Novel missense mutations and unexpected multiple changes of RYR1 gene in 75 malignant hyperthermia families.

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle characterized by disturbance of intracellular calcium homeostasis in the sarcoplasmic reticulum. Mutations of the ryanodine receptor 1 (RYR1) gene account for most cases, with some studies claiming up to 86% of mutations in this locus. However, RYR1 gene is large and variants are common even in the normal population. We examined 54 families with MH susceptibility and 21 diagnosed with equivocal MH. Thirty-five were selected for an anesthetic reaction, whereas the remainder for hyperCKemia. In these, we studied all 106 exons of the RYR1 gene. When no mutation was found, we also screened: sodium channel voltage-gated, type IV alpha subunit (SCN4A), calcium channel voltage-dependent, L type, alpha 1S subunit (CACNA1S), and L-type voltage-gated calcium channel alpha 2/delta-subunit (CACNL2A). Twenty-nine different RYR1 mutations were discovered in 40 families. Three other MH genes were tested in negative cases. Fourteen RYR1 amino acid changes were novel, of which 12 were located outside the mutational 'hot spots'. In two families, the known mutation p.R3903Q was also observed in malignant hyperthermia-nonsusceptible (MHN) individuals. Unexpectedly, four changes were also found in the same family and two in another. Our study confirms that MH is genetically heterogeneous and that a consistent number of cases are not due to RYR1 mutations. The discordance between in vitro contracture test status and the presence of a proven causative RYR1 mutation suggests that the penetrance may vary due to as yet unknown factors.

Postoperative pain treatment SIAARTI Recommendations 2010. Short version.

The aim of these recommendations is the revision of data published in 2002 in the "SIAARTI Recommendations for acute postoperative pain treatment". In this version, the SIAARTI Study Group for acute and chronic pain decided to grade evidence based on the "modified Delphi" method with 5 levels of recommendation strength. Analgesia is a fundamental right of the patient. The appropriate management of postoperative pain (POP) is known to significantly reduce perioperative morbidity, including the incidence of postoperative complications, hospital stay and costs, especially in high-risk patients (ASA III-V), those undergoing major surgery and those hospitalized in a critical unit (Level A). Therefore, the treatment of POP represents a high-priority institutional objective, as well as an integral part of the treatment plan for "perioperative disease", which includes analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A). In order to improve an ACUTE PAIN SERVICE organization, we recommend: --a plan for pain management that includes adequate preoperative evaluation, pain measurement, organization of existing resources, identification and training of involved personnel in order to assure multimodal analgesia, early mobilization, early enteral nutrition and active physiokinesitherapy (Level A); --the implementation of an Acute Pain Service, a multidisciplinary structure which includes an anesthetist (team coordinator), surgeons, nurses, physiotherapists and eventually other specialists; --referring to high-quality indicators in establishing an APS and considering the following key points in its organization (Level C): --service adoption; --identifying a referring anesthetist who is on call 24 hours a day; --patient care during the night and weekend; --sharing, drafting and updating written therapeutic protocols; --continuous medical education; --systematic pain assessment; --data collection regarding the efficacy and safety of the implemented protocols; --at least one audit per year. --a preoperative evaluation, including all the necessary information for the management of postoperative analgesia (Level C); --to adequately inform the patient about the risks and benefits of drugs and procedures used to obtain the maximum efficacy from the administered treatments (Level D). We describe pharmacological and loco-regional techniques with special attention to day surgery and difficult populations. Risk management pathways must be the reference for early identification and treatment of adverse events and chronic pain development.

Efficacy of treatment with percutaneous vertebroplasty and kyphoplasty for traumatic fracture of thoracolumbar junction.

AIM: The aim of this paper was to assess the efficacy of a minimally invasive treatment with percutaneous vertebroplasty and kyphoplasty for traumatic fracture of thoracolumbar junction. Treatment of stable traumatic vertebral fractures of the thoracolumbar junction without neurological deficit is still controversy. Conservative treatment, characterized by discomfort and limitation in patient mobility, was progressively replaced by minimally invasive techniques such as percutaneous vertebroplasty and kyphoplasty. METHODS: Between January 2003 and August 2005, 34 patients suffering from 42 thoracolumbar fractures were treated at Neurosurgical Department of Istituto Galeazzi (Milan). The treatment selected (vertebroplasty versus kyphoplasty), depended on age of patients, timing and type of fracture. Results were clinically assessed by Visual Analogue Score (VAS) and Oswestry Disability Index. RESULTS: Mean preoperative VAS was 8.32 (range 5-10). Percutaneous vertebroplasty was performed in 25 cases (73.5%); while 9 patients were treated by kyphoplasty (27.5%); 27 patients showed a single level and 7 multilevel of the fractures. No complications occurred (infection, neurological deficit, embolic events) after treatment. At the early follow-up 91.7% of the patients achieved a good pain control already after 24 hours. Pain relief and disability, analyzed by VAS and Oswestry Disability Index, showed a good results at late follow-up time. CONCLUSIONS: Percutaneous vertebroplasty and kyphoplasty are two safe and effective techniques for treatment of thoracolumbar traumatic fractures and allow a good pain-control and return to normal working activity and social life.

Follow-up of patients tested for malignant hyperthermia susceptibility.

BACKGROUND AND OBJECTIVE: Malignant hyperthermia is an inherited disorder of skeletal muscle characterized by muscle contracture and hypermetabolic crisis following exposure to halogenated anaesthetics and depolarizing muscle relaxants. We planned this follow-up to get more information about the safety of non-triggering anaesthesia in susceptible patients; the safety of the use of trigger agents in non-susceptible patients and any minor sequelae following the biopsy. METHODS: A questionnaire was sent to 244 patients tested for susceptibility between 1998 and 2004 enquiring about sequelae from the biopsy, subsequent experience with anaesthesia and difficulties encountered because of the investigation. RESULTS: Replies were received from 129 patients. Thirty-four complained about sequelae from the biopsy: 10 reported headache and nausea; 16 experienced pain and a lack of strength in the biopsed leg and 8 found the scar less than satisfactory. Ten patients found it difficult to find a diagnostic centre. Eighteen reported problems and/or delay when they had needed a subsequent anaesthetic. Fourteen patients found the anaesthesiologist reluctant to anaesthetize them and four experienced a delay. Forty-three patients received anaesthesia since their biopsy. Complete medical records were available for 24 anaesthetic exposures in 23 patients. No documented perioperative complications occurred. Only three non-susceptible patients received one trigger agent. CONCLUSIONS: It is safe to use trigger-free anaesthesia in susceptible patients. The difficulties encountered by patients to be anaesthetized and the management of the majority of non-susceptible patients during general anaesthesia show the need of more accurate educational programmes and methods for promoting patient-centred care.

Monitored anesthesia care and loco-regional anesthesia. Vascular surgery use.

Association of locoregional techniques such as deep and superficial cervical block, lumbar epidural and/or peripheral blocks, and conscious sedation with hypnotic drugs (propofol 1-3 mg/kg/h or midazolam 2-4 mg/h) and/or opiates drugs (sufentanil 5-10 mcg or remifentanil 0.05-0.1 mcg/kg/min) is actually, the gold standard for vascular surgery. Our personal experience is based on 328 patients submitted to carotid endarterectomy, aneurysm repair and peripheral surgery.

Sufentanil: an overview of its use for acute pain management.

UNLABELLED: The knowledge of pharmacodynamics and pharmacokinetics of new opioid drugs is necessary so that anaesthesiologists can choose which one to use, considering the patient's pathophysiology, the surgical procedure, and the dose required to obtain the desired effect. Aim of this review was to evaluate relevant trials on perioperative sufentanil in order to design an optimal strategy for administration. METHODS: Randomised controlled trials on perioperative sufentanil analgesia were identified by Medline research, Embase, Biosis, Scisearch and references mentioned in relevant reviews were hand searched from 1988 to June 2001. RESULTS: Twenty-four trials were considered eligible; they were divided according to the use of sufentanil in abdominal surgery, paediatric surgery and other types of surgery (orthopaedic, maxillo-facial, thoracotomy, lithotripsy, etc.). It was possible to compare the use of iv and epidural sufentanil, in iv PCA and PCEA, in continuous infusion, alone or in combination with local anaesthetics (various concentrations of ropivacaine, bupivacaine), with clonidine, adrenaline and ketamine. CONCLUSIONS: Efficacy of sufentanil in perioperative epidural or intravenous analgesia resulted the same or better than other drugs used commonly despite context-sensible half-life advantages. Its association with local anaesthetics or adjuvant drugs prolongs its action and sometimes decreases the side effects. From the examined trials results that sufentanil can be used at very low doses and its association with local anaesthetics, clonidine, ketamine, and adrenaline by epidural, intravenous or intrathecal route for perioperative analgesia (intra and postoperative) and by various types of administration (PCA, PCEA, fixed intervals doses, continuous infusion, etc.).

[Systemic review of trials on the use of tramadol in the treatment of acute and chronic pain]. / Revisione sistematica dei trials sull'impiego del tramadolo nel trattamento del dolore acuto e cronico.

BACKGROUND: The purpose of the study was to verify the effectiveness of tramadol in the treatment of non-oncologic chronic pain, oncologic chronic pain and postoperative acute pain, applying the principles of meta-analytic analysis to randomized clinical trials (TCR). METHODS: I: Medline research of the TCR on the question in the period between 1989-1999, II: exclusion of single TCR through the question of Moore and Mcquay; calculation of the relative risk reduction (RRR), of the number needed to treat (NNT), of the odds ratio (OR) and of the typical odds ratio (TOR) of the trials which responded to characteristics of correct randomization and blindness, which expressed citation of the patients excluded from trial, and patients with measurable analgesic effectiveness (number of patients with reduction of the pain intensity 50%). RESULTS: 52 trials extracted from Medline: 10 on the treatment of non-oncologic chronic pain, 36 on the treatment of postoperative acute pain and 6 on the treatment of oncologic chronic pain. Responded fully to requirements: 8 studies (3 for non-oncologic chronic pain, 3 for postoperative acute pain and 2 for oncologic pain). The OR was 0.55 (-0.31/1.41); 0.44 (1.04/1.92) and 0.98 (0.5/1.46); the RRR was 0.26 (-0.19/0.71), 0.38 (0.15/0.61), 0.005 (0.19/0.20) and the NNT 6.6 (6.39/6.81), 5.26 (5.12/5.4), infinity in the 3 trials selected between those that concern the treatment of the nononcologic chronic pain (with TOR: 0.57 and confidence index: 0.23-0.9); the OR was 0.36 (1.06/1.78), 0.78 (-0.08/-1.64) and 1.12 (0.54/1.69); the RRR was 0.26 (-0.18/0.7), 0.07 (-0.2/0.35), -0.01 (-0.09/0.07) and the NNT 4.7 (4.42/4.58), 20 (19.8/20.20), infinity in the trials on the treatment of postoperative acute pain (with TOR: 0.4 and confidence index: -0.6-0.86); the OR was 0.53 (-0.67/1.73), 0.27 (-0.71/1.12); the RRR was 0.19 (-0.33/0.72), 0.35 (0.02/0.68) and the NNT 7.1 (6.78/7.42), 3.57 (3.37/3.76) in those that involved the treatment of oncologic chronic pain (with TOR: 0.49 and confidence index: 0.36-0.8). CONCLUSIONS: Although the short number of trials which can treated by the metanalytic technique the treatment with tramadol, compared comparison's to drugs (morphine, pentazocine, bupremorphine, etc.) determined a slight improvement in analgesic parameters or at least in analgesic effectiveness.

Peri-operative prophylaxis with phenytoin: dosage and therapeutic plasma levels.

Early postoperative epilepsy is a frequent complication of supratentorial intracranial surgery. The lack of consensus on prophylaxis of early postoperative seizures with phenytoin (PHT) may be due to the different dosages used in several studies, owing to inadequate therapeutic plasma level. The aim of this study was to evaluate which dosage of PHT can maintain the therapeutic range in the early postoperative period. Twenty patients operated on for supratentorial neoplasms were randomly allocated to receive, during the last hour of the surgical procedure, loading doses of either 10 mg/kg (group A, n = 10) or 15 mg/kg (group B, n = 10) of PHT. PHT infusion rate never exceeded 30 mg/min. Six hours after the loading dose, PHT maintenance treatment (250 mg, i.v., every 8 hours) was started in all patients. PHT plasma levels were evaluated from the end of the intra-operative loading infusion up to 24 h. During the first six hours after the loading dose, phenytoin plasma levels fell below the therapeutic range (10-20 mg/l) in 7 out of the 10 patients receiving 10 mg/kg, while in the patients treated with 15 mg/kg, PHT plasma levels were always in the therapeutic range (P < or = 0.0001). PHT maintenance dose was sufficient to keep plasma levels within the therapeutic range in 8 patients in group A, and in all the patients in group B. It is concluded that a loading dose of 15 mg/kg, followed by postoperative treatment, is necessary to guarantee therapeutic plasma levels of phenytoin in the immediate postoperative period, when seizure risk is very high.

[Risk of postoperative epilepsy in acute surgery of cerebral aneurysms]. / Rischio di epilessia post-operatoria nella chirurgia acuta degli aneurismi cerebrali.

Forty-nine patients operated during an early clipping phase of cerebral aneurysm were reviewed; none had an associated ventricular flooding and/or intraparenchymal hematoma. Starting from the day of operation 37 patients were treated with anticonvulsant drugs using methods and dosages where were unlikely to guarantee efficacious cover. Forty-two patients made a satisfactory recovery, 5 patients died and 2 had severe neurological sequelae; 2 patients (4.4%) had early seizures during the first week after operation. In view of the inadequate cover of the anticonvulsant drugs and the homogeneous clinical characteristics of patients included in the study, the low number of attacks suggests an overall re-evaluation of anticonvulsant treatment and the need to select patients with a higher risk of an epileptic attack.

[Early epilepsy in surgery of extra-axial supratentorial neoplasms]. / Epilessia precoce nella chirurgia delle neoplasie extra-assiali sopratentoriali.

A retrospective study was performed to evaluate the incidence of seizure and anticonvulsant prophylaxis in 138 patients operated from september 1987 to august 1989 for extra-axial supratentorial tumors. 15 patients (10.9%) developed seizures in the early post-operative period. We have considered the importance of histological type and side of lesions, a previous history of epilepsy and the pre and intraoperative prophylaxis. We can say that there is a statistical significance between sellar and middle cranial fossa tumors and the frequency of post-operative epilepsy and that anticonvulsant prophylaxis can reduce post-operative seizure. There is no statistical significance between the previous history of epilepsy the type of anesthesia and post-operative seizure.