Magnesium & Anaesthesia

MAGNESIUM & ANAESTHESIA

Introduction Magnesium… •Is the 4th most plentiful cation in the body •intake averages 20-30mEq/d (240-370mg/d) in adults - Only about 30-40% is absorbed, mainly in the distal small bowel -About 50% is sequestered in bone and is not readily exchangeable with other compartments. -The ECF contains only about 1% of total body Mg2+.The remainder resides in the intracellular compartment. •Normal plasma Mg concentration : 1.4 to 2.1 mEq/L (0.70 to 1.05 mmol/L). •The maintenance of plasma Mg2+ concentration -dietary intake -effective renal and intestinal conservation. -Within 7 days of initiation of a Mg-deficient diet, renal and stool Mg2+ excretion each fall to about 1 mEq/day (0.5 mmol/day). •Renal excretion is the primary route of elimination - 25% of filtered Mg2+ is reabsorbed in the proximal tubule - 50-60% is reabsorbed in the thick ascending limb of the loop of Henle

•Factors that increase Mg2+ reabsorption in the kidneys: -hypoMg2+ -PTH -hypoCa2+ -ECF depletion -metabolic alkalosis •Factors that increase renal excretion: -hyperMg2+ -acute volume expansion -hyperaldosteronism -hyperCa2+ -ketoacidosis -diuretics -PO4- depletion -alcohol ingestion •Plasma Mg2+ concentration and either total body Mg2+ or intracellular Mg2+ content are not closely related. However, severe plasma hypoMg2+ may reflect diminished body stores of Mg2+.

•Many uses of Mg2+: -many enzymes are Mg2+ activated or dependent. -required by all enzymatic processes involving ATP and by many of the enzymes involved in nucleic acid metabolism. -required for thiamine pyrophosphate cofactor activity and appears to stabilize the structure of macromolecules such as DNA and RNA. -related to Ca2+ and K+ metabolism -Muscle relaxation may be observed at serum Mg2+ concentrations above 2.5 mmol/L •Mg2+ preparations are usually well tolerated even when given at large dosages. •In healthy patients plasma concentrations in the range 2–3.5mmol/L are considered to be safe. •The most common side-effects are -heat sensation, pain at the injection site, -myocardial conduction abnormalities -rarely, hypotension, sedation and neuromuscular depression.

Hypomagnesemia •Plasma Mg2+ concentration < 1.4 mEq/L (< 0.70 mmol/L). •Common to have associated deficiencies of other intracellular components such as K+ & PO4•Causes of Hypomagnesemia

Cause Alcoholism

Comment Due to both inadequate intake and excessive renal excretion

Gl losses

Chronic diabetes, Steatorrhea, Severe diarrhoea, Prolonged NG suctioning, Small bowel bypass, Acute pancreatitis, dietary deprivation

Pregnancy-related Pre-eclampsia /eclampsia,  Lactation (increased Mg requirements) 1° renal loss

Rare disorder(s), Inappropriately high urinary Mg excretion without apparent cause (eg.Gitelman's syndrome)

2° renal losses

Loop and thiazide diuretics, Hypercalcemia, After removal of parathyroid tumor, DKA, Hypersecretion of aldosterone, thyroid hormones or ADH,  Nephrotoxins (amphotericin B, cisplastin, cyclosporine, aminoglycosides)

Cutaneous losses

Burns, excessive sweating

Clinical Features •Symptomatic Mg2+ depletion is associated with refractory hypoK+(due to renal K+ wasting), hypoCa2+(impaired PTH secretion) & metabolic alkalosis •Facilitates development of digoxin toxicity •Features are: •Tremors, muscle wasting •Positive Trousseau’s & Chvostek’s signs •Generalised weakness, confusion, ataxia, anorexia •Vertical nystagmus •Tetany, seizures •ECG -Mild to moderate :prolongation of QT or QU intervals, bifid T waves, U wave, supraventricular & ventricular ectopics -Severe: PSVT, R-on-T phenomena, torsades de pointes, VT

Torsade de pointes •refers to VT characterized by polymorphic QRS complexes that change in amplitude and cycle length, giving the appearance of oscillations around the baseline. •This rhythm is, by definition, associated with QT prolongation (QTc > 500ms) . Normal QTc = QT/√RR interval = 0.38-0.46s •May result from -electrolyte disturbances (particularly hypoK+ and hypoMg2+) -use of a variety of antiarrhythmic drugs (especially quinidine) -phenothiazines and tricyclic antidepressants -liquid protein diets -intracranial events -bradyarrhythmias, particularly third-degree AV block -It also may occur as a congenital anomaly that most often presents with torsade de pointes (syncope or sudden death) at a young age.

•Rhythm strips of patients with drug (disopyramide)-induced torsade de pointes. •The polymorphic ventricular tachycardia is associated with very long QT intervals. •Polymorphic VT preceded by marked QT prolongation, often in excess of 0.60 s. •These patients often have multiple episodes of nonsustained polymorphic VT associated with recurrent syncope, but they also may develop VF and sudden cardiac death.

Therapy •directed at removing the precipitating factors, i.e., correcting metabolic abnormalities and removing drugs that have induced the prolonged QT interval. •In the setting of drug-induced torsade de pointes -atrial or ventricular overdrive pacing -and the administration of IV Mg2+ (8mmol as a bolus over 2-5min followed by a 60mmol infusion over 24h) •For patients with the congenital prolonged QT interval syndrome -adrenergic blocking agents have been the mainstay of therapy; -agents that shorten the QT interval may also be useful (e.g.phenytoin). -Pacing in combination with beta blockers and sympathectomy when beta blockers fail, but it is not uniformly successful -ICDs with dual chambered pacing capability and beta blockers have become the treatment of choice for patients with recurrent episodes despite beta blockers.

Management •Recommended daily allowance of Mg2+ in adults : -350mg (14.5mmol) for men -280mg (11.67mmol) for women •Serum Mg2+ < 0.6mmol/L or 1.4mg/dL in isolated asymptomatic hypoMg2+ should be treated •Correct hypoMg2+ in patients with significant underlying cardiac or seizure disorder, concurrent severe hypoCa2+ or hypoK+ •Treat underlying cause •Reduce the rate of correction by 25-50% in patients with renal failure as overzealous correction will cause hyperMg2+

Mild or Chronic HypoMg2+ -Oral elemental Mg2+ 240mg od-bd. Major side effect: diarrhoea -Refractory cases: K+ sparing diuretics eg. amiloride & triamterene -Gitelman’s syndrome & cisplatin toxicity: amiloride Severe HypoMg2+ -IV Mg2+ comes in 49.3% 5ml solution (2.47g/5ml) -IV MgSO4 1-2g over 15min (25-30mg/kg dilute in NS). Then maintain similar dose given in 4-8h for a day & then over 24h again -Monitor Mg2+, Ca2+, K+, ECG -Administration of MgSO4 in hypoCa2+ asymptomatic pt. may further lower the ionized Ca2+ level & thereby precipitate tetany -Sulphate in MgSO4 can increase urinary K+ excretion

Anaesthetic Considerations •Although no specific anaesthetic interactions are described, coexistent electrolyte disturbances such as hypoK+, hypophosphataemia & hypoCa2+ are often present & should corrected prior to surgery •Isolated hypoMg2+ should be corrected prior to elective procedures because of its potential for causing cardiac arrhythmias •Mg2+ appears to have intrinsic antiarrhythmic properties & possibly cerebral protective effects such that it is increasingly being administered prior to coming off cardiopulmonary bypass.

Hypermagnesemia •Plasma Mg concentration > 2.1 mEq/L (> 1.05 mmol/L). •Causes -renal failure (GFR <30mL/min) or -excessive intake (Mg-containing antacids or laxatives), or both -iatrogenic : MgSO4 therapy for gestational HPT -less common: adrenal insufficiency hypothyroidism rhabdomyolysis lithium administration

Clinical manifestation -at >10mmol/dL(>24mg/dL):

Vasodilation, bradycardia & myocardial depression can lead to hypotension -at 5 to 10 mEq/L (2.5 to 5 mmol/L) : the ECG shows prolongation of the PR interval, widening of the QRS complex, and increased T-wave amplitude -marked hyperMg2+ can cause respiratory arrest -at 10 mEq/L (5.0 mmol/L) : impairment of acetylcholine release & decrease in motor end plate sensitivity to acetylcholine in muscle: hyporeflexia, skeletal muscle weakness -sedation - >12 to 15 mEq/L (6.0 to 7.5 mmol/L) : cardiac arrest may occur

Management •Stop all sources of Mg2+ intake (most often antacids) •IV 10% Ca gluconate 10 to 20 mL may reverse many of the Mg-induced changes, including respiratory depression •A loop diuretic along with an infusion of ½ NS in 5% dextrose enhances urinary Mg2+ excretion. •Diuresis with NS is generally not recommended to decrease the likelihood of iatrogenic hypoCa2+, because the latter potentiates the effects of hyperMg2+ •Hemodialysis may be valuable in severe hypermagnesemia, because a relatively large fraction (about 70%) of blood Mg is not protein bound and thus ultrafilterable. •If hemodynamic compromise occurs and hemodialysis is impractical, peritoneal dialysis is an option.

Anaesthetic Considerations •Requires close monitoring of the ECG, BP & neuromuscular function •Potentiation of the vasodilating & negative inotropic properties of anaesthetics should be expected •Dosages of NMBAs should be redduced by 25-50% •CBD is required when diuretic & saline infusions are used to enhance Mg2+ excretion •Serial measurements of Ca2+ and Mg2+ may be useful

British Journal of Anaesthesia 97 (3): 389–92 (2006)

Intra-articular magnesium is effective for postoperative analgesia in arthroscopic knee surgery R. S. Bondok1 * and A. M. Abd El-Hady2 1Department of Anaesthesiology and Intensive Care and 2Department of Orthopaedic Surgery, Ain-Shams University Hospitals, Cairo, Egypt Accepted for publication: May 31, 2006

Background. Several medications are commonly injected intra-articularly for postoperative analgesia after arthroscopic knee surgery. Among the potentially efficient substances, Mg could be of particular interest through its NMDA-receptor blocking properties. Methods. A total of 60 patients undergoing arthroscopic knee surgery were randomly and double-blindly assigned to two groups to receive intra-articular injection of either 10 ml of MgSO4 (50 mg/ml) (Group M) or 10 ml of normal saline (Group C). Analgesic effect was evaluated by measuring pain intensity (visual analogue scale; VAS) 1, 2, 6, 8, 12, 18 and 24 h after operation and the time delay between MgSO4 or saline administration and the first requirement of supplementary analgesic medication by the patient (diclofenac). Results. Intra-articular Mg administration resulted in a significant reduction in pain scores in Group M compared with Group C 1, 2, 6 and 8 h after the end of surgery [1.7 (0.59), 2.2 (0.69), 2.8 (1.01) and 3.5 (1.10) in Group M; 8.0 (1.25), 5.9 (1.12), 4.4 (0.67) and 4.5 (1.13) in Group C, respectively]. A longer delay between intra-articular injection of the study medication and first administration of diclofenac was observed in Group M [667 (198) min] as compared with Group C [49 (13) min]. Total diclofenac consumption was significantly lower in Group M [37.5 (38.14) mg] than in Group C [117.5 (46.95) mg]. No early side-effects were noted. Conclusion. Intra-articular Mg is effective for postoperative analgesia in arthroscopic knee surgery.

British Journal of Anaesthesia 2006 96(4):444-449;

Magnesium moderately decreases remifentanil dosage required for pain management after cardiac surgery B. Steinlechner1,*, M. Dworschak1, B. Birkenberg1, G. Grubhofer1, M. Weigl2, A. Schiferer1, T. Lang1 and A. Rajek1 1Division of Cardiothoracic and Vascular Anaesthesia and Intensive Care, University Hospital Vienna Austria 2Division of General Anaesthesia and Intensive Care, University Hospital Vienna Austria

Accepted for publication January 18, 2006.

Background. Mg2+ is a Ca2+and an NMDA-receptor antagonist and can modify important mechanisms of nociception. We evaluated the co-analgesic effect of Mg2+ in the postoperative setting after onpump cardiac surgery. Methods. 40 patients randomly received either magnesium gluconate as an i.v. bolus of 0.21 mmol kg–1 (86.5 mg kg–1) followed by a continuous infusion of 0.03 mmol–1 kg–1 h–1 (13.8 mg kg–1 h–1) or placebo for 12 h after tracheal extubation. After surgery, remifentanil was decreased to 0.05 µg kg–1 min–1 and titrated according to a pain intensity score (PIS, range 1–6) in the intubated, awake patient and a VAS scale (range 1–100) after extubation. If PIS was 3 or VAS 30, the infusion was increased by 0.01 µg kg–1 min–1; if ventilatory frequency was 10 min–1 it was decreased by the same magnitude. Results. Mg2+ lowered the cumulative remifentanil requirement after surgery (P<0.05). PIS 3 was more frequent in the placebo group (P<0.05). Despite increased remifentanil demand, VAS scores were also higher in the placebo group at 8 (2 vs 8) and 9 h after extubation (2 vs 7) (P<0.05). Dose reductions attributable to a ventilatory frequency 10 min–1 occurred more often in the Mg2+ group (17 vs 6; P<0.05). However, time to tracheal extubation was not prolonged. Conclusions. Magnesium gluconate moderately reduced the remifentanil consumption without serious side-effects. The opioid-sparing effect of Mg2+ may be greater at higher pain intensities and with increased dosages.

British Journal of Anaesthesia. 89(4):594-598, October 2002.

Evaluation of effects of magnesium sulphate in reducing intraoperative anaesthetic requirements. Telci, L. 1; Esen, F. 1,*; Akcora, D. 1; Erden, T. 1; Canbolat, A. T. 2; Akpir, K. 1

Background The present randomized, placebo-controlled, double-blind study was designed to assess the effect of peroperatively administered i.v. magnesium sulphate on anaesthetic and analgesic requirements during total i.v. anaesthesia. Methods 81 patients (36 women, 45 men) undergoing elective spinal surgery were included in one of two parallel groups. The Mg2+ group received magnesium sulphate 30 mg/kg as a bolus before induction of anaesthesia and 10 mg/kg/h by continuous i.v. infusion during the operation period. The same volume of isotonic solution was administered to the control group. Anaesthesia was maintained with propofol (administered according to the bispectral index) and remifentanil (adjusted according to heart rate and arterial blood pressure) infusions. Results A significant reduction in hourly propofol consumption was observed with Mg2+ administration. For example, the mean infusion rate of propofol in the second hour of the operation was 7.09 mg/kg/h in the control group vs 4.35 mg kg/h in the Mg2+ group (P<0.001). The Mg2+ group required significantly less remifentanil (P<0.001) and vecuronium (P<0.001). No side-effects were observed with Mg2+ administration. Conclusion The administration of Mg2+ led to a significant reduction in the requirements for anaesthetic drugs during total i.v. anaesthesia with propofol, remifentanil and vecuronium.

Paediatric Anaesthesia. 13(1):43-47, January 2003.

The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. GULHAS, NURCIN MD; DURMUS, MAHMUT MD; DEMIRBILEK, SEMRA MD; TOGAL, TURKAN MD; OZTURK, ERDOGAN MD; ERSOY, M. OZCAN MD

Background Laryngospasm is the most common cause of upper airway obstruction after tracheal extubation. Mg2+ has a central nervous system depressant property, which contributes to the depth of anaesthesia. It also has Ca2+ antagonist properties, which provide muscle relaxation. In this study, we aimed to determine the effect of Mg2+ on preventing laryngospasm. Methods After approval of the Ethics Committee and informed parental consent, 40 patients, ASA I-II, aged 3-12 years, who were scheduled for tonsillectomy or/and adenoidectomy, were randomly divided into 2 groups. Anaesthesia was induced with sevoflurane, lidocaine 1 mg/kg, alfentanil 10 mcg/kg, vecuronium 0.1 mg/kg & maintained with sevoflurane 2% and 60% nitrous oxide in oxygen. After intubation, patients in group I received 15 mg/kg Mg2+ in 30 ml 0.9% NaCl over 20 min. Patients in group II received 0.9% NaCl alone in the same volume. After reversal of neuromuscular blockade, all patients were extubated at a very deep plane of anaesthesia. The incidence of laryngospasm was determined until the time of discharge from the postanaesthesia care unit. Results Although laryngospasm was not observed in group I, it was observed in five patients in group II (25%). The incidence of laryngospasm in group II was significantly higher than group I. The plasma Mg2+ concentrations were significantly higher in group I than group II. Conclusions We found a significant decrease in the incidence of laryngospasm in paediatric patients receiving Mg2+. It is suggested that the use of intravenous Mg2+ intraoperatively may prevent laryngospasm.

Summary •Mg2+ is an important intracellular cation that functions as a cofactor in many enzyme pathways •HypoMg2+ is a common & frequently overlooked problem, particularly in ill patients. Associated deficiencies of other intracellular components such as K+ & phosphorus are common •Mg2+ affects the activity of neurones, of myocardial & skeletal muscle fibres & of the myocardial conduction system. It also effects vasomotor tone & hormone receptor binding

N-methyl-D-aspartate (NMDA) receptors •Play a major role in central nociceptive transmission, modulation and sensitization of acute pain states •In addition to their central location, recent studies identified NMDA receptors peripherally in the skin, muscles and knee joints, and found that they play a role in sensory transmission of noxious signals. •In its inactive state, the NMDA receptor is blocked by the presence of a centrally positioned Mg ion. Mg2+ exerts a non-competitive voltage-dependent block of the NMDA receptor-operated ion channel, which prevents extracellular Ca2+ from entering the cell. Afferent activity in nociceptor fibres dislodges the central Mg ion from the NMDA receptor, therefore allowing Ca2+ influx into the cell.

•Mg2+ can be considered as a physiological blocker of NMDA receptors. Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials. •More recently, it has been demonstrated to reduce postoperative analgesic requirements. The mechanism of peripheral antinociceptive effect of NMDA antagonism has not been precisely defined. It has been hypothesized to occur through an analgesic and antiinflammatory effect. •NMDA antagonists reduce the excitability of nociceptive input terminals of C-fibres, which play a role in the central processing of pain. •The anti-inflammatory action in the peripheral tissues occurs through antagonizing the release of inflammatory mediators such as histamine, cytokines and serotonin, which in turn excite nociceptors.

NMDA Receptor

Legend: 1. Cell membrane 2. Channel blocked by Mg2+ at the block site (3) 3. Block site by Mg2+ 4. Hallucinogen compounds binding site 5. Binding site for Z2+ 6. Binding site for agonists(glutamate) and/or antagonist ligands 7. Glycosilation sites 8. Proton biding sites 9. Glycine binding sites 10. Polyamines binding site 11. Extracellular space 12. Intracellular space