Skeletal Muscle

Anesthetic complications in muscular disorders

The past several years have brought an explosion in knowledge concerning the molecular basis of muscular disorders (1). Not only has information on specific genetic defects been bountiful, but new insights into the pathomechanisms have also been gained. Skeletal muscle makes up over 50% of the human body mass, yet little is known about the effects of volatile anesthetic agents (i.e., halothane, isoflurane, enflurane, desflurane and sevoflurane) on the function of skeletal muscle.

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Perhaps the reason for this is that only very rarely does the response of skeletal muscle to these agents become a consideration during a surgical procedure. Nevertheless, such effects can be life threatening in those exceptional instances, such as during an episode of malignant hyperthermia (MH) or during an anesthetic complication in a patient with an inherited dystrophic myopathy or myotonia (2). One dramatic sign of an acute MH episode is generalized and sustained activation of skeletal muscles (3). These force responses can be initiated in vitro and are well correlated with increases in intracellular [Ca2+] (4,5). Prolonged increases in intracellular [Ca2+] result in contractures, substrate (ATP) depletion, grossly elevated oxygen consumption, increased production of carbon dioxide and the build-up of vast quantities of metabolic acids. Eventually, membrane function is disrupted and metabolites, potassium and myoglobin are released into the circulation. It is hypothesized that although an abnormal regulation of intracellular Ca2+may be the common underlying cause of anesthetic complications in each of the aforementioned disorders, the primary site of an abnormal response to a volatile anesthetic which initiates this cascade is distinct for each agent (2). Hence, the aim of laboratories' work in this area is to identify the exact mechanism by which volatile anesthetics ultimately cause undesired contractures or contractions (exacerbated myotonia) in such patients. We are determining the effects of various volatile anesthetic agents on gating properties of sarcolemmal ion channels and/or the mobilization of intracellular calcium within skeletal muscle. The investigations are being performed on muscles from: 1) normal humans and patients with an inherited form of myotonia, muscular dystrophy or malignant hyperthermia; 2) normal mice, adr/adr myotonic mice (those with a mutated sarcolemmal Cl- channel) or mdx mice; and 3) normal swine and those susceptible to MH (i.e., animals with a substitution of cysteine for arginine 614 in the RYR1 calcium release channel). Our laboratories are also in the midst of developing a transgenic mouse model for hyperkalemic periodic paralysis. Isolated muscles will be studied intact or as resealed fiber segments. The following electrophysiological techniques are being used to study the effects of these agents on sarcolemmal ion channels: 1) the measurement of extracellularly and intracellularly recorded action potentials; 2) the three-electrode voltage clamp; and 3) the on-cell patch clamp recording of single channel activity. It is expected that the results of these studies will not only clearly define the pathomechanisms induced by such agents which underlie anesthetic complications in myotonic, dystrophic and MH disorders, but will also be of biophysical importance (i.e., considering each volatile anesthetic agent will distinctly modify the lipid matrix of various membranes).

  1. Neuromuscular Disorders: gene location. Neuromusc Disord 5/6: 529-531, 1994.
  2. Lehmann-Horn F, Iaizzo PA: Are myotonias and periodic paralyses associated with susceptibility to malignant hyperthermia? Brit J Anaesth 65: 692-697, 1990.
  3. Iaizzo PA, Palahniuk RJ. Malignant hyperthermia: diagnosis, treatment, genetics and pathophysiology. Invest Radiol 26: 1013-1018, 1991.
  4. Iaizzo PA, Klein W, Lehmann-Horn F. Fura-2 detected myoplasmic calcium and its correlation with contracture force in skeletal muscle from normal and malignant hyperthermia susceptible pigs. Pflügers Arch 1988; 411:648-653.
  5. Iaizzo PA, Seewald MJ, Oakes S, Lehmann-Horn F. The use of Fura-2 to estimate myoplasmic [Ca2+] in human skeletal muscle. Cell Calcium 1989;10:151-158.

Stimulated Muscle Force Measurements in Neuromuscular Diseases

Muscle strength assessment is necessary for determining distribution of weakness, disease progression, and/or treatment efficacy for patients with neuromuscular diseases or those with long-term critical illnesses. Manual testing is the standard method used to assess muscle strength, yet it relies on subjective assessment by the clinician and is thus inadequate to quantify small changes in muscle strength. Devices to quantify force objectively (i.e., hand-held dynamometry and isokinetic devices) have been developed and used clinically, however they still rely on voluntary effort.

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Additionally, neurologically impaired or critically ill patients generally have difficulty with voluntary force assessment tasks. Our labs have designed and tested a noninvasive muscle force assessment device to objectively quantify muscle strength for clinical use (Figure 1). Specifically, we have investigated the following areas related to the muscle force assessment system:

Measure force of ankle dorsiflexors (Figure 1) and thumb adductors muscle groups (Figure 2) in patients with chronic inflammatory demyelinating polyneuropathy (CIPD) or another peripheral neuromuscular disorder. The measurement system offered several advantages: 1) improved objectivity and reliability compared to other methods, 2) ability to distinguish weakness due to peripheral nerve or muscle disorders from that caused by central nervous system disorders, and 3) ability to measure temporal aspects of muscle contraction, leading to better understanding of the pathophysiology of neuromuscular diseases [1].

Study of ankle dorsiflexion force during induced paralytic attacks in hyperkalemic and hypokalemic patients. It was found that stimulated force measurements can characterize phenotypic muscle function in these neuromuscular diseases; additionally, it offered several advantages in characterizing muscle dysfunction in periodic paralysis: 1) force measurement was independent of patient effort, 2) it showed a definitive abnormal response early during provocative maneuvers; 3) characteristics of muscle contraction could be measured that were unobservable during voluntary contraction [2].

Adaptation of the muscle force assessment system to measure arm flexor contractile responses of normal subjects (Figure 3). This modified system provided a high degree of reproducibility in generating twitch and/or multiple-pulse stimulations of the arm flexors elicited by either superficially applied motor-point or nerve stimulation [3].

Configuration of the muscle force assessment system for quantitative evaluation of neck muscles (sternocleidomastoid) using normal subjects (Figure 4). The adapted system provided for consistent stimulated force responses in repeated trials, and could be used clinically for patients affected by alterations in head/neck stability (i.e., neck injury, cervical dystonia) [4].

Quantification of isometric skeletal muscle forces in critically ill patients (ankle dorsiflexors), baseline and after one week of ventilation and immobilization in the ICU (Figure 5). It was determined that muscle weakness begins during the early stages of critical illness for patients that are immobilized and ventilated (i.e., reduced torques, shorter contraction times, prolonged relaxation times) and that this system should be further evaluated for use in a long-term ICU setting [5].

Measurement of muscle torque (ankle dorsiflexors) in long-term mechanically ventilated and immobilized ICU patients. The researchers/clinicians determined that this muscle force measurement system was feasible for use in a long-term ICU environment; further, there is clinical merit for monitoring patient status and they plan to modify the existing system for optimal application to the ICU environment (i.e., light-weight plastics)[6].

  1. Journal of Medical Engineering and Technology 20: 67-74, 1996.
  2. Day JW, Sakamoto C, Parry GJ, Lehmann-Horn F, Iaizzo PA: Force assessment in periodic paralysis after electrical muscle stimulation. Mayo Clinic Proceedings 77: 232-240, 2002.
  3. Hong J, Iaizzo PA: Force assessment of the stimulated arm flexors: quantification of contractile propoerties. Journal of Medical Engineering & Technology 26:28-35, 2002.
  4. Hong J, Falkenberg JH, Iaizzo PA: Stimulated muscle force assessment of the sternocleidomastoid muscle in humans. Journal of Medical Engineering & Technology 29: 82-89, 2005.
  5. Ginz HF, Iaizzo PA, Girard T, Urwyler A, Pargger H: Decreased isometric skeletal muscle force in critically ill patients. Swiss Medical Weekly 135:555-561, 2005.
  6. Ginz HF, Iaizzo PA, Urwyler A, Pargger H: Use of non-invasive stimulation muscle force assessment in long-term critically ill patients: a future standard in the intensive care unit? Acta Anaesthesiologica Scandinavica (in press) 2007.

Doxorubicin Chemomyectomy

Chronic spasms in facial and cervical skeletal muscle can often be painful and functionally disabling. Common treatments for these disorders include oral medications, surgical denervation of the affected muscle groups and, more commonly, injection of botulinum toxin into the affected muscle. The effects of botulinum toxin are temporary and require reinjection every 3-4 months for treatment of cervical dystonia. Furthermore, botulinum in higher doses can cause systemic problems distant from the injection site. Meanwhile, patients can also produce antibodies to the toxin, rendering it ineffective for future treatment.

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In comparison, doxorubicin is a myotoxin that causes loss of myofibers, resulting in a permanent reduction of uncontrolled muscle spasms. Studies in our labs have focused on identifying the effectiveness of using doxorubicin for the treatment of cervical dystonia. These studies involved directly injecting doxorubicin into rabbit sternocleidomastoid, a large neck muscle, and identifying changes in that muscle group over 1 to 6 months. In vitro [1] and in situ [2] studies showed that doxorubicin-treated sternocleidomastoid muscle produced less force than untreated muscles; further, histological studies showed that doxorubicin reduced muscle cross-sectional area between 75-98% over control [3]. Additionally, the remaining fibers contained a higher proportion of slow and neonatal myosin heavy chain isoforms. From a translational research perspective, our labs have also developed a force assessment approach for measuring human sternocleidomastoid function in vivo [4]. Thus, we have means to assess the relative effectiveness of a given experimental approach in a human patient population.

  1. Falkenberg JH, Iaizzo PA, McLoon LK: Physiological assessment of muscle strength in vitro after direct injection of doxorubicin into rabbit sternocleidomastoid muscle. Movement Disorders 16: 683-692, 2001.
  2. Falkenberg JH, Iaizzo PA, McLoon LK. Muscle strength following direct injection of doxorubicin into rabbit sternocleidomastoid muscle in situ. Muscle and Nerve 25: 735-741, 2002.
  3. McLoon LK, Falkenberg JH, Dykstra D, Iaizzo PA. Doxorubicin chemomyectomy as a treatment for cervical dystonia: histological assessment after direct injection into the sternocleidomastoid muscle. Muscle and Nerve 21: 1457-1464, 1998.
  4. Hong J, Falkenberg JH, Iaizzo PA: Stimulated muscle force assessment of the sternocleidomastoid muscle in humans. Journal of Medical Engineering & Technology 29: 82-89, 2005.