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Evidence-Based Clinical Question Does Dantrolene Sodium Prevent Recurrent Exertional Rhabdomyolysis in Horses? M

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Evidence-Based Clinical Question Does Dantrolene Sodium Prevent Recurrent Exertional Rhabdomyolysis in Horses? M EQUINE VETERINARY EDUCATION / AE / March 2007 97 Evidence-based Clinical Question Does dantrolene sodium prevent recurrent exertional rhabdomyolysis in horses? M. A. HOLMES University of Cambridge, Department of Veterinary Medicine, Madingley Road, Cambridge CB3 0ES, UK. Three part question of any other clinical manifestation of disease. An arbitrary level of >900 iu/l was selected as a case definition to provide In Thoroughbred horses (population) does treatment with a means of counting the number of animals that might be dantrolene sodium (intervention) reduce the recurrence of described as constituting a case of exertional rhabdomyolysis exertional rhabdomyolysis (outcome)? (ER). Clinical cases of ER may exhibit considerably greater levels of CK and it should not be implied that lower CK levels Clinical scenario may not be associated with clinical signs of ER. The key results are presented as absolute risk reductions A client requests advice on the prevention of recurrent (ARR) and relative risk reductions (RRR). The ARR indicates the exertional rhabdomyloysis (RER) for a Thoroughbred horse proportion of all horses in the treatment group that have an with a history of this condition. The veterinarian is aware that improved clinical outcome as a result of the treatment (i.e. the dantrolene sodium has been suggested as a suitable proportion of horses that benefit from dantrolene treatment). preventive treatment. Both the trials described here are unusual in that a number of horses are being treated that might not be considered Search strategy appropriate candidates for prophylactic treatment. There were 74 horses in the Edwards trial and 3 horses in the McKenzie Pubmed/Medline (1966–Jan 2007) (http://pubmed.org/): trial that failed to develop high CK levels either with or dantrolene AND equine. without treatment. For this reason the RRR may be considered to better represent the expected clinical results in practice (i.e. Search outcome the proportion of horses that developed high CK levels when treated with a placebo that had low levels of CK when treated A total of 11 papers were retrieved. Nine papers (Waldron-Mease with dantrolene). et al. 1981; Beech 1982; Manley et al. 1983; Court et al. 1987; As part of the appraisal process for a CAT, the author would Klein et al. 1989; Valverde et al. 1990; Fletcher et al. 1993; Lopez normally establish the confidence intervals of the ARR (and any et al. 1995; Wooldridge et al. 2002) were deemed to be values derived from it). Even when the results would indicate irrelevant to the clinical question. Two papers (Edwards et al. complete success it is not possible to provide a meaningful 2003; McKenzie et al. 2004) provided useful data resulting from estimate of the confidence intervals of the results when the studies using appropriate methodology (Table 1). numbers involved are <5. In both the clinical trials appraised The trial described by Edwards et al. (2003) used a well- statistical significance was achieved when the overall analysis defined, clinically relevant population (Thoroughbreds in of the changes in plasma CK levels were examined. It is only training) that had returned to exercise after a 2-day lay off on when the data is converted to ‘clinical cases’ that it becomes 2 separate occasions (following public holidays). The horses impossible to establish statistical certainty (or to be more exact used by McKenzie et al. (2004) were related horses with a - a lack of uncertainty) due to the low numbers of ‘cases’. history of RER that were maintained in a university facility. The number needed to treat (NNT) is a figure representing These horses might be regarded as a less clinically relevant the number of animals that would need to receive the population as they may not represent the type of spontaneous intervention (dantrolene in this case) in order to have one case seen by equine practitioners. animal with a favourable outcome (i.e. to prevent one horse The case definition used has been created for the developing exertional rhabdomyolysis). The NNT is calculated purposes of this critically appraised topic (CAT). In both as the inverse of the ARR (1/ARR). When a treatment is 100% clinical trials the authors concentrated on the actual effective the NNT = 1 (every time you treat a patient you have differences in plasma CK levels following exercise regardless a favourable outcome). 98 EQUINE VETERINARY EDUCATION / AE / March 2007 TABLE 1: Comparison of 2 relevant studies on the treatment of equine rhabdomyolysis with dantrolene Author, date, Clinical country Study type Population Dose Case definition Numbers Key results interpretation Edwards et al. Randomised Thoroughbred 800 mg/horse Plasma creatine Incidence ARR: 4%1 NNT2 = 25 2003 blinded placebo racehorses per os kinase levels (placebo): 3/77 RRR: 100% (all horses) UK controlled age 2–5 years (given 1 h >900 iu/l after Incidence NNT = 1 (cases) cross-over in training before exercise) training exercise (treated): 0/77 (minimum 1 h of trotting) McKenzie et al. Randomised Related 4 mg/kg bwt Median plasma Incidence ARR: 40% NNT = 3 2004 placebo Thoroughbred per os creatine kinase (placebo): 2/5 RRR: 100% (all horses) US controlled horses age 5–12 (given 1.5 h levels >900 iu/l Incidence NNT = 1 (cases) cross-over years with before exercise) 4 h after exercise (treated): 0/5 history of RER (repeated treadmill sessions, alternating walk, trot and canter for a minimum of 0.5 h) ARR = absolute risk reduction; RRR = relative risk reduction; NNT = number need to treat. 1 When a treatment is being compared (to a placebo or another treatment) the absolute risk reduction or ARR (the proportion of patients with an improved outcome) is a good clinical measure for practical use. 2 The NNT can be calculated from the ARR. The NNT represents the number of patients we would have to treat to have one extra patient with a successful outcome. Conclusion is provided in the next section. Having established the clinical question the first task in the There is some evidence that dantrolene sodium is an effective authoring process is to perform the literature search. In this prophylactic treatment for the prevention of RER in case a search of the National Library of Medicine database, Thoroughbred horses. Neither of the 2 papers describing Medline was performed using Pubmed. There have not been clinical trials is of sufficient power to provide conventional many papers published on the use of dantrolene in horses and statistical confidence in the absolute risk reduction (see notes so a relatively simple query consisting of the terms Table 1). However, the best evidence available, based on the ‘dantrolene’ and ‘equine’ was used in this case which turned results from these 2 studies, suggests that dantrolene is 100% up 11 papers of possible interest. The inclusion of the search effective in preventing an episode of exertional rhabdomyloysis terms helps readers and potential updaters of the CAT to in susceptible animals. Different dosing regimes were used in repeat the search at a later date and identify any papers that should also be considered that weren’t appraised when the the 2 trials; the lower dose of 800 mg/horse given 1 h before CAT was first written. From the titles and abstracts that result exercise would appear to be sufficient. from the literature search it is possible to eliminate any that Background and discussion are not of direct relevance to question. The main task of the CAT author is to obtain full copies of the papers to be included and formally appraise the Critically appraised topics (CATs) are well established in human methodology and the results. While objectivity is essential medicine as a useful educational resource. They are designed there is inevitably some need for the author to make to help practitioners quickly assimilate the take-home message judgements and interpretations. The aim is to distil the from the primary scientific literature in a summary form while contents of the primary literature into a succinct report of the still providing the raw data from which any clinical conclusions methods used and results obtained in such a form that they are made. In order to write a CAT the author does not need a can be applied in a clinical situation. For this CAT, the author particular expertise in the veterinary discipline being appraised needed to provide a case definition that was applicable for although the appraisal process does require a systematic both the papers that were included. The authors of the approach following the principles of evidence-based original papers had no particular need to do this in the context veterinary medicine, and an understanding of clinical research of their studies and the fact that they did not provide a case methodology. definition is no criticism of their work; however, in order to This CAT seeks to appraise the current literature on the use develop a clinical conclusion from the combined results a case of dantrolene to prevent exertional rhabdomyolysis in horses. definition is required. To some extent the precise definition The CAT starts with a 3-part question that carefully defines the used was arbitrary and readers or reviewers may have different population, intervention and the outcome. These elements are views on what they consider important or relevant. important because they define the literature from which the The question addressed by the CAT is answered in the conclusions are to be reached - in other words they provide conclusion which provides the reader with the take home the definition of the literature search. It also helps to describe message. Looking at all the evidence provided: Does the the clinical scenario in which the CAT might be used and this intervention work? What clinical outcome could a veterinarian EQUINE VETERINARY EDUCATION / AE / March 2007 99 expect to obtain based on the evidence from the literature Edwards, J.G.T., Newton, J.R., Ramzan, P.H.L., Pilsworth, R.C.
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