818
SHORT REPORTS Inhaled nitric oxide in
persistent pulmonary hypertension of the newborn
Nitric oxide (NO) has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at FO2 0·9 for up to 30 minutes by 6 infants with persistent pulmonary hypertension of the newborn (PPHN). In all infants this treatment rapidly and significantly increased preductal oxygen saturation (SpO2); in 5 infants postductal SpO2 and oxygen tensions also increased. Inhalation of NO did
systemic hypotension or raise methaemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxaemia due to PPHN. not
cause
Lancet 1992; 340: 818-19.
precise cause of pulmonary vasoconstriction in persistent pulmonary hypertension of the newborn (PPHN) is unknown. Pulmonary vasodilators are often ineffective and can produce systemic hypotension. Nitric oxide (NO) seems to have identical activity to endothelium-derived relaxing factoris produced in endothelial cells,3A and diffuses into underlying vascular smooth muscle. When NO diffuses into the intravascular space, it rapidly binds with haemoglobin, thereby limiting its vasodilatory effects to the pulmonary vasculature.z Inhaled NO reduces pulmonary vascular resistance in adults with primary pulmonary hypertension,s and it is a pulmonary vasodilator in hypoxic sheep.’ In the hypoxic newborn lamb inhaled NO rapidly reduces pulmonary artery pressure and increases pulmonary blood flow without reducing systemic vascular resistance or dilating the ductus arteriosus.7 We therefore examined whether inhaled NO could improve preductal and postductal oxygen saturation and postductal oxygen tension in babies with severe systemic hypoxaemia due to PPHN. The
Seven trials of NO inhalation were done in 6 severely hypoxaemic full-term infants with a clinical diagnosis of PPHN. While intubated and mechanically ventilated with a fraction of inspired oxygen (F,Oz) of 1-0, the 6 infants were hypoxaemic with a descending aorta (postductal) arterial oxygen pressure (Pa02) of 5-2 (SEM 0-4) kPa before treatment with inhaled NO. Hypoxaemia had not improved despite mechanical ventilation at high rates and high mean airway pressures, and treatment with narcotics and neuromuscular blocking agents. 1 patient (no 6) received two trials of NO inhalation; each inhalation was begun when severe hypoxaemia recurred on removal of cannulas after one week of extracorporeal membrane oxygenation (ECMO). 3 patients had meconium aspiration at delivery and/or pneumothoraces treated with thoracostomy tubes before treatment with NO inhalation. 4 infants were receiving infusions of sodium bicarbonate; 5 were receiving infusions of 10 )ig/kg per min or more of dopamine. Echocardiograms showed right-to-left shunting of blood across the ductus arteriosus, interventricular septal flattening, tricuspid regurgitation, and no structural heart disease. A postductal arterial
catheter allowed measurement of mean aortic pressure, and intermittent measurement of blood gas tensions. Right arm (preductal) and postductal oxygen saturation (Sp02) were continuously monitored by pulse oximetry. Pressure-limited mechanical ventilation as well as vasopressor and fluid administration rates remained constant. To measure the effects of inhaling low concentrations of NO, F,O, was first reduced to 09 to allow the administration of NO diluted in nitrogen. NO gas (800-1000 parts per million [ppm] in N2) was mixed with N2 with a standard low-flow blender. The NO and N2 gas mixture was introduced into the inspiratory limb of the breathing circuit of a continuous flow, pressure-limited ventilator. For was measured after NO-containing gases mixed with ventilator gases. Inspired NO concentration and F O2 were regulated separately. Inhaled concentrations of NO and N02 were measured continuously at the endotracheal tube with chemiluminescence. Exhaled gases, as well as those discharging from the chemiluminescence instrument were scavenged. To decrease the residence time within the breathing circuit total gas flow rate from the ventilator was maintained above 10 1/min, producing inhaled N02 concentrations that were never more than 2% of the NO level. We investigated the effects of sequentially breathing 20, 40, and 80 ppm NO. Postductal arterial blood gas tensions, preductal and postductal Sp02’ and mean systemic arterial pressures (Po) were assessed after 10 min periods. These investigations were done with approval by the hospital subcommittee for human studies and an investigational new drug approval by the US Food and Drug Administration. Informed consent was obtained from each infant’s family. All data are shown as mean (SEM). Analysis of variance with repeated measures was used; a posteriori testing was done with a Scheffe F-test. p values of 5% or less were regarded as significant.
Reducing the F O2 to 0 9 did not alter the postductal Pa02 (table). In each patient with low preductal saturation, breathing 80 ppm NO rapidly increased the preductal Sp02’ In all but 1 patient inhaled NO raised postductal Sp02 (figure). Inhalation of 80 ppm NO for 10 min raised the postductal Pa02 in five of seven trials (p < 005). Inhaling less than 80 ppm NO did not lead to much improvement in
postductal oxygen tension. In none of the seven trials did inhaling NO cause systemic hypotension or a change in pHa or PaC02. Methaemoglobin concentrations were not changed after 30 min of NO (before 0-8 SEM [0-4]%, after 0,9 [0’1]%, n = 5). After the 30 min trial, inhaled NO
was
discontinued.
Only the systemic oxygenation of patient 1 continued to improve. Mechanical ventilation was rapidly reduced and this patient was extubated by day 3 of life. Hypoxaemia returned within 5 min in the other 5 infants (patients 2-6). NO was again inhaled by patients 4 and 5 to reverse hypoxaemia while ECMO cannulation was instituted. After a second inhaled NO trial, patient 6 breathed low concentrations of NO for 23 days since a third cannulation for ECMO was not possible. On each day inhaled NO was reduced over 30 min; a median concentration of 20 ppm NO (range 15-80 ppm) was needed to maintain the postductal Pa02 between 65 and 8-0 kPa. The F,02 ventilatory support level and inspired NO concentration were decreased over three weeks as postductal oxygen tensions improved. The highest daily methaemoglobin value was 2-3% in an infant PREDUCTAL AND POSTDUCTAL OXYGENATION DURING TREATMENT WITH INHALED NO
*Sp02 is oxygen saturation tn %, tin itia oxygen saturation and tensions before study, #values after baseline period of breathing at F,O, 0 9 without inhaled NO
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
SHORT REPORTS Inhaled nitric oxide in
persistent pulmonary hypertension of the newborn
Nitric oxide (NO) has vasodilatory effects on the pulmonary vasculature in adults and animals. We examined the effects on systemic oxygenation and blood pressure of inhaling up to 80 parts per million by volume of NO at FO2 0·9 for up to 30 minutes by 6 infants with persistent pulmonary hypertension of the newborn (PPHN). In all infants this treatment rapidly and significantly increased preductal oxygen saturation (SpO2); in 5 infants postductal SpO2 and oxygen tensions also increased. Inhalation of NO did
systemic hypotension or raise methaemoglobin. These data suggest that low levels of inhaled NO have an important role in the reversal of hypoxaemia due to PPHN. not
cause
Lancet 1992; 340: 818-19.
precise cause of pulmonary vasoconstriction in persistent pulmonary hypertension of the newborn (PPHN) is unknown. Pulmonary vasodilators are often ineffective and can produce systemic hypotension. Nitric oxide (NO) seems to have identical activity to endothelium-derived relaxing factoris produced in endothelial cells,3A and diffuses into underlying vascular smooth muscle. When NO diffuses into the intravascular space, it rapidly binds with haemoglobin, thereby limiting its vasodilatory effects to the pulmonary vasculature.z Inhaled NO reduces pulmonary vascular resistance in adults with primary pulmonary hypertension,s and it is a pulmonary vasodilator in hypoxic sheep.’ In the hypoxic newborn lamb inhaled NO rapidly reduces pulmonary artery pressure and increases pulmonary blood flow without reducing systemic vascular resistance or dilating the ductus arteriosus.7 We therefore examined whether inhaled NO could improve preductal and postductal oxygen saturation and postductal oxygen tension in babies with severe systemic hypoxaemia due to PPHN. The
Seven trials of NO inhalation were done in 6 severely hypoxaemic full-term infants with a clinical diagnosis of PPHN. While intubated and mechanically ventilated with a fraction of inspired oxygen (F,Oz) of 1-0, the 6 infants were hypoxaemic with a descending aorta (postductal) arterial oxygen pressure (Pa02) of 5-2 (SEM 0-4) kPa before treatment with inhaled NO. Hypoxaemia had not improved despite mechanical ventilation at high rates and high mean airway pressures, and treatment with narcotics and neuromuscular blocking agents. 1 patient (no 6) received two trials of NO inhalation; each inhalation was begun when severe hypoxaemia recurred on removal of cannulas after one week of extracorporeal membrane oxygenation (ECMO). 3 patients had meconium aspiration at delivery and/or pneumothoraces treated with thoracostomy tubes before treatment with NO inhalation. 4 infants were receiving infusions of sodium bicarbonate; 5 were receiving infusions of 10 )ig/kg per min or more of dopamine. Echocardiograms showed right-to-left shunting of blood across the ductus arteriosus, interventricular septal flattening, tricuspid regurgitation, and no structural heart disease. A postductal arterial
catheter allowed measurement of mean aortic pressure, and intermittent measurement of blood gas tensions. Right arm (preductal) and postductal oxygen saturation (Sp02) were continuously monitored by pulse oximetry. Pressure-limited mechanical ventilation as well as vasopressor and fluid administration rates remained constant. To measure the effects of inhaling low concentrations of NO, F,O, was first reduced to 09 to allow the administration of NO diluted in nitrogen. NO gas (800-1000 parts per million [ppm] in N2) was mixed with N2 with a standard low-flow blender. The NO and N2 gas mixture was introduced into the inspiratory limb of the breathing circuit of a continuous flow, pressure-limited ventilator. For was measured after NO-containing gases mixed with ventilator gases. Inspired NO concentration and F O2 were regulated separately. Inhaled concentrations of NO and N02 were measured continuously at the endotracheal tube with chemiluminescence. Exhaled gases, as well as those discharging from the chemiluminescence instrument were scavenged. To decrease the residence time within the breathing circuit total gas flow rate from the ventilator was maintained above 10 1/min, producing inhaled N02 concentrations that were never more than 2% of the NO level. We investigated the effects of sequentially breathing 20, 40, and 80 ppm NO. Postductal arterial blood gas tensions, preductal and postductal Sp02’ and mean systemic arterial pressures (Po) were assessed after 10 min periods. These investigations were done with approval by the hospital subcommittee for human studies and an investigational new drug approval by the US Food and Drug Administration. Informed consent was obtained from each infant’s family. All data are shown as mean (SEM). Analysis of variance with repeated measures was used; a posteriori testing was done with a Scheffe F-test. p values of 5% or less were regarded as significant.
Reducing the F O2 to 0 9 did not alter the postductal Pa02 (table). In each patient with low preductal saturation, breathing 80 ppm NO rapidly increased the preductal Sp02’ In all but 1 patient inhaled NO raised postductal Sp02 (figure). Inhalation of 80 ppm NO for 10 min raised the postductal Pa02 in five of seven trials (p < 005). Inhaling less than 80 ppm NO did not lead to much improvement in
postductal oxygen tension. In none of the seven trials did inhaling NO cause systemic hypotension or a change in pHa or PaC02. Methaemoglobin concentrations were not changed after 30 min of NO (before 0-8 SEM [0-4]%, after 0,9 [0’1]%, n = 5). After the 30 min trial, inhaled NO
was
discontinued.
Only the systemic oxygenation of patient 1 continued to improve. Mechanical ventilation was rapidly reduced and this patient was extubated by day 3 of life. Hypoxaemia returned within 5 min in the other 5 infants (patients 2-6). NO was again inhaled by patients 4 and 5 to reverse hypoxaemia while ECMO cannulation was instituted. After a second inhaled NO trial, patient 6 breathed low concentrations of NO for 23 days since a third cannulation for ECMO was not possible. On each day inhaled NO was reduced over 30 min; a median concentration of 20 ppm NO (range 15-80 ppm) was needed to maintain the postductal Pa02 between 65 and 8-0 kPa. The F,02 ventilatory support level and inspired NO concentration were decreased over three weeks as postductal oxygen tensions improved. The highest daily methaemoglobin value was 2-3% in an infant PREDUCTAL AND POSTDUCTAL OXYGENATION DURING TREATMENT WITH INHALED NO
*Sp02 is oxygen saturation tn %, tin itia oxygen saturation and tensions before study, #values after baseline period of breathing at F,O, 0 9 without inhaled NO
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
