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Anaesthetic implications of vascular type Ehlers-Danlos syndrome.

SUMMARY

Vascular type Ehlers-Danlos syndrome is an inherited connective tissue disease, which is typified by tissue fragility, joint hypermobility, a tendency to bleed excessively and rupture of the uterus, the bowel and arteries. Two case reports are presented which describe the anaesthetic management of patients with spontaneous bowel perforations due to vascular type Ehlers-Danlos syndrome. Both cases were associated with relatively minor problems. The implications of this condition for anaesthesia include difficulty (and risk of complications) with vascular access, a risk of spontaneous arterial rupture in the perioperative period, possible cervical spine instability and airway trauma on intubation. There is also a risk of excessive bleeding, potentially difficult neuraxial anaesthesia and an increased risk of epidural haematoma. There also may be associated cardiac or pulmonary disease. However, these two cases and the limited previously published literature suggest that such potential complications are actually rare and that anaesthesia may be conducted in a relatively standard manner in most circumstances.

Key Words: anaesthesia, vascular type Ehlers-Danlos syndrome

Ehlers-Danlos syndrome (EDS) is a connective tissue disease with multiple subtypes, which produces joint hypermobility, skin extensibility and tissue fragility. Subtypes of EDS are classified by both clinical features and biochemical or genetic markers of the underlying pathology in collagen production. Vascular type EDS is particularly noteworthy, as it confers a risk of sudden organ or arterial rupture which is not a typical feature of other forms of EDS (1). The scientific literature on the anaesthetic management of patients with vascular type EDS is limited to a small number of case reports. The case reports presented here and the brief review which follows aim to further expand on this limited information, to summarize the known possible complications of interest to the anaesthetist and to determine what special precautions, if any, are required when anaesthetizing patients with this condition.

CASE HISTORIES

Case 1

A 34-year-old man presented to the emergency department with a history of several hours of severe lower abdominal pain on a background of episodic lower abdominal pain of three months duration. He was febrile, had tachycardia, was dehydrated and had abdominal tenderness. A CT scan of the abdomen showed multiple dilated colonic and small bowel segments, with an area of diffuse mesenteric infiltration and a suggestion of small bowel perforation.

Further history was obtained which included a diagnosis of EDS at age five years. Complications of this had included a dislocated elbow and frequent fingerjoint subluxations. While he had a history of easy bruising, dental extractions had not caused excessive bleeding. His family history included a brother with EDS and his mother had a history of lax finger ligaments but had never had any formal diagnosis made. He had an 11-month-old daughter who had not as yet shown any signs of EDS.

A clinical diagnosis of vascular type EDS was made on the basis of the bowel perforation in the setting of known EDS. He was transferred to the operating theatre for an urgent laparotomy. Routine noninvasive monitoring was established (ECG, noninvasive blood pressure, pulse oximetry). A right subclavian triple-lumen central line had already been inserted on his arrival in the emergency department. An arterial cannula was avoided due to the presence of EDS. Following a rapid sequence induction with fentanyl, propofol and suxamethonium, the trachea was intubated with a size 8.0 endotracheal tube with cricoid pressure being maintained. A grade I Cormack and Lehane view of the larynx was obtained. Given the history of EDS, special care was taken holding the facemask to avoid excessive pressure and the endotracheal tube was well lubricated and inserted extremely carefully to minimize the risk of airway trauma. Gaining further intravenous access required multiple attempts as veins on the forearm and hand were perforated easily.

Following intubation a lubricated nasogastric tube was inserted with the aid of a laryngoscope and Magill forceps. This resulted in a large tongue haematoma and brisk bleeding from the pharyngeal mucosa which stopped spontaneously. Anaesthesia was maintained with sevoflurane in an air/oxygen mixture with an [F.sub.i][O.sub.2] of 0.6 throughout the operation. Muscle relaxation was maintained with boluses of rocuronium, which was reversed with neostigmine and atropine at the end of the operation. Morphine was given intraoperatively. At laparotomy two small bowel perforations were found. A resection of a small bowel loop and an anastomosis was performed. The surgeon found the tissues to be very delicate, which caused the operation to be prolonged. However, bleeding was not problematic.

Following skin closure the patient was extubated and transferred to the intensive care unit. A morphine patient-controlled analgesia system (PCA) was provided for analgesia. An epidural was not considered as an option preoperatively due to potential difficulty with insertion and an increased risk of misplacement or epidural haematoma with EDS. A referral to a geneticist was made to further investigate and confirm the subtype of EDS and counsel the patient and his family. He was discharged from ICU on day 5 postoperatively and discharged from hospital on day 11. His postoperative course was uneventful.

Case 2

A 25-year-old man presented to the emergency department with a one-hour history of severe lower abdominal pain of sudden onset. His past history included varicose vein surgery at age 19, a spontaneous rectus sheath haematoma at age 22, idiopathic kyphoscoliosis, an inguinal hernia repair as a neonate and a tendency to easy bruising and excessive bleeding. His significant family history was that his father had died from a ruptured aortic aneurysm.

An abdominal CT scan showed thickened small bowel and intraluminal gas in the distal ileum suggestive of inflammatory bowel disease. He was admitted for observation, fasted and had a nasogastric tube inserted, which caused copious nasal bleeding. Soon after he had increasing pain and was found to have gas under the diaphragm on chest X-ray so an urgent laparotomy was performed. In the operating theatre routine non-invasive monitoring was established and a rapid sequence induction was performed with fentanyl, propofol, suxamethonium and cricoid pressure. Grade I laryngoscopy allowed easy intubation. He underwent a three-hour procedure to oversew a perforation of the sigmoid colon. The surgery was complicated by excessive bleeding, which made surgery laborious. Total blood loss was one litre. His haemodynamics remained stable. Anaesthesia was maintained with sevoflurane in air and oxygen with an [F.sub.i][O.sub.2] of 0.5. Rocuronium was used for muscle relaxation and later reversed with neostigmine and atropine. He was extubated at the end of surgery. Morphine was given intraoperatively and a morphine PCA was provided for postoperative analgesia.

Postoperatively, a peripherally inserted central line (PICC) was placed via the cubital fossa to enable parenteral nutrition to be given. However, this dislodged and became extravascular within hours. Dehiscence of the abdominal wound occurred after six days and he was returned to theatre. During this operation a radial arterial cannula and an internal jugular central catheter were inserted without incident. Again anaesthesia was instituted with a rapid sequence induction using fentanyl, propofol, suxamethonium and was uneventful. The wound was found to be necrotic and there were areas of bowel infarction. The wound was left open and he was left intubated and sent to the intensive care unit. He was extubated the following day.

A further laparotomy was undertaken to achieve wound closure, at which further bowel perforations were noted and repaired. His postoperative course was complicated by further wound breakdown and bowel perforations requiring re-operation. His wound continued to fail to heal and a suspicion of an underlying connective tissue disorder was confirmed by a geneticist who reviewed him after he had been an inpatient for three months. A clinical diagnosis of vascular type Ehlers-Danlos syndrome was then made. The patient declined further testing to confirm the diagnosis.

He remained an inpatient for the next six months during which time he had recurrent bowel perforations, a non-healing abdominal wound and became cachectic despite enteral and parenteral nutrition. He underwent a further six surgical procedures to debride and skin graft his wound and to repair recurrent bowel perforations. Anaesthesia was similar to the previous occasions and remained uneventful. There was no note of further excessive bleeding or other difficulties. The central venous access was changed four times without complication using both subclavian and both internal jugular veins. With ongoing perforations despite multiple repairs and extensive supportive treatment, further therapy was eventually withdrawn due to futility and he died ten months after admission.

DISCUSSION

The above case reports give some indication of the context in which anaesthetists may be presented with patients who have vascular type EDS and the extremes that may be encountered. The diagnosis may or may not be known preoperatively. The two cases are somewhat reassuring for anaesthetists, as in neither case did any of the major potential complications occur, whether or not allowance was made for the syndrome.

Vascular type Ehlers-Danlos syndrome is an autosomal dominant condition which results from a mutation in the COL3A1 gene which causes production of abnormal Type III collagen (2), which is an essential component of many connective and elastic tissues including the skin, blood vessels, gastrointestinal tract and uterus. The clinical diagnosis of the vascular type is strongly suggested by the presence of two or more of the following: thin translucent skin; arterial, intestinal, or uterine fragility or rupture; extensive bruising; and a characteristic facial appearance, consisting of a thin nose, large eyes and thin lips due to decreased subcutaneous adipose tissue. Joint hypermobility is usually limited to the fingers. Other manifestations may include pneumothoraces, scoliosis and early onset varicose veins (1).

A serious complication such as a bowel, uterine or arterial rupture may be the initial presentation. Life expectancy is shortened due to the risk of organ and vessel rupture causing premature death and the median lifespan is estimated at 48 years (3). The clinical diagnosis can be confirmed by fibroblast culture from a skin biopsy to detect abnormal type III collagen or by detection of a mutation in the COL3A1 gene (2). The estimated prevalence of vascular type EDS is 1 in 50,000 (4). Bowel rupture due to vascular type EDS accounts for about 25% of the complications of the syndrome and contributes to death in 8% (3). The classification of EDS is by six descriptive terms but was previously numbered arbitrarily, hence vascular type EDS has also been known as Type IV EDS (Table 1). (1) Many patients do not fit neatly into a particular type and remain unclassified.

The problems that may have been related to vascular type EDS in the above cases included difficulty with intravenous access, prolonged surgery, excessive bleeding and mucosal bleeding with nasogastric tube insertion. However none of these problems is unique to EDS and may have occurred in normal patients. Only five other cases of anaesthesia for vascular type EDS have been previously published. One of these cases involved a laparotomy for bowel perforation (5), two cases involved a laparotomy for post partum haemorrhage (6, 7), one case was an elective caesarean section (8) and one was a forceps delivery under epidural blockade (9).

The relevance of vascular type EDS to the anaesthetist includes the potential complications of vascular access, the risk of skin damage and joint dislocation when positioning for surgery, risks of trauma during airway management, an associated bleeding diathesis and the complication of sudden arterial rupture. Other concerns include special considerations during pregnancy and delivery if anaesthesia is required, the potentially increased risk of epidural haematoma with neuraxial blockade and cardiac and pulmonary problems that may be associated with the syndrome.

The hyperelastic, fragile skin and thin-walled vessels typical of most types of EDS may make gaining vascular access difficult or hazardous, with the potential to pass readily through arterial or venous walls with needles, cause the formation of large haematomas or aneurysms and the potential for catheters to erode through vessels easily. These potential complications have led to the suggestion that such vascular access should be minimized or avoided if possible (7). However, as with our two cases, few complications with vascular access have been reported. While central venous cannulation was complicated by carotid artery punctures and subsequent erosion through a vein wall in one case report (5), it has been uneventful in most others (6,7). No complications of arterial line placement have been reported (5-8). In our first case, a decision was made to avoid an arterial cannula because of the potential risks with this procedure in EDS, but in case 2 when the diagnosis was not made for some three months after admission and no such precautions were taken, no complications arose from arterial cannulation.

While extravasation did occur after the initial PICC line in case 2, this did not continue with subsequent central lines and therefore may not have necessarily been due to EDS. Multiple central lines were subsequently inserted without any problems and without taking any special precautions since the diagnosis was unknown for some time, which perhaps supports the notion that the purported hazards of invasive monitoring are uncommonly encountered in reality.

Peripheral venous cannulation is also potentially difficult in these patients as unintentional perforation of thin vein walls can occur easily and subsequent extravasation of fluid into the subcutaneous tissues may go unrecognized due to the hyperelasticity of the skin allowing large volumes of fluid to easily accumulate (7). Also the skin may be fragile and easily bruised when handling and positioning patients. In our first case, multiple attempts at cannulation were required, but no other problems from the successfully placed cannula were encountered.

Intubation could be potentially hazardous due to a risk of atlantoaxial subluxation caused by cervical ligamentous laxity. This was investigated in one study, where the cervical spines of 26 patients with EDS were X-rayed (10). Of these, two patients out of the three with vascular type EDS had radiographic evidence of atlantoaxial subluxation. This was not present in the other 23 patients with other types of EDS. However, this is clearly a very small number of patients and this finding could have been due to chance alone. Also, intubation may be potentially complicated by bruising or haematoma formation in the airway due to the increased tissue fragility and tendency to bruising.

Preoperative coagulation tests are usually normal in vascular type EDS despite a known tendency to bleed excessively (11). As the syndrome can have variable severity in this regard, the patient's past history can also be used as a guide to the likelihood of bleeding. The nature of the surgery can also be a guiding factor in anticipating blood loss, with vascular surgery, including varicose vein surgery, being well recognized as conferring a particularly high risk for severe haemorrhage (12). In our cases, bleeding caused by nasogastric tube insertion was self-limiting in both cases and while bleeding did slow surgery in case 2, this was not associated with blood loss great enough to need blood transfusion or to cause haemodynamic instability.

Arterial rupture is a common cause of death from vascular type EDS (3). Patients with vascular type EDS are prone to arterial aneurysms, including cerebral aneurysms, which may unexpectedly rupture. The risk of aneurysm rupture is particularly high in the postoperative period and in pregnancy (13). Continuous blood pressure monitoring during anaesthesia and the postoperative period could help detect and treat hypertension so as to minimize the risk of aneurysm rupture and this benefit may outweigh any concern about the hazards of invasive arterial blood pressure monitoring.

Pregnancy in vascular type EDS is high risk. The risk of death during or immediately after pregnancy has been estimated as 1 in 23 (3). Risks include rupture of the uterus or major vessels in pregnancy and the peripartum period, premature rupture of membranes and severe lacerations of the perineum at delivery. Epidural and spinal anaesthesia have been used successfully in vascular type EDS without complication (8,9). The theoretically increased risk of neuraxial haematoma due to a tendency to bleed excessively may make the use of smaller spinal needles potentially safer than epidurals; however difficulties with haemostasis can potentially prolong surgery beyond the duration of a single-shot spinal which may then expose the patient to the further risks of general anaesthesia. While the risk of uterine rupture during labour may make elective caesarean section the preferred mode of delivery this management may then increase the risk of uterine rupture in subsequent pregnancies.

A lack of normal feedback sensation during insertion due to the abnormal ligaments may make insertion of epidural or spinal needles hazardous, with risk of misplacement and nerve damage (14). Due to this risk, and also the risk that the bleeding diathesis of vascular type EDS could predispose to an epidural haematoma, an epidural was avoided in case 1. However, regardless of these potential problems, a morphine PCA was considered a satisfactory alternative for postoperative analgesia. Should a strong indication for an epidural exist, the published description of the safe use of epidurals referred to above may give some reassurance (9). One other potential problem with epidurals is that local anaesthetic solutions may be less effective than usual in this syndrome (15).

Patients with vascular type EDS are at risk of developing pneumothoraces due to weakened pleura and bullous lung disease (16). There is also an association with myocardial ischaemia and infarction due to friable coronary artery endothelium predisposing to plaque formation (14,17). Other cardiac problems encountered include aortic regurgitation, tricuspid regurgitation and mitral valve prolapse (17).

Vascular type Ehlers-Danlos syndrome is an uncommon disorder with multiple anaesthetic implications. While only minor problems occurred during the anaesthetic management of our two reported cases, there are potentially many problems that could arise as described here. However, the relative paucity of case reports of the anaesthetic management of vascular type EDS may suggest that such problems are rarely actually encountered. Also, most complications that could occur are nonspecific and could occur in normal patients. The important distinguishing feature of the syndrome remains the potential for sudden arterial rupture and exsanguination, bowel perforation and uterine rupture.

The most likely problem during anaesthesia may be difficulty with vascular access, however even this may not be problematic. The use of arterial lines, central lines and neuraxial anaesthesia should probably be as per usual indications so long as the potential hazards are recognised. Invasive monitoring may even be particularly indicated, given the risks of perioperative arterial rupture and excessive bleeding, but it remains unclear how frequently such events occur.

Overall it seems likely that anaesthesia can be undertaken safely with standard techniques for patients with vascular type EDS without special precautions. However, awareness of the potential problems may assist the anaesthetist in the safe management of patients with this rare syndrome.

Accepted for publication on May 9, 2006.

REFERENCES

(1.) Beighton P, De Paepe A, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK). Am J Med Genet 1998; 77:31-37.

(2.) Pyeritz RE. Ehlers-Danlos syndrome. N Engl J Med 2000; 342: 730-732.

(3.) Pepin M, Schwarze U, Superti-Furga A, Byers P Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. N Engl J Med 2000; 342:673-680.

(4.) Byers PH. Ehlers-Danlos syndrome type IV. a genetic disorder in many guises. J Invest Dermatol 1995; 105:311-313.

(5.) Solan K, Davies P Anaesthetic and intensive care management of a patient with Ehlers-Danlos Type IV syndrome after laparotomy. Anaesthesia 2004; 59:1224-1227.

(6.) Yamashita M, Narita M, Ishihara H, Matsuki A, Oyama T. Uterine Rupture in a case with Ehlers-Danlos Syndrome Type IV--anesthetic considerations. Middle East J Anesthesiol 1987;9:277-281.

(7.) Dolan P, Sisko F, Riley E. Anesthetic considerations for Ehlers-Danlos syndrome. Anesthesiology 1980; 52:266-269.

(8.) Brighouse D, Guard B. Anaesthesia for caesarean section in a patient with Ehlers-Danlos syndrome type IV Br J Anaesth 1992; 69:517-519.

(9.) Campbell N, Rosaeg O. Anesthetic management of a parturient with Ehlers-Danlos Syndrome Type IV Can J Anaesth 2002;49:493-496.

(10.) Halko GJ, Cobb R, Abeles M. Patients with type IV Ehlers-Danlos syndrome may be predisposed to atlantoaxial subluxation. J Rheumatol 1995; 22:2152-2155.

(11.) De Paepe A, Malfait F. Bleeding and bruising in patients with Ehlers-Danlos syndrome and other collagen vascular disorders. Br J Haematol 2004; 127:491-500.

(12.) Oderich GS, Panneton JM, Bower TC et al. The spectrum, management and clinical outcome of Ehlers-Danlos syndrome type IV. a 30-year experience. J Vase Surg 2005; 42:98-106.

(13.) Barabas A. Ehlers-Danlos Syndrome Type IV N Engl J Med 2000; 343:366.

(14.) Price CM, Ford S, St John Jones L, Murday V Myocardial ischaemia associated with Ehlers-Danlos syndrome. Br J Anaesth 1996; 76:464-466.

(15.) Glynn JC, Yentis SM. Epidural analgesia in a parturient with classic type Ehlers-Danlos syndrome. Int J Obstet Anesth 2005; 14:78-79.

(16.) Dowton SB, Pincott S, Demmer L. Respiratory complications of Ehlers-Danlos syndrome type IV Clin Genet 1996. 50:510-514.

(17.) Kitazono T, Imazumi T, Imayama S et al. Two cases of myocardial infarction in type IV Ehlers-Danlos syndrome. Chest 1989;95:1274-1277.

D. LANE *

Department of Anaesthesia, Calvary Hospital, Australian Capital Territory, Australia

* M.B., B.S., Senior Registrar.

Address for reprints: Dr Daniel Lane, Department of Anaesthesia, Calvary Hospital, Haydon Drive, Bruce, A.C.T 2617.
TABLE 1
Classification of Ehlers-Danlos Syndrome(1)

Type (previously
numbered type in Defective Protein Defective Gene
parentheses)

Classical (I/II) type V procollagen COL5A1/COL5A2

Hypermobility (III) not known not known

Vascular (IV) type III procollagen COL3A1

Kyphoscoliotic (VI) lysyl hydroxylase1 PLOD1

Arthrochalasis type I procollagen COL1A1/COL1A2
(VIIA/B)

Dermatospraxis procollagen-N-proteinase ADAMTS-2 gene
(VIIC)

Type (previously
numbered type in Major diagnostic criteria
parentheses)

Classical (I/II) skin hyperextensibility, widened atrophic
 scarring, joint hypermobility

Hypermobility (III) generalized joint hypermobility, mild skin

Vascular (IV) involvement excessive bruising, thin and
 translucent skin, arterial/intestinal/
 uterine fragility or rupture,
 characteristic facial appearance

Kyphoscoliotic (VI) severe muscular hypotonia at birth,
 generalized joint laxity, kyphoscoliosis at
 birth, scleral fragility and rupture
 of the globe

Arthrochalasis partial loss or complete skipping of exon 6
(VIIA/B) severe generalized joint hypermobility with
 recurrent subluxations, congenital bilateral
 hip dislocation

Dermatospraxis severe skin fragility, sagging, redundant
(VIIC) skin, excessive bruising
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Author:Lane, D.
Publication:Anaesthesia and Intensive Care
Date:Aug 1, 2006
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