Case Report

Anesthetic Management of an Infant with Williams Syndrome for Cardiac Catheterization After Cardiac Arrest During Previous Cardiac Catheterization: A Case Report

By Mark Dziuba, MD
Clinical Assistant Professor of Anesthesia
University of Iowa Health Care
Iowa City, Iowa 

By Lori Q. Riegger, MD
Chief of Congenital Cardiac Anesthesiology, Associate Professor of Anesthesiology
Michigan Medicine
Ann Arbor, Michigan

Abstract
Williams Syndrome is a congenital, multisystem disorder with cardiovascular, neurologic and connective tissue involvement. Cardiovascular abnormalities are found in 80% of patients with Williams Syndrome.1 Patients requiring cardiac interventions in early childhood most often have supravalvar aortic stenosis (SVAS), pulmonary artery stenosis, or both. We describe the anesthetic management of a 10 month old child presenting for a cardiac catheterization seven months after suffering a cardiac arrest during anesthesia induction for a previous cardiac catheterization at an outside institution.

Introduction
Williams Syndrome occurs in approximately 1/10,000 births. Although it may occur with familial inheritance, it is most often a spontaneous mutation.2 Clinically, patients have a pattern of facial features including broad forehead, flattened nasal bridge with upturned tip, stellate iris, wide mouth, plump lips, round cheeks and pointed chin. They typically have outgoing, friendly personalities and moderate mental deficiencies with median IQs in the 50-60 range. During the first year of life up to 50% can have an increased risk of hypercalcemia but this usually resolves after infancy.3 Hypothyroidism can be found in 10%.3

Patients with Williams Syndrome have a hemizygous deletion on chromosome 7 in the region of 7q11.23, which includes a loss of 26-28 genes, one of which is the gene for the protein elastin.4 The heterozygosity of the elastin gene leads to production of only 15% of the elastin normally produced, and that produced is often damaged and disorganized.5 The lack of normal elasticity in the walls of arteries causes increased arterial stiffness.6 Stenotic arteries which can lead to obstruction of blood flow is a hallmark of Williams Syndrome.1 Cytogenic analysis with fluorescence in-situ hybridization (FISH) demonstrating hemizygosity for the elastin gene is used to confirm the diagnosis of Williams Syndrome.

Structural cardiovascular lesions occur in 80% of patients with Williams Syndrome1 and of those patients diagnosed with Williams Syndrome in their first year of life 93% of them have cardiovascular abnormalities.7 SVAS is the most common manifestation of cardiovascular disease, found in 45-75% of patients with Williams Syndrome.7 Pulmonary artery stenosis is the second most common lesion and is found in 37-75% of patients.1 Coronary artery abnormalities are found in 5-9% of patients and the most common coronary lesion is ostial stenosis.1 The systemic nature of the arteriopathy in Williams Syndrome is exhibited by the varying sites of symptomatic stenoses including thoracic and abdominal aorta, renal arteries, neck and limb vessels, mesenteric arteries and intracranial vessels. Several intracardiac structural abnormalities may be found in Williams Syndrome including ventricular septal defects and aortic valve defects. Additionally, these patients are at risk of prolonged corrected QT (QTc) on electrocardiogram.

Case
We present a 10-month-old 8.4 kg female with Williams Syndrome, pulmonary valve stenosis, and bilateral branch pulmonary artery stenoses for cardiac catheterization and possible pulmonary artery intervention.

Her past medical history is significant for pulmonary stenosis, diagnosed at an outside hospital shortly after birth, for which a cardiac catheterization intervention was planned. At three months of age, while in the catheterization laboratory, during inhalational induction with sevoflurane, the patient suffered a cardiac arrest. After successful resuscitation including epinephrine boluses followed by an epinephrine infusion, the catheterization procedure proceeded and pulmonary valve and bilateral pulmonary artery balloon dilatations were performed. After the procedure the patient went to the intensive care unit on an epinephrine infusion and remained intubated and ventilated for two days. She was discharged home on postoperative day four on no medications. After discharge she was diagnosed with Williams Syndrome. She continued to be well at home followed every month by her local pediatric cardiologist with physical exams and echocardiograms. She was referred to our institution recently due to increasing branch pulmonary artery stenoses.

Prior to her presentation at our hospital, her echocardiogram demonstrated a dilated and mildly hypertrophic right ventricle, normal biventricular function, mild supravalvar aortic narrowing, valvar and supravalvar pulmonary stenosis with peak systolic gradient of 72 mmHg, and severe left and right pulmonary artery stenoses with peak instantaneous pressure gradients of 65-80 mmHg. Her electrocardiogram was normal including a normal QTc.

Her vitals in the preoperative area demonstrated a heart rate of 132, blood pressure 90/50, oxygen saturation 98%, respiratory rate 24, temperature 36.6C and weight 8.4 kg. She was premedicated with 6 mg oral midazolam which led to effective sedation.

The patient was taken to the cardiac catheterization laboratory and a 24 g peripheral IV was placed. Lactated ringers solution was infused (10 ml/kg) and then dexmedetomidine (1 mcg/kg/hr) and remifentanil (0.1 mcg/kg/min) infusions were begun. The patient was preoxygenated with an FiO2 of 1.0 and then anesthesia was induced with 1 mg etomidate, 5 mg rocuronium and 0.5 mg midazolam. After grade 1 mask ventilation and grade 1 laryngoscopic view with a Miller 1 blade, the patient was successfully intubated with a 3.5 mm cuffed endotracheal tube. A second 24 g peripheral IV was secured at this time.

Remifentanil and dexmedetomidine infusions were titrated to maintain stable hemodynamics. The patient required a single 3 mcg bolus of phenylephrine for a blood pressure of 63/39 during the middle of the procedure. Inhalational agent was not used, the patient was kept paralyzed during the procedure and midazolam (0.5 mg) was given every 45 minutes for amnesia. Her procedural results showed proximal left and right pulmonary artery aneurysms and severe distal vessel hypoplasia bilaterally. No catheter interventions were performed. Her neuromuscular blockade was reversed at the end of the procedure and the patient was extubated awake. She was taking oral nourishment within 10 minutes of admittance to the recovery area and was discharged home after a mandatory four-hour observation for catheter site hemostasis.

Discussion
This patient had a history of a cardiac arrest at three months of age at an outside hospital during inhalational induction of anesthesia. Please discuss the concerns.

Cardiovascular events are the major cause of death in patients with Williams Syndrome and their risk of sudden cardiac death is 25 to 100 times the risk for people without Williams Syndrome.8 The etiology of this is not yet completely understood. The majority of these occur in periprocedural areas.9 Thus, these patients are at increased risk for adverse events when undergoing sedation or anesthesia. The literature has numerous reports of sudden cardiac arrest in children with Williams Syndrome during general anesthesia.10,11,12 In our patient, the diagnosis of Williams Syndrome had not yet been made, making it difficult to prevent. We suggest maintaining vigilance and a degree of suspicion for a diagnosis of Williams Syndrome when caring for infants with the diagnosis of SVAS and/or pulmonary stenosis.

What is the pathophysiology of Williams Syndrome arteriopathy?
Vascular abnormalities are related to the elastin deficiency. Elastin allows for reversible distensibility in arterial vessels and it is this characteristic that allows for storage of energy in the form of arterial distension during systole and later release of the stored energy via vascular recoil during diastole. This process significantly improves the efficiency of the cardiovascular system, and is known as the Windkessel effect. Elastin had been found to be involved in the modulation of vascular smooth muscle cells, which was thought might play a role in proliferation and obstruction of arteries. However, recent data suggest that the stenosis of the vascular lumen may be due in fact to diminished circumferential growth of the arteries, rather than proliferation of smooth muscle cells.13 This data may offer options in treatment not previously recognized.

Discuss the anatomic findings of supravalvular aortic stenosis, pulmonary stenosis, and coronary abnormalities in Williams Syndrome?
SVAS which occurs at the level of the sinotubular junction (STJ) gives the classic hourglass shape to the aorta. This is seen in about 75% of SVAS cases. In the remainder of SVAS cases, there is diffuse tubular narrowing of the ascending aorta.1 Over time the severity of these lesions may progress, however the majority of them remain stable.14 The aortic valve may also be involved in outflow tract obstruction. In a normal heart the STJ expands during systole, allowing room for aortic valve leaflets to open fully. However, when there is narrowing at the STJ, valve leaflets are not able to align themselves fully in the direction of blood flow. Turbulence then may lead to thickening of the aortic valve leaflets over time. Limited mobility and fusion of the aortic valve leaflets to the aortic wall may lead to mechanical obstruction of coronary blood flow.  

Stenoses seen in the pulmonary circulation usually occur in the branch and peripheral pulmonary arteries. These are often long-segment diffuse stenoses. The pressure overload caused by this pathology can lead to right ventricular hypertrophy. Patients with these pulmonary lesions tend to require frequent pulmonary vascular rehabilitation procedures in the catheterization laboratory.15

Coronary lesions may present as ostial stenosis, diffuse stenoses, or combinations of both. Elastin deficiency may cause narrowing and stiffness of the coronary vessels, and thickened aorta may lead to ostial obstruction. High pre-stenotic pressures from SVAS may cause coronary vessel dilation and tortuosity, and accelerate the development of atherosclerosis and aneurysm formation. Coronary artery lesions are found in 45% of those patients with SVAS.1 Fatal myocardial infarction has been reported with and without significant SVAS, suggesting that isolated, coronary lesions may be present and potentially unidentified.9.16, 17

Describe the preoperative assessment of a patient with Williams Syndrome.
A thorough history and physical, particularly examining clinical manifestations expected in children with Williams Syndrome, should be performed. Preoperative anxiety levels should be assessed along with developmental delay. Although they have friendly outgoing natures, children with Williams Syndrome may have a high level of preprocedural anxiety.15 Preoperative sedation and anxiolysis should be considered.

Patients with Williams syndrome have distinctive facial features which can include mandibular hypoplasia and dental abnormalities. Comprehensive airway assessment is necessary to evaluate potential difficulties. Connective tissue problems and joint laxity may cause delay in reaching milestones as well as problems with positioning. Gastroesophageal reflux and failure to thrive in childhood are common.

There are those who recommend that children with Williams Syndrome be seen by their cardiologist within a month of an anesthetic, with an echocardiogram to assess the aortic outflow and ventricular function as well as state of the pulmonary arteries and with an electrocardiogram to assess the QTc and ischemia.18 To assess the status of the coronary arteries, the gold standard is computed tomography (CT) scan or coronary angiography. However, obtaining one of these can be clinically problematic since most young children require an anesthetic or sedation to obtain accurate information from these studies.

How can a patient with Williams Syndrome be optimized prior to an anesthetic for a non-cardiac procedure?
A patient with Williams Syndrome should be seen regularly by their cardiologist and be optimized with respect to catheter-based or surgical management of their cardiovascular lesions. The procedure should take place at a center with extra-corporeal membrane oxygenation (ECMO) rescue available. At our institution we have multidisciplinary discussions with congenital cardiologists as well as intensive care physicians so that the patient is known to those services on the day of the procedure. Hydration before the procedure is important and, depending on the patient, some are admitted the night before for intravenous hydration. If the patient is an outpatient, we stress to the parents to continue fluids until two hours before the start of the procedure. Below is one set of preprocedural recommendations from Collins.18

Preprocedural Management of Patients with Williams Syndrome18

Fig 1

Discuss risk factors for patients with Williams Syndrome requiring general anesthesia
Some researchers recommend that every child with SVAS be considered at risk for myocardial ischemia.9,19 Some believe that all patients with Williams Syndrome are high risk for anesthetic complications.15,17,20,21 There are a number of risk stratification strategies which have been published in the past several years.3,15,18,22 These strategies have similarities but are not exactly the same, which is likely due to the fact that the strategies have not been validated in large studies and are based on case reports, small studies, and expert consensus. See below for Collins’ recent modifications to his risk strategy.22

Risk Stratification for Anesthetic Administration in Patients with Williams Syndrome22

Fig 2
IV, intravenous catheter; ms, milliseconds; PAS, pulmonary artery stenosis; PICC, peripherally inserted central venous catheter; QTc, corrected QT interval on ECG; SVAS, supravalvar aortic stenosis.
Adapted with permission from18
a -  If patient has prior history of obstructive lesions that have been surgically repaired, then he/she should NOT be considered to be high risk. Rather, determination of risk should be based on current anatomic issues.
b - Reliable IV placement is imperative. Strong consideration should be given to having placement performed by the vascular access team. In addition, for certain patients with particularly high-risk lesions (significant coronary arterial stenosis and outflow tract obstruction), placement of a PICC line should be considered, especially if the patient is to go on to have a surgical procedure.

What are hemodynamic goals in a patient with Williams Syndrome undergoing anesthesia?
For outflow tract obstructive lesions such as SVAS and pulmonary stenosis, it is important to maintain preload. Therefore, minimizing fasting time is important in these patients. Quick intravenous access and carefully administered fluid before induction can ameliorate hypovolemia.  

Maintaining afterload and systemic vascular resistance (SVR) is critical.  With the elastin deficiency and impaired Windkessel effect, Williams Syndrome patients may have difficulty maintaining diastolic pressures, which may cause significant impairment in coronary perfusion which may already be compromised in the patient. Avoiding agents which can cause decreases in SVR, as we did in this case, may be one technique. Others will treat expeditiously with an alpha adrenergic agonist, such as phenylephrine, when using agents which can decrease SVR.

Blunting sympathetic responses and especially avoiding tachycardia may also be critical. Tachycardia with its concomitant increase in oxygen demand in a heart which may already be limited in myocardial energy from stenosis and ventricular hypertrophy, can markedly impair blood supply to the myocardium. Anesthetics which maintain afterload and minimize the sympathetic response, in conjunction with narcotics, may be a useful multimodal anesthetic approach. See below for periprocedural medications for consideration in patients with Williams Syndrome from Collins.18

Summary of Periprocedural Pharmacologic Agents18

Fig 3

Conclusion
Children with Williams Syndrome have an increased risk of serious complications when undergoing anesthesia for procedures. No single anesthetic technique has been found to be appropriate for all variations of Williams Syndrome. However, if one combines a thorough preoperative assessment including history, physical exam, imaging studies and a multidisciplinary approach, with careful perioperative management to ensure hemodynamic stability, the risks can be reduced to allow safe and successful anesthetic care of these patients.9,18,20,23

References

  1. Collins RT II, Kaplan P, Somes GW, et al. Long-term outcomes of patients with cardiovascular abnormalities and Williams Syndrome. Am J Cardiol. 2010;105:874-8
  2. Stromme P, Bjornstad PG, Ramstad K. Prevalence estimation of Williams Syndrome. J Child Neurol. 2002;17:269-71
  3. Matisoff AJ, Olivieri L, Schwartz JM, et al. Risk assessment and anesthetic management of patients with Williams syndrome: a comprehensive review. Pediatric Anesthesia. 2015;25:1207-15
  4. Pober BR. Williams-Beuren syndrome. N Engl J Med. 2010;362:239-52Z
  5. Urban Z, Peyrol S, Plaucha H, et al. Elastin gene deletions in Williams syndrome patients result in altered deposition of elastic fibers in skin and a subdermal phenotype. Pediatr Dermatol 2000;17:12-20
  6. Salaymeh KJ, Banerjee A. Evaluation of arterial stiffness in children with Williams Syndrome: Does it play a role in evolving hypertension? Am Hear J. 2001;142:549-55
  7. Collins RT II, Kaplan P, Somes GW, et al. Cardiovascular abnormalities, interventions, and long-term outcomes in infantile Williams syndrome. J Pediatr. 2010;156:253-8
  8. Wessel A, Gravenhorst V, Buchhorn R, et al. Risk of sudden death in Williams-Beuren Syndrome. Am J Med Genet A. 2004;127A:234-7
  9. Burch TM, McGowan FX, Kussman BD, et al. Congenital supravalvular aortic stenosis and suddent death associated with anesthesia: What’s the mystery? Anesth Anal. 2008;107:1848-54
  10. Gupta P, Tobias JD, Goyal S, et al. Sudden cardiac death under anesthesia in pediatric patient with Williams syndrome: A case report and review of literature. Ann Card Anaesth. 2010;13:44
  11. Toit-Prinsloo LD, Dippenaar JM, Honey EM. Case report of sudden death in a child with Williams syndrome following administration of anaesthesia. South Afr J of Anaesth and Analg. 2015;21(1):23-6
  12. Dunlap JD, Green MC, Shah AM. Cardiac arrest after induction of anesthesia in a 2 month old infant with undiagnosed Williams Syndrome. Ann Card Anaesth. 2019;22:210-2
  13. Jiao Y, Li G, Korneva A, et al. Deficient circumferential growth is the primary determinant of aortic obstruction attributable to partial elastin deficiency. Arterioscler Thromb Vasc Biol. 2017;37:930-41
  14.  Collins RT. Cardiovascular disease in Williams Syndrome. Circulation. 2013;127:2125-34
  15. Staudt GE, Eagle SS. Anesthetic Considerations for patients with Williams Syndrome. Journal of Cardiothoracic and Vascular Anesthesia. 2020. https://doi.org.10.1053/jcva.2020.01.022
  16. Van Pelt NC, Wilson NJ, Lear G. Severe coronary artery disease in the absence of supravalvar aortic stenosis in a patient with Williams Syndrome. Pediatr Cardiol. 2005;26:665-7
  17. Dadlani GH, Mercado C, Roberts V, et al. Cardiovascular Screening in Williams Syndrome. Progress in Pediatric Cardiology 2020;58:101267  https://doi.org/10.1016/j.ppedcard.2020.101267
  18. Collins II RT, Collins MG, Schmitz ML, et al. Peri-procedural risk stratification and management of patients with Williams Syndrome. Congenit Heart Dis. 2017;12:133-42
  19. Stamm C, Friehs I, Ho SY, et al. Congenital supravalvar aortic stenosis: a simple lesion? Eur J Cardiothorac Surg 2001;19:195-202
  20. Brown ML, Nasr VG, Toohey R, et al. Williams syndrome and anesthesia for non-cardiac surgery: High risk can be mitigated with appropriate planning. Pediatric Cardiology 2018;39:1123-8
  21. Hornik CP, Collins RT II, Jaquiss RD, Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. J Thorac Cardiovasc Surg. 2015;149:1516-22
  22. Collins RT II. Cardiovascular Disease in Williams Syndrome. Curr Opin Pediatr. 2018;30:609-15
  23. Twite MD, Stenquist S, Ing RJ. Williams Syndrome. Pediatr Anesth. 2019;29:483-90

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