Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study

Abstract Introduction Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. Objective To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. Methods We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). Results Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). Conclusions Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

Predictive factors of the contracture test for diagnosing malignant hyperthermia in a Brazilian population sample: a retrospective observational study.

INTRODUCTION: Malignant Hyperthermia (MH) is a pharmacogenetic, hereditary and autosomal dominant syndrome triggered by halogenates/succinylcholine. The In Vitro Contracture Test (IVCT) is the gold standard diagnostic test for MH, and it evaluates abnormal skeletal muscle reactions of susceptible individuals (earlier/greater contracture) when exposed to caffeine/halothane. MH susceptibility episodes and IVCT seem to be related to individual features. OBJECTIVE: To assess variables that correlate with IVCT in Brazilian patients referred for MH investigation due to a history of personal/family MH. METHODS: We examined IVCTs of 80 patients investigated for MH between 2004‒2019. We recorded clinical data (age, sex, presence of muscle weakness or myopathy with muscle biopsy showing cores, genetic evaluation, IVCT result) and IVCT features (initial and final maximum contraction, caffeine/halothane concentration triggering contracture of 0.2g, contracture at caffeine concentration of 2 and 32 mmoL and at 2% halothane, and contraction after 100 Hz stimulation). RESULTS: Mean age of the sample was 35±13.3 years, and most of the subjects were female (n=43 or 54%) and MH susceptible (60%). Of the 20 subjects undergoing genetic investigation, 65% showed variants in RYR1/CACNA1S genes. We found no difference between the positive and negative IVCT groups regarding age, sex, number of probands, presence of muscle weakness or myopathy with muscle biopsy showing cores. Regression analysis revealed that the best predictors of positive IVCT were male sex (+12%), absence of muscle weakness (+20%), and personal MH background (+17%). CONCLUSIONS: Positive IVCT results have been correlated to male probands, in accordance with early publications. Furthermore, normal muscle strength has been confirmed as a significant predictor of positive IVCT while investigating suspected MH cases.

Impact of a digital manual for guidance on malignant hyperthermia: patient education.

BACKGROUND: Malignant hyperthermia (MH) is a rare, hereditary disease with a hypermetabolic response to volatile anesthetics/succinylcholine. Susceptible patients face difficulties due to a lack of knowledge about MH. As informational materials could increase knowledge and adherence to prevention/therapy, digital information about rare diseases validated for patients is needed. Our objective was to evaluate the following: (1) the impact of digital manuals on the knowledge/quality of life of MH patients and (2) access to MH services. MATERIALS AND METHODS: Fifty MH-susceptible patients filled out a virtual questionnaire twice (demographic/economic/clinical data, MH knowledge and impact on daily life, and SF-36 quality of life). Test groups 1 (n = 17) and 2 (n = 16) were evaluated 30 and 180 days after receiving a digital manual, and the control group (n = 17; without manual) was evaluated after 180 days. We collected the MH service data about the number of contacts. RESULTS: Twenty-four (48%) patients reported problems in personal/professional life, sports, clinical/surgical/dental treatments, and military service, in addition to concerns about emergency care and complaints of sequelae. The percentage of correct answers in the second MH knowledge questionnaire increased for test group 2 (62% vs. 74.1%; unpaired t test, p < 0.01), was significantly greater in test groups 1 (68.1%) and 2 (74.1%) than in the control group (56.5%; Kruskal-Wallis, p < 0.05), and correlated with more time studying the manual and reports of MH-related problems (multiple regression, p < 0.05). CONCLUSIONS: The digital manual improved patients' MH knowledge. Online contacts with the MH service increased, allowing greater information dissemination. As informational materials could increase knowledge/adherence to prevention/therapy, digital information about MH validated for patients should be implemented.

Implementation of sepsis bundles in public hospitals in Brazil: a prospective study with heterogeneous results.

BACKGROUND: Public hospitals in emerging countries pose a challenge to quality improvement initiatives in sepsis. Our objective was to evaluate the results of a quality improvement initiative in sepsis in a network of public institutions and to assess potential differences between institutions that did or did not achieve a reduction in mortality. METHODS: We conducted a prospective study of patients with sepsis or septic shock. We collected baseline data on compliance with the Surviving Sepsis Campaign 6-h bundles and mortality. Afterward, we initiated a multifaceted quality improvement initiative for patients with sepsis or septic shock in all hospital sectors. The primary outcome was hospital mortality over time. The secondary outcomes were the time to sepsis diagnosis and compliance with the entire 6-h bundles throughout the intervention. We defined successful institutions as those where the mortality rates decreased significantly over time, using a logistic regression model. We analyzed differences over time in the secondary outcomes by comparing the successful institutions with the nonsuccessful ones. We assessed the predictors of in-hospital mortality using logistic regression models. All tests were two-sided, and a p value less than 0.05 indicated statistical significance. RESULTS: We included 3435 patients from the emergency departments (50.7%), wards (34.1%), and intensive care units (15.2%) of 9 institutions. Throughout the intervention, there was an overall reduction in the risk of death, in the proportion of septic shock, and the time to sepsis diagnosis, as well as an improvement in compliance with the 6-h bundle. The time to sepsis diagnosis, but not the compliance with bundles, was associated with a reduction in the risk of death. However, there was a significant reduction in mortality in only two institutions. The reduction in the time to sepsis diagnosis was greater in the successful institutions. By contrast, the nonsuccessful sites had a greater increase in compliance with the 6-h bundle. CONCLUSIONS: Quality improvement initiatives reduced sepsis mortality in public Brazilian institutions, although not in all of them. Early recognition seems to be a more relevant factor than compliance with the 6-h bundle.

Intrathecal sufentanil for coronary artery bypass grafting.

CONTEXT: Cardiac surgery patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. OBJECTIVE: Evaluate the effect of adding intrathecal sufentanil to general anesthesia on hemodynamics. DESIGN: Prospective, randomized, not blinded study, after approval by local ethics in Research Committee. SETTING: Monocentric study performed at Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil. PATIENTS: 40 consenting patients undergoing elective coronary artery bypass, both genders. EXCLUSION CRITERIA: Chronic kidney disease; emergency procedures; reoperations; contraindication to spinal block; left ventricular ejection fraction less than 40%; body mass index above 32kg/m(2) and use of nitroglycerin. INTERVENTIONS: Patients were randomly assigned to receive intrathecal sufentanil 1µg/kg or not. Anesthesia induced and maintained with sevoflurane and continuous infusion of remifentanil. MAIN OUTCOME MEASURES: Hemodynamic variables, blood levels of cardiac troponin I, B-type natriuretic peptide, interleukin-6 and tumor necrosis factor alfa during and after surgery. RESULTS: Patients in sufentanil group required less inotropic support with dopamine when compared to control group (9.5% vs 58%, p=0.001) and less increases in remifentanil doses (62% vs 100%, p=0.004). Hemodynamic data at eight different time points and biochemical data showed no differences between groups. CONCLUSIONS: Patients receiving intrathecal sufentanil have more hemodynamical stability, as suggested by the reduced inotropic support and fewer adjustments in intravenous opioid doses.

Malignant hyperthermia in Brazil: analysis of hotline activity in 2009.

BACKGROUND AND OBJECTIVES: Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in São Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009. METHODS: Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009. RESULTS: Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In five episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isoflurane; 3, sevoflurane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the five MH episodes were tachycardia (5), increased expired carbon dioxide (4), hyperthermia (3), acidemia (1), rhabdomyolysis (1), and myoglobinuria (1). One patient received dantrolene. All five patients with MH episodes were follow-up in the intensive care unit and recovered without sequelae. Susceptibility to MH was later confirmed in two patients by in vitro muscle contracture test. CONCLUSIONS: The number of calls per year in the Brazilian hotline service for MH is still low. The characteristics of MH episode were similar to those reported in other countries. The knowledge of MH in Brazil needs to be increased.

Update on cardiopulmonary resuscitation guidelines of interest to anesthesiologists.

BACKGROUND AND OBJECTIVES: The new cardiopulmonary resuscitation (CPR) guidelines emphasize the importance of high-quality chest compressions and modify some routines. The objective of this report was to review the main changes in resuscitation practiced by anesthesiologists. CONTENTS: The emphasis on high-quality chest compressions with adequate rate and depth allowing full recoil of the chest and with minimal interruptions is highlighted in this update. One should not take more than ten seconds checking the pulse before starting CPR. The universal relationship of 30:2 is maintained, modifying its order, initiating with chest compressions, followed by airways and breathing (C-A-B instead of A-B-C). The procedure "look, listen, and feel whether the patient is breathing" was removed from the algorithm, and the use of cricoid pressure during ventilations is not recommended any more. The rate of chest compressions was changed for at least one hundred per minute instead of approximately one hundred per minute, and its depth in adults was changed to 5 cm instead of the prior recommendation of 4 to 5 cm. The single shock is maintained, and it should be of 120 to 200 J when it is biphasic; and 360 J when it is monophasic. In advanced cardiac life support, the use of capnography and capnometry to confirm intubation and monitoring the quality of CPR is a formal recommendation. Atropine is no longer recommended for routine use in the treatment of pulseless electrical activity or asystole. CONCLUSIONS: Updating the phases of the new CPR guidelines is important, and continuous learning is recommended. This will improve the quality of resuscitation and survival of patients in cardiac arrest.

Effects of prophylactic continuous infusion of phenylephrine on reducing the mass of local anesthetic in patients undergoing spinal anesthesia for cesarean section.

BACKGROUND AND OBJECTIVES: Reducing the mass of local anesthetic minimizes the effects of hypotension after spinal anesthesia for cesarean section and the incidence of maternal adverse events preserving fetal well-being, but it may result in insufficient anesthesia. Hypotension associated with greater masses of subarachnoid anesthesia can be controlled by prophylactic continuous infusion of phenylephrine. The effects of prophylactic continuous infusion of phenylephrine on pressure control on maternal and fetus results in cesarean sections with different doses of hyperbaric bupivacaine in spinal anesthesia. METHODS: A non-randomized prospective study of 60 gravidas at term scheduled for elective cesarean sections was undertaken. Patients were allocated into two groups depending on hyperbaric bupivacaine dose administered for spinal anesthesia, 12 or 8 mg, along with 5 µg of sufentanil and 100 µg of morphine. Patients were hydrated with 10 mL.kg(-1) of Ringer's lactate before the anesthesia. Shortly after, continuous infusion of 100 µg.min(-1) of phenylephrine was initiated to maintain blood pressure at baseline levels. The following parameters were evaluated: level of anesthetic blockade, consumption of vasopressors, incidence of maternal events, and conditions of the newborn. RESULTS: Maternal data was similar in both groups regarding the level of anesthetic blockade, phenylephrine consumption along time, incidence of hypotension, hypertension, bradycardia, nausea, vomiting, dyspnea, pain, and tremors. Conceptual data showed similarities between both groups regarding blood gases and umbilical vein lactate levels. The pH of all newborns was > 7.2. CONCLUSIONS: On maintaining the blood pressure with prophylactic continuous infusion of phenylephrine the incidence of maternal adverse events and conditions of birth do not differ whether spinal anesthesia is performed with 12 mg or 8 mg of hyperbaric bupivacaine.

Clonidine as pre-anesthetic medication in cataract extraction: comparison between 100 microg and 200 microg.

BACKGROUND AND OBJECTIVES: The objective of the present study was to evaluate the degree of sedation, intraocular pressure, and hemodynamic changes with premedication with low doses of oral clonidine, 100 microg and 200 microg, in outpatient cataract surgeries. METHODS: This is a randomized, double-blind, clinical study undertaken at the Universidade Federal de São Paulo with 60 patients of both genders, physical status ASA 1 and 2, ages 18 to 80 years. Patients were separated into three groups: placebo, clonidine 100 microg, and clonidine 200 microg. Intraocular pressure, heart rate, and blood pressure besides assessment of sedation were measured before and 90 minutes after the administration of clonidine. Sedation levels were classified according to the Ramsay sedation scale. RESULTS: Patients who received placebo and 100 microg of clonidine did not show reduction in heart rate, while a reduction in heart rate was observed in patients who received 200 microg of clonidine, and this difference was statistically significant. Patients who received 200 microg of clonidine also had a reduction in systolic and diastolic blood pressure (p < 0.05). One patient who received 200 microg of clonidine developed severe hypotension, with systolic pressure < 80 mmHg. Patients treated with clonidine had a reduction in intraocular pressure (p < 0.05). Ninety minutes after the oral administration of placebo and 100 microg and 200 microg of clonidine, 25%, 60%, and 80% of the patients respectively were classified as Ramsay 3 or 4. CONCLUSIONS: Clonidine 100 microg can be indicated as premedication for fasciectomies, being effective in sedation and reduction of intraocular pressure, without adverse effects on blood pressure and heart rate.

[Comparison between two methods for hemodynamic measurement: thermodilution and oesophageal doppler]. / Comparação dos valores de débito cardíaco obtidos por termodiluição e dopplerfluxometria transesofágica.

OBJECTIVES: Thermodilution (TD) is the "gold standard method" for hemodynamic monitoring. Some parameters can be measured by Oesophageal Doppler (OD), which is simpler and less invasive. To evaluate the accuracy of OD, we compared this method with TD in measurement of cardiac output (CO). METHODS: One hundred and ninety two simultaneous measurements were made in 10 patients (5 male and 5 female) with different clinical situations, 8 with sepsis using vasoactive drugs and 2 monitored for laryngectomy and liver transplantation. Measurements were taken during 4 hours at 30 minute intervals. The two oesophageal dopplers used DeltexR and ArrowR, were introduced between 35 and 45 cm from the nose and located at the point of largest diameter of the descending aorta. In TD, we used the pulmonary artery catheter (Swan Ganz BaxterR) and the DX- 2001 monitorR positioning was confirmed with support of radiology and of pressures curves. Measurements of CO carried out by means of TD were achieved using an iced saline solution considering the mean of four measurements with less than a 5% difference. The statistical method used was the Bland-Altman scatter plot and dispersion graphic. RESULTS: No statistically significant difference was found between the two methods for hemodyamic measurement with a correlation coefficient of 0.8 for CO (Deltex DopplerR and Baxter Swan GanzR) and a correlation coefficient of 0.99 for CO (Arrow DopplerR and Baxter Swan GanzR). CONCLUSION: Homodynamic measurements with OD have the same accuracy as those with TD and were easily obtained in the 10 patients.

[The effect of oral ondansetron in the prevention of postoperative nausea and vomiting]. / Ondansetrona oral na prevenção de náuseas e vômitos pós-operatórios.

OBJECTIVES: Not so many years ago, the incidence of postoperative nausea and vomiting used to reach 40% to 50%. More recent publications indicate that this complication still reaches considerable frequency: 20 to 30%. The present study had the objective of evaluating the impact of oral administration of ondansetron on the incidence of postoperative nausea and vomiting among patients submitted to general anesthesia. METHODS: This was a prospective, randomized, controlled, double-blind study. It included 178 patients divided into two groups: Ondansetron (n = 89) and Placebo (n = 89). Fast-dissolving oral tablets specially prepared for this study were utilized. The medication was administered between 60 and 30 minutes before anesthesia was induced. Factors with possible influence on the event were noted down, such as gender, age, history of dyskinesia or postoperative nausea and vomiting, smoking, type of surgery, body mass index, reversal of neuromuscular blockade using neostigmine, and the severity of postoperative pain. RESULTS: There was no significant difference between the characteristics of the groups regarding the factors annotated, except in relation to smoking and body mass index, which were greater in the Placebo group. These factors did not interfere in the analysis of the results. Postoperative nausea and vomiting were observed in 23 patients (26%) of the Ondansetron group and 38 patients (43%) of the Placebo group (p < 0.05). CONCLUSION: Ondansetron, 16 mg orally, administered before the operation significantly reduced the incidence of postoperative nausea and vomiting. The simplicity of administration and low cost of this presentation justify the choice of this administration route.

Hemodynamics and renal function during administration of low-dose dopamine in severely ill patients.

CONTEXT: Although a large number of studies have been performed regarding the renal and hemodynamic effects of the infusion of low-dose dopamine (LDD) in severely ill patients, there is still controversy on this subject. OBJECTIVE: To evaluate the effects of dopamine (2 microg/kg/min) on systemic hemodynamics (lowest mean arterial pressure, MAP, highest heart rate, HR, central venous pressure, CVP), creatinine clearance (CLcr), diuresis and fractional sodium excretion (FENa+). TYPE OF STUDY: A non-randomized, open, prospective clinical trial. SETTING: An intensive care unit in a tertiary university hospital. PARTICIPANTS: 22 patients with hemodynamic stability admitted to the intensive care unit. PROCEDURES: Patients were submitted to three two-hour periods: without dopamine (P1), with dopamine (P2) and without dopamine (P3). MAIN MEASUREMENTS: The above mentioned variables were measured during each period. CLcr was assessed based upon the formula U x V/P, where U is urinary creatinine (mg/dl), V is diuresis in ml/min and P is serum creatinine (mg/dl). FENa+ was calculated based upon the formula: urinary sodium (mEq/l) x P/plasma sodium (mEq/l) x U) x 100. Results were presented as mean and standard deviation. The Student t test was used and results were considered significant if p was less than 0.05. RESULTS: Twelve patients (seven males and five females) were included, with a mean age of 55.45 years. There was no significant variation in MAP, HR, CVP, CLcr or FENa+ with a dopamine dose of 2 microg/kg/min. On the other hand, diuresis significantly increased during P2, from 225.4 to 333.9 ml. CONCLUSION: Infusion of 2 microg/kg/min of dopamine for 2 hours increases diuresis. At the doses studied, dopamine does not induce significant alterations in MAP, HR, CVP, CLcr and FENa+.

Influence of sedation on morbidity and mortality in the intensive care unit.

CONTEXT: Although 30 to 50% of hospitalized patients in a critical care unit are under sedation, there is sparse data on the impact of sedation on morbidity and case-fatality rates in Brazil. Sedation is associated with higher risks of infection and death rate among patients. However, it is difficult to assess the clinical impact of sedation. OBJECTIVE: To evaluate the impact of sedation on the incidence of nosocomial infection and all-cause deaths at a critical care unit. TYPE OF STUDY: Prospective study. SETTING: Tertiary-care teaching hospital. PARTICIPANTS: After the exclusion of patients hospitalized for less than 24 hours, 307 patients were assigned to two groups, considering their states of sedation. After confirmation of heterogeneity in relation to the Acute Physiology and Chronic Health Evaluation (APACHE II) prognostic system, 97 sedated and 97 non-sedated patients were matched in relation to this severity index. MAIN MEASUREMENTS: Impact of sedation on deep venous thrombosis, incidence of decubital eschars, presence of infection, mortality and length of hospital stay. RESULTS: There was no difference in the incidence of deep venous thrombosis between the sedated and non-sedated groups, while the frequency of decubital eschars was significantly higher among sedated patients (p = 0.03). Infection was detected in 45.4% of patients under sedation and 21.6% of patients not under sedation (p = 0.006). Mortality for patients that did not receive any kind of sedative was 20.6% and, for those that were sedated during hospitalization, the role was 52.6% (p < 0.0001). The sedated patients had longer hospitalization (11 vs. 4 days) (p < 0.0001). CONCLUSION: We concluded that sedation is associated with higher infection risk and case-fatality rate, and longer hospital stay.

Characterization of the in vivo cardiac electrophysiologic effects of high-dose cocaine in closed-chest, anesthetized dogs with normal hearts.

OBJECTIVE: To characterize the cardiac electrophysiologic effects of cocaine. METHODS: In 8 dogs (9-13 kg), electrophysiologic parameters and programmed stimulation were undertaken using transvenous catheters at baseline, and after cocaine intravenous infusion (12 mg/kg bolus followed by 0.22 mg/kg/min for 25 minutes). RESULTS: Cocaine plasma levels (n=5) rose to 6.73 +/- 0.56 mg/mL. Cocaine did not affect sinus cycle length and arterial pressure. Cocaine prolonged P wave duration (54 +/- 6 vs 73 +/- 4 ms, P<0.001), PR interval (115 +/- 17 vs 164 +/- 15 ms, P<0.001), QRS duration (62 +/- 10 vs 88 +/- 14 ms, P<0.001), and QTc interval (344 +/- 28 vs 403 +/- 62 ms, P=0.03) but not JT interval (193 +/- 35 vs 226 +/- 53 ms, NS). Cocaine prolonged PA (9 +/- 6 vs 23 +/- 8 ms, P<0.001), AH (73 +/- 16 vs 92 +/- 15 ms; P=0.03), and HV (35 +/- 5 vs 45 +/- 3 ms; P<0.001) intervals and Wenckebach point (247 +/- 26 vs 280 +/- 28 ms, P=0.04). An increase occurred in atrial (138 +/- 8 vs 184 +/- 20 ms; P<0.001) and ventricular (160 +/- 15 vs 187 +/- 25 ms; P=0.03) refractoriness at a cycle length of 300 ms. Atrial arrhythmias were not induced in any dog. Ventricular fibrillation (VF) was induced in 2/8 dogs at baseline and 4/8 dogs after cocaine. CONCLUSION: High doses of cocaine exert significant class I effects and seem to enhance inducibility of VF but not of atrial arrhythmias.