379
Saugstad et al, Plasma hypoxanthine and natural surfactant
J. Perinat. Med. 20(1992)379-385
Raised plasma hypoxanthine levels äs a prognostic sign in preterm babies with respiratory distress syndrome treated with natural surfactant Ola D. Saugstad1, T. Richard J. Tubman2, Kari Gloppestad1, Henry L. Halliday2, Stephanie öyasaeter1, Tore Curstedt3, and Bengt Robertson4
Department of Pediatrics, Pediatric Research and Institute for Surgical Research, Rikshospitalet, Oslo, Norway, 2The Royal Maternity Hospital, Belfast and Department of Child Health, the Queens University of Belfast, UK, 3 Department of Clinical Chemistry, Danderyd's Hospital, and 4Research Unit for Experimental Perinatal Pathology, St. Göran's Hospital, Stockholm, Sweden
l
Introduction
Since the introduction of natural surfactant treatment for babies with respiratory distress syndrome (RDS) [6] a series of reports have documented its positive effects on oxygenation, requirement for artificial Ventilation, oxygen supplementation, mortality and morbidity [2, 4, 8, 11, 22]. However, the optimal timing and dose of each surfactant preparation need to be assessed. Furthermore, although physiological [7, 10, 13] and biochemical effects of surfactant instillation have been emphasised in recent years, it is still not known whether or not surfactant treatment may induce potentially harmful changes in the baby. In tliis study we have measured plasma hypoxanthine concentrations in babies with RDS treated with a natural porcine surfactant. Plasma hypoxanthine is a marker of hypoxia and therefore may serve äs an indicator of the severity of the disease [19, 24]. Further, it is a potential free radical generator and therefore can be harmful [5, 12, 18]. In addition, we know that the hypoxanthine-xanthine oxidase System may act äs a regulator of the circulation since the combination of hypoxanthine and xanthine oxidase potently dilates the ductus arteriosus in the lamb [1] and constricts the pulmonary vessels in the rabbit and pig [15, 20, 23].
2
Patients and methods
Twelve preterm babies with RDS were treated with a porcine surfactant (Curosurf) according to criteria previously described [2]. Nine of the babies were enrolled from Oslo and three from Belfast. In brief, babies with a birth weight of 700 — 2000 g were eligible for Curosurf treatment if they had severe RDS requiring artificial ventilation with ^ 60% oxygen. RDS was defmed according to well established clinical and radiological criteria [9]. Babies with complicating diseases such äs congenital infection, prolonged rupture of membranes (^ 3 weeks), intracranial hemorrhage of grade III — IV (grading according to Papile et al [14], birth asphyxia äs indicated by seizures during first 12 hours, and major congenital anomalies were excluded. After stabilisation correcting any hypotension, metabolic acidosis, anemia, or hypoglycemia the babies were given surfactant 200 mg/kg (2.5 ml/kg), half of the dose being instilled into each main bronchus. Surfactant administration was given at a mean postnatal age of 6.8 hrs (SD 3.2 hrs, ränge 2.5-11.5hrs). Samples for blood gas and hypoxanthine analysis were taken 5 minutes before and 5, 15, 30 and 60 minutes after surfactant instillation. After surfactant was given PaO2 increased rapidly äs previously demonstrated [2]. In Oslo FiO2 was
1992 by Walter de Gruyter & Co. Berlin · New York Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
380
Saugstad et al, Plasma hypoxanthine and natural surfactant
reduced after five minutes according to the PaO2 on blood gas analysis. In Belfast it was, however, reduced more rapidly, within the first five minutes of surfactant instillation, using continuous oxygen Saturation monitoring (pulse oximetry) for guidance. Babies from the two centers were treated equally in all other respects. Blood (0.5 ml) for hypoxanthine analysis was spun down immediately and plasma frozen at -20°C until analysis by HPLC. The plasma samples were prepared by centrifugation for 30 minutes through a filter with 30.000 MW cut-off (YMT-filter, MPS-1 System, Amicon corp., Danvers, MA, USA). The chromatography was performed on a reversed-phase column (0.45 15 cm) of 5 micron material (pecosphere-5C C18, Perkin-Elmer, Norwalk, Conn, USA). The mobile phase used for the chromatography was 0.005 M KH2PO4, pH 5.7. The eluting compounds were detected at 254 nm [21, 25]. All pure Standards used for HPLC were obtained from Sigma Chemicals, St. Louis, MO, USA. The babies were divided into two groups with respect to the short-term (7 days) outcome: 1) Sunivors (seven babies) who were stabilised and initially weaned successfully from the Ventilator. Two of these babies subsequently died in the postneonatal period, one because of broncho-
pulmonary dysplasia (5 weeks of age) and one of sudden infant death syndrome (13 months of age). 2) Non-survivors, i. e. babies who after an initially favorable response to surfactant treatment with an increase in PaO2 and decrease in FiO2, could not be stabilised and weaned from the respirator and died during the first postnatal week. The project was approved by the ethical committees of each of the two hospitals and informed consent was given by the parents of the babies. 3
Results
Mean gestational age was 28.3 (SD 1.1) weeks in survivors and 27.5 (SD 2.4) weeks in nonsurvivors (NS). Mean birth weights in the two groups were 1196 (SD 162) grams and 1014 (SD 205) grams respectively (NS). 3.1
FiO2 and oxygenation
FiO2 could be reduced rapidly from a mean of 0.93 (SD 0.09) in survivors and 0.90 (SD 0.09) in non-survivors (NS) before surfactant instillation to 0.40 (SD 0.14) and 0.52 (SD 0.24) in survivors and non-survivors respectively after one hour (NS).
FiO ?
1.0
0.90.80.70.60.50.40.30.20.1 0.0
PaO 2 kPa 45 4035302520151050
SD
15
15
30
60
30
60
MIN
Figure 1. Top: FiO2 and bottom: PaO2 5min before (0 value) and 5—60 min after surfactant administration. Values are given äs mean and SD for all babies together. J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
381
Saugstad et al, Plasma hypoxanthine and natural surfactant
Before surfactant instillation mean PaO2 for surviving babies was 7.2 (SD 1.8) and 7.1 (SD 1.7) kPa for non-surviving babies (NS). Five minutes after surfactant instillation there was a rapid rise in PaO2 to a mean of 25.7 (SD 13.9) kPa in survivors and 19.6 (SD 13.5) kPa in non-survivors (NS between the two groups). PaO2 then decreased gradually, reaching a mean of 7.6 (SD 1.7) kPa and 6.5 (SD 2.0) kPa (NS) in the survivors and non-survivors respectively after 60 minutes. Figure l shows the mean FiO2 (top) and PaO2 (bottom) during the first hour after surfactant instillation. 3.2
reaching the highest level after 15 minutes (14.2, SD 7.5 μηιοΐ/l), significantly higher (p < 0.05, Mann Whitney test) when compared with survivors. After 60 minutes plasma hypoxanthine was not significantly different from initial values (mean 10.5, SD 5.9 μηιοΐ/ΐ). The maximal hypoxanthine concentration in each baby was found either at 15 or 30 minutes after surfactant instillation. The survivors had a mean maximal plasma hypoxanthine increase of only 1.9 (SD 2.9) μηιοΙ/1 compared with 9.4 (SD 8.1) μηιοΐ/ΐ in non-survivors (p < 0.05, MannWhitney U-test).
Plasma hypoxanthine and survival
The mean hypoxanthine concentration before surfactant treatment was 5.1 (SD 1.9) μηιοΐ/ΐ in survivors and 6.8 (SD 3.5) μηιοΐ/ΐ in non-survivors (NS). After surfactant was given these two groups showed two different patterns with regarcl to changes in plasma hypoxanthine concentrations (figure 2). In the surviving babies there was no significant change in plasma hypoxanthine concentration throughout the one hour study period. By contrast, in non-survivors mean plasma hypoxanthine concentration increased
3.3
Plasma hypoxanthine and intracranial hemorrhage (ICH)
Four out of five non-survivors developed intracranial hemorrhage of grade II —IV in contrast to two of the seven surviving babies (NS). The six babies with intracranial hemorrhage (grade II —IV) had a mean maximal increase of plasma hypoxanthine of 9.6 (SD 7.2) umol/1 by contrast to 1.1 (SD 0.7) umol/1 in the six babies who did not develop intracranial hemorrhage (p < 0.01, Mann Whitney U-test).
Hx micromol/l 24
201612-
8415 MIN
30
60
Figure 2. Plasma hypoxanthine (HX) concentration 5min before (0 value) and 5 — 60 min after surfactant administration. "Survivors" · —· (N = 7), were successfully weaned from the Ventilator and survived the neoriatal period. "Nonsurvivors" Δ — Δ (Ν = 5) were never weaned from the Ventilator and died during the first postnatal weck of life. Values are given s mean and SD. * p < 0.05 versus zero time values (non-survivors) and survivors versus non-survivors at 15 minutes. J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
382
Saugstad et al, Plasma hypoxanthine and natural surfactant
4 Discussion In babies with severe RDS, surfactant administration has positive effects on morbidity and mortality. Treatment with Curosurf reduces mortality by 40% in infants with severe RDS requiring artificial Ventilation with 60% oxygen or more [2]. There have been no published reports indicating that a biochemical substance can serve s a prognostic marker in surfactant treated babies. The present non-randomized report, albeit based on limited number of babies, suggests that changes in plasma hypoxanthine concentration after surfactant instillation may serve s such an indicator both for survival and development of intracranial hemorrhage. A high peak hypoxanthine concentration after surfactant instillation seems to be a poor prognostic sign since the mean maximal plasma hypoxanthine elevation was approximately five times higher in non-survivors than in surviving babies. Further, there was a significantly greater increase in plasma hypoxanthine in babies who developed intracranial hemorrhage of grade II —IV compared to babies who did not develop intracranial hemorrhage. These data should be compared with data from a recent clinical collaborative trial [3] where we noted that babies developing a high PaO2 peak (> 15 kPa) within 30 minutes of surfactant instillation had a higher incidence of grade I — II intracranial hemorrhage than babies with a PaO2 peak less than 15 kPa, although the total incidence of brain hemorrhage was not increased among surfactant treated babies. There seems to be two interpretations of the present findings: flrst, perhaps the sickest babies have the highest hypoxanthine concentration in the tissues before surfactant instillation. After surfactant is given PaO2 will increase to induce vasodilatation, resulting in a release of hypoxan-
thine from the tissues into the circulation. In such a case the augmentation of plasma hypoxanthine concentration merely reflects the severity of the respiratory distress before surfactant treatment. Judged by oxygen requirements and PaO2 before surfactant was given there was, however, no significant difference in severity of the disease between the two groups. A second explanation is that hypoxanthine generates potentially harmful oxygen radicals. Hypoxanthine is a potential oxygen radical generator in the presence of xanthine oxidase and oxygen. The combination of a high PaO2 and a high plasma hypoxanthine concentration occurring immediately after surfactant treatment may then produce an explosion in oxygen radical production [12, 18]. Babies who for some reason have a high hypoxanthine concentration in the plasma or tissues immediately after surfactant has been instilled, may therefore be more prone to injury due to free radical production. The free radicals may exert a direct damaging effect on different tissues contributing to the so called "oxygen radical disease in neonatology" [16, 17]. Although it is not known if the hypoxanthine-xanthine oxidase System exerts circulatory effects in the preterm baby s in animals [l, 15, 20, 23], this may be a reasonable assumption. It therefore seems wise to limit the rise in PaO2 after surfactant instillation by reducing the FiO2 s soon s possible [3]. In conclusion, augmentation of plasma hypoxanthine concentration after surfactant instillation may serve s a prognostic factor for survival and intracranial hemorrhage in preterm babies with severe RDS. Whether hypoxanthine also serves s a prognostic marker for complications such s retinopathy of prematurity and bronchopulmonary dysplasia remains to be elucidated.
Abstract
Plasma hypoxanthine concentration was measured in twelve preterm babies with respiratory distress syndrome (RDS) treated with 200 mg/kg of a porcine surfactant (Curosurf). Five of the babies died within one week and seven survived the neonatal period. Surviving babies had no significant changes in plasma hypoxanthine concentration throughout a one hour study period following the administration of surfactant. By contrast, in nonsurvivors the mean plasma hypoxanthine concentrations increased from 6.8 μηιοΙ/1 before surfactant administration to 14.2 μηιοΙ/1
15 minutes after surfactant treatment. Survivors had a mean maximal increase in plasma hypoxanthine of 1.9 μηιοΙ/1 15 — 30 min factor surfactant treatment compared with 9.4 μιηοΐ/ΐ in nonsurvivors (p < 0.05). The babies who developed intracranial hemorrhage had significantly higher maximal plasma hypoxanthine increase (mean 9.6 μιηοΐ/ΐ) compared with babies who did not develop intracranial hemorrhage (mean 1.1 umol/1) (p < 0.01). The combination of high PaO2 and high hypoxanthine concentration could lead to an increased production of oxygen radicals which might be
J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
Saugstad et al, Plasma hypoxanthine and natural surfactant harmful. We conclude that plasma hypoxanthine concentration may serve äs an indicator of the prognosis in preterm babies treated with natural surfactant. Fur-
383
ther, it seems important to reduce oxygen supplementation äs soon äs surfactant is given to possibly limit oxygen radical production.
Keywords: Hyperoxia, hypoxanthine, intracranial hemorrhage, oxygen radicals, respiratory distress syndrome, surfactant treatment, survival. Zusammenfassung Erhöhte Hypoxanthinspiegel im Plasma als prognostische]· Parameter bei Frühgeborenen mit RDS unter Behandlung mit natürlichem Surfactant
In dieser Untersuchung bestimmten wir die Hypoxanthinspiegel im Plasma bei Neugeborenen unter Behandlung mit natürlichem Surfactant (Curosurf). In den vergangenen Jahren wurde viel über die physiologischen und biochemischen Effekte des Surfactant berichtet. Ob jedoch auch schädliche Nebenwirkungen durch die Surfactantbehandlung induziert werden können, ist nicht bekannt. Die Hypoxanthinkonzentration im Plasma ist ein Indikator für eine Hypoxie. Darüberhinaus können aus Hypoxanthin Sauerstoffradikale gebildet werden. Nach der Behandlung mit natürlichem Surfactant steigt die Sauerstoffspannung im arteriellen Blut stark an. Zusammen mit einer hohen Hypoxanthinkonzentration könnte dies für das Kind schädlich sein. Auch ist bekannt, daß sie durch das Hypoxanthin-XanthinOxidasesystem gebildeten Sauerstoffradikale den Ductus Botalli dilatieren und die Lungengefaße verengen können. Eine hohe Hypoxanthinkonzentration nach Surfactantinstillation hat somit auch einen Einfluß auf den ]
Saugstad et al, Plasma hypoxanthine and natural surfactant
J. Perinat. Med. 20(1992)379-385
Raised plasma hypoxanthine levels äs a prognostic sign in preterm babies with respiratory distress syndrome treated with natural surfactant Ola D. Saugstad1, T. Richard J. Tubman2, Kari Gloppestad1, Henry L. Halliday2, Stephanie öyasaeter1, Tore Curstedt3, and Bengt Robertson4
Department of Pediatrics, Pediatric Research and Institute for Surgical Research, Rikshospitalet, Oslo, Norway, 2The Royal Maternity Hospital, Belfast and Department of Child Health, the Queens University of Belfast, UK, 3 Department of Clinical Chemistry, Danderyd's Hospital, and 4Research Unit for Experimental Perinatal Pathology, St. Göran's Hospital, Stockholm, Sweden
l
Introduction
Since the introduction of natural surfactant treatment for babies with respiratory distress syndrome (RDS) [6] a series of reports have documented its positive effects on oxygenation, requirement for artificial Ventilation, oxygen supplementation, mortality and morbidity [2, 4, 8, 11, 22]. However, the optimal timing and dose of each surfactant preparation need to be assessed. Furthermore, although physiological [7, 10, 13] and biochemical effects of surfactant instillation have been emphasised in recent years, it is still not known whether or not surfactant treatment may induce potentially harmful changes in the baby. In tliis study we have measured plasma hypoxanthine concentrations in babies with RDS treated with a natural porcine surfactant. Plasma hypoxanthine is a marker of hypoxia and therefore may serve äs an indicator of the severity of the disease [19, 24]. Further, it is a potential free radical generator and therefore can be harmful [5, 12, 18]. In addition, we know that the hypoxanthine-xanthine oxidase System may act äs a regulator of the circulation since the combination of hypoxanthine and xanthine oxidase potently dilates the ductus arteriosus in the lamb [1] and constricts the pulmonary vessels in the rabbit and pig [15, 20, 23].
2
Patients and methods
Twelve preterm babies with RDS were treated with a porcine surfactant (Curosurf) according to criteria previously described [2]. Nine of the babies were enrolled from Oslo and three from Belfast. In brief, babies with a birth weight of 700 — 2000 g were eligible for Curosurf treatment if they had severe RDS requiring artificial ventilation with ^ 60% oxygen. RDS was defmed according to well established clinical and radiological criteria [9]. Babies with complicating diseases such äs congenital infection, prolonged rupture of membranes (^ 3 weeks), intracranial hemorrhage of grade III — IV (grading according to Papile et al [14], birth asphyxia äs indicated by seizures during first 12 hours, and major congenital anomalies were excluded. After stabilisation correcting any hypotension, metabolic acidosis, anemia, or hypoglycemia the babies were given surfactant 200 mg/kg (2.5 ml/kg), half of the dose being instilled into each main bronchus. Surfactant administration was given at a mean postnatal age of 6.8 hrs (SD 3.2 hrs, ränge 2.5-11.5hrs). Samples for blood gas and hypoxanthine analysis were taken 5 minutes before and 5, 15, 30 and 60 minutes after surfactant instillation. After surfactant was given PaO2 increased rapidly äs previously demonstrated [2]. In Oslo FiO2 was
1992 by Walter de Gruyter & Co. Berlin · New York Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
380
Saugstad et al, Plasma hypoxanthine and natural surfactant
reduced after five minutes according to the PaO2 on blood gas analysis. In Belfast it was, however, reduced more rapidly, within the first five minutes of surfactant instillation, using continuous oxygen Saturation monitoring (pulse oximetry) for guidance. Babies from the two centers were treated equally in all other respects. Blood (0.5 ml) for hypoxanthine analysis was spun down immediately and plasma frozen at -20°C until analysis by HPLC. The plasma samples were prepared by centrifugation for 30 minutes through a filter with 30.000 MW cut-off (YMT-filter, MPS-1 System, Amicon corp., Danvers, MA, USA). The chromatography was performed on a reversed-phase column (0.45 15 cm) of 5 micron material (pecosphere-5C C18, Perkin-Elmer, Norwalk, Conn, USA). The mobile phase used for the chromatography was 0.005 M KH2PO4, pH 5.7. The eluting compounds were detected at 254 nm [21, 25]. All pure Standards used for HPLC were obtained from Sigma Chemicals, St. Louis, MO, USA. The babies were divided into two groups with respect to the short-term (7 days) outcome: 1) Sunivors (seven babies) who were stabilised and initially weaned successfully from the Ventilator. Two of these babies subsequently died in the postneonatal period, one because of broncho-
pulmonary dysplasia (5 weeks of age) and one of sudden infant death syndrome (13 months of age). 2) Non-survivors, i. e. babies who after an initially favorable response to surfactant treatment with an increase in PaO2 and decrease in FiO2, could not be stabilised and weaned from the respirator and died during the first postnatal week. The project was approved by the ethical committees of each of the two hospitals and informed consent was given by the parents of the babies. 3
Results
Mean gestational age was 28.3 (SD 1.1) weeks in survivors and 27.5 (SD 2.4) weeks in nonsurvivors (NS). Mean birth weights in the two groups were 1196 (SD 162) grams and 1014 (SD 205) grams respectively (NS). 3.1
FiO2 and oxygenation
FiO2 could be reduced rapidly from a mean of 0.93 (SD 0.09) in survivors and 0.90 (SD 0.09) in non-survivors (NS) before surfactant instillation to 0.40 (SD 0.14) and 0.52 (SD 0.24) in survivors and non-survivors respectively after one hour (NS).
FiO ?
1.0
0.90.80.70.60.50.40.30.20.1 0.0
PaO 2 kPa 45 4035302520151050
SD
15
15
30
60
30
60
MIN
Figure 1. Top: FiO2 and bottom: PaO2 5min before (0 value) and 5—60 min after surfactant administration. Values are given äs mean and SD for all babies together. J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
381
Saugstad et al, Plasma hypoxanthine and natural surfactant
Before surfactant instillation mean PaO2 for surviving babies was 7.2 (SD 1.8) and 7.1 (SD 1.7) kPa for non-surviving babies (NS). Five minutes after surfactant instillation there was a rapid rise in PaO2 to a mean of 25.7 (SD 13.9) kPa in survivors and 19.6 (SD 13.5) kPa in non-survivors (NS between the two groups). PaO2 then decreased gradually, reaching a mean of 7.6 (SD 1.7) kPa and 6.5 (SD 2.0) kPa (NS) in the survivors and non-survivors respectively after 60 minutes. Figure l shows the mean FiO2 (top) and PaO2 (bottom) during the first hour after surfactant instillation. 3.2
reaching the highest level after 15 minutes (14.2, SD 7.5 μηιοΐ/l), significantly higher (p < 0.05, Mann Whitney test) when compared with survivors. After 60 minutes plasma hypoxanthine was not significantly different from initial values (mean 10.5, SD 5.9 μηιοΐ/ΐ). The maximal hypoxanthine concentration in each baby was found either at 15 or 30 minutes after surfactant instillation. The survivors had a mean maximal plasma hypoxanthine increase of only 1.9 (SD 2.9) μηιοΙ/1 compared with 9.4 (SD 8.1) μηιοΐ/ΐ in non-survivors (p < 0.05, MannWhitney U-test).
Plasma hypoxanthine and survival
The mean hypoxanthine concentration before surfactant treatment was 5.1 (SD 1.9) μηιοΐ/ΐ in survivors and 6.8 (SD 3.5) μηιοΐ/ΐ in non-survivors (NS). After surfactant was given these two groups showed two different patterns with regarcl to changes in plasma hypoxanthine concentrations (figure 2). In the surviving babies there was no significant change in plasma hypoxanthine concentration throughout the one hour study period. By contrast, in non-survivors mean plasma hypoxanthine concentration increased
3.3
Plasma hypoxanthine and intracranial hemorrhage (ICH)
Four out of five non-survivors developed intracranial hemorrhage of grade II —IV in contrast to two of the seven surviving babies (NS). The six babies with intracranial hemorrhage (grade II —IV) had a mean maximal increase of plasma hypoxanthine of 9.6 (SD 7.2) umol/1 by contrast to 1.1 (SD 0.7) umol/1 in the six babies who did not develop intracranial hemorrhage (p < 0.01, Mann Whitney U-test).
Hx micromol/l 24
201612-
8415 MIN
30
60
Figure 2. Plasma hypoxanthine (HX) concentration 5min before (0 value) and 5 — 60 min after surfactant administration. "Survivors" · —· (N = 7), were successfully weaned from the Ventilator and survived the neoriatal period. "Nonsurvivors" Δ — Δ (Ν = 5) were never weaned from the Ventilator and died during the first postnatal weck of life. Values are given s mean and SD. * p < 0.05 versus zero time values (non-survivors) and survivors versus non-survivors at 15 minutes. J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
382
Saugstad et al, Plasma hypoxanthine and natural surfactant
4 Discussion In babies with severe RDS, surfactant administration has positive effects on morbidity and mortality. Treatment with Curosurf reduces mortality by 40% in infants with severe RDS requiring artificial Ventilation with 60% oxygen or more [2]. There have been no published reports indicating that a biochemical substance can serve s a prognostic marker in surfactant treated babies. The present non-randomized report, albeit based on limited number of babies, suggests that changes in plasma hypoxanthine concentration after surfactant instillation may serve s such an indicator both for survival and development of intracranial hemorrhage. A high peak hypoxanthine concentration after surfactant instillation seems to be a poor prognostic sign since the mean maximal plasma hypoxanthine elevation was approximately five times higher in non-survivors than in surviving babies. Further, there was a significantly greater increase in plasma hypoxanthine in babies who developed intracranial hemorrhage of grade II —IV compared to babies who did not develop intracranial hemorrhage. These data should be compared with data from a recent clinical collaborative trial [3] where we noted that babies developing a high PaO2 peak (> 15 kPa) within 30 minutes of surfactant instillation had a higher incidence of grade I — II intracranial hemorrhage than babies with a PaO2 peak less than 15 kPa, although the total incidence of brain hemorrhage was not increased among surfactant treated babies. There seems to be two interpretations of the present findings: flrst, perhaps the sickest babies have the highest hypoxanthine concentration in the tissues before surfactant instillation. After surfactant is given PaO2 will increase to induce vasodilatation, resulting in a release of hypoxan-
thine from the tissues into the circulation. In such a case the augmentation of plasma hypoxanthine concentration merely reflects the severity of the respiratory distress before surfactant treatment. Judged by oxygen requirements and PaO2 before surfactant was given there was, however, no significant difference in severity of the disease between the two groups. A second explanation is that hypoxanthine generates potentially harmful oxygen radicals. Hypoxanthine is a potential oxygen radical generator in the presence of xanthine oxidase and oxygen. The combination of a high PaO2 and a high plasma hypoxanthine concentration occurring immediately after surfactant treatment may then produce an explosion in oxygen radical production [12, 18]. Babies who for some reason have a high hypoxanthine concentration in the plasma or tissues immediately after surfactant has been instilled, may therefore be more prone to injury due to free radical production. The free radicals may exert a direct damaging effect on different tissues contributing to the so called "oxygen radical disease in neonatology" [16, 17]. Although it is not known if the hypoxanthine-xanthine oxidase System exerts circulatory effects in the preterm baby s in animals [l, 15, 20, 23], this may be a reasonable assumption. It therefore seems wise to limit the rise in PaO2 after surfactant instillation by reducing the FiO2 s soon s possible [3]. In conclusion, augmentation of plasma hypoxanthine concentration after surfactant instillation may serve s a prognostic factor for survival and intracranial hemorrhage in preterm babies with severe RDS. Whether hypoxanthine also serves s a prognostic marker for complications such s retinopathy of prematurity and bronchopulmonary dysplasia remains to be elucidated.
Abstract
Plasma hypoxanthine concentration was measured in twelve preterm babies with respiratory distress syndrome (RDS) treated with 200 mg/kg of a porcine surfactant (Curosurf). Five of the babies died within one week and seven survived the neonatal period. Surviving babies had no significant changes in plasma hypoxanthine concentration throughout a one hour study period following the administration of surfactant. By contrast, in nonsurvivors the mean plasma hypoxanthine concentrations increased from 6.8 μηιοΙ/1 before surfactant administration to 14.2 μηιοΙ/1
15 minutes after surfactant treatment. Survivors had a mean maximal increase in plasma hypoxanthine of 1.9 μηιοΙ/1 15 — 30 min factor surfactant treatment compared with 9.4 μιηοΐ/ΐ in nonsurvivors (p < 0.05). The babies who developed intracranial hemorrhage had significantly higher maximal plasma hypoxanthine increase (mean 9.6 μιηοΐ/ΐ) compared with babies who did not develop intracranial hemorrhage (mean 1.1 umol/1) (p < 0.01). The combination of high PaO2 and high hypoxanthine concentration could lead to an increased production of oxygen radicals which might be
J. Perinat. Med. 20 (1992) Brought to you by | New York University Bobst Library Technical Services Authenticated Download Date | 6/14/15 7:16 PM
Saugstad et al, Plasma hypoxanthine and natural surfactant harmful. We conclude that plasma hypoxanthine concentration may serve äs an indicator of the prognosis in preterm babies treated with natural surfactant. Fur-
383
ther, it seems important to reduce oxygen supplementation äs soon äs surfactant is given to possibly limit oxygen radical production.
Keywords: Hyperoxia, hypoxanthine, intracranial hemorrhage, oxygen radicals, respiratory distress syndrome, surfactant treatment, survival. Zusammenfassung Erhöhte Hypoxanthinspiegel im Plasma als prognostische]· Parameter bei Frühgeborenen mit RDS unter Behandlung mit natürlichem Surfactant
In dieser Untersuchung bestimmten wir die Hypoxanthinspiegel im Plasma bei Neugeborenen unter Behandlung mit natürlichem Surfactant (Curosurf). In den vergangenen Jahren wurde viel über die physiologischen und biochemischen Effekte des Surfactant berichtet. Ob jedoch auch schädliche Nebenwirkungen durch die Surfactantbehandlung induziert werden können, ist nicht bekannt. Die Hypoxanthinkonzentration im Plasma ist ein Indikator für eine Hypoxie. Darüberhinaus können aus Hypoxanthin Sauerstoffradikale gebildet werden. Nach der Behandlung mit natürlichem Surfactant steigt die Sauerstoffspannung im arteriellen Blut stark an. Zusammen mit einer hohen Hypoxanthinkonzentration könnte dies für das Kind schädlich sein. Auch ist bekannt, daß sie durch das Hypoxanthin-XanthinOxidasesystem gebildeten Sauerstoffradikale den Ductus Botalli dilatieren und die Lungengefaße verengen können. Eine hohe Hypoxanthinkonzentration nach Surfactantinstillation hat somit auch einen Einfluß auf den ]
