EVALUATION OF SUSCEPTIBILITY
Evaluation includes a history and physical examination for the
detection of subclinical abnormality. A genealogy with specific information about
anesthetic exposure and agents can estimate the likelihood of exposure to triggering
agents. Blood CK values, when determined in a resting, fasting state without recent
trauma, reflect muscle membrane stability. When CK level is elevated in a close
relative of a person with known MH susceptibility, the relative may be considered
to have MH susceptibility without contracture testing. If the CK level is normal
on several occasions, there is no predictive value, and contracture studies are necessary.
The patient must travel to the test center for surgical biopsy to ensure viability
and accurate results.
Muscle biopsy contracture studies, performed at about 30 centers
around the world, use exposures to halothane, caffeine, halothane plus caffeine,
and ryanodine.[33]
4-Chloro-m-cresol
may add to precision.[130]
There is a crisis in
the United States, with only six test centers (December 2003), in part because of
medical care limitations. This is inappropriate considering geography and population.
Contracture responses are sometimes positive in patients with myopathies that bear
no direct relationship to MH and therefore may not indicate susceptibility. Dantrolene
must be avoided before the biopsy, because it masks the response to contracture-producing
drugs. After a patient is diagnosed with MHS, DNA testing for mutations should follow.
When one is detected, other relatives with that mutation are considered to have
MHS without the need for the invasive contracture test, and they need not travel
to a testing center (see "Genetics").
For the student of anesthesia, susceptible individuals have a
lower threshold to contracture-producing drugs. The muscle specimen must be viable
(i.e., twitch when stimulated electrically) because the contracture threshold may
vary if the fiber is deteriorating. Bath kinetics are stable with the use of experienced
laboratories, and variations in temperature have less effect than anticipated on
contracture thresholds.[131]
Advice should be given to the susceptible patient. Precautions
are necessary in regard to general anesthesia, and triggers include all potent volatile
agents and succinylcholine. Awake episodes are uncommon, and if not experienced
before the diagnosis, they are an unlikely problem. Military personnel may have
restrictions because of the necessary avoidance of combat trauma and the possible
mandatory use of triggers, and soldiers with MH susceptibility may be less desirable
because some authorities believe that they may fatigue sooner with harsh military
conditioning because of their subclinical myopathy.
The predictive value (i.e., percentage of positive results that
are true positives) or efficiency (i.e., percentage of all results that are true,
whether positive or negative) of contracture testing in determining susceptibility
cannot be estimated. False-positive results resulting from cautious interpretation
or decreased specificity are masked because the patient will never be exposed to
triggering agents. European and North American contracture protocols have yielded
sufficient multicenter data to confirm acceptable test results.[132]
[133]
Separation of control patients from MH patients
was based on purely clinical information using the clinical grading scale.[115]
Both protocols have 97% to 99% sensitivity (i.e., frequency of positive results
in the patients with clinically established MH) and acceptable (78% to 94%) specificity
(i.e., frequency of negative results in low-risk controls). Threshold values attempt
to provide 100% sensitivity to detect all MHS patients; this restriction limits specificity.
The North American testing protocol (CHCT) uses incremental caffeine
concentrations of 0.5, 1, 2, 4, 8, and 32 mM and uses 3% halothane as a bolus application.
It yields two diagnoses: normal (MHN) or abnormal (MHS). The European testing protocol
(IVCT) uses additional steps in its increments: caffeine concentrations of 0.5,
1, 1.5, 2, 3, 4, and 32 mM, and halothane in concentrations of 0.5%, 1%, 2%, and
sometimes 3%. Greater fractionation of caffeine and halothane increments in the
European protocol results in lower diagnostic thresholds (i.e., 0.2 g for both drugs).
[132]
The lesser fractionation of increments in
the North American protocol leads to greater thresholds (0.3 g) for caffeine and
a relatively large gray area for halothane of about 0.5 to 0.8 g.[133]
Interpretation of IVCT yields three diagnoses: MHS, for which halothane and caffeine
results are abnormal; MHN, for which both results are normal; and equivocal (MHE),
for which only one result is abnormal. Fewer MHE diagnoses and better genetic correlations
exist when contractures are markedly abnormal instead of near threshold; this may
lessen discordance.[134]
[135]
What is needed in MH testing is an accurate, noninvasive or nondestructive
measure of susceptibility that has no overlap between the ranges of normal and susceptible
responses. A promising innovative in vivo human application involves physiologically
based microdialysis infusion of caffeine or halothane into muscle of MH-susceptible
patients, triggering exaggerated localized changes in acid-base balance.[136]
[137]
White blood cells express MH mutations and
provide a substrate for genetic analysis.[75]
[76]
[138]
[139]
Nuclear
magnetic resonance has promise;[140]
the difficulty
is to standardize a stress, such as forearm ischemia, that can differentiate susceptible
tissue from normal. Although early ultrasound results were encouraging, study results
for skeletal muscle were inaccurate in humans with MH susceptibility.[141]
Adnet and coworkers[142]
examined masseter muscle
in a skinned fiber in vitro preparation in attempts to explain its propensity for
contracture. They observed greater sensitivity to Ca2+
and caffeine than
that in quadriceps muscle. Their findings were contradicted in a contracture study
of masseter biopsy specimens taken during major craniofacial cancer surgery.[143]
These responded similarly to quadriceps.
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