Acta PRdiatr Scand 79: 881-892, 1990

REVIEW ARTICLE Oxygen Toxicity in the Neonatal Period OLA DIDRIK SAUGSTAD From the Department of Paediatrics and Paediatric Research, Institute for Surgical Research, Rikshospitalet, Oslo, Norway

ABSTRACT. Saugstad, 0. D. (Department of Paediatrics and Paediatric Research, and Institute for Surgical Research, Rikshospitalet, Oslo, Norway). Oxygen toxicity in the neonatal period. Acta Paediatr Scand 79: 881,1990. Oxygen is toxic because it produces oxygen radicals. One important oxygen radical generating system is hypoxanthine-xanthine oxidase. Hypoxic newborn babies who have elevated concentrations of hypoxanthine in tissues and body fluids and simultaneously are treated with supplementary oxygen, may therefore produce oxygen radicals in excess overwhelming the body’s natural defence systems against free radicals. Further, the capacity of many of these defence systems are probably reduced in the preterm baby. A series of conditions in neonates may, at least partly, be caused by oxygen radicals, e.g. bronchopulmonary dysplasia, retinopathy of prematurity, necrotising enterocolitis and patent ductus arteriosus. These conditions may be different facets of one disease; the “Oxygen radical disease in neonatology”. It is speculated that oxygen radicals play a role in regulating the perinatal circulation. This new insight concerning the role of oxygen radicals may have fundamental consequences for treatment and handling of sick newborn babies. Key words: bronchopulmonary dysplasia, hypoxanthine, necrotising enterocolitis, oxygen radicals, oxygen toxicity, patent ductus arteriosus, retinopathy of prematurity.

Life was first created in a reducing atmosphere, but 700 million years ago, with the advent of multicellular organisms, oxygen became a prerequisite for development and growth. One of the biggest leaps forward in evolution occurred when certain organisms, blue-green algae, developed with defence systems against oxygen. One could say this was the first recognition that oxygen is not only life giving but also toxic (1). Oxygen was discovered independently by Scheele and Priestly in 1772 and 1774 respectively (2). Priestly understood very early that oxygen produces toxic effects and several scientists in the nineteenth century, as Smith (3), described these effects scientifically.

Clinical effects of hyperoxia Today we know that oxygen exerts acute and chronic toxic effects on a number of organs such as the lung and brain. It influences the circulation, endocrinological functions, enzyme systems and molecular organisation (4).The acute clinical effects of hyperoxia on the brain are: vertigo, nausea, involuntary movements, convulsions, auditory hallucinations and paraesthesia (5-7). Exposure of the lung to high oxygen concentrations produces dyspnoea, tachypnoea and respiratory inhibition. The content of bacteria in the lung increases rapidly, partly because both the

This article is based on the Arvid Wallgren lecture presented at the annual meeting of the Swedish Society of Medicine, Stockholm, December 1988. 56-908308

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epithelium in the airways and the cilia are affected. The blood-air barrier becomes thicker and after a while the type I alveolar cells disappear and the type I1 cells increase in thickness. The interstitium also becomes thickened by increased oedema and the influx and proliferation of fibroblasts. An oxygen injured lung therefore becomes stiff and fibrotic, with a reduced lung compliance. Cells become smaller, the mitochondria increase in number and size, and eventually such cells may degenerate and die (8-1 1). Since oxygen treatment of newborn babies was introduced new effects of hyperoxia have been discovered, including retrolental fibroplasia (retinopathy of prematurity (ROP) is a more common term today) (12). Lungs exposed to artificial ventilation and extra oxygen occasionally develop bronchopulmonary dysplasia (BPD) (1 3) (many authors today prefer to call this condition chronic lung disease). A series of other conditions affecting the sick newborn may partly be caused by hyperoxia as well.

Oxygen radicals Why is oxygen toxic? To answer this question it is necessary to know something about oxygen free radicals. It is 36 years since Rebecca Gerschmann et al. (14) published the hypothesis that the toxicity is caused by the creation of oxygen radicals. These radicals are formed during X-irradiation as well, so that toxic effects of X-irradiation and hyperoxia are mediated by identical mechanisms. Free radicals are compounds with one or more unpaired electrons. They are highly reactive and can initiate chain reactions, which form new free radicals. They injure membranes by lipid peroxidation, inactivate enzymes, injure DNA, and degrade structural proteins. the hydroxyl Oxygen radicals are oxygen species like the superoxide radical, O F , radical, OH., and singlet oxygen. These are produced in the normal metabolism but also by activated leukocytes (15) as a part of the defence mechanism against bacteria. They are also formed by several enzyme systems, the most important of which may be the hypoxanthine (HX)-xanthine oxidase (XO) system (16):

+

+ +

HX O23 uric acid 0 2 H z 0 2

111

When hypoxanthine is oxidized to uric acid in the presence of xanthine oxidase, a fraction of the oxygen involved is reduced to the superoxide radical. Since hydrogen peroxide is formed during this process as well, the latter compound reacts with superoxide thus generating the very toxic hydroxyl radical. In the post-hypoxic reoxygenation period with the presence of both high hypoxanthine and oxygen concentrations, a burst of oxygen radicals may therefore be formed (17). This hypothesis is illustrated in Fig. 1.

Oxygen radical scavengers. The defence systems against oxygen radicals The body contains a series of systems that form a defence against free radicals. Several vitamins (vitamins A, C, and E) have antioxidative properties. Antioxyenzymes as superoxide dismutase (SOD), catalase and glutathione peroxidase constitute important parts of this defence. SOD, of which several different types have been described (18, 19), protects against the superoxide radical and catalyses the transformation from superoxide to hydrogen peroxide. Catalase and glutathione peroxidase are necessary for a rapid conversion of hydrogen peroxide to molecular

Oxygen toxicity in the neonatal period 883

Acta Paediatr S a n d 79 HYPOXIA ATP

HYPEROXIA

AMP

Adenosine

I

lnosine

1

HYPOXANTHINE

xanthine oxidase

uric A&

-7TP 0 2

H,O,+

0;-

Fig. I. Formation of oxygen radicals in the hypoxanthine-xanthine oxidase system. Hypoxanthine is accumulated in hypoxia. During reoxygenation hypoxanthine is oxidised to xanthine and uric acid in the presence of xanthine oxidase. Simultaneously oxygen radicals are formed. Uric acid acts as an oxygen radical scavenger. (Reproduced by permission of Pediatrics, ref. 68.)

OH.

oxygen and water. Glutathione peroxidase is selenium-dependent and selenium therefore forms an important part of the natural defence against free radicals. A series of compounds and metabolites like mannitol, uric acid and bilirubin act as so called oxygen radical scavengers (20-22).

Development of antioxyenzy m es The concentrations of antioxyenzymes increase during pregnancy. This has been shown by several investigators by measuring SOD, catalase and glutathione peroxidase concentrations in the fetal rat and rabbit lung (23, 24, 25). At present it is unclear whether the concentrations of these enzymes reach a peak at term followed by a gradual decrease toward adult levels (25), or whether the concentration continues to increase post partum (24, 26). Frank et al. found that the development of antioxyenzymes in the fetal rabbit lung runs parallel to that of the maturation of lung surfactant (27, 28). On the other hand, adult animals are known to be less resistant to hyperoxia than newborn ones. In one study, all the newborn rats which were exposed to 95% oxygen for 72 hours survived. In 60-day-old rats only 20% survived under similar conditions (27, 29, 30). One reason for this difference between the newborn and adult rat may be that only the newborn rat can adapt to hyperoxia by increasing the concentration of antioxyenzymes. This adaptive mechanism seems to be present only during a short period post partum (31). It is unclear whether humans also have such adaptive mechanisms to hyperoxia although some recent studies indicate this is the case (32, 33). The hypoxanthine-xanthine oxidase system The hypoxanthine-xanthine oxidase system probably plays an important role in clinical medicine because of its generation of free radicals. In hypoxia the hypoxanthine concentration may become very high (34-43) and levels close to 1 mmol/l has been measured in the cerebrospinal fluid of hypoxic infants (39). After a normal birth there is a rapid increase in the plasma hypoxanthine concentration, with a peak 10-20 min post partum. After intrauterine hypoxia such a washing out of hypoxanthine into the circulation is even more pronounced (36). This phenomenon

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160i

= 4.39 r = 0.86

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P < 0.005

120

. m

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0I

0

I

I

6

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Fig. 2. Washing out of hypoxanthine during resuscitation. Endotoxic shock was induced in dogs. Terminally they were resuscitated with artificial ventilation and volume therapy. A dramatic increase in Inferior Caval Vein (ICV) plasma hypoxanthine concentration was found. (Reproduced by permission of Circulatory Shock, ref. 44.)

12

is illustrated in an experimental model in which endotoxic shock was induced in dogs by infusion of Escherichia coli endotoxin. During the shock phase the plasma hypoxanthine concentrations were low. When the animals were resuscitated with volume therapy and artificial ventilation there was, however, an enormous washing out of hypoxanthine into the circulation with an increase from almost zero to approximately 100 pmol/l in the course of 10 min (44) (Fig. 2). It seems possible that these findings may reflect the clinical condition when hypotensive or hypoxic patients are resuscitated. If oxygen is added during resuscitation, large amounts of oxygen radicals may thus be produced by the hypoxanthine-xanthine oxidase system. These oxygen radicals may attack several organs, and if the defence systems are overcome many organs may be injured simultaneously. This is the basis for our hypothesis of posthypoxic reoxygenation injury published for the first time in 1980 (17). To what extent xanthine oxidase is present in the different organs of the human body is not known, but I have hypothesised that the enzyme may be released from the liver during shock or severe hypoxia, and hence circulates in the body (45). This enzyme is mainly in the dehydrogenase form, which does not produce oxygen radicals, but it is transformed to the oxidase form in hypoxia. Granger et al. (46) have postulated that this conversion is brought about by a protease which is activated during hypoxia.

Bronchopulmonary dysplasia Since Northway et al. (13) more than twenty years ago described bronchopulmonary dysplasia in newborn babies who were ventilated artifically because of the Respiratory distress syndrome (RDS), this entity has become a dreaded complication in every neonatal intensive care unit. The list of aetiological factors is long (Table 1) (47-50). In addition to prematurity itself, two particular factors have been especially discussed: first the role of high pressure applied to the airways by the ventilator, and second the consequence of a high concentration of oxygen in the

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Oxygen toxicity in the neonatal period 885

inspired air (50). I think the oxygen radical hypothesis can now explain the effects of both these two factors and how they are connected. In fact, most of the factors mentioned in Table 1 are related to an increased oxygen radical production or a lowered defence against them. Experimental data. Instillation of xanthine oxidase into the trachea of rats (51) and guinea pigs (52) produced oedema and hemorrhage, and the lung compliance was reduced (52-55). This effect could be prevented to some extent by the addition of superoxide dismutase (52,53). Further, intravenous infusion of hypoxanthine in rats breathing 100°/o oxygen for 48 hours also produced lung hemorrhage and oedema, there was an increase in the protein concentration of bronchoalveolar lavage compared;with controls, and the surfactant function was abolished (56). Similar findings were done by Holm et al. in rats breathing 100°/o oxygen for 64 hours. In bronchoalveolar lavage fluid there was a three-fold increase in protein content and a 30% decline in the phospholipid levels (57). Twenty-four hours after exposure to oxygen the phospholipid concentration was reduced even more, down to 5 1 O/o of values of controls and the protein level in the lavage fluid was increased to eight time the control values. These lavages exhibited severely impaired dynamic surface activity (57). Koyama et al. showed that lung lobes from dogs reperfused with 100Yo oxygen during ischaemia had massive weight gain and a marked increase in pulmonary shunt. The same was found when the lobes were ventilated with room air, by contrast, lobes ventilated with nitrogen during the ischaemia gained significantly less weight and did not show any increase in pulmonary shunt (58). Since the dog lung contains xanthine oxidase, the hypoxanthine-xanthine oxidase system may have played a role in generation of these changes as well. Hypothesis for development of bronchopulmonary dysplasia. From these and other experimental data it seems clear that the hypoxanthine-xanthine oxidase system may seriously injure the lungs both directly since it induces oedema and haemorrhage, and indirectly since it inactivates surfactant. The low-compliant lung with areas of ischaemia probably has elevated hypoxanthine concentration. Such lungs are usually exposed to high concentrations of oxygen, and the stage is therefore set for excess production of oxygen radicals. A high ventilatory pressure will contribute to higher hypoxanthine concentration in the lung tissue, since it may render some Table 1. Aetiological factors in bronchopulmonary dysplasia Prematurity Hyperoxia Mechanical ventilation Peak inspiratory pressure Mean airway pressure Surfactant deficiency Barotrauma Persistent ductus arteriosus Pulmonary oedema Pulmonary inflammation Fluid overload Vitamin E deficiency Familial predisposition Oxygen radicals Aetiological factors contributing to the development of bronchopulmonary dysplasia. (From references 47, 48, 49, SO.)

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VENTILATORY PRESSURE

I -I

Hx

02

\/ Q 2-

I

LUNG INJURY

Fig. 3. Pathogenesis of bronchopulmonary dysplasia (BPD). The figure illustrates the hypothesis that oxygen radicals are created both by a high oxygen concentration in the inspired air (FiOz), and by a high ventilatory pressure. These two factors may act alone or in combination and contribute to lung tissue injury. A lung requiring a high ventilatory pressure may have an elevated hypoxanthine concentration (Hx) in the lung tissue which may contribute to an increased production of oxygen radicals.

parts of the lungs ischaemic during inspiration. I therefore believe that both a high ventilatory pressure and a high oxygen concentration alone or in combination may injure the lung and contribute to chronic lung disease in the newborn through oxygen radical production. Fig. 3 attempts to illustrate this hypothesis.

Retinopathy of prematurity Retinopathy of prematurity (ROP) was the first disease entity, at least in neonatology, which was referred to the effect of hyperoxia (12). When the relation between hyperoxia and ROP became known, fairly strict guidelines were laid down for oxygen treatment, and the use of more than 40% oxygen was to be avoided. Consequently the incidence of ROP decreased, however, mortality and the number of babies with cerebral palsy increased dramatically (59-61). During the last decade or so a new rise in the number of ROP cases has been observed in most developed countries. This may be caused by a higher survival rate of very low birthweight preterm babies. Today it is clear that a series of aetiological factors contribute to ROP (62-67) (Table 2) including both hyperoxia and hypoxia as well as low birthweight per se. Such a long list of aetiological factors may indicate that the pathogenesis of this disease is still hidden. Most of these factors are, however, in some respects related to free radicals either because they contribute to a higher oxygen radical production or a lowered defence against them. Transfused blood for instance contains very high concentrations of hypoxanthine. We have therefore proposed that the hypoxanthine-xanthine oxidase system also plays a role in development of ROP (38, 54). This free radical hypothesis contributes to explain why the incidence of ROP increases with decreasing gestational age since it is reasonable to suggest, although it has to my knowledge to date not been proven, that the defence against radicals in the eye is lower early in pregnancy than at term. To explore this hypothesis we measured the hypoxanthine concentration in the vitreous fluid post mortem in preterm babies who died from RDS. In RDS babies we found significantly higher hypoxanthine concentrations than in the controls (68). These data do not prove that an increased production of oxygen radicals takes

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place in the eyes of babies at risk for developing ROP. They do, however, show that such babies have high concentration in the eye of one substrate for oxygen radical production, i.e. hypoxanthine. We do not know to what extent xanthine oxidase is present in the human eye, for instance in the retinal vascular endothelium. We know that oxygen radicals have vasoactive properties, but nothing is known about the effects on the retinal vessels. It is, however, reasonable to speculate that oxygen radicals affect the retinal circulation. It seems clear that the aetiology of ROP is multifactorial but the considerations above may elucidate important aspects of the pathogenesis of this condition.

Persistence of ductus arteriosus and pulmonary hypertension Oxygen exerts a potent vasoconstricting effect on the ductus arteriosus, while prostaglandins, like PGE2, dilate it (69). The oxygen tension and prostaglandin concentration therefore seem to control the tone of the ductal wall. Clyman et al. (70) studied the effect of oxygen radicals on the isolated ductal ring from lamb fetuses. Maximally constricted isolated lamb ductal rings were dilated when exposed to a high concentration of hypoxanthine (> 100 pmol/l). When xanthine oxidase was added as well, the dilatation occurred already at physiological concentration of hypoxanthine (1-10 pmol/l), simultaneously there was a marked increased production of PGE2. Indomethacin and catalase could prevent the dilatation mediated by hypoxanthine-xanthine oxidase and inhibit the production of prostaglandin. It therefore seems evident that oxygen radicals are potent dilatators of the isolated ductus arteriosus of fetal lambs. This is probably due to the initiation of prostaglandin production in the ductal wall. Tate et al. (71) have shown that oxygen radicals have a strong vasoconstricting effect on the isolated rabbit pulmonary circulation. Recently Sanderud et al. (72, 73) have shown that the hypoxanthine-xanthine oxidase system constricts the intact pulmonary circulation of pigs. This effect is inhibited by allopurinol (xanthine oxidase inhibitor), indomethacin (prostaglandin inhibitor) or catalase (oxygen radical scavenger). From these data I speculate that oxygen radicals may be of importance in regulating the perinatal circulation by constricting the pulmonary circulation and Table 2. Aetiological factors in retinopathy of prematurity Prematurity Hyperoxia Hypoxia Duration of oxygen treatment Transfusions Apnea Sepsis Persistent ductus arteriosus Hypercarbia Hypocarbia Light Vitamin E deficiency Lactic acidosis Oxygen radicals ~

~~

Aetiological factors contributing to the development of retinopathy of prematurity. (From references 62, 63, 64, 65, 66, 67.)

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dilating the ductus arteriosus. This fits in with the knowledge that persistent fetal circulation may be precipitated by hypoxia (10, 74).

Necrotising enterocolitis and intracranial haemorrhage There is a substantial body of experimental data supporting the hypothesis that reactive oxygen metabolites mediate the microvascular and mucosal permeability changes observed after reperfusion of the ischaemic intestine in adult animals (75, 76). It seems to be two major sources of oxygen radicals in the postischaemic intestine: xanthine oxidase and activated phagocytes (77). It is interesting that the small intestine is one of the two organs in man containing the highest concentration of xanthine dehydrogenase/oxidase, and recently Vettenranta & Raivio (78) found a substantial amount of xanthine oxidase in the hugan fetal intestine. Several investigators have speculated that oxygen radicals are involved in the pathogenesis of intracranial haemorrhage in preterm babigs, $owever, few data exist concerning this aspect. The possible relation between fiiygen radicals and intracranial haemorrhage in the preterm baby deserves, according to my opinion, a thorough examination in the future. ‘pl 4.

Is there an “Oxygen radical disease in neonatology”? Although a great amount of experimental data have been accumulated indicating that oxygen radicals play an important pathogenetic role in a series of diseases, the clinical data supporting this hypothesis are so far rather meager. It seems, however, reasonable to suggest, as I recently have hypothesised: if oxygen radicals affect a series of organs in the newborn there must exist an “Oxygen radical disease in neonatology” (4 1). Bronchopulmonary dysplasia, retinopathy of prematurity, persistent ductus arteriosus, necrotising enterocolitis, and perhaps to some extent intracranial haemorrhage, are only different aspects of one disease. The clinical expression of this disease differs according to the organ which is mainly affected. This may be the reason why previous investigators have thought we are dealing with different diseases. This hypothesis has several clinical implications. If it is correct, it opens for a completely new understanding of the pathogenesis of some of the most intransigeant problems in neonatology. This might open up for new treatment modalities, for example by administration of different oxygen radical scavengers or xanthine oxidase inhibitors to patients. In fact, superoxide dismutase has already been tried in preterm babies (79), and Thiringer et al. (80) have shown that the combination of an oxygen radical scavenger and a calcium blocker protects against post-hypoxic brain injury in the fetal lamb. Some authors also claim that allopurinol has beneficial effects on newborn babies with RDS (81). The present hypothesis clearly indicates that the alternation between hypoxia and hyperoxia may be harmful and should be avoided. During the resuscitation of hypoxic newborns it is probably wise to use as low an extra oxygen concentrat n as possible since most of them can be resuscitated with room air (82). This parti ular point should, however, be evaluated in experimental and clinical studies, and s p e are already under way. .$U Post-hypoxic reoxygenation injury caused by oxygen radicals may be only ode factor in the pathogenesis of the conditions mentioned above. The hypoxanthinexanthine oxidase system could play a central role in the development of all these conditions, although other oxygen radical generating systems obviously are in-

9

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Oxygen toxicity in the neonatal period 889

volved as well. The activated phagocyte has been mentioned, and the role of iron has also been focused upon (83). In recent years we have begun to understand far more of the pathogenesis of oxygen toxicity in neonatology, although I believe we are only at the very beginning of a new era that may completely change our understanding and treatment of the diseases discussed in this article. I also believe we will soon have access to tools for preventing and eradicating the “Oxygen radical disease in neonatology”.

ACKNOWLEDGEMENTS This study has been supported by The Norwegian Cancer Association, The Norwegian Council for Cardiovascular Diseases, The Norwegian Research Council for Science and the Humanities, The Lserdal Foundation for Acute Medicine, Odd Fellow Medical Research Foundation, and Anders Jahres Research Foundation.

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49. O’Brodovich HM, Mellins RB. Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis 1985; 132: 694-709. 50. Philips AGS. Oxygen plus pressure plus time: The etiology of bronchopulmonary dysplasia. Pediatrics 1975; 55: 44-50. 51. Johnson KJ, Fantone JC, Kaplan J, Ward PA. In vivo damage of rat lungs by oxygen metabolites. J Clin Invest 1981; 67: 983-93. 52. Saugstad OD, Becher G, Grossmann M, Oddoy A, Merker G, Lachmann B. Acute and

chronic lung damage in guinea pigs induced by xanthine oxidase. Intensive Care Med 1987; 13: 30-32. 53. Saugstad OD, Hallman M, Becher G, Oddoy A, Lachmann B. Respiratory failure caused by intratracheal saline: additive effect of xanthine oxidase. Biol Neonate 1988; 54: 61-67. 54. Lachmann B, Saugstad OD, Erdmann W. Effects of surfactant replacement on respiratory

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Oxygen toxicity in the neonatal period.

Oxygen is toxic because it produces oxygen radicals. One important oxygen radical generating system is hypoxanthine-xanthine oxidase. Hypoxic newborn ...
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