Diagnostic Sensitivity of Plasma Endothelin-1 for Cerebral Vasospasm After Subarachnoid Hemorrhage, a Multicentre Double-Blind Study

The purpose of this study is to establish the diagnostic sensitivity of Endothelin-1 for risk stratification and screening of clinical vasospasm after subarachnoid hemorrhage. This is a multicentre, observational study, correlating daily blood Endothelin-1 with clinical variables. Binary logistic regression used to examine if Endothelin-1 levels could be used to predict clinical vasospasm. Bivariate modelling used to explore associations between patient characteristics and vasospasm. A Receiver Operating Curve used to explore cut-off values for Endothelin-1. Sensitivity and specificity was used to validate the cut-point found in the pilot study. A total of 96 patients were enrolled over two years. Median Endothelin-1 was higher for patients who experienced clinical vasospasm except for day-5, where median endothelin for patients without vasospasm was higher (3.6 IQR = 5.3), compared to patients with vasospasm (3.3 IQR = 8.5) although differences were not significant. The Receiver Operating Curve analysis confirmed that day-5 Endothelin-1 was not a good indicator of vasospasm, with an area under the curve of 0.506 (95% CI: 0.350-0.663, p = 0.938). The levels of Endothelin-1 in blood do not discriminate patients who may develop symptomatic vasospasm. The high variability in Endothelin-1 levels, aligns with the pathophysiological variability of most biomarkers, decreasing their ability to predict a clinical event.

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Clinical characteristics and radiological domains among patients with recurrent strokes-a descriptive cross-sectional study from a tertiary care center in central Nepal

F1000Research ◽

10.12688/f1000research.54981.1 ◽

2021 ◽

Vol 10 ◽

pp. 757

Author(s):

Binod Bhattarai ◽

Shashi Bhushan Sah

Keyword(s):

Multivariate Analysis ◽

Tertiary Care ◽

Area Under The Curve ◽

Medical Advice ◽

Receiver Operating Curve ◽

Motor Score ◽

Against Medical Advice ◽

Decision To Leave ◽

Recurrent Strokes ◽

Receiver Operating

Background: Stroke is a significant global health hazard that ripples continuum multi-spectral effects to the patients as well their caretakers. Methods: We studied 28 consecutive cohorts of patients with recurrent strokes managed in our centre within the last two years. Results: The most common recurrence stroke pattern was of that of hemorrhagic to hemorrhagic subtype observed in 50% of the patients. The most common anatomical region of involvement was cortical – cortical seen in 39.28% of our cohorts. The surgical intervention was required in 17.85% whereas 42.85% of them were managed conservatively. Paradoxically, 39.28% of patients left against medical advice. The receiver operating curve (ROC) predicting mode of management was highest (area under the curve (AUC) =0.635) for compliance to therapy followed by stroke territory (AUC=0.578), age (AUC=0.457) and motor grading (AUC=0.374). The receiver operating curve (ROC) for influencing decision to leave against medical advice was highest (area under the curve (AUC) =0.861) for motor score followed by sex (AUC=0.701) and age (AUC=0.564). The analysis of variance (ANOVA) study pertaining to the mode of management was significantly connoted by the motor score and the stroke territory only. The ANOVA study pertaining to the decision to leave against medical advice was significantly governed by the motor score, stroke territory, and sex respectively. The multivariate analysis for variables governing mode of management was significant for motor score and the stroke territory only. The multivariate analysis for variables governing leave against medical advice was significant for sex, motor score and the stroke territory. Conclusions: This study aims to appraise early dichotomization of high-risk patients for recurrent strokes to reduce the continuum of neurological events as well as to mitigate the financial aspects governing stroke care.

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Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive hiv-infected individuals with CD4 cell counts between 50 and 250/mm3

Revista do Instituto de Medicina Tropical de São Paulo ◽

10.1590/s0036-46652000000100005 ◽

2000 ◽

Vol 42 (1) ◽

pp. 27-36 ◽

Cited By ~ 6

Author(s):

David S. LEWI ◽

Jamal M. SULEIMAN ◽

David E. UIP ◽

Rogerio J. PEDRO ◽

Rosa A. SOUZA ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Clinical Event ◽

Double Blind Study ◽

Double Blind ◽

Cd4 Cell Count ◽

Hiv Rna ◽

Cell Counts ◽

Cd4 Cell Counts ◽

Risk Of Disease ◽

Cd4 Cell

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0.0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.

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Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled trial

Journal of Neurosurgery ◽

10.3171/jns-07/12/1092 ◽

2007 ◽

Vol 107 (6) ◽

pp. 1092-1100 ◽

Cited By ~ 35

Author(s):

Ming-Yuan Tseng ◽

Peter J. Hutchinson ◽

Carole L. Turner ◽

Marek Czosnyka ◽

Hugh Richards ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Ldl Cholesterol ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Biological Effects ◽

Laboratory Data ◽

Density Lipoprotein ◽

Double Blind Study ◽

Double Blind ◽

Cholesterol Levels ◽

Cell Counts

Object The authors previously demonstrated that acute pravastatin therapy in patients after aneurysmal subarachnoid hemorrhage (SAH) ameliorates vasospasm-related delayed ischemic neurological deficits. The object of this study was to continue to examine potential mechanisms of these beneficial effects. Methods Eighty patients with aneurysmal SAH (age range 18–84 years; time to onset 1.8 ± 1.3 days) were enrolled in a double-blind study and randomized to receive 40 mg of oral pravastatin or placebo daily for as long as 14 days. Daily transcranial Doppler ultrasonography and blood tests every 3 days (including full blood cell counts, coagulation profiles, fasting glucose and lipid profiles, and serum biochemistry) were performed during the trial period. Results No significant differences were found in baseline laboratory data between the trial groups. Subsequent measurements during the 14-day trial showed reduced low-density lipoprotein (LDL) cholesterol levels and total/high-density lipoprotein cholesterol ratios between Days 3 and 15 (p < 0.05), and increased D-dimer levels (p < 0.05) on Day 6, in the pravastatin group. Patients who received pravastatin but developed vasospasm had significantly lower baseline LDL cholesterol levels or a less extensive reduction in LDL cholesterol levels (p < 0.05), and greater increases in plasma fibrinogen (p = 0.009) and serum C-reactive protein on Day 3 (p = 0.007), compared with those patients without vasospasm. The reduction in LDL cholesterol levels on Day 3 in the placebo group correlated with the duration of normal cerebral autoregulation on the ipsilateral side of the ruptured aneurysm (p = 0.002). Conclusions In addition to functioning through a cholesterol-independent pathway, cerebrovascular protection from acute statin therapy following aneurysmal SAH may also function through cholesterol-dependent mechanisms.

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PREDICTORS OF CEREBRAL INFARCTION IN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE

Neurosurgery ◽

10.1227/01.neu.0000255396.23280.31 ◽

2007 ◽

Vol 60 (4) ◽

pp. 658-667 ◽

Cited By ~ 175

Author(s):

Sherise Ferguson ◽

R. Loch Macdonald

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Infarction ◽

Odds Ratio ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Multivariable Analysis ◽

Double Blind ◽

Poor Outcome ◽

Symptomatic Vasospasm ◽

Explained Variance ◽

The Impact

Abstract OBJECTIVE Cerebral infarction would be expected to be associated with poor outcome after aneurysmal subarachnoid hemorrhage (SAH), although there are few data on which to base this assumption. The goals of this study were to determine the impact of cerebral infarction on outcome and to examine predictors of infarction in these patients. METHODS Univariate and multivariable statistical methods were used to examine the impact of cerebral infarction on the Glasgow Outcome Scale score 3 months after SAH among 3567 patients entered into four prospective, randomized, double-blind, placebo-controlled trials of tirilazad conducted in neurosurgical centers around the world between 1991 and 1997. Patient demographics, clinical variables, radiographic characteristics, and treatment variables associated with cerebral infarction were also determined by the same methods. RESULTS Seven hundred and seven (26%) out of 2741 patients with complete data had cerebral infarction on computed tomographic scans 6 weeks after SAH. Multivariable logistic regression showed that cerebral infarction increased the odds of unfavorable outcome by a factor of 5.4 (adjusted odds ratio, 5.4; 95% confidence interval, 4.2–6.8; P < 0.0001), which was a higher odds ratio than all other factors associated with outcome. The proportion of explained variance in outcome was also highest for cerebral infarction and accounted for 39% of the explained variance. Multivariable analysis found that cerebral infarction was significantly associated with increasing patient age, worse neurological grade on admission, history of hypertension or diabetes mellitus, larger aneurysm, use of prophylactically or therapeutically induced hypertension, temperature more than 38°C 8 days after SAH, and symptomatic vasospasm. CONCLUSION Cerebral infarction was strongly associated with poor outcome after aneurysmal SAH. The most important potentially treatable factor associated with infarction was symptomatic vasospasm.

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The Role of Lung Ultrasound as an Early Diagnostic Tool for Need of Surfactant Therapy in Preterm Infants with Respiratory Distress Syndrome

American Journal of Perinatology ◽

10.1055/s-0040-1714207 ◽

2020 ◽

Author(s):

Gonca Vardar ◽

Nilgun Karadag ◽

Guner Karatekin

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Preterm Infants ◽

Distress Syndrome ◽

Lung Ultrasound ◽

Area Under The Curve ◽

Surfactant Therapy ◽

Double Blind Study ◽

Double Blind ◽

Cpap Failure

Objective This study aimed to determine the accuracy of neonatal lung ultrasound (LUS) in predicting the need for surfactant therapy compared with chest X-ray (CXR) in preterm infants. Study Design A prospective double-blind study was conducted in infants with a gestational age <34 weeks with respiratory distress syndrome (RDS) by evaluation with LUS and CXR on admission. Results Among 45 preterm infants, the median (interquartile range [IQR]) LUS score was 4 (2–8) in the mild RDS group, whereas it was 10 (IQR: 9–12) in the severe RDS group (p < 0.01). The LUS score showed a significant correlation with the need for total surfactant doses (ρ = 0.855; 95% confidence interval [CI]: 0.801–0.902; p < 0.001). A cut-off LUS score of four predicted the need for surfactant with 96% sensitivity and 100% specificity (area under the curve [AUC]: 1.00; 95% CI: 0.97–1.00; p < 0.01). LUS scores predicted continuous positive airway pressure (CPAP) failure accurately (AUC: 0.804; 95% CI: 0.673–0.935; p = 0.001). A significant correlation was observed between LUS scores and positive end-expiratory pressure levels (ρ = 0.782; p < 0.001). During the study period, the CXR number per infant with RDS decreased significantly when compared with preceding months (p < 0.001). The LUS score in the first day of life did not predict the development of bronchopulmonary dysplasia (AUC: 0.274; 95% CI: 0.053–0.495; p = 0.065). Conclusion The LUS score in preterm infants accurately predicts the severity of RDS, the need for surfactant and CPAP failure. The routine use of LUS can decrease the frequency of CXRs in the neonatal intensive care units. Key Points

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Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3501 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3501-3501 ◽

Cited By ~ 4

Author(s):

Charles L. Loprinzi ◽

Rui Qin ◽

Shaker R. Dakhil ◽

Louis Fehrenbacher ◽

Philip J. Stella ◽

...

Keyword(s):

Randomized Study ◽

Area Under The Curve ◽

Phase Iii ◽

Double Blind Study ◽

Double Blind ◽

Acute Neuropathy ◽

Before And After ◽

Secondary Endpoints ◽

Calcium Magnesium ◽

Eortc Qlq

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

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Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2009.4.jns081377 ◽

2010 ◽

Vol 112 (3) ◽

pp. 681-688 ◽

Cited By ~ 60

Author(s):

Philippe Gomis ◽

Jean Pierre Graftieaux ◽

Richard Sercombe ◽

Dominique Hettler ◽

Bernard Scherpereel ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Functional Outcome ◽

Doppler Ultrasonography ◽

Pilot Trial ◽

Group Versus ◽

High Dose ◽

Double Blind ◽

Double Blind Placebo ◽

Symptomatic Vasospasm ◽

Poor Outcomes

Object The object of this study was to determine the efficacy of methylprednisolone in reducing symptomatic vasospasm and poor outcomes after subarachnoid hemorrhage (SAH). Methods Ninety-five patients with proven SAH were recruited into a double-blind, placebo-controlled, randomized trial. Starting within 6 hours after angiographic diagnosis of aneurysm rupture, placebo or methylprednisolone, 16 mg/kg, was administered intravenously every day for 3 days to 46 and 49 patients, respectively. Deterioration, defined as development of a focal sign or decrease of more than 1 point on the Glasgow Coma Scale for more than 6 hours, was investigated by using clinical criteria and transcranial Doppler ultrasonography, cerebral angiography, or CT when appropriate. The end points were incidence of symptomatic vasospasm (delayed ischemic neurological deficits associated with angiographic arterial narrowing or accelerated flow on Doppler ultrasonography, or both) and outcome 1 year after entry into the study according to a simplified Rankin scale (Functional Outcome Scale [FOS]) in living patients and the Glasgow Outcome Scale in all patients included. Results All episodes of deterioration and all living patients with a 1-year outcome were assessed by a review committee. In patients treated with methylprednisolone, the incidence of symptomatic vasospasm was 26.5% compared with 26.0% in those given placebo. Poor outcomes according to FOS were significantly reduced in the Methylprednisolone Group at 1 year of follow-up; the risk difference was 19.3% (95% CI 0.5–37.9%). The outcome was poor in 15% (6/40) of patients in the Methylprednisolone Group versus 34% (13/38) in the Placebo Group. Conclusions A safe and simple treatment with methylprednisolone did not reduce the incidence of symptomatic vasospasm but improved ability and functional outcome at 1 year after SAH.

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Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1992.76.4.0571 ◽

1992 ◽

Vol 76 (4) ◽

pp. 571-577 ◽

Cited By ~ 301

Author(s):

Masato Shibuya ◽

Yoshio Suzuki ◽

Kenichiro Sugita ◽

Isamu Saito ◽

Tomio Sasaki ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Double Blind Trial ◽

Double Blind ◽

Content Type ◽

Blind Trial ◽

Symptomatic Vasospasm ◽

Delayed Cerebral Vasospasm ◽

Number Of Patients ◽

Fine Print

✓ With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.

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Prostaglandin E2 (PGE2) Induces Headache in Healthy Subjects

Cephalalgia ◽

10.1111/j.1468-2982.2008.01748.x ◽

2009 ◽

Vol 29 (5) ◽

pp. 509-519 ◽

Cited By ~ 40

Author(s):

T Wienecke ◽

J Olesen ◽

PS Oturai ◽

M Ashina

Keyword(s):

Healthy Subjects ◽

Rating Scale ◽

Superficial Temporal Artery ◽

Area Under The Curve ◽

Temporal Artery ◽

Prostaglandin E ◽

Double Blind Study ◽

Mean Flow ◽

Sensory Afferents ◽

Double Blind

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E2 (PGE2) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE2 might induce headache and vasodilation of cranial vessels. PGE2 (0.40 μg kg−1 min−1) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (VMCA) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE2 day and no subjects reported headache on the placebo day ( P = 0.001). During the immediate phase (0–30 min) ( P = 0.005) and the postinfusion phase (30–90 min) ( P = 0.005), the area under the curve for headache score was significantly larger on the PGE2 day compared with the placebo day. PGE2 caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE2 induces headache by activation and sensitization of cranial perivascular sensory afferents.

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Daptomycin Pharmacokinetics and Safety following Administration of Escalating Doses Once Daily to Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.4.1318-1323.2003 ◽

2003 ◽

Vol 47 (4) ◽

pp. 1318-1323 ◽

Cited By ~ 241

Author(s):

Barry H. Dvorchik ◽

David Brazier ◽

Michael F. DeBruin ◽

Robert D. Arbeit

Keyword(s):

Healthy Subjects ◽

Phase 1 ◽

Area Under The Curve ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Double Blind Study ◽

Double Blind ◽

Once Daily ◽

Lipopeptide Antibiotic ◽

To Receive

ABSTRACT The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight (∼20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life (∼9 h), volume of distribution (∼0.1 liters/kg), systemic clearance (∼8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h (∼54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.

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