Clinical management of malignant hyperpyrexia

Experience with eight cases of malignant hyperpyrexia are presented. The different types are described and illustrated by clinical cases. Early recognition of this condition is the cornerstone in the successful management of the complication. Early diagnosis and methods of treatment are described.     

Ten cases of malignant hyperthermia in Norway

Data are presented on ten cases of anaesthesia-induced malignant hyperthermia in Norway. Seven of the patients died, three recovered. The fatal cases were all boys in the age group 11-20 years. This age and sex distribution suggests that puberty with the increase in androgens is a precipitating factor in malignant hyperthermia. One of the victims who survived was a 4 1/2-year-old pseudohermaphrodite girl with the adrenogenital syndrome. The coincidence of malignant hyperthermia in a patient with such a rare syndrome points to the excessive formation of androgens in patients with this syndrome as a predisposing factor. The indications for surgery were traumatic injuries in five cases, congenital abnormalities in three and appendicitis in two cases. These conditions in themselves may cause an increased sensitivity to suxamethonium. One patient received only hexobarbitone, halothane and suxamethonium. After the last drug jaw rigidity and temperature rise to 41.3 degrees C prompted the anaesthetist to end the anaesthetic. The fact that the patient survived proves that suxamethonium induced jaw rigidity is valuable as a warning. The absence of cardiovascular depression after procaine 3.5 g in one patient is ascribed to the correction of acidosis at the time of infusion of this drug. It is suggested that procaine should be withheld until other measures such as cooling, correction of acidosis and steroid therapy have been tried.     

双膦酸盐对骨转移癌骨痛治疗及血清钙磷影响

Objective: Bisphosphonates were widely used with the rate of malignant tumor with bone metastases increasing rapidly. The aim of this study was to evaluate zoledronic acid and pamidronic acid on treating osteatgia of malignant tumor with bone metastases and serum calcium, phosphorus and alkaline phosphorus movement. Methods: One Hundred cancer patients with bone metastases were diagnosed according to pathological and imaging methods. After zoledronic acid or pamidronic acid intravenous infusion one and two months, ostealgia degree, serum calcium, serum phosphorus and alkaline phosphorus were observed before bisphosphonates treatment, one and two months after treatment, respectively. Results:Ostealgia degree did not change significantly after diphosphonates treatment from one to two months (P ＞ 0.05). The linear correlation between serum calcium and serum phosphorus on bone metastases cancer patients before therapy was dismissed after bisphosphonates treatment one month and did not recover in two months. The incidence of hypo-calcium after diphosphonate treatment one month (54%) and two months (56%) were significantly increased than that before treatment (36%) (x2 = 6.55, P = 0.011; x2 = 8.05, P = 0.005). Serum calcium and serum phosphorus were both decreased after treatment one month (t = 4.39, P = 0.000; t = 2.50, P = 0.014) and two months (t = 4.32, P = 0.000; t = 2.49, P = 0.010). There had no difference between zoledronic acid and pamidronic acid on treating of ostealgia and serum calcium and phosphorus changing.Conclusion: Zoledronic acid and pamidronic acid can relief ostealgia of cancer patients with bone metastases and inducehypo-calcium, break the linear relationship between calcium and phosphorus. There have no difference between zoledronic acid and pamidronic acid on treating ostealgia and inducing hypo-calcium and hypo-phosphorus.     

Neuroleptic malignant syndrome associated with olanzapine

OBJECTIVE: To report a case of neuroleptic malignant syndrome (NMS) associated with the use of olanzapine. CASE SUMMARY: A 67-year-old white man with bipolar disorder developed nausea and vomiting. After 12 days, he became confused, delirious, and manic. His only medications were olanzapine 10 mg/d and divalproex sodium 500 mg bid. He was admitted to a hospital and treated for dehydration and mania. Olanzapine was given on 6 of the first 7 hospital days. On hospital day 6, typical NMS developed with the body temperature increasing to 39.9 degrees C, obtundation, rigidity, tremor, diaphoresis, fluctuating pupillary diameter, labile tachycardia and hypertension, hypernatremia, and elevated serum creatine kinase. Olanzapine was stopped after hospital day 7, and the syndrome resolved by hospital day 12. DISCUSSION: The patient had all of the major manifestations of NMS. There was no other likely explanation for his illness and he received no other drug likely to be associated with the syndrome. This is the first case reported in which NMS was associated with olanzapine.     

The PACT model

Topical application of the vitamin D analogue calcipotriol has been found to be of clinical value in the treatment of dermatological disorders. This is considered to be safe with respect to alterations in calcium homeostasis. We report a 17-year-old female patient who developed hypercalcaemic crisis after excessive use of calcipotriol for ichthyosis. The clinical condition and serum calcium improved after cessation of calciprotiol treatment and rehydration with intravenous fluids and electrolytes. The case emphasizes the importance of limiting the topical use of calcipotriol as recommended by the manufacturer.     

Hypothyroidism and hypercalcemia: report of a case with a parathyroid adenoma and review of the literature

A woman with hyperthyroidism, hypercalcemia, and a parathyroid adenoma is described. Various studies indicate that in hypothyroid subjects given an acute dose of calcium, the serum calcium levels remain elevated for longer periods than in control subjects. In part, this may be due to diminished bone uptake. Despite these studies which would tend to support the contention that hypothyroid patients "have a propensity to hypercalcemia" (Lowe et al), overt and significant hypercalcemia is unusual. Hypothyroidism is listed as a possible cause of hypercalcemia. This does not seem to be warranted by a review of the literature. The reference most often cited is that of Lowe et al. In their particular case, the hypercalcemia improved with thyroid replacement therapy. This also happened in our case. However, the measurement of IPTH levels led to the correct diagnosis. IPTH levels were not available at the time of Lowe's report and hyperparathyroidism was not completely excluded. Therefore, at this time, the reported association of hypercalcemia with adult hypothyroidism needs further examination to determine if this association is real.     

Contact system in healthy term newborns: reference values in cord blood

Humoral hypercalcemia refers to the elevated blood calcium levels caused by neoplasms which release a bone resorptive substance into the circulation. Previously reported infants with malignant and benign solid tumors causing humoral hypercalcemia have presented with large abdominal masses. The case we describe, a hypercalcemic infant due to an occult parathyroid hormone-related protein-containing metanephric adenoma of the kidney, shows that radionuclide bone scanning can be a useful test to identify humoral hypercalcemia. Humoral hypercalcemia stemming from a soft tissue neoplasm should be ruled out, even in the absence of clinical signs of a tumor, if bone scans show generalized uptake in the absence of hypervitaminosis D or radiological signs of bone lesions, and serum parathyroid hormone is low.     

The luminescence immunoassay S-100: a sensitive test to measure circulating S-100B: its prognostic value in malignant melanoma

In this study we measured S-100B using a recently developed luminometric immunoassay with a detection limit of 0.02 microg l(-1). By measuring serum S-100B concentrations in 58 apparently healthy individuals a reference value of 0.16 microg l(-1) was found. To assess the sensitivity of the assay we measured levels of S-100B protein in the serum of 251 patients with cutaneous malignant melanoma before the start of treatment. Only one of 179 patients with limited disease had a serum concentration higher than the reference value, whereas elevated levels were seen in 79% of patients with metastasized disease. In the latter group the NSE serum concentration was elevated in 42%. Using a receiver operating characteristic (ROC) curve it is shown that S-100B is a significantly better parameter than neuron-specific enolase (NSE) for distinguishing patients with limited disease from those with extensive melanoma. Pretreatment S-100B values were highly predictive for the period of survival. Patients with limited disease have increased risk for early death with increasing levels of S-100B protein. Within the group of patients with positive lymph nodes and/or with distant metastases, elevated S-100B levels strongly identified high-risk patients. Our study indicates that the measurement of S-100B as a tumour marker in the management of patients with cutaneous malignant melanoma has clinical significance.     

Malignant hypertension in a patient with primary aldosteronism with elevated active renin concentration

A 40-year-old male, with a past history of hypertension but receiving no medical treatment, was referred. He manifested malignant hypertension (190/130 mmHg; Keith-Wagener III), renal dysfunction (serum creatinine, 3.8 mg/dl), and elevated plasma aldosterone (450 pg/ml) and active renin concentration (ARC, 104 pg/ml). His blood pressure was controlled with multiple antihypertensive agents and ARC thus decreased (4.3 pg/ml), but aldosterone remained elevated. Abdominal magnetic resonance imaging (MRI) revealed a right adrenal adenoma, and aldosterone-producing adenoma was confirmed by adrenal venous sampling. Primary aldosteronism very rarely develops to malignant hypertension, and even in that case ARC is suppressed. Therefore this is a rare case of primary aldosteronism complicated with malignant hypertension and high ARC.     

Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol

Intravenous calcitriol is known to directly suppress PTH secretion and release. We evaluated the effect of four months of treatment with low-dose intravenous calcitriol on PTH levels in 83 hemodialysis patients. The criteria for including patients in the study were a serum PTH levels at least four times the normal limit, a serum total calcium less than 10 mg/dl and good control of the serum phosphorus level. All patients underwent standard bicarbonate or acetate dialysis; dialysate calcium level was maintained at the usual 3.5 mEq/liter concentration. Initial calcitriol dose was 0.87 +/- 0.02 (SEM) micrograms (0.015 micrograms/kg body wt) thrice weekly at the end of dialysis, and it was reduced in case of hypercalcemia or elevated calcium-phosphate product. Seven out of 83 patients dropped out during treatment. Among the 76 patients who completed the study, 58 (76%) showed a highly significant decrease of intact PTH levels (average reduction 48%) and of alkaline phosphatase levels after four months of therapy. Total serum calcium increased slightly but significantly in the responder group but remained unchanged in the non-responders. No significant changes in ionized calcium levels could be detected, even in responders. Treatment was well tolerated by patients, but 60% of them had transient episodes of hyperphosphatemia. Mean serum phosphate was 4.95 mg/dl at the beginning of the study. It increased significantly after four months of treatment in patients who showed a decrease of PTH levels, although it remained within acceptable limits, below 5.5 mg/dl. Twenty-eight of 76 patients (37%) reduced the dose of calcitriol because their calcium-phosphate products exceeded 60.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neuroleptic malignant syndrome and mivacurium: a safe alternative to succinylcholine?

Neuroleptic malignant syndrome (NMS) and malignant hyperthermia (MH) may have a common pathogenic mechanism; therefore, it has been suggested that known triggering agents for MH (such as succinylcholine) should be avoided in patients with NMS. Electroconvulsive therapy (ECT) continues to play a major therapeutic role in contemporary psychiatry, and succinylcholine has been the muscle relaxant of choice in attenuating violent muscle contractions induced by ECT. Mivacurium is a non-depolarizing muscle relaxant with a relatively rapid onset and a short duration of action, and to date it has been proved safe in MH-susceptible patients. In this case report, following succinylcholine use during ECT, a patient with NMS developed an increase in temperature and serum creatine kinase (CK) level, possibly due to an MH reaction. Since the patient's mental status necessitated further ECT, mivacurium was administered during subsequent treatment and resulted in effective attenuation of muscle contractions without elevation of patient temperature or CK levels. In addition, there was no marked prolongation of the anaesthetic. Mivacurium is a suitable agent for patients with NMS undergoing ECT, as it has not been associated with precipitation of an MH response.     

Malignant hyperthermia--still a current and dangerous problem

Malignant hyperthermia is a potentially fatal condition inducible by volatile anaesthetics and/or suxamethonium in genetically susceptible individuals. A disturbed calcium homeostasis in skeletal muscle (possibly in the ryanodin receptor) results in elevated myoplasmatic calcium. The latter causes muscle contraction and a hypermetabolic state, clinically observed as rigidity, fever, hypercarbia, metabolic acidosis and hyperkalemia. Arythmia ensues. Dantrolene inhibits the release of calcium and can halt the process if the diagnosis is made early. A fatal incident of probable malignant hyperthermia in a 13 year old boy is described and evaluated according to a multifactorial clinical grading scale. The value of the in vitro contracture test to diagnose malignant hyperthermia is discussed. Suggestions concerning the treatment of masseterspasm rigidity, an acute episode of malignant hyperthermia, and safe anaesthesia for susceptible patients are presented.     

Voltage-dependent calcium release in human malignant hyperthermia muscle fibers

Malignant hyperthermia (MH) results from a defect of calcium release control in skeletal muscle that is often caused by point mutations in the ryanodine receptor gene (RYR1). In malignant hyperthermia-susceptible (MHS) muscle, calcium release responds more sensitively to drugs such as halothane and caffeine. In addition, experiments on the porcine homolog of malignant hyperthermia (mutation Arg615Cys in RYR1) indicated a higher sensitivity to membrane depolarization. Here, we investigated depolarization-dependent calcium release under voltage clamp conditions in human MHS muscle. Segments of muscle fibers dissected from biopsies of the vastus lateralis muscle of MHN (malignant hyperthermia negative) and MHS subjects were voltage-clamped in a double vaseline gap system. Free calcium was determined with the fluorescent indicator fura-2 and converted to an estimate of the rate of SR calcium release. Both MHN and MHS fibers showed an initial peak of the release rate, a subsequent decline, and rapid turn-off after repolarization. Neither the kinetics nor the voltage dependence of calcium release showed significant deviations from controls, but the average maximal peak rate of release was about threefold larger in MHS fibers.     

Determination of circulating parathyroid hormone levels and differential diagnosis of hypercalcemia

Primary hyperparathyroidism is the most frequent cause of hypercalcemia in outpatients. In contrast, this electrolyte disorder is very often associated with cancer when detected in hospital, particularly in the frame of tumors of breast, lung or lympho-hematopoietic system. Hypercalcemia results from an imbalance between the fluxes of calcium entering and leaving the extracellular space. Theses fluxes, mainly those at the levels of bone and kidney, are the main regulators of calcium homeostasis. Depending on the etiology, increases in either bone resorption or renal tubular calcium reabsorption can predominate as the cause of elevated calcemia. Thus, an increment of renal tubular reabsorption of calcium plays a prominent role in hypercalcemia resulting from increased serum concentrations of parathyroid hormone, but can also be detected in 50% of malignant hypercalcemias. The ectopic production of authentic parathyroid hormone has convincingly been demonstrated in very few cases. The syndrome of pseudohyperparathyrodism encountered in malignant hypercalcemia can be accounted for by the tumoral secretion of an analog of parathyroid hormone, parathyroid hormone-related protein. Both proteins, which are produced by different genes located on different chromosomes, interact with the same cell membrane receptors and display identical spectrum of actions. Since they are immunologically quite distinct, there is no cross-reactivity in the various competitive or radiometric immunoassays actually available. The determination of circulating levels of parathyroid hormone is an essential step in the differential diagnosis of hypercalcemias, provided the assays offer adequate sensitivity and specificity. Nowadays, this appears to be generally the case.     

Serum lysozyme as a marker of host resistance. II. Patients with malignant melanoma, hypernephroma or breast carcinoma

Serum lysozyme activity was measured in groups of untreated patients with malignant melanoma, hyperneophroma and breast carcinoma. Significant elevation of serum levels of the enzyme was confined to patients with localized disease. In the presence of metastatic disease such elevation was not detected. The rise in serum lysozyme activity was not due to renal damage or any infective process and in the case of malignant melanoma was shown to be associated with infiltration of the tumour mass by macrophages. In vitro studies demonstrated that the macrophages resident in a tumour mass are responsible for relasing lysozyme in large amounts. It is proposed that the elevation of serum lysozyme in these cases may be an indicator of macrophage-mediated host resistance and that the measurement of macrophage products such as lysozyme in the extracellular fluid may under well defined conditions provide useful clinical information concerning host reactions.     

Metastasis results from preexisting variant cells within a malignant tumor

Clones derived in vitro from a parent culture of murine malignant melanoma cells varied greatly in their ability to produce metastatic colonies in the lungs upon intravenous inoculation into syngeneic mice. This suggests that the parent tumor is heterogeneous and that highly metastatic tumor cell variants preexist in the parental population.     

Natural killing activity in patients with spontaneous regression of malignant lymphoma

Previously, we proposed a new analysis of natural killing activity, for comparison, employing an "individual effector/target cell ratio" according to the number of effector cells in blood. The activity could be measured in four patients with spontaneous regression of malignant lymphoma. Despite the absence of episodes suggesting viral infections, patients with spontaneous regression had significantly higher activities prior to their regressions than either controls or patients without regression. In one patient who had a spontaneous regression accompanied by a high level of natural killing activity, subsequent exacerbation of the disease with a reduced activity was never followed by a regression and became life-threatening. In another patient, a spontaneous regression was accelerated after greater augmentation of natural killing activity was induced by a superimposed viral infection. These facts suggest that highly elevated natural killing activity may be one of the possible mechanisms responsible for spontaneous regression of malignant lymphoma.     

Social medicine and public health]

A case of Sipple's syndrome is reported, in which the full phenotype was expressed. The patient had the typical marfanoid habitus, with thickened lips and alae nasi, neuromas on lips and tongue, medullary carcinoma of the thyroid gland, phaeochromocytomas, and medullated corneal nerve fibres. The plasma calcitonin level was initially elevated, rose on calcium infusion before thyroidectomy, and was undetectably after thyroidectomy. The urinary catecholamine excretion was elevated. The plasma parathyroid hormone, adrenocorticotrophin and growth hormone levels and the serum calcium level were normal.     

Delayed positive thallium uptake in large B-cell non-Hodgkin's malignant lymphoma

We report an unusual finding in an AIDS patient who presented with a large mediastinal mass and multiple lymphadenopathy. A sequential thallium and gallium scan to specify the nature of the mediastinal mass was requested. The early thallium images, acquired 15 min after the intravenous injection, showed no uptake in the mass. The delayed images 2 hr later showed intense thallium uptake. A gallium scan performed 48 hr later also showed intense gallium uptake in the mediastinal mass. Biopsy from the inguinal lymph node confirmed the presence of large-cell diffuse noncleaved malignant lymphoma. This case raises questions about the optimum time of imaging for thallium in high-grade lymphoma, whether delayed imaging is essential, about previous reports of low sensitivity of thallium in undifferentiated lymphoma and about the mechanism of thallium uptake in this type of tumor.     

Multiple malignant melanoma and squamous-cell carcinoma in a burn scar

Malignant melanoma arising in a burn scar is very rare. Only 12 cases have been reported until now. We report a case of multiple malignant melanoma and squamous-cell carcinoma arising in the same burn scar. Reported cases of malignant melanoma arising in burn scars are also reviewed. Results of immunohistochemical studies and HLA typing of our patient and a review of previous cases suggest the aggressive behavior of malignant melanoma in burn scars.