Factors Associated with Headache and Nausea During Magnetic Resonance–Guided Focused Ultrasound for Tremor

ABSTRACT

Background

During magnetic resonance–guided focused ultrasound for essential or parkinsonian tremor, adverse events (headache, nausea/vomiting, or anxiety) may alter the outcome of the procedure despite being mostly transient and mild.

Objectives

Our aim was to analyze the relationship between demographic, procedural, and anesthetic characteristics with magnetic resonance/ultrasound‐related events.

Methods

This was a retrospective study at the Clinica Universidad de Navarra of patients undergoing thalamotomy with magnetic resonance–guided focused ultrasound between September 2018 and October 2019. The anesthesia protocol included headache and nausea/vomiting prophylaxis and rescue therapy. Dexmedetomidine was used for anxiolysis in some patients after thorough multidisciplinary assessment.

Results

A total of 123 patients were included. Headache was directly related to skull density ratio (P < 0.001) and skull thickness (P = 0.02). Patients with a skull density ratio less than 0.48 had 3 times the odds of experiencing moderate or severe headache (odds ratio [OR], 3.08; 95% confidence interval [CI], 1.21–7.82) and had a higher odds of aborting sonication due to pain. Sex was associated with increased nausea (P = 0.007). Women had 4 times the odds of nausea than men (OR, 4.4; 95% CI, 1.61–12.11). Dexmedetomidine did not reduce headache or nausea incidence. Patients who received dexmedetomidine had a higher number (P = 0.01) and total minutes of sonication (P = 0.01).

Conclusions

Patients with lower skull density ratios and higher skull thicknesses could benefit from an aggressive analgesic prophylaxis. Women are more likely to experience nausea. Dexmedetomidine did not reduce headache and nausea, but increased the number and duration of sonications. Its exact effect on tremor is still unclear.

The ablation of thalamic nuclei or basal ganglia structures through magnetic resonance–guide focused ultrasound (MRgFUS) has become a therapeutical option for patients with essential tremor (ET) ¹ , ² , ³ , ⁴ or Parkinson's disease–related tremor (PT) ⁵ , ⁶ who have their quality of life severely affected despite medical treatment.

The irreversible lesion by MRgFUS is performed only after appropriate target combining magnetic resonance imaging (MRI) findings and patient feedback. After each sonication, the patient is assessed for tremor reduction and potential adverse effects. These can be thalamotomy and MRI/ultrasound related. ⁵ The latter include those caused by the environment (such as anxiety; neck, back, or shoulder pain; magnetic field generated by the powerful magnets) and by the sonication, which induces a progressive increase of temperature in brain, skull, and/or scalp, which can give rise to headache, vertigo, a “roller‐coaster” feeling, nausea, and/or vomiting. ⁵ , ⁷ , ⁸ Although usually transitory and mostly mild, MRI/ultrasound‐related events can interfere with the procedure, resulting in a partial treatment. The anesthesiologist's role is relevant to prevent and treat these complications. ⁷ , ⁸

The aim of this study was to analyze the relationship between demographic, procedural, and anesthetic characteristics of patients who underwent MRgFUS in our center with the incidence of MRI/ultrasound‐related events during the procedure.

Patients and Methods

The Spanish Agency of Medicines and Medical Devices codified this study as retrospective no postauthorization (CUN‐DEX‐2019‐01), and ethical approval was provided by the Ethical Committee of the University of Navarra (Ethical Committee no. 2020.078), Pamplona, Spain (Chairperson Professor A.J. Idoate) on June 18, 2020, for patients who underwent MRgFUS ventralis intermedius (Vim) thalamotomy for ET or PT between September 2018 and October 2019 at the Clinica Universidad de Navarra.

Procedure Protocol

Patient selection was made by a neurologist who specialized in movement disorders and a neurosurgeon. All patients were preoperatively assessed by an anesthesiologist. Patients were asked to undergo a preoperative fasting of 6 hours and were admitted the same morning of the procedure. Tremor and antiparkinsonian medications and any drugs used for their medical condition that could affect tremor, such as β‐blockers or benzodiazepines, had been tapered off previously according to their pharmacokinetic half‐life to ensure that the severity of tremor would be as great as possible during the procedure.

MRgFUS was performed with the Insightec's Exablate Neuro (Insightec). The ultrasonic beams were directed to the Vim through the helmet‐like focused ultrasound transducer (Exablate 4000; InSightec). Sonications were administered following a protocol similar to those used in other institutions. ² , ³ Following each sonication, the patient was clinically assessed to detect improvement in tremor and to rule out any possible adverse effects via a thorough neurological examination.

In all patients, a 20‐gauge intravenous (iv) catheter was inserted for medication, and the Invivo Expression (Invivo Corporation) system was employed for standard anesthetic monitoring. Supplemental oxygen (2 L) was administered, and capnography was performed through a dual nasal cannula.

Based on patient safety and comfort, our anesthetic management protocol was focused on the prevention and control of MRI/ultrasound‐related complications, especially headache and nausea/vomiting. All of the patients received prophylaxis, and if moderate or severe headache or any degree of nausea were reported during the procedure, treatment was administered (Table 1). Patients were able to stop the sonication by pressing the emergency button if they felt unbearable headache or nausea or if they believed they were on the verge of vomiting.

TABLE 1.

Anesthetic management protocol for MRI or ultrasound‐related complications during MRgFUS thalamotomy

Indications	Medications	Special Considerations
Headache prophylaxis	Dexamethasone 8 mg iv Dipyrone 2 g iv Paracetamol 1 g iv	When the patient lies down on the magnetic resonance table Just before beginning sonication Just before beginning sonication
Headache treatment	First: ketorolac 30 mg iv Rescue: fentanyl or remifentanil	Administered in this stepwise fashion if the patient presents moderate or severe pain during sonication or pushes the emergency button because of pain
Nausea and vomiting prophylaxis	Ondansetron 4 mg iv Dexamethasone 8 mg iv	When the patient lies down in the magnetic resonance table
Nausea treatment	First: ondansetron 4 mg iv (second doses) Rescue: droperidol 0.625 mg iv	Administered in this stepwise fashion if the patient presents nausea during sonication or pushes the emergency button for nausea
Vomiting treatment	Suction First: ondansetron 4 mg iv (second doses) Rescue: droperidol 0.625 mg iv	Urgent call for help; administered in this stepwise fashion if the patient presents vomiting during sonication or pushes the emergency button for vomiting
Anxiety/claustrophobia	Dexmedetomidine 0.2–0.3 μg/kg/h	Initially, only during planning magnetic resonance imaging scan; administration during treatment (0.2–1 μg/kg/h) was assessed in each case by the multidisciplinary team
Generalized tremor of such intensity that could jeopardize the treatment	Dexmedetomidine 0.2–0.3 μg/kg/h	Initially only during planning magnetic resonance imaging scan; administration during treatment (0.2–1 μg/kg/h) was assessed in each case by the multidisciplinary team
Vertigo	None	None
Miscellaneous	Emergency button that shuts down sonication	Urgent call for help if necessary

Abbreviations: MRI, magnetic resonance imaging; MRgFUS, magnetic resonance–guide focused ultrasound; iv, intravenous.

Dexmedetomidine, due to its anxiolytic effect, minimal respiratory depression, low repercussion on hemodynamic status, and analgesic and antiemetic properties was the sedative drug of choice in our protocol (Table 1). Based on multidisciplinary agreement (neurologist, neurosurgeon, and anesthesiologist), dexmedetomidine (0.2–0.3 μg/kg/h), with no loading dose was given during the planning MRI scan to patients with high degrees of anxiety and discomfort related to the procedure and patients with mild or moderate claustrophobia. In addition, it was also administered to patients with generalized tremor of an intensity that could jeopardize the treatment. Before starting the sonications, the requirement for sedation was reassessed, and maintenance doses (0.2–1 μg/kg/h) throughout the sonication procedure were given only when deemed absolutely necessary.

Statistical Analysis

The mean with the standard deviation (SD), the median with the 25th percentile (p25) and the 75th percentile (p75), and percentages were used to summarize the demographic and clinical characteristics of patients. Differences between groups were assessed using the Student t test, the Wilcoxon rank‐sum test, the Pearson chi‐square test, and the Fisher exact test. Logistic regression analysis was used to estimate odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). Correlations were evaluated with the estimation of the product–moment correlation coefficient (r). All analyses were performed with Stata 14 (release 14; StataCorp).

Results

The study included 123 patients, most of them with ET (69.1%). Table 2 shows the demographic and clinical characteristics. No statistical differences were observed in the skull, ultrasonic, or sonication characteristics between the patients with ET and those with PT (Table 2).

TABLE 2.

Demographic and clinical characteristics of patients, subcategorized by tremor etiology

Demographic and clinical characteristics	Essential (n=85)	Parkinsonian (n=38)	P
N	85	38
Men	62 (73)	32 (84.2)	0.17
Age, years	74.16 ± 8.86	69.45 ± 6.71	0.004
BMI, kg/m2	22.76 ± 3.09	22.11 ± 3.83	0.31
Hypertension	43 (50.6)	25 (65.8)	0.12
Diabetes mellitus	67 (78.82)	32 (84.21)	0.49
Respiratory disease	17 (20)	2 (5.26)	0.037
Anxiolytics	21 (24.71)	15 (39.47)	0.096
Rest tremor	1 (0–2)	3 (2–3)	<0.001
Postural tremor	2 (2–3)	2 (2–3)	0.080
Action tremor	3 (3–4)	2 (2–3)	<0.001
Skull density ratio	0.49 ± 0.08	0.48 ± 0.08	0.68
Skull thickness, mm	6.49 ± 0.91	6.47 ± 1.2	0.94
Skull area with ultrasound, cm2	339.7 ± 29.6	347.1 ± 18.4	0.09
Sonication, n	9.77 ± 4.31	8.92 ± 3.45	0.28
Maximum energy in 1 treatment, joules	20031.3 ± 9409.5	19728.8 ± 9564.9	0.87
Maximum power in 1 treatment, watts	810.56 ± 124.81	822.58 ± 198.95	0.73
Sonication accumulated time, min	63.61 ± 35.6	63.86 ± 44.95	0.97
Temperature mean, °C	58.15 ± 2.43	58.09 ± 2.15	0.89
Temperature maximum, °C	62.95 ± 3.38	63.52 ± 5.65	0.56

Note: Values are presented as N, n (%), mean ± SD, or median (25th percentile– 75th percentile).

Abbreviation: BMI, body mass index.

Despite prophylaxis, we observed an incidence of moderate or severe headache of 20.3% (Table 3). Headache was significantly associated with skull density ratio (SDR), skull thickness (ST), maximum energy, maximum power, and sonication accumulated time (Table 3). Patients with an SDR less than 0.48 showed 3 times the odds of moderate or severe headache (OR, 3.08; 95% CI, 1.21 to 7.82). Maximum power and sonication accumulated time are directly related to energy. In addition, maximum energy during a sonication showed a significant direct and inverse correlation with ST and SDR, respectively (Fig. 1). A total of 23 (18.7%) patients pressed the emergency button during the treatment, 15 (65.2%) of them because of intolerable headache (Table 4). Patients who stopped sonication because of headache also showed statistically significant differences in SDR and ST (Table 4). There was also a difference in the number of sonications in these 2 subgroups of patients.

TABLE 3.

Associations of demographic, skull, and sonication characteristics with headache and antiemetic requirements

	Headache Protocol		P	Antiemetic Protocol		P
	Prophylaxis	Treatment		Prophylaxis	Treatment
N	98	25		103	20
Men	76 (77.6)	18 (72.0)	0.56	84 (81.6)	10 (50)	0.007
Age, years	73.32 ± 8.4	70.28 ± 8.7	0.11	73.0 ± 8.9	71.4 ± 6.1	0.455
Skull density ratio	0.48 ± 0.08	0.44 ± 0.05	<0.001	0.49 ± 0.08	0.49 ± 0.01	0.91
Skull thickness, mm	6.4 ± 0.9	6.9 ± 1.2	0.02	6.49 ± 1.03	6.45 ± 0.92	0.89
Skull area with ultrasound, cm2	341.2 ± 24.7	345.3 ± 34.4	0.58	343.6 ± 25.9	333.5 ± 30.1	0.12
Sonication, n	9.1 ± 3.4	11.2 ± 5.8	0.12	9.7 ± 4.3	8.5 ± 1.9	0.06
Maximum energy in 1 treatment, joules	18284.6 ± 8657.1	26418.7 ± 1930.9	<0.001	20367.6 ± 9575.8	17724.9 ± 8444.2	0.25
Maximum power in 1 treatment, watts	798.8 ± 152.7	870.24 ± 143.3	0.038	815.44 ± 155.52	809.82 ± 142.01	0.89
Sonication accumulated time, min	57.8 ± 32.6	86.9± 50.5	0.01	64.9 ± 39.3	57.5 ± 34.5	0.56
Temperature mean, °C	58.4 ± 2.3	57 ± 2.3	0.006	58.1 ± 2.3	58.2 ± 2.4	0.89
Temperature maximum, °C	63.4 ± 3.4	62.1 ± 5.2	0.02	63.2 ± 4.4	62.9 ± 3.1	0.96

Note: Values are presented as N, n (%), or mean ± SD.

FIG. 1.

Correlations between maximum energy and skull features. E max (J), maximum energy (joules); r, correlation coefficient.

TABLE 4.

Associations of demographic, skull, and sonication characteristics with emergency button–pressing because of headache

Demographic, skull, and sonication characteristics	Emergency Button–Pressing Because of Headache		P
	No	Yes
N	108	15
Men	82 (75.9)	12 (80)	>0.999
Age, years	72.9 ± 8.7	71.1 ± 7.1	0.44
Skull density ratio	0.5 ± 0.08	0.44 ± 0.06	<0.001
Skull thickness, mm	6.4 ± 0.09	7 ± 0.32	0.028
Skull area with ultrasound, cm2	343.5 ± 24.3	335.5 ± 35.7	0.31
Sonication, n	9.1 ± 3.5	11.3 ± 5.6	0.01
Maximum energy in 1 treatment, joules	18674.1 ± 9142.3	25432.5 ± (8780.2	0.001
Maximum power in 1 treatment, watts	808.15 ± 156.92	860.21 ± 115.79	0.23
Sonication accumulated time, min	57.4 ± 32.1	90.9 ± 51.3	0.006
Temperature mean, °C	58.4 ± 1.9	57.1 ± 3.3	0.1
Temperature maximum, °C	63.5 ± 4.1	61.4 ± 4.2	0.03

Note: Values are presented as N, n (%), or mean ± SD.

Regarding emesis, despite prophylaxis, 20 (16.3%) patients required treatment through the procedure (Table 3). Only 1 patient vomited, fortunately with no significant consequences for the patient or for the execution of the procedure. The incidence of nausea was only associated with the sex of the patient (Table 3). The odds of nausea in women were more than 4 times higher than in men (OR, 4.4; 95% CI, 1.61 to 12.11). Only 8 (6.5%) patients stopped sonication because of nausea or vomiting. These were more likely to be women (62.5%) compared with those who did not press the button (20.9%; P = 0.018).

Only 5 patients (4.06%) presented combined moderate or severe headache and nausea during the procedure.

A total of 52 (42.3%) patients received dexmedetomidine during the planning MRI scan, with no statistically significant differences between PT and ET (52.6% vs. 37.6%; P = 0.12). The severity of tremor was not an indication for dexmedetomidine administration. Pretreatment action tremor was statistically higher in the patients who did not receive dexmedetomidine (median [p25–p75]: 3 [2–3] with dexmedetomidine vs. 3 [2–4] without; P = 0.02), with no significant differences in rest or postural tremor. Among the patients who initially received dexmedetomidine, 23 (44.2%) required maintenance doses throughout the procedure. Dexmedetomidine maintenance dosage ranged between the mean ± SD minimum and maximum doses of 0.29 ± 0.07 μg/kg/h and 0.34 ± 0.16 μg/kg/h, respectively. Of note is the fact that 23 of these patients already required sedation or general anesthesia during the pretreatment MRI: 14 patients with ET and 9 patients with PT.

The distribution of demographic and skull characteristics appeared to be similar between the group with dexmedetomidine and the group without dexmedetomidine. Patients who received dexmedetomidine had a higher number of sonications (mean ± SD: 10.5 ± 4.5 with dexmedetomidine vs. 8.7 ± 3.5 without; P = 0.01) and more accumulated minutes of sonication (mean ± SD: 73.7 ± 45.6 with dexmedetomidine vs. 56 ± 30.6 without; P = 0.01). No statistically significant differences were observed at maximum energy, power, or temperature between the patients with and without dexmedetomidine. The percentages of patients with analgesic (25% with dexmedetomidine vs. 16.9% without) and antiemetic (19.2% with dexmedetomidine vs. 14.1% without) treatment requirements were slightly higher in the dexmedetomidine group, although these differences were not statistically significant (P = 0.27 and 0.44, respectively).

Discussion

MRgFUS is a fairly well‐tolerated procedure that most patients undergo with no significant adverse events. In our study, all patients withstood the treatment until its completion. No MRI/ultrasonic‐related adverse events required treatment discontinuation, and both headache and nausea were successfully controlled with the drugs in our protocol. The incidence of moderate or severe headache and nausea in our study was of 20.3% and 16.3%, respectively, and only 4.06% of patients presented both. The main determining factor for the incidence of headache treatment during MRgFUS were the characteristics of the patient's skull: SDR and ST.

In previous studies, the reported incidence of headache during sonication ranges between 24.3% and 60%. ⁵ , ⁷ , ⁹ , ¹⁰ , ¹¹ Discrepancy in the incidence of headache could be based on whether it is quantified as the degree or the presence of headache (based on the need for therapy). In our study, we administered headache prophylaxis to all patients (dexamethasone 8 mg iv + dipyrone 2 g iv + paracetamol 1 g iv). Despite this, we still observed an incidence of moderate or severe headache of 20.3% of patients. Of the patients, 15 (12.2%) aborted at least 1 sonication because of intolerable headache. Sinai et al. ⁸ administered dexamethasone 12 mg iv + paracetamol 1 g iv 1 hour before the procedure as their prophylactic medication for headache. They also employed Eutectic Mixture of Local Anesthetics (lidocaine 25 mg/g + prilocaine 25 mg/g) for lubrication of the skull before fitting the silicone membrane. This group did not report an incidence of headache. ⁸ Chapman et al. ⁷ reported an incidence of 31% in their study. Of the patients in their study, 97% received fentanyl, 60% received paracetamol, and 35% received nonsteroidal anti‐inflammatory drugs, but they did not disclose their protocol. ⁷ In our study, the main determining factor for headache during MRgFUS were skull properties, namely, SDR and ST. Patients with a lower SDR and a higher ST required a greater amount of delivered energy during sonication to reach the desired temperature. This relationship has been previously defined in the literature. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ This same association was observed regarding aborted sonication because of unbearable headaches. Patients with a lower SDR and a higher ST could benefit from a more aggressive analgesic prophylaxis, including opioids. Further studies with a higher number of patients are warranted to confirm this assumption.

We found a relatively higher homogeneity in previously published data with respect to the incidence of nausea, with values between 20% and 26.8%. ⁷ , ⁹ , ¹⁰ , ¹¹ These reported incidences are slightly higher than the incidence observed in our study (16.3%) in which we used a protocol based on the administration of 2 antiemetic drugs (dexamethasone 8 mg iv + ondansetron 4 mg iv). Besides a slightly lower incidence of nausea, it is noteworthy that only 1 patient presented vomiting (0.8%) in our case series. Sinai et al. administered dexamethasone 12 mg iv + granisetron 3 mg iv, ondansetron 4 mg iv, or metoclopramide hydrochloride 10 mg iv 1 hour before the procedure, but they did not report their incidence. ⁸ Chapman et al. observed an incidence of nausea in 21% of the patients in their study, with 2 (2.6%) cases of vomiting; only 61% of the patients received antiemetic drugs, and they provided no specific protocol. ⁷ None of the MRgFUS‐related variables or anesthetic characteristics analyzed in our study was associated with the incidence of nausea. We found that women, in comparison with men, are at greater risk of nausea. These results are in line with the literature focusing on other procedures. Female sex has been described as one of the strongest patient‐specific predictors for procedural nausea. ¹⁹ Nausea prophylaxis in our study seems to provide an adequate control of this symptom during MRgFUS. Whether the combination or addition of other antiemetic drugs could show better results for nausea in women warrants further studies.

Propofol, benzodiazepines, and other γ‐aminobutyric acid agonists have a direct effect on tremor, ²⁰ , ²¹ and they could therefore interfere with the clinical assessment of tremor reduction during MRgFUS, so we avoided the use of such drugs. Opioids can produce anxiolysis and could reduce the incidence of pain during the procedure and have been used by other groups. ⁷ The fear of increasing the probability of vomiting and pulmonary aspiration with opioids led us to the use of dexmedetomidine because of its analgesic and antiemetic properties. ²² , ²³ , ²⁴ , ²⁵ In our study, dexmedetomidine does not seem to play a role in MRI/ultrasound‐related events. Its use was not associated with a decrease in headache or nausea treatment requirements. Dexmedetomidine did succeed as an anxiolytic agent because patients who required sedation to tolerate the procedure, and even those who needed a deeper sedation or general anesthesia to perform the pretreatment MRI, could withstand the whole procedure. Despite this, in our results, patients with dexmedetomidine showed a significant increase in the number of sonications and the accumulated sonication time throughout MRgFUS, but did not require higher maximum energy, power, or temperature. Skull characteristics do not appear to play confounding factors in these findings as no association was observed between them and the dexmedetomidine requirements, and neither did the degree of tremor of the target limb. The exact role of dexmedetomidine on tremor assessment is unclear, and its potential confounding effect might impact the global procedure. We had already observed this effect on some patients with PT, ²⁶ , ²⁷ but we did not know if such finding could also be observed in patients with ET, especially at low doses and without a loading dose. Subsequent long‐term analyses are necessary to determine if the use of dexmedetomidine could have interfered in the final outcome. Further studies are needed to determine the ideal agent for sedation in MRgFUS procedures.

This is an retrospective study in a single center. One of the limitations of our study was to not quantify the degree of headache with a validated system, such as the visual or verbal analog scale for pain. Moreover, the discontinuation of tremor and antiparkinsonian medications, such as β‐blockers or benzodiazepines, to ensure a greater severity of tremor during the procedure, could contribute to induce rebound anxiety and interfere in the tremor assessment or anxiolytic requirements.

In conclusion, MRI/ultrasound‐related effects, although transient and minor, could interfere with the correct outcome of MRgFUS thalamotomy for tremor. In our study, the main determining factors for headache treatment were skull characteristics, namely, the SDR and ST. Patients with an SDR less than 0.48 showed 3 times the odds of moderate or severe headache. This same association was observed for sonication abortion attributed to intolerable headache. We also observed an association between sex and both nausea treatment requirement and emergency button–pressing attributed to nausea. The odds of nausea in women showed to be 4 times higher than men. When anxiolysis was necessary, dexmedetomidine was successfully used. Nevertheless, dexmedetomidine did not reduce the need for headache and nausea treatment. Patients with dexmedetomidine were found to have a higher number of sonications and longer accumulated sonication times. Its exact effect on tremor is still unclear. Further studies are needed to determine the ideal agent for those patients who may need sedation in MRgFUS procedures.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

E.C.‐A.: 1A, 1B, 1C, 2A, 2C, 3A, 3B

C.H.‐C.: 1A, 1B, 1C, 2A, 2C, 3A, 3B

J.M.N.‐C.: 1A, 2A, 2B, 2C, 3A, 3B

M.F.‐M.: 1A, 1B, 1C, 2B, 2A, 2C, 3B

L.H.G.‐Q.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

I.A.‐O.: 1A, 1B, 1C, 2A, 2C, 3B

M.A.G.: 1A, 1B, 1C, 2A, 2C, 3B

A.P.: 1A, 1B, 1C, 2A, 2C, 3B

M.C.R.‐O.: 1A, 1B, 1C, 2A, 2C, 3B

J.G.: 1A, 1B, 1C, 2A, 2C, 3B

A.M.‐S.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement

Ethical approval was provided by the Ethical Committee of the University of Navarra (Ethical Committee no. 2020.078), Pamplona, Spain (Chairperson ProfessorA.J. Idoate) on June 18, 2020. The Spanish Agency of Medicines and Medical Devices codified this study as no postauthorization (CUN‐DEX‐2019‐01), so informed patients consent was not necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflict of Interest

The authors declare that there are no funding sources or conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months

The authors declare that there are no additional disclosures to report.