Use of non-invasive-stimulated muscle force assessment in long-term critically ill patients: a future standard in the intensive care unit?

BACKGROUND: This study's main purpose was to test the feasibility of employing a non-invasive-stimulated muscle force assessment approach in long-term critically ill patients. METHODS: A case series was performed over a 4-year period in the intensive care unit (ICU). Of the 25 patients initially recruited, eight patients required long-time mechanical ventilation for a median of 3.8 weeks (range 2-10 weeks) and were immobilized for 5 weeks (range 2-10 weeks). With a previously tested non-invasive measuring device, we weekly assessed peak torques and rates of force development and relaxation of patients' ankle dorsiflexor contractile responses, induced via peroneal nerve stimulation. Subsequently, we derived each patient's time course of observed progressive weakness and/or recovery. RESULTS: During their critical illnesses, seven out of eight patients elicited significant decreases in measured peak torques. In survivors (n = 6) during their recovery periods, torques gradually recovered. In the two patients who died, their strengths decreased continuously until death. The rate of force development data elicited similar trends as peak torque responses, whereas relative relaxation rates differed more widely between individuals. CONCLUSION: This approach of non-invasive-stimulated muscle force assessment can be used in long-term critically ill patients and may eventually become a standard in the intensive care unit, e.g. for assessing recovery. This method is easy to employ, reproducible, provides important phenotypic quantification of skeletal muscle contractile function, and can be used for long-term outcomes assessment.

Hibernating bears conserve muscle strength and maintain fatigue resistance.

Black bears spend several months each winter confined to a small space within their den without food or water. In nonhibernating mammals, these conditions typically result in severe muscle atrophy, causing a loss of strength and endurance. However, an initial study indicated that bears appeared to conserve strength while denning. We conducted an in vivo, nonsubjective measurement of strength, resistance to fatigue, and contractile properties on the tibialis anterior muscle of six hibernating bears during both early and late winter using a rigid leg brace and foot force plate. After 110 d of anorexia and confinement, skeletal muscle strength loss in hibernating bears was about one-half that in humans confined to bed rest. Bears lost 29% of muscle strength over 110 d of denning without food, while humans on a balanced diet but confined to bed for 90 d have been reported to lose 54% of their strength. Additionally, muscle contractile properties, including contraction time, half-relaxation time, half-maximum value time, peak rate of development and decay, time to peak force development, and time to peak force decay did not change, indicating that no small-scale alterations in whole-muscle function occurred over the winter. This study further supports our previous findings that black bears have a high resistance to atrophy despite being subjected to long-term anorexia and limited mobility.

Stimulated muscle force assessment of the sternocleidomastoid muscle in humans.

The aim of this study was to configure a force assessment device and determine potential testing protocols for quantitative evaluation of human neck muscles. The study design consisted of non-randomized control trials, with repeated measures; data from 12 normal subjects were obtained. Several apparatuses were designed, constructed and tested, i.e. single or short trains of supramaximal stimuli were used to activate sternocleidomastoid muscles in a seated position with strain gauges (6.2% variability with double-pulse stimulations) or in supine positions with load cells (5.2% variability with similar activation). Using a final configuration, maximum elicited peak forces were 1742 +/- 323 g for single-pulse and 3976 +/- 484 g for double-pulse stimulations (n = 12). There were no significant differences in maximum recorded peak torques between sessions per individual. Yet, detectable muscle activities were simultaneously recorded in the contralateral sternocleidomastoid muscles. This non-invasive, quantitative assessment approach has novel value for determining treatment efficacy, disease progression, and/or approach has novel value for determining determining treatment efficacy, disease progression, and/or relative distribution of muscle strength in patients with abnormal neck muscle function.

Investigation of the thermal and tissue injury behaviour in microwave thermal therapy using a porcine kidney model.

Minimally invasive microwave thermal therapies are being developed for the treatment of small renal cell carcinomas (RCC, d<3 cm). This study assessed the thermal history and corresponding tissue injury patterns resulting from microwave treatment of the porcine renal cortex. Three groups of kidneys were evaluated: (1) in vitro treated, (2) in vivo with 2-h post-treatment perfusion (acute) and (3) in vivo with 7-day post-treatment perfusion (chronic). The kidneys were treated with an interstitial water-cooled microwave probe (Urologix, Plymouth, MN) that created a lesion centered in the renal cortex (50 W for 10 min). The thermal histories were recorded at 0.5 cm radial intervals from the probe axis for correlation with the histologic cellular and vascular injury. The kidneys showed a reproducible 2 cm chronic lesion with distinct histologic injury zones identified. The thermal histories at the edge of these zones were found using Lagrangian interpolation. The threshold thermal histories for microvascular injury and stasis appeared to be lower than that for renal epithelial cell injury. The Arrhenius kinetic injury models were fit to the thermal histories and injury data to determine the kinetic parameters (i.e. activation energy and frequency factor) for the thermal injury processes. The resultant activation energies are consistent in magnitude with those for thermally induced protein denaturation. A 3-D finite element thermal model based on the Pennes bioheat equation was developed and solved using ANSYS (V7.0). The real geometry of the kidneys studied and temperature dependent thermal properties were used in this model. The specific absorption rate (SAR) of the microwave probe required for the thermal modelling was experimentally determined. The results from the thermal modelling suggest that the complicated change of local renal blood perfusion with temperature and time during microwave thermal therapy can be predicted, although a first order kinetic model may be insufficient to capture blood flow changes. The local blood perfusion was found to be a complicated function of temperature and time. A non-linear model based on the degree of vascular stasis was introduced to predict the blood perfusion. In conclusion, interstitial microwave thermal therapy in the normal porcine kidney results in predictable thermal and tissue injury behaviour. Future work in human kidney tissue will be necessary to confirm the clinical significance of these results.

Effect of three anaesthetic techniques on isometric skeletal muscle strength.

BACKGROUND: Our aim was to quantify human involuntary isometric skeletal muscle strength during anaesthesia with propofol, sevoflurane, or spinal anaesthesia using bupivacaine. METHODS: Thirty-three healthy patients undergoing anaesthesia for elective lower limb surgery were investigated. Twenty-two patients received a general anaesthetic with either propofol (n=12) or sevoflurane (n=10); for the remaining 11 patients spinal anaesthesia with bupivacaine was used. We used a non-invasive muscle force assessment system before and during anaesthesia to determine the contractile properties of the ankle dorsiflexor muscles after peroneal nerve stimulation (single, double, triple, and quadruple stimulation). We measured peak torques; contraction times; peak rates of torque development and decay; times to peak torque development and decay; half-relaxation times; torque latencies. RESULTS: Males elicited greater peak torques than females, medians 6.3 vs 4.4 Nm, respectively (P=0.0002, Mann-Whitney rank-sum test). During sevoflurane and propofol anaesthesia, muscle strength did not differ from pre-anaesthetic values. During spinal anaesthesia, torques were diminished for single-pulse stimulation from 3.5 to 2.0 Nm (P=0.002, Wilcoxon signed rank test), and for double-pulse from 7.6 to 5.6 Nm (P=0.02). Peak rates of torque development decreased for single-pulse stimulation from 113 to 53 Nm s(-1) and for double pulse from 195 to 105 Nm s(-1). Torque latencies were increased during spinal anaesthesia. CONCLUSIONS: At clinically relevant concentrations, propofol and sevoflurane did not influence involuntary isometric skeletal muscle strength in adults, whereas spinal anaesthesia reduced strength by about 20%. Muscle strength assessment using a device such as described here provided reliable results and should be considered for use in other scientific investigations to identify potential effects of anaesthetic agents.

Axial unloading therapy device for cervical spine rehabilitation.

There is an ongoing need for therapeutic cervical traction to treat chronic idiopathic neck pain. A device was designed to perform low-load cervical traction (unloading) with the patient in an upright, seated, neutral spine position. A prototype device meeting these requirements was constructed. During subsequent use, several methods for assessing the outcome of such unloading were proposed, including radiographic images, cervical range-of-motion measurements and muscle EMG activity. The prototype and measurement methods were tested on a population of normal subjects. The results demonstrated that the device design is safe and effectively transfers load into the occipital region of the skull. The use of low-load cervical unloading induced lateral rotation and posterior lengthening of the spine. Device refinements were identified. The results demonstrated that the methods described may be safely employed on a patient population.

Force assessment of the stimulated arm flexors: quantification of contractile properties.

The primary objective was to develop equipment and evaluate protocols for non-invasive assessment of contractile properties of human arm flexors. The research design consisted of a non-randomized control trial, with repeated measures. Data from six males and two females were gathered in a clinical research laboratory. The elbow flexor torque following motor point or direct nerve stimulation was measured in response to single pulses or short trains of electrical pulses. Length--tension relationships were determined; comparative data were obtained at the identified optimal muscle lengths. Twitch waveforms and peak torques following either type of stimulation were reproducible (within 10%). Peak torques following a 4-pulse small interpulse interval stimulation were nearly identical for motor-point activation and direct nerve stimulation (15.2+/- 6.6Nm for motor point stimulation; 14.5 +/- 6.6Nm for nerve stimulation). Average perceived pain indexes associated with 4-pulse stimuli were slightly higher following nerve stimulation (782 for nerve versus 6.23 for motor-point, n=8). A reliable methodology (motor-point stimulation) has been identified to perform stimulated force assessment of human arm flexors.

Surface EMG activity of the back musculature during axial spinal unloading using an LTX 3000 Lumbar Rehabilitation System.

Electromyographic (EMG) analysis has been used successfully to identify back muscle impairment in patients with low back pain. EMG signals from normal subjects during axial spinal unloading using an LTX 3000 device were obtained and spectral parameters of the electromyographic (EMG) signal were analyzed. The purpose of the study was to determine the optimal time for effective traction using the LTX 3000 rehabilitation device. These data will serve as a baseline for future studies to help assess back muscle function in low back patients undergoing rehabilitation. Three time points during axial spinal unloading were compared to pre-unloading to detect alterations in median power frequency (MPF), root-mean-square (RMS) and rectified integrated EMG (riEMG) during axial spinal unloading. There were reductions of riRMG during 0-10 minutes of axial spinal unloading in all muscle groups, followed by an increase in riEMG value from 10 to 15 minutes. A similar trend was seen in the RMS values. The MPF did not change during the course of unloading, indicating that there was likely no change in fatigue properties of the paraspinal muscles during axial spinal unloading. The optimal time for effective axial spinal unloading on the basis of muscle activity was determined to be 10 minutes of axial spinal unloading, and a back assessment procedure was presented that uses surface EMG electrodes to objectively characterize muscle activity and relative fatigue properties. Future studies will use this methodology to assess treatment outcome in a chronic low back pain population.

Opioid preconditioning: myocardial function and energy metabolism.

BACKGROUND: Opioid receptor agonists are involved in ischemic preconditioning and natural hibernation. The aim of this study was to determine whether pretreatment with D-Ala2-Leu5-enkephalin or morphine confers cardioprotection in large mammalian hearts. We assessed myocardial functional recovery and global energy metabolism after ischemic cold storage. METHODS: After pretreatment with D-Ala2-Leu5-enkephalin, morphine sulfate, or saline (n = 6 each), swine hearts were excised and stored for 75 minutes at 4 degrees C, then reperfused in a four-chamber isolated working heart apparatus. Serial myocardial biopsies were performed to assess cellular energy metabolism. RESULTS: Improved systolic (cardiac output, contractility) and diastolic (tau) left ventricular functions were observed in hearts pretreated with D-Ala2-Leu5-enkephalin or morphine. These benefits were not correlated with changes in high-energy phosphate levels. Cardiac enzyme leakage (creatine kinase, troponin-I) was similar among treated and control groups. Lactate efflux increased significantly in controls, but not in opioid-pretreated hearts (p < 0.01) at 75 minutes of reperfusion. CONCLUSIONS: D-Ala2-Leu5-enkephalin and morphine pretreatments improve postischemic function after cold storage of swine hearts. Postischemic lactate reduction, but not high-energy phosphate levels, may account for the observed cardioprotective effects.

Shiver suppression using focal hand warming in unanesthetized normal subjects.

BACKGROUND: A decrease of 1 or 2 degrees C in core temperature may provide protection against cerebral ischemia. However, during corporeal cooling of unanesthetized patients, the initiation of involuntary motor activity (shiver) prevents the reduction of core temperature. The authors' laboratory previously showed that focal facial warming suppressed whole-body shiver. The aim of the current study was to determine whether the use of hand warming alone could suppress shiver in unanesthetized subjects and hence potentiate core cooling. METHODS: Subjects (n = 8; healthy men) were positioned supine on a circulating water mattress (8-15 degrees C) with a convective-air coverlet (14 degrees C) extending from their necks to their feet. A dynamic protocol was used in which focal hand warming was used to suppress involuntary motor activity, enabling noninvasive cooling to decrease core temperatures. The following parameters were monitored: (1) heart rate; (2) blood pressure; (3) core temperature (rectal, tympanic); (4) cutaneous temperature and heat flux; (5) subjective shiver level (SSL scale 0-10) and thermal comfort index (scale 0-10); (6) metabolic data (n = 6); and (7) electromyograms. RESULTS: During cooling without hand warming, involuntary motor activity increased until it was widespread. After subjects reported whole-body shiver (SSL > or = 7), applied hand warming, in all cases, reduced shiver levels (SSL < o r= 3), decreased electromyographic root mean square amplitudes, and allowed core temperature to decrease from 37.0 +/- 0.2 to 35.9 +/- 0.5 degrees C (measured rectally). CONCLUSIONS: Focal hand warming seems to be valuable in minimizing or eliminating the need to suppress involuntary motor activity pharmacologically when it is desired to induce or maintain mild hypothermia; it may be used in conjunction with facial warming or in cases in which facial warming is contraindicated.

Physiological assessment of muscle strength in vitro after direct injection of doxorubicin into rabbit sternocleidomastoid muscle.

Doxorubicin chemomyectomy is a potent method for the permanent removal of a muscle or group of muscles after direct local injection, and has been used successfully to treat blepharospasm and hemifacial spasm patients. The efficacy of doxorubicin chemomyectomy on reducing muscle strength after direct injection of doxorubicin into rabbit sternocleidomastoid muscle was tested. One- and 6-month postinjection force assessment was performed in vitro to measure alterations in peak twitch and tetanic force generation, as well as fatigue responses for the treated muscles compared to control. There were significant reductions of both twitch and tetanic peak amplitudes in the doxorubicin-treated muscles. One month after treatment, the decreases in force were greater after 2 mg doxorubicin injections than after 1 mg doxorubicin. While there was a significant reduction in force generation after doxorubicin treatment, fatigue resistances for the doxorubicin-treated muscles were increased compared to the controls. There were significant reductions in muscle mass after doxorubicin treatment, and by 6 months, the myosin heavy chain isoform distribution was similar to normal sternocleidomastoid, except for an increase in slow myosin-positive fibers. Doxorubicin chemomyectomy resulted in a significant reduction in functional force generation in the treated sternocleidomastoid muscles. These findings suggest a potential clinical use of doxorubicin chemomyectomy to treat cervical dystonia patients.

Isolated four-chamber working swine heart model.

BACKGROUND: Isolated heart models separate cardiac characteristics from systemic characteristics with subsequent findings used in cardiac research, including responses to pharmacologic, mechanical, and electrical components. The model objective was to develop the ability to represent in situ physiologic cardiac function ex vivo. METHODS: Swine hearts were chosen over rat or guinea pig models due to their notably greater anatomical and physiologic similarities to humans. An in vitro apparatus was designed to work all four chambers under simulated in situ physiologic conditions. Using standard cardiac surgical techniques, 12 porcine hearts (mean weight 331 +/- 18 g) were explanted into the apparatus. Preload and afterload resistances simulated in situ input and output physiologic conditions. Hemodynamic characterizations, including cardiac output, max +/- dP/dt, and heart rate, were used to determine in situ function leading to explantation (prethoracic operation, postmedial sternotomy, and postperidectomy) and during in vitro function (t = 0, 60, 120, and 240 minutes). RESULTS: In vitro performance decayed with time, with statistical differences from base line (t = 0) function at t = 240 minutes (p > 0.05). CONCLUSIONS: An isolation and in vitro explantation protocol has been improved to aid in the study of isolated cardiac responses, and to determine cardiac hemodynamic function during open chest operation, transplantation, and in vitro reanimation with a crystalloid perfusate. The resulting model offers similar working physiologic function, with real-time imaging capabilities. The resulting model is advantageous in representing human cardiac function with regard to anatomic and physiologic functions, and can account for atrial and ventricular interactions.

The effect of chronic dexamethasone-induced hyperglycemia and its acute treatment with insulin on brain glucose and glycogen concentrations in rats.

BACKGROUND: In the rat model of forebrain ischemia, long-term dexamethasone treatment is reported to cause hyperglycemia and worsen postischemic functional and histologic injury. This effect was assumed to result from glucose enhancement of intraischemic lactic acidosis within the brain. Short-term insulin therapy restored normoglycemia but did not return histologic injury completely to baseline values. Using a nonischemic rat model, the current study attempted to identify a metabolic basis for such outcome data. METHODS: Fifty-eight halothane-anesthetized (1.3% inspired) Sprague-Dawley rats were assigned randomly to be administered either no treatment (N = 18) or 2 mg/kg intraperitoneal dexamethasone (N = 40). The latter were administered dexamethasone 3 h before the study only (N = 8) or for 3 h before the study plus daily for 1 day (N = 8), 2 days (N = 8), or 4 days (N = 16). Of the rats treated with dexamethasone for 4 days, one half (N = 8) were administered an insulin-containing saline infusion subsequently to restore normoglycemia short-term. All other rats (N = 50) were administered an infusion of saline without insulin. Plasma glucose was quantified, and brains were excised after in situ freezing. Brain glucose and glycogen concentrations were measured using enzymatic fluorometric analyses. RESULTS: After 4 days of dexamethasone treatment, plasma glucose was 159% greater than in rats administered placebo (i.e., 22.01 +/- 4.66 vs. 8.51 +/- 1.65 micromol/ml; mean +/- SD; P < 0.0001). Brain glucose concentrations increased parallel to plasma glucose. An insulin infusion for 27 +/- 5 min restored normoglycemia but resulted in a brain-to-plasma glucose ratio that was 32% greater than baseline values (P < 0.01). Neither dexamethasone nor the combination of dexamethasone plus insulin affected brain glycogen concentrations. CONCLUSIONS: In a nonischemic rat model, dexamethasone alone had no independent effect on the brain-to-plasma glucose ratio. However, short-term insulin therapy caused a dysequilibrium between plasma and brain glucose, resulting in an underestimation of brain glucose concentrations when normoglycemia was restored. The dysequilibrium likely was caused by the rapid rate of glucose reduction. The magnitude of the effect may account for the failure of insulin to reverse dexamethasone enhancement of neurologic injury completely in a previous report that used the rat model of forebrain ischemia.

Malignant hyperthermia phenotype: hypotension induced by succinylcholine in susceptible swine.

BACKGROUND: Succinylcholine causes immediate and severe arterial hypotension in swine with the malignant hyperthermia phenotype. The underlying mechanisms are unknown. METHODS: Malignant hyperthermia-susceptible (MHS; n = 10) and normal swine (n = 5) were anesthetized with thiopental. The following were monitored: electrocardiogram; arterial blood pressure; pulmonary artery, central venous, and left and right ventricular pressure; cardiac output; end-tidal carbon dioxide; core temperature; peripheral-blood flows; and arterial blood gases. After a control period, 2 mg/kg succinylcholine was given intravenously. Three MHS animals received 1 mg/kg vecuronium and two MHS animals received 2.5 mg/kg dantrolene intravenously. The effects of succinylcholine on left and right ventricular pressure and contractility were analyzed in isolated hearts. The effects of 0.06 mm succinylcholine on isometric tension development were recorded in isolated femoral artery rings. RESULTS: Succinylcholine caused an early, severe decrease in blood pressure, cardiac output, left ventricular pressure, and left ventricular contractility in MHS swine but not in normal swine; no significant differences were found in heart rate, right ventricular parameters, systemic vascular resistance, and preload (pulmonary diastolic pressure, central venous pressure). The succinylcholine-induced hypotension and associated effects were not prevented by dantrolene. However, pretreatment with high-dose vecuronium prevented not only the cardiovascular depression, but also MH. In addition, no phenotypic differences of succinylcholine on contractility or left ventricular pressure were observed in the isolated working hearts. Similary, succinylcholine did not cause a significantly different relaxation in rings in either phenotype. CONCLUSION: Succinylcholine-induced hypotension occurred before muscle hypermetabolism in MHS swine. Succinylcholine had no differential physiologic effects on either the isolated heart or on isolated arteries. This hypotension could not be prevented by dantrolene but was prevented by pretreatment with high-dose vecuronium. Thus, an indirect mechanism such as the release of a cardiac depressant from skeletal muscle may have caused this hypotensive response.

Facial warming increases the threshold for shivering.

A decrease of 1-2 degrees C core temperature provides protection against cerebral ischemia. However, shivering usually prevents reduction in core temperature in unanesthetized patients. Therefore, it was tested whether facial and airway heating increases the shivering threshold and enables core cooling in unanesthetized patients. Nine trials were performed on seven healthy male volunteers. Each subject was positioned supine on a circulating-water mattress (8-15 degrees C) with a convective-air coverlet (15-18 degrees C) extending from the neck to the feet. A dynamic study protocol governed by individualized physiological responses was used. Focal facial (and airway) warming was employed to suppress involuntary motor activity (muscle tensing, shivering) and, thereby, enabling noninvasive cooling to lower the core temperature. The following parameters were monitored: 1) heart rate, 2) blood pressure, 3) core temperature (tympanic, axilla, and rectal), 4) cutaneous temperatures, and 5) a subjective shiver index (scale 1-10). In three, electromyograms and infrared thermographs were also obtained. Upon cooling without facial and airway warming, involuntary motor activity increased until it was widespread. This vigorous motor activity prevented any significant lowering of core temperature or caused it to slightly increase. Subsequently, in all subjects, within seconds after the application of facial focal warming, motor activity was suppressed almost completely, and within minutes core temperatures significantly decreased. Preliminary studies described here indicate that focal facial warming applied during active whole body cooling to initiate mild hypothermia might minimize the need to pharmacologically suppress involuntary motor activity. Such a procedure might be useful for initiating as soon as possible (such as during emergency transport), cerebral mild hypothermia in order to maximize protection and thus improve outcome in neurologically injured patients (head trauma, stroke).

Hemodynamic and metabolic manifestations of acute endotoxin infusion in pigs with and without the malignant hyperthermia mutation.

BACKGROUND: The hypermetabolic state induced by acute endotoxemia and malignant hyperthermia (MH) may be indistinguishable. The aims of this study were (1) to investigate the differences between MH and sepsis, (2) to determine whether acute endotoxemia can trigger MH, and (3) to establish the effects of dantrolene in these two disorders. METHODS: Three groups of swine were studied. All pigs were invasively monitored and initially anesthetized with nontriggering agents. A placebo MH-susceptible group (n = 5) received normal saline whereas the endotoxin groups (MH-susceptible, n = 6; MH-negative, n = 4) received intravenous endotoxin (250 microg/kg total) during 2.5 h. Halothane (1.5%) and succinylcholine (2-4 mg/kg) were then administered, followed by two doses of dantrolene (4 mg/kg total). RESULTS: Endotoxin infusion resulted in pulmonary hypertension and systemic hypotension in pigs with and without the MH mutation, but did not trigger MH. Halothane and succinylcholine triggered MH, evidenced by a markedly higher oxygen consumption in the MH-susceptible pigs that received endotoxin (325+/-196 ml/min) and those that did not (374+/-110 ml/min) compared to the MH-negative pigs (69+/-15 ml/min, P<0.0009), as well as muscular rigidity in the susceptible animals. Dantrolene reversed these changes. Three of the six MH-susceptible pigs that received endotoxin died; two died soon after triggering and one after dantrolene administration. In contrast, none of the MH-negative pigs or the MH-susceptible pigs that did not receive endotoxin died (0 of 9 vs. 3 of 6, P = 0.044). CONCLUSION: Endotoxemia does not trigger MH, but may worsen outcome if it occurs.

4-chloro-m-cresol triggers malignant hyperthermia in susceptible swine at doses greatly exceeding those found in drug preparations.

BACKGROUND: Chlorocresols are used as preservatives in numerous commercial drugs that have been shown to induce myoplasmic Ca2+ release; the most potent isoform is 4-chloro-m-cresol. The aims of this study were to (1) examine the in vivo effects of 4-chloro-m-cresol on swine susceptible to malignant hyperthermia and (2) contrast in vivo versus in vitro dose-response curves. METHODS: Susceptible swine (weight: 38.5 kg+/-3.55 kg) were anesthetized and monitored for variations in physiological responses, including end-tidal CO2, heart rate, blood pressure, blood chemistry, and temperatures. In the first animals studied, 4-chloro-m-cresol, at equivalent cumulative doses of 0.14, 0.28, 0.57, 1.14, 2.27, 4.54, and 9.08 mg/kg (n = 3; 12.5, 25, 50, 100, 200, 400, and 800 micromol) were administered, and in a second group, larger doses were used: 1.14, 3.41, 7.95, 17.04 (n = 4), and/or 35.22 (n = 1) mg/kg (100, 300, 700, 1,500, and/or 3,100 micromol). For comparison, in vitro rectus abdominis muscle preparations obtained from normal and susceptible swine were exposed to 4-chloro-m-cresol, at cumulative concentrations of 6.25, 12.5, 25, 50, 100, 200, 400, 800, and 1,600 micromol; standard caffeine and halothane contracture testing was also performed. RESULTS: Episodes of malignant hyperthermia were not triggered in response to administration of low doses of 4-chloro-m-cresol, but transient cardiovascular reactions (e.g., tachycardia, arrhythmias, and hypotension) were observed. Subsequently, episodes in these animals were triggered when halothane (0.87; 1 MAC) and succinylcholine (2 mg/kg) were given. Animals administered the higher doses of 4-chloro-m-cresol all had fulminant episodes of malignant hyperthermia that were fatal, when equivalent cumulative concentrations were greater than 1,500 micromol. The levels of 4-chloro-m-cresol in the plasma rapidly decreased: e.g., 5 min postadministration of the 1,500-micromol dose, the mean plasma level was only 52+/-18 micromol (n = 4). Hemolysis was detected following 4-chloro-m-cresol administration at concentrations > 200 micromol. In vitro, muscle from susceptible animals elicited contractures > 200 mg at 50-micromol bath concentrations of 4-chloro-m-cresol (n = 29), whereas normal muscle did not elicit such contractures until bath concentrations were > 800 micromol (n = 10). CONCLUSIONS: 4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine, but only when serum concentrations are far above those likely to be encountered in humans. A relatively low concentration of 4-chloro-m-cresol, 50 micromol, is sufficient to activate sarcoplasmic [Ca+2] release in vitro (e.g., contractures); this same bolus dose administered in vivo (0.57 mg/kg) has minimal effects due to the rapid decrease in its plasma levels.