MAGNESIUM SULFATE FOR ACUTE SEVERE ASTHMA KINETICS AND CLINICAL RESPONSE Lucian K. DeNicola, M.D., FCCM Brian Blackwelder, Pharm. D. University of Florida Health Science Center/Jacksonville

INTRODUCTION Magnesium sulfate has been administered to patients to treat acute severe asthma when conventional therapy with oxygen, corticosteroids and continuous aerosol beta agonists fail to provide adequate relief. Reported benefits have been limited to 11 case reports involving 199 patients. in these reports doses varied from mg/kg and serum levels varied from mg/dl. Clinical results were inconsistant but tended to show a 9-25 % improvement in airway resistance or clinical asthma scores. We studied the pharmacokinetic and clinical effects of intravenous magnesium sulfate in children with acute severe asthma.

METHODS - I 1.Children who met the following inclusion criteria were studied: a) Absence of chronic cardiac or pulmonary disease b) Within 2 standard deviations of normal height and weight c) Acute asthma with clinical asthma score > 4 d) Failure to demonstrate a 40% improvement in CAS after 40 minutes of oxygen, steroids and continuous albuterol aerosol ( mg/kg/hr) 2.Administer mg/kg intravenuous magnesium sulfate (10%) over 20 minutes while continuing continuous albuterol aerosol. 3.Monitoring: Continuous: HR, RR, O2 Sat At 0 time, 20 and 60 min: BP, CAS, SAT/FIO2, serum Mg levels When possible: PaO2, pCO2, PEFR, lung compliance file:mgmethd1

METHODS - II 4. Serum magnesium levels were determined colorimetrically using the Formazan Dye reaction and reported in mg/dl 5. Volume of Distribution (Vd) = Administered Dose / Concentration 6. Elimination Rate Ke = (logn Concentration 1 - logn Concentration 2)/ change time 7. Half-life = 0.693/Ke 8. Adverse reactions were determined to be: a) Decreased deep tendon reflexes b) Hypotension c) Arrythmias file: mgmthds2

RESULTS - Pharmacokinetics 1.Study population: a) 14 children b) months of age c) 5-73 kg, one patients, 216 months, 115 kg was eliminated due to obesity (>2SD for wt) 2.Population averages: a) Weight: /- 21 b) Age : / c) Dose: / d) MG levels: 0 Time: / Min: / Min: / e) Vd: / ml/kg f) 1/2 life: / hours 3.No adverse effects observed file: mgrslts1

LEGEND Results of 14 administrations of intravenous magnesium sulfate to determine baseline, 20 minute and 60 minute serum magnesium levels, volumes of distribution and serum half lives. Serum magnesium levels reported in mg/dl. Vd reported as ml/kg. Half life reported in hours. Compilations reported as mean +/- standard deviation.

INCREASE IN SERUM MG LEVELS WITH VARIOUS DOSES OF MAGNESIUM SULFATE Serum Mg levels measured at baseline, 20' & 60' after a 20 min infusion file:mg-02060

KINETICS OF MgSO4 IN CHILDREN CONCLUSIONS OF SINGLE DOSE TRIAL (Dose = / mg/kg) 1.BASELINE SERUM Mg LEVELS WERE / MG/DL Avg 20' level = / Avg 60' level = / VOLUME OF DISTRIBUTION = / ML/KG 3.1/2 LIFE = / HOURS 4.RECOMMENDED DOSE TO ACHIEVE SERUM LEVEL = 4.2 MG/DL:* with high baseline and small Vd: 49.9 mg/kg with low baseline and large Vd: mg/kg with avg baseline and avg Vd: 73.6 mg/kg 5.FOR OUR PURPOSES WE ARE GOING TO CONTINUE OUR STUDIES WITH 70 MG/KG *Fesmire FM: intravenous Magnesium for Acute Asthma. Annals of Emergency Medicine. 1993;22: file:mgkinclu

EFFECT OF MgSO4 ON MULTIPLE VARIABLES PERCENT CHANGE AT 20 AND 60 MINUTES MEAN DOSE = 52.6+/-15.5 MEAN PEAK MG LEVEL = 3.73+/-0.94 file: mg_reslt PARAMETERBASELINEN-20"% CHANGE 20"N-60"% CHANGE-60" RESPIRATIONS35+/ / /-23 pO282+/ / /-6 CAS5.8+/ / /-17 SAT/FIO2242+/ / /-33 COMPLIANCE11.8+/ / /-10 HR153+/ / /-6 pCO248+/ / /-4 PEFR159+/ / /-11

EFFECT OF MgSO4 - CAS MG-CAS

MgSO4 EFFECT ON MULTIPLE VARIABLES PERCENT CHANGE AT 20 MINUTES MGRSLT2

MgSO4 EFFECT ON MULTIPLE VARIABLES PERCENT CHANGE AT 60 MINUTES MGRSLT3

CONCLUSIONS 1.FOR CHILDREN MONTHS OF AGE THE VOLUME OF DISTRIBUTION FOR MgSO4 IS / ml/kg. 2.HALF-LIFE OF A SINGLE DOSE OF MgSO4 IN THESE CHILDREN IS /-.93 HOURS. 3.THE CLINICAL PARAMETERS MEASURED DID NOT CHANGE SIGNIFICANTLY WITH A MEAN DOSE OF 52.6 MG/KG, ACHIEVING A PEAK SERUM MG LEVEL OF 3.73 MG/DL 4.HOWEVER, THERE WAS A DISTINCT TENDENCY FOR CLINICAL PARAMETERS TO IMPROVE SUGGESTING THAT OPTIMIZING THE DOSE AND SERUM LEVELS MAY PRODUCE MEASURABLE IMPROVEMENT 5.INTRAVENOUS MgSO4 ADMINISTRATION APPEARS TO BE SAFE IN DOSES UP TO 70 MG/KG FILE:MGCONCLU

IMPLICATIONS 1.FUTURE STUDIES SHOULD OPTIMIZE THE DOSE OF MgSO4 TO ATTEMPT TO ACHIEVE SERUM LEVELS OF 4.2 MG/DL 2.SINCE INTRAVENOUS MgSO4 IN DOSES UP TO 70 MG/KG SEEMS TO BE SAFE, MORE LIBERAL INCLUSION CRITERIA MAY BE USED IN FUTURE STUDIES 3.SINCE IT IS DIFFICULT TO ADMINISTER EFFORT DEPENDANT TESTS, IE, PEFR TO YOUNG CHILDREN FUTURE STUDIES MIGHT BEST BE PERFORMED ON OLDER, MORE COOPERATIVE CHILDREN IN OUTPATIENT SETTINGS. 4.DEFINITIVE RESULTS REQUIRE RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED STUDIES 5.THIS STUDY NEITHER ENCOURAGES NOR DISCOURAGES THE USE OF CONTINUOUS MgSO4 INFUSIONS IN FUTURE STUDIES. file:mg-impl

REFERENCES 1.Fesmire FM: Intravenous Magnesium for acute asthma. Annals of Emergency Medicine. 1993;22: DeNicola LK, Monem GF, Gayle MO, Kissoon N: Treatment of Critical Status Asthmaticus in Children. Peds. Clin N A. 1994;41: Okayama h, Okayama M, Aikawa T, et al: Treatment of Status Asthmaticus with Intravenous Magnesium Sulfate. J Asthma. 1991;28: McNamara RM, Spivey WH, Skobeloff E: Intravenous Magnesium Sulfate in the Management of Respiratory Failure Complicating Asthma. Annals Emergency Med. 1989;18: Noppen M, Vanmaele L, Impens N, Schandevyl W: Bronchodilating Effect of Intravenous Magnesium Sulfate in Acute Severe Bronchial Asthma. Chest. 1990;97: file:mg-ref