[Bilateral diaphragmatic palsy due to Lyme neuroborreliosis]. / Une paralysie diaphragmatique bilatérale révélant une neuroborréliose de Lyme.

INTRODUCTION: Lyme disease is not uncommon and can sometimes progress to neurological complications. We report here an unusual case of bilateral diaphragmatic paralysis secondary to Lyme neuroborreliosis. CASE REPORT: A 79-year-old man was admitted to the intensive care unit for acute respiratory distress requiring intubation and the long-term use of nocturnal non-invasive ventilation. Three months beforehand he had been bitten by a tick and developed erythema migrans which was treated with Doxycycline for 10 days. This clinical presentation became complicated a few days later by the progressive onset of severe dyspnoea. At admission, chest radiography revealed bilateral elevation of the diaphragm. Pulmonary function tests revealed a severe restrictive disorder aggravated by decubitus. A diaphragmatic electromyogram showed bilateral axonal polyneuropathy of the phrenic nerves. IgG and IgM antibodies to Borrelia burgdorferi were detectable in serum and cerebrospinal fluid, leading to the diagnosis of Lyme disease. He was treated with intravenous ceftriaxone 2g per day for 21 days, leading to a substantial improvement in symptoms. CONCLUSION: In the presence of unilateral or bilateral diaphragmatic paralysis of undetermined aetiology, it seems relevant to perform Lyme serology in the blood and, in positive cases, to follow up with a lumbar puncture in order to detect intrathecal IgG synthesis.

3,4-diaminopyridine reverses paralysis in botulinum neurotoxin-intoxicated diaphragms through two functionally distinct mechanisms.

Botulinum neurotoxins (BoNTs) are exceedingly potent neurological poisons that prevent neurotransmitter release from peripheral nerve terminals by cleaving presynaptic proteins required for synaptic vesicle fusion. The ensuing neuromuscular paralysis causes death by asphyxiation. Although no antidotal treatments exist to block toxin activity within the nerve terminal, aminopyridine antagonists of voltage-gated potassium channels have been proposed as symptomatic treatments for botulism toxemia. However, clinical evaluation of aminopyridines as symptomatic treatments for botulism has been inconclusive, in part because mechanisms responsible for reversal of paralysis in BoNT-poisoned nerve terminals are not understood. Here we measured the effects of 3,4-diaminopyridine (DAP) on phrenic nerve-elicited diaphragm contraction and end-plate potentials at various times after intoxication with BoNT serotypes A, B, or E. We found that DAP-mediated increases in quantal content promote neurotransmission from intoxicated nerve terminals through two functionally distinguishable mechanisms. First, DAP increases the probability of neurotransmission at non-intoxicated release sites. This mechanism is serotype-independent, becomes less effective as nerve terminals become progressively impaired, and remains susceptible to ongoing intoxication. Second, DAP elicits persistent production of toxin-resistant endplate potentials from nerve terminals fully intoxicated by BoNT/A, but not serotypes B or E. Since this effect appears specific to BoNT/A intoxication, we propose that DAP treatment enables BoNT/A-cleaved SNAP-25 to productively engage in fusogenic release by increasing the opportunity for low-efficiency fusion events. These findings have important implications for DAP as a botulism therapeutic by defining conditions under which DAP may be clinically effective in reversing botulism symptoms.

Total spinal block after local anesthetic administration through the wrong access port of a spinal infusion pump. / Bloqueo espinal total tras administración de anestésico local por el puerto de acceso equivocado de una bomba de infusión intratecal.

We present a case reported on the SENSAR database. A patient with a spinal infusion pump was admitted for reservoir refill. On administration of 22ml of 0.75% bupivacaine the patient suffered a total spinal block with widespread loss strength and respiratory arrest. The patient required emergency orotracheal intubation, mechanical ventilation and admission to ICU, where extubation was achieved within two hours without incidences. At a later stage it was stated that the local anaesthetic had been administered via the access port for bolus or contrast administration instead of via the access to the reservoir. Analysis of the incident showed up latent factors related to absence lack of personnel training and internal protocols. The following measures were taken: pain unit meeting, alert sent to SENSAR bulletin and training request for members of the service.

Valoración ecográfica de la función diafragmática y sus aplicaciones en el paciente crítico, en ventilación mecánica y en la anestesia del plexo braquial / Ultrasound evaluation of diaphragm function and its application in critical patients, mechanical ventilation and brachial plexus block

La valoración de la función diafragmática ha sido clásicamente poco considerada debido a la dificultad de su exploración. La aparición de la ecografía diafragmática ha aportado luz al problema y ofrece un terreno amplio que mejora significativamente nuestra capacidad diagnóstica y terapéutica en el paciente crítico o en los pacientes sometidos a anestesia regional del plexo braquial. La parálisis o la hipoquinesia diafragmática aparece como un problema mucho más frecuente de lo que se creía. La ecografía permite su diagnóstico precoz así como la cuantificación dinámica del problema facilitando la toma de decisiones preventivas y terapéuticas precoces. También se está delineando como un instrumento de guía en el proceso de destete de la ventilación mecánica y en el abordaje más seguro del plexo braquial. En este trabajo presentamos la sistemática de su exploración y su utilización clínica (AU)

Before diaphragm ultrasonography, assessment of diaphragm function was very difficult due to the complex nature of its exploration. The use of this new technique has shed light on diagnostic problems and treatment with an improvement in final outcomes for critically ill patients, in whom the incidence of diaphragm weakness or dysfunction has been underestimated. Better knowledge of diaphragm function enables us earlier diagnosis by quantification of diaphragm contractile activity or evaluation of functional status after delivery of plexus block anaesthesia, facilitating therapeutic decisions. It is also being used as a guide in the process of weaning from mechanical ventilation or as the safest approach for braquial plexus block. In this review we present how to perform a systematic exploration of diaphragm function and its clinical implications (AU)

Transporter Protein-Coupled DPCPX Nanoconjugates Induce Diaphragmatic Recovery after SCI by Blocking Adenosine A1 Receptors.

Respiratory complications in patients with spinal cord injury (SCI) are common and have a negative impact on the quality of patients' lives. Systemic administration of drugs that improve respiratory function often cause deleterious side effects. The present study examines the applicability of a novel nanotechnology-based drug delivery system, which induces recovery of diaphragm function after SCI in the adult rat model. We developed a protein-coupled nanoconjugate to selectively deliver by transsynaptic transport small therapeutic amounts of an A1 adenosine receptor antagonist to the respiratory centers. A single administration of the nanoconjugate restored 75% of the respiratory drive at 0.1% of the systemic therapeutic drug dose. The reduction of the systemic dose may obviate the side effects. The recovery lasted for 4 weeks (the longest period studied). These findings have translational implications for patients with respiratory dysfunction after SCI. SIGNIFICANCE STATEMENT: The leading causes of death in humans following SCI are respiratory complications secondary to paralysis of respiratory muscles. Systemic administration of methylxantines improves respiratory function but also leads to the development of deleterious side effects due to actions of the drug on nonrespiratory sites. The importance of the present study lies in the novel drug delivery approach that uses nanotechnology to selectively deliver recovery-inducing drugs to the respiratory centers exclusively. This strategy allows for a reduction in the therapeutic drug dose, which may reduce harmful side effects and markedly improve the quality of life for SCI patients.

[A case of refractory generalized myasthenia gravis with anti-acetylcholine receptor antibodies treated with rituximab].

We report a case of a 57-year-old woman with thymoma-associated generalized myasthenia gravis (MG) showing severe bulbar and respiratory symptoms, moderate weakness of the neck muscles, and mild weakness of extremity muscles. Corticosteroid treatment with various types of immunosuppressive agents, such as cyclosporine, tacrolimus, and azathioprine, did not improve her symptoms. Plasma exchange transiently improved her symptoms, and she was required to undergo plasmapheresis every 4 weeks. At first, cyclophosphamide pulse therapy was administered, which improved her symptoms transiently. Thereafter, rituximab (RTX) was administered. Six months after RTX administration, respiratory distress and dysphagia improved gradually, and reduction in the dosage of corticosteroids from 30 mg/day to 10 mg/day did not result in symptom deterioration. Therefore, the interval between successive plasmapheresis treatments was increased from 4 to 9 weeks 19 months after the first RTX administration. During a 26-month period from the first administration of RTX, the number of CD20+ B cells in peripheral blood decreased and remained at 0% to 26% of that before RTX treatment. The titer of anti-acetylcholine receptor antibodies did not change during the first course of treatment (0.6-0.9 nmol/l). The clinical symptom worsened with the increase of the number of CD20+ B cells in peripheral blood in the 27 month after 1st RTX administration. Therefore, RTX was administered a second time, after which the patient's clinical symptoms again improved gradually. The titer of anti-acetylcholine receptor antibodies came to be stable with 0.5-0.7 nmol and low level during the 2nd course. Corticosteroids could be discontinued in the 16th month. The findings suggest that RTX can be one of the choices for pharmacological therapy in patients with intractable MG accompanied by the presence of anti-acetylcholine receptor antibodies.

Shrinking lung syndrome in pregnancy complicated by antiphospholipid antibody syndrome.

BACKGROUND: Shrinking lung syndrome is characterized by pulmonary compromise secondary to unilateral or bilateral paralysis of the diaphragm. CASE: Shrinking lung syndrome was diagnosed in a patient with antiphospholipid syndrome after a cesarean delivery at 28 4/7 weeks of gestation. Signs and symptoms included unexplained right-side chest pain, dyspnea, tachypnea, and absent breath sounds at the right base of the lungs. After initiation of corticosteroids, her symptoms resolved. CONCLUSION: Although seen in association with systemic lupus erythematosus, shrinking lung syndrome has not been described with antiphospholipid syndrome or during pregnancy. Diagnosis and awareness are important because treatment with moderate- to high-dose corticosteroids appears to improve the clinical outcome.

A controlled clinical trial of a novel antivenom in patients envenomed by Bungarus multicinctus.

In northern Vietnam, a majority of severely envenomed patients are bitten by Bungarus multicinctus. Hitherto, these victims have received supportive care only. The aims of this study were to assess the possible efficacy and side effects of a new antivenom. This trial (ClinicalTrials.gov Identifier: NCT00811239) was performed during 2004-2006 at an ICU in Hanoi. For ethical reasons, the study was not randomized. All patients who fulfilled the inclusion criteria during 2004-2005 were prospectively enrolled, carefully recorded, and treated with optimal supportive therapy (control group). The patients who entered the study 2006 were treated with antivenom in addition to supportive care (antivenom group). The inclusion criteria were: envenomation by B. multicinctus, presence of systemic envenomation, and (during 2006) provision of written informed consent. Predefined endpoints were number of patients requiring mechanical ventilation, duration of mechanical ventilation, length of ICU stay, duration of muscle paralysis, and number of patients with ventilator-associated pneumonia. Eighty-one patients were included, 54 during 2004-2005 and 27 during 2006. Baseline characteristics were similar in the groups. The antivenom-group patients had a shorter duration of muscle paralysis of the limbs (p < 0.001), of the diaphragm (p < 0.001), and of ptosis (p < 0.001). The duration of mechanical ventilation and length of ICU stay were shorter in the antivenom group (p < 0.001). The rate of ventilator-associated pneumonia was lower in the antivenom group (p < 0.02). However, the relative number of patients requiring mechanical ventilation was not reduced in the antivenom group. The rate of adverse reactions to the antivenom was 7.4%. A favorable efficacy and acceptable safety of this antivenom were demonstrated.

Use of the muscle volume analyzer to evaluate enzyme replacement therapy in late-onset Pompe disease.

The muscle volume analyzer (MVA) can predict limb muscle weight based on bioelectric impedance analysis, whereas the conventional handheld dynamometer (HHD) measures muscle strength. In this study, a 26-year-old female on invasive ventilation due to late-onset Pompe disease was treated with enzyme replacement therapy (ERT) for 12 months. MVA measurements demonstrated time-dependent improvement from the baseline compared to HHD measurements, showing remarkably fluctuating muscle strength. Thus, the MVA can be used as an alternative, particularly for patients suffering from severe limb muscle weakness.

[Incidence and complications of post operative residual paralysis]. / Incidence et risques de la curarisation résiduelle postopératoire.

A 0.9 train-of-four ratio, measured at the thumb, is currently considered to reflect adequate recovery of neuromuscular block. Recent studies have documented that a train-of-four ratio <0.9 is associated with a decrease in chemoreceptor sensitivity to hypoxia and with a functional impairment of the pharyngeal muscles. These residual effects of neuromuscular blocking agents promote insufficient ventilatory response to hypoxia and regurgitation/aspiration. As a result, the incidence of pulmonary complications have been found to be higher in both early and late postoperative period in patients with residual curarisation. Clinical tests such as the head lift test and visual or tactile evaluation of the response to peripheral nerve stimulation are no longer sufficient to exclude postoperative residual curarisation. Residual curarisation is still present at the time of extubation despite the use of subject if monitoring of neuromuscular function, clinical tests and/or reversal of neuromuscular blocking agents. In contrast, acceleromyographic monitoring provides a valuable tool to avoid residual curarisation and to reduce the related-side effects.

[Monitoring of neuromuscular block and prevention of residual paralysis]. / Monitorage de la curarisation et prévention de la curarisation résiduelle.

Neuromuscular monitoring and routine use of reversal agents are key elements in the prevention of residual paralysis. According to a nation-wide survey up to 52 % of anaesthesiologists in France apply regularly neuromuscular monitoring after a single intubating dose of a neuromuscular blocking agent and 74 % in case of repetitive administration. However, reversal is rather the exception than routine and, still according to this survey, the risk of residual paralysis largely underestimated. The development of a new class of reversal agents (cyclodextrins) may further modify the management of neuromuscular blockade in clinical practice. The article aims to revise the principles of neuromuscular monitoring and evaluate whether its use is still mandatory when sugammadex is used.

[Indications and clinical use of sugammadex]. / Indications et utilisation clinique du sugammadex.

Sugammadex, a cyclodextrin, is a novel agent designed to encapsulate selectively steroidal neuromuscular blocking agents such as rocuronium and vecuronium as well. One molecule of sugammadex is able to encapsulate only one molecule of muscle relaxant. This original pharmacological property allows a very rapid reversal of muscle paralysis. After sugammadex injection, a train of four ratio higher than 0.9 is obtained in less than 5 minutes in all the patients whatever the degree of muscle paralysis at the time of reversal and even when anesthesia is maintained with halogenated agents. However, in order to preserve this efficacy, the dose of sugammadex needs to be adjusted to the degree of muscle paralysis at the time of reversal : 2 mg/kg after obtaining 2 responses at the adductor pollicis muscle after a train of four stimulation, 4 mg/kg with a post-tetanic count between 1 and 3 responses, and 12 to 16 mg/kg in case of rescue reversal (3 to 15 minutes after 0.6 to 1.2 mg/kg rocuronium). Even if the original property of sugammadex lets us think that per-operative neuromuscular transmission monitoring would not be furthermore useful, the assessment of the exact degree of muscle paralysis before reversal is mandatory for choosing the right dose of sugammadex.

[Pharmacology of sugammadex]. / Pharmacologie du sugammadex.

Sugammadex is a new molecule derived from a known pharmacological class : the cyclodextrins known and used in human for many years. It was recently demonstrated that cyclodextrins could encapsulate and bind strongly steroidal neuromuscular blocking agents. Among cyclodextrins gamma-cyclodextrins proved to be more efficient. The binding of cyclodextrins to rocuronium and compound's water solubility was greatly improved by addition of 8 side chains to glycopyranoses units and the presence of a negative charge to the end of these side-chains. Animal studies have clearly demonstrated that sugammadex is faster in onset than anticholinesterase agents and is specific of steroidal neuromuscular blocking agents. It cannot reverse neuromuscular block induced by succinylcholine or benzylisoquinolines such as atracurium or cisatracurium. In human, the dose of sugammadex required to reverse shallow block is 2 mg/kg approximately whereas 4 mg/kg is needed to reverse deep level of neuromuscular block with a few responses at the post tetanic count at the adductor pollicis. The use of sugammadex was not associated with recurrence of block when an adequate dose was administered.

[Sugammadex: something new to improve patient safety or simply a gadget?]. / Le sugammadex : une nouveauté qui s'inscrit dans le cadre de l'amélioration de la sécurité des patients ou un simple gadget ?

The launch on the market of a new compound is always an important event for a specialty, particularly when the mechanism of action is completely new. It is the case with sugammadex, a cyclodextrin able to encapsulate specifically and only nondepolarizing steroidal muscles relaxant, rocuronium or vecuronium. The clinical trials which have been performed for sugammadex approval have demonstrated promising results. Sugammadex is able to rapidly reverse (2-5 min) different levels of neuromuscular blockade: moderate (e.g., T2 recovery), deep (e.g., PTC 1-2 recovery) and also few minutes (3-15) after rocuronium administration. Thus, the sugammadex's onset time is about 10 times more rapid than neostigmine without the need of concomitantly atropine administration. Sugammadex has only been tested in small sample size of patients. Therefore, the exact place in the anesthetic practice, the potential indications, the safety profile on a large-scale, thus remain to determine. In particular, how it will modify our current practices characterized to date by 1) under-use of neuromuscular monitoring, 2) a marginal practice of reversal and 3) a wide use of benzylisoquinolines : atracurium and cis-atracurium? Finally, what will be the medical strategies to justify an additional cost when compared to neostigmine?

Recovery of respiratory activity after C2 hemisection (C2HS): involvement of adenosinergic mechanisms.

Consequences of spinal cord injury (SCI) depend on the level and extent of injury. Cervical SCI often results in a compromised respiratory system. Primary treatment of SCI patients with respiratory insufficiency continues to be with mechanical ventilatory support. In an animal model of SCI, an upper cervical spinal cord hemisection paralyzes the hemidiaphragm ipsilateral to the side of injury. However, a latent respiratory motor pathway can be activated to restore respiratory function after injury. In this review, restoration of respiratory activity following systemic administration of theophylline, a respiratory stimulant will be discussed. Pharmacologically, theophylline is a non-specific adenosine receptor antagonist, a phosphodiesterase inhibitor and a bronchodilator. It has been used in the treatment of asthma and other respiratory-related diseases such as chronic obstructive pulmonary disease (COPD) and in treatment of apnea in premature infants. However, the clinical use of theophylline to improve respiration in SCI patients with respiratory deficits is a more recent approach. This review will focus on the use of theophylline to restore respiratory activity in an animal model of SCI. In this model, a C2 hemisection (C2HS) interrupts the major descending respiratory pathways and paralyzes the ipsilateral hemidiaphragm. The review also highlights involvement of central and peripheral adenosine receptors in functional restitution. Biochemical binding assays that highlight changes in adenosine receptors after chronic theophylline administration are discussed as they pertain to understanding adenosine receptor-mediation in functional recovery. Finally, the clinical application of theophylline in SCI patients with respiratory deficits in particular is discussed.

Defining survival as an outcome measure in amyotrophic lateral sclerosis.

OBJECTIVES: To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis. DESIGN AND SETTING: We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with chi(2) and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points. PATIENTS: In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline. MAIN OUTCOME MEASURES: Death or combined death, tracheostomy, or permanent assisted ventilation. RESULTS: Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone. CONCLUSIONS: Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

Idiopathic diaphragmatic paralysis: Bell's palsy of the diaphragm?

STUDY OBJECTIVES: Idiopathic diaphragm paralysis is probably more common and responsible for more morbidity than generally appreciated. Bell's palsy, or idiopathic paralysis of the seventh cranial nerve, may be seen as an analogous condition. The roles of zoster sine herpete and herpes simplex have increasingly been recognized in Bell's palsy, and there are some data to suggest that antiviral therapy is a useful adjunct to steroid therapy. Thus, we postulated that antiviral therapy might have a positive impact on the course of acute idiopathic diaphragm paralysis which is likely related to viral infection. METHODS: Three consecutive patients with subacute onset of symptomatic idiopathic hemidiaphragm paralysis were empirically treated with valacyclovir, 1,000 mg twice daily for 1 week. Prior to therapy, diaphragmatic function was assessed via pulmonary function testing and two-dimensional B-mode ultrasound, with testing repeated 1 month later. Diaphragmatic function pre- and post-treatment was compared to that of a historical control group of 16 untreated patients. RESULTS: All three subjects demonstrated ultrasound recovery of diaphragm function 4-6 weeks following treatment with valacyclovir. This recovery was accompanied by improvements in maximum inspiratory pressure (PI(max)) and vital capacity (VC). In contrast, in the untreated cohort, diaphragm recovery occurred in only 11 subjects, taking an average of 14.9 +/- 6.1 months (mean +/- SD). CONCLUSIONS: The results of this small, preliminary study suggest that antiviral therapy with valacyclovir may be helpful in the treatment of idiopathic diaphragm paralysis induced by a viral infection.