Longitudinal CT evaluation of transdermal scopolamine for aspiration pneumonia with sialorrhea in severe chronic brain injury: A case series

Abstract

Sialorrhea is a major cause of recurrent aspiration pneumonia in severe chronic brain injury. Previous reports have shown that transdermal scopolamine can decrease saliva production. We present four patients with severe chronic brain injury who experienced repeat aspiration pneumonia with sialorrhea. Longitudinal computed tomography examinations to assess the therapeutic effect were performed in all four cases before and after transdermal scopolamine. Transdermal scopolamine was applied as a patch (0.1 g/2.5 cm²) behind the earlobe every 24 h after confirming the absence of glaucoma. Patches were formulated as an in-hospital preparation (scopolamine butylbromide 0.25 g and hydrophilic cream 4.75 g) under the approval of our institutional review board. Longitudinal computed tomography after transdermal scopolamine use showed a decrease in pleural effusions associated with continuous aspiration pneumonia in all four cases. The data from repeat computed tomography suggest that long-term transdermal scopolamine for reducing saliva production may be a reasonable option for appropriate palliative care in severe chronic brain injury patients.

Introduction

Severe chronic traumatic brain injury (scTBI), including minimally conscious state or unresponsive wakefulness syndrome (UWS), is often accompanied by functional dysphagia, which can trigger repeat aspiration pneumonia associated with sialorrhea. In particular, UWS is a disorder of consciousness in which some people awaken from their comas (open their eyes) but remain unresponsive (i.e. they display only reflex movements without responding to commands). ¹ Aspiration pneumonia is observed in nearly 10% of these patients during the course of treatment, and the condition is a common cause of death in scTBI. ² Although protective endotracheal intubation or tracheostomy is recommended for long-term care, sialorrhea-induced pneumonia is not always preventable and interferes with rehabilitation.

Scopolamine butylbromide is a competitive inhibitor of the muscarinic receptors of acetylcholine and is commonly used for the prevention of motion-induced nausea in the form of transdermal scopolamine. ³ Recently, transdermal scopolamine has drawn attention for its effects in reducing saliva production, and it has been used for treating sialorrhea in patients with amyotrophic lateral sclerosis and stroke. ⁴ , ⁵

We present a case series in which longitudinal computed tomography (CT) was used to assess the therapeutic effect of transdermal scopolamine treatment in four UWS patients with scTBI.

Case 1

Case presentation

A 51-year-old man had an accident involving a car while riding a bicycle. He sustained traumatic subarachnoid hemorrhage, diffuse brain injury, and fractures to the mandible, left clavicle, and C6 vertebra. He was admitted to our hospital 7 months after the injury. The Coma Recovery Scale-Revised (CRS-R) score at admission was 5 (3-0-1-0-0-1), which is classified as UWS. ⁶ A tracheostomy tube was placed at admission. The patient experienced seven episodes of aspiration pneumonia in 9 months after admission.

Case management and outcome

When transdermal scopolamine was started in July 2019, the left pleural effusion decreased. Furthermore, right pulmonary consolidation decreased, and bilateral dorsal ground-glass opacities and atelectasis improved (Figure 1(a) and Table 1). ⁷ Transdermal scopolamine was discontinued after 1 month of continuous use. However, because the left pleural effusion gradually increased again over 2 months, transdermal scopolamine was restarted in November 2019. Thereafter, a decrease in pleural effusion was again observed on CT, and bilateral dorsal pulmonary consolidation, ground-glass opacities, and atelectasis also improved. No obvious side effects were observed during the use of transdermal scopolamine. Ultimately, in February 2020, the man’s family chose tracheoesophageal diversion after consulting with an otolaryngologist for the prevention of aspiration at home after discharge because the use of transdermal scopolamine was off-label (Figure 1(b)).

Figure 1.

Longitudinal imaging of case 1. (a) Longitudinal CT images. CT scan before transdermal scopolamine patches 1^st use: 3.8 cm pleural effusion. CT scan 1 months after 1^st use: 1.9 cm pleural effusion. CT scan before 2^nd use 2.0 cm pleural effusion. CT scan 1 months after 2^nd use: 0.9 cm pleural effusion. (b) Neck CT images before and after tracheoesophageal diversion for the prevention of aspiration. (c) Representative image after tracheoesophageal diversion.

Table 1.

Summary of the CT findings.

CT findings	Case 1-1st		Case 1-2nd		Case 2		Case 3		Case 4
	Before	After 1 month	Before	After 1 month	Before	After 7 months	Before	After 2 months	Before	After 7 months
Bronchiectasis (Yes/No)	Yes	Yes	No	No	No	No	No	No	No	No
Bronchial wall thickening (Yes/No)	Yes	Yes	Yes	Yes	No	No	Yes	Yes	Yes	Yes
Pulmonary nodules	No	No	No	No	No	No	No	No	No	No
Consolidations	Yes	No	Yes	Yes (improve)	Yes	Yes (improve)	No	No	No	No
Ground-glass opacity	Yes	Yes (improve)	Yes	Yes (improve)	Yes	Yes (improve)	No	No	Yes	Yes (improve)
Atelectasis	Yes	Yes (improve)	Yes	Yes (improve)	Yes	No	Yes	Yes	Yes	Yes
Interlobular septal thickening	Yes	Yes	Yes	Yes	No	No	Yes	Yes	No	No
Fibrosis	No	No	No	No	No	No	No	No	No	No
Air trapping	No	No	No	No	No	No	Yes	Yes	Yes	Yes
Pleural effusion category (small/moderate/large) a	moderate	small	small	small	small	small	moderate	small	moderate	moderate
Maximum anteroposterior depth of pleural effusion (cm) a	3.8	1.9	2	0.9	2	0.7	3	0.7	3.4	1.8

CT: computed tomography.

a

Refer to Chest 2013;143: 1054–1059.

Case 2

Case presentation

A 41 year-old man had an accident involving a car while walking and presented in cardiogenic shock. He was treated for brain stem contusion and left putaminal hemorrhage, and he had sustained fractures to the right clavicle, right rib, left tibia, fibula, and pelvis. He was admitted to our hospital 5 months after the accident. The CRS-R score at admission was 7 (2-3-1-0-0-1), which was classified as UWS.

Case management and outcome

During the first 22 months after admission, he experienced six episodes of aspiration pneumonia before transdermal scopolamine was started. Thereafter, CT showed decreased pleural effusion, resolution of the right lung atelectasis, and improved bilateral dorsal pulmonary consolidation, and ground-glass opacities (Figure 2(a) and Table 1). Fourteen months after starting transdermal scopolamine, he continued rehabilitation without pneumonia and was discharged from the hospital. The CRS-R at discharge was 14 (2-3-5-1-0-3). After using transdermal scopolamine, there were no obvious side effects until discharge.

Figure 2.

Longitudinal CT examinations of (a) case 2 (CT scan pre scopolamine patches: 2.0 cm pleural effusion. CT scan 7 months after: 0.7 cm pleural effusion) (b) case 3 (CT scan pre scopolamine patches: 3.0 cm pleural effusion. CT scan 2 months after: 0.7 cm pleural effusion), and (c) case 4 (CT scan pre scopolamine patches: 3.4 cm pleural effusion. CT scan 7 months after: 1.8 cm pleural effusion).

Case 3

Case presentation

A 76-year-old man was involved in a car accident during his job working in security. He was diagnosed with traumatic subarachnoid hemorrhage, diffuse brain injury, left iliac wing/left central pelvic fracture, and right femoral fracture. On admission, he had a CRS-R score of 4 (1-0-2-0-0-1), which was classified as UWS.

Case management and outcome

During the first 12 months after admission, he experienced three episodes of aspiration pneumonia. Transdermal scopolamine was administered after April 2020, and pneumonia did not occur for 10 months thereafter. CT showed decreased right pleural effusion after transdermal scopolamine use (Figure 2(b) and Table 1). During transdermal scopolamine use, there were no evident negative effects. Because of the off-label use of transdermal scopolamine, the family selected tracheoesophageal separation after consulting with an otolaryngologist, for patient management at home after discharge in January 2021.

Case 4

Case presentation

A 58-year-old man was involved in a car accident in March 1984. He sustained cerebral contusions and a right lower leg fracture. He developed pneumonia once every 6 months and frequently used continuous oxygen because of low blood oxygen levels. On admission, he had a CRS-R score of 11 (1-4-2-1-0-3), which was classified as UWS.

Case management and outcome

On longitudinal CT, the right pleural effusion decreased, and bilateral dorsal pulmonary ground-glass opacities improved after transdermal scopolamine use (Figure 2(c) and Table 1). Continuous oxygen use was not required after transdermal scopolamine, and pneumonia did not recur until 17 months later with continuous use of scopolamine.

Discussion

Saliva—normally produced at a rate of 0.5–1.5 L per day—helps maintain a hygienic environment in the oral cavity, contributing to oral health, and mouth lubrication and swallowing, and preventing bacterial overgrowth and tooth decay. ⁸ However, in patients with scTBI, including UWS and minimally conscious state, sialorrhea can cause drooling, external skin irritation, choking, poor oxygenation, and life-threatening pneumonia. ⁹ Although transdermal scopolamine is currently used as a treatment for motion sickness, using this drug and formulation for reducing saliva production is an off-label use. In accordance with previous reports, we used an in-hospital preparation of transdermal scopolamine (scopolamine butylbromide 0.25 g and hydrophilic cream 4.75 g) based on previous reports under the approval of the Rehabilitation Center for Traumatic Apallics Chiba Review Board (2019-26). ¹⁰ Transdermal scopolamine was used as a 0.1 g/2.5 cm² patch behind the earlobe every 24 h after confirming the absence of glaucoma because the anticholinergic effect might increase intraocular pressure. Our scopolamine patch was based on the previous article because commercialized scopolamine skin patches (Scopoderm TTS, Novartis Consumer Healthcare, UK) are off-label in Japan. ¹⁰ However, a phase I clinical study will be required in the future to examine the safety, side effects, appropriate dose, and timing of the medication for other patients.

In our four cases, Table 1 shows the detailed changes on longitudinal CT with reference to previous reports. ⁷ Long-term repeat CT showed a decrease in pleural effusion associated with continuous aspiration pneumonia in all four cases. The average number and standard deviation of aspiration suctions per day was calculated before, after 1, 2, and 3 months of transdermal scopolamine use, however no tendency was seen (Supplementary Table 1). The number of aspiration suctions may vary depending on the severity of pneumonia. It may be necessary to measure the amount of salivation to accurately indicate the therapeutic effect of transdermal scopolamine, in future.

In two of our four cases, tracheoesophageal diversion was selected after the family consulted with an otolaryngologist regarding quality-of-life after discharge. As sialorrhea treatments, oral anticholinergic agents, botulinum toxin A injection into the salivary glands, surgery, and radiation therapy have been reported, and each has advantages and disadvantages. ¹¹ Recently, the usefulness of submandibular gland excision or two-duct ligation has also been reported. ¹² If the use of transdermal scopolamine in our patients had not been off-label, it could have been used for a longer period at a lower cost, offering an option for less invasive palliative care. The treatment aims in our patients were to reduce cough caused by saliva aspiration, have the family perform odor and taste rehabilitation, and reduce saliva-induced skin disorders following discharge.

Scopolamine suppresses the autonomic reflex via its anti-acetylcholine action, resulting in improvement in nausea and dizziness. ³ In 1985, Gordon et al. ¹³ showed that dry mouth with scopolamine patches was because of a significant decrease in saliva production in healthy individuals, suggesting the potential for therapeutic use for persistent drooling. Of note, scopolamine discontinuation can result in overstimulation of the vestibular nuclei and the vomiting center in the reticular formation and hence the sensation of motion sickness. This phenomenon—known as scopolamine patch withdrawal syndrome—has been reported, however, the incidence is unknown. ¹⁴ Owing to the inability to communicate with the patients in our four cases, we were unable to obtain information about the patients' subjective reactions to the transdermal scopolamine patch, such as sleepiness, blurred vision, or dry mouth. However, during our observation period, no objective side effects such as pupillary dilatation, urinary retention, constipation, or tachycardia were observed.

Case reports describe the use as a therapeutic agent for aspiration pneumonia in otorhinolaryngology surgery, cerebral palsy, neurodevelopmental disorder, amyotrophic lateral sclerosis, and stroke. However, there are no reports using longitudinal radiological imaging following long-term transdermal scopolamine use for aspiration pneumonia in patients with severe head trauma. ⁴ , ⁵ , ⁹ Mato et al. ¹⁵ reported the effectiveness of transdermal scopolamine for drooling control in a prospective, randomized, placebo-controlled clinical trial. In our report, detailed endoscopic examinations would have been ideal, but this was impossible owing to trismus, clenching, and non-cooperative behaviors. The information presented in this case series shows the possibility that repeat CT could be an index for accurate evaluation of the efficacy of transdermal scopolamine in future multicenter, controlled studies investigating the expansion of the indications.

Conclusion

After transdermal scopolamine administration in all four of our patients, longitudinal CT revealed pulmonary improvement comprising a reduction in pleural effusion associated with repeat aspiration pneumonia. For similar patients to those in this report, long-term transdermal scopolamine to lower saliva production could be a viable alternative for appropriate palliative treatment.

Supplemental Material

sj-xlsx-1-sco-10.1177_2050313X221096227 – Supplemental material for Longitudinal CT evaluation of transdermal scopolamine for aspiration pneumonia with sialorrhea in severe chronic brain injury: A case series

Supplemental material, sj-xlsx-1-sco-10.1177_2050313X221096227 for Longitudinal CT evaluation of transdermal scopolamine for aspiration pneumonia with sialorrhea in severe chronic brain injury: A case series by Tomohiro Yamaki, Kyoko Takahashi, Osamu Azuhata, Daisuke Itou, Madinum Yakufujiang, Nobuo Oka, Masaru Odaki and Shigeki Kobayashi in SAGE Open Medical Case Reports