Wooden Chest syndrome: The atypical pharmacology of fentanyl overdose.

WHAT IS KNOWN AND OBJECTIVE: A large percentage of opioid overdose fatalities involve fentanyl or one of its legal or illegal analogs (F/FAs). Is there something about the pharmacology of these drugs that make them unusually dangerous in an overdose? COMMENT: Some of the reasons for the dangers of overdose of F/FAs is their high potency and low cost (that leads to wide distribution). But it is rarely asked if the basic pharmacology of F/FAs differ in some fundamental way from conventional opioids such as morphine and heroin. In addition to centrally mediated respiratory depression via opioid receptors, F/FAs cause rigidity in the key respiratory muscles of the chest, upper airway and diaphragm ("wooden chest syndrome," WCS) by a non-opioid mechanism. WHAT IS NEW AND CONCLUSION: WCS is an atypical pharmacology of F/FAs. Because of its rapid onset and non-opioid mechanism, WCS makes F/FA overdose particularly dangerous.

Paroxysmal Laryngospasm: A Rare Condition That Respiratory Physicians Must Distinguish from Other Diseases with a Chief Complaint of Dyspnea.

Background: In recent years, we have observed respiratory difficulty manifested as paroxysmal laryngospasm in a few outpatients, most of whom were first encountered in a respiratory clinic. We therefore explored how to identify and address paroxysmal laryngospasm from the perspective of respiratory physicians. Methods: The symptoms, characteristics, auxiliary examination results, treatment, and prognosis of 12 patients with paroxysmal laryngospasm treated in our hospital from June 2017 to October 2019 were analyzed. Results: Five males (42%) and 7 females (58%) were among the 12 Han patients sampled. The average age of the patients was 49.25 ± 13.02 years. The disease course ranged from 14 days to 8 years and was characterized by sudden dyspnea, an inability to inhale and exhale, a sense of asphyxia, and voice loss during an attack. Eight patients with gastroesophageal reflux were cured after antacid treatment. One case of upper respiratory tract infection (URI) was completely relieved after symptomatic treatment. One patient with left vocal cord paralysis experienced complete relief after specialist treatment by an otorhinolaryngologist. Episodes in 1 patient were significantly reduced after lifestyle improvement. One patient experienced spontaneous relief after rejecting treatment. Conclusions: Paroxysmal laryngospasm is a rare laryngeal disease that generally occurs secondary to gastroesophageal reflux disease (GERD), and antireflux therapy is frequently effective for its treatment. A respiratory physician should master and identify the symptoms and differentiate this condition from hysterical stridor, reflux-related laryngospasm, and asthma. Timely referral to otolaryngologists, gastroenterologists, and other specialists for standardized examination and regular treatment should be provided when necessary.

Mechanisms and prevention of acid reflux induced laryngospasm in seizing rats.

OBJECTIVE: Recent animal work and limited clinical data have suggested that laryngospasm may be involved in the cardiorespiratory collapse seen in sudden unexpected death in epilepsy (SUDEP). In previous work, we demonstrated in an animal model of seizures that laryngospasm and sudden death were always preceded by acid reflux into the esophagus. Here, we expand on that work by testing several techniques to prevent the acid reflux or the subsequent laryngospasm. METHODS: In urethane anesthetized Long Evans rats, we used systemic kainic acid to acutely induce seizure activity. We recorded pH in the esophagus, respiration, electrocorticography activity, and measured the liquid volume in the stomach postmortem. We performed the following three interventions to attempt to prevent acid reflux or laryngospasm and gain insights into mechanisms: fasting animals for 12 h, severing the gastric nerve, and electrical stimulation of either the gastric nerve or the recurrent laryngeal nerve. RESULTS: Seizing animals had significantly more liquid in their stomach. Severing the gastric nerve and fasting animals significantly reduced stomach liquid volume, subsequent acid reflux, and sudden death. Laryngeal nerve stimulation can reverse laryngospasm on demand. Seizing animals are more susceptible to death from stomach acid-induced laryngospasm than nonseizing animals are to artificial acid-induced laryngospasm. SIGNIFICANCE: These results provide insight into the mechanism of acid production and sudden obstructive apnea in this model. These techniques may have clinical relevance if this model is shown to be similar to human SUDEP.

Vibratory Onset of Adductor Spasmodic Dysphonia and Muscle Tension Dysphonia: A High-Speed Video Study✰.

OBJECTIVE: Adductor spasmodic dysphonia (AdSD) is a challenging voice disorder to diagnose, often erroneously diagnosed as muscle tension dysphonia (MTD) or vocal tremor, due to its similarity in auditory and perceptual presentation. Assessments using laryngoscopy or strobolaryngoscopy procedures have demonstrated limited utility in the diagnosis of spasmodic dysphonia. High-speed videoendoscopy (HSV) provides visualization of the precise vibratory pattern of phonatory onset and thus, offers an alternative to previous diagnostic strategies for visual diagnosis of AdSD. The purpose of this study was to examine vibratory onset of patients with AdSD and patients with MTD using HSV methodology. METHODS: HSV of six adults with AdSD and five adults with MTD were captured during sustained phonation. Digital kymography was used to obtain precise vibrogram data at the mid-membranous region of the vocal fold prior to and at the onset of phonation. Voice onset delay was examined by (1) quantifying timing of prephonatory delay and steady state delay and (2) describing vocal fold onset movements qualitatively in each diagnosis. RESULTS: HSV adequately captured the phonatory onset of the vocal folds. Voice onset delay was not significantly different between AdSD and MTD. However, there were distinct differences in voice onset gestures. Both AdSD and MTD patients presented with vocal hyperfunction during the onset of phonation. In a subset of AdSD patients, a rapid sustained adduction occurred following the initial vibratory motion. Vocal fold vibration then continued until steady phonation was achieved. This oscillatory break pattern was not observed in patients with MTD. Therefore, there appears to be differences in vocal fold vibratory onset motion between MTD and AdSD. CONCLUSION: HSV captures the precise vibratory onset in patients with MTD and AdSD. Differences were most notable after vibratory onset as opposed to vibratory delay measurements. Examination of voice onset gesture may offer an additional laryngeal parameter to assist in the differential diagnosis of spasmodic dysphonia.

Original Research: Aerosolized Lidocaine: Effective for Safer Arousal After Suspension Laryngoscopy.

AIM: To examine the systemic and local effects of the lidocaine on the larynx and trachea which is applied after the end of the surgery and through various application methods. STUDY DESIGN: Randomized controlled prospective study. METHOD: The study is composed of patients who underwent suspension laryngoscopy (SL) for benign laryngeal diseases (cysts, polyp, granuloma, etc) and American Society of Anesthesiologists (ASA) I, between January 2017 and January 2018. The patients were randomly divided into 3 groups. In the first group nothing is applied at the end of the surgery and called as control group, second group received 7 pufs of aerosolized 10% lidocaine solution (70 mg) over larynx and trachea and third group received cotton swaps that impregnated in 1 ml of 20 mg lidocaine solution over surgical area for 1 minutes. Operation and arousal times, heart rate and mean arterial blood pressure levels were noted and compared. Also laryngospasm, cough, and agitation scores were obtained during arousal. RESULTS: 64 patients were included in the study. Laryngospasm was not observed in any of the patients. In group 2 (aerosolized lidocaine group), patients' blood pressure remained similar while increased in other groups (P < 0.05). Agitation scores were significantly lower in group 2 compared to the other groups (P = 0.012). Cough reflex is observed less in group 2 but result was not statistically significant (P = 0.13) CONCLUSION: The usage of aerosolized lidocaine after suspension laryngoscopy is very effective in blocking the stimulation of superior laryngeal nerve and sympathetic nerves which were responsible for the pressor reflexes. The inhibition of these reflexes before or during arousal could secure a safer arousal.

Myasthenic congenital myopathy from recessive mutations at a single residue in NaV1.4.

OBJECTIVE: To identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, SCN4A. METHODS: A combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and Xenopus oocytes. RESULTS: Missense mutations of the same residue in the skeletal muscle sodium channel, R1460 of NaV1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes. CONCLUSIONS: Novel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia.

Paroxysmal laryngospasm: Episodic closure of the upper airway.

Paroxysmal laryngospasm is an episodic event, resulting in complete closure of the larynx caused by hypersensitization of laryngeal tissue and protective laryngeal reflexes. This condition most often occurs secondary to laryngopharyngeal reflux. Prognosis generally is good after treatment is initiated; however, often because of a misunderstanding of the clinical course and potential causes, patients with paroxysmal laryngospasm can go untreated. This article describes paroxysmal laryngospasm, similarly presenting diseases, and treatment strategies.

Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy.

OBJECTIVE: Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve. APPROACH: We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long-Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter. MAIN RESULTS: In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls. SIGNIFICANCE: The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans.

Ictal laryngospasm monitored by video-EEG and polygraphy: a potential SUDEP mechanism.

A 56-year-old man with refractory bitemporal epilepsy was monitored in the Epilepsy Monitoring Unit (EMU). In a video-EEG captured seizure, brief oroalimentary automatisms were followed by increased inspiratory effort, accompanied by prominent, visible tracheal movements and audible inspiratory stridor. The patient's oxygen saturation rapidly declined to 62%; persistent severe hypoxemia ended with spontaneous effective respiration commencing at seizure end. Subsequent seizures necessitated intensive care unit admission for respiratory distress, and ventilator support. This case suggests that ictal laryngospasm, a rare seizure manifestation, may represent another potential mechanism of sudden unexpected death in epilepsy (SUDEP). [Published with video sequence on www.epilepticdisorders.com].

Obstructive apnea due to laryngospasm links ictal to postictal events in SUDEP cases and offers practical biomarkers for review of past cases and prevention of new ones.

Seizure spread into autonomic and respiratory brainstem regions is thought to play an important role in sudden unexpected death in epilepsy (SUDEP). As the clinical dataset of cases of definite SUDEP available for study grows, evidence points to a sequence of events that includes postictal apnea, bradycardia, and asystole as critical events that can lead to death. One possible link between the precipitating seizure and the critical postictal sequence is seizure-driven laryngospasm sufficient to completely obstruct the airway for an extended period, but ictal laryngospasm is difficult to fully assess. Herein, we demonstrate in a rat model how the electrical artifacts of attempts to inspire during airway obstruction and features of the cardiac rhythm establish this link between ictal and postictal activity and can be used as practical biomarkers of obstructive apnea due to laryngospasm or other causes of airway obstruction.

Inhaled Mannitol as a Laryngeal and Bronchial Provocation Test.

OBJECTIVES: Timely diagnosis of vocal cord dysfunction (VCD), more recently termed "inducible laryngeal obstruction," is important because VCD is often misdiagnosed as asthma, resulting in delayed diagnosis and inappropriate treatment. Visualization of paradoxical vocal cord movement on laryngoscopy is the gold standard for diagnosis, but is limited by poor test sensitivity. Provocation tests may improve the diagnosis of VCD, but the diagnostic performance of current tests is less than ideal. Alternative provocation tests are required. This pilot study demonstrates the feasibility of using inhaled mannitol for concurrent investigation of laryngeal and bronchial hyperresponsiveness. METHODS: Consecutive patients with suspected VCD seen at our institution's asthma clinic underwent flexible laryngoscopy at baseline and following mannitol challenge. VCD was diagnosed on laryngoscopy based on inspiratory adduction, or >50% expiratory adduction of the vocal cords. Bronchial hyperresponsiveness after mannitol challenge was also assessed. We evaluated the interrater agreement of postmannitol laryngoscopy between respiratory specialists and laryngologists. RESULTS: Fourteen patients with suspected VCD in the context of asthma evaluation were included in the study. Mannitol provocation demonstrated VCD in three of the seven patients with normal baseline laryngoscopy (42.9%). Only two patients had bronchial hyperresponsiveness. There was substantial interrater agreement between respiratory specialists and laryngologists, kappa = 0.696 (95% confidence interval: 0.324-1) (P = 0.006). CONCLUSION: Inhaled mannitol can be used to induce VCD. It is well tolerated and can evaluate laryngeal and bronchial hyperresponsiveness at the same setting.

Laryngospasm, central and obstructive apnea during seizures: Defining pathophysiology for sudden death in a rat model.

Seizure spread into the autonomic nervous system can result in life-threatening cardiovascular and respiratory dysfunction. Here we report on a less-studied consequence of such autonomic derangements-the possibility of laryngospasm and upper-airway occlusion. We used parenteral kainic acid to induce recurring seizures in urethane-anesthetized Sprague Dawley rats. EEG recordings and combinations of cardiopulmonary monitoring, including video laryngoscopy, were performed during multi-unit recordings of recurrent laryngeal nerve (RLN) activity or head-out plethysmography with or without endotracheal intubation. Controlled occlusions of a tracheal tube were used to study the kinetics of cardiac and respiratory changes after sudden obstruction. Seizure activity caused significant firing increases in the RLN that were associated with abnormal, high-frequency movements of the vocal folds. Partial airway obstruction from laryngospasm was evident in plethysmograms and was prevented by intubation. Complete glottic closure (confirmed by laryngoscopy) occurred in a subset of non-intubated animals in association with the largest increases in RLN activity, and cessation of airflow was followed in all obstructed animals within tens of seconds by ST-segment elevation, bradycardia, and death. Periods of central apnea occurred in both intubated and non-intubated rats during seizures for periods up to 33s and were associated with modestly increased RLN activity, minimal cardiac derangements, and an open airway on laryngoscopy. In controlled complete airway occlusions, respiratory effort to inspire progressively increased, then ceased, usually in less than 1min. Respiratory arrest was associated with left ventricular dilatation and eventual asystole, an elevation of systemic blood pressure, and complete glottic closure. Severe laryngospasm contributed to the seizure- and hypoxemia-induced conditions that resulted in sudden death in our rat model, and we suggest that this mechanism could contribute to sudden death in epilepsy.

Laryngeal stridor in multiple system atrophy: Clinicopathological features and causal hypotheses.

Laryngeal stridor is recognized as a characteristic clinical manifestation in patients with multiple system atrophy (MSA). However, the pathogenic mechanisms underlying this symptom are controversial. Neurogenic atrophy of the posterior cricoarytenoid muscle has been identified in cases of MSA, suggesting that laryngeal abductor weakness contributes to laryngeal stridor. However, dystonia in the laryngeal adductor muscles has also been reported to cause laryngeal stridor. Depletion of serotonergic neurons in the medullary raphe nuclei, which exert tonic drive to activate the posterior cricoarytenoid muscle, has recently been identified in MSA cases. This adds weight to the possibility that laryngeal abductor weakness underlies laryngeal stridor in MSA. Continuous positive airway pressure therapy is currently used in the treatment of laryngeal stridor, but should be used with caution in patients showing contraindications. Current knowledge of the clinical and neuropathological features of laryngeal stridor is summarized in this paper, and the hypothesized causes and possible therapeutic options for this symptom are discussed.

Laryngospasm as a Cause of Unsuccessful Placement of Laryngeal Mask Airway ProSeal: A Case Report.

Laryngospasm is a potential complication encountered during anesthesia using a laryngeal mask airway (LMA). We report a case in which laryngospasm resulted in unsuccessful placement of an LMA ProSeal Airway (Teleflex Inc), and we discuss the various causes of unsuccessful placement of this type of airway device. Laryngospasm causes increased resistance to gas flow by inducing closure of vocal cords, aryepiglottic fold, and periglottic tissue. In this case report, the laryngospasm-induced increased resistance to gas flow was manifested by exaggerated outward movement of the LMA ProSeal following its connection to gas flows and thus resulted in failed airway placement. The possibility of laryngospasm as a cause of failed placement of an LMA ProSeal must be considered in clinical practice.

Spasmodic dysphonia: a seven-year audit of dose titration and demographics in the Indian population.

OBJECTIVES: This study aimed to evaluate the demographics of spasmodic dysphonia in the Indian population and to analyse the optimum dose titration of botulinum toxin type A in this group. A comparative analysis with international studies was also performed. METHOD: The study involved a retrospective analysis and audit of botulinum toxin type A dose titration in spasmodic dysphonia patients who visited our voice clinic between January 2005 and January 2012. RESULTS: The average total therapeutic dose required for patients with adductor spasmodic dysphonia was 4.2 U per patient per vocal fold (total 8.4 U per patient), and for patients with abductor spasmodic dysphonia, it was 4.6 U per patient. CONCLUSION: Our audit revealed that 80 per cent of the spasmodic dysphonia patients were male, which contrasts dramatically with international studies, wherein around 80 per cent of spasmodic dysphonia patients were female. Our study also revealed a higher dose titration of botulinum toxin for the Indian spasmodic dysphonia population in both adductor and abductor spasmodic dysphonia cases.