Malignant Hyperthermia Flashcards
Malignant hyperthermia-it is
1) MH is a pharmacogenetic clinical syndrome that, occurs during anesthesia with volatile halogenated alkanes such as:
1. halothane,
2. isoflurane/sevoflurane, /desflurane,
3. administration of the depolarizing muscle relaxant succinylcholine.
2) The fulminant MH episode observed clinically produces muscle hypermetabolism with rapidly increasing body temperature ( much as 1°C in 5 minutes), acute loss of control of intracellular ionized calcium (Ca2+)⇒ extreme acidosis .
High levels of sarcoplasmic Ca2+ rapidly drives skeletal muscle into a hypermetabolic state⇒ may proceed to severe rhabdomyolysis.
mortality rate of malignant hyperthermia
1) 60%,
2) earlier diagnosis and the use of dantrolene have reduced the mortality to less than 1.4%
Mechanism of Normal muscle contraction
1) nerve impulses arriving at the neuromuscular junction⇒ release of acetylcholine from the nerve terminal.
2) acetylcholine activates nAChR (nonselective cation channels located at the postsynaptic neuromuscular junction)⇒ local depolarization of the surface muscle membrane (sarcolemma)⇒initiating action potentials.
3) Invaginations of the sarcolemma ( T tubules) conduits to direct-action potentials deep within the myofibrils⇒ transduce a conformational change in the “voltage sensor” protein CaV1.1.
4) Conformational changes in CaV1.1 residing within the T-tubule are mechanically transmitted to RyR1(Ca2+ release channels in a terminal cisternae element) residing in the junctional face of the SR.
four CaV1.1 (dihydropyridine receptor) units to every second RyR1 channel -triadic junctions.
5) Release of SR Ca2+ causes the free, cytoplasmic (sarcoplasmic) Ca2+ concentration to increase from 10–7 M to about 10–5 M.
6) This released Ca2+ binds to contractile proteins (troponin C and tropomyosin) in the thin filament to expose myosin’s actin binding sites which allow shortening and force development by the muscle fibers (i.e., muscle contraction). The entire process is termed excitation-contraction coupling (EC coupling)
7) Intracellular Ca2+ pumps (i.e., sarcoplasmic/endoplasmic reticulum Ca2+-adenosine triphosphatase [ATPase], or SERCA) rapidly sequester Ca2+ back into the SR lumen, and muscle. relaxation begins when the Ca2+ concentration falls below 10–6 M and ends when the resting sarcoplasmic Ca2+ concentration is restored to 10–7 M
Mechanism of fulminant MH syndrome
1) persistent increase in the concentration of sarcoplasmic Ca2+. ⇒The increased activity of pumps and exchangers trying to correct the increase in sarcoplasmic Ca2+ associated with triggered MH increases the need for ATP, which in turn produces heat.
2) The rigidity that is frequently seen during a fulminant MH episode is the result of the inability of the Ca2+ pumps and transporters to reduce the unbound sarcoplasmic Ca2+ below the contractile threshold (10–6 M).
3) Dantrolene is an effective therapeutic for treatment of fulminant MH because it reduces the concentration of sarcoplasmic Ca2+ to below contractile threshold. Dantrolene’s ability to suppress Ca2+ release from SR appears to depend on elevated sarcoplasmic Mg2+ concentration, however the drug also attenuates depolarized-triggered Ca2+ entry mediated by CaV1.1, whether dantrolene directly inhibits RyR1 or requires additional intermediates within the triad junctions remains to be clarified.
Ryanodine Receptors
1) Ryanodine receptors (RyRs) = junctional foot protein/SR calcium release channel :specifically bind the toxic plant alkaloid ryanodine, which can activate or inhibit the channel depending on its concentration.
2)In all mammals there are three RyR isoforms: “skeletal” (RyR1), “cardiac” (RyR2), and “brain” (RyR3) isoforms, respectively.
3) Ca2+ release unit (CRU) -protein-protein interactions that regulate both the release and sequestration of Ca2+ within skeletal muscle, localized within junctional regions of T-tubule and SR membranes. RyR1 is a high-conductance channel that regulates release of SR Ca2+ and is the central component of the CRU. The functional RyR1 tetramer anchored within the SR membrane physically spans the junctional space to interact with tetrads composed of four voltage-activated CaV1.1 subunits within the T-tubule membrane
Dantrolene
1) Pharmacologic Category-Skeletal Muscle Relaxan
2) Indications: Malignant hyperthermia, preoperative prophylaxis
Malignant hyperthermia, treatment
Neuroleptic malignant syndrome, moderate to severe
Spasticity, chronic
3) Dose: Crisis: Initial: 2.5 mg/kg, then 1 or 2.5 mg/kg every 5 minutes as frequently as needed until treatment goals reached Doses >10 mg/kg may be required for patients with persistent contractures or rigidity;
Postcrisis follow-up: IV: 1 mg/kg/dose every 4 to 6 hours (preferred to minimize extravasation risk) if within 6 hours of initial reaction; if outside of 6-hour window, a higher dose of 2 or 3 mg/kg/dose may be needed. Treatment may be stopped or interval between doses increased to every 8 to 12 hours when the following criteria are met: metabolic stability for 24 hours, core temperature <38°C, creatinine kinase continues to decrease, no evidence of ongoing myoglobinuria, and muscle rigidity has resolved
The gold standard for diagnosis of MH
is the halothane and caffeine muscle contracture test, also known as the IVCT or the CHCT.
Anesthetic drugs that trigger MH
1)halothane,
2)enflurane,
3)isoflurane,
4)desflurane,
5) sevoflurane,
6) depolarizing muscle relaxants, the only currently used of which is succinylcholine
clinical manifestations of fulminant MH syndrome :
scenario 1
igidity after induction with thiopental and succinylcholine, but successful intubation, followed rapidly by the symptoms listed after scenario 2.
clinical manifestations of fulminant MH syndrome :
scenario 2
Normal response to induction of anesthesia and uneventful anesthetic course until onset of the following symptoms:
▪ Unexplained sinus tachycardia or ventricular arrhythmias, or both
▪ Tachypnea if spontaneous ventilation is present
▪ Unexplained decrease in O2 saturation (because of a decrease in venous O2 saturation)
▪ Increased end-tidal PCO2 with adequate ventilation (and in most cases unchanged ventilation)
▪ Unexpected metabolic and respiratory acidosis
▪ Central venous desaturation
▪ Increase in body temperature above 38.8°C with no obvious cause
Masseter spasm
1) The masseter and lateral pterygoid muscles contain slow tonic fibers that can respond to depolarizing neuromuscular blockers with a contracture. .This is manifested clinically on exposure to succinylcholine as an increase in jaw muscle tone
2) This jaw rigidity may occur even after pretreatment with a “defasciculating” dose of a nondepolarizing relaxant. If there is rigidity of other muscles in addition to trismus, the association with MH is absolute
more than 80% of patients with trismus but no rigidity of other muscles, it is a variant found in normal patients. If trismus occurs, proper monitoring should include end-expired CO2, examination for pigmenturia, and arterial or venous blood sampling for CK, acid-base status, and electrolyte levels, particularly potassium- .
Clinical Signs of Malignant Hyperthermia
1) Early Signs
Elevated end-tidal CO2
Tachypnea and/or tachycardia
Masseter spasm if succinylcholine has been used
Generalized muscle rigidity
Mixed metabolic and respiratory acidosis
Profuse sweating
Mottling of skin
Cardiac arrhythmias
Unstable blood pressure
2) Late Signs
Hyperkalemia
Rapid increase of core body temperature
Elevated creatine phosphokinase levels
Gross myoglobinemia and myoglobinuria
Cardiac arrest
Disseminated intravascular coagulation
King-Denborough syndrome (KDS)
King-Denborough syndrome (KDS) is an autosomal dominant disorder characterized by the triad of congenital myopathy, dysmorphic features, and susceptibility to malignant hyperthermia
King-Denborough syndrome (KDS)
is an autosomal dominant disorder characterized by the triad of congenital
1)myopathy,
2) dysmorphic features,
3) susceptibility to malignant hyperthermia
Noonan syndrome
1)autosomal dominant condition
2)typical Noonan syndrome features delayed puberty, down-slanting or wide-set eyes, hearing loss, low-set or abnormal shaped ears, mild mental retardation (in about 25% of the cases), ptosis, short statue, small penis and undescended testicles in males, pectus excavatum, and a webbed and short neck
3) Prevalence of bleeding disorders in Noonan syndrome was reported to be from 20% to 89%,164 ranging from thrombocytopenia to platelet dysfunction to von Willebrand disease to factor deficiencies
4) The high palatal arch, dental malocclusion, and the webbed neck of Noonan syndrome make tracheal intubation potentially risky.
5) odontoid hypoplasia and atlanto-axial instability may result in cervical cord compression. Preoperative cervical spine evaluation is advisable.
6)Right ventricular function needs to be monitored closely because 30% to 50% of the patients with Noonan syndrome have pulmonary stenosis.
7)Regional anesthesia in Noonan patients may be technically challenging due to the prevalence of scoliosis. The spread of local anesthetic can be unpredictable.
