Summary

An interesting spectrum of articles have been looked at

• The now ubiquitous and extensively used Magnesium Sulphate
• The difficult issue of Malignant Hypermetabolic Syndrome and its linkage to Central Core Disease
• An interesting look at pre-emptive analgesia from an immunological view point.

You may also wish to briefly browse our editorial comment

• Physiology
• Magnesium deficiency & therapy
• Magnesium in obstetrics
• Magnesium in cardiology
• Other clinical uses

Magnesium has a suggested role in nearly every physiological system. It is an important cation distributed principally between bone (53%) and intracellular compartments of muscle (27%) & soft tissues (19%). Almost all the intracellular Mg ⁺⁺ is bound to organic matrices.

Serum Mg ⁺⁺ (< 1% total body Mg ⁺⁺) may be in one of three states:

• ionised
• protein bound
• complexed to anions

Mechanisms of action include calcium antagonism at Ca++ channels, regulation of energy transfer and membrane sealing or stabilization.

1g MgS0 ₄ = 4 mmol = 8mEq or 98mg elemental Mg ⁺⁺ .
MgS0 ₄ ampoules = 500mg/ml.
The estimated daily requirement is 200mg (females) and 250mg (males).

• Cereals & legumes are rich in Mg ⁺⁺ but modern food processing may deplete Mg ⁺⁺ content.
• Mg ⁺⁺ is absorbed mainly in the ileum & colon, absorption being inversely proportional to intake. The kidneys are responsible for excretion & control of serum Mg ⁺⁺ levels.

The normal range for serum Mg ⁺⁺ level is 0.8 – 1.00 mmol/litre.

Mg ⁺⁺ deficiency is not uncommon in hospitalised patients and frequently co-exists with other electrolyte disturbances particularly hypokalaemia, hypophosphataemia, hyponatraemia & hypocalcaemia.

There is a well-described relationship between Mg ⁺⁺ and Ca ⁺⁺. Their absorption is inter-related and concomitant deficiencies have been noted. Hypocalcaemia causes release of parathyroid hormone (PTH). This release is impaired by hypomagnesaemia and corrected within minutes of infusion of Mg ⁺⁺. Mg ⁺⁺ is also required for the sensitivity of the target tissues to PTH and vitamin D metabolites. PTH release increases Mg ⁺⁺ reabsorption in the kidney, absorption from the GIT and release from bone.

Mg ⁺⁺ interacts with other ions at a cellular level as well. It acts as a non-competitive inhibitor of Ca ⁺⁺ channels and as such may be regarded as an intracellular Ca ⁺⁺ antagonist.

In addition to interactions with Ca ⁺⁺, Mg ⁺⁺ has marked effects on the regulation of transmembrane Na ⁺ and K ⁺ movements.

Prior to Mg ⁺⁺ administration it is necessary to ascertain that renal function is adequate.

Side effects of Mg ⁺⁺ therapy are bradycardia, hypotension & loss of deep tendon reflexes. Treatment should be stopped if any of these occurs.

Mg ⁺⁺ has a depressant effect at synapses related to competition between Ca ⁺⁺ & Mg ⁺⁺ causing inhibition of neurotransmitter release. Its anticonvulsant action is secondary to antagonism at NMDA receptors. Mg ⁺⁺ has been used successfully as an anticonvulsant in eclampsia but is much less effective as an anticonvulsant in other circumstances.

Mg++ reduces catecholamine release. The mechanism is attributed to interference with storage and release of catecholamines.

Although MgS0 ₄ has been advocated for use in both pre-eclampsia and eclampsia, there is little direct evidence for a beneficial effect of MgS0 ₄ in pre-eclampsia.

Large randomised, controlled studies have produced data to support the use of MgS0 ₄ in eclamptic patients. MgS0 ₄ was compared with phenytoin and diazepam and results showed that MgS0 ₄ reduced the risk of recurrent convulsions. The magnesium group were less likely to require ICU or develop pulmonary problems, and their babies were less likely to require special care facilities or intubation.

Because the proportion of women with pre-eclampsia who progress to eclampsia is small it has been calculated that over 600 women would have to receive MgS0 ₄ in order to prevent one seizure. A recent study showed benefit in using MgS0 ₄ in severe pre-eclampsia where the number treated to prevent one convulsion was reduced to 34. There are currently no certain predictors of which patients will progress from pre-eclampsia to eclampsia leaving the prophylactic use of MgS0 ₄ in pre-eclampsia debatable.

The precise mechanism of action of magnesium is not known, however it has been shown experimentally to block NMDA glutamate channels and prevent calcium entry into the cell.

Hypertensive disorders of pregnancy can lead to severe intubation responses. Conventional strategies for obtunding these responses are less effective in pre-eclampsia.
MgS04 has been shown to be effective in pre-eclamptic patients.

1. A dose of 40mg/kg MgS0 ₄ OR alfentanil 10mg/kg
   • prevented an increase in systolic pressure on intubation but at these doses there were side effects such as tachycardia (MgS04) and neonatal depression (alfentanil).
2. A combination of 30mg/kg MgS0 ₄ AND alfentanil 7.5mg/kg
   • allows for blood pressure control without causing neonatal depression.

The proposed mechanism of action appears to be inhibition of catecholamine release from the adrenal medulla. MgS0 ₄ lowers systemic vascular resistance in pre-eclamptics in pre-term labour. It may also have a beneficial effect on the uteroplacental unit, increasing uterine blood flow and foetal PO ₂ .

Regional block appears safe in the presence of MgS0 ₄ .

Monitoring of serum Mg ⁺⁺ levels may be used to assess therapeutic concentrations & adverse effects. Target levels suggested have been from 2 to 4 mmol/litre. Monitoring of patellar reflexes and ventilatory frequency may be of equal benefit as loss of patellar reflexes occurs well before respiratory depression and arrest. Extra caution is needed when administering Mg ⁺⁺ to patients in renal failure and the dose should be adjusted.

Three areas of anaesthetic relevance are myocardial infarction, arrhythmias and cardiac surgery.

Acute myocardial infarction : During ischaemia, intracellular ATP is depleted with the cessation of aerobic metabolism. As the greater proportion of the intracellular ATP is in the form of the Mg ⁺⁺ salt, cellular Mg ⁺⁺ is also depleted. ATP synthesis is further depleted by the consequences of anaerobic metabolism and the cell is flooded with calcium due to increased mitochondrial Ca ⁺⁺ uptake. Mg ⁺⁺ may provide some cellular protection by driving Ca++ into the sarcoplasmic reticulum and preventing increases in intracellular Ca ⁺⁺, which are known to be detrimental to cellular function.

Mg ⁺⁺ also improves the contractile response of the stunned myocardium and limits infarct size by an as yet unknown mechanism. Mg ⁺⁺ has actions resembling those of calcium antagonists and on infusion causes a reduction in peripheral resistance with a secondary increase in cardiac index. There is almost no concomitant change in arterial pressure or heart rate.

Magnesium inhibits smooth muscle contraction and also has a direct vasodilator effect. It reduces the reactivity of vascular smooth muscle cells to pressor agents and inhibits the contractility of coronary arteries. Other important actions attributed to Mg ⁺⁺ in the context of acute myocardial infarction include inhibition of catecholamine release and inhibition of platelet function thus modulating coagulation.

Whether Mg ⁺⁺ should be routinely administered as first line therapy for acute myocardial infarction is still the subject of debate as large international trials have shown conflicting results (LIMIT 2 and ISIS 4). If there is indeed a place for Mg ⁺⁺ in the treatment of these patients, evidence to date supports its administration before spontaneous reperfusion or thrombolysis and in high-risk patients.

Magnesium and arrhythmias : The multiple roles of Mg ⁺⁺ in cardiac muscle and the close interaction of Mg ⁺⁺ and K ⁺ metabolism have confounded interpretation of data on hypomagnesaemia as a cause of arrhythmias.

Causes of Mg ⁺⁺ and K ⁺ depletion are similar and hypomagnesaemia results in renal wasting of potassium. Hypomagnesaemia may exacerbate potassium-mediated arrhythmias by a complex interaction that modifies the action potential. It is recommended that both Mg ⁺⁺ and K ⁺ be administered for rapid control of arrhythmias associated with K ⁺ depletion.

Cardiac glycosides : Mg ⁺⁺ is a co-factor for the enzyme sodium-potassium ATPase that is inhibited by the cardiac glycosides. Normomagnesaemia is essential for digoxin to effectively control atrial arrhythmias. Hypomagnesaemia exacerbates digitalis-induced arrhythmias, which may be terminated by Mg ⁺⁺ administration. The mechanism by which magnesium depletion increases the risk of digoxin toxicity is uncertain. However, animal studies have suggested a direct membrane-stabilizing effect as a possibility.

Overall, the relationship between Mg ⁺⁺ and the genesis and treatment of arrhythmias is uncertain. Intravenous Mg ⁺⁺ should be considered for all refractory arrhythmias, even in the presence of normal serum levels, particularly if the patient has received digoxin and diuretics.

Compromised renal function, bradycardia and atrioventricular conduction defects are relative contra-indications to magnesium administration.

Magnesium and cardiac surgery : Patients undergoing cardiac surgery are frequently Mg ⁺⁺ depleted because of pre-operative diuretic therapy and heart failure. Hypomagnesaemia is common after cardiopulmonary bypass surgery and may contribute to post-operative arrhythmias.

Suggested causes for this are a bypass prime poor in magnesium, intermittent ischaemia and release of intracellular Mg ⁺⁺ by catecholamine-induced b receptor stimulation.

The effect of prophylactic postoperative Mg ⁺⁺ administration is contentious and recommendations vary. Some investigators have even shown that administration of Mg ⁺⁺ may be detrimental.

Magnesium is a competitive antagonist of calcium at prejunctional sites. High concentrations of Mg ⁺⁺ inhibit acetylcholine release whereas high calcium concentrations increase release from the presynaptic terminal.

Magnesium administration has implications for anaesthetists, especially when used in conjunction with neuromuscular blocking agents. Mg ⁺⁺ potentiates the actions of non-depolarizing neuromuscular blockers. It reduces onset time and increases recovery time. The reduction in onset time has been used clinically to produce intubation conditions more rapidly. As recovery times are prolonged after Mg ⁺⁺, it has no place in rapid sequence intubation as an alternative to succinylcholine.

Mg ⁺⁺ acts as a NMDA antagonist in the CNS. Animal studies have shown a protective role for Mg ⁺⁺ but these have not been translated to humans.

Magnesium sulphate is of little benefit in the treatment of epilepsy or status epilepticus but there is evidence that it may be useful in treating some types of seizures other than eclamptic seizures.

Mg ⁺⁺ is known to have an anti-adrenergic effect largely due to calcium antagonism. The combination of this effect with its anti-arrhythmic action & vasodilator effect has lead to the use of Mg ⁺⁺ during surgery for phaeochromocytoma.

In patients with phaeochromocytoma, marked haemodynamic changes may occur during induction, intubation, tumour handling and after devascularization of the tumour. Magnesium sulphate has been used successfully in such patients to control cardiovascular changes associated with anaesthesia and surgery.

The mechanism of action of Mg ⁺⁺ in asthma is probably multifactorial. It inhibits smooth muscle contraction as well as histamine and acetylcholine release. Low serum Mg ⁺⁺ concentrations can cause respiratory muscle weakness, which improves on administration of Mg ⁺⁺.

However, current knowledge suggests that the response to Mg ⁺⁺ in asthmatics is variable.

Decreased gastrointestinal absorption, malnutrition, drug-induced renal wasting, diabetes mellitus, hypocalcaemia and hypokalaemia that occur commonly in critically ill patients may all lead to Mg ⁺⁺ deficiency.

Mg ⁺⁺ has also been used in the treatment of respiratory failure, neonatal pulmonary hypertension and tetanus.

Although the role of Mg ⁺⁺ in obstetrics is well established, its role in other areas is still evolving and shrouded in controversy. Further investigation and clinical studies will help to elucidate its role, both in terms of treating deficiency and as a pharmacological agent.

2. Segregation of Malignant Hyperthermia, Central Core Disease and chromosome 19 markers

Summary :

Malignant hyperthermia (MH) is an autosomal dominant condition presenting under general anaesthesia in otherwise healthy susceptible individuals. Central core disease (CCD) is also a dominantly inherited neuromuscular disorder, named after its predominant histochemical characteristic. The severity of the symptoms of CCD is variable and may range from neonatal hypotonia to lower limb muscle weakness that remains undiagnosed until later in life.

Patients with CCD are prone to MH crises and it has been widely assumed that a single genetic defect is responsible for co-inheritance of CCD and MH. Earlier reports have suggested linkage of the MH locus to chromosome 19 in the same region as the gene that codes for the skeletal muscle calcium release channel, the ryanodine receptor gene (RYR1 )

This study was performed on a group of families with a history of MH and/or CCD. DNA was obtained and tested for the presence or absence of ryanodine receptor gene mutations.

None of the individuals tested (38) showed mutations of the ryanodine receptor gene. However, insufficient numbers of CCD patients have been examined, as it is a relatively uncommon disorder. Consequently, not all RYR1 sequence variations have been documented in order to establish whether these are a consistent feature of CCD.

The families studied in this project can be separated into 3 main groups:  

1. Families that are consistent with the hypothesis that CCD and MH are allelic and that the gene is close to RYR1 on chromosome 19. 
2. Families in whom CCD and MH could be caused by unrelated defects in different genes or that a defect in chromosome 19 leads to CCD but that an additional genetic component is required for the individual to be MHS. 
3. Families in whom there is no association between CCD and MH.

It is thus essential that potential genetic differences between MH & CCD are appreciated to ensure appropriate management of these patients, particularly under general anaesthesia.

3.  Acutepain induces an instant increase in natural killer cell cytotoxicity in humans and this response is abolished by local anaesthesia.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is an integrated part of trauma, exercise, infections and surgery. The effects of these conditions on immune function have been investigated. However, little is known about the consequences of pain alone on immune function as the above-mentioned conditions all include both pain and tissue damage.

Natural killer (NK) cells are lymphocytes, which have spontaneous cytotoxicity against a variety of cells and therefore play a leading role as a primary defence against viral infections and certain tumours. Physical stress such as surgery and exercise increases NK cell activity, as does mental stress. The endocrine stress response of increased adrenaline and cortisol secretion influences the NK cell response.

In this study, the immunological consequences of severe, controlled and standardised pain without concomitant tissue injury were investigated. The effect of local anaesthesia on these responses was also studied.

Only 10 subjects were included in this study, which was conducted in 2 experimental sessions. In the first session painful stimuli were applied to the abdominal skin of volunteers via a hand-held potentiometer. The subjects were instructed to maintain a particular pain intensity for a specified duration. The electric intensity profiles were recorded and stored on computer.

4 to 5 weeks later, at the second session, local anaesthetic was applied to the abdominal skin by subcutaneous injection. The electric intensity profile, recorded in the first session, was reproduced exactly and applied in the same place.

Analysis of blood obtained from the subjects showed an increase in NK cell activity in response to painful stimulation. The number of NK cells increased slightly, but not significantly.

After local anaesthesia, neither the NK cell activity nor the numbers changed.

During the first session there was an increase in the leucocyte count (neutrophils), which did not occur after local anaesthetic administration.

During the painful stimulation of the first session, adrenaline levels increased to a peak and then returned to baseline levels. After block, no changes were seen during or after stimulation.

This study raises the question of whether infiltrating the surgical field with local anaesthetic for pain relief is beneficial. The endocrine response to surgery may be blocked to such an extent that the increase in NK cell cytotoxicity is also prevented. Hence infiltration with local anaesthetic may impair the NK cell response to infection and dissemination of tumour cells.