Open Journal of Anesthesiology, 2020, 10, 13-29

https://www.scirp.org/journal/ojanes

ISSN Online: 2164-5558

https://www.scirp.org/pdf/ojanes_2019123013435518.pdf

Perioperative Care in Patients with Ehlers Danlos Syndromes

Pradeep Chopra1*, Linda Bluestein2

1Brown Medical School, Pain Management Center, Rhode Island, USA

2Medical College of Wisconsin, Central Wisconsin, Wisconsin, USA

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How to cite this paper: Chopra, P. and Bluestein, L. (2020) Perioperative Care in Patients with Ehlers Danlos Syndromes. Open Journal of Anesthesiology, 10, 13-29.https://doi.org/10.4236/ojanes.2020.101002

Received: December 7, 2019

Accepted: December 28, 2019

Published: December 31, 2019

Copyright © 2020 by author(s) and Scientific Research Publishing Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

Open Access

Abstract

Background: There is an increasing recognition of patients with Ehlers Dan- los Syndromes. The laxity of the ligaments and the weakness of the connec- tive tissue has resulted in increasing number of patients requiring surgical in- tervention. Ehlers Danlos Syndromes are not about hypermobile joints only, they are associated with multiple co-existing conditions such as Chiari mal- formation, Tethered Cord Syndrome, spinal instability, abdominal pain, Dy- sautonomia and Mast Cell Activation Syndrome. The combined incidence of Ehlers Danlos Syndromes is 1 in 5000 people. Most experts believe that the actual incidence is much higher. Many of these cases are under-diagnosed. Nevertheless, patients with Ehlers Danlos Syndromes, diagnosed or undiag- nosed often require surgical intervention. This review article has been written to shed light on the need for special consideration during anesthesia. Objec- tives: Our objective was to conduct a review of anesthetic considerations in patients with Ehlers Danlos Syndromes. Study Design: We used a narrative review design. Methods: This review was done using searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articlesfrom inception to 2019. Other data sources included hand searches of publications driven by manuscript authors. Search terms included concepts of “Ehlers Danlos Syndrome”, “EDS”, “pain”, “anesthesia”, “surgery” and combination of terms. Search method was not re- stricted to any one language. Results: Articles were screened by title, abstract, and full article review. They were then analyzed by specific clinical indica- tions and appropriate data was presented based on critical analysis of those articles. Limitations: More studies about the effect of anesthetic techniques and Ehlers Danlos Syndromes are required. Conclusions: Patients with Eh- lers Danlos Syndromes may present with an array of coexisting medical con- ditions such as Dysautonomia, Mast Cell Activation Syndrome, Chiari Mal- formation, Tethered CordSyndrome, Craniocervical instability, Gastroparesis, altered sensitivity to local anesthetics. Anesthetic techniques need to be modified according to the presentation. Preoperatively, a note should be made of the joints that sublux most often, craniocervicalinstability. They are prone to temporomandibular joint subluxation, obstructive sleep apnea and tracheomalacia, spontaneous pneumothorax, POTS, MCAS, insensitivity to local anesthetics and coagulation disorders. Intraoperative considerations should include fiberoptic intubation, IV fluidloading for POTS, avoid drugs that release histamine, unpredictable response to opioids, precautions forga- stroparesis. Patient should be positioned to avoid joint subluxation and over stretching nerves. Postoperative considerations include maintaining hemo- dynamic stability, avoid exacerbation ofsymptoms of MCAS, high suspicion of occult bleeding, high risk of post dural puncture headache in patients un- dergoing spinal procedure or neuroaxial block.

Keywords

Anesthesia, Ehlers Danlos Syndromes, POTS, MCAS, Mast Cell Activation Syndrome, Postural Orthostatic Tachycardia Syndrome

1.  Introduction

This comprehensive review of perioperative care in patients with Ehlers Danlos Syndromes focuses on current understanding of anesthetic needs of this special population. As our understanding of Ehlers Danlos Syndromes has grown ex- ponentially so has the need to understand perioperative management of these cases. There is a rising recognition of patients with Ehlers Danlos Syndromes. The laxity of the ligaments and the weakness of the connective tissue has re- sulted in increasing number of patients requiring surgical intervention. Ehlers Danlos Syndromes are not about hypermobile joints only, theyare associated with multiple co-existing conditions such as Chiari malformation, Tethered CordSyndrome, spinal instability, abdominal pain, Dysautonomia and Mast Cell Activation Syndrome. The combined incidence of Ehlers Danlos Syndromes is 1 in 5000 people [1]. Most experts believe that the actual incidence is much higher. Many of these cases are under-diagnosed. Nevertheless, patients with Ehlers Danlos Syndromes, diagnosed or undiagnosed often require surgical in- tervention. This review article has been written to shed light on the need for spe- cial consideration during anesthesia.

The Ehlers-Danlos Syndromes (EDS) are heritable connective tissue disorders characterized by joint hypermobility, skin hyperextensibility and connective tis- sue fragility. The 2017 International Classification for the Ehlers-Danlos Syn- dromes recognized 13 subtypes (Table 1). The diagnosis of EDS is based on a set of major and minor clinical criteria. A definitive diagnosis for all subtypes (ex- cept hypermobile type) depends on a molecular confirmation with identification of the causative variant(s) in the respective gene. As the genetic basis of hypermobile EDS subtype is unknown, its diagnosis relies on a strict set of clinical findings. In 2017, updated and much more strict criteria were established for the Hypermobile type of Ehlers-Danlos Syndrome (hEDS), by far the most common subtype of the Ehlers-Danlos Syndromes. At this same time, a new di- agnostic category, Hypermobility Spectrum Disorders (HSD), is a group of con- ditions related to joint hypermobility (JH). HSD are intended to be diagnosed after other possible diagnoses are excluded, such as any of the subtypes of Ehlers Danlos Syndromes (EDS) [2].

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Patients with EDS present for surgical procedures frequently due to their tis- sue fragility, joint instability, vascular fragility, and association with neurosur- gical co-existing conditions. This article willdiscuss principles of perioperative care in patients undergoing major or minor surgery.

4.  Preoperative

It is important to understand which subtype of EDS the patient has as well as have an awareness of the occasional possibility of overlap in pathologic features between the different subtypes. For example, a patient with cEDS may have fea- tures of vEDS such as aortic root dilatation or a vascular anomaly.

In a preoperative history and physical examination, it is important to note which joints are prone to recurrent subluxations or dislocations. Patients will have some joints that sublux more easily than others. These joints need to be protected by keeping them in the anatomical position during the intraoperative and postoperative periods. Additionally, positioning changes need to be carefully planned due to the potentialfor trauma to neural structures as well as any weak connective tissue such as ligaments, tendons, jointcapsules etc.

Patients with EDS can have Craniocervical instability (CCI) with related de- formation of the brainstem and upper spinal cord, basilar invagination or ven- tral brainstem compression. They can also have Chiari malformation with re- stricted CSF flow, Idiopathic Intracranial Hypertension, C4-C5 osteochondrosis and mid-thoracic osteochondrosis.

This population is also prone to Temporomandibular Joint Dysfunction (TMJ) [6]. Younger patients have a greater incidence of subluxations, whereas older patients develop restricted range of motion. With recurrent subluxations, the temporomandibular joint (TMJ) has a tendency to become arthritic, further restricting range of motion [7] [8]. Any of these conditions should lead one to strongly consider fiberoptic intubation in order to avoid manipulation of the cervical spine and minimize the risk of TMJ injury.

Obstructive sleep apnea has been reported in patients with EDS [9]. Patients with a history of stridor on expiration may have tracheomalacia. On palpation of the suprasternal notch, the trachea may feel soft.

A history of spontaneous pneumothorax or bullae on chest x-ray should be elicited. Rib subluxations are common in EDS and should be considered in the differential diagnosis of chest pain. If the patient hassignificant kyphosis and/or scoliosis pulmonary function testing should be considered. The level of the ky-

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phosis or scoliosis should be noted in case a neuraxial block is planned. Patients with EDS usually have a dynamic scoliosis.

Dysautonomia is a common comorbid condition in EDS [10] [11]. Postural orthostatic tachycardia syndrome (POTS) is the most common type of dysauto- nomia in the EDS population. They may also present with neurally mediated hypotension, orthostatic hypotension or orthostatic intolerance [12].Patients usually complain of palpitations, lightheadedness, blurry vision, mental fog, and/or fatigue. On examination, patients with POTS have a sustained increase in heart rate of ≥30 beats/minute (≥40 beats/minutes in patients age 18 or younger) within 10 minutes of standing with an absence of orthostatic hypotension (>20 mmHg drop in systolic blood pressure) [12]. These patients are treated with oral (or occasionally intravenous) sodium chloride, electrolyte fluids, vasopressors (midodrine) and/or beta blockers [13] [14].

Mast Cell Activation Syndrome (MCAS) is another common comorbid condi- tion in EDS [15] [16].Patients with MCAS present with multisystemic symp- toms related to inappropriate activation of mastcells and subsequent effects due to the release of mast cell mediators [17] [18]. Clinical presentation ofMCAS in- cludes skin abnormalities (rashes, hives), unexplained pruritus, flushing, diarr- hea, abdominal cramping, anaphylaxis, peptic ulcer, osteoporosis, dermato- graphism, asthma, gastroparesis, and nausea[19]. It is important to note triggers for MCAS exacerbations. Some of the more common triggers are changes in temperature, stress, physical stimuli such as pressure or friction, fever, infection, invasiveprocedures (general anesthesia, surgery), heat, radiologic contrast me- dia, and drugs (opioids, non-steroidal anti-inflammatory drugs, neuromuscular blocking drugs, and antibiotics) [20]. Treatment ofMCAS includes minimizing exposure to any triggering agents, antihistamines (H1 and H2 receptorantagon- ists), and mast cell stabilizers such as sodium cromoglycate. In the perioperative setting, severe flares can be handled with histamine H1 and H2 receptor anta- gonists, glucocorticoids(methylprednisolone 10 - 250 mg IV/IM or 2 mg/kg for pediatric patients), and benzodiazepines [21]. If administering diphenhydramine IV push, it should be given over at least five minutes as these patients may be hyperreactive to chemicals leached from IV tubing. Occasionally, a continuous infusion ofdiphenhydramine is required. Exacerbation of Mast Cell Activation Syndrome (MCAS) may alsoexacerbate symptoms of POTS [16].

Gastrointestinal complaints are very common in the EDS population. Dysmo-

tility (usually gastroparesis) is common [22]. Patients often complain of abdo- minal fullness or bloating after eating a small portion of food, as well as alter- nating diarrhea and constipation [23]. These patients may need to be kept NPO longer and should be considered full stomach at all times. Due to the risk of hy- povolemia, liberalizing NPO for liquids should be considered. Caution should be exercised while doing mask ventilation to minimize the risk of intestinal rupture. Gastroparesis, MCAS and POTS all may increase the risk of postoperative nau- sea and vomiting [24]. Nausea in EDS can be particularly difficult to treat as it may stem from numerous causes including gastrointestinal slowing, MCAS,

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POTS, craniocervical instability (CCI), or centrally mediated causes (Chiari malformation, intracranial hypertension, intracranial hypotension, spontaneous CSF leak) [25].

Opioids administered during the perioperative period may increase nausea and gastroparesis. Opioids,especially kappa opioid receptor agonists inhibit the release of antidiuretic hormone and oxytocin, leadingto a diuretic effect. Opio- ids also cause release of histamine which can cause hypotension. Morphine can cause peripheral venous and arteriolar dilation, reduced peripheral resistance, and inhibition of baroreceptor reflexes. Opioids may increase orthostatic into- lerance in this population. Fentanyl and sufentanil do not have a significant ef- fect on hemodynamics partly because they do not release histamine[26]. Anec- dotally, it has been noticed that patients with EDS have a weak response to the analgesic effects of opioids. In the preoperative evaluation it is helpful to elicit any history of response to opioids in the past or past surgeries.

Neuropathic pain often occurs in patients with EDS [27]. This can be due to Small Fiber PeripheralNeuropathy, Complex Regional Pain Syndrome, and En- trapment Neuropathy [5]. The patient may present with allodynia, dysesthesia, and hyperalgesia. The preoperative evaluation may reveal possible Central Sensi- tization. The limb or body part with neuropathic pain will need careful handling so as not to exacerbate pain [28]. Ketamine, an effective analgesic for neuro- pathic pain, can be considered forperioperative use in order to minimize opioid requirements thus lowering the risk of gastroparesis andhistamine release.

Patients with EDS often have an abnormal response to lidocaine [29]. They may have local anestheticresistance and/or delayed onset. Alternatively, they may have local anesthetic sensitivity or a prolonged effect. Inquiry into any pre- vious experience with local anesthetics may provide useful information. Atypical reactions to lidocaine are the most commonly reported, however it is unknown if this population responds abnormally to other local anesthetic agents. Anecdo- tally, mepivicaine may be a better choice [30].

Neuraxial blocks may be challenging in the patient with EDS. The potential for unpredictable effects of lidocaine should be taken into consideration. Pa- tients with EDS are at increased risk of developing post-dural puncture head- aches (PDPH) [31]. Kyphosis or scoliosis is unlikely to affect the spread of the local anesthetic unless it is very severe, as the spinal changes are usually dynamic in EDS and limited to the cervical and thoracic regions.

Peripheral nerve blocks also present certain additional considerations in EDS patients. The duration and density of the nerve block may be less than antic- ipated due to local anesthetic resistance. Preexistingmotor and sensory deficits should be sought and documented. Additionally, if special positioning of the pa- tient is required (extreme head rotation, prone position etc.), joints at increased risk ofdislocation/subluxation should be protected as much as possible [32].

EDS patients may also present with an increased risk of complications due to bleeding disorders and/or tissue fragility [33]. Patients with EDS may have bleeding disorders. Easy bruising is a common featureof all EDS subtypes. It is unclear if this is due to platelet dysfunction, capillary fragility or both. Although vascular fragility is a feature of vEDS and in the rare subtype dermatosparaxis type EDS (dEDS), it can be present to a certaindegree in almost any subtype of EDS. Bleeding in EDS may be from a coagulopathy or structural fragilityof the vascular tree and its supporting matrix [34]. Desmopressin (DDAVP) has been shown to reduce transfusion requirements in EDS [35] [36]. When given preo- peratively it reduces complications ofbleeding significantly. When handling tis- sues, surgeons should be aware of potential tissue fragility andincreased risk of bleeding. Ligating or stapling vessels may be preferred over cauterization [37].

5.  Intraoperative

Patients with POTS should have an intravenous line placed as early as possible in order to be preloaded with normal saline. The amount of normal saline admi- nistered should be based on their duration of NPO status as well as other com- orbidities. These patients may present with hypovolemia and tachycardia. Typi- cally, adult patients with POTS are administered 1 to 2 liters of normal saline preoperatively.

Monitoring should be maintained as per standardized guidelines. A non-invasive blood pressure cuff is unlikely to cause significant bruising al- though providing padding may help prevent cutaneous injury. Exposure to ad- hesives from tape and ECG leads may result in cutaneous and/or systemic reaction.

Patient positioning should take into consideration joints that have a history of recurrent subluxationsand/or dislocations [38]. Extreme caution should be paid to range of motion. Maintain limbs less than their limit of range of motion to avoid overstretching ligaments and joint capsules [32].

Patients with EDS are prone to pneumothorax, cervical spine abnormalities and TMJ subluxation/dislocation. Caution with mask ventilation is recom- mended.

All patients with EDS should be considered candidates for fiberoptic intuba- tion in order to minimize manipulation of the head and neck. The laxity of the spinal ligaments puts these patients at significant riskfor CCI and/or atlantooc- cipital instability.

Endotracheal intubation should be performed with the smallest acceptable endotracheal tube and cuff pressures should be minimized. There has been one reported case of tracheal rupture after intubation[39]. Patients with gastropare- sis should be considered full stomach at all times. In cases involving rapid se- quence induction with cricoid pressure, pressure should be applied gently given that tracheomalacia is a common feature in EDS.

There are no specific contraindications to using any specific anesthetic agents. Caution must be used with agents that release histamine in patients with coex- isting MCAS. Induction agents that produce minimalchange in hemodynamics such as etomidate or ketamine may be preferred. Fentanyl, sufentanil or ketamine are good analgesics to use because of their ability to maintain hemody- namic stability without releasing histamine. Consideration can be given to uti- lizing intravenous acetaminophen and/or ketorolac perioperatively in order to minimize opioid requirements. Anecdotally, many patients with EDS have an unpredictable response to a number of opioids. They may respond more consis- tently to hydromorphone.Intraoperative neuromuscular monitoring should take into consideration that myopathy is common in EDS.

POTS and other forms of dysautonomia are common in EDS patients. Close monitoring for hemodynamic changes is important. Hypotension is best ma- naged with boluses of normal saline with orwithout small doses of vasopressors. There may be wide fluctuations in heart rate, usually with an elevated baseline heart rate. Vital signs may not be a reliable indicator of the depth of anesthesia, therefore consideration should be given to using processed EEG to monitor depth of anesthesia.

6.  Postoperative

In the immediate postoperative period, concerns specific to patients with EDS include hemodynamicinstability (most notably in patients with POTS), exacer- bation of MCAS symptoms, and visceral rupture. Other general concerns in- clude pain management, bleeding, nausea and vomiting. There should be a high suspicion for occult bleeding in patients who have undergone any procedure, even a relatively non-traumatic one such as an endoscopy. Patients with tra- cheomalacia may have airway compromise in the postoperative period and should be observed closely. Patients with neuropathic pain may respond well to intravenous ketamine in the immediate postoperative period. Acetaminophen may be a good option for postoperative pain.

In the event of an exacerbation of MCAS, treatment should be started as soon as possible. The administration of histamine H1 and H2 receptor antagonists, cromolyn (oral or nebulized), or benzodiazepines may be beneficial [18].

Patients who have undergone neuraxial block and spinal surgeries such as te- thered cord lysis ordecompression for Chiari malformation should be carefully screened for post-dural puncture headache[31]. Pain may be a result of a dislo- cated joint and repositioning may alleviate pain significantly thusdecreasing the need for analgesics. Some spine surgeries require lying supine for an extended period of time which can pose additional challenges for postoperative pain management.

7.  EDS in Pregnancy

Pregnancy in EDS presents its own unique set of challenges. Although all types of EDS may predispose the parturient to higher rates of preterm delivery, peri- neal lacerations and postpartum hemorrhage, patients with hypermobile EDS (hEDS) appear to pose little added risk in pregnancy [40]. EDS patientsrequire special consideration due to the risk of uterine rupture, uterine incision dehiscence, and postpartum hemorrhage [41].

Musculoskeletal complaints may increase in pregnancy due to hormonal in- fluences increasing joint laxity, however some women report being less symp- tomatic during pregnancy. Pubic symphysis dysfunction as well as increased instability of the sacroiliac joints is important considerations forpositioning of the pregnant patient. Hormonal changes may increase laxity of the TMJ and/or cervical spine making airway management even more challenging. Gastroparesis may increase the risk of aspiration even further in this population.

In addition to the routine evaluation of the perioperative pregnant patient, details of the patient’s history regarding EDS subtype, bleeding diathesis, spinal pathology, arterial dissection, arterial rupture, spontaneous organ rupture, and effectiveness of local anesthesia should be elucidated. Special considerations for analgesia/anesthesia options include possible atypical response to local anesthet- icsand hemodynamic changes due to dysautonomia [42]. Early fluid loading may minimize hypotension.

One study revealed a risk of approximately one in five for intra and postpartum hemorrhage irrespective of mode of delivery in EDS patients. No life-threatening complications or technique related-complications (e.g. spinal hematoma, intu- bation difficulties or hypotension) occurred in his study [40].

8.  Vascular EDS in Pregnancy

Rudd et al reported maternal mortality rates as high as 25% in vascular EDS (vEDS). (69) However, survival analysis from a 2014 study suggests that al- though the pregnancy related death rate is almost 300 times as high as the rate in the general US population, pregnancy in vEDS does not significantly affect over- all survival [43].

Severe bleeding must always be anticipated. For cesarean delivery in vEDS, prophylaxis with DDAVPand/or tranexamic acid [35] should be considered in addition to crossmatching sufficient amounts of RBCand autotransfusion. The optimal choice for anesthesia and/or analgesia should be based on the individual patient’s presentation.

In vEDS, there is no clear preferred mode of delivery. Vaginal delivery may be complicated by vascularor uterine rupture. Cesarean section (CS) poses risks of wound dehiscence. The prevalence of vEDS is low(1:100,000 - 1:200,000) [44] Anesthetic considerations in this population have been addressed primarily through case reports. Some reports strongly advise against neuraxial blockade in vEDS [43] (67) althoughthere are several more recent case reports/case series of successful neuraxial anesthesia in patients with vEDS and other subtypes [45]. No relevant studies have been performed, however PDPH may occur with greater frequency due to tissue fragility.

In a study by Murray et al in 2014 [43], interviews with 39 women with vEDS demonstrated that 46% of deliveries were uncomplicated, 19% of deliveries were preterm, 10.5% had hemorrhage sufficient torequire transfusion or extended hospital care, 9.2% had arterial dissection/rupture, and 2.6% had uterine rup- ture. Five maternal deathsoccurred in 76 deliveries (6.5%) due to arterial dissec- tion/rupture in 4 patients and complications related to dehiscence of a CS inci- sion in one patient. Two fatal aortic ruptures occurred during labor and one oc- curred 7 days after an uncomplicated cesarean delivery. Nonfatal complications included antenatal coronaryartery dissection, splenic artery dissection, multiple arterial dissections, uterine rupture and bladder/venous tears during CS. The diagnosis of vEDS was not established in >85% of women until after delivery, therefore these complication rates reflect routine perioperative management [43].

9.  Conclusions

Patients with EDS have a unique set of medical conditions that must be unders- tood when presenting forsurgery and anesthesia. Although there are 13 subtypes of EDS, with three subtypes being more prevalent,similar precautions need to be applied to all of these patients. Knowing which subtype the patient has ishelpful but does not exclude risks unique to other subtypes. For example, a patient with hEDS may or may not be at risk for vascular fragility. A team approach with close communication is essential to optimize outcomes.

EDS patients are at risk of Craniocervical Instability and/or TMJ dysfunction, therefore special consideration should be given to performing endotracheal in- tubation utilizing a fiberoptic or video laryngoscopic approach. These patients may present with hypovolemia as a result of their dysautonomia requiring ag- gressive IV fluid management. Positioning may pose additional challenges due to the increased risk of joint dislocation and subluxation. Patients with MCAS may react unpredictably tovarious environmental factors. They may react to rapid temperature changes, extreme temperatures, medications, contact with fa- brics and plastics and airborne substances.

Caution should be exercised with regional or neuraxial blocks due to an un- predictable response to local anesthetics as well as potential increased risk of complications secondary to tissue fragility. A detailed preoperative history and physical examination will help understand each patient’s baseline condition and issues. Further studies are needed in order to better understand the effects of anesthesia and surgery in patients with EDS.

The limitations of this review are that it was based on compiling information from different sources on EDS and anesthesia. No specific studies have been done on the effect or techniques of anesthesia in patients with EDS. In the fu- ture, more direct studies will be needed to understand the pharmacokineticsand hemodynamic effects of anesthesia in EDS.

10.  Other Considerations

There is a paucity of literature on the optimal surgical techniques with regards to safe handling of tissue inEDS. Cutaneous sutures should be left in place twice as long and additional fixation of adjacent skin with adhesive tape can help prevent stretching of the scar. Surgical wounds should be closed without tension, pre- ferably in two layers. It is important to avoid tension on sutures in order to avoid risk of tissue tear. Multiple layers of sutures may be required. Deepsutures should be applied generously and in close proximity to each other. Allografts for bone and tendon may be preferred to avoid using weak connective tissue from autografts.

Patients with EDS are prone to spontaneous CSF leaks. There is also a higher incidence of structuralneurological issues such as Chiari malformation, Crani- ocervical Instability, idiopathic intracranial hypertension and Tethered Cord Syndrome.

11.  Results

Perioperative anesthetic care of patients with EDS requires a coordinated effort by all providers. The most common type of EDS is the Hypermobile type (hEDS). Patients with EDS present for surgical procedures frequently due to their tissue fragility, joint instability, vascular fragility, and association with neurosurgical co-existing conditions. In a preoperative history and physical ex- amination, it is important to note which joints are prone to recurrent subluxa- tions or dislocations. Patients with EDS can have Craniocervical instability (CCI) with related deformation of the brainstem and upper spinal cord, basilar invagination or ventral brainstem compression. They can also have Chiari mal- formation with restrictedCSF flow, Idiopathic Intracranial Hypertension, C4-C5 osteochondrosis and mid-thoracic osteochondrosis. This population is also prone to Temporomandibular Joint Dysfunction (TMJ). Obstructive sleep apnea has been reported in patients with EDS. Rib subluxations are common in EDS and should be considered in thedifferential diagnosis of chest pain. Dysautono- mia is a common comorbid condition in EDS Mast Cell Activation Syndrome (MCAS) is another common comorbid condition in EDS. Postural orthostatic tachycardia syndrome (POTS) is the most common type of dysautonomia in the EDS population.Dysmotility (usually gastroparesis) is common. Opioids admi- nistered during the perioperative period mayincrease nausea and gastroparesis. Neuropathic pain often occurs in patients with EDS. This can be due to Small Fiber Peripheral Neuropathy, Complex Regional Pain Syndrome, and Entrap- ment Neuropathy. Patients with EDS often have an abnormal response to lido- caine. They may have local anestheticresistance and/or delayed onset. EDS pa- tients may also present with an increased risk of complications due to bleeding disorders and/or tissue fragility.

Patients with POTS should have an intravenous line placed as early as possible

in order to be preloaded with normal saline. Patient positioning should take into consideration joints thathave a history of recurrent subluxations and/or disloca- tions. Patients with EDS are prone topneumothorax, cervical spine abnormali- ties and TMJ subluxation/dislocation. Caution with mask ventilation is recom- mended. Endotracheal intubation should be performed with the smallest acceptable endotracheal tube and cuff pressures should be minimized. There are no specific contraindications to using any specific anesthetic agents. Caution must be used with agents that release histamine in patients with coexisting MCAS. Close monitoring for hemodynamic changes is important.Hypotension is best managed with boluses of normal saline with or without small doses of vasopressors. In the immediate postoperative period, concerns specific to pa- tients with EDS include hemodynamicinstability (most notably in patients with POTS), exacerbation of MCAS symptoms, and visceral rupture. Other general concerns include pain management, bleeding, nausea and vomiting. Pregnancy in EDS presents its own unique set of challenges. EDS patients require special consideration due to the risk ofuterine rupture, uterine incision dehiscence, and postpartum hemorrhage.

Author Contributions

Pradeep Chopra, MD and Linda Bluestein, MD had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. Pradeep Chopra, MD and Linda Bluestein, MD designed the study protocol. Drs. Pradeep Chopra and Dr. Linda Bluestein managed the lite- rature searches and summaries of previous related work and wrote the first draft of the manuscript. Pradeep Chopra, MD and Linda Bluestein, MD provided re- vision for intellectual content and final approval of the manuscript.

Conflicts of Interest

All the authors have no conflicts of interest to report. None of the authors of the manuscript received any remuneration. Further, the authors have not received any reimbursement or honorarium in any othermanner. The authors are not af- filiated in any manner with any pharmaceutical industry. There was noexternal funding in the preparation of this manuscript. Each author certifies that he or she, or a member ofhis or her immediate family, has no commercial association (i.e., consultancies, stock ownership, equity interest, patent/licensing arrange- ments, etc.) that might pose a conflict of interest in connection with thesubmit- ted manuscript.

References

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List of Abbreviations

AAI (Atlantoaxial Instability) CCI (Craniocervical Instability) DDAVP (Desmopressin)

EDS (Ehlers Danlos Syndrome) cEDS (classic type EDS) clEDS (classic-like type EDS)

cvEDS (cardiovascular type EDS) dEDS (dermatosparaxis type EDS) hEDS (hypermobile type EDS) vEDS (vascular type EDS)

HSD (hypermobility spectrum disorder) MCAS (Mast CellActivation Syndrome) PDPH (Post-Dural Puncture Headache)

POTS (Postural Orthostatic Tachycardia Syndrome) TMJD (Temporomandibular joint dysfunction) TMJ (Temporomandibular joint)

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