Evaluation of Perioperative Anesthetic Outcomes in Patients with Williams Syndrome Based on the Risk Stratification

ABSTRACT

Introduction:

Williams syndrome (WS) is associated with morbidity and mortality during surgical and nonsurgical procedures. The primary objective of the study was to assess the incidence of perioperative mortality in patients with WS among the risk groups. The secondary objectives were to analyze the mortality cause and study the various perioperative outcomes among the WS risk groups.

Materials and Methods:

In this retrospective observational study, we included patients with WS who underwent anesthesia for elective corrective surgical repair and nonoperative procedures like radiological imaging and cardiac catheterization procedures in our institute from January 2009 to April 2024. The patients were stratified into high-, medium-, and low-risk groups based on the risk factors recorded from the hospital medical records. We analyzed the incidence of perioperative mortality and associated outcomes among the three risk groups of patients with WS.

Results:

Medical records of 30 patients with WS were studied. The incidence of mortality in the high-risk group was 11.8%, whereas there was no mortality in the other risk groups. The mortality occurred in high-risk group patients who underwent sedation with inhalational anesthesia for a radiological imaging procedure. There was no significant difference in the duration of mechanical ventilation, vasoactive inotropic score, or length of intensive care unit and hospital stay among the three risk groups.

Conclusion:

Mortalities were observed in the high-risk group who underwent sedation with inhalational anesthesia for radiological imaging. Preoperative risk stratification is needed to identify the risk category and alleviate the major perioperative cardiac events in patients with WS.

Williams syndrome (WS) is a congenital and multisystem genetic disorder due to a recurrent microdeletion on chromosome 7q11.23. It is an autosomal dominant disorder attributed to an elastin coding gene mutation. The deletions in the chromosome are responsible for the hemizygosity of the elastin gene. This genetic aberration is the basis for the disease manifestations.[1] This leads to elastin arteriopathy, resulting in widespread vascular abnormalities and other connective tissue impairment. Most notable is supravalvular aortic stenosis (SVAS) and present in up to 75% of cases.[2] Peripheral pulmonary artery stenosis (PPAS) is also reported in these patients, but it usually improves as age progresses and severity resolves by itself.[2] Biventricular hypertrophy is noted in patients with combined SVAS and PPAS, risking patients to myocardial ischemia, arrhythmias, and sudden arrest.[2,3] Coronary artery abnormalities are found in 10%–30% of cases, with stenosis occurring at the sinus of Valsalva along with sinotubular junction narrowing, causing restricted coronary flow, which is a significant contributor to mortality.[2,3] Additionally, many individuals are affected by hypertension, which can be secondary to renal artery stenosis and stiffened vasculature.

The risk of sudden cardiac deaths in WS was reported as 1 in 1000 patient years and was 25 to 100 times higher than that in the normal population.[4] The reason for mortality, although not completely understood, could be due to biventricular outflow tract obstruction, especially in the setting of coronary artery stenosis, leading to impaired myocardial oxygen supply and demand. In patients without coronary issues, it is often the malignant arrhythmias that can contribute to mortality.[4]

Patients with WS for perioperative procedures under sedation or general anesthesia are at higher risk of adverse cardiovascular events, including cardiac arrest and mortality. This cardiovascular event can be attributed to coronary perfusion compromise and oxygen supply imbalance.[5] Such a high-risk disease needs to be addressed with risk stratification that can help plan and prepare the procedure in WS. Although management guidelines have been developed for patients with WS with goals to maintain optimum coronary flows, limited data were found regarding perioperative management of WS based on the risk stratification. We retrospectively investigated the medical records of patients with WS who underwent anesthesia for operative and nonoperative (radiological imaging and cardiac catheterization) procedures and risk-stratified them into low-, moderate-, and high-risk groups based on the specific factors proposed by Matisoff et al. [Table 1].[6] We evaluated the perioperative anesthetic outcome in these patients based on different risk categories. The primary objective of the study was to examine the incidence of perioperative mortality in patients with WS undergoing various surgical and nonsurgical procedures under sedation or general anesthesia (GA) based on the risk stratification groups. The secondary objectives were: (1) to compare the incidence of perioperative mortality between (a) GA and sedation, (b) intravenous and inhalational induction, and (c) operative and nonoperative procedures, and (2) to study the incidence of malignant arrhythmias, duration of mechanical ventilation, vasoactive inotropic score, stroke, renal failure and, length of intensive care unit (ICU) and, hospital stay among the three risk groups.

Table 1.

Cardiac risk stratification of Williams syndrome patients[6]

Low risk

• Normal electrocardiograph

• Normal echocardiogram

• No clinical signs of heart failure, ischemia

• Patient age >3 years

Moderate risk

• Mild/moderate supravalvar aortic stenosis mean gradient <40 mm Hg

• Mild pulmonary artery stenosis

• Repaired supravalvar aortic or pulmonary stenosis (no residual gradient)

• Presence of systemic hypertension

• Mild left ventricular hypertrophy

• Mild associated cardiac anomalies

High risk

• Patient age <3 years

• Severe supravalvar aortic stenosis mean gradient >40 mmHg

• Moderate/severe pulmonary artery stenosis

• Biventricular outflow tract obstruction

• Coronary artery anomalies

• QTc prolongation, electrocardiographic changes associated with ischemia

METHODS

Study design and patient population

The Institutional Ethics Committee (IEC) approved the study (SCT/IEC/2063/MAY/2023), and the waiver requirement for written informed consent was obtained from the IEC, as this was a retrospective observational study conducted from our hospital medical records. We studied the past medical records of patients with WS who underwent anesthesia for various operative and nonoperative procedures in our tertiary care hospital from January 2009 to April 2024. Patients’ medical records were studied for preoperative, intraoperative, and postoperative parameters, and the patients were risk-stratified into low-, medium-, and high-risk groups. The type of anesthesia technique (sedation or GA), mode of induction (inhalational or intravenous), and the type of procedure (operative or nonoperative) were noted among the risk groups. Preoperative transthoracic echocardiography details were evaluated for ventricular hypertrophy and function, aortic and pulmonary artery abnormalities, and coronary artery anomalies. The incidence of mortality, cardiac arrest, malignant arrhythmias, duration of mechanical ventilation, vasoactive inotropic score, ICU stay, and hospital stay were noted among the three risk groups. Patients with incomplete medical records were excluded from the study. This manuscript adheres to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines.

Statistical analysis

All statistical analyses were performed using SPSS version 21.0 for Windows (IBM Software, Chicago, IL 60606). Descriptive statistics were calculated and reported as percentages for categorical variables and means ± standard deviation for continuous data. The Shapiro–Wilk test was conducted for the normality of data. Given potential non-normal distribution and outliers, we utilized the Kruskal–Wallis test to compare the median across the risk groups, mitigating the influence of outliers. Fisher’s exact test was used to compare the categorical variables. A P value of < 0.05 was considered statistically significant.

RESULTS

A total of 38 patients with WS had undergone anesthesia for operative and nonoperative procedures in our hospital during January 2009 to April 2024. Eight patients were excluded due to incomplete medical records, and 30 patients were included in our study. The demographic data, preoperative clinical data, and preoperative echocardiographic data are given in Table 2. The risk categories of the study groups are shown in Figure 1. The procedure details, technique of anesthesia, mode of anesthetic induction, and the need for vasopressors before induction are given in Table 3. The incidence of perioperative mortality was 11.8% in the high-risk category, whereas there were no mortalities in the medium and the low-risk groups. The two mortalities in high-risk group occurred in patients who had inhalational induction for the computed tomography imaging. There was no significant difference in the incidence of mortality among the types of anesthesia technique, mode of anesthesia induction, and kind of procedure undergone [Table 4]. The incidence of malignant arrhythmias was 41.2% (7 patients) in the high-risk group and 18.2% (2 patients) in the moderate-risk group. There were no incidences of arrhythmias in the low-risk group. In the high-risk group, two patients had malignant arrhythmias during inhalational induction for computed tomography imaging and progressed to fatal cardiac arrest. The other five patients in the high-risk group and two patients in the moderate-risk group had malignant arrhythmias during corrective surgery and were cardioverted to sinus rhythm. Even though the duration of mechanical ventilation, vasoactive inotropic score, and the length of ICU and hospital stay were higher in the high-risk group, the difference was not statistically significant [Table 5]. There was no incidence of stroke or renal failure among the study cohort.

Table 2.

Demographic data, preoperative clinical data, and preoperative echocardiographic data of the study cohorts

Demographic data	(n=30)
Age (years)
<10	18 (60%)
≥10	12 (40%)
Sex
Male	16 (53.3%)
Female	14 (46.7%)
Weight (kg)
<10	6 (20%)
10–20	10 (33.3%)
20–30	7 (23.3%)
>30	7 (23.3%)
Preoperative clinical data
Signs of ischemia, heart failure	0
SVAS	30 (100%)
Pulmonary stenosis	6 (20%)
Systemic hypertension	5 (16.7%)
Hypothyroidism	8 (26.7%)
Preoperative echocardiographic data
Left ventricular hypertrophy	30 (100%)
Branch pulmonary stenosis	12 (40%)
Isolated supravalvar pulmonary stenosis	5 (16.6%)
SVAS mean gradient <40 mmHg	11 (36.6%)
Biventricular outflow tract disease	1 (3.3%)
SVAS mean gradient >40 mmHg	19 (63.3%)
Coronary artery anomalies	2 (6.6%)

SVAS: supravalvular aortic stenosis. Values are expressed as a number (proportion)

Figure 1.

Risk categories of patients with Williams syndrome

Table 3.

Procedure details, technique of anesthesia, mode of anesthetic induction, and the need for vasopressors before induction among the study population

Procedures	Total (n=30)	Low-risk group (n=2)	Moderate risk group (n=11)	High-risk group (n=17)
Computed tomography scan	14 (46.6%)	2	6	6
Magnetic resonance imaging	3 (10%)	–	2	1
Cardiac catheterization study	2 (6.7%)	–	1	1
Balloon aortic valvotomy	2 (6.7%)	–		2
Corrective surgery	9 (30%)	–	2	7
Doty aortoplasty		–	–	4
Combined aortoplasty + COA repair		–	–	1
Brom aortoplasty		–	2	1
Pericardial patch aortoplasty		–	–	1
Technique of anesthesia		(n=30)
Sedation		14 (47%)
General anesthesia		16 (53%)
Mode of anesthesia induction		(n=30)
Inhalational		17 (57%)
Intravenous		13 (43%)
Requirement of vasopressors before anesthesia		(n=30)
Required		4 (13%)
Not required		20 (67%)

COA: coarctation of the aorta. Values are expressed as a number (proportion)

Table 4.

Comparison of mortality concerning type of anesthesia technique, mode of anesthesia induction, and type of procedure

	Mortality		P
	Yes	No
Anesthesia technique
General anesthesia	0	14	0.4850
Sedation	2	14
Mode of anesthesia induction
Inhalational	0	13	0.4919
Intravenous	2	15
Procedure underwent
Nonoperative (Imaging/catheterization)	2	17	0.5195
Operative	0	11

Table 5.

Comparison of duration of mechanical ventilation, vasoactive inotropic score, length of intensive care unit, and hospital stay between the risk groups

Parameter	Low risk		Moderate risk		High risk		P
	Mean±SD	Median (IQR)	Mean±SD	Median (IQR)	Mean±SD	Median (IQR)
Duration of mechanical ventilation (hours)	0±0	0 (0– 0)	4.4±6.8	0 (0–12)	8.4±7.6	8 (0–16)	0.153
Vasoactive inotropic score	0±0	0 (0– 0)	0.8±1.9	0 (0–0)	4.1±5.2	3 (0–6.5)	0.053
Length of ICU stay (hours)	4±0	4 (4–4)	26.4–33.9	4 (4–48)	39.5±32.4	48 (4–72)	0.246
Length of hospital stay (days)	1±0	1 (1–1)	3.2±3.1	1 (1–6)	4.1±2.6	5 (1–6.5)	0.275

ICU: intensive care, IQR: interquartile range, SD: standard deviation. Values expressed as mean±standard deviation and median (IQR)

DISCUSSION

In our single-centre, retrospective observational study, we observed that patients with WS of high-risk category, who had undergone sedation with inhalational induction for nonoperative procedures, had a greater risk of major adverse cardiac events. Also, the occurrence of malignant arrhythmia requiring intervention was higher in the high-risk group. The cause of sudden cardiac death in patients with WS was not completely understood. Still, we noticed that all the patients had supravalvar component of aortic stenosis, out of which 19 (63%) cases had SVAS mean gradient more than 40 mm Hg and left ventricular hypertrophy was found to be present in all patients. The high SVAS gradient and left ventricular hypertrophy might have caused left ventricular outflow tract obstruction due to a decrease in preload and afterload during the induction of anesthesia. Similarly, in a study by Pham et al.,[7] patients with WS undergoing cardiac catheterization had a higher risk of mortality, which was attributed to bilateral outflow tract hypertrophy and obstruction.

In our study, PPAS was the second most common occurrence in WS patients with an incidence of 40%. In WS patients with PPAS, there is a reduction in the elastin component of the pulmonary vessels as age progresses, and there will be a reduction in the symptoms and gradient across the stenotic segment in late childhood.[8] However, we observed that our study cohorts had symptomatic PPAS (40%) and isolated supravalvar pulmonary stenosis (16%). There was coronary ostial narrowing in two patients (6.6%) of the high-risk category who had cardiac arrest during an aesthesia induction, which could have contributed to the mortality.[8] Studies had shown that there is about an 11% risk of adverse cardiac events while providing anesthesia for WS patients.[9] Anesthesia induction is the critical phase for the perianesthetic cardiac arrest in WS patients.[9]

The patients with WS have anxiety disorders and neurodevelopmental issues, which make them uncooperative for anesthesia induction.[1] This leads to anesthesia induction by high concentrations of inhalational agents to secure the intravenous access. In our study, we observed that the incidence of cardiac arrest occurred during the inhalational induction due to the myocardial depressant effect of high concentrations of volatile anesthetics and a fall in coronary perfusion pressure.[10] The reduced poststenotic aortic pressures during anesthetic induction reduce the diastolic flow in the coronaries, leading to myocardial ischemia. Also, the reduced coronary perfusion coupled with left ventricular hypertrophy aggravates the microvascular coronary ischemia, leading to refractory cardiac arrest.[11] The high prestenotic aortic pressure in WS leads to coronary artery dysplasia, resulting in coronary artery musculature hypertrophy and luminal narrowing.[12] Therefore, WS patients of the high-risk category should be monitored with extreme caution during inhalational induction. A multimodal approach must be utilized using nonpharmacological measures and oral anxiolytics to calm the child before an aesthesia induction. Preprocedural anxiety can be triggered in the WS patients by noise, needle injection, medical equipment, and the operation theatre environment, which makes them extremely aggressive during anesthesia induction. Also, the sympathetic activation and tachycardia can increase the myocardial oxygen supply-demand mismatch, leading to myocardial ischemia.[13] In our study, inhalational induction was done in patients undergoing nonoperative procedures. In contrast, the patients undergoing operative surgical procedures had intravenous induction through the intravenous cannula, which was secured in the hospital ward on the morning of surgery. Studies had recommended using intravenous induction with boluses of vasoactive agents like phenylephrine to counteract the hypotension episodes during anesthesia induction in patients with WS.[6,14]

Conduct of anesthesia is a critical transition and is subject to the occurrence of adverse cardiac events in patients with WS. A preoperative understanding and stratification of risk factors can help healthcare providers to counsel the patient or the child’s parents regarding the perioperative anesthetic concerns involved in the procedure. Risk assessment is a helpful tool based on the available medical evidence, which is used to identify the preoperative risk factors and assess the procedure’s outcomes. In this study, we attempted to retrospectively risk-stratify the patients with WS from the data of hospital medical records (based on the risk stratification criteria by Matisoff et al.[6]). We studied the factors contributing to perioperative mortality and poor postoperative outcomes. In our study, most patients in the low-risk and moderate-risk groups were planned for radiological imaging, whereas corrective surgeries were higher among high-risk patients. The incidence of arrhythmias was 47.2% in patients of the high-risk group, among whom two patients had fatal cardiac arrest. The incidence of arrhythmias was due to pre-existing QTc prolongation and associated ischemic changes in the preoperative electrocardiograph. Studies have recommended electrocardiograph screening, arrhythmia evaluation, and intermittent rhythm monitoring in WS patients in the high-risk category during the entire perioperative period.[15] Avoiding drugs that prolong QTc during the perioperative period may reduce incidence of malignant arrhythmias in high-risk groups.

The incidence of mortality observed in our study was 6.6% comprising patients who were planned for presurgical radiological workup. These observations were more in comparison to the study by Zinyandu et al.,[16] where the observed mortality was 2.5%. The two deceased patients had coronary ostial stenosis and QTc prolongation in preoperative electrocardiograph, which was considered to be a high-risk factor for mortality.[17] Both mortalities occurred in the nonoperating room area, highlighting the importance of nonoperating room cardiac anesthesia (NORCA) care in the radiology suite or cardiac catheterization laboratory. Corrective surgery was performed in 30% of the study cohorts. The postoperative requirement of vasoactive medications and duration of mechanical ventilatory support were higher in high-risk patients who underwent surgical correction. All the patients who underwent corrective surgery had an uneventful recovery, and there was no need for mechanical circulatory support in the postoperative period.

We acknowledge that our study had a few limitations. First, being a retrospective and single-centre study, there were limitations in the available data, diagnostic tests, and incompleteness of specific parameters that could be used for evaluation. Second, the risk stratification model used in the study was not validated across different ethnic study populations. Third, although our hospital is a high-volume cardiac surgery centre, our study’s sample size was small. This was due to the low prevalence of WS in the population. Fourth, long-term outcomes after hospital discharge were not assessed. However, our study is the first to evaluate the WS patients’ perioperative outcomes based on the risk stratification criteria. Future prospective multicentric studies were needed to develop and validate the risk prediction models for the perioperative outcome in patients with WS.

CONCLUSION

In conclusion, WS patients of the high-risk category who were planned for sedation with inhalational induction for nonoperative procedures had a higher incidence of perioperative major adverse cardiac events. Since early identification of high-risk patients is crucial and anesthesia induction is a big challenge, intravenous induction is preferred over inhalational for better control of hemodynamics and to resuscitate the patients during major adverse cardiac events. A special emphasis should be placed on whether exposing the patients to NORCA procedures may be beneficial in changing the disease outcome. A risk stratification model and perioperative guidelines are the need of the hour to prepare, plan, and mitigate the perioperative major adverse cardiac events in patients with WS.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.