ESA Clinical Trials Network 2012

This article is accompanied by the following Invited Commentary: Wittmann M, Matot I, Hoeft A. ESA Clinical Trials Network 2012. Eur J Anaesthesiol 2013; 30:208–210. The number of patients suffering from critical limb ischaemia is large and growing. For the population aged 60 to 90 years, the prevalence is estimated at 1% and increasing.1 Current literature suggests that about 25% of these patients will need to undergo amputation.2 Even with the increased use of interventional treatment of vascular disease, amputation remains a frequently performed procedure and for the United States alone, current projections estimate that the number of patients living with loss of a limb due to vascular disease will rise from the current number of 850 000 to 2 200 000 by the year 2050.3 The prevalence of phantom pain following surgical amputation is high. A recent study confined to patients undergoing lower limb amputation for peripheral vascular disease reported phantom limb pain in 79% of patients.4 Several studies have addressed the potential of analgesic interventions to reduce the incidence of chronic phantom pain. However, these have been hampered by small numbers of patients, and heterogeneous patient groups. A recent systematic review by Ypsilantis and Tang5 concluded that robust evidence to support a positive impact of anaesthetic interventions in the prevention of phantom limb pain is, to date, lacking. In a randomised controlled trial conducted by Karanikolas et al.,6 it was suggested that strict perioperative pain control using fixed regimens of nonopioid analgesics and patient-controlled opiate analgesia could reduce the incidence of phantom limb pain from 75 to 53%. Pilot studies investigating preventive effects of peripheral nerve blockade have shown conflicting results.7,8 Borghi et al.9 reported their experience in 71 patients treated with an elastomeric infusion system connected to a sciatic nerve catheter in place for a median duration of 1 month. Here, the incidence of phantom limb pain was 15%, and phantom limb sensations were present in 39% after 12 months. However, the incidence of severe phantom limb pain was only 3%. Therefore, peripheral nerve blockade may represent a safe and effective option to prevent phantom limb pain, but no adequately powered prospective randomised trial has investigated this possibility. Why certain patients develop ongoing pain postoperatively while in others, the pain resolves, is largely unknown and, to date, unpredictable, and is the reason for a genetic component of this study. Recent mono-zygotic versus dizygotic twin studies show that heritable components contribute up to two-thirds of the risk of developing chronic pain.10 Such data clearly suggest a genetic predisposition for the development of chronic pain. An additional aim of the present study is to advance identification of these genetic factors. This study is designed to compare two interventions thought to contribute to a decreased incidence of phantom limb pain (strict intravenous pain control versus strict intravenous pain control along with peripheral nerve block). There are two main research questions. First, under optimised intravenous perioperative analgesia, what is the incidence of chronic phantom limb pain 12 months after transtibial amputation for peripheral vascular disease? Second, what is the value of continuous sciatic nerve block added to optimised perioperative analgesia in patients undergoing transtibial amputation for peripheral vascular disease? The aim of the study is to test the hypothesis that a combination of optimised intravenous pain therapy and continuous sciatic nerve block decreases the prevalence of phantom limb pain 12 months after transtibial amputation for peripheral vascular disease when compared with optimised intravenous pain therapy alone. The study is interventional, prospective, randomised and double-blinded (blinding of patient and physician). Online computer-based randomisation, stratified according to planned anaesthetic technique (spinal/general anaesthesia), will be used. Previous outcome studies investigating the effect of optimised perioperative analgesia alone have indicated a prevalence of phantom limb pain 1 year after amputation of 45%.6 A meaningful clinical effect will be assumed when the prevalence of phantom limb pain 12 months after amputation can be reduced from 45 to 30%. Taking an alpha level of 0.05 and a power of 80%, the estimated sample size per group is 163 patients; assuming a drop-out rate of approximately 20%, the trial will recruit 163/0.8 = 200 patients per treatment group. The primary efficacy variable is the prevalence of chronic phantom limb pain at 12 months. This variable will be presented for both treatment groups as proportions together with 95% confidence intervals. Logistic regression analyses will be performed to assess the effect of potential influential variables such as single nucleotide polymorphisms, preamputation pain and surgical technique. The last observation carried forward procedure will be applied in case of withdrawals. For the intention-to-treat analysis, the incidence of phantom limb pain at 7 days, 1 and 6 months will be carried forward to 1 year in case the (1-year) observation is missing. The aim is to recruit a total of 10 to 15 centres through the European Society of Anaesthesiology Clinical Trial Network. We aim to generate a network of hospitals performing approximately 400 transtibial amputations for peripheral vascular disease per year. Assuming a 50% inclusion rate and a desired inclusion of 400 patients, the recruitment period is predicted to last between 2 and 2.5 years, followed by 1-year follow-up. Thus, including follow-up, the study is projected to last for an estimated 3.5 years. Patients undergoing elective transtibial amputation for peripheral vascular disease, aged more than 18 years and with the American Society of Anesthesiologists’ (ASA) status II to IV, will be included. We will exclude patients with a contraindication to peripheral regional anaesthesia, allergy to local anaesthetics, prior amputation resulting in current phantom limb pain, severe psychiatric disease, pregnancy or breastfeeding amputation for tumour surgery, traumatic amputation and inability of the patient to give written and informed consent. All patients will receive ‘optimised intravenous pain control’. The key components of this regimen are the administration of low-dose ketamine, patient-controlled analgesia using strong opioids, and the use of nonopioids (for example paracetamol and/or metamizol). A sciatic nerve catheter will be inserted using ultrasound guidance preoperatively in all patients. Patients will receive general or spinal anaesthesia at the discretion of the treating physician. Global anaesthesia parameters will be recorded. Surgical methods are at the discretion of the treating surgeon, but will be recorded. The only interventions and standardisations will be those performed in relation to perioperative pain therapy. According to their randomisation, patients will follow one of the two standardised pain therapy regimens until 1 week postoperatively: optimised intravenous treatment (‘Control’, n = 200) with administration of isotonic saline via the sciatic nerve catheter; or optimised intravenous treatment along with sciatic nerve block (‘Intervention’, n = 200) with administration of a local anaesthetic via the sciatic nerve catheter. For all patients, participation in this study results in a thorough and continuous evaluation and strict treatment of perioperative pain. For ethical reasons, a true ‘conventional’ pain control group as described in previous trials (opioids administered intramuscularly or subcutaneously as needed, no strict control of pain scores and therapy) will not be included in the present study because these groups have featured excessive pain scores and a very high probability of chronic phantom limb pain.6,11 Data entries will be made on a paper version of the case report form. These will then be transferred to an electronic case report form (eCRF) in the OpenClinica software (Waltham, Massachusetts, USA). All investigators will ‘log-in’ with a personal code. All changes or additions to the data are tracked by the data management system in the audit trail. Access to the data entry system and eCRF is managed by the European Society of Anaesthesiology Research Office and protected by a personalised user name and password. The primary outcome measure is the prevalence of phantom limb pain 12 months postoperatively defined (yes/no) as follows: pain in the amputated area of the limb with a corresponding numerical rating scale score of at least 2 during the preceding 4 weeks (constant or at least three episodes) or ingestion of drugs administered specifically to treat phantom limb pain (classified as none, nonopioid, weak opioid, strong opioid, antidepressant, anticonvulsant, other). Selected secondary outcome measures include the incidence of phantom limb pain at 7 days, 1 and 6 months; McGill Pain Questionnaire (short-form MPQ) preoperatively and postoperatively at day 7, and 1, 6 and 12 months postoperatively; SF-12 quality of life score; overall benefit of analgesia score (OBAS) during the first postoperative week; recording of surgical handling of nerves and surgical technique; and genotype of patients assessed preoperatively. Gene haplotype will be assayed for association with acute to chronic pain conversion using single nucleotide polymorphisms from known risk factor genes including GCH1, KCNS1, Nav1.7 and P2X7R.12 This study will be conducted by the Academic Medical Center, University of Amsterdam (sponsor) and will be supported by the Clinical Trial Network, European Society of Anaesthesiology. The aim is to make a scientific case for or against the routine use of perioperative peripheral nerve blockade to prevent phantom limb pain after transtibial amputations. Acknowledgements Assistance with the article: none declared. Financial support and sponsorship: the study is funded by the European Society of Anaesthesiology (ESA). Submitted on behalf of the members of the Steering Committee: D.A. Legemate (Department of Surgery, Academic Medical Center, University of Amsterdam, The Netherlands), F. Nollet (Department of Rehabilitation Medicine, Academic Medical Center, University of Amsterdam, The Netherlands), H. Ulmer (Department of Medical Statistics, Informatics and Health Economics, Innsbruck Medical University, Austria) and J.P. Rathmell (Center for Pain Medicine, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA). Conflicts of interest: none declared. Comment from the Editor: this article was checked by the editors but was not sent for external peer review.

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