magnesium disorder in critically ill patients

DR SURENDRA PATEL

FNB-CCMNH-RTIICS KOLKATA

INTRODUCTION

Magnesium – one of the most abundant ions in the body

Involved in over 300 enzymatic reactions

It is the major intracellular divalent cation.

2nd most abundant intracellular ion

It forms a key complex with ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids required for normal cellular function, replication, and energy metabolism.

Almost all extraskeletal magnesium is present within cells[99%]. 2

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50-60%store

30% 15%

1% of total

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Total body content = 2000 mEq

Half life of Mg is 28 hrs—imp.. In case of toxicity

Hypomagnesemia stimulates and hypermagnesemia inhibits this absorption

Most dietary absorption occurs in the ileum and jejunum (upto 65%)

RDA - 420 mg for males and 320 mg for females

Normal concentrations of extracellular magnesium and calcium are crucial for normal neuromuscular activity

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Conversion

Ionised Magnesium ~70% of total

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RENAL AND INTESTINE HANDLING OF MAGNESIUM

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Figure in above slideEpithelial magnesium transport in intestine and kidney

A, intestinal absorption follows two transport mechanisms: 1. a saturable transcellular transport (dotted line) which is of functional

importance at low intraluminal concentrations and 2. a paracellular passive transport (dashed line) linearly rising with

intraluminal magnesium concentrations.

B, in thick ascending limb magnesium is reabsorbed via the paracellular route. Here, a specific tight juntion protein, paracellin-1 or claudin-16, permits the selective paracellular flux of calcium and magnesium. Defects in paracellin-1 lead to combined calcium and magnesium wasting.

C, DCT reabsorbs magnesium in a transcellular fashion, consisting of an apical entry into DCT cell through a magnesium-selective ion channel, probably consisting of TRPM6/TRPM7 heterotetramers, and a basolateralextrusion of unknown molecular identity.

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HYPOMAGNESEMIA

Surveys of serum Mg levels in hospitalized patients indicate a high incidence of hypomagnesemia

Ranges between 11% - 60%

Patients with hypomagnesemia had increased mortality compared with normomagnesemicpatients

Measurements of serum magnesium levels may not accurately reflect the level of total body magnesium stores [Because only 1% of body magnesium resides in the ECF]

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ETIOLOGY OF HYPOMAGNESEMIA

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hyperparathyroidism

----fall of 20%

Pancreatitis

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A. Intracellular redistribution- ECF TO ICF

1. Recovery from DKA

2. Refeeding syndrome

3. Correction of respiratory acidosis

4. Catecholamines

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When the cause is undetermined from the history and physical examination alone –

Helpful to distinguish between renal Mg2+

wasting and extrarenal causes of Mg deficiency

By assessing urinary Mg excretion.

24 hr urine magnesium

Fractional excretion of Magnesium (FEMg)

A urine Mg excretion rate greater than 24 mg/day suggests renal Mg wasting

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Etiology of Hypomagnesemia1

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Fractional excretion of Magnesium – calculated by

The factor of 0.7 is applied - to estimate free Mg2+

FEMg of more than 2% in an individual with normal GFR - indicates inappropriate urinary Mg loss

If no renal wasting – extrarenal loss to be considered 13

Etiology of Hypomagnesemia1

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RENAL MAGNESIUM RETENTION TEST

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RENAL MAGNESIUM WASTING

2. Extracellular Fluid Volume Expansion

Mg reabsorption is passive and is driven by the reabsorption of sodium and water in the PCT

Extracellular volume expansion - decreases proximal sodium and water reabsorption – hence reducing magnesium reabsorbtion

3. Diuretics

Loop diuretics’ inhibition of the NaK2Cl co transporter abolish the transepithelial potential difference

as a result, magnesium resorption is inhibited

Hypomagnesemia is a frequent finding in pts receiving long-term loop diuretic therapy

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3. Diuretics

Long-term treatment with thiazide diuretics, which inhibit the NaCl cotransporter (DCT) also cause renal Mg wasting

Thiazides downregulate the expression of TRPM6

may explain the mechanism of the magnesuria

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4. Epidermal Growth Factor Receptor Blockers

cetuximab and panitumumab--Used in treating metastatic colorectal carcinoma

FEMg is inappropriately elevated

Recent studies suggest that the EGF receptor is located basolaterally in the DCT - redistribution of TRPM6 to the apical membrane – mediating Mg absorption

Hypercalcemia

It Inhibits magnesium reabsorption

However, in hyperparathyroidism – PTH stimulates Mg resorption – Thus normal levels maintained

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6. Drugs

i. Cisplatin

Suggested that the reabsorption defect may be in the DCT

Occurrence of Mg wasting does not correlate with cisplatin-induced acute renal failure

Carboplatin – considerably less magnesuria and renal failure

ii. Amphotercin B

Causes dose dependent renal Mg wasting and hypomagnesemia

Suggested that the functional tubule defect resides in the DCT

The calcineurin inhibitors cause hypomagnesemia in renal transplant patients - downregulation of the Mg channel TRPM6

Pentamidine & foscarnet-induced hypomagnesemia - associated with significant hypocalcemia. 18

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6. Drugs

iii. Aminoglycosides

Cause a syndrome of renal Mg and K wasting with hypomagnesemia, hypokalemia, hypocalcemia, and tetany

Hypomagnesemia may occur despite levels in the appropriate therapeutic range

it is the cumulative dose of aminoglycoside that is the key predictor of toxicity (>8g)

No correlation between the occurrence of aminoglycoside-induced ATN and hypomagnesemia.

Hypomagnesemia occurs ~ 3 - 4 days after the start of therapy and readily reverses after cessation of therapy. 19

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Several genetic magnesium-wasting syndromes have been

described, including inactivating mutations of :-

1. genes encoding the DCT NaCl co-transporter (Gitelman's syndrome),

2. proteins required for cTAL Na-K-2Cl transport (Bartter's syndrome),

3 paracellin-1 (autosomal recessive renal hypomagnesemia with

hypercalciuria),

4. a DCT Na+,K+-ATPase γ-subunit (autosomal dominant renal

hypomagnesemia with hypocalciuria), and

5 a mitochondrial DNA gene encoding a mitochondrial tRNA.

Severe phosphate depletion may impair magnesium reabsorption, as

can various forms of renal injury, including those caused by drugs.

A rising blood concentration of ethanol directly impairs tubular

magnesium reabsorption,

Magnesium depletion is aggravated by metabolic acidosis, which causes

intracellular losses as well.

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7. Inherited Renal Magnesium-Wasting Disordersi. Bartter’s syndrome --AR disorder

Sodium wasting, hypokalemic metabolic alkalosis, and hypercalciuria, and usually occurs in infancy or early childhood., 30-35% have hypomagnesemia *

Physiology of bartter’s syndrome - identical to that of long-term loop diuretic therapy

Gitelman’s syndrome

Variant of Bartter’s syndrome - distinguished primarily by hypocalciuria

usually > 6 yrs, mild symptoms

Hypomagnesemia occurs in 100%

Resembles the effects of long-term thiazide diuretic therapy 21

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CLINICAL MANIFESTATIONS

Hypomagnesemia may cause symptoms and signs of disordered functions of

Cardiovascular system

Neuromuscular system

Central nervous system

Skeletal System

Associated with an imbalance of other electrolytes such as potassium and calcium*

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Cardiovascular System

Mg is an obligate cofactor in all reactions that require ATP (includes Na-K-ATPase)

In hypomagnesemia, Impaired Na- K-ATPase function fall in intracellular K+

depolarized resting membrane potentialpredisposes to ectopic excitation and tachyarrhythmias

ECG changes - bifid T waves, U waves, QT prolongation

Also, hypomagnesemia facilitates the development of digoxin cardiotoxicity (additive

effects on Na- K-ATPase)24

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One study - Low dietary Mg level appeared to increase the risk for supraventricular and ventricular ectopydespite absence of frank hypomagnesemia, hypokalemia, and hypocalcemia

Framingham Offspring Study - lower levels of serum Mg were associated with higher prevalence of ventricular premature complexes

Also, Mg treatment was associated with an approximately 25% lower mortality in Acute MI in one study (LIMIT-2) The results of the ISIS-4 trial stand in stark contrast to those of LIMIT-2.

Recent studies show no difference in mortality

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Mg deficiency is associated with systemic hypertension

Mechanism is not clear, however - Mg does regulates vascular tone and reactivity and attenuates agonist-induced vasoconstriction

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Neuromuscular System

Symptoms and signs of neuromuscular irritability, including tremor, muscle twitching, Trousseau’s and Chvostek’s signs and frank tetany, may develop in patients with isolated hypomagnesemia

Seizures - generalized and tonic-clonic or multifocal motor seizures (noise induced)

The effects of Mg deficiency – mediated by N-methyl-D-aspartate (NMDA)–type glutamate receptors – excitatory receptors in the brain

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Extracellular Mg normally blocks NMDA receptors, Mg deficiency releases the inhibition

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Hypocalcemia is often observed in Mg deficiency and may also contribute to the neuromuscular hyperexcitability

Vertical nystagmus is a rare but diagnostically useful neurologic sign of severe hypomagnesemia

Only recognized metabolic causes of vertical nystagmus are Wernicke’s encephalopathy and severe Mg deficiency*

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Skeletal System

Hypomagnesemia - decreased skeletal growth and increased fragility

Mg is mitogenic for bone cell growth, deficiency may directly result in a decrease in bone formation

It also affects crystal formation; Mg deficiency results in a larger, more perfect crystal (which is brittle)

Mg deficiency may result in a fall in both serum PTH and Vitamin D levels

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Electrolyte Homeostasis

Patients with hypomagnesemia are frequently also hypokalemic

Hypomagnesemia by itself can induce hypokalemia* (release of inhibition of ROMK channels)

The cause of the hypokalemia is increased secretion in the distal nephron

Hypocalcemia occurs in ~20% pts -impairment of PTH secretion by Mg deficiency

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Others

Hypomagnesemia worsens insulin resistance and also accelerates progression of nephropathy and retinopathy in diabetics

Mg deficiency has been associated with migraine headache

Some evidence in Mg deficiency resulting in smooth muscle spasm and has been implicated in asthma

Finally, a high dietary Mg intake has been associated with reduced risk of colon cancer

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ACUTE CEREBRAL ISCHEMIA

Magnesium has been reported to increase regional CBF by vasodilatation of cerebral arteries.

In addition, reduction of extracellular magnesium is directly correlated with the intensity of cerebral vasospasm in experimental animals.

Direct neuronal effects include blockade of the NMDA receptor ion channel, calcium antagonism at voltage gated channels, enhanced buffering of intracellular calcium ions, and enhanced regeneration of ATP.

Further studies needed.

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TREATMENT

Identifying and treating the underlying cause where possible

Oral bioavailability is ~33% (Normal intestine)

Parenteral administration for inpatients (IM/IV) replenished.

Magnesium oxide at 0.4 mEq/kg/day enterally

MgSO4 at 0.1-0.2mEq/kg/day intravenouslyI

f no IV access then MgSO4 can be given IM in doses of 4 g every 4-6 hours

Magnesium oxide tablets = 111 mg elemental magnesium = 4.5 mmol = 9 mEq

Magnesium oxide is the preferred enteral agent because of its higher bioavailability.

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The oral preparations can be used for daily maintenance therapy (5 mg/kg /day in normal subjects).

However, because intestinal absorption of oral magnesium is erratic, parenteral magnesium is advised for managing hypomagnesemia

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MILD, ASYMPTOMATIC HYPOMAGNESEMIA

The following guidelines can be used for a serum Mg of 1–1.4 mEq/L with no apparent complications:

Assume a total magnesium deficit of 1–2 mEq/kg.

Because 50% of the infused magnesium can be lost in the urine, assume that the total magnesium requirement is twice the magnesium deficit.

Replace 1 mEq/kg for the first 24 hours, and 0.5 mEq/kg daily for the next 3–5 days.

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MODERATE HYPOMAGNESEMIA

The following protocol is recommended for a serum Mg <1 mEq/L, or for a low serum Mg that is accompanied by other electrolyte abnormalities:

Add 6 g MgSO4 (48 mEq of Mg) to 250 or 500 mL isotonic saline and infuse over 3 hours.

Follow with 5 g MgSO4 (40 mEq of Mg) in 250 or 500 mL isotonic saline infused over the next 6 hours.

Continue with 5 g MgSO4 every 12 hours (by continuous infusion) for the next 5 days.

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LIFE-THREATENING HYPOMAGNESEMIA

The following is recommended for serious cardiac arrhythmias (e.g., torsade de pointes) or generalized seizures:

Infuse 2 g MgSO4 (16 mEq of Mg) intravenously over 2–5 minutes.

Follow with 5 g MgSO4 (40 mEq of Mg) in 250 or 500 mL isotonic saline infused over the next 6 hours.

Continue with 5 g MgSO4 every 12 hours (by continuous infusion) for the next 5 days.

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TREATMENT

oTorsade de pointes [acls]….1-2 gm slow IV [ Diluted in 50-100 ml D5W] over 5-60 min then 0.5-1 gm/hr IV

oCardiac arrest [acls]—1-2 gm slow IV [diluted in 10 ml D5W] over 5-20 min.

oPotassium sparing (ENaC blocker) diuretics

o Distal tubule epithelial Na channel, such as amilorideand triamterene, may reduce renal Mg losses

o Useful in patients refractory to oral replacement or patients not tolerating high Mg doses (diarrhea)

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MONITORING REPLACEMENT THERAPY

Serum Mg levels may normalize after 1 to 2 days, but it will take several days to replenish the total body magnesium stores.

The magnesium retention test can be valuable for identifying the end-point of potassium replacement therapy; i.e., magnesium replacement is continued until urinary magnesium excretion is ≥80% of the infused magnesium load.

In renal insufficiency- no more than 50% of the magnesium in the standard replacement protocols should be administered [ not exceed >20gm/48 hr]. to start continuous infusion at 0.25 g/hr.

Monitored serum Mg carefully.

The best indicator of magnesium repletion is the urinary retention test

Administration of MgSO4 may further lower the ionized Ca2+

level and there by precipitate tetany 43

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MGSO4

MgSO4 : 1 gram = 98 mg elemental Mg = 4 mmol = 8 mEq

A 50% magnesium sulfate solution (500 mg/mL) has an osmolarity of 4,000 mosm/L , so it must be diluted to a 10% (100 mg/mL) or 20% (200 mg/mL) solution for intravenous use.

Ringer’s solutions should not be used as the diluent for MgSO4 because the calcium in Ringer’s solutions will counteract the actions of the infused magnesium.

Bolus doses of magnesium are rapidly excreted by the kidneys, making smaller dose continuous infusions a better choice in most situations.

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TOXICITY

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HYPERMAGNESEMIA

The kidney has a very large capacity for Mg excretion

Once the renal threshold is exceeded, most of the excess filtered Mg is excreted unchanged into urine

After this point, serum Mg is determined by GFR

Thus Hypermagnesemia occurs only in

1. Renal insufficiency

2. Excessive intake/correction

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CAUSES

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•Renal failure is most common. o In CKD –the remaining nephrons adapt to the decreased filtered load of Mg by markedly increasing their fractional excretion of Mg. This mechanism is compromised as renal failure worsens.

•Other causes include the following:oExcessive intake(oral/I.V/Antacids/ Laxatives)oLithium therapyoBone metastasisoHypothyroidismoAddison diseaseoFamilial hypocalciuric hypercalcemiaoMilk alkali syndromeoDepression

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SYMPTOMS---PLASMA MG CONC…….

4 to 6 meq/L (4.8 to 7.2 mg/dL or 2 to 3 mmol/L) –nausea, flushing, headache, lethargy, drowsiness, ileus, urinary retention and diminished DTR.

6 to 10 meq/L (7.2 to 12 mg/dL or 3 to 5 mmol/L) –somnolence, hypocalcemia, absent DTR, hypotension, bradycardia, and ECG changes.

Above 10 meq/L (12 mg/dL or 5 mmol/L) –muscle paralysis, respiratory paralysis. In most cases, respiratory failure precedes cardiac collapse.

Complete heart block and cardiac arrest may occur at a above 15 meq/L.

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CARDIOVASCULAR EFFECTS

Magnesium is an effective calcium channel blocker both extracellularly and intracellularly; in addition, intracellular magnesium profoundly blocks several cardiac potassium channels. These changes can combine to impair cardiovascular function

ECG Changes: prolongation of the P-R interval, an increase in QRS duration, and an increase in Q-T interval.

Depression of CNS

Neuromuscular Effects

High magnesium decreases impulse transmission across the NMJ producing a curare-like effect-Loss of

deep tendon reflexes (DTRs)

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HYPOCALCEMIA

Moderate hypermagnesemia can inhibit the secretion of PTH, leading to a reduction in the plasma calcium concentration

However this fall is usually transient and produces no symptoms.

The actions of Magnesium are antagonized by Calcium

However, Calcium should be reserved for pts with life-threatening symptoms, such as arrhythmia or severe respiratory depression.)

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DIAGNOSIS

Diagnosis is usually straightforward and involves measuring serum magnesium levels, as many cases are unsuspected.

A clue to the existence of hypermagnesemiawould be the disease context (preeclampsia, renal failure), the presence of magnesium-containing preparations, or a decreased anion gap.

Think about underlying cause.

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TREATMENT

In mild cases, withdrawing magnesium supplementation is often sufficient.

Adequate hydration

Diuretics can be used If Renal Function is adequate

IV Calcium Gluconate: [Calcium Chloride] 1g over 2-5 minutes, repeated after 5 min if necessary

Dialysis needs to be done( >8mEq/L, poor renal function, life threatening symptoms). Mg free dialysate (causes muscle cramps)

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MAGNESIUM—NEW RESEARCHES

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Supplements offer clinically significant reductions in BP.

Supplementation in overweight individuals for four weeks “led to distinct changes in gene expression and proteomic profiling consistent with favorable effects on several metabolic pathways.”

Four weeks of magnesium supplementation was also associated with a decrease in c-peptide levels.

The decrease in c-peptide in type 2 diabetics is a positive signal that insulin resistance is decreasing and that the load on the pancreas is lessening.

A reduction in the concentrations of fasting insulin levels was also noted.

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magnesium disorder in critically ill patients

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