Nimodipine for the treatment of otolaryngic indications

Nimodipine, a dihydropyridine calcium channel blocker, is an important pharmacologic agent in the practice of neurocritical care, specifically for its ability to reduce the risk of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage (aSAH). Nimodipine is currently indicated for the improvement of neurologic outcomes in adult patients with aSAH. Numerous randomized clinical trials have supported its use for this purpose since its approval in the 1980s.^1,–7 Current clinical practice guidelines strongly recommend the use of nimodipine in all patients with aSAH based on high-quality evidence, and it has been well-accepted as a standard of care in the pharmacologic management of this patient population.⁸,⁹ Currently, nimodipine is commercially available as a capsule and an oral solution in the United States. It is also available as an i.v. solution in Europe.

Interestingly, other oral and i.v. calcium channel blockers have not exhibited the same beneficial effects in patients with aSAH,¹⁰ leading clinicians to believe that nimodipine possesses unique neuroprotective effects in addition to its calcium channel–blocking and vasodilatory properties.^11,–13 Nimodipine is highly lipophilic and readily crosses the blood-brain barrier. Proposed neuroprotective effects include increased cerebral perfusion and oxygenation, protection of hair cells from acoustic trauma, and improved nerve axon regeneration and collateral sprouting. The exact cellular and pharmacologic mechanisms of these effects are unclear, though research into nimodipine’s neuroprotective effects is ongoing.¹⁴,¹⁵

Clinical investigations of nimodipine have been conducted for purposes other than aSAH, namely otolaryngic based indications, including cochlear and facial nerve preservation after vestibular schwannoma (VS) surgery, symptomatic management of Ménière’s disease and peripheral vertigo, and recovery of vocal cord paralysis after laryngeal nerve injury. This article summarizes the available literature describing the aforementioned off-label otolaryngic uses of nimodipine.

Literature review

A literature search was conducted using MEDLINE and the Cochrane Database of Systematic Reviews for articles published from 1983 through February 2017 with the following terms: nimodipine, otolaryngology, neuroprotection, vestibular schwannoma, acoustic neuroma, Ménière’s disease, vertigo, hearing loss, facial paresis, recurrent laryngeal nerve injuries, vocal cord paralysis, vocal fold paralysis, and oral surgery. The search was limited to human subjects and English-language articles. All identified peer-reviewed studies and case reports were included. A bibliographic search of all original articles was manually performed to identify additional manuscripts relevant to these clinical indications.

VS surgery

VSs, also known as acoustic neuromas, are benign intracranial tumors that affect the superior vestibular nerve. In recent decades, the rate of diagnosed VS increased, likely due to more widespread availability of audiological testing equipment and magnetic resonance imaging.¹⁶,¹⁷ Treatment strategies include watchful waiting with serial imaging, stereotactic radiosurgery, and microsurgical resection. Microsurgery offers the greatest chance of cure, but it is also the most invasive approach and carries numerous risks. These include cochlear and facial nerve injury, nerve edema, and disrupted circulation, potentially leading to hearing loss and facial paralysis.^18,–21

The most robust evidence regarding the use of nimodipine for otolaryngic indications is for the preservation of cochlear and facial nerve function after VS surgery. To date, there have been 3 prospective randomized studies exploring the utility of vasoactive treatment in this setting.^21,–23 In addition, the results of several published retrospective reviews and 1 prospective observational study are briefly summarized in Table 1.^24,–27

Prospective randomized studies. Strauss et al.²¹ conducted a prospective randomized study in Germany of 41 consecutive patients undergoing surgical removal of VS via the lateral suboccipital approach from 1990 through 1999. Patients were included if they met the following 2 criteria: (1) preoperative baseline audiological testing resulting in hearing class A, B, or C according to the American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) Foundation²⁸ and (2) intraoperative brainstem auditory evoked potential (BAEP) monitoring demonstrating a gradual reversible loss of potentials. Patients were randomized intraoperatively to receive vasoactive treatment with nimodipine and hydroxyethyl starch (n = 21) or no vasoactive treatment (n = 20). The treatment group received a nimodipine-soaked gelatin sponge in a 1:19 dilution with lactated Ringer’s solution applied to the exposed cranial nerve. After the operation, a continuous infusion of nimodipine was started immediately at 15 mg/kg/hr for 2 hours and then increased to a mean of 30 mg/kg/hr. Hydroxyethyl starch 6% was initiated 24 hours after the procedure up to a maximum of 500 mL twice daily, with the dosage adjusted to achieve a hematocrit level of <35% for hemodilution, with the proposed benefits of decreasing blood viscosity and improving regional microcirculation. The average duration of both agents was 9 days. During the postoperative course, 14 patients (67%) in the treatment group and 6 patients (30%) in the control group demonstrated preserved hearing (p < 0.05). All 41 patients had anatomically preserved cochlear nerves. Two patients developed dose-dependent hypotension attributed to nimodipine, and 2 patients experienced transient pruritus associated with hydroxyethyl starch. The authors concluded that initiating vasoactive treatment intraoperatively improved hearing outcomes in this patient population, prompting numerous subsequent studies. Of note, characteristics of the treatment group included patients who were younger, had better baseline hearing, and smaller tumor size.

Scheller et al.²² conducted a prospective, open-label, randomized pilot study in Germany investigating the utility of vasoactive prophylaxis on cochlear and facial nerve function after VS surgery. Thirty patients who had VS surgery via a suboccipitolateral approach between 2004 and 2006 were randomized preoperatively to receive vasoactive prophylaxis with continuous infusion nimodipine 15–30 mg/kg/hr and hydroxyethyl starch 10% (targeting a hematocrit value of 30–35%) starting the day before surgery and continued until postoperative day 7 (n = 14) or no vasoactive prophylaxis (n = 16). Intraoperatively, all patients received BAEP and continuous facial electromyelography monitoring. Patients in the control group who developed intraoperative cochlear or facial disturbances were immediately initiated on vasoactive treatment during the procedure (9 patients). Before the procedure, 12 patients in the prophylaxis group and 13 in the control group had baseline hearing class A, B, or C according to AAO-HNS. Seven patients (58%) in the prophylaxis group and 2 patients (15%) in the control group demonstrated hearing preservation during the postoperative course (p = 0.041); the remaining patients’ hearing deteriorated to class D. For the facial nerve function analysis, none of the patients in the prophylaxis group exhibited a postoperative facial nerve function of grade III or worse compared with 6 (38%) in the control group (p = 0.045) using the House-Brackmann grading system. This grading system ranges from I (normal facial function) to VI (total paralysis).²⁹ Of the 9 control patients who received intraoperative vasoactive treatment due to hearing or facial disturbances, none had hearing preservation, and 6 demonstrated noteworthy facial nerve paresis. No serious adverse events were observed in the prophylaxis group. Based on these findings, vasoactive prophylaxis with nimodipine and hydroxyethyl starch initiated preoperatively produced better results in terms of hearing preservation and facial nerve function. Intraoperative initiation of vasoactive treatment did not seem to confer the same benefit.

A prospective, open-label, randomized, multicenter, Phase III trial was subsequently undertaken in Germany, again by Scheller et al.,²³ to confirm the results of their previous pilot study. A total of 112 patients undergoing VS resection via a planned retrosigmoid approach in 2010 and 2011 were identified, 95 of whom were included in the analysis. Patients were randomized preoperatively to receive vasoactive prophylaxis with continuous infusion nimodipine 1–2 mg/hr and hydroxyethyl starch 6% (targeting a hematocrit value of 30–35%) starting the day before surgery and continued until postoperative day 7 (n = 47) or no vasoactive prophylaxis (n = 48). As with the previous pilot study, patients in the control group were initiated on vasoactive therapy intraoperatively if there was evidence of cochlear or facial nerve dysfunction (17 patients). For the primary outcome of facial nerve function at 12 months after surgery, 38 (84%) of 45 patients in the prophylaxis group (2 patients were excluded from this analysis due to loss of anatomical continuity of the facial nerve during the operation) were classified as House-Brackmann grade II or better, compared with 40 (83%) in the control group. When evaluating hearing preservation at 12 months after surgery, 18 (42%) of 43 patients in the prophylaxis group (4 patients were excluded from this analysis due to occlusion of the internal auditory artery during the operation) achieved hearing preservation (defined as Gardner-Robertson class I–IV), compared with 15 (31%) in the control group (p = 0.38). Class I of the Gardner-Robertson scale denotes good-to-excellent hearing, and class V is representative of deafness.³⁰ Significantly more patients experienced dose-dependent hypotension in the prophylaxis group (55% versus 12%, p < 0.001). Of note, patients in the prophylaxis group had larger tumors. After adjusting for tumor size and extent of resection using a logistic regression analysis, there was no difference between the 2 groups for deterioration of facial nerve function (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.34–3.43; p = 0.91). The risk for hearing deterioration to Gardner-Robertson class V did not significantly differ between groups (OR, 0.49; 95% CI, 0.18–1.30; p = 0.15). The ORs suggest that there may be a potential benefit of vasoactive prophylaxis for hearing preservation but not for facial nerve function.

Scheller et al.³¹ then conducted a combined retrospective analysis of the latter 2 randomized studies. Patients who received vasoactive prophylaxis with nimodipine and hydroxyethyl starch had a lower risk of hearing loss at 12 months after surgery compared with the control group (OR, 0.46; 95% CI, 0.22–0.97; p = 0.04). A multiple logistic regression analysis was performed and, after adjusting for tumor size and extent of resection, the results remained statistically significant (OR, 0.26; 95% CI, 0.1–0.65; p = 0.004), favoring vasoactive prophylaxis. However, no differences were seen between groups for the risk of facial nerve deterioration in the crude or regression analyses. Notably, the rate of dose-dependent hypotension was higher in patients who received vasoactive prophylaxis (51% versus 10%, p < 0.001).

Although the results of the separate randomized studies were not consistent, the results of this combined analysis support the use of vasoactive prophylaxis for hearing preservation in VS surgery, with the caveat that patients may potentially experience dose-dependent hypotension.

Discussion and recommendations. The applicability of the results of these studies may play a role when deciding whether to implement nimodipine therapy in the setting of VS resection. Technology, techniques, and surgeon experience for resection may have advanced from when these studies were performed, which may affect hearing and facial nerve outcomes. In addition, the published literature in Germany described the use of weight-based parenteral nimodipine, which is not currently available in the United States. Pharmacokinetic studies in this population have demonstrated that parenteral administration of nimodipine produces significantly higher serum, cerebrospinal fluid, and cerebrovascular tissue concentrations of the drug and potentially exhibits more neuroprotective effects compared with enteral nimodipine (Table 2).³²,³³ Furthermore, the prospective studies all used hydroxyethyl starch for hemodilution in addition to nimodipine, so it is unclear if the proposed theoretical benefits are conferred with combination therapy or with nimodipine alone. As an aside, recent literature in the critical care and cardiac surgery settings has suggested serious risks and adverse effects associated with hydroxyethyl starch, and the studies described in this review article were performed before the release of a Food and Drug Administration (FDA) safety communication regarding the risk associated with hydroxyethyl starch and kidney injury and mortality in critically ill patients and excessive bleeding in open heart surgery patients.³⁴ The only retrospective correlation study that investigated nimodipine without hydroxyethyl starch (n = 47) concluded that use of nimodipine was associated with very good long-term facial nerve function (defined as House-Brackmann grade I or II) at least 6 months after surgery (p = 0.016).³⁵ When the investigators performed a multivariate regression analysis, nimodipine was also deemed an independent predictor of very good long-term facial nerve function (p = 0.0349).

Nimodipine has not been routinely recommended in this clinical setting, but positive results from several of the previous studies suggest that it may serve a pharmacologic role. Recently, the Congress of Neurological Surgeons issued guidelines with a level 3 recommendation based on the available class III evidence: “Perioperative treatment with nimodipine (or with addition of hydroxyethyl starch) should be considered to improve postoperative facial nerve outcomes and may improve hearing outcomes.”³⁶ Given the acceptable safety profile, initiating prophylaxis with nimodipine preoperatively and continuing for 7–10 days postoperatively seems to be a reasonable option to potentially reduce the risk of cochlear and/or facial nerve deterioration. In the studies performed in Germany, parenteral nimodipine 15–30 mg/kg/hr or 1–2 mg/hr was used, which is not available in the United States. Thus, an enteral dose of 60 mg every 4 hours may be considered, which is the highest recommended dose approved by FDA for the indication of aSAH. Although this regimen may not necessarily achieve the same concentrations as parenteral administration, there is no existing evidence to support enteral doses exceeding 60 mg every 4 hours for this otolaryngic indication. The decision to implement this therapy should be based on clinician judgment and patient-specific preferences. If used, monitoring for adverse events is warranted, and the patient should discontinue treatment if undesirable effects occur, such as dose-dependent hypotension, due to the limited evidence on efficacy. Further research evaluating the use of nimodipine alone, without hydroxyethyl starch, in patients undergoing VS surgery, as well as optimal dosing and route of administration, is needed before a definitive conclusion can be made.³⁷

Ménière’s disease and peripheral vertigo

Ménière’s disease, named after a French physician who recognized that vertigo may have been due to abnormalities in the inner ear, is characterized by recurrent episodes of vertigo accompanied by cochlear symptoms such as hearing loss, tinnitus, and a sense of aural fullness.³⁸ The underlying pathophysiology is presumed to be endolymphatic hydrops (i.e., swelling of the membranous labyrinth of the inner ear). The swelling of the vestibular system and cochlear duct may be a causative factor for recurrent episodes.³⁹ Current management options include dietary modifications, pharmacologic therapies, and vestibular ablation via chemical or surgical methods.⁴⁰ Of note, vertigo induced by Ménière’s disease has a different pathophysiologic mechanism when compared with other causes of peripheral vertigo, such as benign paroxysmal positional vertigo, vestibular neuronitis, labyrinthitis, and ear trauma.⁴¹

Ménière’s disease. Lassen et al.⁴² published their clinical experience of nimodipine in the United States for the management of Ménière’s disease in 12 patients during 1992–95. The patients had ongoing unilateral symptoms despite dietary restrictions and other pharmacologic therapies (e.g., triamterene–hydrochlorothiazide, meclizine, diazepam) and were offered treatment with oral nimodipine 30 mg twice daily as salvage therapy. Eight patients reported satisfactory control of vertigo with nimodipine, based on the available criteria for evaluation of therapy at the time of the study.⁴³ The remaining 4 patients who did not report adequate control ultimately progressed to surgical management. One patient reported gastrointestinal upset, leading to discontinuation of nimodipine therapy. Due to its proposed benefits, potential to defer the need for invasive management options, and well-tolerated safety profile, the investigators recommended a trial of nimodipine for Ménière’s disease when conventional therapy has failed.

A retrospective review was performed by Monzani et al.⁴⁴ in Italy investigating the effects of nimodipine in the long-term treatment of Ménière’s disease. Patients with a definite diagnosis of unilateral Ménière’s disease between 1999 and 2009 were included in the review as long as they were not receiving other pharmacologic therapies simultaneously or had a history of a vestibular ablative procedure. Patients received either combination therapy with betahistine 16 mg twice daily and nimodipine 20 mg twice daily for 6 months (n = 60) or monotherapy with betahistine 16 mg twice daily for 6 months (n = 53). Betahistine, a histamine H₁-receptor agonist and H₃-receptor antagonist, is not currently approved by FDA for use in the United States; it was approved briefly in the 1960s before this status was rescinded in 1970 after FDA determined that some of its efficacy claims were unsubstantiated. Monzani et al. evaluated the coprimary effectiveness outcomes of therapy control of vertigo, disease staging, and functional level, all of which were assessed according to AAO-HNS guidelines.⁴⁵ The results demonstrated that the addition of nimodipine to betahistine, as compared with betahistine monotherapy, led to an improved vertigo control score (mean ± S.D. of 13.3 ± 25.3 versus 30.7 ± 30.8, p = 0.001), fewer patients classified as having stage 4 disease (6 versus 17, p = 0.034), and fewer patients being classified as functional level scale 4 or 5 (7 versus 26, p = 0.001). In addition, pure-tone audiometry and tinnitus annoyance results significantly improved after combination therapy; however, these same results were not witnessed in the monotherapy group. After the end of follow-up, 4 patients in the combination therapy group compared to 13 patients in the monotherapy group who continued to experience frequent relapses of vertigo ultimately underwent intratympanic gentamicin instillation as next-line therapy (p = 0.008). The results of this retrospective study suggest that the addition of nimodipine offers improved symptomatic control in patients with Ménière’s disease and may potentially help to defer more invasive management techniques.

Peripheral vertigo. Nimodipine has also been a pharmacologic agent of interest for other causes of vestibular peripheral vertigo. Pianese et al.⁴⁶ conducted a randomized, double-blind, pilot study from sites in Mexico, Colombia, and Chile comparing patients with diagnosed vertigo of peripheral origin who received nimodipine 30 mg 3 times daily (n = 89) with another group who received the calcium channel blocker cinnarizine 150 mg daily (n = 92) for 12 weeks. In the nimodipine group, the rate of moderate vertigo episodes decreased by 79%, the rate of severe episodes decreased by 85%, and the severity index score decreased by 62% at week 4 and by 83% posttreatment when compared with baseline (p < 0.001 for all). At the end of treatment, significant reductions in the number of patients experiencing hypoacousia, tinnitus, and abnormal electronystagmography results were observed in the nimodipine group when compared with baseline. Similar positive results were also seen in the cinnarizine group. In the group treated with nimodipine, 16 patients reported headaches, 4 patients had altered liver function test values, 5 patients experienced weight gain, and 1 patient exhibited somnolence. Only 1 serious adverse event, near syncope, was deemed to have a causal relationship with nimodipine. Based on these study results, nimodipine may serve as a pharmacologic option with an acceptable safety profile for the symptomatic treatment of vertigo.

Lisbeth et al.⁴⁷ compared 2 formulations of enteral nimodipine in patients with peripheral vertigo of various etiologies. Patients in Venezuela were randomized to conventional immediate-release nimodipine 30 mg 3 times daily (n = 25) or extended-release nimodipine 90 mg daily (n = 26) for 8 weeks. At the end of treatment, both groups experienced a decrease of ≥50% in the mean vertigo severity index and the mean vestibular disability index, which was defined as treatment success. Associated symptoms of hearing loss, tinnitus, and aural fullness also improved by 8 weeks regardless of which nimodipine formulation the patients received. Several adverse events were reported, including drowsiness, syncope, and tachycardia, but none resulted in the discontinuation of treatment. The investigators deemed nimodipine a viable pharmacologic treatment option in the symptomatic management of peripheral vertigo.

Discussion and recommendations. The available clinical evidence for administering nimodipine in patients with Ménière’s disease and vertigo of peripheral origin suggests a benefit in terms of symptomatic management. Both retrospective studies in Ménière’s disease showed positive results with nimodipine in patients with persistent unilateral symptoms despite other pharmacologic agents and/or dietary restrictions. In the study by Monzani et al.,⁴⁴ all patients received betahistine, but the group with the addition of nimodipine exhibited improved vertigo control and reduction of cochlear symptoms, suggesting the most benefit lies with the addition of nimodipine. Despite this, that study did not address the true benefit of using nimodipine alone. Of note, the results of both retrospective studies suggest the use of nimodipine may have prevented or deferred more invasive management techniques. Similarly, patients with peripheral vertigo not related to Ménière’s disease may also benefit from nimodipine therapy. In these clinical settings with patients who are still experiencing symptoms despite other pharmacologic and nonpharmacologic therapies, enteral nimodipine 30 mg twice or thrice daily could be considered. However, data from randomized clinical trials are needed before a formal guideline recommendation can be made.

Recurrent laryngeal nerve injury and vocal fold paralysis

Nimodipine use has also been evaluated in patients experiencing intraoperative injury to the recurrent laryngeal nerve (RLN), most commonly seen after thyroid or parathyroid surgery. The effect of this injury varies from transient dysphonia, dysphagia, and aspiration issues to permanent vocal fold paralysis (VFP). Antagonism of voltage-gated calcium channels may help promote axonal growth and regeneration in addition to improving recovery after RLN axonal injury.⁴⁸

The first published human case from Sweden supporting the use of nimodipine in this setting showed evidence of reinnervation and functional recovery of the vocal cord after RLN resection.⁴⁹ A small, prospective pilot study was subsequently performed in Sweden by Hydman et al.,⁵⁰ in which 15 patients who experienced VFP after thyroid surgery were identified. A total of 6 patients accepted treatment with nimodipine 60 mg thrice daily. Ultimately, only 7 of the 15 patients had evidence of RLN axonal injury and were split into 2 groups for the final analysis: patients who received nimodipine for 3 months after thyroid surgery (n = 3) or no nimodipine (n = 4). All 3 patients who received nimodipine recovered to normal or near-normal vocal fold mobility at 6 months. Of the 4 patients who did not receive enteral nimodipine, 2 experienced complete VFP at the conclusion of the study period. Due to the low number of patients, the authors could not form a strong definitive conclusion regarding the benefits of administering nimodipine after RLN injury.

The majority of evidence for the use of nimodipine for VFP comes from a prospective, open-label study performed at the University of Pittsburgh Voice Center, where nimodipine was utilized in a protocolized fashion.⁵¹ Patients were eligible for nimodipine therapy if they had unilateral or bilateral VFP of <4 months’ duration, had laryngeal electromyographic evidence of RLN axonal injury, and were deemed to have a poor-to-fair prognosis for recovery. Fifty-three patients were initially offered nimodipine therapy. Twenty-eight patients, representing 30 paralyzed vocal folds, were included and received nimodipine for up to 3 months. Therapy was initiated at 30 mg thrice daily, followed by an increase in dosage to 60 mg thrice daily if tolerated. Nimodipine was discontinued if patients demonstrated clear improvement during routine laryngoscopies assessing for vocal fold motion. Ultimately, 18 (60%) of paralyzed vocal folds demonstrated meaningful recovery and purposeful motion. This may be of clinical significance when taking into consideration historical data that suggest a ≤20% recovery rate.^52,–54 Of the 28 patients included in the analysis, 3 patients reported adverse effects: headache, dyspnea on exertion, and asymptomatic hypotension. Subsequently, a retrospective review of these data was performed to determine optimal timing of nimodipine initiation after RLN injury.⁵⁵ When comparing nimodipine initiation within 15 days postinjury (n = 19), 15–30 days postinjury (n = 23), or greater than 30 days postinjury (n = 11), there were no differences noted in the rates of recovery.

Based on the limited available evidence, routine use of nimodipine in patients with RLN axonal injury and VFP cannot be recommended. However, nimodipine does seem to be a promising agent in these patients if initiated within 4 months after injury. A prospective, randomized trial would be ideal to identify a more conclusive recommendation. If used, nimodipine should be implemented for recovery in a protocolized manner for patients with a poor-to-fair prognosis based on laryngeal electromyographic evaluation. We suggest careful utilization of nimodipine with slow dosage adjustments, starting at 30 mg thrice daily. Clinicians should have a low threshold for discontinuation in patients demonstrating clear improvement during evaluation and in patients experiencing intolerable adverse effects associated with its use.

Maxillofacial surgery

Given the potential beneficial effects of nimodipine on facial nerve function after VS surgery, a recent prospective pilot study was conducted in Germany involving patients who developed facial weakness after maxillofacial surgery.⁵⁶ Thirteen patients were enrolled; 12 suffered from severe paresis (House-Brackmann grade V–VI) and 1 suffered from moderate paresis (grade II–III). The dosage of nimodipine was 60 mg 6 times daily for 10–14 days, at which point facial nerve function was reevaluated. The dosage was slowly decreased when patients displayed evidence of recovery, defined as an improvement by at least 1 grade. After 2–3 weeks of treatment, the mean House-Brackmann grade improved to 2.8 (p < 0.001); after 6–8 weeks of treatment, the mean grade improved to 1.54 (p < 0.001). No serious adverse events related to nimodipine treatment were observed.

Due to the small number of patients enrolled, a recommendation cannot yet be made to routinely administer nimodipine to patients with facial weakness after maxillofacial surgery. A prospective, randomized clinical trial may shine more light on the proposed benefit of nimodipine in this clinical scenario and potentially confirm the results of this pilot study.

Conclusion

Due to its proposed vasoactive and neuroprotective effects, nimodipine may play a role in the treatment of a number of otolaryngic pathologies including VS, Ménière’s disease, peripheral vertigo, RLN injury, and facial weakness after maxillofacial surgery. Small studies have shown improved symptom control and recovery after surgery. Since all of the aforementioned indications are still considered off label, clinicians and patients should collaboratively assess the risks and benefits before initiating treatment.

Disclosures

The authors have declared no potential conflicts of interest.

References