Hirotsugu Miyoshi

Several Ryanodine Receptor Type 1 Gene Mutations of p.Arg2508 Are Potential Sources of Malignant Hyperthermia.

BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic disorder that occurs in predisposed individuals after exposure to volatile anesthetics or depolarizing muscle relaxants. Genetic mutations of ryanodine receptor 1 (RYR1), which are considered to cause MH, are found mainly in 3 regions called “hotspots.” There are sometimes multiple mutations at the same site of RYR1. Although p.Arg2508 of RYR1 is located outside hotspots, several mutations or variants (including the known MH causative mutation p.Arg2508Cys) have been identified in this region. We hypothesized that any mutations or variants in RYR1 p.Arg2508 cause important changes in pathological conditions related to MH. In this study, we analyzed the functions of 4 different RYR1 variants containing mutations at p.Arg2508. METHODS: We prepared and analyzed the functions of 4 mutated RYR1 genes: p.Arg2508His and p.Arg2508Gly are MH-related variants, whereas p.Arg2508Ser and p.Arg2508Lys have not been previously reported. Because the biochemical characteristics of lysine are similar to arginine, we assumed that p.Arg2508Lys RYR1 would have characteristics most similar to those of the wild-type RYR1. We introduced these 4 mutated RYR1 genes, p.Arg2508His, p.Arg2508Gly, p.Arg2508Ser, and p.Arg2508Lys into rabbit RYR1 cDNA and transfected the resultant clones into human embryonic kidney 293 cells. Using the ratiometric dye Fura-2 AM, we used the 340/380 nm ratio to analyze alterations in calcium homeostasis after stimulation with caffeine and 4-chloro-m-cresol (4CmC). We calculated the half-maximal activation concentrations (EC50) of cells transfected with each mutant and compared the EC50 value of cells expressing each mutant with that of cells expressing wild-type RYR1. Statistical significance between EC50 values were calculated using an unpaired 2-tailed t test. We used 300 different cells, by 30 cells in each of the wild type or mutant. RESULTS: Cells transfected with each of the 4 mutants, p.Arg2508His, p.Arg2508Gly, p.Arg2508Ser, or p.Arg2508Lys, were more sensitive to caffeine and 4CmC than cells transfected with the wild type (all 4 P ⩽ 0.0004). Mean ± SD of EC50 values for caffeine of wild type, p.Arg2508His, p.Arg2508Gly, p.Arg2508Ser, and p.Arg2508Lys were 2.53 ± 0.89, 1.72 ± 0.72, 1.73 ± 0.79, 1.69 ± 0.80, and 1.61 ± 0.74 mM, respectively, and those for 4CmC were 125.92 ± 38.11, 70.42 ± 27.09, 79.30 ± 39.04, 73.03 ± 19.20, and 72.81 ± 28.44 mM, respectively. CONCLUSIONS: Any of these 4 mutations in RYR1 p.Arg2508 may cause important changes related to MH. Studying the effects of changes in amino acids at 2508 in RYR1 on the movement of this large protein may lead to a better understanding of the pathology of MH events.

A case of coronary artery spasm caused by manipulation of the neck: heart rate variability analysis

A 66-year-old man with no history of ischemic heart disease underwent cervical lymph node dissection. General anesthesia was induced and maintained with remifentanil, along with propofol. With manipulation of the neck and a subcutaneous injection of lidocaine supplemented with adrenaline before the operation, a sudden decrease in blood pressure (BP) and elevation of the ST-T segment appeared on the monitoring electrocardiogram (ECG). Ephedrine, phenylephrine, adrenaline, and nitroglycerin were administered; however, the hypotension was sustained and the ECG abnormalities progressed, along with further elevation of the ST-T segment and a complete atrioventricular block. Following an injection of atropine, the changes in ECG and BP were attenuated. Heart rate variability (HRV) was analyzed using fully recorded monitor variables, and revealed an increase in the high-frequency domain at the time of the cervical manipulation, suggesting simultaneous vagal stimulation and coronary artery spasm. We concluded that the cervical manipulation had increased the vagal tone and we note that HRV analysis was useful to interpret this coronary event.

Transient symptomatic worsening by atropine in opsoclonus-myoclonus syndrome

Opsoclonus–myoclonus syndrome (OMS) is characterized by abnormal eye and systemic involuntary movements, as well as cerebellar ataxia. Some sedatives and anesthetics worsen movements associated with OMS, while there is no known report of a negative effect of atropine. We report on sedation in two patients with OMS. Involuntary movements were transiently worsened after using atropine with midazolam or thiamylal in both, but were not seen when atropine was not used. We speculated that atropine has the potential to exacerbate involuntary movements in OMS due to vulnerability to this agent via unknown mechanisms.

A Case of Nephrogenic Diabetes Insipidus During Transsphenoidal Pituitary Adenomectomy.

Central diabetes insipidus (DI) is a known complication of pituitary surgery and the symptoms are improved by replenishing antidiuretic hormone (ADH). We treated a patient with DI that developed during the perioperative period which was not responsive to ADH administration. A 66-year-old woman underwent transsphenoidal adenomectomy for an adrenocorticotrophic hormone-producing pituitary tumor. She had bipolar depression, and was treated with clonazepam, chlorpromazine, and lithium carbonate. Polyuria was noted on the hospitalization, which was diagnosed as psychogenic because of polyposia. The patient’s oral intake was >3000mL/d with normal renal function, serum electrolytes, blood glucose, plasma osmotic pressure, and low urinary specific gravity. Before surgery, drinking was prohibited. Polyuria continued at 200 to 300mL/h, whereas the specific gravity of urine remained unchanged. Hypernatremia and hypokalaemia were found after the beginning of surgery (Na 159, K 2.6mmol/L). Although we gave 12U of vasopressin and changed bicarbonate Ringer solution to dextrose 5%, half normal saline with added potassium, hypernatremia, and hypokalaemia continued (Na 161, K 2.9mmol/L). Polyuria remained even though intranasal desmopressin was properly administered, and then disorientation occurred postoperatively. On postoperative day 1, polyuria continued and hypernatremia deteriorated (Na 164, K 3.2mmol/L). We suspected nephrogenic DI due to a side effect of lithium carbonate although the blood concentration of lithium was 0.35mEq/ L (normal range, <1.5mEq/L). Therefore, we administered thiazide diuretic trichlormethiazide in addition to nonsteroid anti-inflammatory drugs. Two hours after trichlormethiazide administration, urine volume decreased to 100mL/h and urine specific gravity increased, whereas hypernatremia improved to 152mmol/L. On postoperative day 2, trichlormethiazide was continued, and serum sodium was normalized to 137mmol/L (Fig. 1). Next in our differential diagnosis was psychogenic polydipsia, which was later excluded because urine volume did not decrease during fluid restriction, and there was no response to vasopressin. Finally, nephrogenic DI was diagnosed because urine volume decreased and hypernatremia promptly improved with administration of trichlormethiazide. Lithium carbonate is a well-known cause of nephrogenic DI.1 As the present patient had been taking lithium carbonate for a long period, it was regarded as the cause of nephrogenic DI. Thiazide diuretic1 and nonsteroid anti-inflammatory drugs have been reported as treatments for nephrogenic DI. Thiazide diuretic inhibits the NaCl cotransporter in the distal convoluted tubule and enhances sodium excretion in urine by suppression of sodium reabsorption, after which water and sodium reabsorption in the proximal convoluted tubule are promoted. As a

Abstract PR592: Precise Prediction of Right Atrium Position During Expiratory Phase of Thorax.

Background & Objectives: Central venous pressure (CVP) is routinely used as an indicator of hemodynamics in patients receiving surgery and intensive care. When measuring CVP in a supine position, it is necessary to adjust the location of the pressure transducer to the uppermost level of the right atrium (RA) for accurate measurement. This study was aimed to reveal the most appropriate prediction of the RA during expiratory phase by using inspiratory phase computed tomography (CT) images.

Abstract PR293: Association Between Age and Frequency of Side Effects Associated with Postoperative Analgesia

Background & Objectives: Although patient controlled analgesia (PCA) is a valid analgesic method, it is necessary to pay attention to associated side effects, especially in elderly cases. We have been using postoperative pain management with PCA while monitoring side effects over the past several years.1) In the present study, we examined the frequency of side effects associated with postoperative analgesia. In addition, the association between side effects and age was investigated to confirm whether these side effects are likely to occur only in the elderly patients.

Asystole following skull clamp to Chiari malformation.

To the Editor: Although several complications related to the use of a skull clamp have been reported, serious arrhythmia has not been reported. A 17-year-old woman with Arnold–Chiari malformation type I was scheduled for an operation for worsening of syringomyelia (Fig. S1). After induction of general anesthesia, the head was fixed with a Mayfield skull clamp (Ohio Medical Instrument, Cincinnati, OH, USA). Cardiac asystole occurred a few seconds after clamping, and then continued for about 10 s, followed by single electrical activity, even though the clamp was removed immediately. The heart rate spontaneously recovered to 30 beats per minute with escape rhythm, and then gradually increased to 60 beats per minute with sinus rhythm. After administration of atropine, the heart rate increased to 120 beats per minute with sinus rhythm, and hemodynamics became stable (Figs. S2, S3). The cardiac asystole was determined to be caused by vagal reflex due to the skull clamp because hemodynamics suddenly changed and recovered only after administration of atropine. We finally considered that either pinning stimulation to the peripheral trigeminal nerve [1] or direct compression of the herniated brainstem due to malformation [2] by clamp manipulation was the trigger provoking vagal reflex. We should understand the pathophysiology of Arnold– Chiari malformation and consider the use of atropine premedication for prevention of vagal reflex. When a skull clamp is applied for such patients, attention to electrocardiogram status is needed. Use of local anesthetic infiltration is also effective to prevent the trigeminal reflex. If asystole occurs, use of the skull clamp should be discontinued immediately, and administration of atropine may be useful.