Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review

Neurocritical Care - For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral...     

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Chronic Administration of Glucocorticoids Directly Upregulates Prepro-Neuropeptide Y and Y1-Receptor mRNA Levels in the Arcuate Nucleus of the Rat

The complete sequence of the cDNA encoding the neuropeptide Y (NPY) Y₁-receptor has recently been deduced from a rat brain library, and the presence of messenger ribonucleic acid (mRNA) encoding Y₁-receptor protein has been demonstrated within the brain. Using quantitative in situ hybridization histochemistry, the content and distribution of Y₁receptor and preproNPY mRNAs have been investigated in the hypothalamic arcuate nucleus of adrenalectomized rats receiving glucocorticoid replacement therapy for 12 days by means of either high doses of dexamethasone in their drinking water or by subcutaneous corticosterone pellets. Basal metabolic parameters such as weight gain or loss, blood glucose and plasma insulin were monitored: Dexamethasone treatment induced weight loss and a state of hyperinsulinemia with normoglycemia, while corticosterone treated animals displayed metabolic parameters identical to sham ADX animals. Within the arcuate nucleus of glucocorticoid treated animals, levels of Y₁receptor and preproNPY mRNAs were increased. In contrast, adrenalectomy itself had no effect upon Y₁-receptor mRNA levels or preproNPY mRNA levels in the arcuate nucleus. These studies demonstrate that glucocorticoids exert a stimulatory action on levels of Y₁-receptor mRNA and preproNPY mRNA levels in the hypothalamic arcuate nucleus. This is the first evidence to suggest that the expression of a neuropeptide-receptor gene in the central nervous system may be directly sensitive to peripheral hormonal signals.     

Plasmodium falciparum-infected erythrocytes contain an adenylate cyclase with properties which differ from those of the host enzyme

It has been postulated that differentiation of the human malaria parasite, Plasmodium falciparum, is controlled by cAMP levels. We have determined that P. falciparum synthesizes an adenylate cyclase with several properties distinct from those of the mammalian host cell enzyme. Adenylate cyclase activity was compared in P. falciparum-infected erythrocytes, isolated parasites free of host cell material, and uninfected erythrocyte membranes. The parasite enzyme was unaffected by GTP gamma S, AlF4-, and forskolin, while the erythrocyte enzyme was markedly stimulated by each of these compounds. The parasite adenylate cyclase also exhibited a striking preference for Mn2+ over Mg2+, which was not evident in the erythrocyte enzyme. Moreover, differing cation and pH sensitivities were observed for adenylate cyclase activity in the two cell types. When infected and uninfected erythrocytes were compared, the basal adenylate cyclase activity of infected cells was 7 and 49 times that measured in uninfected erythrocytes in the presence of Mg2+ and Mn2+, respectively. Furthermore, adenylate cyclase activity in infected cells exhibited properties typical of the parasite enzyme. This indicates that synthesis of the parasite enzyme rather than stimulation of the host enzyme accounts for the increased activity in infected cells.     

Visualization of efferent retinal projections by immunohistochemical identification of cholera toxin subunit B.

The present study describes the use of cholera toxin subunit B as an anterograde and retrograde neuronal tracer for studying retinal projections of the rat, mouse, gerbil, and hamster. The tracer was pressure injected in the posterior chamber of the eye and the labeled neurons were identified using an avidin-biotin immunoperoxidase technique using diaminobenzidine as chromagen. Doses of 3-8 microliters (30-80 micrograms) cholera toxin subunit B and a survival for 24 h resulted in an optimal transport of the tracer in all rodent species investigated. The cholera toxin subunit B-containing retinal efferents were effectively stained and yielded the presence of axons with delicate boutons on passage and nerve endings. Smooth and thick fibers were also observed, indicating a distinction between passing and terminating axons, respectively. Immunoreactive axons were observed in the hypothalamus, thalamus, ad mesencephalon, and the precise distribution of positive nerves could be identified in counterstained sections, some of them as delicate endings in apposition to neuronal surfaces. Labeled cell bodies were observed in the oculomotor nucleus and the pretectum, indicating that the tracer is transported retrogradely as well. Because the tracer is identified immunohistochemically, the retinofugal and retinopetal pathways can be mapped more precisely, perhaps in combination with immunohistochemical detection of other antigens.     

Nimodipine treatment of subarachnoid hemorrhage

In a pilot study of 6 patients with subarachnoid hemorrhage caused by a ruptured intracranial (grade IV (Hunt and Hess) aneurysm the hemodynamics and plasma-nimodipine concentrations have been observed during a 3-week period of treatment. We found that 3 patients developed reversible hypotension during the nimodipine treatment and that the hypotension tendency could be related to the plasmanimodipine level and not to a more or less severe sensitivity to nimodipine.

Repeated measurements of blood pressure, plasma-nimodipine and regional cerebral blood flow (rCBF) are necessary for the purpose of obtaining the optimum treatment and for evaluating the effect of treatment.     

An occipito-temporal syndrome in adolescents with optimally controlled hyperphenylalaninaemia

Summary The study included 16 adolescents with optimally controlled hyperphenylalaninaemia (McKusick 26160), of whom six did not require treatment according to conventional criteria. All except the two patients with lowest median serum phenylalanine level throughout childhood (most values at 200–300 µmol/L) had white matter abnormalities detectable with magnetic resonance imaging. The lesions were particularly prominent in the watershed regions between the posterior and middle cerebral arteries. In most patients with moderate or severe hyperphenylalaninaemia frontal white matter lesions were present as well. Normal proton magnetic resonance spectra indicated that the lesions were stable. Occipital EEG abnormalities were frequent, and deficient performance on a pattern-recognition test was a characteristic neuropsychological finding. Serum phenylalanine levels at about 300 µmol/L or below throughout childhood and early adolescence may be required to avoid lesions. The present study demonstrates the limitations of even an optimally controlled dietary regimen in hyperphenylalaninaemia.     

Spontaneous abortion following mid-trimester amniocentesis. Clinical significance of placental perforation and blood-stained amniotic fluid

The clinical significance of placental perforation and blood-stained amniotic fluid was studied in a group of 7238 Danish women undergoing mid-trimester amniocentesis for prenatal diagnosis under ultrasound guidance. The risk of spontaneous abortion was significantly increased both in pregnancies where the placenta was perforated and in those with blood-stained amniotic fluid. The risk estimate nearly doubled after placental perforation and more than doubled with a bloody tap. It is concluded that for women at relatively low risk of a fetal genetic abnormality, the indication of the amniocentesis should be reconsidered if a placental perforation is unavoidable.     

Effects of heat treatment on selected plasma therapeutic drug concentrations.

OBJECTIVE: We investigated the heat stability of six common therapeutic drugs routinely assayed in pharmacokinetic and clinical laboratories. DESIGN: Serum samples were spiked at three concentrations (subtherapeutic, therapeutic, and potentially toxic) with amikacin, gentamicin, tobramycin, phenytoin, theophylline, and phenobarbital. The samples were then heated at 56 degrees C and assayed by fluorescence polarization immunoassay at 15-minute intervals for one hour. SETTING: The study was conducted at a clinical research laboratory using standard laboratory methods. MAIN OUTCOME MEASURES: Drug concentrations of heated samples were compared with unheated controls using ANOVA to determine if degradation occurred over time with heating. RESULTS: Analysis of data revealed no degradation of any of the samples. CONCLUSIONS: Heat treatment of samples from high-risk individuals may be a mechanism to protect healthcare workers from exposure to the human immunodeficiency virus.