Recommendations for anesthesia and perioperative management in patients with Ehlers-Danlos syndrome(s)

Ehlers-Danlos Syndrome (EDS, Orphanumber: ORPHA98249) is an umbrella term for a growing number of heritable connective tissue disorders, mainly featuring joint hypermobility and instability, skin texture anomalies and vascular and internal organ fragility [[1]–[3]]. The overall incidence is 1:10,000 to 1:25,000 with no ethnic predisposition [[4]], resulting in a presumed number of at least 20,000-50,000 EDS patients in the Northern America. However, the real frequency is probably underestimated due to the general lack of awareness among the various disciplines of such a protean condition, especially for the most atypical presentations. Clinical manifestations range from extremely mild phenotypes to life-threatening complications. The current Villefranche nosology recognizes six major subtypes, comprising classic (corresponding to EDS type I and II of the “old” Berlin nosology), hypermobile (EDS type III), vascular (EDS type IV), kyphoscoliotic (type VIA), arthrochalasia (types VIIA and VIIB) and dermatosparaxis (type VIIC), most of which are linked to mutations in one of the genes encoding for fibrillar collagen proteins or enzymes involved in post-translational modification of these proteins. Recently, several new EDS variants have been defined clinically and genetically. In addition, there has recently been suggested a possible connection between hypermobile EDS and the joint hypermobility syndrome [[5]], a relatively neglected rheumatologic condition recognized by specific diagnostic criteria [[6]]. However, not all researchers and clinicians agree with this view, which may be clarified by future molecular studies [[7]].

For the purposes of this review, we will use the last Villefranche classification. Most EDS subtypes are transmitted as autosomal-dominant or recessive traits; a general overview is presented in Table 1. For a comprehensive overview of genetic and clinical features, there are several published reviews on EDS [[2],[7]]. Surgery is a concern [[8]]. Vascular EDS and the other rarer EDS variants with increased vascular fragility, e.g. classic-like EDS with arterial rupture due to arginine-to-cysteine substitutions in type I collagen [[9]] and kyphoscoliotic EDS are associated with an increased frequency of arterial aneurysms and dissections. Vascular EDS is associated with spontaneous visceral ruptures. Due to the involvement of peri-articular non-ossified connective tissue, many EDS subtypes, especially the hypermobile and arthrochalasis types, may predispose to the need for orthopedic surgery.

A literature search was conducted in PubMed and EMBASE for all published literature on the clinical management of EDS. The searches, performed in November 2013, spanned the literature from 1950 to 2013. The following search string was used: Ehlers-Danlos [OR] EDS [AND] anesthesia [OR] anaesthesia [OR] perioperative management. A supplementary search was performed using the references of the selected papers, as well as from personal literature databases (TW, MC and FM). The retrieved literature was screened for information on anesthetic and perioperative management. Interventional studies (experimental or quasi-experimental designs) were defined as those in which an investigator determined the treatment regimen. Observational studies were defined as those in which treatment was decided on the basis of the clinical characteristics of each individual patient. Studies were labeled as case reports or case series when patients were individually described.

This review article does not include data obtained in clinical or laboratory animal studies. Thus, no ethical approval by clinical ethical committees or governmental responsibilities was needed for this article.

A Pubmed search retrieved 102 articles, and EMBASE 72 articles. Three further articles were obtained from the personal databases of the authors. There was one clinical trial [[10]], the rest were case reports (one or more patients undergoing anesthesia for surgical or obstetrical purposes), retrospective case series or reviews, guideline recommendations or expert opinion. Most case reports and case series deal with vascular EDS, a systematic publication bias towards the relatively rare vascular subtype (EDS subtype IV) (5% of all EDS patients). Furthermore, most retrieved case reports focus on peripartal management (i.e. obstetrical anesthesia). Five retrieved papers offered guidelines for EDS, dealing in part with anaesthetic [[11]], perioperative [[12]–[14]] or peripartal [[15]] topics. Dolan et al. [[16]] published the first recommendations for anesthesia in EDS, and Kuczkowski [[15]] published guidelines for obstetric anesthesia. Castori [[14]] summarized the relevant aspects for surgery and anesthesia in patients with hypermobile EDS. A guideline by Orphanet UK [[12]] focuses on emergencies in vascular EDS. Finally, the authors of this review published a comprehensive peer-reviewed guideline in 2013 at the web-based project “OrphanAnesthesia” (funded by the DGAI, the German society of anesthesiology and Intensive Care medicine) dealing with anesthesia and perioperative issues in patients with EDS of all subtypes.

Literature search did not identify any data with high level of evidence concerning anesthetic issues of EDS; it is mostly single case reports, case series, narrative reviews and expert opinion. We decided to present the published information and discuss its implications, based clinical heuristics, for providing general, regional and local anesthesia and perioperative care. Recommendations for surgical emergency management, obstetrical care and delivery are published elsewhere [[8],[9],[17]]. Main issues regarding perioperative management in patients with EDS are presented in Table 2 and are discussed in the following section.

Classic EDS commonly presents with various degrees of skin fragility and hyperextensibility, defective wound healing, easy bruising and generalized joint hypermobility. Hypermobile EDS is also characterized by minor but often-recognizable skin anomalies and chronic musculoskeletal pain. Vascular EDS features thin, easily bruised, translucent skin, with very marked fragility of blood vessels. The gastro-intestinal tract and gravid uterus, and, less commonly, lungs, spleen and liver, are prone to spontaneous rupture. The natural history and phenotypic spectrum of the other three major variants and all the emerging ones are less well known, but most share tissue fragility and its complications with the more common subtypes. Therefore, carrying out a detailed interview and clinical examination as well as contacting the local/regional reference center is essential in order to estimate the individual anesthetic/procedural risks for each patient. Subtype classification, with particular attention to those variants with increased vascular fragility (especially vascular EDS), should be obtained before surgery.

EDS is challenging for the anesthetist, and there is little evidence-based knowledge.

Therefore, a registry for perioperative complications in patients with EDS might help to improve safety for anesthesia and perioperative medicine in this specific population. However, safe anesthesia can be provided with adequate preparations and personal, organizational and technical resources. The above recommendations must be adequately crosschecked for each patient. The authors recommend prospective acquisition of previous anesthesia charts in any specific patient population to make realistic risk estimation with regard to airway difficulties, bleeding complications and neuraxial techniques and complication rates.