In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: Results of testing patients surviving fulminant MH and unrelated low-risk subjects

Background: Determination of sensitivity and specificity of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility using the European MH Group (EMHG) protocol has been performed in some laboratories but only on a small sample from the combined EMHG. Thus, the purpose of the present study was to determine combined EMHG sensitivity and specificity of the test. Methods: Results of IVCT of patients with previous fulminant MH and normal, low-risk subjects (controls) were collected from 22 centresof the EMHG. IVCT was performed according to the EMHG protocol. Patients were included inthe study if the clinical crisis had a score of at least 50 points with the Clinical Grading Scale. Low-risk subjects were included provided they did not belong to a family with known MH susceptibility, they had not developed any signs of MH at previous anaesthetics, and they did not suffer from any neuromuscular disease. For inclusion of both MH patientsand low-risk subjects, at least 1 muscle bundle in the IVCT should have twitches of 10 mN(1 g) or more. For evaluation of individual tests, only muscle bundles with twitch heights of 10 mN (1 g) or more were used. Results: A total of 1502 probands had undergone IVCT because of a previous anaesthesia with symptoms and signs suggestive of MH. Of these, 119 had clinical scores of 50 and above. From these 119 MH-suspected patients and from 202 low-risk subjects, IVCT data were collected. Subsequently, 14 MH-suspected patients were excluded from further analysis for thefollowing reasons: In 3 patients, the suspected MH episode could be fully explained by diseases other than MH; in 11 MHS patients, IVCT was incomplete (n=l), data were lost (n=3), or none of the muscle bundles fulfilled twitch criteria (n=7). Of the remaining 105 MH-suspected patients, 89 were MHS, 10 MHEh, 5 MHEc, and one MHN. Thus, we observed a diagnostic sensitivity of the IVCT of 99.0% if the MHE group is considered susceptible(95% confidence interval 94.8–100.0%). Of the 202 low-risk subjects, 3 were MHS, 5 MHEh, 5 MHEc, and 189 MHN. This gives a specificity of the IVCT of 93.6% (95% confidence interval 89.2–96.5%). Conclusion: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.     

Immunotherapy and whole-body hyperthermia as combined modality treatment of a subcutaneous murine sarcoma

Interleukin–2 and hyperthermia have been used individually to treat a variety of tumors in both experimental and human trials. Combined adoptive immunotherapy and hyperthermia is an exciting new line of investigation. Previous work in our laboratory has shown that combined local hyperthermia and rIL-2 therapy can significantly decrease the rate of tumor growth. In this study, we investigated the effect of combined whole-body hyperthermia (WBHT) and rIL-2 on the growth of subcutaneous MCA-105 murine tumors in C57BL/6 mice. Treatment of both microscopic (day 3) and macroscopic (day 10) tumors was evaluated. In the treatment of microscopic tumors, animals received either no treatment; rIL-2 (3 × 10⁵ IU ip tid) on days 3–7; plus WBHT(41°C for 30 min) on days 3, 5, and 7; or WBHT only on days 3, 5, and 7. In treating macroscopic tumors, animals received either no treatment; rIL-2 on days 10–14; plus WBHT on days 10, 12, and 14; or WBHT only on days 10, 12, and 14. While combined treatment and WBHT alone had no significant effect on the growth of microscopic tumors, combined IL-2 and WBHT significantly reduced the rate of tumor growth of macroscopic tumors. These results suggest that the tumor microenvironment plays a critical role in combined WBHT and rIL-2 therapy, and may be due to effects of WBHT on the tumor vasculature. © 1993 Wiley-Liss, Inc.     

Age, fiber type composition and in vitro contracture responses in human malignant hyperthermia

Muscle fiber typing and in vitro contracture tests were performed in 59 patients investigated for susceptibility to malignant hyperthermia (MH). Eighteen patients were found to be susceptible to MH. There was no difference in age or fiber type distribution between MH susceptible and non-susceptible patients. No correlation was found between age and fiber type distribution. Separate analyses for each diagnostic group revealed no relationship between age or fiber type distribution and response to halothane or caffeine. When all caffeine results were pooled, however, there was a significant effect of age on the caffeine specific concentration (the concentration eliciting a contracture of 1 g), but not on the caffeine threshold concentration (the minimal concentration eliciting an increase in tension). It is concluded that age and fiber type distribution have no influence on MH diagnosis, if the protocol of the European MH Group for evaluation of susceptibility to MH is followed.     

Fever and feeding in the rat: Actions of intrahypothalamic interleukin-6 compared to macrophage inflammatory protein-1β (MIP-1β)

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1β, induce an intense fever in the rat when they are injected directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (T_b) of MIP-1β with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T_b continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 μl of pyrogen-free artificial CSF, recombinant murine MIP-1β, or recombinant human IL-6. MIP-1β in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in T_b of 2.4 ± 0.21°C reached by 3.7 ± 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T_b of 1.2 ± 0.25°C, 1.8 ± 0.15°C, and 2.1 ± 0.22°C and duration of 6.2 ± 1.28 hr, 6.7 ± 0.49 hr, and 6.8 ± 0.65 hr when given in doses of 25, 50, and 100 ng, respectively. These results show that MIP-1β and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-1β exerts its action in a much lower concentration. Thus, the de novo synthesis and subsequent action of the MIP-1 family of cytokines on neurons of the AH/POA in response to a pyrogen challenge apparently play a functional role in the pathogenesis of fever. Further, the endogenous activity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute phase response to a bacterial challenge. Copyright © 1994 Wiley-Liss, Inc.     

Fluidity state of lymphocyte plasma membrane in malignant hyperthermia susceptible pigs and humans

Recent studies suggest that abnormalities occur at the lipid level in malignant hyperthermia susceptible humans and pigs. To test this hypothesis, we first investigated the physical state of plasma membranes of lymphocytes isolated from normal and malignant hyperthermia susceptible swine. In halothane-challenged pigs, malignant hyperthermia susceptibility was also assessed by ryanodine binding assay on purified sarcoplasmic reticulum membranes. The results clearly show that plasma membrane of lymphocytes from malignant hyperthermic pigs are significantly more fluid than controls. We then attempted to apply the same methodology to lymphocytes prepared from human patients previously diagnosed by the halothane and caffeine contracture test. In that case, there was no clear relationship between malignant hyperthermia susceptibility and the fluidity state of lymphocyte plasma membranes.     

Laser interstitial thermotherapy in stereotactical neurosurgery

The authors present their first experience with laser interstitial thermotherapy, (ITT). Four patients with deep-seated non-infiltrative benign tumours (three astrocytomas, one oligodendrocytoma) underwent ITT. Previously, a stereotactic procedure had been performed to determine the exact location of the tumour, its spatial configuration and its histological diagnosis. The MRI controls confirmed the efficacy of hyperthermia on the tumour tissues. The authors discuss the possible ITT mechanisms. The indications of such laser ITT in neurosurgery should be enlarged to malignant tumours (gliomas, metastases) and to certain hypophyseal adenomas.     

Fulminant malignant hyperthermia associated with ketoacidotic diabetic coma

Malignant hyperthermia (MH) in humans is usually triggered by volatile anaesthetics and depolarizing muscle relaxants. However, other factors or drugs (e.g. cresol) are thought to induce MH. We report a case of fulminant MH associated with a ketoacidotic diabetic coma. After therapy for diabetic coma with insulin (containing the preservative cresol) and electrolyte solutions was started, the patient complained of increasing myalgia, developed a high fever and respiratory and metabolic acidosis and lost consciousness. MH was treated immediately with dantrolene; the patient recovered within 14 days. Five months later the patient was diagnosed as MH-susceptible by the in vitro caffeine and halothane contracture test. This case supports the assessment that MH and diabetes are associated diseases and that cresol could possibly trigger MH. Furthermore, therapy with dantrolene has been demonstrated to the beneficial in the treatment of MH associated with diabetic coma.     

MR monitoring of MR-guided radiofrequency thermal ablation of normal liver in an animal model

The purpose of this study was to determine the suitability of MRI to accurately detect radiofrequency (RF) thermoablative lesions created under MR guidance. In vivo RF lesions were created in the livers of six New Zealand White rabbits using a 2-mm-diameter titanium alloy RF electrode with a 20-mm exposed tip and a 50-W RF generator. This was performed using a 0.2T clinical C-arm MR imager for guidance and monitoring. Each animal was sacrificed and gross evaluation was performed. Histologic correlation was performed on the first two animals. The MR-compatible RF electrode was easily identified on rapid gradient-echo images used to guide electrode placement. A single lesion was created in each rabbit liver. Lesions ranged from approximately 10 to 17 mm in diameter (mean, 13.5 mm). T2-weighted and short T1 inversion recovery (STIR) images demonstrated lesions ranging in diameter from 12 to 18 mm (mean, 14.6 mm). Lesion dimensions determined from images closely correlated with those determined at gross examination with the discrepancy never exceeding 2 mm, for an r² value of .87. MRI performed at the time of MR-guided RF ablation accurately demonstrated created lesions. This modality may provide a new option for the treatment of local and regional neoplastic disease.     

Hyperthermic modulation of macrophage-tumor cell interactions

Hyperthermia in the febrile (41° C) or tumor therapeutic (42° C) ranges is known to alter tumor-host interactions: there are reports of either inhibitory or enhancing effects on tumor metastasis and various host defense mechanisms. Historically, this has been an area of conflicting and often anecdotal reports, and there are still significant gaps in our knowledge of the effects of temperature on tumor-host interactions. However, we believe that the tools are now available to further our understanding of the complex relationships between febrile episodes or therapeutically applied heat and various tumor-host cytotoxic mechanisms, and that potentially important and exploitable relationships can be defined. In this review we give an overview of the current status of this field and the factors that have shaped it. We also describe our recent experimental work with macrophages and their monokines, primarily tumor necrosis factor (TNF), which we feel offers new scientific and clinical opportunities for future studies.