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Biomedical subjects

D G Grosset

Publications and source records attributed to D G Grosset.

At least 19 recordsLinked to original sources
PubMed2000

Randomized trial of graded compression stockings for prevention of deep-vein thrombosis after acute stroke.

Graded compression stockings are commonly used to prevent deep-vein thrombosis (DVT) after stroke, but their efficacy in this setting has not been evaluated. Extrapolation of effectiveness from trials in patients undergoing elective surgery may be inappropriate. We undertook a randomized, controlled trial, with blinded data review, in a University hospital Acute Stroke Unit. Patients were allocated to graded compression stockings or to standard care alone. DVT incidence was determined at baseline and at day 7+/-2 by colour-flow Doppler ultrasound. Ninety-eight patients with acute, immobilizing stroke were randomized; 97 had full outcome data. One patient had clinically manifest DVT, and no patient had pulmonary thromboembolism. DVT was detected in 7/65 patients allocated stockings, and 7/32 controls (odds ratio 0.43, 95% CI 0.14-1.36); DVT involving femoral veins was detected in 3/65 and 2/32. In the first week after stroke, radiologically-detected DVT remains common, but is usually clinically silent. Proximal DVT is less common. Graded compression stockings produced a reduction in DVT incidence comparable to that in other patient groups, but the reduction was not statistically significant, and the magnitude of effect size requires confirmation. There is greater doubt over efficacy in early prevention of proximal DVT.

Aged↗
PubMed2000

Identification of echocardiographic "smoke" in a bench model with transcranial Doppler ultrasound.

BACKGROUND AND PURPOSE: Spontaneous echo contrast in cardiac chamber has been indicated as a source of cerebral embolism. The nature of the echocardiographic smokelike signal is still not fully understood. This study was designed to regenerate spontaneous echo contrast and verify its thromboembolic characters in an in vitro model. METHODS: Spontaneous echo contrast was reproduced in an expansion chamber under low flow conditions in a close circulation system. The spontaneous echo contrast was monitored and recorded with a 2-dimensional cardiosonography system and a transcranial Doppler device. Meanwhile, clinically commonly encountered embolic materials such as whole-blood clots, platelet aggregate-rich plasma, air bubbles, and 100-mL normal saline were injected into this monitored circuit. The differentiation of spontaneous echo contrast from emboli was performed by both visual observations of the echo images and offline Doppler signal intensity analysis. Average signal intensities produced by spontaneous contrast and injection of embolic materials and saline were compared. Furthermore, the effect of Doppler-detected flow velocity on generation of spontaneous contrast was also evaluated. RESULTS: Spontaneous echo contrast was reproduced at low flow settings (90 to 120 mL/min) in this model. There was no significant difference in average signal intensity between the flow with spontaneous echo contrast and that without the echo (P=0.71). However, injection of embolic materials or normal saline did not generate smokelike image but caused much higher average signal intensity than the flow with spontaneous contrast (P<0.001). Injection of normal saline also increased average signal intensity. CONCLUSIONS: Our results suggest that smokelike echo is a special echo phenomenon occurring at low flow situations and does not itself produce material capable of embolizing into the systemic circulation.

Blood Flow Velocity↗
PubMed2000

Accurate differentiation of parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group.

OBJECTIVE: To evaluate whether visual assessment of [123I]-FP-CIT (DaTSCAN, Nycomed Amersham, plc) single photon emission computerized tomography (SPECT) images can differentiate between parkinsonism and essential tremor (ET). METHODS: [123I]-FP-CIT SPECT imaging was conducted in a six-center study of 158 patients with a clinical diagnosis of parkinsonism compared with 27 ET cases and 35 healthy volunteers. Striatal uptake of the radioligand was graded normal or abnormal, and abnormal images were further graded to three levels of severity. An institutional read whereby each center visually assessed the images blinded to the clinical data and a consensus blinded read by a panel of five was undertaken. RESULTS: The institutional reading scored 154 of 158 cases of parkinsonism abnormal, all 27 cases of ET as normal, and 34 of 35 healthy volunteers as normal compared with the consensus blinded read scoring 150 cases of parkinsonism as abnormal, 25 ET cases as normal, and 33 healthy volunteers as normal. Sensitivity for the clinical diagnosis of parkinsonism was 97% and specificity for ET was 100% for the institutional read, whereas sensitivity was 95% and specificity 93% for the consensus blinded read. Semiquantitative analysis of specific: nonspecific caudate and putamen uptake were consistent with the results of visual inspection. CONCLUSION: Visual assessment of [123I]-FP-CIT SPECT images is an easily applied diagnostic test which is helpful in the differential diagnosis of tremor disorders and in confirming a clinical diagnosis of a hypokinetic-rigid syndrome.

Adult↗
PubMed1999

Neuroprotection for acute stroke: making clinical trials work.

BACKGROUND: With the exception of the National Institutes of Neurological Disorders and Stroke trial of recombinant tissue plasminogen activator, clinical trials in stroke have failed to show improved outcome. If further negative results such as those of recent large neuroprotective trials are to be avoided, trial methodology must be reevaluated. SUMMARY: Because there is little evidence from animal focal ischemia models for protection of white matter, glia, or subcortical neurons, the logical target population for initial clinical trials is patients with middle cerebral artery stroke involving cerebral cortex. Clinical differentiation of moderate to large middle cerebral stroke from lacunar stroke is possible with the Oxfordshire Community Stroke Project classification but less readily achieved by numerical stroke scales. Several imaging techniques can further distinguish middle cerebral stroke patients with a "penumbra" potentially amenable to intervention from those without a penumbra, in whom outcome appears already determined. The window for intervention may be better defined by imaging than by time alone. Shortened follow-up periods may reduce variation in outcome attributable to differences in provision of rehabilitation or secondary preventative treatments among centers, and imaging may provide useful surrogate end points. CONCLUSIONS: Clinical trials restricted to patients with large middle cerebral stroke accompanied by radiological evidence of a penumbra should be an essential component of drug development. Slower recruitment may be offset by extended time windows and requirements for fewer patients. Imaging may define surrogate evidence of biological effect prior to embarking on a phase 3 program.

Acute Disease↗
PubMed1998

Consensus on microembolus detection by TCD. International Consensus Group on Microembolus Detection.

Transcranial Doppler ultrasound is capable of detecting microembolic material, both gaseous and solid, within the intracranial cerebral arteries. To avoid discrediting this promising and exciting new technique, experts in this field met in January 1997 in Frankfurt, Germany, to discuss the limitations and problems of embolus detection and to determine guidelines for its proper use in clinical practice, as well as in scientific investigations. In particular, the authors suggest that studies report the following parameters: (1) ultrasound device, (2) transducer type and size, (3) insonated artery, (4) insonation depth, (5) algorithms for signal intensity measurement, (6) scale settings, (7) detection threshold, (8) axial extension of sample volume, (9) fast Fourier transform (FFT) size (number of points used), (10) FFT length (time), (11) FFT overlap, (12) transmitted ultrasound frequency, (13) high-pass filter settings, and (14) recording time. There was agreement that no current system of automatic embolus detection has the required sensitivity and specificity for clinical use.

Humans↗
PubMed1997

Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers.

Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.

Adolescent↗
PubMed1997

Perindopril reduces blood pressure but not cerebral blood flow in patients with recent cerebral ischemic stroke.

BACKGROUND AND PURPOSE: The relationship between high blood pressure and the incidence of stroke is well established. Currently the effects of lowering blood pressure in patients with established cerebrovascular disease is undetermined, and there is continuing concern regarding the treatment of patients soon after a stroke event. Angiotensin-converting enzyme inhibitors maintain cerebral blood flow despite lowering blood pressure in patients with heart failure and otherwise uncomplicated hypertension. We tested the hypothesis that perindopril, an angiotensin-converting enzyme inhibitor with a gradual onset of action and a minimal first-dose hypotensive effect, lowers blood pressure without adversely affecting cerebral blood flow in patients 2 to 7 days after symptoms of cerebral infarction. METHODS: Patients were randomized to receive 15 days of oral perindopril (4 mg) or placebo in a double-blind study. Blood pressure was monitored semiautomatically. Cerebral blood flow was calculated from internal carotid artery and vertebral Doppler ultrasound, supplemented by middle cerebral artery blood velocities. RESULTS: Twenty-four patients completed the protocol; four additional patients were withdrawn for reasons unrelated to treatment. Patients on perindopril had a placebo-corrected reduction in blood pressure of 19/11 mm Hg. Blood pressure remained reduced after 2 weeks of treatment. In contrast, total cerebral blood flow was unaffected by perindopril. Neurological symptoms improved similarly in both groups. CONCLUSIONS: Perindopril was well tolerated and effectively reduced blood pressure without reducing carotid territory blood flow in patients with symptoms of recent cerebral ischemia.

Aged↗
PubMed1996

Detection of microemboli by transcranial Doppler ultrasound.

Doppler ultrasound detection of abnormally high-pitched signals within the arterial waveform offers a new method for diagnosis, and potentially for prediction, of embolic complications in at-risk patients. The nature of Doppler "microembolic" signals is of particular interest in patients with prosthetic heart valves, where a high prevalence of these signals is observed. Monitoring the middle cerebral artery with 2-MHz transcranial Doppler ultrasound (TC-2000, Nicolet Biomedical; Warwick, UK), we looked for microemboli signals in 150 patients (95 women and 55 men), and found 1 or more signals during a 30-min recording in 89% of 70 patients with Bjork-Shiley valves (principally monostrut), 54% of 50 patients with Medtronic-Hall valves, and 50% of 30 patients with Carpentier-Edwards valves (p < 0.001, chi 2). In the patients with Bjork-Shiley valves, the mean number of signals per hour was 59 (range, 42-86; 95% confidence interval), which was significantly higher than the mean in patients with Medtronic-Hall and Carpentier-Edwards valves (1.5[range, 0.5-2.5] and 1 [range, 0-5.3], respectively; both p < 0.04, multiple comparisons. Bonferroni correction). In the patients undergoing serial pre- and postoperative studies, the causative role of the valve implant was emphasized. There was no correlation between the number of emboli signals and a prior history of neurologic deficit, cardiac rhythm, previous cardiac surgery, or the intensity of oral anticoagulation, in patients with prosthetic heart valves. In Bjork-Shiley patients, dual (mitral and aortic) valves were associated with more signals than were single valves. In Medtronic-Hall patients, the signal count was greater for valves in the aortic position than it was for valves in the mitral position. Comparative studies of Doppler emboli signals in other clinical settings suggest a difference in composition or size of the underlying maternal between prosthetic valve patients and patients with carotid stenosis. These studies also suggest that the signals are of gaseous origin in valve patients. The clinical significance of continuing microembolism remains to be determined.

Carotid Stenosis↗
PubMed1995

Clinical pharmacology of CNS 1102 in volunteers.

The high affinity noncompetitive N-methyl-D-aspartate receptor antagonist CNS 1102 (aptiganel hydrochloride, Cambridge NeuroScience, Cambridge, MA.) is neuroprotective in preclinical models of stroke when administered as pretreatment or up to 60 minutes postischemia, and has potential for treatment of acute stroke or traumatic brain injury in man. A total of 55 healthy male subjects have participated in three separate studies to determine the clinical pharmacology of CNS 1102, 43 of whom have received CNS 1102 in doses of up to 100 micrograms/kg. Administration of CNS 1102 has been studied as a 15-minute intravenous infusion, as a 15-minute loading intravenous infusion followed by a 4-hour maintenance infusion, or as a fixed-dose intravenous bolus over 90 seconds. CNS 1102 in normal volunteers is well tolerated in total doses up to 32 micrograms/kg whether as a bolus injection, 15-minute infusion or 4-hour infusion. Central nervous system affects are evident within minutes of administration, implying rapid drug penetration. CNS 1102 has a large and variable volume of distribution (mean +/- standard deviation, 6.2 +/- 1.9 l/kg), variable clearance (115 +/- 77 l/h), and plasma half-life of approximately 4.5 hours. Adjustment of doses by subject weight does not improve variability of these parameters, and fixed doses may thus be administered. CNS 1102 causes dose-dependent elevation of blood pressure, accompanied by clinical evidence of vasoconstriction. Global cerebral blood flow is maintained, whilst middle cerebral artery flow velocity increases. Symptoms of light-headedness, disorientation and paresthesia progress through euphoria, disinhibition, and hallucinations to psychomotor retardation, paranoia and catatonia as total administered dose increases.

Adult↗
PubMed1995

Systemic and cerebral hemodynamic responses to the noncompetitive N-methyl-D-aspartate (NMDA) antagonist CNS 1102.

The excitatory amino acid antagonists are being developed as neuroprotective drugs aimed at limiting ischemic neuronal damage. Their hemodynamic and neurologic side effects are important in assessing safety and tolerability. We studied CNS 1102, a high-affinity noncompetitive N-methyl-D-aspartate (NMDA) receptor-channel antagonist, in normal volunteers. The effects of 2 mg CNS 1102 were assessed in a single-blind, placebo-controlled, fixed-dose, cross-over trial comparing administration by intravenous infusion for 15 min or bolus for 2 min in 8 healthy male subjects. Cerebral hemodynamics were studied with carotid and vertebral duplex ultrasound imaging, common carotid artery walltracking, and middle cerebral artery velocity readings. CNS 1102 administration was associated with light-headedness, mild disorientation, perioral and peripheral paresthesias, and flushing. Mean arterial blood pressure (MAP) increased significantly from baseline 1 h after CNS 1102 administration, with a maximal increase of 17 mm Hg over placebo. Pulse rate was unchanged. Common carotid artery pulsatility decreased by 38.4% [8.3-64.5, 95% confidence interval (CI)] and vertebral pulsatility by 43.8% [11.5-74.1], both p < 0.02. No significant differences were detected for other velocity and flow parameters. Middle cerebral artery mean velocity increased by 4.6 cm/s (1.6-7.8 cm/s) and diastolic velocity by 4.6 cm/s (2.4-7.3 cm/s) (both p < 0.01), but systolic velocity was unchanged. The middle cerebral pulsatility index decreased by 11% (3.8-16.1), p < 0.001. CNS 1102 is well tolerated at a fixed dose of 2 mg in normal volunteers. Cerebral arteriolar constriction is inferred from the ultrasound results.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Ultrasonic evaluation of movement of the diaphragm after acute cerebral infarction.

Respiratory dysfunction is an important complication of acute stroke but its mechanisms are poorly understood. Previous indirect assessments suggest that paralysis of the diaphragm occurs contralateral to the cerebral lesion. Diaphragmatic excursion was studied with real time ultrasound during quiet and deep breathing in 50 patients within 72 hours of acute stroke and 40 controls. During quiet breathing, hemidiaphragmatic movements were not significantly different between right hemispheric stroke, left hemispheric stroke, and controls. During deep inspiration, there was a significant bilateral reduction in hemi-diaphragmatic excursion in patients with stroke, for both right hemispheric stroke and left hemispheric stroke when compared with controls (both P < 0.001). Thus isolated hemidiaphragmatic paresis does not occur but maximal excursion of the diaphragm is reduced bilaterally in patients with acute stroke. This is a likely contributor to the respiratory dysfunction after acute stroke.

Acute Disease↗
PubMed1995

A pilot study of streptokinase for acute cerebral infarction.

We evaluated intravenous streptokinase in the treatment of cerebral infarction. Following neurological assessment and cerebral computed tomography (CT), patients aged 40-80 years with symptoms of anterior circulation acute ischaemic stroke were given 1.5 M units streptokinase or saline placebo in a double-blind randomized study. Twenty patients (10 streptokinase, 10 placebo), 11 males, 9 females, aged 57-79 years, were treated out of 512 consecutive admissions to the acute stroke unit over a 2-year period. Initial CT was normal in 11 (6 placebo, 5 streptokinase) and showed early signs of cerebral infarction in nine (4 placebo, 5 streptokinase). Median times from symptom onset to treatment were 5.2 h (placebo) and 5.8 h (streptokinase). Streptokinase treatment was associated with symptomatic hypotension in one patient. Repeat CT at 72 h demonstrated intracerebral haematoma in two patients and haemorrhagic infarction in one patient in the streptokinase group; the two cases of haematoma formation were associated with neurological deterioration and death. One patient in the placebo group had evidence of haemorrhagic infarction at 72 h. There were three deaths in each treatment group, all within the first 14 days. Patients with acute stroke can be evaluated with CT and treated with streptokinase within 6 h, but the opportunity for treatment is currently limited to few patients. Streptokinase treatment is not without risk, but potential clinical benefit justifies ongoing multicentre randomized trials.

Acute Disease↗