Characterising the Photoplethysmography Pulse Waveform for Use in Human Neuroscience: The Hybrid Excess and Decay (HED) Model

Photoplethysmography (PPG) offers a widely-used, convenient and non-invasive approach to monitoring basic indices of cardiovascular function such as heart rate and blood oxygenation. However, while the pulse waveform, generated by PPG comprises features that are shaped by physiological and psychological factors, it is frequently overlooked in analyses of such data. We suggest that studies could be enriched by exploiting the possibilities afforded by a systematic analysis of PPG waveforms. To do this we initially require a robust and automated means of characterising it, thereby allowing us to examine variations across individuals and between different physiological and psychological contexts. We present a psychophysiologically-relevant model, the Hybrid Excess and Decay (HED) Model, which characterises pulse wave morphology in terms of three underlying pressure waves and a decay function. We show that these parameters capture PPG data with a high degree of precision and, moreover, are sensitive to specific, physiologically-relevant changes within individuals. We present the theoretical and practical basis for the model and demonstrate its performance when applied to a pharmacological dataset of 105 participants receiving intravenous administrations of the sympathomimetic drug isoproterenol (Isoprenaline). We conclude by discussing the possible value in using the HED model to complement standard measures of PPG outputs.

Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight.

Acute Salbutamol Exposures in ChildrenRetrospective five - year study

Salbutamol (Albuterol) is a sympathomimetic drug which is indicated as first therapeutic line in the treatment of bronchial asthma. In this study we’ve analyzed the cases with exposure to Salbutamol hospitalized and treated in the Department of Toxicology and Intensive Care of Clinical Emergency Hospital for Children Grigore Alexandrescu, from Bucharest. This is a retrospective and descriptive study, which lasted 5 years, from January 2012, until December 2016. The results showed that the administration of Salbutamol orally or inhalatory by nebulization in pediatric population is easy but frequently associated with accidental or iatrogenic overdoses. Keywords: Salbutamol, intoxication, children

Synergistic Effects of Weightlessness, Isoproterenol, and Radiation on DNA Damage Response and Cytokine Production in Immune Cells

The implementation of rotating-wall vessels (RWVs) for studying the effect of lack of gravity has attracted attention, especially in the fields of stem cells, tissue regeneration, and cancer research. Immune cells incubated in RWVs exhibit several features of immunosuppression including impaired leukocyte proliferation, cytokine responses, and antibody production. Interestingly, stress hormones influence cellular immune pathways affected by microgravity, such as cell proliferation, apoptosis, DNA repair, and T cell activation. These pathways are crucial defense mechanisms that protect the cell from toxins, pathogens, and radiation. Despite the importance of the adrenergic receptor in regulating the immune system, the effect of microgravity on the adrenergic system has been poorly studied. Thus, we elected to investigate the synergistic effects of isoproterenol (a sympathomimetic drug), radiation, and microgravity in nonstimulated immune cells. Peripheral blood mononuclear cells were treated with the sympathomimetic drug isoproterenol, exposed to 0.8 or 2 Gy γ-radiation, and incubated in RWVs. Mixed model regression analyses showed significant synergistic effects on the expression of the β2-adrenergic receptor gene (ADRB2). Radiation alone increased ADRB2 expression, and cells incubated in microgravity had more DNA strand breaks than cells incubated in normal gravity. We observed radiation-induced cytokine production only in microgravity. Prior treatment with isoproterenol clearly prevents most of the microgravity-mediated effects. RWVs may be a useful tool to provide insight into novel regulatory pathways, providing benefit not only to astronauts but also to patients suffering from immune disorders or undergoing radiotherapy.

Falsely elevated plasma metanephrine in patients taking midodrine

Plasma metanephrines have become the biochemical test of choice for suspected phaeochromocytomas and paragangliomas in many institutions. We encountered two separate cases of significantly elevated plasma metanephrines in patients taking midodrine, a sympathomimetic drug used in the treatment of severe postural hypotension, in the absence of a diagnosis of phaeochromocytomas and paragangliomas. Upon stopping midodrine treatment, plasma metanephrine concentrations returned to normal in both patients. To explore the hypothesis that midodrine or its metabolite desglymidodrine might interfere with the metanephrines assay, we tested the interaction of midodrine with metanephrine assays from two different centres. High-performance liquid chromatography tandem mass spectrometry on plasma samples and on methanolic extract of midodrine demonstrated co-elution of the metabolite desglymidodrine with metanephrine. We conclude that patients taking midodrine may have falsely elevated plasma metanephrine as a result of analytical interference, and clinicians need to be aware of this problem.

Hemorrhagic primary CNS angiitis and vasoconstrictive drug exposure

Background:Primary angiitis of the CNS (PACNS) typically manifests with accumulating neurologic deficits from ischemic strokes. Intracerebral hemorrhage (ICH) is an uncommon complication. There is limited knowledge about the risk factors and features of hemorrhagic PACNS.Methods:We identified 49 patients (20 biopsy-proven) with PACNS diagnosed at our hospital from 1993 to 2015. We compared the features of hemorrhagic and nonhemorrhagic PACNS and analyzed the hemorrhagic PACNS cases in detail.Results:The mean age was 51 ± 15 years; 13 patients were men. Five patients had ICH (mean age 52 ± 14 years; 4 men) including 4 where ICH was the first manifestation of PACNS. All ICH patients reported recent exposure to sympathomimetic drugs (e.g., diet pills, nasal decongestants). Patients with ICH had higher rates of headache (100% vs 43%, p = 0.022), especially thunderclap headache (60% vs 0%, p = 0.001), and eosinophilic vascular infiltrates on brain biopsy (50% vs 9%, p = 0.084). In all ICH patients, brain MRI showed lobar hemorrhages with concurrent punctate diffusion-restricted lesions, suggesting an acute inflammatory process. Four received a short course of immunosuppressive therapy. All patients showed complete clinical resolution or significant improvement within weeks.Conclusions:In this study, hemorrhagic PACNS was exclusively associated with sympathomimetic drug exposure. The high rate of thunderclap headache, lobar hemorrhages, and the self-limited clinical course suggests a shared mechanism between hemorrhagic PACNS and the reversible cerebral vasoconstriction syndrome (RCVS), a PACNS mimic. This RCVS-PACNS overlap syndrome may result from sympathomimetic drug–induced prolonged distal vasoconstriction, culminating in inflammation.

Diffuse cerebrovascular dilation: Case report of amezinium metilsulfate-induced reversible cerebral vasoconstriction syndrome

Background Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries. Case description A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months. Discussion Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS.