In vitro and in vivo models of drug ototoxicity: studying the mechanisms of a clinical problem.

INTRODUCTION: Drug ototoxicity represents one of the main preventable causes of deafness. Ototoxicity is a trait shared by aminoglycoside and macrolide antibiotics, antimalarial medications, loop diuretics, platinum-based chemotherapeutic agents, some NSAIDs and most recently described, acetaminophen when abused with narcotic medication. These medications are prescribed despite their side effects, which includes inner ear toxicity, because they are life-saving drugs or there is a lack of better treatment. AREAS COVERED: This review will discuss in vitro and in vivo models of ototoxicity highlighting recently published ototoxicity research. The reader will learn the strengths and limitations of different ototoxicity models and what molecular insights have been gained from their application. A better understanding of the cellular mechanisms of these ototoxins will help in the discovery of ways to prevent and treat hearing loss associated with ototoxic medications. EXPERT OPINION: There are benefits to both in vitro and in vivo models of ototoxicity. Research of a particular medication and its ototoxic mechanisms should draw from several models, enabling a better answer to the clinical question of prevention and treatment of inner ear drug toxicity.

Acetaminophen ototoxicity after acetaminophen/hydrocodone abuse: evidence from two parallel in vitro mouse models.

OBJECTIVE: Acetaminophen/hydrocodone, a commonly used analgesic preparation, has been linked to rapidly progressing sensorineural hearing loss in human patients. The cellular and molecular mechanisms underlying the ototoxic effects of this drug combination are currently unknown, but are usually associated with high doses of hydrocodone. This study was aimed at identifying the specific agent responsible for hearing loss from toxic killing of cochlear sensory cells. STUDY DESIGN: Dose-response study. SETTING: University laboratory and private research facility. SUBJECTS AND METHODS: Math1 green fluorescent protein neonatal mouse cochlear cultures as well as a mouse auditory cell line (HEI-OC1) were exposed in vitro to different concentrations of acetaminophen, hydromorphone (the active metabolite of hydrocodone), and the micronutrient L-carnitine, either alone or combined. Using fluorescent and light microscopy, we quantified the sensory hair cells from a 600-microm basal segment before and after treatment. Acetaminophen/hydrocodone-induced apoptosis of HEI-OC1 was evaluated by caspase 3-activation studies. Statistically significant cell survival was determined with Student t test and analysis of variance. RESULTS: Cell death was associated mainly with exposure to acetaminophen, was slightly potentiated when combined with hydromorphone, and was partially prevented by L-carnitine. Exposure to hydrocodone or hydromorphone alone failed to kill either cochlear hair cells or HEI-OC1 cells. CONCLUSION: Our findings point to acetaminophen, rather than hydrocodone, as the primary cytotoxic agent. Hydrocodone, however, may work synergistically with acetaminophen, increasing the damage to auditory cells. These findings are an important first step toward understanding the mechanism of acetaminophen/hydrocodone ototoxicity and may lead to future treatment strategies for hearing loss from ototoxic medications.

The role of intraoperative auditory brainstem response testing for infants and difficult-to-test children.

OBJECTIVE: To assess the validity of intraoperative auditory brainstem response in infants and difficult-to-treat older children. STUDY DESIGN: Case series with chart review. SETTING: Tertiary-level children's hospital. SUBJECTS AND METHODS: Twenty-six patients were identified (mean age, 20 +/- 18 months) who underwent both intraoperative auditory brainstem response (ioABR) testing and a follow-up hearing evaluation at five (standard deviation 4) months. Ears were analyzed separately for mean threshold change, and a sub-analysis was performed accounting for the presence or absence of fluid at the time of surgery. RESULTS: A paired t test analysis indicated a statistically significant difference at 1 kHz. There was not a statistically significant difference between the two groups with click or 4-kHz testing. Fifteen ears (58%) at 1 kHz and 17 ears (49%) at 4 kHz frequencies, however, improved by 10 dB or more; 67 percent and 65 percent of these ears, respectively, had middle ear fluid intraoperatively. Eight ears (35%) in the click ABR group had a similar improvement, four of which had fluid at the time of surgery. Four ears in the 1-kHz (11.5%), in the 4-kHz (11.4%), and in the click ABR group (17.4%) demonstrated a 10-dB or worse threshold. The range of the discrepancy varied from a worsening in thresholds up to 20 dB and improvement in thresholds up to 45 dB. CONCLUSIONS: We observed a significant discrepancy between ioABR and follow-up hearing thresholds. If ioABR indicates a hearing loss, audiologic testing should be performed at least several weeks later to confirm the results.

Understanding drug ototoxicity: molecular insights for prevention and clinical management.

Ototoxicity is a trait shared by aminoglycoside and macrolide antibiotics, loop diuretics, platinum-based chemotherapeutic agents, some NSAIDs and antimalarial medications. Because their benefits in combating certain life-threatening diseases often outweigh the risks, the use of these ototoxic drugs cannot simply be avoided. In this review, the authors discuss some of the most frequently used ototoxic drugs and what is currently known about the cell and molecular mechanisms underlying their noxious effects. The authors also provide suggestions for the clinical management of ototoxic medications, including ototoxic detection and drug monitoring. Understanding the mechanisms of drug ototoxicity may lead to new strategies for preventing and curing drug-induced hearing loss, as well as developing new pharmacological drugs with less toxic side effects.

Decompressive hemicraniectomy for poor-grade aneurysmal subarachnoid hemorrhage patients with associated intracerebral hemorrhage: clinical outcome and quality of life assessment.

OBJECTIVE: Decompressive hemicraniectomy has been proposed as a potential treatment strategy in patients with poor-grade aneurysmal subarachnoid hemorrhage presenting with focal intracerebral hemorrhage causing significant mass effect. Although hemicraniectomy improves overall survival rates, the long-term quality of life (QoL) for survivors in this patient population has not been reported. METHODS: Using adjudicated outcome assessments, we compare long-term clinical outcomes and QoL between a group of patients with poor-grade aneurysmal subarachnoid hemorrhage receiving decompressive hemicraniectomy (n=12) and a control group of similar patients managed more conservatively (n=10). RESULTS: Patients receiving decompressive hemicraniectomy experienced a statistically insignificant decrease in short-term mortality compared with controls (25 versus 42%); however, long-term QoL in hemicraniectomy survivors was generally poor. Furthermore, hemicraniectomy patients did not experience an increase in mean quality-adjusted life years over control patients (2.31 versus 2.22 yr). CONCLUSION: Decompressive hemicraniectomy prolongs short-term survival in patients with poor-grade aneurysmal subarachnoid hemorrhage with associated intracerebral hemorrhage; however, this trend is not statistically significant, and the overall QoL experienced by survivors is poor. Decompressive hemicraniectomy may be indicated if performed early in a select subset of patients. On the basis of our preliminary data, large prospective studies to investigate this issue further may not be warranted.

Endoscopic decompression of tension pneumosella following transsphenoidal pituitary tumor resection.

OBJECTIVE AND IMPORTANCE: Tension pneumosella is an extremely rare complication of transsphenoidal surgery, having been reported only three times previously. Patients who develop this expanding pneumocele confined to the sella present with visual field changes consistent with optic chiasm compression. If left untreated, this condition can lead to permanent visual deficits. We report a case of tension pneumosella after transsphenoidal resection of a benign pituitary adenoma that was successfully treated endoscopically. CLINICAL PRESENTATION: Six months after transsphenoidal resection of a pituitary tumor, a 70-year-old man presented with subjective vision loss and was found on formal testing to have bitemporal hemianopsia. A diagnosis of tension pneumosella was made with a head CT after tumor recurrence was ruled out with MRI. The expanding pneumocele developed after vigorous nose blowing in the setting of a surgical sellar floor defect and an intact diaphragma sellae. INTERVENTION: The pneumocele was endoscopically decompressed using a transnasal approach guided by frameless stereotaxy. An immediate decrease in the amount of air was confirmed with intraoperative fluoroscopy. The defect was subsequently repaired with a hemostatic agent and fibrin glue. The patient rapidly recovered his vision and went home on postoperative day one with no further visual complications. CONCLUSION: Tension pneumosella should be considered as a possible diagnosis in patients presenting with subacute visual field deficits after transsphenoidal pituitary region surgery. Endoscopy may play a valuable role in the diagnosis and management of this rare phenomenon, as well as other more common complications of transsphenoidal surgery.