Severe autonomic nervous system imbalance in Lennox-Gastaut syndrome patients demonstrated by heart rate variability recordings.

OBJECTIVE: Patients diagnosed with Lennox Gastaut syndrome (LGS), an epileptic encephalopathy characterized by usually drug resistant generalized and focal seizures, are often considered as candidates for vagus nerve stimulation (VNS). Recent research shows that heart rate variability (HRV) differs in epilepsy patients and is related to VNS treatment response. This study investigated pre-ictal HRV in generalized onset seizures of patients with LGS in correlation with their VNS response. METHODS: In drug resistant epilepsy (DRE) patients diagnosed with LGS video-electroencephalography recording was performed during their pre-surgical evaluation. Six HRV parameters (time and-, frequency domain, non-linear parameters) were evaluated for every seizure in epochs of 10 min at baseline (60 to 50 min before seizure onset) and pre-ictally (10 min prior to seizure onset). The results were correlated to VNS response after one year of VNS therapy. RESULTS: Seven patients and 31 seizures were included, two patients were classified as VNS responders (≥ 50 % seizure reduction). No difference in pre-ictal HRV parameters between VNS responders and VNS non-responders could be found, but high frequency (HF) power, reflecting the parasympathetic tone increased significantly in the pre-ictal epoch in both VNS responders and VNS non-responders (p = 0.017, p = 0.004). SIGNIFICANCE: In this pilot data pre-ictal HRV did not differ in VNS responders compared to VNS non-responders, but showed a significant increase in HF power - a parasympathetic overdrive - in both VNS responders and VNS non-responders. This sudden autonomic imbalance might have an influence on the cardiovascular system in the ictal period. Generalized tonic-clonic seizures are regarded as the main risk factor for SUDEP and severe seizure-induced autonomic imbalance may play a role in the pathophysiological pathway.

Near-field airborne particle concentrations in young children undergoing high-flow nasal cannula therapy: a pilot study.

BACKGROUND: High-flow nasal cannula therapy (HFNC) may increase aerosol generation, putting healthcare workers at risk, including from SARS-CoV-2. AIM: To examine whether use of HFNC increases near-field aerosols and whether there is an association with flow rate. METHODS: Subjects aged four weeks to 24 months were recruited. Each child received HFNC therapy at different flow rates. Three stations with particle counters were deployed to measure particle concentrations and dispersion in the room: station 1 within 0.5 m, station 2 at 2 m, and station 3 on the other side of the room. Carbon dioxide (CO2) and relative humidity were measured. Far-field measurements were used to adjust the near-field measurements. FINDINGS: Ten children were enrolled, aged from 6 to 24 months (median: 9). Elevated CO2 indicated that the near-field measurements were in the breathing plane. Near-field breathing plane concentrations of aerosols with diameter 0.3-10 µm were elevated by the presence of the patient with no HFNC flow, relative to the room far-field, by 0.45 particles/cm3. Whereas variability between subjects in their emission and dispersion of particles was observed, no association was found between HFNC use, at any flow rate, and near-field particle counts. CONCLUSION: This method of particle sampling is feasible in hospital settings; correcting the near-patient aerosol and CO2 levels for the room far-field may provide proxies of exposure risk to pathogens generated. In this pilot, near-patient levels of particles with a diameter between 0.3 and 10 µm and CO2 were not affected by the use of HFNC.

Study protocol training for life: a stepped wedge cluster randomized trial about emergency obstetric simulation-based training in a low-income country.

BACKGROUND: Globally perinatal and maternal mortality rates remain unacceptably high. There is increasing evidence that simulation-based training in obstetric emergencies is associated with improvement in clinical outcomes. However, the results are not entirely consistent. The need for continued research in a wide variety of clinical settings to establish what works, where and why was recommended. The aim of this study is to investigate the effectiveness of an emergency obstetric simulation-based training program with medical technical and teamwork skills on maternal and perinatal mortality in a low-income country. METHODS: A stepped wedge cluster randomized trial will be conducted at the medium to high-risk labour ward at Mulago Hospital, Kampala, Uganda, with an annual delivery rate of over 23,000. The training will be performed using a train-the-trainers model in which training is cascaded down from master trainers to local facilitators (gynaecologists) to learners (senior house officers). Local facilitators will be trained during a four-day train-the-trainers course with an annual repetition. The senior house officers will be naturally divided in seven clusters and randomized for the moment of training. The training consists of a one-day, monodisciplinary, simulation-based training followed by repetition training sessions. Scenarios are based on the main local causes of maternal and neonatal mortality and focus on both medical technical and crew resource management skills. Kirkpatrick's classification will be used to evaluate the training program. Primary outcome will be the composite of maternal and neonatal mortality ratios. Secondary outcome will comprise course perception, evaluation of the instructional design of the training, knowledge, technical skills, team performance, percentage of ventouse deliveries, percentage of caesarean sections, and a Weighted Adverse Outcome Score. DISCUSSION: This stepped wedge cluster randomized trial will investigate the effect of a monodisciplinary simulation-based obstetric training in a low-income country, focusing on both medical technical skills and crew resource management skills, on patient outcome at one of the largest labour wards worldwide. We will use a robust study design which will allow us to better understand the training effects, and difficulties in evaluating training programs in low-income countries. TRIAL REGISTRATION: ISRCTN98617255 , retrospectively registered July 23, 2018.

Neurophysiological investigations of drug resistant epilepsy patients treated with vagus nerve stimulation to differentiate responders from non-responders.

BACKGROUND AND PURPOSE: In patients treated with vagus nerve stimulation (VNS) for drug resistant epilepsy (DRE), up to a third of patients will eventually not respond to the therapy. As VNS therapy requires surgery for device implantation, prediction of response prior to surgery is desirable. It is hypothesized that neurophysiological investigations related to the mechanisms of action of VNS may help to differentiate VNS responders from non-responders prior to the initiation of therapy. METHODS: In a prospective series of DRE patients, polysomnography, heart rate variability (HRV) and cognitive event related potentials were recorded. Polysomnography and HRV were repeated after 1 year of treatment with VNS. Polysomnography, HRV and cognitive event related potentials were compared between VNS responders (≥50% reduction in seizure frequency) and non-responders. RESULTS: Fifteen out of 30 patients became VNS responders after 1 year of VNS treatment. Prior to treatment with VNS, the amount of deep sleep (NREM 3), the HRV high frequency (HF) power and the P3b amplitude were significantly different in responders compared to non-responders (P = 0.007; P = 0.001; P = 0.03). CONCLUSION: Three neurophysiological parameters, NREM 3, HRV HF and P3b amplitude, were found to be significantly different in DRE patients who became responders to VNS treatment prior to initiation of their treatment with VNS. These non-invasive recordings may be used as characteristics for response in future studies and help avoid unsuccessful implantations. Mechanistically these findings may be related to changes in brain regions involved in the so-called vagal afferent network.

Retinal microcirculation imaging in sickle cell disease patients.

OBJECTIVES: To explore the feasibility of a new quantitative method for microvascular function: non-invasive retinal function imaging (RFI). in sickle cell disease (SCD) patients and healthy controls and have it benchmarked against Laser Speckle Contrast Imaging (LSCI) measurements. METHODS: The variability of Microvascular measurements was assessed in 8 SCD patients and 8 healthy matched controls. Measurements were conducted twice on two different study days. RFI was performed for assessment of arterial and venous retinal blood flow. LSCI measurements included post occlusive reactive hyperemia and IBH challenges. Measured variables included basal flow, flow upon occlusion-reperfusion and flow during an IBH. RESULTS: RFI arterial flow and venous flow and LSCI basal flow and peak flow showed excellent intra subject repeatability between days (CVC of 8.5% 9.5%, 7.6% and 7.7% respectively) and between measurements on one day (CVC of 7.0%, 7.7%, 7.6% and 4.7% respectively). RFI arterial flow (p<0.002), and RFI venous flow (p=0.007) differed significantly between SCD patients and controls in as did LSCI basal flow, maximal flow and delta flow during IBH (p<0.0001). CONCLUSIONS: RFI showed low variability for all readout measures, comparable with most microvascular measures from LSCI. The discriminating power of the RFI between SCD patients and controls demonstrate the feasibility of this device for quantitative assessment of the microcirculation in clinical research.

The effect of neuropeptide FF in the amygdala kindling model.

OBJECTIVE: Neuropeptide FF (NPFF) and its receptors (NPFF1 R and NPFF2 R) are differentially distributed throughout the central nervous system. NPFF reduces cortical excitability in rats when administered intracerebroventricularly (i.c.v.), and both NPFF and NPFF1 R antagonists attenuate pilocarpine-induced limbic seizures. In this study, our aim was to determine whether NPFF exerts anticonvulsant or anti-epileptogenic effects in the rat amygdala kindling model for temporal lobe seizures. METHODS: Male Wistar rats were implanted with a recording/stimulation electrode in the right amygdala and a cannula in the left lateral ventricle. In a first group of animals, the afterdischarge threshold (ADT) was determined after a single i.c.v. infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; n = 10). Subsequently, daily infusion of saline (n = 8) or NPFF (1 nmol/h for 2 h; i.c.v.; n = 9) was performed, followed by a kindling stimulus (ADT+200 µA). Afterdischarge duration and seizure severity were evaluated after every kindling stimulus. A second group of rats (n = 7) were fully kindled, and the effect of saline or a high dose of NPFF (10 nmol/h for 2 h, i.c.v.) on ADT and the generalized seizure threshold (GST) was subsequently determined. RESULTS: In naive rats, NPFF significantly increased the ADT compared to control (435 ± 72 µA vs 131 ± 23 µA [P < 0.05]). When rats underwent daily stimulations above the ADT, NPFF did not delay or prevent kindling acquisition. Furthermore, a high dose of NPFF did not alter ADT or GST in fully kindled rats. CONCLUSIONS: I.c.v. administration of NPFF reduced excitability in the amygdala in naive, but not in fully kindled rats, and had no effect on kindling acquisition.

Intensity-dependent modulatory effects of vagus nerve stimulation on cortical excitability.

OBJECTIVES: Vagus nerve stimulation (VNS) is an effective treatment for refractory epilepsy. It remains unknown whether VNS efficacy is dependent on output current intensity. The present study investigated the effect of various VNS output current intensities on cortical excitability in the motor cortex stimulation rat model. The hypothesis was that output current intensities in the lower range are sufficient to significantly affect cortical excitability. MATERIAL AND METHODS: VNS at four output current intensities (0 mA, 0.25 mA, 0.5 mA and 1 mA) was randomly administered in rats (n = 15) on four consecutive days. Per output current intensity, the animals underwent five-one-hour periods: (i) baseline, (ii) VNS1, (iii) wash-out1, (iv) VNS2 and (v) wash-out2. After each one-hour period, the motor seizure threshold (MST) was measured and compared to baseline (i.e. ∆MSTbaseline , ∆MSTVNS 1 , ∆MSTwash-out1 , ∆MSTVNS 2 and ∆MSTwash-out2 ). Finally, the mean ∆MSTbaseline , mean ∆MSTwash-out1 , mean ∆MSTwash-out2 and mean ∆MSTVNS per VNS output current intensity were calculated. RESULTS: No differences were found between the mean ∆MSTbaseline , mean ∆MSTwash-out1 and mean ∆MSTwash-out2 within each VNS output current intensity. The mean ∆MSTVNS at 0 mA, 0.25 mA, 0.5 mA and 1 mA was 15.3 ± 14.6 µA, 101.8 ± 23.5 µA, 108.1 ± 24.4 µA and 85.7 ± 18.1 µA respectively. The mean ∆MSTVNS at 0.25 mA, 0.5 mA and 1 mA were significantly larger compared to the mean ∆MSTVNS at 0 mA (P = 0.002 for 0.25 mA; P = 0.001 for 0.5 mA; P = 0.011 for 1 mA). CONCLUSIONS: This study confirms efficacy of VNS in the motor cortex stimulation rat model and indicates that, of the output current intensities tested, 0.25 mA is sufficient to decrease cortical excitability and higher output current intensities may not be required.

Surgical successes and failures of invasive video-EEG monitoring in the presurgical evaluation of epilepsy.

Invasive monitoring with intracranial electrodes continues to play a critical role in the presurgical evaluation of patients with medically intractable epilepsy. Intracranial monitoring helps in localizing the epileptogenic zone and can be used to delineate eloquent cortical areas adjacent to this zone. In this review we analyzed surgical successes and failures of invasive video-electroencephalography (EEG) monitoring. Thorough understanding of all potential complications is of paramount importance not only for detection and successful management of intractable epilepsy but also for medicolegal purposes, as patients and their relatives need to be fully informed about the possible risks associated with invasive monitoring. A mortality rate between 0.5% and 2.8% has been reported. Cerebrospinal fluid (CSF) leaks and infections are the most frequent complications, with an incidence ranging from 0-31.3% and from 0-17.4%, respectively. The incidence of intracranial hemorrhage is reported to be up to 14% with subdural hematomas being the most prevalent. Epidural hematomas are less frequent and encountered in up to 2.6% of cases. Intraparenchymal hematomas are even less frequent and are typically associated with the placement of depth electrodes. In 47-98% of cases, invasive video-EEG monitoring results into resective surgery. Invasive video-EEG monitoring is a reasonably safe and effective method to help delineate the epileptogenic zone and its relation to eloquent cortex.

Undertriage in the Manchester triage system: an assessment of severity and options for improvement.

BACKGROUND: The Manchester Triage System (MTS) determines an inappropriately low level of urgency (undertriage) to a minority of children. The aim of the study was to assess the clinical severity of undertriaged patients in the MTS and to define the determinants of undertriage. METHODS: Patients who had attended the emergency department (ED) were triaged according to the MTS. Undertriage was defined as a 'low urgent' classification (levels 3, 4 and 5) under the MTS; as a 'high urgent' classification (levels 1 and 2) under an independent reference standard based on abnormal vital signs (level 1), potentially life-threatening conditions (level 2), and a combination of resource use, hospitalisation, and follow-up for the three lowest urgency levels. In an expert meeting, three experienced paediatricians used a standardised format to determine the clinical severity. The clinical severity had been expressed by possible consequences of treatment delay caused by undertriage, such as the use of more interventions and diagnostics, longer hospitalisation, complications, morbidity, and mortality. In a prospective observational study we used logistic regression analysis to assess predictors for undertriage. RESULTS: In total, 0.9% (119/13,408) of the patients were undertriaged. In 53% (63/119) of these patients, experts considered undertriage as clinically severe. In 89% (56/63) of these patients the high reference urgency was determined on the basis of abnormal vital signs. The prospective observational study showed undertriage was more likely in infants (especially those younger than three months), and in children assigned to the MTS 'unwell child' flowchart (adjusted OR<3 months 4.2, 95% CI 2.3 to 7.7 and adjusted ORunwell child 11.1, 95% CI 5.5 to 22.3). CONCLUSION: Undertriage is infrequent, but can have serious clinical consequences. To reduce significant undertriage, the authors recommend a systematic assessment of vital signs in all children.

Repeatability of the Manchester Triage System for children.

OBJECTIVE: The authors aimed to assess the repeatability of the Manchester Triage System (MTS) in children. METHODS: All emergency department nurses (n=43) from a general teaching hospital and a university children's hospital in The Netherlands triaged 20 written case scenarios using the Manchester Triage system. Second, at two emergency departments (EDs), real-life simultaneous triage of patients (<16 years) was performed by ED nurses and two research nurses. The written case scenarios and the patients included in the real-life simultaneous triage study were representative of children attending the ED, in age, problem and urgency level. The authors assessed inter-rater agreement using quadratic weighted kappa values. RESULTS: The weighted kappa between the nurses, triaging the case scenarios, was 0.83 (95% CI 0.74 to 0.91). In total, 88% (N=198) of the eligible ED patients were triaged simultaneously, with a weighted kappa of 0.65 (95% CI 0.56 to 0.72). CONCLUSIONS: The MTS showed good to very good repeatability in paediatric emergency care.

[Diagnostic image (346). A child with prominent cranial fissures]. / Diagnose in beeld (346). Een kind met geprononceerde schedelnaden.

A 2-week-old boy was presented with prominent cranial fissures. He was diagnosed with malleability post partum.

Validity of the Manchester Triage System in paediatric emergency care.

OBJECTIVE: To assess the validity of the Manchester Triage System (MTS) in paediatric emergency care, using information on vital signs, resource utilisation and hospitalisation. METHODS: Patients were eligible if they had attended the emergency department of a large inner-city hospital in The Netherlands from August 2003 to November 2004 and were <16 years of age. A representative sample of 1065 patients was drawn from 18,469 eligible patients. The originally assigned MTS urgency levels were compared with resource utilisation, hospitalisation and a predefined reference classification for true urgency, based on vital signs, resource utilisation and follow-up. Sensitivity, specificity and percentage of overtriage and undertriage of the MTS were calculated. RESULTS: The number of patients who used more than two resources increased with a higher level of MTS urgency. The percentage of hospital admissions increased with the increase in level of urgency, from 1% in the non-urgent patients to 54% in emergent patients. According to the reference classification, the sensitivity of the MTS to detect emergent/very urgent cases was 63%, and the specificity was 78%. Undertriage occurred in 15% of patients, of which 96% were by one urgency category lower than the reference classification. Overtriage occurred in 40%, mostly in lower MTS categories. In 36% of these cases, the MTS classified two or more urgency categories higher than the reference classification. CONCLUSIONS: The MTS has moderate sensitivity and specificity in paediatric emergency care. Specific modifications of the MTS should be considered in paediatric emergency care to reduce overtriage, while maintaining sensitivity in the highest urgency categories.

Pharmacokinetics of rectal tramadol in postoperative paediatric patients.

BACKGROUND: Postoperative analgesia in children may be improved by using tramadol. The pharmacokinetics of rectal tramadol in young children were therefore investigated. METHODS: The pharmacokinetics of rectal tramadol and its active metabolite were studied in 12 young children (age: 1-6 yr) postoperatively. On the basis of these data, a population model was constructed. Using this model, the pharmacokinetics of different doses of tramadol were calculated. RESULTS: The pharmacokinetics of rectal tramadol could be adequately described by a one-compartment model. The pharmacokinetic parameters derived from the model indicate that a low variability was present. Elimination half-life was 4.3 (0.2) h (sem) and the apparent clearance was 16.4 (1.5) litre h(-1) (sem). CONCLUSIONS: The study showed that after rectal administration, tramadol is absorbed at a reasonable rate and with a low inter-individual variability in small children. The data also suggested that a rectal dose of tramadol 1.5-2.0 mg kg(-1) is therapeutic.

Problems in interhospital pediatric intensive care transport in The Netherlands: results from a survey of general pediatricians.

OBJECTIVE: Interhospital pediatric intensive care transport accompanied by non-trained specialists usually occurs with inadequate equipment and has been associated with high incidence of complications. These facts have serious consequences for patients but also can be very disconcerting for specialists. This survey was undertaken to gain insight into the problems encountered in organizing pediatric intensive care transport in The Netherlands to measure the specialist's satisfaction or dissatisfaction with the current state of affairs in the organization of such transports, and additional workload and feelings of insecurity experienced during self-organized transports. DESIGN: Survey, retrospective. SETTING: A postal questionnaire sent to all pediatricians of community hospitals in The Netherlands. METHODS: Results of direct questioning are given as discrete frequencies. After factor and reliability analysis 5-point Likert scale items are summed up in scale constructions. Relationships between scales are examined in regression analysis. RESULTS: Pediatricians appear to be satisfied with current specialist retrieval teams if these teams are available in their region, and highly dissatisfied if not available. Many nontrained specialists consider these transports burdening tasks with a high workload, and they feel insecure during these transports, especially if they report lack of knowledge of the transport equipment. CONCLUSIONS: The need for pediatric specialist retrieval teams in The Netherlands is seen not only in the insufficient level of care delivered by accompanying nontrained specialists and the reported high incidence of complications as shown in the literature but also in the dissatisfaction and high stress of these specialists.

Extramedullary plasmacytoma of the cavernous sinus.

We present the case of an 80-year-old male with an history of multiple myeloma (MM) stage I with extramedullary plasmacytoma of the neck, diagnosed 18 months before and in complete remission after radiation therapy and melphalan-prednisone therapy. He was admitted with signs and symptoms characteristic for cavernous sinus syndrome, including diplopia, exophthalmia, ptosis and orbital pain. Magnetic resonance imaging showed a mass lesion in the cavernous sinus, consistent with relapsing extramedullary plasmacytoma. The patient received palliative radiation therapy and high dose dexamethasone, but treatment failed and the patient died. This case represents one of the few reports of extramedullary plasmacytoma of the cavernous sinus. The development of a clinical presentation of cavernous sinus syndrome in a patient with a history of MM or extramedullary plasmacytoma should raise the suspicion of a plasmacytic involvement of the cavernous sinus.

Lactobacilli and acidosis in children with short small bowel.

BACKGROUND: In patients with a short small bowel, D-lactic acidemia and D-lactic aciduria are caused by intestinal lactobacilli. The purpose of this study was to obtain a detailed picture of the metabolic acidosis in young children with short small bowel. METHODS: Feces, blood, and urine of children with short small bowel and acidosis were studied microbiologically and/or biochemically. RESULTS: Previous findings were confirmed that more than 60% of the fecal flora of patients with small short bowel, who are not receiving antibiotics, consists of lactic acid-producing lactobacilli. In blood, D-lactic acid was the most prominent metabolite: the highest serum D-lactate (15.5 mmol/l) was observed in a sample taken immediately after the onset of hyperventilation. The highest D-lactate excretion was in urine collected some hours after the onset of hyperventilation, and amounted to 59 mol/mol creatinine. Acidosis in the patients with short small bowel was related to strongly increased serum D-lactate and anion gap and to strongly decreased serum bicarbonate and pH. CONCLUSION: In children with small short bowel and acidosis, the common intestinal flora of mainly lactobacilli abundantly produces D-lactic acid from easily fermentable carbohydrates. Thus, these bacteria directly cause shifts of bicarbonate, pH, and base excess and indirectly cause shifts of the anion gap, as well as hyperventilation. These kinetic parameters are strongly associated.

[Clinical drug research in children: current international guidelines. Committee for Proprietary Medicinal Products]. / Klinisch geneesmiddelenonderzoek bij kinderen: nieuwe internationale richtlijnen. Committee for Proprietary Medicinal Products.

Drugs research in children entails a number of problems: medical-ethical, pharmacological (owing to the immaturity of the organs and the growth and development of the child) and financial (because children do not use many drugs). Consequently, children are exposed to insufficiently tested drugs and new therapeutic possibilities are withheld from them. Currently, little clinical drugs research in children is being carried out, but this is about to change. By now, European guidelines have been drawn up for the performance of clinical drugs trials according the 'good clinical practice' standards in children. In the Netherlands, a cooperative body has been set up (the Pediatric Pharmacology Network), which is to promote and coordinate paediatric pharmacological research in according with these guidelines.