Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. METHODS: The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. RESULTS: Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. CONCLUSION: In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. TRIAL REGISTRATION: clinicaltrials.gov (NCT03987139; 14 June 2019).

Vancomycin-resistant Enterococcus faecium: should we screen on admission?

Denmark has experienced an increase in the proportion of invasive vancomycin-resistant Enterococcus faecium (VRE) since 2002 (e.g. <4% in 2015, 7.1% in 2017 and 12% in 2018). At Rigshospitalet, we employ active screening at departments with high prevalence or in case of outbreaks. This includes the collection of rectal swabs specifically for VRE screening. Our purpose was to describe the carrier prevalence of vancomycin-resistant enterococci among acute patients admitted to the Neurointensive Care Unit, Department of Neuroanaesthesiology, Rigshospitalet, Copenhagen, Denmark (NICU). Between April 2018 and January 2019, we investigated 99 consecutive rectal swabs from patients admitted to NICU. The primary outcome was prevalence of VRE carriage. The median age was 64 years (range 23-87) and gender was equally distributed (Female = 47, Male = 46). 26 (28%) had previously been admitted within 179 days and 67 patients (72%) had no hospital admissions within 180 days prior to the admission to NICU. Of the 93 rectal swabs, 2 (2%, 95% CI 0.26-7.55%) were positive for vanA and none were positive for vanB. Routine screening of all patients at admission may be effective in hospital settings with high VRE prevalence, whereas the benefit of screening for VRE in hospitals with a low prevalence may be restricted to specific patient populations.

Microbiome Compositions and Resistome Levels after Antibiotic Treatment of Critically Ill Patients: An Observational Cohort Study.

Hospitalization and treatment with antibiotics increase the risk of acquiring multidrug-resistant bacteria due to antibiotic-mediated changes in patient microbiota. This study aimed to investigate how broad- and narrow-spectrum antibiotics affect the gut microbiome and the resistome in antibiotic naïve patients during neurointensive care. Patients admitted to the neurointensive care unit were treated with broad-spectrum (meropenem or piperacillin/tazobactam) or narrow-spectrum antibiotic treatment (including ciprofloxacin, cefuroxime, vancomycin and dicloxacillin) according to clinical indications. A rectal swab was collected from each patient before and after 5-7 days of antibiotic therapy (N = 34), respectively. Shotgun metagenomic sequencing was performed and the composition of metagenomic species (MGS) was determined. The resistome was characterized with CARD RGI software and the CARD database. As a measure for selection pressure in the patient, we used the sum of the number of days with each antibiotic (antibiotic days). We observed a significant increase in richness and a tendency for an increase in the Shannon index after narrow-spectrum treatment. For broad-spectrum treatment the effect was more diverse, with some patients increasing and some decreasing in richness and Shannon index. This was studied further by comparison of patients who had gained or lost >10 MGS, respectively. Selection pressure was significantly higher in patients with decreased richness and a decreased Shannon index who received the broad treatment. A decrease in MGS richness was significantly correlated to the number of drugs administered and the selection pressure in the patient. Bray-Curtis dissimilarities were significant between the pre- and post-treatment of samples in the narrow group, indicating that the longer the narrow-spectrum treatment, the higher the differences between the pre- and the post-treatment microbial composition. We did not find significant differences between pre- and post-treatment for both antibiotic spectrum treatments; however, we observed that most of the antibiotic class resistance genes were higher in abundance in post-treatment after broad-spectrum treatment.

Automated pupillometry and the FOUR score - what is the diagnostic benefit in neurointensive care?

INTRODUCTION: The Glasgow Coma Scale (GCS) and visual inspection of pupillary function are routine measures to monitor patients with impaired consciousness and predict their outcome in the neurointensive care unit (neuro-ICU). Our aim was to compare more recent measures, i.e. FOUR score and automated pupillometry, to standard monitoring with the GCS and visual inspection of pupils. METHODS: Supervised trained nursing staff examined a consecutive sample of patients admitted to the neuro-ICU of a tertiary referral centre using GCS and FOUR score and assessing pupillary function first by visual inspection and then by automated pupillometry. Clinical outcome was evaluated 6 months after admission using the Glasgow Outcome Scale-Extended. RESULTS: Fifty-six consecutive patients (median age 63 years) were assessed a total of 234 times. Of the 36 patients with at least one GCS score of 3, 13 had a favourable outcome. All seven patients with at least one FOUR score of ≤ 3 had an unfavourable outcome, which was best predicted by a low "brainstem" sub-score. Compared to automated pupillometry, visual assessment underestimated pupillary diameters (median difference, 0.4 mm; P = 0.006). Automated pupillometry detected a preserved pupillary light reflex in 10 patients, in whom visual inspection had missed pupillary constriction. DISCUSSION: Training of nursing staff to implement frequent monitoring of patients in the neuro-ICU with FOUR score and automated pupillometry is feasible. Both measures provide additional clinical information compared to the GCS and visual assessment of pupillary function, most importantly a more granular classification of patients with low levels of consciousness by the FOUR score.

Synthesis and structure-activity relationship for a novel class of potent and selective carbamate-based inhibitors of hormone selective lipase with acute in vivo antilipolytic effects.

Hormone-sensitive lipase (HSL) is an intracellular enzyme that has a central role in the regulation of fatty acid metabolism. The enzyme, therefore, is a potentially interesting pharmacological target for the treatment of insulin resistance and dyslipidemic disorders. Based on a high throughput screening, a carbamate based HSL inhibitor was identified and optimized into the selective HSL inhibitors 4-hydroxymethyl-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13f) and 4-hydroxy-piperidine-1-carboxylic acid 4-(5-trifluoromethylpyridin-2-yloxy)-phenyl ester (13g), with IC50 values of 110 and 500 nM, respectively. Both inhibitors were active in acute antilipolytic experiments in vivo and none of the inhibitors inhibited the cytochrome P450 (CYP) isoforms 2D6, 3A4, and 1A2.

Design of a partial PPARdelta agonist.

Structure based ligand design was used in order to design a partial agonist for the PPARdelta receptor. The maximum activation in the transactivation assay was reduced from 87% to 39%. The crystal structure of the ligand binding domain of the PPARdelta receptor in complex with compound 2 was determined in order to understand the structural changes which gave rise to the decrease in maximum activation.

New 3-alkylamino-4H-thieno-1,2,4-thiadiazine 1,1-dioxide derivatives activate ATP-sensitive potassium channels of pancreatic beta cells.

Compound 1a (NN414) is a potent opener of Kir6.2/SUR1 K(ATP) channels. Compound 1a inhibits insulin release in vitro and in vivo and preserves beta cell function in preclinical animal models suggesting that such a compound could find use in treatment or prevention of type 1 and type 2 diabetes. The crystal structure and a convergent synthesis of 1a are presented together with a range of new analogues of 1a. Several compounds, e.g., 6-chloro-3-(1-methyl-1-phenylethyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1h), were found to be potent openers of Kir6.2/SUR1 K(ATP) channels and were able to suppress glucose-stimulated insulin release from rat islets in vitro (EC(50) = 0.04 +/- 0.01 muM) and in vivo after intravenous or peroral administration to hyperinsulinemic obese Zucker rats (ED(50) = 4.0 mg/kg). Structural modifications of this series of K(ATP) channel openers have provided compounds with promising pharmacokinetic properties indicating that brief periods of beta cell rest can be achieved.

Structure-activity relationship for aryl and heteroaryl boronic acid inhibitors of hormone-sensitive lipase.

A range of aryl and heteroaryl boronic acids were tested for their in vitro hormone-sensitive lipase inhibitory properties. (2-Benzyloxy-5-fluorophenyl)boronic acid, (2-benzyloxy-5-chlorophenyl)boronic acid and 5-bromothiophene-2-boronic acid were found to be the most potent HSL inhibitors with IC(50) values of 140, 17 and 350 nM, respectively.

Synthesis and structure-activity relationship for a novel class of potent and selective carbamoyl-triazole based inhibitors of hormone sensitive lipase.

The central role of the intracellular enzyme hormone-sensitive lipase (HSL) in regulating fatty acid metabolism makes it an interesting pharmacological target for the treatment of insulin resistant and dyslipidemic disorders where a decrease in delivery of fatty acids to the circulation is desirable, e.g., in individuals with type 2 diabetes, metabolic syndrome, or impaired glucose tolerance. On the basis of a lead structure from high throughput screening, we have identified a very potent type of carbamoyl-triazole inhibitors of HSL. As part of the lead optimization program, four new classes of carbamoyl-triazoles were synthesized and tested with respect to potency, efficacy and selectivity. Methyl-phenyl-carbamoyl-triazoles were identified as potent and efficacious HSL inhibitors. These compounds do not inhibit other hydrolases such as hepatic lipase, lipoprotein lipase, pancreatic lipase, and butyrylcholine esterase. However, the inhibitors 4b and 4g with IC(50) values for HSL of 0.17 and 0.25 microM, respectively, were the only inhibitors selective against acetylcholine esterase. A reversible pseudosubstrate inhibition mechanism is proposed for this class of inhibitors.

Synthesis of 2,3-substituted thienylboronic acids and esters.

A noncryogenic protocol for the synthesis of 2-substituted 3-thienylboronic acids and esters as well as 3-substituted 2-thienylboronic acids and esters has been developed. Electrophiles were introduced regiospecifically in the 2-position of 2,3-dibromothiophene and in the 3-position of 2-bromo-3-iodothiophene by halogen-magnesium exchange followed by quenching with electrophiles. Palladium-catalyzed borylation of the 2,3-substituted halothiophenes with pinacolborane and P(t-Bu)3 as ligand for Pd produced 9 and 10. The borylation protocol was tolerated by a range of functional groups; however, strongly electron-withdrawing substituents decreased the stability of the thienylboronic acids and esters.

Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar.

A new and improved synthesis of the peroxisome proliferator-activated receptor (PPAR) agonist ragaglitazar applicable for large-scale preparation has been developed. The convergent synthetic procedure was based on a novel enzymatic kinetic resolution step. The conformation of ragaglitazar bound to the hPPARgamma receptor was quite different compared to the single-crystal structures of the l-arginine salt of ragaglitazar. In particular, the phenoxazine ring system had varying orientations. Ragaglitazar had high affinity for the hPPARalpha and -gamma receptors with IC(50) values of 0.98 and 0.092 microM, respectively. The lack of hPPARdelta activity could be explained by the absence of binding in the tail-up pocket in the hPPARdelta receptor, in contrast to the hPPARdelta agonist GW2433, which was able to bind in both the tail-up and tail-down pockets of the receptor.