Intravenous dantrolene in hypermetabolic syndromes: a survey of the U.S. Veterans Health Administration database.

BACKGROUND: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings. METHODS: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons. RESULTS: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene. CONCLUSIONS: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 2 Safety: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, a public-private partnership with the US Food and Drug Administration, convened a second meeting of sedation experts from a variety of clinical specialties and research backgrounds to develop recommendations for procedural sedation research. The previous meeting addressed efficacy and patient- and/or family-centered outcomes. This meeting addressed issues of safety, which was defined as "the avoidance of physical or psychological harm." A literature review identified 133 articles addressing safety measures in procedural sedation clinical trials. After basic reporting of vital signs, the most commonly measured safety parameter was oxygen saturation. Adverse events were inconsistently defined throughout the studies. Only 6 of the 133 studies used a previously validated measure of safety. The meeting identified methodological problems associated with measuring infrequent adverse events. With a consensus discussion, a set of core and supplemental measures were recommended to code for safety in future procedural clinical trials. When adopted, these measures should improve the integration of safety data across studies and facilitate comparisons in systematic reviews and meta-analyses.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

Malignant hyperthermia: human stress triggering.

Letter to the Editor concerns the question of a discussion of awake porcine malignant hyperthermia that erroneously omits the awake human stress reaction of malignant hyperthermia.

Jumpstarting Academic Careers: A Workshop and Tools for Career Development in Anesthesiology.

CONTEXT: Career development is essential and has the potential to assist in building a sustained faculty within academic departments of Anesthesiology. Career development is essential for growth in academic medicine. Close attention to the details involved in career management, goal setting as part of career planning, and professional networking are key elements. METHODS: This article examines the specific educational strategies involved in a 120 minute workshop divided into four 25 minute segments with 20 minutes at the end for discussion for training junior faculty in career development. The teaching methods include 1) brief didactic presentations, 2) pre-workshop completion of two professional development tools, 3) facilitated small group discussion using trained facilitators and 4) use of a commitment to change format. Three major learning tools were utilized in conjunction with the above methods: a professional network survey, a career planning and development form and a commitment to change form. RESULTS: Forty one participants from 2009 reported 80 projected changes in their practice behaviors in relation to career management: Build or enhance professional network and professional mentoring (36.3%); Set career goals, make a plan, follow though, collaborate, publish (35.1%); Increase visibility locally or nationally (10.0%); Building core skills, such as clinical, teaching, leading (36.3%); Identify the criteria for promotion in own institution (5.0%); Improved methods of documentation (2.5%). Over the past two years, the workshop has been very well received by junior faculty, with over 95% marking each of the following items as excellent or good (presentation, content, audiovisuals and objectives met). CONCLUSIONS: The challenge for continuing development and promotion of academic anesthesiologists lies in the explicit training of faculty for career advancement. Designing workshops using educational tools to promote a reflective process of the faculty member is the one method to meet this challenge. We believe that this national workshop has initiated an increasing awareness of a core of junior faculty nationally having now delivered the material to almost 200 junior faculty and having trained seven facilitators in the usage of these materials.

Use of pharmaceuticals 'off-label' in the neonate.

Neonates are frequently not studied in the development of a novel pharmacological agent. With lack of data to support safe and effective use of a new agent in this population, sponsors will not receive approval for labelling the agent for use in this age group from the United States Food and Drug Administration (USFDA). This causes a significant conundrum for the clinician. Neonates are often precluded the benefits of new pharmaceuticals until investigators begin to report their clinical experience with novel agents. This article provides the clinician with an introductory understanding of the approval process of pharmaceuticals in the United States by USFDA. Models of clinical trial design are noted. Examples of anaesthetic and non-anaesthetic agents and their development and use are discussed as either 'labelled' or 'off-label' indications.

Neuroprotective effects of estrogen therapy for cognitive and neurobiological profiles of monkey models of menopause.

Many postmenopausal women question whether to start or continue hormone therapy because of recent clinical trial negative results. However, evidence from other studies of postmenopausal women, and from studies in menopausal monkeys, indicate that estrogen has neurocognitive protective effects, particularly when therapy is initiated close to the time of menopause before neural systems become increasingly compromised with age. In this review, we present studies of menopausal women and female monkeys that support the concept that estrogen therapies protect both cognitive function and neurobiological processes.

Effects of two years of conjugated equine estrogens on cholinergic neurons in young and middle-aged ovariectomized monkeys.

The effect of estrogen on the number and size of cholinergic neurons in the basal forebrain was examined in surgically menopausal young and middle-aged cynomolgus monkeys. Young and middle-aged female monkeys were ovariectomized and treated with conjugated equine estrogens (Premarin) at doses that are equivalent to those currently prescribed to postmenopausal women. In the medial septum/diagonal band (MS/DB), no effect of treatment with Premarin was observed in the cholinergic neurons in either ovariectomized young or middle-aged monkeys. However, the number and size of cholinergic neurons in the MS/DB of middle-aged monkeys was greater than that in the young monkeys. In the nucleus basalis of Meynert (NBM) of middle-aged monkeys, the number of cholinergic neurons in the intermediate region (Ch4i) was greater in Premarin-treated monkeys as compared to controls and numbers of neurons in this region were greater at higher levels of estrogen. No effects of estrogen were observed in other NBM regions in the middle-aged monkeys and the size of cholinergic neurons was unaffected by Premarin. These findings suggest that treatment with Premarin has selective beneficial effects on cholinergic neurons in the basal forebrain but that these effects are both age and region specific.

Developing consensus on appropriate standards of disaster care for children.

BACKGROUND: Neither professional consensus nor evidence exists to guide the choice of essential hospital disaster interventions. The objective of our study was to demonstrate a method for developing consensus on hospital disaster interventions that should be regarded as essential, quantitatively balancing needs and resources. METHODS: A panel of pediatric acute care practitioners developed consensus using a modified Delphi process. Interventions were chosen such that workload per staff member would not exceed the previously validated maximum according to the Therapeutic Intervention Scoring System. Based on published models, it was assumed that the usual numbers of staff would care for a disaster surge of 4 times the usual number of intensive care and non-intensive care hospital patients. RESULTS: Using a single set of assumptions on constrained resources and overwhelming needs, the panel ranked and agreed on essential interventions. A number of standard interventions would exceed crisis workload constraints, including detailed recording of vital signs and fluid balance, administration of vasoactive agents, invasive monitoring of pressures (central venous, intraarterial, intracranial), dialysis, and tube feedings. CONCLUSIONS: The quantitative methodology and consensus development process described in the present report may have utility in future planning. Groups with appropriate expertise must develop action plans according to authority within each jurisdiction, addressing likely disaster scenarios, according to the needs in each medical service region, using available regional resources, and accounting for the capabilities of each institution.

Postoperative malignant hyperthermia: an analysis of cases from the North American Malignant Hyperthermia Registry.

BACKGROUND: The initial presentation of malignant hyperthermia (MH) may begin in the postoperative period. However, the maximal latency period between the end of anesthesia care and the onset of postoperative MH is unknown. The authors hypothesized that this latency period is short and is not manifested by hyperthermia as the initial presenting sign. The authors sought to test this hypothesis and to describe the clinical characteristics of postoperative MH by analysis of suspected cases in the North American Malignant Hyperthermia Registry. METHODS: Of 528 possible or suspected cases of MH in the North American Malignant Hyperthermia Registry, the authors identified 64 possible reports of postoperative MH. The records were reviewed in detail by the authors, each of whom assigned a qualitative score of "likely," "not likely," "not enough information available," or "not applicable" (where MH was not the final definitive diagnosis). Postoperative MH was confirmed after a consensus meeting of the three senior authors who reviewed in detail all possible "likely" cases. RESULTS: The authors identified postoperative MH in 10 subjects. All received volatile agents and 5 also received succinylcholine. All demonstrated signs characteristic of acute MH, including generalized rigidity, hypercapnia and/or tachypnea, tachycardia, and hyperthermia. No subject demonstrated hyperthermia as the presenting sign. The latency period between the anesthesia finish time and the onset of a sign indicative of acute MH ranged from 0 to 40 min. CONCLUSIONS: Postoperative MH is uncommon, occurring in 10 of 528 suspected MH cases (1.9%) reported to the North American Malignant Hyperthermia Registry. Postoperative MH began shortly after completion of the anesthetic care. Hyperthermia was not a presenting sign of MH.

Pharmacokinetics And Pharmacodynamics Of Fenoldopam Mesylate For Blood Pressure Control In Pediatric Patients.

BACKGROUND: Fenoldopam mesylate, a selective dopamine1-receptor agonist, is used by intravenous infusion to treat hypertension in adults. Fenoldopam is not approved by the FDA for use in children; reports describing its use in pediatrics are limited. In a multi-institutional, placebo controlled, double-blind, multi-dose trial we determined the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and side-effect profile of fenoldopam in children. METHODS: Seventy seven (77) children from 3 weeks to 12 years of age scheduled for surgery in which deliberate hypotension would be induced were enrolled. Patients were randomly assigned to one of five, blinded treatment groups (placebo or fenoldopam 0.05, 0.2, 0.8, or 3.2 mcg/kg/min iv) for a 30-minute interval after stabilization of anesthesia and placement of vascular catheters. Following the 30-minute blinded interval, investigators adjusted the fenoldopam dose to achieve a target mean arterial pressure in the open-label period until deliberate hypotension was no longer indicated (e.g., muscle-layer closure). Mean arterial pressure and heart rate were continuously monitored and were the primary endpoints. RESULTS: Seventy-six children completed the trial. Fenoldopam at doses of 0.8 and 3.2 mcg/kg/min significantly reduced blood pressure (p < 0.05) during the blinded interval, and doses of 1.0-1.2 mcg/kg/min resulted in continued control of blood pressure during the open-label interval. Doses greater than 1.2 mcg/kg/min during the open-label period resulted in increasing heart rate without additional reduction in blood pressure. Fenoldopam was well-tolerated; side effects occurred in a minority of patients. The PK/PD relationship of fenoldopam in children was determined. CONCLUSION: Fenoldopam is a rapid-acting, effective agent for intravenous control of blood pressure in children. The effective dose range is significantly higher in children undergoing anesthesia and surgery (0.8-1.2 mcg/kg/min) than as labeled for adults (0.05-0.3 mcg/kg/min). The PK and side-effect profiles for children and adults are similar.

Spinal nerve ligation increases alpha2-adrenergic receptor G-protein coupling in the spinal cord.

Intrathecal and epidural administration of the alpha2-adrenergic receptor agonist clonidine in humans results in analgesia to both acute nociceptive and chronic neuropathic pain. The potency of clonidine increases with hypersensitivity to mechanical stimuli after nerve injury, although the reasons for this change are unknown. In the present study, we tested the hypothesis that peripheral nerve injury alters either spinal alpha2-adrenergic receptor-mediated G-protein activity or alpha2-adrenergic receptor number. Rats were randomized to left spinal nerve ligation (SNL) or sham surgery. Tactile hypersensitivity in the hindpaw was confirmed and lumbar spinal cords were removed for binding assays. To examine agonist-induced G-protein coupling, [35S]GTP gamma S binding experiments were performed in spinal cord membranes and sections using norepinephrine as an alpha2-adrenergic agonist. SNL was associated with an increase in maximal efficacy, but not potency, of norepinephrine-stimulated [35S]GTP gamma S binding in dorsal horn. SNL had no effect on basal [35S]GTP gamma S binding or on muscarinic cholinergic-stimulated [35S]GTP gamma S binding. [35S]GTP gamma S autoradiography showed that this increase in alpha2-adrenergic-activated G-proteins occurred both ipsilateral and contralateral to SNL surgery. SNL did not alter total alpha2-adrenergic receptor number or affinity to [3H]-rauwolscine binding, and displacement studies with the alpha2A-adrenergic antagonist BRL44408 revealed that most of the binding was associated with the alpha2A-adrenergic subtype. These data suggest that the increased potency of clonidine in neuropathic pain could reflect increased efficiency of G-protein coupling from spinal alpha2-adrenergic receptors.

Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population.

BACKGROUND: Malignant hyperthermia (MH) is a life-threatening and frequently fatal disorder triggered by commonly used anesthetics. MH susceptibility is a genetically determined predisposition to the development of MH. Mutations in the ryanodine receptor type 1 (RYR1) gene are the major cause of MH susceptibility. The authors sought to develop a reliable genetic screening strategy based on efficient and relatively inexpensive mutation-detection procedures. METHODS: A cohort (n = 30) of North American MH patients and MH-susceptible individuals was studied. RNA and DNA extracted from muscle tissue or blood lymphocytes were used for analysis. The entire RYR1 coding region was amplified in 57 overlapping fragments and subjected to denaturing high-performance liquid chromatography analysis followed by direct nucleotide sequencing to characterize RYR1 alterations. RESULTS: Nine previously reported and nine unknown RYR1 mutations were identified in 21 of 30 studied patients (70%). Some of the new mutations were located outside of known mutational "hot spots," suggesting that RYR1 contains previously unknown mutation-prone areas requiring analysis. The North American MH/MH-susceptible population is characterized by a high RYR1 allelic heterogeneity. CONCLUSIONS: Denaturing high-performance liquid chromatography analysis of RNA samples extracted from the biopsied skeletal muscle followed by DNA sequencing is a highly efficient methodology for RYR1 mutation detection. This approach allows increasing the rate of mutation detection to 70% and identifying mutations in the entire RYR1 coding region.

Preoperative sciatic nerve block decreases mechanical allodynia more in young rats: is preemptive analgesia developmentally modulated?

Postoperative sensitivity to tactile stimuli differs as a function of age. In this study, we hypothesized that preoperative sciatic nerve block (SNB), by providing preemptive analgesia, would result in better analgesia than postoperative SNB in the young rat. With the paw incision model of postoperative pain, male Sprague-Dawley rats, aged 2 or 4 wk, underwent general anesthesia and then received a left SNB with 5 microL/g of 0.5% bupivacaine or normal saline. SNB was performed either before or after surgery. Mechanical allodynia was assessed by using von Frey filaments before and at various times after SNB and surgery. In the 2-wk-old rats, preoperative SNB produced a significant reduction in mechanical allodynia, as reflected by a higher threshold at 2, 5, and 24 h when compared with saline control (P < 0.03). At 24 h, the threshold was 4.0 +/- 0.7 g in the preoperative SNB group compared with 1.6 +/- 0.3 g in the postoperative SNB group (P = 0.004). There was no difference at any time point between the preoperative and the postoperative SNB in the 4-wk-old animals. These results suggest that preoperative SNB in young animals provides a preemptive analgesic effect on mechanical allodynia that is age or developmentally dependent.

Cavernous sinus thrombosis complicating sinusitis.

BACKGROUND: Septic cavernous sinus thrombosis is a rare complication of paranasal sinusitis. OBJECTIVE: To familiarize the clinician with the pathogenesis, diagnosis, and appropriate management of septic cavernous sinus thrombosis. DESIGN: Case report and literature review. SETTING: Pediatric intensive care unit in a university hospital. PATIENT: We present a 12-yr-old female with a 1 wk history of an upper respiratory tract infection with worsening dyspnea, cough, and swelling of the left eye progressing to adult respiratory distress syndrome. Secondary to the need for significant mechanical ventilatory support, venovenous extracorporeal membrane oxygenation was initiated. Computed tomography scan of the head and neck with contrast revealed bilateral cavernous sinus thrombosis. After broad-spectrum intravenous antibiotics and aggressive supportive care in conjunction with surgical intervention (maxillary sinus lavage and right orbital exploration) and anticoagulation therapy, the patient recovered. Blood cultures were positive for Viridans streptococcus. At discharge 3 wks later, the patient had improved, but had right-eye blindness. CONCLUSIONS: The diagnosis of septic cavernous sinus thrombosis requires a high index of suspicion and confirmation by imaging; early diagnosis and surgical drainage of the underlying primary source of infection in conjunction with long-term intravenous antibiotic therapy are critical for an optimal clinical outcome.