Calcium channel blockers are inadequate for malignant hyperthermia crisis.

PURPOSE: Malignant hyperthermia (MH) results from disordered calcium (Ca(2+)) homeostasis in skeletal muscle during general anesthesia. Although Ca(2+) channel blockers may be given to treat the tachycardia and circulatory instability, coadministration of Ca(2+) channel blockers and dantrolene is contraindicated during MH crisis. We evaluated the effect of Ca(2+) channel blockers on Ca(2+) homeostasis and their interactions with dantrolene in human skeletal muscle. METHODS: Human skeletal muscle samples were obtained by biopsy and divided into two groups according to the results of the Ca(2+)-induced Ca(2+) release rate test. Differentiated myotubes were labeled with Fura-2, and changes in the 340/380-nm ratio were used to calculate changes in Ca(2+) concentration following nifedipine treatment in the absence or presence of dantrolene. RESULTS: Nifedipine induced a transient increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a dose-dependent manner. The half-maximal concentration (EC(50)) for nifedipine was 0.718 ± 0.329 µM in the accelerated group and 1.389 ± 0.482 µM in the nonaccelerated group (P = 0.009). The addition of 50 µM dantrolene attenuated by 15.4% the increase in [Ca(2+)](i) caused by the 0.5 µM nifedipine. CONCLUSION: Ca(2+) channel blockers led to increased [Ca(2+)](i) in human skeletal muscle cells. The increase is thus scarcely affected by dantrolene treatment. Data provide a greater physiologic basis for avoiding the use of Ca(2+) channel blockers during MH crisis.

[Case of large vein perforation caused by pumping using central venous catheter revealed by postoperative CT].

A 72-year-old woman, 157 cm in height and weighing 45 kg, was scheduled for emergency surgery for acute abdomen suggestive of gastrointestinal perforation. During the procedure, a triluminal central venous catheter (CVC) was inserted via the left internal jugular vein; venous blood could be aspirated separately through its lumens. On attempting blood transfusion, we noticed that the opening of one the CVC lumen tips was blocked and blood pumping was thus performed to achieve rapid transfusion. Colostomy was then performed and the transverse colon resection surgery was completed. Postoperative CT revealed right-sided hemothorax, a mediastinal hematoma located in the anterior region, and extravascular findings of CVC. The CT findings suggested a perforation of the left internal jugular vein due to the catheter tip. In the present case, the intraoperative pumping performed to enable rapid blood transfusion was believed to have caused blood vessel perforation. After the intraoperative blood vessel perforation, the condition may have been aggravated by steroid use, amyloidosis, and blood vessel fragility, ultimately presenting the extravascular findings observed on CT. We thus believe that in cases where CVC is inserted via the left internal jugular vein, blood pumping in particular is believed to be dangerous. Although the risks of blood vessel perforation when using CVC are relatively low, the possibility of unexpected complications should be borne in mind.

Mutated p.4894 RyR1 function related to malignant hyperthermia and congenital neuromuscular disease with uniform type 1 fiber (CNMDU1).

BACKGROUND: Ryanodine receptor 1 (RyR1) is a Ca(2+) release channel located in the sarcoplasmic reticulum membrane of skeletal muscle. More than 200 variants in RyR1 have been identified in DNA from patients with malignant hyperthermia (MH) and congenital myopathies; only 30 have been sufficiently studied so as to be identified as MH-causative mutations. The Ala4894Thr RyR1 variant was found in a Japanese patient with susceptibility to MH, and the Ala4894Pro variant in a rare case of myopathy: congenital neuromuscular disease with uniform type 1 fiber (CNMDU1). We hypothesized that different Ala4894 variants of RyR1 cause different pathophysiological changes that are identifiable by having differing pharmacological sensitivities to RYR1 agonists. METHODS: Expression vector with a mutation in RYR1 corresponding to the Ala4894Thr, Ala4894Pro, Ala4894Ser, or Ala 4894Gly variant of human RyR1 was transfected into human embryonic kidney 293 cells. At 72 hours after transfection, we determined the intracellular Ca(2+) changes induced by caffeine and 4-chloro-m-cresol (4CmC), in the presence or absence of dantrolene. RESULTS: Ala4894Thr-transfected cells and Ala4894Ser-transfected cells were more sensitive to caffeine than the wild type, and Ala4894Thr-transfected cells were also more sensitive to 4CmC than the wild type, whereas Ala4894Pro-transfected cells had no response to caffeine or 4CmC. Ala4894Gly-transfected cells were significantly less sensitive to caffeine than the wild type. In addition, the responses of Ala4894Thr-transfected cells and Ala4894Ser-transfected cells to caffeine were suppressed by dantrolene. CONCLUSION: We concluded that different Ala4894 variants of RyR1 lead to different agonist/antagonist sensitivities, which may predict differing RYR1 functionality during excitation-contraction coupling and sensitivity to MH. The hypersensitive Ala4894Thr-RyR1 is associated with MH and the poorly functional Ala4894Pro-RyR1 with CNMDU1.

[Preoperative management of malignant hyperthermia].

Malignant hyperthermia (MH) is a potentially fatal complication of general anesthesia following exposure to a depolarizing muscle relaxant and/or volatile anesthetics. MH is inherited as autosomal dominant and is thought to result from disordered Ca2+ regulation by the sarcoplasmic reticulum of the skeletal muscle. The mortality is still approximately 15% in Japan. It is difficult to diagnose by usual examinations preoperatively. Therefore, early detection, prompt treatment, discontinuation of triggering agents, and sufficient administration of dantrolene are needed.

Functional analysis of ryanodine receptor type 1 p.R2508C mutation in exon 47.

PURPOSE: Malignant hyperthermia (MH) is a pharmacogenetic disorder of intracellular calcium homeostasis with an autosomal dominant inheritance. Most of the reported mutations in exon 47 were identified in Asian patients. However, no functional analysis of p.R2508C has been performed. We therefore conducted a functional analysis of the mutation by altering calcium homeostasis in human embryonic kidney (HEK) 293 cells transfected with the p.R2508C mutation in exon 47 of the ryanodine receptor 1 (RYR1). METHODS: The entire RYR1 coding region from genomic DNA, which was extracted from the biopsied muscle specimens of two patients, was sequenced. The p.R2508C mutation was introduced into rabbit RYR1 cDNA, and wild-type or p.R2508C mutant cDNAs were transfected into HEK-293 cells. Using the calcium-sensitive probe Fura 2, we utilized the 340/380 nm ratio to analyze alterations in calcium homeostasis following treatment with caffeine and 4-chloro-m-cresol (4CmC). RESULTS: Genetic analysis revealed a C-->T point mutation of RYR1 exon 47 at position 7522, resulting in an amino acid exchange of arginine for cysteine at amino acid 2508. The half-maximal activation concentrations (EC(50)) of caffeine and 4CmC for HEK-293 cells transfected with the p.R2508C mutation were 1.86 +/- 0.23 mM and 73.14 +/- 19.44 microM, while those for wild-type RYR1 were 2.62 +/- 0.23 mM and 179.31 +/- 35.23 microM, respectively. CONCLUSION: We demonstrated that the transfected RYR1 mutant was more sensitive to caffeine and 4CmC than wildtype RYR1. These findings suggest that the p.R2508C mutation may be pathogenetic for susceptibility to MH.

Fulminant-type malignant hyperthermia in Japan: cumulative analysis of 383 cases.

We investigated the transition of clinical signs of fulminant-type malignant hyperthermia (f-MH) by analyzing a database consisting of 383 cumulative cases of f-MH from 1961 to 2004. The cases were divided by time period into group 1 (1961-1984), group 2 (1985-1994), and group 3 (1995-2004). The variables considered were age, sex, type of agents used (succinylcholine and volatile anesthetics), dantrolene administration, clinical signs, laboratory data, and mortality. The level of statistical significance was considered to be less than 5%. Groups 1, 2, and 3 consisted of 196, 127, and 60 cases, respectively. In groups 1, 2, and 3, the rates of dantrolene administration were 18.4%, 93.6%, and 86.7%; the rates of occurrence of ventricular arrhythmia were: 75.2%, 55.6%, and 35.0%; and the rates of generalized muscle rigidity were 64.7%, 60.9%, and 23.9%, respectively. The mortality rate decreased over time, from 42.3% in group 1, to 15.0% in group 2 and group 3. We considered that this decrease occurred because of the increased use of dantrolene and the early diagnosis of malignant hyperthermia in the latter two groups.

[Anesthesia for anticoagulated patients].

BACKGROUND: Anticoagulated patients who undergo surgry have been increasing in number. They may develop thrombo-embolic and/or bleeding complications. METHODS: We studied 79 patients retrospectively who had undergone elective surgery from April 2002 through December 2003. We studied their basal diseases, types of anticoagulants, stopping or continuing anticoagulants during their surgical period, thrombo-embolic and/or bleeding complications and changing of the anesthetic method. RESULTS: Thrombo-embolic complications occurred in 2 patients (2.5%) who developed brain emboli. Both of them had arythmia. Bleeding complications occurred in 4 patients (5.1%), of whom 3 patients developed bleeding during spinal or epidural anesthesia and one of them had hematoma from the surgical wound. There was no mortality, and 28.8% of patients underwent change of anesthetic method where only general anesthesia was used. CONCLUSIONS: It is recommended that patients at high risk of thrombo-embolism should continue to receive anticoagulant or heparin during surgical period.

[Cesarean section in a patient with severe mitral stenosis after mitral valve replacement].

A 30-year-old woman with mitral stenosis after mitral valve replacement was scheduled for cesarean section at 28 weeks and 6 days of pregnancy. Cesarian section was decided at a conference of obstetrics, cardiac surgery, neonatology and anesthesiology. Anesthesia was successfully managed with epidural block and pulmonary arterial pressure monitoring. During operation, blood pressure was controlled by dopamine, milrinone and phenylephrine. Patient did not develop cardiac insufficiency perioperatively. Cardiac function deteriorated gradually and reoperation of mitral valve replacement was performed 2 months later.

[Epidemiological study of hepatitis B and C in 34,336 patients operated at Hiroshima Prefectural Hospital during the period from 1993 to 2000].

BACKGROUND: We have many chances to deal with blood transfusion in the operation room, and it is important for us to pay more attention to prevent hospital infection. METHODS: We surveyed epidemiologically the prevalence of hepatitis B virus surface antigen (HBV) and hepatitis C virus antibody (HCV) in 34,336 patients operated at Hiroshima Prefectural Hospital from April 1993 through March 2001. RESULTS: The prevalence of HBV seropositivity was 1.8% in total, 1.6% in scheduled, and 2.5% in emergent cases. The prevalence of HCV seropositivity was 7.1% in total, 6.8% in scheduled, and 8.0% in emergent cases. Prevalences of both of them in emergent cases were higher than scheduled. The prevalence of HBV was highest (3.4%) in patients with age of 40's, and the prevalence of HCV increased with age. The prevalences of HBV and HCV were highest (4.5% and 19.0%) in the division of surgery and dialysis-kidney disease center. CONCLUSIONS: It is important to carry out standard precautions for all patients to prevent hospital infection. Furthermore, we should pay attention to emergent operative cases and operative cases in dialyzed patients.