Magnesium therapy in birth asphyxia
http://www.100md.com
《美国医学杂志》
1 Department of Paediatrics, Pt BDS PGIMS, Rohtak, India
2 Department of Chemistry; MD University, Rohtak, India
Abstract
Objective : Glutamate plays a critical role in the hypoxic ischaemic neuronal death. Two mechanisms of glutamate- induced neuronal death have been identified. One is rapid cell death that occurs in minutes and the second is delayed cell death that occurs over hours and is initiated principally by the activation of the N-methyl D-Aspactate (NMDA) receptor. Magnesium (Mg) is an NMDA receptor blocker. Systemic administration of Mg after a simulated hypoxic ischaemic insult has been shown to limit neuronal injury in several animal models. However, before embarking on to the use of Mg for neuronal protection in the human neonate it is important to study the safety and side effects of Mg administration. Methods : Forty terms, appropriate for gestational age babies with severe birth asphyxia (1 min Apgar score <3 and 5min Apgar score <6), were randomly assigned to either the study group or the control group. Infants in both groups were treated as per unit protocol except that babies in the study group received intravenous injection of magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life. Results : The mean cord blood serum Mg levels were 0.78 (± 0.047) mmol/L in the control group and 0.779(±0.045) mmol/L in the study group. The serum Mg levels at 3, 6, 12, 24, 48 and 72 hours of life were 1.87(±0.6), 1.65(±0.059), 1.468 (±0.91), 1.881 (± 0.053), 1.916 (± 0.053) and 1.493 (± 0.084) mmol/L respectively in the study group. All these values were significantly higher than those obtained in the control group (p<0.001). No significant alterations in heart rate, respiratory rate, oxygen saturation and mean arterial pressure were seen, following magnesium infusion with either 250 mg/kg or 125 mg/kg dose. The serum Mg levels in the study group ranged between 1.493 (± 0.084) and 1.916(±0.053) mmol/L, which are considered to be in the neuroprotective range. Conclusion : Injection MgSO[4] administered in a dose of 250 mg/kg and 125 mg/kg as an intravenous infusion is safe, and the Mg levels obtained are in the range considered to be neuroprotective.
Keywords: Magnesium; Asphyxia; Neuronal protection
Perinatal asphyxia is one of the leading causes of perinatal death and a recognized cause of neuromotor disability. Neurobiological research has unraveled the mechanisms that culminate into neuronal loss after a hypoxic ischaemic insult. Neuronal necrosis may occur at the time of the hypoxic ischemic insult but this is relatively insignificant in terms of eventual morbidity after the insult. It appears that a cascade of biochemical events is set in motion by the asphyxial insult, which eventually causes irreversible neuronal loss. This process of cellular destruction may take days or even weeks before completion.
The critical role of glutamate in the mediation of hypoxic ischaemic neuronal death is established by a large body of experimental information.[1] Two mechanisms of glutamate-induced neuronal death have been identified.[2] One of these is rapid cell death that occurs in minutes and is initiated by glutamate receptor activation, Na+ entry through all three ionotropic receptors, passive influx of Cl- down the electrochemical gradient with water following, and ultimately cell swelling and lysis. The second, so called delayed cell death, occurs over many hours, is initiated principally by activation of the N-Methyl D- Aspartate (NMDA) receptor with influx of Ca++; activation of several enzymes including phospholipases, proteases, nucleases and others, leading eventually to cell death.
Magnesium (Mg) has been found to block the NMDA ion channel under resting conditions, occupying a binding site within the ion channel.[3] This block is voltage- dependent and is overcome during axonal depolarization that occurs with hypoxia -ischaemia. If the extracellular magnesium concentration is raised, this blockade can be restored.
The systemic administration of magnesium after a simulated hypoxic ischaemic insult has been shown to limit neuronal injury in several animal models.[4],[5],[6],[7],[8],[9],[10] The plausibility of Mg in the prevention of delayed neuronal death following perinatal asphyxia in the human neonate has been discussed.[11],[12] However, before embarking on to the use of Mg for neuronal protection, it is important to study the effects of MgSO 4 administration on physiological functions such as blood pressure, heart rate and respiration. The present study aimed at obtaining this information and the serum Mg levels obtained during the first 72 hours of life, with the dosage schedule suggested by Levene et al.[13]
Materials and Methods
The study was conducted in the neonatology unit, department of pediatrics, on 40 inborn babies delivered between 2nd August 2000 and 25th December 2001. Babies were randomly assigned to the study group (n=20) and control group (n=20), using a random number table. A written, informed consent was taken from the parents of the babies in the study group. The study was cleared by the hospital ethics committee.
The selection criteria included inborn, term, appropriate for gestational age babies, admitted to the NICU with an Apgar score of less than 3 at 1 min and less than 6 at 5 minutes. Babies with congenital malformations and those born to mothers receiving general anesthesia, magnesium sulfate, pethidine, phenobarbitone and other drugs likely to depress the baby were excluded from the study.
The gestational age was assessed from maternal dates and confirmed by clinical examination as described by Ballard.[14] The classification of "appropriate for gestational age" was done according to the charts prepared by Lubchenco et al .[15] Apgar score and umbilical artery pH at birth were recorded for all babies.
Babies in the study group received magnesium sulphate (hydrated MgSO 4 injections; 2ml ampoules containing 500 mg of MgSO 4 per ml) as an infusion (in 5% dextrose) over a period of half an hour, through an infusion pump. The initial loading dose of 250 mg/kg body weight was given within half an hour of birth. This was followed by two further infusions in a dose of 125mg/kg at 24 and 48 hours of birth. This dosage schedule was in accordance with the recommendations of Levene et al and aimed to bring the magnesium concentration of blood in the range of 1.2-2.5 mmol/ltr.[8] During magnesium infusions, the heart rate and oxygen saturation were monitored continuously using pulse oximetry (BCI-Capnocheck II). Blood pressure - systolic, diastolic and mean were monitored using non-invasive blood pressure monitoring (BCI-Mini-Torr-Plus) every 10 minutes for 1 hour and then every one hourly for 12 hours. Respiratory rate was similarly documented every 10 minutes for the first one hour and then hourly for 12 hours.
The magnesium level was estimated at 0, 3, 6, 12, 24, 48 and 72 hours of magnesium infusion using the method described by Sunderman and Carrol.[16] To 0.5 ml of serum in a centrifuge tube was added 4.5 ml of 10% trichloracetic acid. The contents were mixed and allowed to stand for 10 minutes. It was then centrifuged at 2500 rpm for 15 minutes. The sample was then analyzed with the help of an atomic absorption spectrophotometer (model ECIL-AAS-4129) The lab personnel were blinded to the group to which the patient belonged. The statistical tests used for data analysis included the t-test and the chi square test.
Results
A total of 40 terms appropriate for gestational babies with severe birth asphyxia were studied. Twenty of these formed the study group and 20 the control group.
The mean (±SD) birth weight was 2.78 (±0.26) kg in the control group and 2.8 (± 0.33) kg in the study group (p>0.05). The gestational age was 38.9 (±0.4) weeks in the control group and 38.7 (±0.5) weeks in the study group (p>0.05). There were 15 males and 5 females in the control group vs 16 males and 4 females in the study group (p>0.05).
The Apgar score at 1 and 5 minutes in the control group {1.75(±0.44) and 4.85(±1.08) respectively} were similar to those in the study group {1.65(±0.58) and 4.8 (±1.19) respectively}. Similarly, the umbilical artery pH at 6.98(±0.03) in the control group was comparable to the 6.97(±0.02) obtained in the study group table1.
The serum magnesium levels in the study and the control group were comparable at 0 hr but were significantly higher (p<0.001) in the study group at 3, 6, 12, 24, 48 and 72 hours table2. The serum magnesium levels in the study group after administration of magnesium ranged between 1.47 (±0.9) and 1.92 (±0.05) mmol/ltr during the first 72 hours of life. In the control group they ranged between 0.78 (±0.04) and 0.88 (±0.03) mmol/ltr.
In the study group the heart rate before magnesium administration was 139.4 (±16.2) bpm and showed no significant fall after magnesium administration. Similarly, the oxygen saturation after magnesium administration
93 (±2.6)% was similar to that of before administration
94 (±2.3)%. The respiratory rate also did not show any significant change with Mg administration {64(±12.3)/min before and 67 (±7.2)/min after Mg administration}. The mean arterial pressure showed some fall from the initial 47.1 (±9.54) mm Hg to 44.5 (±5.6) mm Hg at one hour, but this was again not significant.
Discussion
The study and control groups were comparable for birth weight, gestational age and the extent of asphyxia as assessed by Apgar score and umbilical artery pH. The serum magnesium levels at birth were 0.78 (±0.047) mmol/L and 0.779(±0.045) mmol/L in the control and study group respectively. The normal reported values for serum Mg in neonates on day 1 of life are 0.75 (±0.06) mmol/L.[17] The values obtained in the present study's babies are comparable to these. Plasma Mg levels in babies with hypoxic ischaemic encephalopathy have been shown to be similar to those in normal neonates.[18] This is possibly why the Mg levels at birth in the babies with birth asphyxia were not different from those reported in normal neonates. Levene et al reported similar '0' hour serum Mg levels (0.71 mmol/L) in babies with severe birth asphyxia.[8] We used 3 doses of Mg -250 mg/kg given within half an hour of birth, followed by 125 mg/kg given at 24 and 48 hours of life. The serum Mg levels obtained were between 1.47 (±0.91) and 1.92 (±0.05) mmol/L. Levene et al also used a dosage of 250 mg/kg and reported serum Mg levels of 2.42 mmol/L, 1.52 mmol/L and 1.12 mmol/L at 1,12 and 24 hours respectively.[8] The authors did not estimate serum Mg at 1 hour, but the 12 hour value was 1.47 mmol/L which is similar to that reported by Levene et al.[13] The author's 24-hour value was higher at 1.88 mmol/L because of an additional dose of 125 mg/kg of Mg, which was administered at 24 hours. A loading dose of 200 mg/kg of MgSO[4] in newborn infants was reported to give a mean one hour level of Mg of 4 mmol/L.[18] Infusion of 180-300 mg/kg of MgSO 4 gave median serum Mg levels at 6 and 12 hours of 2.75 mmol/L and 1.38 mmol/L respectively.[19]
Normally the CSF Mg level is maintained above serum levels (ratio1: 1.34) by an active transport system.[20] In severe birth asphyxia in which there is damage in the blood brain barrier, entry of Mg into CSF will be more rapid. It has been calculated that extracellular fluid Mg concentration would only have to increase by 0.5 to 1 mmol/L to produce marked effects on synaptic and neuronal activity.[20] The normal serum Mg levels being 0.75 to 1.04 mmol/L, serum Mg levels between 1.25-2.04 mmol/L may be expected to be neuroprotective. With the dosage schedule used in the present study, serum Mg levels achieved were in the range of 1.47-1.92 mmol/L over a period of 72 hours. The Mg levels reached were therefore in the neuroprotective range. Secondary neuronal injury to the post asphyxial neonatal brain can occur over a period that may last as long as 72 hours.[21] The authors administered the second and third doses of Mg at 24 and 48 hours with an aim to maintain increased serum Mg concentration for a period of 72 hours. With the dosage schedule used in the present study the authors were successful in maintaining serum Mg levels in the neuroprotective range for a period of 72 hours. Babies in the study were monitored during Mg infusion and for 12 hours subsequently for heart rate, respiratory rate, oxygen saturation and mean arterial pressure. There were no significant alterations in these parameters either with 250 mg/kg dose or with the 125 mg/kg dose, and per our experience, these doses are safe. Levene et al who also used a dose of 250 mg/kg in 8 babies with severe birth asphyxia reported this dose to be safe and not associated with significant alterations in mean arterial pressure, heart rate, tone or EEG. However, one of their babies became transiently desaturated with shallow respiration and required 5 minutes of bag and mask ventilation. He did not need endotracheal intubation and breathed satisfactorily subsequently.[13] Abu Osaba used a dose of 200 mg/kg of MgSO 4 infusion in babies with persistent pulmonary hypertension and reported no significant alteration in either the heart rate or the blood pressure. The serum Mg levels documented by him were between 2.88 and 5.67 mmol/L.[19]
Magnesium toxicity has been shown to relate to the serum Mg levels. Reportedly, symptoms of hypermagnesaemia manifest at serum Mg levels above 2 mmol/L.[22] The maximum serum Mg level documented in the present series was 1.91 mmol/L. This is possibly the reason why authors did not see any side effects in the babies. Serum Mg levels of less than 6.5 mmol/L have been reported not to cause any hypotension or hypoventilation and have therefore been considered safe.[23], [24]
References
1. Choi DW, Harley DM. Calcium and Glutamate induced cortical neuronal death. In Waxman SG, ed. Molecular and cellular approaches to the treatment of Neurological Disease. New York;sRaven Press, 1993; 122-129.
2. Barks JDE, Silverstein FS. Excitatory amino acids contribute to the pathogenesis of perinatal hypoxic ischemic brain injury. Brain Pathol 1992; 2: 235-243.
3. Nowak L, Bregestovski P, Ascher P, Herbert A, Prochiantz A. Magnesium gates glutamate activated channels in mouse central neurons. Nature 1984; 307 : 462-465.
4. Dunne JJ, Milligan JE, Thomas BW. The effects of MgSO4 on anoxia and resuscitation in the neonate. Am J Obstet Gynae 1971; 109 : 369-374.
5. McIntosh TK, Vink R, Yamakami I, Faden AI. Magnesium neuroprotects against neurological deficit after brain injury. Brain Res 1989; 482 : 252-260.
6. Robertson CS, Foltz R, Grossman RG, Goodman JC. Protection against experimental ischaemic spinal cord injury. J Neurosurg 1986; 64 : 633-642.
7. Rothman S. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 1984; 4 : 1884-1891.
8. Hoffman DJ, Marro PJ, Mc Gowan JE, Mishra OP, Papadopoulos MD. Protective effects of MgSo4 Infusion on NMDA receptor binding characteristics during cerebral cortical hypoxia in newborn piglet. Brain Res 1994; 644; 144-149.
9. Nakajima W, Ishida A, Takada G. Magnesium attenuates a striatal dopamine increase induced by anoxia in neonatal rat brain: an in vivo micro dialysis study. Brain Res 1997; 41 : 809-814.
10. Thordstein M, Bagenholm R, Thringer K, Kjillmer I. Scavengers of free oxygen radicals in combination with magnesium ameliorate perinatal hypoxic ischemic brain damage in the rat. Brain Res 1993; 34 : 23-26.
11. Levene MI, Evans DJ, Mason S, Brown J. An international Network for evaluating neuroprotective therapy after severe birth asphyxia. Seminars in Perinatol 1999; 23; 223-233.
12. Gathwala G. Neuronal protection with Magnesium. Indian J Pediatr 2001; 68: 417-419.
13. Levene M, Blennow M, Whitelaw A, Hanko E, Fellman V, Hartley R. Acute effects of two different doses of magnesium sulphate in infants with birth asphyxia. Arch Dis Child 1995;73 : F174-F177.
14. Ballard JL. New Ballard score expanded to include extremely premature infants. J Pediatr 1991; 119 : 417-423.
15. Lubchenco L, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatr 1996; 37 : 403-408.
16. Sunderman WF, Carrol JE. Measurements of serum calcium and magnesium by atomic absorption spectrophotometer. Am J Clin Path 1965; 43 : 302-308.
17. Bajpai PC, Sugden D, Ramos A, Stern l. Serum magnesium levels in the newborn and older child. Arch. Dis Child 1966;41 : 424-427.
18. Harrison V, Peat G. Red blood cell magnesium and Hypoxic ischaemic encephalopthy. Early Hum Dev 1997; 47 : 287-296.
19. Ilves P Kiisk M, Soopold T, Talvik T. Serum total magnesium and ionized calcium concentrations in asphyxiated newborn infants with hypoxic ischaemic encephalopathy. Acta Pedatr 2000; 89 : 680-685.
20. Yousef K, Abu Osba, Gala O, Manosral K, Regal A. Treatment of severe persistent pulmonary hypertension of the newborn with MgSO4. Arch Dis Child 1992; 67 : 31-35.
21. Opelt WW, Maclntyre I and Rall DP. Magnesium exchange between blood and cerebrospinal fluid. Am J Physiol 1963; 205: 959-962.
22. Roth SC, Edwards AD, Cady EB, Delpy DT, WyattJS, Azzopardi D Relation between cerebral oxidative metabolism following birth asphyxia and neurodevelopment out come and brain growth at one year. Dev Med Child Neurol 1992; 34: 285-295.
23. Randall RE, Cohen MD, Spray CC, Rossmeisl EC. Hypermagnesaemia in renal failure-etiology and toxic manifestation. Ann Internal Med 1964; 61 : 73-79.
24. Cropp GJA. Reduction of hypoxic pulmonary vasoconstriction by magnesium chloride. J Appl Physiol 1968; 24 : 755-760.(Gathwala Geeta, Khera Atu)
2 Department of Chemistry; MD University, Rohtak, India
Abstract
Objective : Glutamate plays a critical role in the hypoxic ischaemic neuronal death. Two mechanisms of glutamate- induced neuronal death have been identified. One is rapid cell death that occurs in minutes and the second is delayed cell death that occurs over hours and is initiated principally by the activation of the N-methyl D-Aspactate (NMDA) receptor. Magnesium (Mg) is an NMDA receptor blocker. Systemic administration of Mg after a simulated hypoxic ischaemic insult has been shown to limit neuronal injury in several animal models. However, before embarking on to the use of Mg for neuronal protection in the human neonate it is important to study the safety and side effects of Mg administration. Methods : Forty terms, appropriate for gestational age babies with severe birth asphyxia (1 min Apgar score <3 and 5min Apgar score <6), were randomly assigned to either the study group or the control group. Infants in both groups were treated as per unit protocol except that babies in the study group received intravenous injection of magnesium sulphate 250 mg/kg within half an hour of birth, and subsequently 125 mg/kg at 24 and 48 hours of life. Results : The mean cord blood serum Mg levels were 0.78 (± 0.047) mmol/L in the control group and 0.779(±0.045) mmol/L in the study group. The serum Mg levels at 3, 6, 12, 24, 48 and 72 hours of life were 1.87(±0.6), 1.65(±0.059), 1.468 (±0.91), 1.881 (± 0.053), 1.916 (± 0.053) and 1.493 (± 0.084) mmol/L respectively in the study group. All these values were significantly higher than those obtained in the control group (p<0.001). No significant alterations in heart rate, respiratory rate, oxygen saturation and mean arterial pressure were seen, following magnesium infusion with either 250 mg/kg or 125 mg/kg dose. The serum Mg levels in the study group ranged between 1.493 (± 0.084) and 1.916(±0.053) mmol/L, which are considered to be in the neuroprotective range. Conclusion : Injection MgSO[4] administered in a dose of 250 mg/kg and 125 mg/kg as an intravenous infusion is safe, and the Mg levels obtained are in the range considered to be neuroprotective.
Keywords: Magnesium; Asphyxia; Neuronal protection
Perinatal asphyxia is one of the leading causes of perinatal death and a recognized cause of neuromotor disability. Neurobiological research has unraveled the mechanisms that culminate into neuronal loss after a hypoxic ischaemic insult. Neuronal necrosis may occur at the time of the hypoxic ischemic insult but this is relatively insignificant in terms of eventual morbidity after the insult. It appears that a cascade of biochemical events is set in motion by the asphyxial insult, which eventually causes irreversible neuronal loss. This process of cellular destruction may take days or even weeks before completion.
The critical role of glutamate in the mediation of hypoxic ischaemic neuronal death is established by a large body of experimental information.[1] Two mechanisms of glutamate-induced neuronal death have been identified.[2] One of these is rapid cell death that occurs in minutes and is initiated by glutamate receptor activation, Na+ entry through all three ionotropic receptors, passive influx of Cl- down the electrochemical gradient with water following, and ultimately cell swelling and lysis. The second, so called delayed cell death, occurs over many hours, is initiated principally by activation of the N-Methyl D- Aspartate (NMDA) receptor with influx of Ca++; activation of several enzymes including phospholipases, proteases, nucleases and others, leading eventually to cell death.
Magnesium (Mg) has been found to block the NMDA ion channel under resting conditions, occupying a binding site within the ion channel.[3] This block is voltage- dependent and is overcome during axonal depolarization that occurs with hypoxia -ischaemia. If the extracellular magnesium concentration is raised, this blockade can be restored.
The systemic administration of magnesium after a simulated hypoxic ischaemic insult has been shown to limit neuronal injury in several animal models.[4],[5],[6],[7],[8],[9],[10] The plausibility of Mg in the prevention of delayed neuronal death following perinatal asphyxia in the human neonate has been discussed.[11],[12] However, before embarking on to the use of Mg for neuronal protection, it is important to study the effects of MgSO 4 administration on physiological functions such as blood pressure, heart rate and respiration. The present study aimed at obtaining this information and the serum Mg levels obtained during the first 72 hours of life, with the dosage schedule suggested by Levene et al.[13]
Materials and Methods
The study was conducted in the neonatology unit, department of pediatrics, on 40 inborn babies delivered between 2nd August 2000 and 25th December 2001. Babies were randomly assigned to the study group (n=20) and control group (n=20), using a random number table. A written, informed consent was taken from the parents of the babies in the study group. The study was cleared by the hospital ethics committee.
The selection criteria included inborn, term, appropriate for gestational age babies, admitted to the NICU with an Apgar score of less than 3 at 1 min and less than 6 at 5 minutes. Babies with congenital malformations and those born to mothers receiving general anesthesia, magnesium sulfate, pethidine, phenobarbitone and other drugs likely to depress the baby were excluded from the study.
The gestational age was assessed from maternal dates and confirmed by clinical examination as described by Ballard.[14] The classification of "appropriate for gestational age" was done according to the charts prepared by Lubchenco et al .[15] Apgar score and umbilical artery pH at birth were recorded for all babies.
Babies in the study group received magnesium sulphate (hydrated MgSO 4 injections; 2ml ampoules containing 500 mg of MgSO 4 per ml) as an infusion (in 5% dextrose) over a period of half an hour, through an infusion pump. The initial loading dose of 250 mg/kg body weight was given within half an hour of birth. This was followed by two further infusions in a dose of 125mg/kg at 24 and 48 hours of birth. This dosage schedule was in accordance with the recommendations of Levene et al and aimed to bring the magnesium concentration of blood in the range of 1.2-2.5 mmol/ltr.[8] During magnesium infusions, the heart rate and oxygen saturation were monitored continuously using pulse oximetry (BCI-Capnocheck II). Blood pressure - systolic, diastolic and mean were monitored using non-invasive blood pressure monitoring (BCI-Mini-Torr-Plus) every 10 minutes for 1 hour and then every one hourly for 12 hours. Respiratory rate was similarly documented every 10 minutes for the first one hour and then hourly for 12 hours.
The magnesium level was estimated at 0, 3, 6, 12, 24, 48 and 72 hours of magnesium infusion using the method described by Sunderman and Carrol.[16] To 0.5 ml of serum in a centrifuge tube was added 4.5 ml of 10% trichloracetic acid. The contents were mixed and allowed to stand for 10 minutes. It was then centrifuged at 2500 rpm for 15 minutes. The sample was then analyzed with the help of an atomic absorption spectrophotometer (model ECIL-AAS-4129) The lab personnel were blinded to the group to which the patient belonged. The statistical tests used for data analysis included the t-test and the chi square test.
Results
A total of 40 terms appropriate for gestational babies with severe birth asphyxia were studied. Twenty of these formed the study group and 20 the control group.
The mean (±SD) birth weight was 2.78 (±0.26) kg in the control group and 2.8 (± 0.33) kg in the study group (p>0.05). The gestational age was 38.9 (±0.4) weeks in the control group and 38.7 (±0.5) weeks in the study group (p>0.05). There were 15 males and 5 females in the control group vs 16 males and 4 females in the study group (p>0.05).
The Apgar score at 1 and 5 minutes in the control group {1.75(±0.44) and 4.85(±1.08) respectively} were similar to those in the study group {1.65(±0.58) and 4.8 (±1.19) respectively}. Similarly, the umbilical artery pH at 6.98(±0.03) in the control group was comparable to the 6.97(±0.02) obtained in the study group table1.
The serum magnesium levels in the study and the control group were comparable at 0 hr but were significantly higher (p<0.001) in the study group at 3, 6, 12, 24, 48 and 72 hours table2. The serum magnesium levels in the study group after administration of magnesium ranged between 1.47 (±0.9) and 1.92 (±0.05) mmol/ltr during the first 72 hours of life. In the control group they ranged between 0.78 (±0.04) and 0.88 (±0.03) mmol/ltr.
In the study group the heart rate before magnesium administration was 139.4 (±16.2) bpm and showed no significant fall after magnesium administration. Similarly, the oxygen saturation after magnesium administration
93 (±2.6)% was similar to that of before administration
94 (±2.3)%. The respiratory rate also did not show any significant change with Mg administration {64(±12.3)/min before and 67 (±7.2)/min after Mg administration}. The mean arterial pressure showed some fall from the initial 47.1 (±9.54) mm Hg to 44.5 (±5.6) mm Hg at one hour, but this was again not significant.
Discussion
The study and control groups were comparable for birth weight, gestational age and the extent of asphyxia as assessed by Apgar score and umbilical artery pH. The serum magnesium levels at birth were 0.78 (±0.047) mmol/L and 0.779(±0.045) mmol/L in the control and study group respectively. The normal reported values for serum Mg in neonates on day 1 of life are 0.75 (±0.06) mmol/L.[17] The values obtained in the present study's babies are comparable to these. Plasma Mg levels in babies with hypoxic ischaemic encephalopathy have been shown to be similar to those in normal neonates.[18] This is possibly why the Mg levels at birth in the babies with birth asphyxia were not different from those reported in normal neonates. Levene et al reported similar '0' hour serum Mg levels (0.71 mmol/L) in babies with severe birth asphyxia.[8] We used 3 doses of Mg -250 mg/kg given within half an hour of birth, followed by 125 mg/kg given at 24 and 48 hours of life. The serum Mg levels obtained were between 1.47 (±0.91) and 1.92 (±0.05) mmol/L. Levene et al also used a dosage of 250 mg/kg and reported serum Mg levels of 2.42 mmol/L, 1.52 mmol/L and 1.12 mmol/L at 1,12 and 24 hours respectively.[8] The authors did not estimate serum Mg at 1 hour, but the 12 hour value was 1.47 mmol/L which is similar to that reported by Levene et al.[13] The author's 24-hour value was higher at 1.88 mmol/L because of an additional dose of 125 mg/kg of Mg, which was administered at 24 hours. A loading dose of 200 mg/kg of MgSO[4] in newborn infants was reported to give a mean one hour level of Mg of 4 mmol/L.[18] Infusion of 180-300 mg/kg of MgSO 4 gave median serum Mg levels at 6 and 12 hours of 2.75 mmol/L and 1.38 mmol/L respectively.[19]
Normally the CSF Mg level is maintained above serum levels (ratio1: 1.34) by an active transport system.[20] In severe birth asphyxia in which there is damage in the blood brain barrier, entry of Mg into CSF will be more rapid. It has been calculated that extracellular fluid Mg concentration would only have to increase by 0.5 to 1 mmol/L to produce marked effects on synaptic and neuronal activity.[20] The normal serum Mg levels being 0.75 to 1.04 mmol/L, serum Mg levels between 1.25-2.04 mmol/L may be expected to be neuroprotective. With the dosage schedule used in the present study, serum Mg levels achieved were in the range of 1.47-1.92 mmol/L over a period of 72 hours. The Mg levels reached were therefore in the neuroprotective range. Secondary neuronal injury to the post asphyxial neonatal brain can occur over a period that may last as long as 72 hours.[21] The authors administered the second and third doses of Mg at 24 and 48 hours with an aim to maintain increased serum Mg concentration for a period of 72 hours. With the dosage schedule used in the present study the authors were successful in maintaining serum Mg levels in the neuroprotective range for a period of 72 hours. Babies in the study were monitored during Mg infusion and for 12 hours subsequently for heart rate, respiratory rate, oxygen saturation and mean arterial pressure. There were no significant alterations in these parameters either with 250 mg/kg dose or with the 125 mg/kg dose, and per our experience, these doses are safe. Levene et al who also used a dose of 250 mg/kg in 8 babies with severe birth asphyxia reported this dose to be safe and not associated with significant alterations in mean arterial pressure, heart rate, tone or EEG. However, one of their babies became transiently desaturated with shallow respiration and required 5 minutes of bag and mask ventilation. He did not need endotracheal intubation and breathed satisfactorily subsequently.[13] Abu Osaba used a dose of 200 mg/kg of MgSO 4 infusion in babies with persistent pulmonary hypertension and reported no significant alteration in either the heart rate or the blood pressure. The serum Mg levels documented by him were between 2.88 and 5.67 mmol/L.[19]
Magnesium toxicity has been shown to relate to the serum Mg levels. Reportedly, symptoms of hypermagnesaemia manifest at serum Mg levels above 2 mmol/L.[22] The maximum serum Mg level documented in the present series was 1.91 mmol/L. This is possibly the reason why authors did not see any side effects in the babies. Serum Mg levels of less than 6.5 mmol/L have been reported not to cause any hypotension or hypoventilation and have therefore been considered safe.[23], [24]
References
1. Choi DW, Harley DM. Calcium and Glutamate induced cortical neuronal death. In Waxman SG, ed. Molecular and cellular approaches to the treatment of Neurological Disease. New York;sRaven Press, 1993; 122-129.
2. Barks JDE, Silverstein FS. Excitatory amino acids contribute to the pathogenesis of perinatal hypoxic ischemic brain injury. Brain Pathol 1992; 2: 235-243.
3. Nowak L, Bregestovski P, Ascher P, Herbert A, Prochiantz A. Magnesium gates glutamate activated channels in mouse central neurons. Nature 1984; 307 : 462-465.
4. Dunne JJ, Milligan JE, Thomas BW. The effects of MgSO4 on anoxia and resuscitation in the neonate. Am J Obstet Gynae 1971; 109 : 369-374.
5. McIntosh TK, Vink R, Yamakami I, Faden AI. Magnesium neuroprotects against neurological deficit after brain injury. Brain Res 1989; 482 : 252-260.
6. Robertson CS, Foltz R, Grossman RG, Goodman JC. Protection against experimental ischaemic spinal cord injury. J Neurosurg 1986; 64 : 633-642.
7. Rothman S. Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 1984; 4 : 1884-1891.
8. Hoffman DJ, Marro PJ, Mc Gowan JE, Mishra OP, Papadopoulos MD. Protective effects of MgSo4 Infusion on NMDA receptor binding characteristics during cerebral cortical hypoxia in newborn piglet. Brain Res 1994; 644; 144-149.
9. Nakajima W, Ishida A, Takada G. Magnesium attenuates a striatal dopamine increase induced by anoxia in neonatal rat brain: an in vivo micro dialysis study. Brain Res 1997; 41 : 809-814.
10. Thordstein M, Bagenholm R, Thringer K, Kjillmer I. Scavengers of free oxygen radicals in combination with magnesium ameliorate perinatal hypoxic ischemic brain damage in the rat. Brain Res 1993; 34 : 23-26.
11. Levene MI, Evans DJ, Mason S, Brown J. An international Network for evaluating neuroprotective therapy after severe birth asphyxia. Seminars in Perinatol 1999; 23; 223-233.
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