- Email: [email protected]
Surfactant for babies
1387
and certainly does not cause coma. The role of raised intracranial pressure, especially in children, remains to be elucidated.4 The clinical and pathophysiological features are best explained by parasite-induced local release of transient pathological "mediators", or a direct disturbance of neurotransmitter synthesis, which produces a reversible anaesthetic metabolic encephalopathy. Exactly how this happens is not clear. The list of candidates proposed for these mediators closely follows the discovery of elusive
agonal phenomenon
endogenous extracellular biological messengers over the past thirty Histamine, kinins, years. free radicals, cytokines, and nitric prostaglandins, oxide have all been implicated.s Various specific treatments, in addition
Surfactant for babies
antimalarial
therapy, have been suggested—eg, corticosteroids, heparin, urea, mannitol, low molecular weight dextran, prostacyclin, oxpentifylline, cyclosporin, tumour necrosis factor antibody,3 and now desferrioxamine.6 Plasmodia require iron to grow and chelation of available iron inhibits parasite growth.7,8 Iron also to
5. Clark IA, Rockett KA, Cowden WB. Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. Lancet 1992; 340: 894-96. 6. Gordeuk V, Thuma P, Brittenham G, et al. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 1992; 327: 1473-74. 7. Raventos-Suarez C, Pollack S, Nagel RL. Plasmodium falciparum: inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg 1984; 31: 919-22. 8. Hershko C, Peto TEA. Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med 1988; 168: 375-87. 9. Sadozadeh SMM, Graf E, Panner SS, Hallaway PE, Eaton JW. Hemoglobin, a biologic fenton reagent. J Biol Chem 1984; 259: 1435-36. 10. Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989; 71: 441-59.
redox agent and is instrumental in the generation of toxic free radicals.9 Iron chelation can prevent these processes. Gordeuk and colleagues6 conducted a double-blind placebo-controlled study of desferrioxamine (100 mg/kg per day given by constant intravenous infusion over 72 h) in 83 young Zambian children with severe falciparum malaria. In the subgroup of 50 children with unrousable coma, the 28 placebo recipients had a significantly longer duration of coma and longer times to parasite clearance than the 22 desferrioxamine-treated children. Times to recovery of consciousness (median 38-4 h in placebo survivors) were longer than those usually reported in children surviving cerebral malaria.1,10 There was no difference in mortality between the two groups. Was this apparently beneficial result on the duration of coma an antiparasitic effect or did desferrioxamine attenuate free-iron-induced oxidative damage in the brain? The latter explanation would have important implications for the pathophysiology and treatment of severe malaria. Although parenteral desferrioxamine is not ideally suited for the rural tropics (it should be stored at 4°C, it is light sensitive, and it is expensive) there are other antioxidants and other iron-chelators. However, before we try to elucidate the mechanism of action, and certainly before one can recommend desferrioxamine in cerebral malaria, these results need to be confirmed in a larger, rigorously blinded, placebo-controlled study in which the effect on mortality is defmed. serves as a
1. World Health Organization. Severe and complicated malaria. 2nd edition. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1-65. 2. Brewster D, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in childhood. Lancet 1990; 336: 1039-43. 3. White NJ, Ho M. The pathophysiology of malaria. Adv Parasitol 1992; 31: 83-173. 4. Newton CRJC, Kirkham FJ, Winstanley PA, et al. Intracranial pressure in African children with cerebral malaria. Lancet 1991; 337: 573-76.
this week’s issue (p 1363) the OSIRIS Collaborative Group report the results of the largest controlled trial yet conducted in neonatal medicine. 6774 infants from 229 centres in 21 countries were recruited in only 21 months for a study of early versus delayed administration of the synthetic surfactant Exosurf to prevent respiratory distress syndrome (RDS). The results show that early administrationin infants judged soon after birth to be at high risk of RDS—to 32 infants at high risk of the disorder would prevent 1 infant from dying and another from getting chronic lung disease. Giving more than the standard regimen of two doses conferred no clear advantage. These findings are noteworthy. RDS remains an important cause of neonatal death and morbidity and surfactant can cost over 1000 ($1500) per baby. The optimum dose of exogenous surfactant and the best method of administration remain to be determined; nebulisers are being evaluated for this purpose. Equally important is the best type of surfactant preparation, especially in view of the evidence that animal-based preparations have a more immediate effect on lung function than synthetic fonnulations.1 Trials even larger than OSIRIS are needed to show whether this difference is relevant to clinical outcome. Meanwhile, what about antenatal prevention of RDS? A short course of antenatal steroids started more than 24 h before birth at less than 34 weeks gestation reduces mortality and complications due to RDS by 40-50% without significant adverse results in mother or infant. 2,3 This result is similar to the effect of surfactant but at a fraction of the cost.4 Less than a quarter of the mothers whose infants received surfactant therapy in the OSIRIS trial had been started on steroids before the birth. In
Cummings JJ, Holm BA, Hudak MK, et al. A controlled clinical comparison of four different surfactant preparations in surfactantdeficient preterm lambs. Am Rev Respir Dis 1992; 145: 999-104. 2. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence. Br J Obstet Gynaecol 1990; 97: 11-25. 3. Crowley P. Corticosteroids after preterm prelabour rupture of the membranes. In: Chalmers I, ed. Oxford database of perinatal trials. Version 1.2. Disk issue 6. Autumn, 1991: record 4395. 4. Mugford M, Diercy J, Chalmers I. Cost implications of different approaches to the prevention of RDS. Arch Dis Child 1991; 66: 757-64. 1.
and certainly does not cause coma. The role of raised intracranial pressure, especially in children, remains to be elucidated.4 The clinical and pathophysiological features are best explained by parasite-induced local release of transient pathological "mediators", or a direct disturbance of neurotransmitter synthesis, which produces a reversible anaesthetic metabolic encephalopathy. Exactly how this happens is not clear. The list of candidates proposed for these mediators closely follows the discovery of elusive
agonal phenomenon
endogenous extracellular biological messengers over the past thirty Histamine, kinins, years. free radicals, cytokines, and nitric prostaglandins, oxide have all been implicated.s Various specific treatments, in addition
Surfactant for babies
antimalarial
therapy, have been suggested—eg, corticosteroids, heparin, urea, mannitol, low molecular weight dextran, prostacyclin, oxpentifylline, cyclosporin, tumour necrosis factor antibody,3 and now desferrioxamine.6 Plasmodia require iron to grow and chelation of available iron inhibits parasite growth.7,8 Iron also to
5. Clark IA, Rockett KA, Cowden WB. Possible central role of nitric oxide in conditions clinically similar to cerebral malaria. Lancet 1992; 340: 894-96. 6. Gordeuk V, Thuma P, Brittenham G, et al. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med 1992; 327: 1473-74. 7. Raventos-Suarez C, Pollack S, Nagel RL. Plasmodium falciparum: inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg 1984; 31: 919-22. 8. Hershko C, Peto TEA. Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med 1988; 168: 375-87. 9. Sadozadeh SMM, Graf E, Panner SS, Hallaway PE, Eaton JW. Hemoglobin, a biologic fenton reagent. J Biol Chem 1984; 259: 1435-36. 10. Molyneux ME, Taylor TE, Wirima JJ, Borgstein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 1989; 71: 441-59.
redox agent and is instrumental in the generation of toxic free radicals.9 Iron chelation can prevent these processes. Gordeuk and colleagues6 conducted a double-blind placebo-controlled study of desferrioxamine (100 mg/kg per day given by constant intravenous infusion over 72 h) in 83 young Zambian children with severe falciparum malaria. In the subgroup of 50 children with unrousable coma, the 28 placebo recipients had a significantly longer duration of coma and longer times to parasite clearance than the 22 desferrioxamine-treated children. Times to recovery of consciousness (median 38-4 h in placebo survivors) were longer than those usually reported in children surviving cerebral malaria.1,10 There was no difference in mortality between the two groups. Was this apparently beneficial result on the duration of coma an antiparasitic effect or did desferrioxamine attenuate free-iron-induced oxidative damage in the brain? The latter explanation would have important implications for the pathophysiology and treatment of severe malaria. Although parenteral desferrioxamine is not ideally suited for the rural tropics (it should be stored at 4°C, it is light sensitive, and it is expensive) there are other antioxidants and other iron-chelators. However, before we try to elucidate the mechanism of action, and certainly before one can recommend desferrioxamine in cerebral malaria, these results need to be confirmed in a larger, rigorously blinded, placebo-controlled study in which the effect on mortality is defmed. serves as a
1. World Health Organization. Severe and complicated malaria. 2nd edition. Trans R Soc Trop Med Hyg 1990; 84 (suppl 2): 1-65. 2. Brewster D, Kwiatkowski D, White NJ. Neurological sequelae of cerebral malaria in childhood. Lancet 1990; 336: 1039-43. 3. White NJ, Ho M. The pathophysiology of malaria. Adv Parasitol 1992; 31: 83-173. 4. Newton CRJC, Kirkham FJ, Winstanley PA, et al. Intracranial pressure in African children with cerebral malaria. Lancet 1991; 337: 573-76.
this week’s issue (p 1363) the OSIRIS Collaborative Group report the results of the largest controlled trial yet conducted in neonatal medicine. 6774 infants from 229 centres in 21 countries were recruited in only 21 months for a study of early versus delayed administration of the synthetic surfactant Exosurf to prevent respiratory distress syndrome (RDS). The results show that early administrationin infants judged soon after birth to be at high risk of RDS—to 32 infants at high risk of the disorder would prevent 1 infant from dying and another from getting chronic lung disease. Giving more than the standard regimen of two doses conferred no clear advantage. These findings are noteworthy. RDS remains an important cause of neonatal death and morbidity and surfactant can cost over 1000 ($1500) per baby. The optimum dose of exogenous surfactant and the best method of administration remain to be determined; nebulisers are being evaluated for this purpose. Equally important is the best type of surfactant preparation, especially in view of the evidence that animal-based preparations have a more immediate effect on lung function than synthetic fonnulations.1 Trials even larger than OSIRIS are needed to show whether this difference is relevant to clinical outcome. Meanwhile, what about antenatal prevention of RDS? A short course of antenatal steroids started more than 24 h before birth at less than 34 weeks gestation reduces mortality and complications due to RDS by 40-50% without significant adverse results in mother or infant. 2,3 This result is similar to the effect of surfactant but at a fraction of the cost.4 Less than a quarter of the mothers whose infants received surfactant therapy in the OSIRIS trial had been started on steroids before the birth. In
Cummings JJ, Holm BA, Hudak MK, et al. A controlled clinical comparison of four different surfactant preparations in surfactantdeficient preterm lambs. Am Rev Respir Dis 1992; 145: 999-104. 2. Crowley P, Chalmers I, Keirse MJNC. The effects of corticosteroid administration before preterm delivery: an overview of the evidence. Br J Obstet Gynaecol 1990; 97: 11-25. 3. Crowley P. Corticosteroids after preterm prelabour rupture of the membranes. In: Chalmers I, ed. Oxford database of perinatal trials. Version 1.2. Disk issue 6. Autumn, 1991: record 4395. 4. Mugford M, Diercy J, Chalmers I. Cost implications of different approaches to the prevention of RDS. Arch Dis Child 1991; 66: 757-64. 1.