Mapping the neural systems driving breathing at the transition to unconsciousness

After falling asleep, the brain needs to detach from waking activity and reorganize into a functionally distinct state. A functional MRI (fMRI) study has recently revealed that the transition to unconsciousness induced by propofol involves a global decline of brain activity followed by a transient reduction in cortico-subcortical coupling. We have analyzed the relationships between transitional brain activity and breathing changes as one example of a vital function that needs the brain to readapt. Thirty healthy participants were originally examined. The analysis involved the correlation between breathing and fMRI signal upon loss of consciousness. We proposed that a decrease in ventilation would be coupled to the initial decline in fMRI signal in brain areas relevant for modulating breathing in the awake state, and that the subsequent recovery would be coupled to fMRI signal in structures relevant for controlling breathing during the unconscious state. Results showed that a slight reduction in breathing from wakefulness to unconsciousness was distinctively associated with decreased activity in brain systems underlying different aspects of consciousness including the prefrontal cortex, the default mode network and somatosensory areas. Breathing recovery was distinctively coupled to activity in deep brain structures controlling basic behaviors such as the hypothalamus and amygdala. Activity in the brainstem, cerebellum and hippocampus was associated with breathing variations in both states. Therefore, our brain maps illustrate potential drives to breathe, unique to wakefulness, in the form of brain systems underlying cognitive awareness, self-awareness and sensory awareness, and to unconsciousness involving structures controlling instinctive and homeostatic behaviors.Peer ReviewedPostprint (published version

Nutritional status of iodine in pregnant women in Catalonia (Spain): study on hygiene-dietetic habits and iodine in urine

<p>Abstract</p> <p>Background</p> <p>It is a priority to achieve an adequate nutritional status of iodine during pregnancy since iodine deficiency in this population may have repercussions on the mother during both gestation and post partum as well as on the foetus, the neonate and the child at different ages. According to the WHO, iodine deficiency is the most frequent cause of mental retardation and irrreversible cerebral lesions around the world. However, few studies have been published on the nutritional status of iodine in the pregnant population within the Primary Care setting, a health care level which plays an essential role in the education and control of pregnant women. Therefore, <b>the aim of the present study </b>is: 1.- To know the hygiene-dietetic habits related to the intake of foods rich in iodine and smoking during pregnancy. 2.- To determine the prevalence of iodine deficiency and the factors associated with its appearance during pregnancy.</p> <p>Methods/design</p> <p>We will perform a cluster randomised, controlled, multicentre trial. Randomisation unit: Primary Care Team. Study population: 898 pregnant women over the age of 17 years attending consultation to a midwife during the first trimester of pregnancy in the participating primary care centres. Outcome measures: consumption of iodine-rich foods and iodine deficiency. Points of assessment: each trimester of the gestation. Intervention: group education during the first trimester of gestation on healthy hygiene-dietetic habits and the importance of an adequate iodine nutritional status. Statistical analysis: descriptive analysis of all variables will be performed as well as multilevel logistic regression. All analyses will be done carried out on an intention to treat basis and will be fitted for potential confounding factors and variables of clinical importance.</p> <p>Discussion</p> <p>Evidence of generalised iodine deficiency during pregnancy could lead to the promotion of interventions of prevention such as how to improve and intensify health care educational programmes for pregnant women.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01301768">NCT01301768</a></p

Farmacocinética y farmacodinamia del bromuro de rocuronio: Influencia de la terapia crónica con fenitoína.

[spa] ANTECEDENTES: La administración crónica de fármacos antiepilépticos disminuye la intensidad del efecto de los fármacos bloqueantes neuromusculares (BNM), aunque existe cierta discrepancia a la hora de explicar si esta interacción se produce a nivel farmacocinético (PK) y/o farmacodinámico (PD). La cuantificación de fármaco en biofase podría clarificar los posibles mecanismos que producen la interacción entre los BNM y los fármacos antiepilépticos. La microdiálisis tisular es una técnica relativamente nueva que se ha utilizado para determinar concentraciones de sustancias en el fluido extracelular de los tejidos. Podría ser una buena alternativa para explorar de qué forma los BNM alcanzan la unión neuromuscular y de cómo los antiepilépticos pueden afectarla. OBJETIVOS: Los objetivos de este trabajo fueron: en primer lugar definir la relación entre dosis, concentración y efecto bloqueante neuromuscular en el caso del rocuronio utilizando modelos PKPD y posteriormente evaluar la influencia de la terapia crónica con fenitoína (TCF) sobre este modelo. El segundo objetivo fue determinar la posibilidad de recuperar rocuronio desde el tejido intersticial muscular mediante la técnica de la microdiálisis, para explorar las posibles discrepancias entre los pacientes debidas a la TCF. MATERIAL Y MÉTODOS: Se han realizado dos estudios para tratar de abordar el problema: el primero basado en la aproximación poblacional utilizando modelos PKPD y el segundo basado en la técnica de la microdiálisis. En el primer estudio, se incluyeron 21 pacientes sometidos a cirugía intracraneal, 10 de los cuales se encontraban en TCF. Se les administró rocuronio intravenoso, se extrajeron muestras plasmáticas y se registró el efecto obtenido mediante electromiografía. Se utilizó NONMEM para construir, evaluar y validar los modelos PKPD. En el caso de la microdiálisis, se realizó un estudio "In Vitro" para conocer la velocidad de infusión óptima así como el tiempo de extracción entre muestras y se estimó la tasa de recuperación para el rocuronio, utilizando la infusión de diferentes concentraciones de este fármaco. En la siguiente fase se estudiaron 17 pacientes sometidos a cirugía intracraneal (incluidos en el estudio previo), 8 de los cuales se encontraban en TCF. RESULTADOS: En el primer articulo se ha descrito el PKPD del rocuronio utilizando un modelo tricompartimental asociado a un modelo de compartimento del efecto. Se ha observado que la TCF produce un incremento del aclaramiento plasmático de 0,26 hasta 0,75 L·min-1, mientras que el resto de parámetros PK no se afectan. Las estimaciones de los parámetros del modelo PD han sido las siguientes: ke0 = 0,073 min-1, Ce50 = 836 ng·mL-1 y γ = 3,13. En el segundo estudio destaca que la tasa de recuperación estimada para el rocuronio es del 36% para una velocidad de la bomba de microdiálisis de 1 μL·min-1. Se han podido cuantificar las concentraciones de bromuro de rocuronio en el músculo en 25 muestras. Las concentraciones de rocuronio tisular fueron similares en los pacientes con TCF que en los pacientes control, sin embargo, las dosis requeridas con TCF fueron significativamente mayores. Estos resultados confirman a los hallados en el primer estudio, ya que un mecanismo exclusivamente PK podría explicarlos. CONCLUSIONES: Ha sido posible definir la relación entre dosis, concentración y efecto de BNM inducido por el rocuronio mediante modelos PKPD. Nuestros resultados sugieren que únicamente mecanismos PK podrían explicar la mayor dosis requerida en el caso de pacientes con TCF. La TCF incrementa el aclaramiento del rocuronio pero no tiene efecto sobre el resto de parámetros PK ni sobre los parámetros PD. Por otro lado, la cuantificación de fármacos gracias a la microdiálisis es técnicamente posible en el entorno clínico y podría ser de ayuda en el estudio de los mecanismos que producen el efecto de los fármacos.[eng] summary: BACKGROUND: Chronic administration of antiepileptic drugs decrease the intensity of the effect of neuromuscular blocking agents (NMBA), although there is some discrepancy to explain if this interaction occurs on pharmacokinetic and/or pharmacodynamic level. Tissue microdialysis is a relatively new technique used to determine the concentrations of substances in the extracellular fluid of tissues. It could be a good alternative to explore how NMBA could reach the neuromuscular junction and how antiepileptics could affect it. OBJETIVES: The objectives of this study were first to define the relation between dose, concentration and effect of neuromuscular blocking in the case of rocuronium using PKPD models and then to evaluate the influence of chronic phenytoin therapy (CPT) on this model. The second objective was to determine the ability of microdialysis to recover rocuronium from muscle interstitial tissue, to explore possible discrepancies between patients due to CPT. MATERIAL AND METHODS: We performed two studies in order to solve the problem: the first one is based in population approach using PKPD models and the second one is based in the technique of microdialysis. In the first study a total of 21 patients undergoing intracranial surgery were enrolled. In all cases, rocuronium was administered intravenously. Arterial blood samples were drawn and the response derived from electromyogram was continuously recorded. NONMEM software was used to construct, evaluate and validate PKPD models. To know the optimal speed of infusion and microdialysis sampling scheme and estimate the recovery ratio for rocuronium an "In Vitro" study was performed. In the next phase, 17 patients undergoing brain surgery were enrolled (they were included in the previous study). RESULTS: In the first study the PKPD of rocuronium was described using a three-compartment PK model linked to an effect compartment. The CPT therapy was found to affect only total plasma clearance. In the second study the recovery rate for rocuronium was estimated to be 36% at a pump rate of 1 L·min-1. Rocuronium concentrations were similar in patients treated with phenytoin and in controls, although the doses required to obtain a similar effect were significantly higher in patients on CPT. This findings confirm the results in the first study, due to a PK mechanism could be explain them. CONCLUSIONS: We defined the relation between dose, concentration and effect of rocuronium using PKPD models. Our results suggest that only PK mechanisms could explain the biggest dose required in case of CPT. CPT increases the clearance of rocuronium but has no effect on the remaining PK or PD parameters. On the other hand, the quantification of microdialysis is technically feasible in the clinical setting and it might help in studying pharmacologic mecanisms of drug action

Evaluation of the density spectral array in the Wada test: report of six cases

Wada test is an invasive procedure used in the preoperative evaluation for epilepsy surgery to determine language lateralization, postoperative risk of amnesia syndrome, and to assess the risk of memory deficits. It involves injection of amobarbital into internal carotid artery of the affected hemisphere followed by the healthy hemisphere to shut down brain function. We performed an observational study evaluating the density spectral array (DSA) of the bilateral bispectral index VISTA™ Monitoring System (BVMS) in 6 patients with drug-resistant epilepsy undergoing Wada test. DSA revealed the presence of bifrontal alpha waves in absence of loss of consciousness in all patients

La cartografía electroanatómica no fluoroscópica (sistema CARTO) en la ablación de las taquicardias auriculares

Introducción y objetivos. La introducción de los sistemas navegadores ha supuesto un cambio sustancial en la cartografía electrofisiológica cardíaca. Presentamos nuestra experiencia con el uso de la cartografía electroanatómica no fluoroscópica en pacientes con taquicardias auriculares. Pacientes y método. Se incluye a 24 pacientes consecutivos con taquicardias auriculares (10 de ellos con intentos previos de ablación fallidos). En todos los casos se realizó una cartografía auricular electroanatómica mediante el sistema CARTO, que combina información electrofisiológica y espacial y permite la visualización de la activación atrial en una reconstrucción anatómica tridimensional de la aurícula. La cartografía se realizó durante taquicardia (22 pacientes) o en ritmo sinusal (2 pacientes), con abordaje en la aurícula izquierda en 12 pacientes. La ablación se efectuó con un catéter de punta irrigada en 3 pacientes. Resultados. La cartografía tridimensional permitió una clara y rápida distinción entre un mecanismo macrorreentrante (9 pacientes) y un origen focal (15 pacientes). Las aplicaciones de radiofrecuencia se dirigieron hacia el istmo crítico de conducción identificado en las macrorreentradas mediante mapas de voltaje de auriculogramas o hacia el área de mayor precocidad ectópica focal en los mapas de activación. El tratamiento se realizó con éxito en 19 pacientes (79,2%) y se produjo una recurrencia precoz en 2 de ellos. El tiempo de fluoroscopia fue de 60 ± 21 min. Conclusiones. La cartografía electroanatómica con sistema CARTO permitió la visualización tridimensional de la activación auricular, evitando el esfuerzo de integración electrofisiológico y anatómico en estos pacientes con taquicardias auriculares. El apoyo iconográfico que supone podría facilitar el éxito de la ablación con radiofrecuencia en este seleccionado grupo de pacientes

Effects of remifentanil on brain responses to noxious stimuli during deep propofol sedation

Background: the safety of anaesthesia has improved as a result of better control of anaesthetic depth. However, conventional monitoring does not inform on the nature of nociceptive processes during unconsciousness. A means of inferring the quality of potentially painful experiences could derive from analysis of brain activity using neuroimaging. We have evaluated the dose effects of remifentanil on brain response to noxious stimuli during deep sedation and spontaneous breathing. Methods: optimal data were obtained in 26 healthy subjects. Pressure stimulation that proved to be moderately painful before the experiment was applied to the thumbnail. Functional MRI was acquired in 4-min periods at low (0.5 ng ml-1), medium (1 ng ml-1), and high (1.5 ng ml-1) target plasma concentrations of remifentanil at a stable background infusion of propofol adjusted to induce a state of light unconsciousness. Results: at low remifentanil doses, we observed partial activation in brain areas processing sensory-discriminative and emotional-affective aspects of pain. At medium doses, relevant changes were identified in structures highly sensitive to general brain arousal, including the brainstem, cerebellum, thalamus, auditory and visual cortices, and the frontal lobe. At high doses, no significant activation was observed. Conclusions: the response to moderately intense focal pressure in pain-related brain networks is effectively eliminated with safe remifentanil doses. However, the safety margin in deep sedation-analgesia would be narrowed in minimising not only nociceptive responses, but also arousal-related biological stress

Mapping the neural systems driving breathing at the transition to unconsciousness

After falling asleep, the brain needs to detach from waking activity and reorganize into a functionally distinct state. A functional MRI (fMRI) study has recently revealed that the transition to unconsciousness induced by propofol involves a global decline of brain activity followed by a transient reduction in cortico-subcortical coupling. We have analyzed the relationships between transitional brain activity and breathing changes as one example of a vital function that needs the brain to readapt. Thirty healthy participants were originally examined. The analysis involved the correlation between breathing and fMRI signal upon loss of consciousness. We proposed that a decrease in ventilation would be coupled to the initial decline in fMRI signal in brain areas relevant for modulating breathing in the awake state, and that the subsequent recovery would be coupled to fMRI signal in structures relevant for controlling breathing during the unconscious state. Results showed that a slight reduction in breathing from wakefulness to unconsciousness was distinctively associated with decreased activity in brain systems underlying different aspects of consciousness including the prefrontal cortex, the default mode network and somatosensory areas. Breathing recovery was distinctively coupled to activity in deep brain structures controlling basic behaviors such as the hypothalamus and amygdala. Activity in the brainstem, cerebellum and hippocampus was associated with breathing variations in both states. Therefore, our brain maps illustrate potential drives to breathe, unique to wakefulness, in the form of brain systems underlying cognitive awareness, self-awareness and sensory awareness, and to unconsciousness involving structures controlling instinctive and homeostatic behaviors

Misdiagnosis worsens prognosis in subarachnoid hemorrhage with good hunt and hess score

Background and Purpose- Our aim was to describe variables associated with initial misdiagnosis of subarachnoid hemorrhage (SAH). We also analyzed the relationship of misdiagnosis with poor outcome and complications in good Hunt and Hess (HH) cases. Methods- In a prospective cohort of 401 patients with SAH, misdiagnosis was defined as failure to correctly identify, at first physician contact, a subsequently documented SAH; this meant no urgent radiological study and lumbar puncture was performed. Poor outcome was defined as modified Rankin Scale score 3 to 6 at 3-month follow-up. We recorded age, sex, hypertension, diabetes mellitus, current smoking, previous antithrombotic treatment, initial HH and radiological severity, presence of aneurysm, first therapeutic procedure, hydrocephalus, delayed cerebral ischemia (DCI), rebleeding, and procedure-related complications. Results- Misdiagnosis was confirmed in 104/401 (25.9%) patients, who also had a longer time-to-admission to hospital. Misdiagnosis was associated with less clinical and radiological severity, compared with a correct diagnosis; the 2 groups did not differ in age or cardiovascular risk factor profile. Poor outcome was registered in 167/401 patients (41.6%). Age, misdiagnosis, and greater clinical and radiological initial severity were independent predictors of poor outcome. In the 236 patients (58.8% of cohort) with HH 1-2, misdiagnosis was associated with poor outcome in univariate and multivariate analysis, respectively (odds ratio=3.89; 95% CI, 1.89-8.01). Delayed cerebral ischemia (odds ratio=2.47; 95% CI, 1.2-5.09) and procedure-related complications (odds ratio=2.27; 95% CI, 1.07-4.82) were independently associated with misdiagnosis. Conclusions- Misdiagnosis is an unresolved problem in SAH, and it is a missed opportunity for good outcome in patients with HH 1-2. The poor outcome is partially explained by a higher risk of delayed cerebral ischemia and procedure-related complications in misdiagnosed patients. There is a need to improve the diagnostic strategy in patients reporting only a headache (HH 1-2) after SAH