Morbus Parkinson And Anesthetic Consideration (PART 2)

ANESTHETIC CONSIDERATION :


Regarding anesthetics consideration,attention shoud be directed towards maintainance of drugs theraphy associated physiologic disturbance and potential adverse drugs interaction. Parkinson related disturbance of systemic physiology include respiratory dysfunction,dysphagia,autonomic dysfunction and sleep related ventillatory abnormalities.(2)


Respiratory dysfunction is a particularly prominent feature,PD can produce restrictive lung disease secondary to chestwall rigidity but pulmonary function often reveal an obstructive pattern with characteristic sawtooth pattern on flow volume loops.


Upper airway abnormalities also occur,involuntary movements of the glottis and superglottic cause intermittent airway obstruction,a condition that can be  exacerbated by levodopa withdrawal.


Upper airway obstruction laryngospasm and respiratory arrest are documented complications of PD and may occur outside the setting of anesthesia and surgery.Therefore perhaps not surprisingly,laryngospasm has been reported post operatively in awake patient hours after surgery.


Autonomic dysfunction can also be a problem,this condition affects the ability of PD patients to respons the hypovolemia and vasodilatation sometimes ascociated with anestheisa and surgery.


Orthostatic hypotension or thermoregulatory or genitourinary dysfunction suggest preexisting autonomic insufficiency and should heighten awareness of the potential for perioperative hemodynamic instability and altered respons to vasopressor such as nor adrenaline.
Especially PD patients with preexisting disturbance of cardiac conduction or coronair disease,cardiac arrhythmia is often occured.(3)


PD patients are predisposed to aspiration because they often have severe but  asymptomatic,dysphagia and dysmotility that combined with upper airway abnormality,present an especially troublesome situation.
In fact pulmonary aspiration is a common cause of death among patients with PD. Administration of antacids and prokinetic agents should be considered,


Metoclopropamide should be avoided however,because it is dopamine receptor antagoinist and could acutely exacerbate the disease.In contrast,prokinetic agents such casapride or domperidone have no effects on dopaminergic balance and reasonable alternatives.(2)


Emotional stress in the perioperative period can also exacerbate the disease, Levodopa therapy shoud be continued through out the perioperative period because abrupt stopping levodopa may result execerbation of PD symptoms. and to avoid skletal muscle rigidity (3,4).


Long term levodopa treatment can also cause CNS dysfunction ,such as dyskinesia,agitation, confusion, overt psychosis have been reported in the postoperative priod.


Anesthetics and a number of other agents used perioperatively may affect the disease process.


Volatiles anesthetics can alter dopaminergic balance in the brain.


Dopamine that results from levodopa administration can augment cardiac irritability , a result cardiac arrhythmia may occur frequently under halothane anesthesia although this has not proved to be clinically significant.Drugs with dopamine antagonizing properties such as phenothiazine and butyrophenones should also be avoided. In at least one case butyrophenone may have induced parkinsonism in normal patient. Side effects of anticholinergics drugs such as dry mouth,urinary retention,and confusion especially in the elderly can be troublesome.


The use of ketamine has been questioned in those being treated with levodopa because of the possibility of exagerated sympathetics respons, However in a single case report,ketamine temporarily stopped the motor symptoms of the disease. Propofol produces both dyskinesias and ablation of resting tremor, suggesting that it may have both excitatory and inhibitory effects in this patient population.


Opioids are considerably more likely to produce muscular rigidity in a patient with PD,but acute dystonia has been observed in only a single patient with untreated disease. 


Mepiridine should probably be avoided in the patient taking an MAOI because of the potential for development of stupor,rigidity,agitation and hyperthermia.(2)


One case report exist of an exacerbation of PD after fentanyl administration,it was suggested that alfentanyl may have precipitated this reaction through a dopaminergic blocking action in the nigrostriatal system.


The choice of muscle relaxants does not to be influenced by the presence of PD. However succinylcholine should be used with caution there has been report of succinylcholine induced hyperkalemia in a patient with PD.


SUMMARY :


Parkinson's disease is manifestation of relative imbalanced between dopaminergic and chlonergic within the striatum.


The patient PD,the basal ganglia content of dopamine in only 10% of normal,as a result there is an excess of excitatory chlinergic activity manifesting as tremor,skletal muscle rigidity and disturbanced of posture.


-The goal of treatment of PD is to enhance the inhibitory effect of dopamine or reduce the stimulatory effect of acetylcholine.
-Levodopa as the immediated metabolic precursor of dopamine acts by replenishing the depleted store of dopamine in the basal ganglia.
-Abrupt discontinuation of levodopa therapy may result in precipituous return of symptoms


For this reason levodopa therapy should be continued throughout the perioperative period.


-Regarding anesthetic consideration attention should be directed toward maintanance of perioperative drugs therapy,ascociated physiologic disturbance  and 
potential drug interaction.


REFERENCES :


1.Abine M,Solomone D : Neurologic Syndromes and Disorders with their Anesthesia Complication in Textbook of Neuroanesthesia with Neuro Surgical and Neuroscience Perspective,The McGraw-Hill Companies,Newyork,St.Louis 
 ,San Fransisco,1977 pp 409-11.


2.Culley J.Deborah


Cottrell E,Smith C.D. : Neurologic Disease and Anesthesia in Textbook of Neuroanesthesia and Neurosurgery,4th edition, Mosby Company,St.Louis-London, Philadelphia,Sidney,Toronto 2001,pp 611-13.


3. Stoelting Robert : Drugs used for Treatment of Parkinson's Disease in Textbook of Pharmacology and Physiology in Anaesthetic Practice, J.B.Lippincott Company,Philadelphia,1987,pp 508-13.


4 Leisure S.G : Anesthesia for the patient with Neurologic disease in The Neuro Stone J.D. anesthesia Handbook,Mosby Company,St. Louis,Baltimore,Boston, 1996,pp 151-3.

Read More

Morbus Parkinson And Anesthetic Considerations (PART 1)

INTRODUCTION :
         
Parkinson's disease(PD) is a manifestation of an imbalanced between dopaminergic and cholenergic activity transmitted by the extrapyramidal nervous system.


Conceptually dopamine is believed to act principally as an inhibitor neurotransmitter and acetylcholine as an excitatory neurotransmitter in the extrapyramidal system (3).


Dopamin acts by inhibiting the rate of firing of neurons that control the extrapyramidal motor system(4).


Although dopamin is more important, a proper balance with the cholenergic neurotransmitter is also necessary for normal function.About 80% in the brain is concentrated in the basal ganglia mostly in the caudate nucleus and putament. In patients PD the basal ganglia content of dopamin is only about 10% of normal.(3)


First described by James Parkinson in 1817 was often called the shaking palsy.


Usually begins between the age of 40 and 70 years old and is uncommon below 30 years of age. In the USA alone there are approximately 500.000 patients with Parkinson disease(PD) and about 40.000 new cases develops each year,men somewhat more often than woman.(3.4)


Alzheimer's disease is six times more frequent in patients with PD.


PATHOGENESIS :


Involves a loss of pigmented cells in the substantia nigra and other pigmented nuclei such as the locus ceruleus and dorsal motor nucleus of the vagus.


Dopaminergic nerve fibers in the basal ganglia degenerate, leading to a depletion of dopamine in the basal ganglia of the brain.


Consequently, depletion of dopamine leads to decreased inhibition of this system,resulting in many of the clinical signs.


Although, many predispoisng factors have been suggested including enviromental agents,the etiology of PD remains obscure.


CLINICAL PICTURE


As dopmine content in basal ganglia is only 10% in PD, as a result,there is an excess of excitatory cholinergic activity manifesting as tremor,skletal muscle rigidity and disturbance of posture.


This is characterized by expression less facies,slowness of voluntary movement,shuffling gait resting tremor,cogwhell rigidity,stopped posture and a monotonous voice.


Resting tremor is the most characteristic abnormality in PD, and it is presenting symptom in 70% cases. The tremor often referred to as pill-rolling tremor,is noted to be prominent in the resting extrimity,disappearing briefly with intentional movement.


Bradykinesia or slowness in both the initiation and excecution of movement is a hallmark of PD.


Patients are also noted to have facial immobility characterized by infrequent blinking and little emotional respons.As the disease progresses;micrographia develops,the voice becomes progressively less audible, walking is reduced to shuffling and the patient frequently loses balance.


In addition to these classic peripheral manifestation,of PD approximately one fifth of afflicted patients become mentally depressed and one third of patients develop cognitive and memory deficits that may progress to delirium (Lieberman 1979).


Symptoms similar to PD has been labeled as Parkinson 


Syndrome (PS),can be suspected after CNS trauma,encephalitis,brain tumor,metallic intoxication,and drugs such as phenothiazine,butyro phenones,and reserpine.


TREATMENT :


No cure for PD is known,treatment of PD is always palliative and never curative (2,3).


The goal of treatment of PD is to enhance the inhibitory effect of dopamine or reduce the stimulatory effect of acetylcholine by administration of centrally acting drugs.(2).


Medical treatment depend largely on the seriousness of symptoms and stage of the disease.


Hoehn and Yahr have developed a universally recognized scale consisting of 5 stages.(1)


Stage  I  : Unilateral involvement
          II  : Bilateral involvement but no postural      
                abnormalities.
         III : Bilateral involvement with mild postural 
               imbalanced,the patients leads an independent    
               life.
         IV : Bilateral involvement with postural instability;the    
               patients requires substantial help.
          V : Severe fully developed disease;the patients 
               restricted to bed and chair.


In general, patients in stage I&II may require no medication,or only anticholinergic (benzotropine biperidine,procyclidine) or dopamine agonist such as amantadine or combination of both.


These anticholenergic may relieve the slow frequency pill-rolling rest tremor typical of PD. The mayor standby in treatment of PD is L-dehydroxy phenil alanine(L-dopa or levodopa in stage III,IV and V). Levodopa as the immedia-
ted metabolic precursor of dopamine,it is administered in an effort for increase brain concentrating of dopamine.(4)   


Levodopa undergoes decarboxylation in both the peripher and CNS to produce dopamine. Approximately 95% of orally administered levodopa is rapidly decarboxylated to dopamine by the enzyme dopa decarboxylase,reduced absorbtion of levodopa as result of slowed gastric emptying as caused by opioids or anticholinergic and increase gastric acidity.


The resulting dopamine cannot easily cross the blood brain barrier to exert a benefical  therapeutic effect,whereas increased plasma concentration of dopamine often lead to undesirable side effect. At least 30 metabolites of levodopa has been identified,most are converted to doamine,small amounts of which are subsequently metabolized to nor epinephrine and epinephrine(3).


One problem with levodopa is that half life is short (about 1 to 3 hours) there-  
fore even brief interruption in the drug theraphy are undesirable and can be an acute exacerbation of the symptoms of PD so requires frequent dosing interval to maintain a therapeutic tissue concentration.(2)
Abrupt discontinuation of levodopa therapy may result in a precipituous return of symptoms of PD. For this reason levodopa therapy should be continued throughout the perioperative period,being included in the preoperative medication.
Levodopa has been shown to improve the akinesia,postural disorders and at times the rest tremor.
The side effect of levodopa can be hypotension,depression with delusions,de-
velopment of involuntary movement such as choreoathetosis,dystonia of limbs 
necks and trunk,restlessness,grimacing and dyskinesia of tongues and lips.
Orthostatic hypotension (30%),unknown reason in early theraphy.It is interest that dopamine resulting from levodopa will inhibits nor epinephrine production in the sympathetic nervous system through a negative feedback loop or inhi-
bits renin release and promote increases renal blood flow,glomerulo filtration rate and sodium excretion.
In addition dopamine will replace nor epinephrine at some sites and because of its weaker pressor action,fail to support the blood pressure adequately.
Levodopa affects the gastroinstestinal system by causing nausea and vomiting probably through dopaminergic stimulation of the chemoreceptor trigger zone (CTZ)is especially prominent at beginning of treatment ,consequently aspira-
tion in induction should be anticipated.


Concurent administration of carbidopa with levodopa result in increased peripheral availability of levodopa to enter the CNS,as a result of this combination theraphy the dose of levodopa can be reduced up to 75% while maintaining beneficial CNS effects,and at the same time reducing the likelihood of dose dependent side efects,resulting from too high plasma concentration of dopamine.
Carbidopa is inhibitor of the peripheral enzyme activity of dopa decarboxylase does not cross the blood brain barrier (BBB),administered alone carbidopa lacks pharmacologic activity.(3)
Levodopa and carbidopa are absorbed in the small intestines and thus must first traverse the stomach,making administration of tablets through a gastric tube suboptimal,or ineffective because patients with PD have delayed gastric emptying .As such a duodenal feeding is expected.(2).


Intravenous levodopa has been used succesfully in the perioperative period but without coadministration of a decarboxylase inhibitor (not yet available in intravenous form) cardiovascular side effects such as hypertension,hypotension and dysrhythmia can be anticipated.(2).


Bromocriptine are employed because their stimulating effects on dopamine receptors are used in patients not responding well to levodopa.(1)


Amantadine an antiviral drug produces symtomatic improvement in patients with PD presumably by facilitating the release of dopamine from intact dopaminergic terminals that remain in the negrostriatum of patient (Schwab et all 1977).(3)


Deprenyl, a highly selective inhibitor of  Monoamino oxydase(MAO)(the mayor enzyme involved in oxidative metabolism of dopamine in the striatum).(2,3)
It inhibits the intracerebral metabolism of dopamine,thus maximizing the therapeutic efficacy of concomitanly administered levodopa.Deprenyl(selegiline) is itself metbolized to amphetamine derivatives which may exert a weak anti parlkinsonism response.


Anticholenergic drugs :(benzotropine ,cycrimine and trihexyphenedyl)
The presumed mechanism of action of anticholenergic drugs is the ability to blunt the effects of the excitatory neurotransmitter acetylcholine.


More than 50% of patients who respond to levodopa manifest additional beneficial effects when therapy is suplemented with anticholinergic drugs.(3)
Elderly patients receiving combination of levodopa and anticholenergic drugs are particularly vulnerable to development of psychiatric distiurbances.


Propranolol can suppress the fast frequency tremor which sometime occurs in PD patients. Metprosol is also used and may be safer betablockers in patients with asthma.


In patients with PD who become resistant to medical theraphy ,three other approaches are available including stereotactic surgery,tissue transplant and electroconvulsive theraphy.
Neuroblative procedure may be useful not only in these PD patients who are resistant to drugs theraphy but also can employed to treat tremor and rigidity in the younger group. Dyskinesias due to levodopa treatment have been treated by lesion in the ventralis intermedius nucleus (VIM) of the thalamus as well as in the ventralis oralis posterior(VOP).
The study of Kelly and Gillinghan regarding lesioning the thalamic ventralis oralis anterior(VOA) in 58 patients showed that 88% had no signs of rigidity after thalamotomy.
Recently lesions of the internal and external segments of globus pallidus(pallidotomy) have been used for resolution of PD symptoms that are resistant to medical treatment.(1)


Since many of the drugs used in PD and PS therapy have mark systemic effects ,drug interaction response are very important,in the preoperative evaluation,intraoperative management and post operative anesthetic care.


DRUGS INTERACTION TO LEVODOPA :
                 
                 Drug                                          Response
=========================================================
1.Tricyclic antidepressant        Slow gastric emptying,enhance
                                               degradation of levodopa to in-
                                               active form in Gi tract.
   
2. Benzodiazepine                   Mechanism not clear,with 5 ca-
                                               ses reported in deterioration of       
                                               PD after diazepam and chloor-       
                                               diazepoxide.


3. Beta blocker(propranolol)   May antagonized beta adrenergic                                                                  
                                              effect of dopamine due to levo-
                                              dopa intake.May enhance levodo-
                                              pa response in patients witrh PD                                                              
                                              and tremor. May increase levodo-
                                              pa stimulation of growth hormon                                                                 
                                              secretion.


4.Clonidine                             Inhibits levodopa respons by sti
                                              mulating central alpha adrener-
                                              gic receptors.Seven patients had 
                                              exacerbation of PD.


5.Guanethidine                       Hypotensive efects of guanethi-
                                              dine increased with levodopa in
                                              2 patients.


6.Methyldopa                          Inhibits response to levodopa  
                                              and may cause an additive hypo-
                                              tensive response.


7.MAO Inhibitors (MAOI)         The degradation of dopamine in-
                                              volves MAO hence MAO inhibitors
                                              decreases dopamine breakdown.
                                              and levodopa increases dopamine
                                              concentration this will increases 
                                              nor epinephrine formation.
                                              Hypertensive responses have been
                                              reported with nialamide and phenel-
                                              zine.The use of MAOI in patients on 
                                              levodopa can result in worsening of
                                              akinesia and tremor. 
                                              A pavorable clinical response was no-
                                              ted with levadopa and the MAOI
                                              L-deprenal.
                                                                       
8.Papaverine                          PD worsened following papaverine  
                                              possibly due to dopamine receptors 
                                              blockade.


9.Phenylephrine                     Suggested that levodopa or its me-
                                             tabolits involve competitive inhibi-                                                              
                                             tor on alpha receptors since levo-
                                             dopa produces mydriasis following
                                             topical phenylephrine.


10.Pyridoxine                        Increases metabolism of levodopa                                                        
                                             decreasing availability in brain.
                                             Pyridoxine reverses improvement
                                             with levodopa in PD.


11.Phenothiazine and            Phenothiazine may block dopamine
    butyrophenones                 receptors in the CNS                                                                                 
                                             Extrapyramidal symptoms are well-                                                              
                                             known side effects of penothiazine
                                             Halopridol have the same effects.


12.Phenythoin                       Phenythoin controlled levodopa dys-
                                            kinesias but also suppressed the-                                                              
                                            rapeutic effect in controlling PD.
                                            If phenythoin is to be used the dose
                                            of levodopa should be increased.
                                                      
13.Reserpine                        Implicated as a causal agent in PD 
                                            by depleting brain dopamine.


to be continued 

Read More

Malignant Hyperthermia

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.

Read More