Últimas Notícias - Anestesia

Japão - a anestesia em portadores de distrofia muscular apresenta maior risco e deve-se dar preferência a drogas que já foram anteriormente testadas em portadores de distrofia; pais, portadores e médicos que tratam destes pacientes devem estar cientes das drogas que podem ser utilizadas (veja o artigo no site). O sevoflurano (comercializado no Brasil com o nome Sevorane) foi descrito como um medicamento seguro. Neste artigo os autores descrevem um caso de um menino de 6 anos submetido a uma cirurgia de amigdala  utilizando como anestésicos o sevoflurano, óxido nitroso e oxigênio sem o uso de relaxantes musculares. Três horas após a cirurgia ele apresentou urina escura sendo constatada altos níveis de mioglobina e enzima CK, o que indica uma grande destruição muscular. Ele teve elevação discreta da temperatura e não apresentou alterações no eletrocardiograma e nem nos níveis de potássio. Após o tratamento adequado o paciente teve alta no quato dia após a cirurgia sem outras complicações. Este caso indica que o sevoflurano pode estar envolvido com a rabdomiólise e atenção deve ser dada ao seu uso em portadores de distrofia muscular.  

Reino Unido - os anestesistas descrevem um caso de sucesso com anestesia peridural e um sedativo suave para a cirurgia ortopédica em um portador de Distrofia de Emery-Dreifuss. Se você quiser ler mais sobre anestesia clique aqui.

USA - Hipertermia Maligna é uma complicação grave de anestesias e tem uma incidência maior em distrofias musculares. Não existe até o momento um modo adequado de evitá-la. Os pacientes que tem distrofia muscular devem ser anestesiados com drogas que já sabidamente demonstraram ser seguras . Neste estudo os pesquisadores de um hospital especializado em cirurgias ortopédicas e musculoesqueléticas analisaram retrospectivamente os prontuários de 1453 cirurgias analisando a incidência de hipertermia maligna, as doenças que os pacientes apresentavam, os níveis da enzima CK e os anestésicos utilizados. A enzima CK esta muito aumentada em várias formas de distrofia, e em outras doenças. Os resultados observados permitiram chegar as seguintes conclusões: a hipertermia maligna é realmente mais frequente em portadores de doenças neurimusculares; os níveis de CK não são capazes  de predizer os pacientes que irão apresentar hipertermia maligna. A descoberta de um método que possa identificar os pacientes que apresentarão  hipertermia maligna em cirurgia seria muito importante nos pacientes que ainda não tem a sua doença identificada mas também nos que já sabem portar alguma forma de distrofia. Este trabalho, cujo resumo em inglês está a seguir, será apresentado no Congresso da Associação Americana de Anestesiologia em 10/2002 e publicado na revista Anestesiology.

(Usefulness of Preoperative CK Levels as an MH Predictor in a High Risk Population -

Bruce D. Levine, M.D. ; Elizabeth T. Drum, M.D.; Andrew Herlich, M.D.; Henry Rosenberg, M.D.

Department of Anesthesiology, Temple University School of Medicine, Philadelphia, Pennsylvania

Malignant Hyperthermia (MH) is difficult to predict preoperatively. High risk patients may include those with Duchenne's muscular dystrophy (DMD), scoliosis, osteogenesis imperfecta , and arthrogryposis. In the 1970s creatine kinase (CK) was used to identify patients at risk for MH. The specificity and sensitivity of CK was not sufficient to make this a useful screen. The Shriners Hospitals care for patients with orthopedic and musculoskeletal problems. At the Philadelphia Shriners, all patients undergoing surgical procedures requiring anesthesia have had preoperative CK levels measured since the 1970s. Initially, an elevated preop CK contraindicated a triggering anesthetic. By the 1980s, this guideline was not followed. The purpose of this study was to determine the incidence of MH in a population with a high prevalence of musculoskeletal disorders, and to determine the value of CK in predicting MH risk.Methods With IRB approval, 1453 records of surgical patients were reviewed. Demographics, diagnoses, medical history, CK levels, surgical procedures, anesthetics, and complications were noted. Additional review was carried out for: elevated preop CK, patients who received succinylcholine (sux), patients with an elevated CK level who received sux, and patients whose medical record indicated the possibility of MH.
Results:89.7% of patients had normal preop CK. 149 patients had an elevated CK (10.3%), 75 patients received sux (5.2%), 5 had high CK levels and received sux (0.34%), and 6 had the possibility of MH (0.41%).
Two patients had a confirmed MH or MH-like reaction. One had DMD, the other, Perthe's. Excluding the patient with the presumed diagnosis of MH in conjunction with DMD, the incidence of MH in this population is 1/1453= 0.069%. If the patient with known MH is included, the incidence is 2/1453=0.138%. Both are above the generally accepted rate of 1/50,000 (.002%)
Of 149 patients with an elevated CK, 140 received triggering agents. None experienced an MH or MH-like reaction. Of the nine who did not receive triggering agents, 4 had DMD, 1 arthrogryposis, 1 encephalopathy, 1 atlantoaxial subluxation, and 2 CP.
Of the 149 patients with an elevated CK, 28 (18.8%) had diagnoses of a musculoskeletal disorder: 18 scoliosis, 4 DMD, 2 Charcot-Marie-Tooth disease, 1 myotonic dystrophy, 1 spinocerebellar atrophy, and 1 arthrogryposis. Only the DMD patients and the arthrogrypotic received a non triggering anesthetic. Therefore of the 140 patients with elevated CK who received trigger agents(only one had sux), 23 had musculoskeletal disorders. None experienced an MH or MH-like reaction.
Conclusions:1. The incidence of MH in patients with musculoskeletal disorders is higher than the general population.2. Elevated CK in a population at higher risk for MH is not predictive of risk for MH or MH-like reactions. 3 The relationship between MH and musculoskeletal disorders other than DMD remains to be clarified.
Anesthesiology 2002; 96: A1237)

USA - a hipertermia maligna é uma séria complicação de cirurgias; pacientes com  distrofias musculares podem apresentar quadro semelhante ao da hipertermia maligna durante anestesias. Neste artigo é feita uma revisão sobre a hipertermia maligna, as formas de diagnóstico e a importância do tratamento adequado. Pacientes com distrofia muscular não podem receber anestésicos gerais chamados de halogenados e não podem utilizar o relaxante muscular denominado succinilcolina; para mais informações ver o texto sobre anestesia no ítem tratamento (http://www.distrofiamuscular.net/anestesia.htm)

Current Concepts in Malignant Hyperthermia 

Journal of Clinical Neuromuscular Disease 2002; 4(2):64-74 

Josef Finsterer, MD, PhD

Malignant hyperthermia (MH) is a rare, potentially lethal, clinically and genetically heterogeneous pharmacogenic myopathy, which during or after general anesthesia manifests as MH crisis (MHC) in genetically predisposed, but otherwise mostly normal, individuals (MH susceptibles) in response to anesthetic-triggering agents. MHC can also occur in patients with central core disease. MCH-like crises have been reported in those with Duchenne/Becker muscular dystrophy, myotonic dystrophy, mitochondriopathy, and various other conditions. MH susceptibility is diagnosed if there is an MHC in the individual or family history or by the in vitro caffeine-halothane contracture test. Although screening for mutations in the ryanodine-receptor-1 gene and the dihydropyridine-receptor gene, respectively, could further substantiate the diagnosis, the caffeine-halothane-contracture test still remains the gold standard for diagnosing MH susceptibility. The most well-known triggers of an MHC are depolarizing muscle relaxants and volatile anesthetics. Therapy of an MHC comprises discontinuation of triggering agents, oxygenation, and correction of the acidosis and electrolyte disturbances, treatment of arrhythmias, cooling, and dantrolene. If MH susceptibility is not known preoperatively and an MHC unexpectedly interrupts anesthesia, consultation by a specialist in MH susceptibility after anesthesia is essential to investigate the patient for MH susceptibility or subclinical myopathy, guide laboratory investigations, manage therapy, and counsel the family on further risk. To further reduce morbidity and mortality of those with MHC, anesthesiologists and neurologists should be well educated and should strengthen their clinical vigilance. Research should be intensified and extended with regard to the development of new in vitro tests to further elucidate the heterogeneous genetic background of MH susceptibility.

Alemanha - complicações de cirurgias são comuns em pacientes com distrofia muscular de Duchenne. Muitas vezes os sintomas de doença cardíaca podem não ser percebidos. Os autores deste trabalho relatam o caso de um paciente com Duchenne que apresentava eletrocardiograma e ecocardiograma normais antes da cirurgia e que durante a operação da coluna desenvolveu a insuficiência cardíaca.

Alemanha - os pacientes com distrofia muscular devem ter cuidado especial com anestesia geral. Neste artigo os pesquisadores estudaram o recurônio, frequentemente utilizado em anestesia geral para relaxamento dos músculos, em pacientes com distrofia muscular de Duchenne. Os resultados mostraram que estes pacientes respondem diferente ao rocurônio demonstrando um risco em potencial para sua utilização na distrofia muscular de Duchenne.

Brasil - tendo tomado conhecimento de mais um caso fatal de acidente anestésico em portador de Distrofia Muscular de Duchenne resolvi reforçar o alerta aos pais com relação ao risco de anestesia em portador de distrofias em geral. Os portadores de distrofia podem apresentar durante a anestesia um quadro semelhante ao da hipertermia maligna, que é muito grave, e pode ser fatal. Muitas drogas que são usadas em anestesia podem desencadear o quadro como a succinilcolina e os anestésicos halogenados. É muito importante que se discuta com a equipe médicas estas informações além de se realizar uma avaliação pré-operatória bem detalhada. Caso ocorra este quadro grave o hospital deve ter disponível a droga dantrolene que é usada no tratamento da hipertermia maligna. No estado de São Paulo há uma lei do Gov. Geraldo Alckmin (médico anestesista) que obriga a todos os hospitais a dispor de dantrolene para tratamento desta complicação. Para mais informações ler o texto sobre anestesia aqui. 

USA - pacientes com Distrofia muscular as vezes necessitam de cirurgia de coluna por escoliose (desvio); os autores fazem uma revisão dos trabalhos que analisaram a perda sanguínea em diferentes tipos de cirurgia de coluna em diferentes doenças. Os pacientes com distrofia muscular de Duchenne estão entre os que apresentam maior perda sangúinea. As perdas sanguíneas podem chegar a 4000ml. Os trabalhos que estudaram as perdas sanguíneas em Duchenne podem ser vistos aqui

Inglaterra - mulheres que tem um gene defeituoso da distrofia muscular de Duchenne podem apresentar alterações cardíacas e podem apresentar complicações anestésicas como os doentes com distrofia muscular de Duchenne. Neste artigo é descrito um caso de uma grávida portadora do gene da distrofia muscular de Duchenne que utilizou o anestésico propofol associado a anestesia peridural com sucesso. O resumo do artigo em inglês está a seguir:

(In Press: International Journal of Obstetric Anesthesia, 2004) Anaesthetic management during labour of a manifesting carrier of Duchenne muscular dystrophy NEW

M.K. Molyneux  - UK

SUMMARY. We describe the peripartum anaesthetic management of a 36-year-old woman who was a manifesting carrier of Duchenne muscular dystrophy. Duchenne muscular dystrophy is an X-linked recessive disorder affecting young males associated with severe complications during anaesthesia if depolarising neuromuscular blocking drugs and volatile agents are used. A manifesting carrier is a heterozygous female who demonstrates the disease in a milder form than in males. This probably occurs because of skewed X-inactivation. We planned to establish regional anaesthesia should an operation be necessary during labour or delivery and to use propofol total intravenous anaesthesia and rocuronium if general anaesthesia became unavoidable. At 37 weeks, the woman went into spontaneous labour, but fetal distress necessitated caesarean section for which combined spinal-epidural anaesthesia was used.

Alemanha - pacientes com distrofia muscular apresentam maior risco de complicações em anestesia. este trabalho foi apresentado no Congresso Anual da Sociedade Americana de Anestesiologia. Neste trabalho os autores estudaram a droga mivacurônio em crianças com distrofia muscular de Duchenne. Os resultados demonstraram que os pacientes com Duchenne são mais sensíveis ao efeito do mivacurônio e demoram mais para se recuperar da anestesia. os autores concluem que o uso desta droga na distrofia muscular de Duchenne traz risco maior  e seu uso deve ser monitorizado de perto.

No mesmo Congresso foi apresentado um trabalho com o uso da droga cisatracurônio na distrofia muscular oculofaríngea. Não houve diferença na recuperação dos pacientes que receberam esta droga, podendo haver somente uma demora maior para o ínicio de ação. O resumo dos artigos em inglês segue a seguir:

1) Mivacurium in Children with Duchenne’s Muscular Dystrophy: A Comparison of Onset and Duration of Neuromuscular Block with Children without Neuromuscular Diseases

Joachim Schmidt, Tino Munster, Stefanie Wick, Hubert J. Schmitt - Germany

Introduction: Duchenne’s  muscular dystrophy (DMD), an x-linked recessive disorder, is the most common myopathy seen in the pediatric population. Children afflicted with this disease may require anesthesia for muscle biopsy or orthopedic surgery. Of primary concern in children with this disorder is the choice of the neuromuscular blocking agent. Pharmacodynamic data of non-depolarising neuromuscular blocking agents are scarce 1, 2. Succinylcholine is not recommended due to its adverse side effects. Investigation in DMD children with advanced disease state showed prolonged recovery after a standard dosage of rocuronium 2. The aim of this study was to compare the response to 0,2 mg/kg mivacurium in children with DMD and children without neuromuscular diseases (control-group).

Discussion: The results of the present study demonstrate that the recovery of neuromuscular block following a standard dosage of 0,2 mg/kg mivacurium is significantly prolonged in children with DMD compared to controls. Our results confirm a retrospective study where an increased sensitivity to mivacurium in children with DMD was suggested 4. We therefore recommend the monitoring of the neuromuscular function if mivacurium is used in children with DMD.

2) Cisatracurium Pharmacodynamics in Patients with Oculopharyngeal Muscular Dystrophy

Marie-Josee Caron, Francois Girard, Dominique C. Girard, Daniel Boudreault, Bernard Brais, - Canada
The pharmacodynamic of myorelaxants in patients suffering from oculopharyngeal muscular dystrophy (OPMD) has never been studied. This study was designed to compare the pharmacodynamic of cisatracurium in OPMD patients versus a control group.

40 patients were recruited: 20 OPMD patients requiring general anesthesia for cricopharyngeal myotomy and 20 age-matched controls undergoing a similar surgery. Anesthesia was standardized and both groups received a bolus of cisatracurium 0.1 mg•kg-1. Onset time, time to 10 % T1 recovery as well as the intervals 10-25% and 25-75% were calculated for both groups. A subgroup analysis was performed with patients with a severe form of OPMD.

Demographic and intraoperative data were similar. Onset time was significantly longer in OPMD patients compared to the control group (4.6 +/- 1.5 vs 3.4 +/- 1.0 min, p=0.001). There was no difference in recuperation times and indexes between the two groups and that, regardless of the severity of the disease.

In conclusion, there was no difference in recuperation times for a cisatracurium-induced neuromuscular blockade between OPMD patients and a control group. A delayed onset of action of the drug is to be expected.

USA - complicações anestésicas são descritas em portadores de distrofia muscular. Todos os cuidados devem ser tomados para que a cirurgia em um portador de distrofia seja segura; os anestesicos empregados na anestesia geral são selecionados entre os que nunca causaram qualquer problema na distrofia. O maior problema é quando a cirurgia é realizada antes do diagnóstico como neste caso descrito. A criança foi submetida a uma cirurgia cardíaca antes do diagnóstico de Duchenne.  O tratamento da parada cardíaca foi bem sucedido e a criança evoluiu bem. Os autores recomendam que toda criança com retardo de desenvolvimento motor que será submetida a alguma cirurgia sob anestesia geral precisa ser feita a dosagem da enzima CPK no pré-operatório.

USA - Complicações anestésicas são frequentes em pacientes com distrofia muscular de Duchenne e em outras formas de distrofia. Neste relato se descreve um caso de um paciente com 16 anos com distrofia muscular de Duchenne que apresentou parada cardíaca durante anestesia para correção de escoliose. O autor descreve a parada como devida ao uso de desflurano. Relatos como este são importantes para alertar médicos sobre os riscos dos anestésicos em distrofia muscular e para que a escolha do anestésico seja decidida com todas as informações disponíveis. No Brasil o desflurano é comercializado com o nome SUPRANE. O relato deste caso pode ser lido, em inglês, abaixo:

(IN PRESS: Reactions Weekly, 2005) Desflurane: First report of heart arrest in a patient with muscular dystrophy:case report

A 16-year-old boy undergoing surgery for scoliosis correction developed heart
arrest while receiving desflurane-based anaesthesia. The boy, who had muscular dystrophy and a history of mild chronic obstructive pulmonary disease, gastro-oesophageal reflux and symptoms of cardiomyopathy, underwent anaesthesia induction, receiving alfentanil, propofol and rocuronium bromide; anaesthesia was maintained with desflurane [dosage not stated] and piritramide in an oxygen/air mix. After 4 hours of uneventful anaesthesia, he developed ventricular tachycardia followed by ventricular fibrillation. Following external cardiac compression, defibrillation and epinephrine [adrenaline] administration, the boy's HR returned to sinus rhythm within 5 minutes and his BP and cardiac output improved. Postoperatively, his creatine kinase (CK) level and CK-MB fraction peaked at 11 056 and 253 U/L, respectively, and his myoglobulin level peaked at 62 ng/mL. He was discharged from the ICU 10 days later. Author Comment"In our patient other causes for cardiac arrest like hypoxaemia, hypercapnia, hyperkalaemia and hyperthermia were excluded, so the episode was attributed to cardiomyopathy and the use of desflurane."

 1. Smelt WLH.Cardiac arrest during desflurane anaesthesia in a patient with
Duchenne's muscular dystrophy. Acta Anaesthesiologica Scandinavica 49: 267-269,
No. 2, Feb 2005

Editorial Comment: A search of AdisBase and Medline did not reveal any previous case reports of heart arrest associated with desflurane. The WHO Adverse Drug Reactions database contained 12 reports of cardiac arrest associated with desflurane.

Canadá - pacientes com distrofia óculo-faríngea necessitam frequentemente realizar a cirurgia de ressecção do músculo levantador palpebral (LPR) e miotomia cricofaríngea (CPM). O objetivo deste estudo foi avaliar as complicações pós-operatórias com estas duas cirurgias. Os resultados demonstraram que a cirurgia LPR apresenta poucas complicações pós-operatórias, tanto com anestesia geral ou local. A cirurgia CPM apresenta maior número de complicações no pós-operatório como pneumonia, pneumonite aspirativa, obstrução das vias aéreas e hipersecreção pulmonar e tosse. O resumo desta pesquisa foi publicado na Can J Anesth, Jun 2005; 52: 143.

Alemanha - pacientes com distrofia muscular devem ter cuidado redobrado ao se submeterem a cirurgias pelo risco de complicações anestésicas. Os profissionais envolvidos devem estar preparados para atendimento dos portadores de distrofia, inclusive na seleção das drogas que serão utilizadas na anestesia. O mivacurio é um relaxante muscular utilizado durante alguns tipos de anestesia. O estudo desta droga em portadores de distrofia muscular de Duchenne demonstrou que o efeito da droga é prolongado e mais intenso nos portadores de distrofia; tal resultado demonstra que a utilização da droga requer um cuidado maior ou ela deve ser substituída por um outro relaxante mais seguro ou a equipe deve optar pela não utilização de relaxantes musculares.

USA - é comum que os artigos publicados sofram críticas de outros pesquisadores; as vezes, quando as críticas são muito importantes elas são publicadas. Os artigos criticados podem se defender e isto enriquece o conhecimento de todos. Quando a crítica se refere a qualidade do artigo este artigo recebe uma censura e é retirado dos anais da revista. Nesta semana dois artigos foram criticados; o primeiro fala dos bons resultados do perindopril na função cardíaca de pacientes com distrofia muscular de Duchenne. As críticas foram muito severas em especial sobre os métodos de acompanhamento dos pacientes. Os autores do artigo reagiram e conseguiram demonstrar que as suas informações estavam corretas. O segundo artigo que foi criticado fala da necessidade de dosar a CK antes de toda cirurgia para evitar complicações como a hipertermia maligna. O crítico fala que o custo seria muito elevado para fazer o exame indiscriminadamente e sugere que o exame seja feito se houver alguma suspeita de fraqueza muscular ou atraso do desenvolvimento motor. A crítica de ambos os artigos e a réplica podem ser lidas abaixo:

Critics and Reply: Hyperkalemic Cardiac Arrest After Cardiopulmonary Bypass in a Child with Duchenne Muscular Dystrophy

CRITICS:

We read with interest the article by Nathan et al. (1) concerning a hyperkalemic cardiac arrest in a child with unsuspected Duchenne muscular dystrophy. As the authors state in their discussion, children with undiagnosed Duchenne muscular dystrophy are at an increased risk when exposed to depolarizing muscle relaxants; however, the unexpected rhabdomyolysis associated with general anesthesia drugs is still a problem and no specific disease appears to be related to this phenomenon (2– 4). Because of this, we disagree with the authors’ recommendation of routine preoperative screening of all patients for elevated serum creatine kinase. Although an elevated serum creatine kinase is highly sensitive for myopathies, it lacks specificity (4). Serum creatinine kinase may be elevated after trauma and heavy exercise. Universal screening can result in frequent and unnecessary delays in the operating room schedule and also lead to the “Ulysses Syndrome” of “mental and physical disorders which follow the discovery of a false positive result” (5). Careful and thorough preanesthetic evaluation is essential in helping to identify undiagnosed myopathies, but as with the patient in this report and others (6), this method is not foolproof. We agree with the authors that screening in the neonatal period may be helpful but will need a formal cost analysis before this can be accomplished.

Hetam Al-Takrouri, Little Rock, James F. Mayhew, Jackson - USA

REPLY:

We appreciate the comments of Drs. Al-Takrouri and Mayhew. We agree with them that “universal screening” for elevated creatine kinase during the preoperative evaluation is unnecessary. We had been very careful in preparing our manuscript (1) and had only recommended estimating creatine kinase in children with a history of unexplained motor delay. We also agree with them on the need for a cost analysis for neonatal screening.

25 - Critics and Reply:  Can Perindopril Delay the Onset of Heart Failure in Duchenne Muscular Dystrophy?

CRITICS:

With interest we read the study by Duboc et al. (1) about 57 children with Duchenne muscular dystrophy (DMD) and a left ventricular ejection fraction (LVEF) > 55%. Duboc et al. (1) conclude that early treatment with perindopril over 60 months delays both the onset and progression of systolic dysfunction. The study raises the following concerns: First, how to explain that within the first 36 months only one patient in each group developed systolic dysfunction, whereas within the following 24 months eight patients of group 2 (the group that received placebo during the first 36 months) deteriorated? If the deterioration after 60 months was due to not taking perindopril during the first 36 months, why did this effect not become evident earlier? Assuming that perindopril had an effect in preventing the development of systolic dysfunction in group 1 patients (the group that received perindopril during the first 36 months), it remains unclear whether this was really a drug effect, selection bias, or whether these patients were less severely affected when included. Second, did the eight patients in group 2 with LVEF < 45% after 60 months have a lower baseline LVEF than the remaining patients? How do the investigators know that it was the lack of perindopril that led to a decrease in systolic function in these patients? How could it be excluded that this was not the natural course? To claim a positive effect of perindopril in patients with normal systolic function it is not justified to claim a prophylactic effect of the drug despite a nonsignificant difference in mean values of LVEF after 60 months. How then to explain the improvement of LVEF after 36 months in two group 2 patients? Third, because LVEF decreased under angiotensin-converting enzyme (ACE) inhibitor therapy in eight patients below 45% and the mean remained unchanged, there must have been some patients in whom LVEF has improved. How do the investigators explain that the drug given during 24 months improved LVEF in group 2 patients? Fourth, cardiac function was assessed by resting radionuclide ventriculography. As most of the DMD patients develop thoracospinal deformities from age 10 on, the accuracy of scintigraphy is limited (2). Why was no other method, like echocardiography, applied that would yield additional information about cardiac size and diastolic function? Fifth, what was the rationale to give an ACE inhibitor in patients with normal systolic function? Why was the choice perindopril, an ACE inhibitor not previously tested in muscular dystrophy patients (3,4)? Moreover, information is lacking about the exact neurological severity of the patients, especially how rapidly neurologic symptoms deteriorated, and whether respiratory function changed. How many patients had or developed rhythm abnormalities? Did the heart rate increase during follow-up, and was increased heart rate associated with a decrease of LVEF in any of the patients, suggesting tachycardiomyopathy (5)? How to explain that 17 patients developed side effects during placebo therapy? From which drug? Finally, based on the presented data, it is not justified to propose perindopril as a prophylactic medication in DMD. To assess left ventricular function accurately in DMD patients, the application of at least echocardiography is mandatory (4).

Claudia Stöllberger, Josef Finsterer - Austria

REPLY:

We thank Drs. Stöllberger and Finsterer for their comments about our paper (1). They point out several questions, indicating that they probably do not adhere to our conclusion of a preventive effect of perindopril in children with Duchenne muscular dystrophy. The main limitation may be the apparent delay of 60 months to observe a benefit of therapeutics. In fact, this trial investigated a preventive effect very early in the course of Duchenne disease (mean age of children 10.6 years with normal left ventricular ejection fraction [LVEF]); as a consequence, LVEF was preserved at 36 months. These children probably have cardiac involvement that is not accurately detected by conventional measurements; more sensitive methods might be useful in this setting (2). Conversely, after 60 months’ total follow-up, children were older (mean age 15.6 years) and cardiac deterioration could be demonstrated in the group receiving placebo during phase 1; this is in accordance with the natural course of the disease. Such degradation in LVEF is representative of the ineluctable course of the disease, and it was not accurately prevented by a delayed initiation of perindopril. As 1) groups were comparable for demographics, cardiac status, respiratory and peripheral muscle function, 2) drug allocation (placebo or perindopril) during phase 1 was the only difference, thus the natural conclusion is that five years of perindopril may delay the onset and progression of LV dysfunction when compared to later and shorter initiation. The trend in lower mortality in the perindopril group reinforces our conclusion. All adverse effects mentioned in our study were present during the first phase of the study, with no difference between placebo group or perindopril group. Patients with and without LVEF dysfunction at the end of the protocol had similar baseline values (64.9 + 6.5% vs. 65.0 + 5.4%, respectively, p = NS). No patient had significant increased LVEF during the study. Mean LVEF declined moderately in both groups, and some patients exhibited more severe degradation, which reflects heterogeneity in the course of the disease. In our study, radionuclide ventriculography was chosen to determine LVEF, as it is the “gold standard” method. The measurement of LVEF is a direct count of radionuclide activity. Conversely, LVEF determined by echocardiography needs a mathematical hypothesis that may not be valid in cases of severe thoracic deformation (3). Finally, patients with Duchenne disease very frequently have poor quality of acoustic echocardiographic windows. This study was focused on a possible preventive effect of perindopril on LVEF, which is an important prognosis factor, contrary to electrocardiograms, ventricular arrhythmias, and late potential signal-average (4). In conclusion, this correspondence illustrates the need for simple and adequate methodology to limit misinterpretation of investigative results, integrating the difficulties of such necessary controlled trials conducted in a rare disease.

Christophe Meune, Denis Duboc, - France

 

 

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