shown improvement in oxygenation without tachyphylaxis but we need to learn more about the hazards of methaemoglobinaemia, increased N02 production, and increased oxidant stress from formation of peroxynitrite.8 Experimental work on toxicity should include not only healthy animals but also immature animals with decreased host antioxidant defences or with lung inflammation. An advantage over primary pulmonary hypertension in adults is that a short-term reduction in pulmonary vascular resistance will often be sufficient to resolve PPHN. The next stage, before controlled clinical trials, is to determine the most effective timing, dose, and duration of NO treatment in PPHN. We thank J. Schmidt, RRT, J. Griebel, RRT, and D. Swanton, RRT, for support. This work was funded in part by grants from the National Institutes of Health (HL-01932, HL-41012, HL-46481). REFERENCES 1. Levin
DL, Heymann MA, Kitterman JA,
et
al. Persistent
pulmonary
hypertension of the newborn. J Pediatr 1976; 89: 626. 2. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. 3.
4.
5.
Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338: 1173-74. Roberts JD Jr, Polaner DM, Todres ID, Lang P, Zapol WM. Inhaled nitric oxide (NO): a selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Circulation 1991; 84: A1279. Kinsella JP, McCurnin DC, Clark RH, et al. Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO. J Pediatr Surg 1992; 27: 46-47. Ignarro LJ. Biological actions and properties of endothelial-derived nitric
oxide formed and released from artery and vein. Circulation Res 1989; 65: 1-21. 6. Kinsella JP, McQueston J, Rosenberg AA, Abman SH. Hemodynamic effects of exogenous nitric oxide in the ovine transitional pulmonary circulation. Am J Physiol (Heart Circ Physiol 32). 7. Abman SH, Chatfield BA, Hall SL, Mcmurtry IF. Role of EDRF during transition of pulmonary circulation at birth. Am J Physiol 1990; 259: H1921-27. 8. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implicatons for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990; 87: 1620-24.
ADDRESSES:
Department of Pediatrics, Divisions of Neonatology, Cardiology, and Pulmonary Medicine, Children’s Hospital and the University of Colorado School of Medicine, Denver, Colorado, USA (J. P. Kinsella, MD, S R. Neish, MD, E Shaffer, MD, S. H. Abman, MD). Correspondence to Dr John P. Kinsella,
Division of Neonatology, Box B-070, Children’s Hospital, 1056 E. 19th Avenue, Denver, CO 80218-1088, USA
h0=!nspred
oxygen concentration.
hypertension. Lancet 1991; 338: 1173-74. C, Fratacci MD, Wain JC, et al. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991; 83: 2038-47. Roberts JD Jr, Chen TY, Wain J, et al. Inhaled nitric oxide is a selective pulmonary vasodilator of the hypoxic newborn lamb. Am Rev Respir Dis 1992; 145: A208. Clutton-Brock J. Two cases of poisoning by contamination of nitrous oxide with higher oxides of nitrogen during anaesthesia. Br J Anaesth
6. Frostell
7.
8.
1967; 39: 388-92. ADDRESSES Departments of Anesthesia (J. D Roberts, Jr, MD, D. M. Polaner, MD, Prof W. M. Zapol, MD) and Pediatrics (P. Lang, MD), Massachusetts General Hospital, Boston, Massachusetts 02114, USA. Correspondence to Dr Jesse D Roberts Jr.
Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn
Figure-Change of preductal (0) and postductal (D) oxygen saturation (Sp02) in infants with PPHN before and during inhalation of 80 ppm NO at
F;02 09. from breathing F010
without NO. Inhalation tp < 05 value differs of 80 ppm NO increased preductal and postductal Sp02 in patients with Each point represents one hypoxaemic respiratory failure (p 40) or acute deterioration with PaOz < 40 mm Hg (5 33 kPa) despite full medical treatment. The study was approved by the institutional review board of the Children’s Hospital and by the United States Food and Drug Administration under a sponsor/investigator investigational new drug exemption. Parents gave informed consent. The study protocol specified that brief NO exposures (< 4 h) should be assessed in the first patients, with extension to 24 h in subsequent patients if there were no important side-effects. Immediately before NO treatment, echocardiographic measurements were made and post-ductal arterial blood was drawn for determination of pH, blood gas tensions, and methaemoglobin saturation. The NO gas (Airco) contained 450 ppm NO with less than 1 % contamination by other
820
TABLE [-I NDICES OF OXYGENATION AT BASELINE AND DURING FIRST 30 MIN OF NO IN 9 PATIENTS
Results are mean (SE) PaÛ2 in kPa; PaCÛ2 in kPa; ajA02= arterial/alveolar oxygen ratio; 01 =oxygenation mdex; BP=mean blood pressure (mm Hg)
oxides of nitrogen. It was introduced into the afferent limb of the ventilator circuit via an adaptor fitted within 25 cm of the endotracheal tube, thus mixing with the fixed flow rate of circuit gas. The resulting concentrations of inhaled NO were verified on-line by chemiluminescence. NO at 10 and 20 ppm was sequentially administered for 15 min periods with arterial blood gas tensions and methaemoglobin measured at each dose. During the extended treatment protocol, arterial blood gases, methaemoglobin levels, and systemic arterial blood pressure were recorded at baseline, 15 min, 30 min, 60 min, 90 min, 4 h, 12 h, and 24 h. Mean birthweight of the infants was 3295 g (range 2540-4610) and mean gestational age was 39 weeks (range 35-42). 4 had idiopathic PPHN; 5 had meconium aspiration syndrome and/or sepsis. 6 patients had PaOz less than 49
kPa immediately before NO treatment. The first 3 were treated with NO for less than 4 h, followed by ECMO. The next 6 were treated for 24 h and did not require ECMO. TableI shows patient indices for the first 30 min of NO at concentrations of 10 and 20 ppm. The oxygen index fell by 66% over the first 30 min without a fall in systemic arterial blood pressure. Oxygenation improved progressively with 20 ppm NO over the first study period of 4 h. In 6 patients treated with low dose NO (6 ppm), the improvement in oxygenation was sustained (table n and figure). None of the patients had a sustained rise in methaemoglobin to > 1 5%. Systemic arterial blood pressure was stable over the entire period of NO inhalation. These 6 patients subsequently recovered without the need for ECMO, were weaned from ventilator and supplemental oxygen therapy within the first month of life, and showed no evidence of chronic lung disease. Recently recognised as the endothelium-derived relaxing factor (EDRF), NO directly stimulates cyclic GMP in vascular smooth muscle, causing relaxation.5,6 Enhanced EDRF/NO activity has been shown to contribute to the normal decline in pulmonary vascular resistance at birth, and it is possible that decreased production of endogenous NO contributes to the failure of postnatal pulmonary vascular adaptation.’ When administered by inhalation, NO diffuses to vascular smooth muscle from the alveolar side. Avid binding of NO by haemoglobin decreases its availability for causing systemic vasodilatation, allowing for selective pulmonary vasodilatation.6 In our study a selective lowering of pulmonary vascular resistance decreased rightto-left shunting and thus increased pulmonary blood flow and oxygenation. Since NO is administered by inhalation, it will most effectively dilate pulmonary blood vessels that are TABLE II-INDICES OF OXYGENATION WITH LONG-TERM NO IN 6 PATIENTS
TIME (hours) arterial/alveolar oxygen tension ratio changes (a/A02) for 6 patients over 24 h of NO inhalation. in
Serial
associated with the best ventilated
lung units, enhancing ventilation-perfusion matching. This study was designed to investigate the haemodynamic effects of inhaled NO within "non-toxic" concentrations. We have shown improvement in oxygenation without tachyphylaxis but we need to learn more about the hazards of methaemoglobinaemia, increased N02 production, and increased oxidant stress from formation of peroxynitrite.8 Experimental work on toxicity should include not only healthy animals but also immature animals with decreased host antioxidant defences or with lung inflammation. An advantage over primary pulmonary hypertension in adults is that a short-term reduction in pulmonary vascular resistance will often be sufficient to resolve PPHN. The next stage, before controlled clinical trials, is to determine the most effective timing, dose, and duration of NO treatment in PPHN. We thank J. Schmidt, RRT, J. Griebel, RRT, and D. Swanton, RRT, for support. This work was funded in part by grants from the National Institutes of Health (HL-01932, HL-41012, HL-46481). REFERENCES 1. Levin
DL, Heymann MA, Kitterman JA,
et
al. Persistent
pulmonary
hypertension of the newborn. J Pediatr 1976; 89: 626. 2. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. 3.
4.
5.
Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991; 338: 1173-74. Roberts JD Jr, Polaner DM, Todres ID, Lang P, Zapol WM. Inhaled nitric oxide (NO): a selective pulmonary vasodilator for the treatment of persistent pulmonary hypertension of the newborn (PPHN). Circulation 1991; 84: A1279. Kinsella JP, McCurnin DC, Clark RH, et al. Cardiac performance in ECMO candidates: echocardiographic predictors for ECMO. J Pediatr Surg 1992; 27: 46-47. Ignarro LJ. Biological actions and properties of endothelial-derived nitric
oxide formed and released from artery and vein. Circulation Res 1989; 65: 1-21. 6. Kinsella JP, McQueston J, Rosenberg AA, Abman SH. Hemodynamic effects of exogenous nitric oxide in the ovine transitional pulmonary circulation. Am J Physiol (Heart Circ Physiol 32). 7. Abman SH, Chatfield BA, Hall SL, Mcmurtry IF. Role of EDRF during transition of pulmonary circulation at birth. Am J Physiol 1990; 259: H1921-27. 8. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. Apparent hydroxyl radical production by peroxynitrite: implicatons for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 1990; 87: 1620-24.
ADDRESSES:
Department of Pediatrics, Divisions of Neonatology, Cardiology, and Pulmonary Medicine, Children’s Hospital and the University of Colorado School of Medicine, Denver, Colorado, USA (J. P. Kinsella, MD, S R. Neish, MD, E Shaffer, MD, S. H. Abman, MD). Correspondence to Dr John P. Kinsella,
Division of Neonatology, Box B-070, Children’s Hospital, 1056 E. 19th Avenue, Denver, CO 80218-1088, USA
h0=!nspred
oxygen concentration.
