Magnesium and Magnesium and AnaesthesiaAnaesthesia

Dr Manjit George FRCA, FCARCSI, MDDr Manjit George FRCA, FCARCSI, MDAnaesthetist, Thirumalai Mission Hospital, Ranipet, IndiaAnaesthetist, Thirumalai Mission Hospital, Ranipet, India

IntroductionIntroduction

4th most plentiful cation in humans (after Na, K, and Ca)4th most plentiful cation in humans (after Na, K, and Ca)

2nd most important intracellular cation (after K)2nd most important intracellular cation (after K)

Distribution- bones(53%), muscles(27%), soft tissues(19%) and Distribution- bones(53%), muscles(27%), soft tissues(19%) and in serum and RBCs(less than 1%)in serum and RBCs(less than 1%)

S. Mg – 3 forms- ionised(62%), protein bound( 33%), complexed S. Mg – 3 forms- ionised(62%), protein bound( 33%), complexed to anions such as citrate, PO4( 5%)to anions such as citrate, PO4( 5%)

Ionised fraction is physiologically activeIonised fraction is physiologically active

PhysiologyPhysiology

Physiological rolePhysiological role Physiological antagonist of CaPhysiological antagonist of Ca Involvement of Mg in Na K ATPase- essential in maintaining Involvement of Mg in Na K ATPase- essential in maintaining

transmembrane Na and K gradients and normal K conc.transmembrane Na and K gradients and normal K conc. Determinant of electric potential across cell membranesDeterminant of electric potential across cell membranes Generation of C-AMP is Mg dependantGeneration of C-AMP is Mg dependant

Activation of many enzyme systems, including those involved in Activation of many enzyme systems, including those involved in energy metabolismenergy metabolism

Essential role in production of ATPEssential role in production of ATP Synthesis of DNA, RNA and proteinSynthesis of DNA, RNA and protein

Physiological rolePhysiological role Direct effect on myocardium and vascular smooth muscle- depress Direct effect on myocardium and vascular smooth muscle- depress

contractility, block catecholamine receptors, inhibits release of contractility, block catecholamine receptors, inhibits release of catecholamines from adrenal medulla, peripheral adrenergic receptorscatecholamines from adrenal medulla, peripheral adrenergic receptors

Blunts response of vascular tissue to vasoconstrictorsBlunts response of vascular tissue to vasoconstrictors

Bronchodilator, decreases PVRBronchodilator, decreases PVR

Decreases release of acetylcholine at neuromuscular junctionDecreases release of acetylcholine at neuromuscular junction Decreases excitability of nerves and muscles, involved in contraction Decreases excitability of nerves and muscles, involved in contraction

and relaxation of musclesand relaxation of muscles

Suppress epileptic foci and reverse cerebral vasospasmSuppress epileptic foci and reverse cerebral vasospasm

TocolyticTocolytic Inhibits platelet activity, increases bleeding timeInhibits platelet activity, increases bleeding time

Mg homeostasisMg homeostasis Body stores regulated by hormonal and metabolic effects on Body stores regulated by hormonal and metabolic effects on

gi absorption and renal excretion gi absorption and renal excretion Normal levels- 0.7- 1.05mmol/lNormal levels- 0.7- 1.05mmol/l

GI absorption- ileum and colon, inversely proportional to intakeGI absorption- ileum and colon, inversely proportional to intake Absorbed Mg excreted primarily by kidneyAbsorbed Mg excreted primarily by kidney Majority of reabsorption in ascending limb of Henle’s loopMajority of reabsorption in ascending limb of Henle’s loop

Aldosterone increases renal excretionAldosterone increases renal excretion PTH enhances gut absorption, reduces renal excretion of MgPTH enhances gut absorption, reduces renal excretion of Mg

PharmacologyPharmacology

PharmacologyPharmacology 2ml, 5ml and 10 ml ampoules, clear solution for infusion2ml, 5ml and 10 ml ampoules, clear solution for infusion Not to be stored above 25 degrees celsiusNot to be stored above 25 degrees celsius Active substance - Magnesium sulphate heptahydrateActive substance - Magnesium sulphate heptahydrate 2ml= 1g MgSO4= 4mmols= 8 meq= 98 milligram elemental Mg2ml= 1g MgSO4= 4mmols= 8 meq= 98 milligram elemental Mg

Too rapid administration- hypotension and even asystoleToo rapid administration- hypotension and even asystole Reduced dose in elderly and in renal failure- use with cautionReduced dose in elderly and in renal failure- use with caution Use with caution in Myasthenia gravis, muscular dystrophyUse with caution in Myasthenia gravis, muscular dystrophy Contraindications- Heartblock, obstetrics- within 2 hours of deliveryContraindications- Heartblock, obstetrics- within 2 hours of delivery

Drug interactions- Digoxin , Beta blocker and CCB, NDMRDrug interactions- Digoxin , Beta blocker and CCB, NDMR Antidote- resp depression or Heart Block- iv calciumAntidote- resp depression or Heart Block- iv calcium hypotension- iv calcium/ dopamine infusionhypotension- iv calcium/ dopamine infusion

HypomagnesemiaHypomagnesemia Plasma Conc < 0.7mmol/lPlasma Conc < 0.7mmol/l

Plasma Mg is less than 1% of total body MgPlasma Mg is less than 1% of total body Mg Overall deficiency may exist even with normal plasma levelsOverall deficiency may exist even with normal plasma levels

Low serum Mg generally indicates low total body Mg, exceptions- Low serum Mg generally indicates low total body Mg, exceptions- following massive crystalloid infusion, hypoalbuminemiafollowing massive crystalloid infusion, hypoalbuminemia

Suggestions that hypomagnesemia may be the most Suggestions that hypomagnesemia may be the most underdiagnosed electrolyte deficiencyunderdiagnosed electrolyte deficiency

Relatively common disorderRelatively common disorder

Hypomagnesemia - causesHypomagnesemia - causes Decreased intake- elderly, chronic alcoholics, pancreatic Decreased intake- elderly, chronic alcoholics, pancreatic

insufficiency, short bowel syndrome, TPN with insufficient Mginsufficiency, short bowel syndrome, TPN with insufficient Mg

Excessive renal loss- loop diuretics, ACEI, Gentamicin, interstitial Excessive renal loss- loop diuretics, ACEI, Gentamicin, interstitial nephritis, diuretic phase of ATN, hyperaldosteronismnephritis, diuretic phase of ATN, hyperaldosteronism

Extra renal losses- prolonged diarrhoea, long term NG drainageExtra renal losses- prolonged diarrhoea, long term NG drainage

Redistribution- treatment of DKA with insulin dextrose, massive Redistribution- treatment of DKA with insulin dextrose, massive transfusion with citrated bloodtransfusion with citrated blood

Hypomagnesemia-Clinical manifestationsHypomagnesemia-Clinical manifestations

CVS- HTN, Angina, Arrythmias, digoxin toxicity, ECG changesCVS- HTN, Angina, Arrythmias, digoxin toxicity, ECG changes

Neuromuscular- myoclonus, cramps, stridor, Chovstek’s and Neuromuscular- myoclonus, cramps, stridor, Chovstek’s and Trousseau’s signs, convulsions and comaTrousseau’s signs, convulsions and coma

Psychiatric disturbances- confusion, psychosis including Psychiatric disturbances- confusion, psychosis including Wernicke’s encephalopathyWernicke’s encephalopathy

Co existing electrolyte disturbances- hypokalemia, hypocalcemiaCo existing electrolyte disturbances- hypokalemia, hypocalcemia

Hypomagnesemia- TreatmentHypomagnesemia- Treatment Normal homeostasis of Mg requires daily intake of 10-20 mmolNormal homeostasis of Mg requires daily intake of 10-20 mmol

Mg replacement therapy particularly important in critically illMg replacement therapy particularly important in critically ill

Emergency- 10-20 mmol in 50 ml 5% D iv over 15-30mins, Emergency- 10-20 mmol in 50 ml 5% D iv over 15-30mins, followed by 40 mmol over 4 hrs ivfollowed by 40 mmol over 4 hrs iv

Critically ill(c/c deficiency)- 40 mmol iv on day 1 and Critically ill(c/c deficiency)- 40 mmol iv on day 1 and

10-20 mmols on days 2-510-20 mmols on days 2-5

Less severely ill- 15 mmols/day, NG/POLess severely ill- 15 mmols/day, NG/PO

Renal function should be checked before Mg administrationRenal function should be checked before Mg administration IV administration should be stopped if hypotension/ bradycardia, IV administration should be stopped if hypotension/ bradycardia,

if plasma conc. > 2.5 mmol/l or if DTR disappearif plasma conc. > 2.5 mmol/l or if DTR disappear

HypermagnesemiaHypermagnesemia Iatrogenic- overdose in treatment of preeclampsia/eclampsiaIatrogenic- overdose in treatment of preeclampsia/eclampsia End stage renal diseaseEnd stage renal disease High intake of antacids and use of purgativesHigh intake of antacids and use of purgatives

Adverse effects enhanced by hypocalcimeaAdverse effects enhanced by hypocalcimea GI- Nausea, vomiting, diarrhoeaGI- Nausea, vomiting, diarrhoea CVS- Prolongation of PR interval, QRS complex and QT interval, CVS- Prolongation of PR interval, QRS complex and QT interval,

hypotension and bradycardia, Complete HB and cardiac arrest hypotension and bradycardia, Complete HB and cardiac arrest (10-12.5mmol/l) can also occur (10-12.5mmol/l) can also occur

CNS- Disappearance of DTR (levels> 4-5 mmol/l), depressed CNS- Disappearance of DTR (levels> 4-5 mmol/l), depressed respiration and apnoea due to paralysis of voluntary muscles respiration and apnoea due to paralysis of voluntary muscles (5-7.5mmol/l)(5-7.5mmol/l)

Treatment- Treatment- Stop medicationsStop medications iv calcium gluconate 2.5-5mmol bolusiv calcium gluconate 2.5-5mmol bolus Diuretics/ dialysisDiuretics/ dialysis

PIH and EclampsiaPIH and Eclampsia Major cause of maternal mortality and fetal lossMajor cause of maternal mortality and fetal loss Uteroplacental ischaemiaUteroplacental ischaemia

Multisystem disorder affecting CVS, resp, hepatic, renal, Multisystem disorder affecting CVS, resp, hepatic, renal, haemostatic and CNShaemostatic and CNS

Control BP and abnormal haemodynamic state, prevent Control BP and abnormal haemodynamic state, prevent convulsions, ensure safe deliveryconvulsions, ensure safe delivery

MgSO4 is the most widely used anti convulsantMgSO4 is the most widely used anti convulsant

MgSO4 in PreeclampsiaMgSO4 in Preeclampsia

Magpie Trial- Lancet 2002- “ Magpie Trial- Lancet 2002- “ MgSO4 halves the risk of eclampsia MgSO4 halves the risk of eclampsia and probably reduces the risk of maternal death with no and probably reduces the risk of maternal death with no substantive harmful effects to mother or baby in short termsubstantive harmful effects to mother or baby in short term” ”

Intense cerebral vasospasm with increased sensitivity to pressor Intense cerebral vasospasm with increased sensitivity to pressor agentsagents

Reduction in cerebral blood flow causing convulsionsReduction in cerebral blood flow causing convulsions MgSO4 in PIH- reduces intracerebral vasospasm, as measured by MgSO4 in PIH- reduces intracerebral vasospasm, as measured by

Doppler examination of MCADoppler examination of MCA

MgSO4 in EclampsiaMgSO4 in Eclampsia Collaborative Eclampsia trial ( Lancet,1995)– superiority of MgSO4 Collaborative Eclampsia trial ( Lancet,1995)– superiority of MgSO4

over Diazepam & Phenytoin in prevention of reccurent convulsions in over Diazepam & Phenytoin in prevention of reccurent convulsions in eclampsiaeclampsia

Reduction in incidence of eclamptic convulsions in women with PIHReduction in incidence of eclamptic convulsions in women with PIH

Alters cardiovascular response to endotracheal intubation(40mg/kg Alters cardiovascular response to endotracheal intubation(40mg/kg after induction agent, 30mg/kg in a patient on Magnesium therapy)after induction agent, 30mg/kg in a patient on Magnesium therapy)

Less foetal depression than AlfentanilLess foetal depression than Alfentanil For very severe preeclampsia- combination of MgSO4 and Alfentanil For very severe preeclampsia- combination of MgSO4 and Alfentanil

superior to MgSO4 alonesuperior to MgSO4 alone

MgSO4 in PIHMgSO4 in PIH MgSO4 is the DOC for prevention and treatment of eclamptic MgSO4 is the DOC for prevention and treatment of eclamptic

seizuresseizures

Loading dose of 4 g( some centres use 5g) iv over 5 mins Loading dose of 4 g( some centres use 5g) iv over 5 mins followed by iv infusion at 1-2g/hr for 24 hrs after last convulsionfollowed by iv infusion at 1-2g/hr for 24 hrs after last convulsion

If further convulsion occurs, another 2-4 g given iv over 5 minsIf further convulsion occurs, another 2-4 g given iv over 5 mins

Therapeutic range of 2-3.5mmol/l recommendedTherapeutic range of 2-3.5mmol/l recommended

IM route- painful, less predictable plasma concentrations IM route- painful, less predictable plasma concentrations 5 g im, then 2.5g im every 4 hrs until 24 hrs after last seizure5 g im, then 2.5g im every 4 hrs until 24 hrs after last seizure

MgSO4 in cardiovascular anaesthesiaMgSO4 in cardiovascular anaesthesia Hypomagnesemia is common after CPB- Mg widely accepted in Hypomagnesemia is common after CPB- Mg widely accepted in

treatment and prophylaxis of arrythmias after CPBtreatment and prophylaxis of arrythmias after CPB

Anti arrythmic agent- post MI, torsades de pointes, intractable VT/ Anti arrythmic agent- post MI, torsades de pointes, intractable VT/ VF, digoxin induced arrythmias, multifocal atrial tachycardiaVF, digoxin induced arrythmias, multifocal atrial tachycardia

Component of some cardioplegic solutions- protects ischemic Component of some cardioplegic solutions- protects ischemic myocardium especially during reperfusionmyocardium especially during reperfusion

Aortic cross clamping- NMDA antagonsit- protection to spinal Aortic cross clamping- NMDA antagonsit- protection to spinal cord during repair of supra renal anuerysmscord during repair of supra renal anuerysms

Control of hypertensive responses to laryngoscopy and intubation-Control of hypertensive responses to laryngoscopy and intubation- suppress stress response at a dose of 40mg/kgsuppress stress response at a dose of 40mg/kg

Mg and anaesthesiaMg and anaesthesia Both hypo and hyper magnesemia- anaesthetic implicationsBoth hypo and hyper magnesemia- anaesthetic implications Frequently accompanied by other electrolyte disturbancesFrequently accompanied by other electrolyte disturbances If not urgent, postpone procedureIf not urgent, postpone procedure Increased risk of perioperative arrythmiasIncreased risk of perioperative arrythmias

High chances of stridor provoked by airway stimulation, upon High chances of stridor provoked by airway stimulation, upon induction of hypomagnesemic patientsinduction of hypomagnesemic patients

Avoid hyperventilation, as it further lowers Mg levelsAvoid hyperventilation, as it further lowers Mg levels

Vasodilation produced by volatile agents, narcotics may be Vasodilation produced by volatile agents, narcotics may be exacerbated by Mg leading to hypotension exacerbated by Mg leading to hypotension

Mg and anaesthesiaMg and anaesthesia It decreases presynaptic release of acetylcholine and reduces It decreases presynaptic release of acetylcholine and reduces

sensitivity of post junctional membranesensitivity of post junctional membrane NDMR potentiated by MgNDMR potentiated by Mg MgSO4 causes dose related depression of acetylcholine releaseMgSO4 causes dose related depression of acetylcholine release

Mg decreases twitch response without TOF fade, unlike NDMRMg decreases twitch response without TOF fade, unlike NDMR Pancuronium, rocuronium and vecuronium are potentiated by MgPancuronium, rocuronium and vecuronium are potentiated by Mg

Reduce dose of muscle relaxantReduce dose of muscle relaxant Use peripheral nerve stimulatorUse peripheral nerve stimulator

Other clinical uses of MagnesiumOther clinical uses of Magnesium PhaeochromocytomaPhaeochromocytoma crisis -bolus dose of 2-4 g followed by infusion at 1g/hr- crisis -bolus dose of 2-4 g followed by infusion at 1g/hr-

marked anti adrenergic effect, inhibition of release of catecholamines and calcium marked anti adrenergic effect, inhibition of release of catecholamines and calcium channel blocking property allied to its effect on release of acetylcholinechannel blocking property allied to its effect on release of acetylcholine

Anaesthetic management of Anaesthetic management of phaeochromocytomaphaeochromocytoma resection resection

AsthmaAsthma- bronchodilator- calcium antagonism, inhibitory action on smooth muscle - bronchodilator- calcium antagonism, inhibitory action on smooth muscle contraction, on Histamine release from mast cells and Acetylcholine release from contraction, on Histamine release from mast cells and Acetylcholine release from cholinergic nerve terminals. IgE stimulation increases calcium conc intracellularly, cholinergic nerve terminals. IgE stimulation increases calcium conc intracellularly, leading to Histamine releaseleading to Histamine release

TetanusTetanus- MgSO4 in conjunction with sedation eg: clonidine, reduce cardiovascular - MgSO4 in conjunction with sedation eg: clonidine, reduce cardiovascular (autonomic) instability and inhibits release of catecholamines, reduces spasms(autonomic) instability and inhibits release of catecholamines, reduces spasms

Sub arachnoid haemorrhage-Sub arachnoid haemorrhage- neuroprotective mechanisms- inhibition of release neuroprotective mechanisms- inhibition of release of excitatory aminoacids, blockade of NMDA glutamate receptors, non competitive of excitatory aminoacids, blockade of NMDA glutamate receptors, non competitive antagonist of voltage dependant Ca channel, cerebrovascular dilatory activityantagonist of voltage dependant Ca channel, cerebrovascular dilatory activity

From the journalsFrom the journals MgSo4 attenuates arterial pressure increase during lap MgSo4 attenuates arterial pressure increase during lap

cholecystectomy - BJA (2009)103(4)cholecystectomy - BJA (2009)103(4)

MgSO4 as an adjuvant to intrathecal bupivacaine in mild pre MgSO4 as an adjuvant to intrathecal bupivacaine in mild pre eclampsia undergoing CS- reduces post op analgesic requirements- eclampsia undergoing CS- reduces post op analgesic requirements- IJOA 2010;19IJOA 2010;19

MgSO4 in severe tetanus improves muscle spasm and cardiovascular MgSO4 in severe tetanus improves muscle spasm and cardiovascular stability- Anaesthesia 2008;63stability- Anaesthesia 2008;63

Intra articular inj of MgSO4 enhances analgesic effect of intra Intra articular inj of MgSO4 enhances analgesic effect of intra articular Bupivacaine- Anaesth Analg 2008;106articular Bupivacaine- Anaesth Analg 2008;106

ReferencesReferences Cations- Pottasium, Calcium, Cations- Pottasium, Calcium, MagnesiumMagnesium BJA CEACCP 2012 Vol 12,No 4 BJA CEACCP 2012 Vol 12,No 4

MagnesiumMagnesium: an emerging drug in anaesthesia- Editorial, BJA (2009)103(4): an emerging drug in anaesthesia- Editorial, BJA (2009)103(4)

MagnesiumMagnesium and the anaesthetist BJA CEACCP 2001,Vol 1 No 1 and the anaesthetist BJA CEACCP 2001,Vol 1 No 1

MagnesiumMagnesium- Physiology and pharmacology, BJA 1999;83:302-20- Physiology and pharmacology, BJA 1999;83:302-20

Clinical uses of Clinical uses of MagnesiumMagnesium infusions in Anaesthesia, infusions in Anaesthesia, Anaesth Analgesia 1992;74:129-136Anaesth Analgesia 1992;74:129-136