INTRODUCTION :
Malignant hyperthermia is a life threatening syndrome of muscle hypercatabolism and rigor accompanied by a rapid progressive rise in body temperature in response to exposure to general anaesthesia in the susceptible
individual.This condition was first recognized in 1960 in Australia by Denborough and Lovel,who described it as a fatal reaction to anaesthetics which showed the hereditary characteristic of autosomal dominant transmission. In addition there appears to be a genetic predisposition for these subjects to react adversely to certain pharmacologic agents.In a sense, MH is non spesific symptom that may be caused by a variety of genetics ,enviromental and pharmacologic factors. About 20% of cases are sporadic,with autosomal dominant inheritance in one half of the families.(2)
This life threatening disorder of skeletal muscle should be suspected in patients with a suggestive family or personal history of anaesthetics mishap (4).
The subjects at risk are usually healthy,well developed and muscular.(2)
Occurrence is unpredictable but can be diagnosed by vigilant continuous observation of the patients.
The etiology remains uncertain and controversial.
INCIDENSE OF AND MORTALITY RATE FROM MH.(1)
The incidence of MH will vary depending on the prevalence of the genes for MH in any geographic area.
Table Incidence of MH :
Regions Country and reference Incidence No of Anesthetics
North America Canada and USA 1/15.000 - 150.000
Pasific Japan 1/7000 - 110.000
New Zealand 1/5000
Europe UK 1/200.000
Austria 1/23.000
Switzerland 1/95.800
Denmark 1/220.000
The prevalence of susceptible individuals is estimated to be between 1-200 to 1 in 5000 populations.
Most reports describe patients of Causcacian or African descent; many reports have appeared of MH in Asian patients.(2)
MH may occure at any age,however it is more common in children (1: 15.000) than adults (1:50.000) and decreases in frequency post the age of about 40.(1)
MH is exceptionally rare below the age of 3 and over the age 50,although few cases of the MH syndrome proper has been reported in the newborn.
Males predominate after 15 years of age in a ratio of 3 males to 1 female.(2)
Since not all anesthetics trigger MH, the syndrome will be more prevalent where succinylchloline and potent inhalation agents are used commonly compared to nitrous,narcotic non depolarizing relaxant or regional techniques.It has not been reported during local or regional anaesthesia.(4)
Approximately 30 percent of MH sufferers manifest one of a group of non spesific musculoskeletal disorders such as strabismus,congenital ptosis,kyphoscoliosis,subluxation of patellae and recurent joint dislocation.(1)
The mortality from MH at the time it first came to world notice was of the order of 80 percent. During the 1970 increasing awareness of the syndrome with resultant earlier diagnosis and treatment, led to an improvement in prognosis, mortality dropping to 28 percent.This decade, following the introduction of dantrolene sodium,the mortality recorded from MH is now only 7 percent. In Western countries is about ten percents in recent years. Today with correct management survival from MH should be 100 percent (Britt 1985,Gronert 1986).(1)
PATHOPHYSIOLOGY :
The primary defect in MH is in the excitation,contraction coupling (ECC) step involving the sarcoplasmic plasmic reticulum, EEC and its related energy transduction are intergrate function of the sarcolemma, sarcoplasmic reticulum and the mitochondria (Sandow 1965,Endo 1977).In MH muscle,defects have been identified at all points in this cycle.(1)
Most relevant to the MH crisis are those of sarcoplasmic reticulum,the organelle which plays the primary role in the regulation of myoplasmic free calcium.
The MH reaction based on the induction of an abrupt and sustained rise in myoplasmic free calcium and events which initiates muscle contracture ,activates glycolysis and mitochondrial activity and sets in train a series of events which interact to form a vicious cycle.(1)
Rise in myoplasmic free calcium above thresold value activated the topomin/actin/myosin interaction leading to muscle contraction soon to persist as contracture when free calcium elevation is sustained.(1)
With activating glycogen phosphorylase and massive glycolysis,muscle glycogen being depleted with the production of lactate which may rise 15 to 20 fold (Hermann et al 1970).
At an early stage ,heat output may increase 15 to 17 fold (William,Houchins and Shanklin 1975) to equal condition of very severe exercise in a trained athlete.But in contrast to the ten fold increase O2 uptakerecorded by the athlete ,the patient MH records at this time a three fold increase in O2 uptake,and consequently due to predominantly anaerobic glycolysis,manifest a severe acid base disturbance(Gronert 1976).
Exposed to this high calcium load ,mitochondria of MH muscle display only 60 percent of the normal capacity to synthesize ATP(Rutenbeek et al 1984).
The increased compsumtion of ATP exceeds mitochondrial capacity for its regenerarion,ATP levels soon decline rapidly,various membrane ion pumps (eg in mitochondria and sarcoplasmic reticulum ) are deprived of substrate and membrane integrity fails.
In conclusion the pathogenesis of MH as vicious cycle based on derangement in EEC mechanism of which the sudden induction of sustained rise in myoplasmic free calcium.
THE CLINICAL SYNDROME :
During clinical anaesthesia onset of MH is presage usually by a surge of sympathetic activity. This manifest clinically as the sudden appearance of unexplained tachycardia and possibly tachyarrhytmia Tacycardia and hypertension are seen at the onset but are succeeded by arrhythmia and hypotension (2).
Such cardiovascular response due to rigor of the heart muscle initially.
Decreased tissue O2 plays a secondary role along with pH and PaCO2 and electrolyte changes within the heart muscle cell.(2)
An accompanying cyanosis (in the presence of adequate ventilation and inspired oxygen concentration greater than 0,3) reflects the immediately increased oxygen demand)triggered by muscle hypercatabolism.
(excessive muscle oxygen utilisation and enhance exraction.).(2)
Dark blood is often noticed by the surgeon and may be the first indication of MH,but it is usually a later manifestation.
This in turn results in greatly increased carbon dioxide output,which monitored effectively by capnography, provide the earliest evidence of this syndrome's onset(Baundenstel et.al 1984).
The earliest sign of MH include tachycardia,tachypnoe and increased end tidal CO2 levels.
Tachypnoe and hyperpnoe are consequent to increased catabolism with over utilisation of oxygen and over production of carbon dioxide.
Respiratory acidosis is present due to a marked increased in cabon dioxide production.
Profound metabolic acidosis-lactic acidosis with concomitant rise in PCO2 is the hallmark of the syndrome.
A wet sweaty skin may be seen early,but a hot dry skin is observed is often and flushing and mottling skin is common. Muscle hypertonics or rigor appears in a mayority of cases (over 80%),especially involving jaw muscles (1)is often an early sign of MH,and more common in children,and manifest as masseter muscle rigidity or spasm(MMR or MMS) may cause difficulty with tracheal intubation and 60-70% have been shown to be MH on subsequent diagnostic screening (Ellis and Halsell,1984,Flevellyn and Nelson 1984).
A great number of patients who manifest rigidity have preexisting muscle or musculoskletal disorders. Of the common muscular dystrophies,Duchenne Muscular Dystrophy(DMD) is severe and rapidly progressive;MH has been reported in such patients.Myopathies such as myotonias and central core diseases increase the susceptibility to MH.(2)
Temperature elevation is usually a late sign of MH but poor prognoses if the theraphy has not yet been started,Rate of core temperature rise of one degree Celcius every 5-10 min are not unsual (Steward 1979).
This explossive rise may be delayed for 1 to 3 hours after the appearance of other abnormal physiologic signs. These patients whose temperature exceed than 107 F,the mortality increases to 80-90% and below this level mortality between 50 to 60%.(2)
The rapid rise of in temperature is consequent to deranged biological oxidation in skletal muscle where muscle glycogen is decreased and is mobilized for heat production in the violent reactions there is also an intense mobilization of liver glycogen.(2)
Paradoxically death from MH may occur at normothermia even mild hypothermia. Possibly death may follow cardiac arrhytmia due to catecholamine surge and/or hyperkalemia which accompany syndrome before the temperature has rises above normal level.(1)
Elevation are recorded in the serum levels of all electrolytes,total,protein ,glucose and lactate. These indicates glycogenolysis,glycolysis,a shift of water into the cells,and leakage of sodium,potassium,calcium,magnesium,and inorganic phosphorous.
As the syndrome progresses increasing permeability of the sarcolemma becomes manifest by rapid rise in serum levels of the muscle enzym creatinine phosphorkinase(CPK),and lactate dehydrogenase (LDH), as well as alanine amino transaminase(ALT) and aspartate amino transaminase(AST).
The rise of serum levels of creatinine phosphokinase (CPK)often tenfold at 24 hours is considered diagnostic of MH(Denborough 79).(1)
An ominous consequence of the progressive intrinsic muscle damage and sarcolemma permeability is the release into the circulation of myoglobine and tissue thromboplastine.
The myoglobine renal failure and desseminated intravascular coagulopathy(DIC) which may follow worsen the prognosis immesurably (Gronert 1980).
DIAGNOSIS and LABORATORY FINDINGS :
One must be suspicious of this complication in the presence of tachycardia (unexplaines), tachypnoe, arrhytmia, abnormal response to succinylcholine, generalized or localized rigidity and/or rapid rise in body temperature.The normal anaesthetized patient does not become hyperthermia of the room temperature is < 25.5 C.Regard any rise in temperature of more than 0,5 degree Celcius in fifteen minutes as posibble malignant hyperthermia (MH)(4).
The importance of early diagnosis and early termination of anaesthesia lies in the fact that the chances of cardiopulmonary collapse and eventually death increased statistically in proportion to duration of anaesthesia.
To confirm the diagnosis,the anesthetist should:(5)
1.Obtain an arterial samples for blood gases and electolytes.
MH produces hypoxaemia, severe respiratory and metabolic acidosis, profound initial hypercalcemia presumably calcium released SR storage vesicles into both myoplasma and ECF then accompanied hyperkalemia.
hypermagnesemia,hyperphosphatemia,myoglobinaemia,and elevated lactate and pyruvate levels.
Additional findings:(4)
Muscle biopsy abnormalities (Intracellular calcium is elevated in biopsy muscle). Elevated serum enzymes SGOT,LDH,SGPT,and CPK. This indicates that an injury to muscles has occured.
2.Double check the temperature with another thermometer and exclude other causes such as a malfunctioning warming blanket.
Diagnostic test :
Invassive (involving open muscle biopsy)
Contracture test-Muscle Biopsy (2)
Open biopsy of quadriceps or vastus lteralis muscle under local anaesthesia is performed and the spicement preserved in Krebs-Ringers solution. Viability is confirmed by elcreical stimulation and a length tension curve plotted.The muscle is then exposed to particular stimulants in vitro.
1. Caffeine contracture test :
To sequential incremental concentration of 0,25 to 32,0 mM of caffeine in Krebs Ringers bath solution. MH susceptible subjects have a contracture threshold at 2.0 mM concentration of caffeine or less.
2. Exposure of Muscle preparation to halothane :
To 2% halothane for 15 minutes.MH susceptible subjects or those who have an MH episode and survive have enhanced contracture response.
Critical values are 2 mmol/L caffeine,and 2% (0,44 mmol) halothane.
Specimens scoring less than both indices are classified as MH, those greater than both as MHN(negative).
All others are classified as MHE(equivocal). The indications for testing include family history of MH,and suspicious episodes of MH. Contracture testing is done by centers in the USA,Canada,Australia,and Europe over 40 testing centers worldwide.
Non invasive test for MH under study. Calcium release from lymphocytes after halothane exposure. Elevated ratio of inorganic phosphate /ATP. Increased fluidity of erythrocyte membrane in MH susceptibles.
The following test have not been confirmed as valid :
Calcium uptake,Calcium ATP ase,Platelet ATP depletion,RBC fragility,Routine screening by CPK, Myophosphorylase activity,Torniquet twitch test,
TREATMENT: (2,3,4,5)
1.Stop all anaesthetics agents :
a.Remove and replace rubber goods
b.Employe any gas anesthetics machine without vaporizers
c.Change anaesthesia machine if feasible.
2.Hyperventilated the patient with 100 percent oxygen,stop surgeon as soon as possible.
3.Give sodium bicarbonate iv (132 meq for 70 kg adult) as soon as the first arterial blood gases(ABG) sample is sent.
Once the result of ABG are available,administer NaHCO3 according to the following calculations :
base deficit x body weight(kg)
meq HCO3 = ---------------------------------
3
When blood gases unavailable assume a base deficit of 6 mmol/L. Repeated dose may be required. Hypernatremia may result and should be controlled by infusion of furesemid. Place arterial line to follow acid base balance and ABG.
4If hyperkalemia is severe and cardiac arrhytmia appear first give calcium chloride (1000 mg iv over 5 min) then give regular insuline 20 units iv with 50cc of 50% glucose or 100 units regular insulin in 500 ml of 10% dextrose or put insulin in Ringerslactate solution. Transient hypokalemia may be seen but it should not be treated with potassium replacement unless cardiac arrythmia occur. Potassium salts may trigger MH(4). When temperature subsides, stop insuline.
5.Cool the patient :
a.Children have a relatively large surface area compared to body weight and can be effectively cooled with surface method. Apply cooling blanket and place ice bags around the neck,axillae and groin points where mayor vessels are close to the surface.
Iced Ringers lactate may be given iv.
If all these measures fail, immerse the child in a tub of ice water. Shivering must be prevented by alpha adrenergic blocking drugs such as chlorpromazine or dibenziline.
b. Adult can be packed in ice,particularly in the neck,axillae and groin.
Lavage any surgically opened cavities with ice solutions, administer iced.
Ringers lactate iv,and perform gastric,rectal,and bladder irrigations with iced solutions.
Where available instituting cardiopulmonary bypass can be life saving,extra corporal cooling is the most effective method of heat exchange.
c. Stop cooling when temperature reaches 38 C (101 F) to prevent reactive hypothermia and restart when temperature arise again.Temperature should be monitored at least every 5 minutes,preferably continously.
6.Maintain a high urine output (2ml/kg/hour) to protect renal tubules from being damaged by myoglobine and haemoglobine likely produce acute tubular necrosis (ATN).
Give manitol (25 g iv) and furesemide 20 mg iv.
Mannitol also corrects the muscular and cerebral edema.
Agressive hydration with ringers lactate solution in volume of 3-4 liters in 6 hours,CVP monitoring is mandatory in order to detect circulatory overload.
Insert a Folley catether to follow diuresis.
Should the treatment of acidosis have involved heavy sodium loading,the use of furesemide more appropriate.Infus fresh frozen plasma, if the MH has been long lasting and there is anykind of development of DIC.
7.Give drugs to assist uptake of calcium into the sarcoplasmic reticulum,and allow normal muscle metabolism to occur.
a.Procain amide (Pronestyl) is the drug of choice,effective in both rigid and non rigid types of MH to stabilized the cell membrane and calcium storage vesicles of skletalmuscle; in ionized form promote uptake and storage of calcium in the sarcoplasmic reticulum.
High levels of sarcoplasmic calcium increase the risk of initiating skletal muscle contracture. Lowering extracellular and plasma calcium and creating gradient of calcium into sarcoplasmic reticulum minimized contracture.
Give 15 mg/kg in 500 ml of 5%DW over 8-10 minutes or 0,5 -1mg/kg/minute.
Then start a procain amide infusion at 50mg/hour.
b. Procain is a second choice because it is profound myocardial depressant.
Give a loading dose of 30 -40 mg /kg iv,followed by an iv infusion of 0,2 mg/kg/min.
c. Dantrolene appears to be very effective but it is not readily available at this time at all hospitals.
Dantrolene as been accepted as prophylactic and therapeutic agents in the management of human MH. It is a complex imidazoline sodium salt,which is poor soluble in water,but because it is high lipid solubility,it cross cell
membranes readily. Its structurally resembles diphenylhydantoin.
The site action of dantrolene is within the skletal muscle fibre and thus it may be considered an intracellular muscle relaxant. It appears to directly stabilize the sarcoplasmic reticulum membrane containing the vesicles of calcium and also acts on the transverse tubular membrane and terminal
cysternae of the sarcoplasmic reticulum.Thus,the agent limits the availability of calcium ions by attenuating calcium release without affecting uptake.This limits the
excitation coupling reaction of the muscle contractile system.(2)
Preperation as powder consist 20 mg of dantrolene ,3 gm of mannitol and sufficient sodium hydroxide to establish a pH of approximately 9,5 on being dissolved.When the powder is dissolved by the addition of 60 ml of sterile distilled water.
The resulting solution 0.33 mg/ml.
The alkaline pH of the reconstituted drugs may account for irritation of the venous endothelium. Superficial phlebitis has been reported 2 cases in 5000 administration(Kolb).
A multicenter clinical study in the therapy of MH crisis showed that the dose of dantrolene needed to reverse a crisis was approximately 2,5 mg/kg or 1-2 mg/kg iv repeated every 5-10 minutes to a maximal dose of 10 mg/kg.
Prophylaxis in MH susceptible patients is with oral dantrolene 4-8 mg/kg given in devided dose for 1-3 days,with the last dose being administered 1-5 hours before the induction of anaesthesia.
Despite the prophylactic administration of dantrolene MH susceptible patients may still be triggered with an MH crisis.(2)
Recrudescense may occur after treatment.
Calcium antagonist should not be used a long with dantrolene it my cause profound myocardial depression,cardiovascular collapse and marked hyperkalemia (Gallant et all 1985).(3,4).
The most common side effect of dantrolene is skletal muscle weakness may be sufficient to interfere with adequate ventilation or protection of the lung from aspiration of gastric fluid (Watson 1986).
8. Treat tachycardia
Small doses of beta adrenergic blocking drugs are effective and safe. Dont move patient because stimulation by movement incites or increases ventricular arrhythmia.
9. Administer glucocorticoid: methylprednisolon has been effective inpreventing contacture and valuable in treating MH.
10. Use alpha blocking agents : Chlorpromazine or dehydrobenzperiddol provide skin vasodilattion and improve cutaneous blood flow. Shivering and thermogenesis are inhibited. Experimental evidence indicates blocking the transmission of alpha adrenergic mediators can protect the triggering of MH.
11. If a patient survives an episode of MH and requires reoperation,the anesthetist should be fully prepared for a recurrence.
Local or regional anaethesia,using ester agents is preferred.(lidocaine should be avoided).
If the general anaesthesia is necessary,N2O,fentanyl,dropridol seems to be the method with the least risk.
If muscle relaxant has to be achieved for surgery to be done,non depolarizing muscle relaxants maybe cautiously used as vecuronium,pancuronium and atracurium. The anaesthesia machine shoud be purged prior to giving anaesthesia. Temperature and end tidal CO2 should
be monitored.
12. Once the patients temperature has reached normal levels. PaCO2 is normal,and metabolic acidosis has been corrected,spontanous respiration allowed to recommence,and the patient is extubated once conscious.
The patient must be closely monitored and sedated for 24 hours after initial recovery for fear of recurrence of syndrome.(1)
DELAYED COMPLICATION :(1)
1.Hyperactive bleeding (DIC)
Acute activation of clotting result from mechanism :
a.Endothelial damageis produced by hyperthermia and this activates the Hageman(XII) factor.
b.Tissue hypoxia (oxygen over utilization) causes mobilization of tissue thromboplastin and entry of this enzyme into the circulation. Consequences include intravascular consumption of clotting factors :
Depletion of platelets,prothrombin,fibrinogen,and Factors V,VII and XII. This is DIC syndrome.
c.Abnormal platelets agregation appears to occur in susceptible patients which increases by halothane.
2.Erythrocyte Fragility :
Red blood cells show increase fragility.Haemoglobine release from increased RBC breakdown. When levels higher than 200mg/100 ml of blood are reached Hb then appears in the urine. The renal thresold for Hb is 100-150 mg/100 ml of blood.
3. Liver damage :
In patients who survive heat stroke,jaundice is common and liver damage is frequent.
4. Hypothalamic damage :
Disturbed temperature regulation at the hypothalamus undoubtledly occured, If the thermostat is raised,heat production will increase. For each 1 degree C increase in body temperatur there is a 13% increase in heat production.This become vicious cycle,especially if damage to the hypothalamic neurons occurs.
REFERENCES :
1.Gray Cecil T : Malignant hyperthermia in Text book of General Anaesthesia ,fifth edit,Butterwoth International edition,London,Boston,Singapore ,wellington 1989,pp.655-60.
2.Collins J.V. : Temperature Regulation and Heat problem in Textbook of Physiology and Pharmacologic Bases of Anaesthesia,William & Wilkin,A. Waverly Company,Baltimore,Philadelphia,London.1996,pp.328-39
3.Stoelting.K.R : Central Nervous System Stimulants and Muscle Relaxants in the Textbook of Pharmacology and Physiology in Anesthetic Practice,J.B.Lippincott Company, Philadelphia,London,Mexico City,1987. pp.521-2
4.Rosenberg H : Malignant Hyperthermia -An Update in International Anaesthesia Research Society Review Course Lectures Presented at the IARS 3rd Congress International Anaesthesia Society, March 4-8, Florida pp.109-11.
5.Lebowitz W Cs : Malignant Hyperthermia as Emergencies Complicating Anaesthesia inClinical Anaesthesia Procedure of the Massachusetts General Hospital,1st edit,by Little Brown and Company (Inc),1978, pp.355-7.
6.Snow C.John : Malignant Hyperthermia in Manual of Anaesthesia,1st edit,by Little Brown and Company,Boston, Massachusetts ,Tokyo.1997,pp.362-4.
Malignant hyperthermia is a life threatening syndrome of muscle hypercatabolism and rigor accompanied by a rapid progressive rise in body temperature in response to exposure to general anaesthesia in the susceptible
individual.This condition was first recognized in 1960 in Australia by Denborough and Lovel,who described it as a fatal reaction to anaesthetics which showed the hereditary characteristic of autosomal dominant transmission. In addition there appears to be a genetic predisposition for these subjects to react adversely to certain pharmacologic agents.In a sense, MH is non spesific symptom that may be caused by a variety of genetics ,enviromental and pharmacologic factors. About 20% of cases are sporadic,with autosomal dominant inheritance in one half of the families.(2)
This life threatening disorder of skeletal muscle should be suspected in patients with a suggestive family or personal history of anaesthetics mishap (4).
The subjects at risk are usually healthy,well developed and muscular.(2)
Occurrence is unpredictable but can be diagnosed by vigilant continuous observation of the patients.
The etiology remains uncertain and controversial.
INCIDENSE OF AND MORTALITY RATE FROM MH.(1)
The incidence of MH will vary depending on the prevalence of the genes for MH in any geographic area.
Table Incidence of MH :
Regions Country and reference Incidence No of Anesthetics
North America Canada and USA 1/15.000 - 150.000
Pasific Japan 1/7000 - 110.000
New Zealand 1/5000
Europe UK 1/200.000
Austria 1/23.000
Switzerland 1/95.800
Denmark 1/220.000
The prevalence of susceptible individuals is estimated to be between 1-200 to 1 in 5000 populations.
Most reports describe patients of Causcacian or African descent; many reports have appeared of MH in Asian patients.(2)
MH may occure at any age,however it is more common in children (1: 15.000) than adults (1:50.000) and decreases in frequency post the age of about 40.(1)
MH is exceptionally rare below the age of 3 and over the age 50,although few cases of the MH syndrome proper has been reported in the newborn.
Males predominate after 15 years of age in a ratio of 3 males to 1 female.(2)
Since not all anesthetics trigger MH, the syndrome will be more prevalent where succinylchloline and potent inhalation agents are used commonly compared to nitrous,narcotic non depolarizing relaxant or regional techniques.It has not been reported during local or regional anaesthesia.(4)
Approximately 30 percent of MH sufferers manifest one of a group of non spesific musculoskeletal disorders such as strabismus,congenital ptosis,kyphoscoliosis,subluxation of patellae and recurent joint dislocation.(1)
The mortality from MH at the time it first came to world notice was of the order of 80 percent. During the 1970 increasing awareness of the syndrome with resultant earlier diagnosis and treatment, led to an improvement in prognosis, mortality dropping to 28 percent.This decade, following the introduction of dantrolene sodium,the mortality recorded from MH is now only 7 percent. In Western countries is about ten percents in recent years. Today with correct management survival from MH should be 100 percent (Britt 1985,Gronert 1986).(1)
PATHOPHYSIOLOGY :
The primary defect in MH is in the excitation,contraction coupling (ECC) step involving the sarcoplasmic plasmic reticulum, EEC and its related energy transduction are intergrate function of the sarcolemma, sarcoplasmic reticulum and the mitochondria (Sandow 1965,Endo 1977).In MH muscle,defects have been identified at all points in this cycle.(1)
Most relevant to the MH crisis are those of sarcoplasmic reticulum,the organelle which plays the primary role in the regulation of myoplasmic free calcium.
The MH reaction based on the induction of an abrupt and sustained rise in myoplasmic free calcium and events which initiates muscle contracture ,activates glycolysis and mitochondrial activity and sets in train a series of events which interact to form a vicious cycle.(1)
Rise in myoplasmic free calcium above thresold value activated the topomin/actin/myosin interaction leading to muscle contraction soon to persist as contracture when free calcium elevation is sustained.(1)
With activating glycogen phosphorylase and massive glycolysis,muscle glycogen being depleted with the production of lactate which may rise 15 to 20 fold (Hermann et al 1970).
At an early stage ,heat output may increase 15 to 17 fold (William,Houchins and Shanklin 1975) to equal condition of very severe exercise in a trained athlete.But in contrast to the ten fold increase O2 uptakerecorded by the athlete ,the patient MH records at this time a three fold increase in O2 uptake,and consequently due to predominantly anaerobic glycolysis,manifest a severe acid base disturbance(Gronert 1976).
Exposed to this high calcium load ,mitochondria of MH muscle display only 60 percent of the normal capacity to synthesize ATP(Rutenbeek et al 1984).
The increased compsumtion of ATP exceeds mitochondrial capacity for its regenerarion,ATP levels soon decline rapidly,various membrane ion pumps (eg in mitochondria and sarcoplasmic reticulum ) are deprived of substrate and membrane integrity fails.
In conclusion the pathogenesis of MH as vicious cycle based on derangement in EEC mechanism of which the sudden induction of sustained rise in myoplasmic free calcium.
THE CLINICAL SYNDROME :
During clinical anaesthesia onset of MH is presage usually by a surge of sympathetic activity. This manifest clinically as the sudden appearance of unexplained tachycardia and possibly tachyarrhytmia Tacycardia and hypertension are seen at the onset but are succeeded by arrhythmia and hypotension (2).
Such cardiovascular response due to rigor of the heart muscle initially.
Decreased tissue O2 plays a secondary role along with pH and PaCO2 and electrolyte changes within the heart muscle cell.(2)
An accompanying cyanosis (in the presence of adequate ventilation and inspired oxygen concentration greater than 0,3) reflects the immediately increased oxygen demand)triggered by muscle hypercatabolism.
(excessive muscle oxygen utilisation and enhance exraction.).(2)
Dark blood is often noticed by the surgeon and may be the first indication of MH,but it is usually a later manifestation.
This in turn results in greatly increased carbon dioxide output,which monitored effectively by capnography, provide the earliest evidence of this syndrome's onset(Baundenstel et.al 1984).
The earliest sign of MH include tachycardia,tachypnoe and increased end tidal CO2 levels.
Tachypnoe and hyperpnoe are consequent to increased catabolism with over utilisation of oxygen and over production of carbon dioxide.
Respiratory acidosis is present due to a marked increased in cabon dioxide production.
Profound metabolic acidosis-lactic acidosis with concomitant rise in PCO2 is the hallmark of the syndrome.
A wet sweaty skin may be seen early,but a hot dry skin is observed is often and flushing and mottling skin is common. Muscle hypertonics or rigor appears in a mayority of cases (over 80%),especially involving jaw muscles (1)is often an early sign of MH,and more common in children,and manifest as masseter muscle rigidity or spasm(MMR or MMS) may cause difficulty with tracheal intubation and 60-70% have been shown to be MH on subsequent diagnostic screening (Ellis and Halsell,1984,Flevellyn and Nelson 1984).
A great number of patients who manifest rigidity have preexisting muscle or musculoskletal disorders. Of the common muscular dystrophies,Duchenne Muscular Dystrophy(DMD) is severe and rapidly progressive;MH has been reported in such patients.Myopathies such as myotonias and central core diseases increase the susceptibility to MH.(2)
Temperature elevation is usually a late sign of MH but poor prognoses if the theraphy has not yet been started,Rate of core temperature rise of one degree Celcius every 5-10 min are not unsual (Steward 1979).
This explossive rise may be delayed for 1 to 3 hours after the appearance of other abnormal physiologic signs. These patients whose temperature exceed than 107 F,the mortality increases to 80-90% and below this level mortality between 50 to 60%.(2)
The rapid rise of in temperature is consequent to deranged biological oxidation in skletal muscle where muscle glycogen is decreased and is mobilized for heat production in the violent reactions there is also an intense mobilization of liver glycogen.(2)
Paradoxically death from MH may occur at normothermia even mild hypothermia. Possibly death may follow cardiac arrhytmia due to catecholamine surge and/or hyperkalemia which accompany syndrome before the temperature has rises above normal level.(1)
Elevation are recorded in the serum levels of all electrolytes,total,protein ,glucose and lactate. These indicates glycogenolysis,glycolysis,a shift of water into the cells,and leakage of sodium,potassium,calcium,magnesium,and inorganic phosphorous.
As the syndrome progresses increasing permeability of the sarcolemma becomes manifest by rapid rise in serum levels of the muscle enzym creatinine phosphorkinase(CPK),and lactate dehydrogenase (LDH), as well as alanine amino transaminase(ALT) and aspartate amino transaminase(AST).
The rise of serum levels of creatinine phosphokinase (CPK)often tenfold at 24 hours is considered diagnostic of MH(Denborough 79).(1)
An ominous consequence of the progressive intrinsic muscle damage and sarcolemma permeability is the release into the circulation of myoglobine and tissue thromboplastine.
The myoglobine renal failure and desseminated intravascular coagulopathy(DIC) which may follow worsen the prognosis immesurably (Gronert 1980).
DIAGNOSIS and LABORATORY FINDINGS :
One must be suspicious of this complication in the presence of tachycardia (unexplaines), tachypnoe, arrhytmia, abnormal response to succinylcholine, generalized or localized rigidity and/or rapid rise in body temperature.The normal anaesthetized patient does not become hyperthermia of the room temperature is < 25.5 C.Regard any rise in temperature of more than 0,5 degree Celcius in fifteen minutes as posibble malignant hyperthermia (MH)(4).
The importance of early diagnosis and early termination of anaesthesia lies in the fact that the chances of cardiopulmonary collapse and eventually death increased statistically in proportion to duration of anaesthesia.
To confirm the diagnosis,the anesthetist should:(5)
1.Obtain an arterial samples for blood gases and electolytes.
MH produces hypoxaemia, severe respiratory and metabolic acidosis, profound initial hypercalcemia presumably calcium released SR storage vesicles into both myoplasma and ECF then accompanied hyperkalemia.
hypermagnesemia,hyperphosphatemia,myoglobinaemia,and elevated lactate and pyruvate levels.
Additional findings:(4)
Muscle biopsy abnormalities (Intracellular calcium is elevated in biopsy muscle). Elevated serum enzymes SGOT,LDH,SGPT,and CPK. This indicates that an injury to muscles has occured.
2.Double check the temperature with another thermometer and exclude other causes such as a malfunctioning warming blanket.
Diagnostic test :
Invassive (involving open muscle biopsy)
Contracture test-Muscle Biopsy (2)
Open biopsy of quadriceps or vastus lteralis muscle under local anaesthesia is performed and the spicement preserved in Krebs-Ringers solution. Viability is confirmed by elcreical stimulation and a length tension curve plotted.The muscle is then exposed to particular stimulants in vitro.
1. Caffeine contracture test :
To sequential incremental concentration of 0,25 to 32,0 mM of caffeine in Krebs Ringers bath solution. MH susceptible subjects have a contracture threshold at 2.0 mM concentration of caffeine or less.
2. Exposure of Muscle preparation to halothane :
To 2% halothane for 15 minutes.MH susceptible subjects or those who have an MH episode and survive have enhanced contracture response.
Critical values are 2 mmol/L caffeine,and 2% (0,44 mmol) halothane.
Specimens scoring less than both indices are classified as MH, those greater than both as MHN(negative).
All others are classified as MHE(equivocal). The indications for testing include family history of MH,and suspicious episodes of MH. Contracture testing is done by centers in the USA,Canada,Australia,and Europe over 40 testing centers worldwide.
Non invasive test for MH under study. Calcium release from lymphocytes after halothane exposure. Elevated ratio of inorganic phosphate /ATP. Increased fluidity of erythrocyte membrane in MH susceptibles.
The following test have not been confirmed as valid :
Calcium uptake,Calcium ATP ase,Platelet ATP depletion,RBC fragility,Routine screening by CPK, Myophosphorylase activity,Torniquet twitch test,
TREATMENT: (2,3,4,5)
1.Stop all anaesthetics agents :
a.Remove and replace rubber goods
b.Employe any gas anesthetics machine without vaporizers
c.Change anaesthesia machine if feasible.
2.Hyperventilated the patient with 100 percent oxygen,stop surgeon as soon as possible.
3.Give sodium bicarbonate iv (132 meq for 70 kg adult) as soon as the first arterial blood gases(ABG) sample is sent.
Once the result of ABG are available,administer NaHCO3 according to the following calculations :
base deficit x body weight(kg)
meq HCO3 = ---------------------------------
3
When blood gases unavailable assume a base deficit of 6 mmol/L. Repeated dose may be required. Hypernatremia may result and should be controlled by infusion of furesemid. Place arterial line to follow acid base balance and ABG.
4If hyperkalemia is severe and cardiac arrhytmia appear first give calcium chloride (1000 mg iv over 5 min) then give regular insuline 20 units iv with 50cc of 50% glucose or 100 units regular insulin in 500 ml of 10% dextrose or put insulin in Ringerslactate solution. Transient hypokalemia may be seen but it should not be treated with potassium replacement unless cardiac arrythmia occur. Potassium salts may trigger MH(4). When temperature subsides, stop insuline.
5.Cool the patient :
a.Children have a relatively large surface area compared to body weight and can be effectively cooled with surface method. Apply cooling blanket and place ice bags around the neck,axillae and groin points where mayor vessels are close to the surface.
Iced Ringers lactate may be given iv.
If all these measures fail, immerse the child in a tub of ice water. Shivering must be prevented by alpha adrenergic blocking drugs such as chlorpromazine or dibenziline.
b. Adult can be packed in ice,particularly in the neck,axillae and groin.
Lavage any surgically opened cavities with ice solutions, administer iced.
Ringers lactate iv,and perform gastric,rectal,and bladder irrigations with iced solutions.
Where available instituting cardiopulmonary bypass can be life saving,extra corporal cooling is the most effective method of heat exchange.
c. Stop cooling when temperature reaches 38 C (101 F) to prevent reactive hypothermia and restart when temperature arise again.Temperature should be monitored at least every 5 minutes,preferably continously.
6.Maintain a high urine output (2ml/kg/hour) to protect renal tubules from being damaged by myoglobine and haemoglobine likely produce acute tubular necrosis (ATN).
Give manitol (25 g iv) and furesemide 20 mg iv.
Mannitol also corrects the muscular and cerebral edema.
Agressive hydration with ringers lactate solution in volume of 3-4 liters in 6 hours,CVP monitoring is mandatory in order to detect circulatory overload.
Insert a Folley catether to follow diuresis.
Should the treatment of acidosis have involved heavy sodium loading,the use of furesemide more appropriate.Infus fresh frozen plasma, if the MH has been long lasting and there is anykind of development of DIC.
7.Give drugs to assist uptake of calcium into the sarcoplasmic reticulum,and allow normal muscle metabolism to occur.
a.Procain amide (Pronestyl) is the drug of choice,effective in both rigid and non rigid types of MH to stabilized the cell membrane and calcium storage vesicles of skletalmuscle; in ionized form promote uptake and storage of calcium in the sarcoplasmic reticulum.
High levels of sarcoplasmic calcium increase the risk of initiating skletal muscle contracture. Lowering extracellular and plasma calcium and creating gradient of calcium into sarcoplasmic reticulum minimized contracture.
Give 15 mg/kg in 500 ml of 5%DW over 8-10 minutes or 0,5 -1mg/kg/minute.
Then start a procain amide infusion at 50mg/hour.
b. Procain is a second choice because it is profound myocardial depressant.
Give a loading dose of 30 -40 mg /kg iv,followed by an iv infusion of 0,2 mg/kg/min.
c. Dantrolene appears to be very effective but it is not readily available at this time at all hospitals.
Dantrolene as been accepted as prophylactic and therapeutic agents in the management of human MH. It is a complex imidazoline sodium salt,which is poor soluble in water,but because it is high lipid solubility,it cross cell
membranes readily. Its structurally resembles diphenylhydantoin.
The site action of dantrolene is within the skletal muscle fibre and thus it may be considered an intracellular muscle relaxant. It appears to directly stabilize the sarcoplasmic reticulum membrane containing the vesicles of calcium and also acts on the transverse tubular membrane and terminal
cysternae of the sarcoplasmic reticulum.Thus,the agent limits the availability of calcium ions by attenuating calcium release without affecting uptake.This limits the
excitation coupling reaction of the muscle contractile system.(2)
Preperation as powder consist 20 mg of dantrolene ,3 gm of mannitol and sufficient sodium hydroxide to establish a pH of approximately 9,5 on being dissolved.When the powder is dissolved by the addition of 60 ml of sterile distilled water.
The resulting solution 0.33 mg/ml.
The alkaline pH of the reconstituted drugs may account for irritation of the venous endothelium. Superficial phlebitis has been reported 2 cases in 5000 administration(Kolb).
A multicenter clinical study in the therapy of MH crisis showed that the dose of dantrolene needed to reverse a crisis was approximately 2,5 mg/kg or 1-2 mg/kg iv repeated every 5-10 minutes to a maximal dose of 10 mg/kg.
Prophylaxis in MH susceptible patients is with oral dantrolene 4-8 mg/kg given in devided dose for 1-3 days,with the last dose being administered 1-5 hours before the induction of anaesthesia.
Despite the prophylactic administration of dantrolene MH susceptible patients may still be triggered with an MH crisis.(2)
Recrudescense may occur after treatment.
Calcium antagonist should not be used a long with dantrolene it my cause profound myocardial depression,cardiovascular collapse and marked hyperkalemia (Gallant et all 1985).(3,4).
The most common side effect of dantrolene is skletal muscle weakness may be sufficient to interfere with adequate ventilation or protection of the lung from aspiration of gastric fluid (Watson 1986).
8. Treat tachycardia
Small doses of beta adrenergic blocking drugs are effective and safe. Dont move patient because stimulation by movement incites or increases ventricular arrhythmia.
9. Administer glucocorticoid: methylprednisolon has been effective inpreventing contacture and valuable in treating MH.
10. Use alpha blocking agents : Chlorpromazine or dehydrobenzperiddol provide skin vasodilattion and improve cutaneous blood flow. Shivering and thermogenesis are inhibited. Experimental evidence indicates blocking the transmission of alpha adrenergic mediators can protect the triggering of MH.
11. If a patient survives an episode of MH and requires reoperation,the anesthetist should be fully prepared for a recurrence.
Local or regional anaethesia,using ester agents is preferred.(lidocaine should be avoided).
If the general anaesthesia is necessary,N2O,fentanyl,dropridol seems to be the method with the least risk.
If muscle relaxant has to be achieved for surgery to be done,non depolarizing muscle relaxants maybe cautiously used as vecuronium,pancuronium and atracurium. The anaesthesia machine shoud be purged prior to giving anaesthesia. Temperature and end tidal CO2 should
be monitored.
12. Once the patients temperature has reached normal levels. PaCO2 is normal,and metabolic acidosis has been corrected,spontanous respiration allowed to recommence,and the patient is extubated once conscious.
The patient must be closely monitored and sedated for 24 hours after initial recovery for fear of recurrence of syndrome.(1)
DELAYED COMPLICATION :(1)
1.Hyperactive bleeding (DIC)
Acute activation of clotting result from mechanism :
a.Endothelial damageis produced by hyperthermia and this activates the Hageman(XII) factor.
b.Tissue hypoxia (oxygen over utilization) causes mobilization of tissue thromboplastin and entry of this enzyme into the circulation. Consequences include intravascular consumption of clotting factors :
Depletion of platelets,prothrombin,fibrinogen,and Factors V,VII and XII. This is DIC syndrome.
c.Abnormal platelets agregation appears to occur in susceptible patients which increases by halothane.
2.Erythrocyte Fragility :
Red blood cells show increase fragility.Haemoglobine release from increased RBC breakdown. When levels higher than 200mg/100 ml of blood are reached Hb then appears in the urine. The renal thresold for Hb is 100-150 mg/100 ml of blood.
3. Liver damage :
In patients who survive heat stroke,jaundice is common and liver damage is frequent.
4. Hypothalamic damage :
Disturbed temperature regulation at the hypothalamus undoubtledly occured, If the thermostat is raised,heat production will increase. For each 1 degree C increase in body temperatur there is a 13% increase in heat production.This become vicious cycle,especially if damage to the hypothalamic neurons occurs.
REFERENCES :
1.Gray Cecil T : Malignant hyperthermia in Text book of General Anaesthesia ,fifth edit,Butterwoth International edition,London,Boston,Singapore ,wellington 1989,pp.655-60.
2.Collins J.V. : Temperature Regulation and Heat problem in Textbook of Physiology and Pharmacologic Bases of Anaesthesia,William & Wilkin,A. Waverly Company,Baltimore,Philadelphia,London.1996,pp.328-39
3.Stoelting.K.R : Central Nervous System Stimulants and Muscle Relaxants in the Textbook of Pharmacology and Physiology in Anesthetic Practice,J.B.Lippincott Company, Philadelphia,London,Mexico City,1987. pp.521-2
4.Rosenberg H : Malignant Hyperthermia -An Update in International Anaesthesia Research Society Review Course Lectures Presented at the IARS 3rd Congress International Anaesthesia Society, March 4-8, Florida pp.109-11.
5.Lebowitz W Cs : Malignant Hyperthermia as Emergencies Complicating Anaesthesia inClinical Anaesthesia Procedure of the Massachusetts General Hospital,1st edit,by Little Brown and Company (Inc),1978, pp.355-7.
6.Snow C.John : Malignant Hyperthermia in Manual of Anaesthesia,1st edit,by Little Brown and Company,Boston, Massachusetts ,Tokyo.1997,pp.362-4.
