Lessons from Metabonomics on the Neurobiology of Stroke.

The application of metabonomic science to interrogate stroke permits the study of metabolite entities, small enough to cross the blood-brain barrier, that provide insight into neuronal dysfunction, and may serve as reservoirs of biomarker discovery. This systematic review examines the applicability of metabolic profiling in ischemic stroke research. Six human studies utilizing metabolic profiling to analyze biofluids from ischemic stroke patients have been included, employing 1H-NMR and/or mass spectrometry to analyze plasma, serum, and/or urine in a targeted or untargeted fashion. Three are diagnostic studies, and one investigates prognostic biomarkers of stroke recurrence following transient ischemic attack. Two studies focus on metabolic distinguishers of depression or cognitive impairment following stroke. Identified biomarkers from blood and urine predominantly relate to homocysteine and folate, branched chain amino acid, and lipid metabolism. Statistical models are well fitted and reproducible, with excellent validation outcomes, demonstrating the feasibility of metabolic profiling to study a complex disorder with multicausal pathology, such as stroke.

Blood glucose control using a computer-guided glucose management system in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for patients with hematological malignancies. However, is associated with substantial rates of morbidity and mortality. We and others have shown that malglycemia is associated with adverse transplant outcome. Therefore, improving glycemic control may improve transplant outcome. In this prospective study we evaluated the feasibility of using Glucommander (a Computer-Guided Glucose Management System; CGGM) in order to achieve improved glucose control in hospitalized HCT patients. Nineteen adult patients contributed 21 separate instances on CGGM. Patients were on CGGM for a median of 43 h. Median initial blood glucose (BG) on CGGM was 244 mg/dL, and patients on 20 study instances reached the study BG target of 100-140 mg/dL after a median of 6 h. After BG reached the target range, the median average BG level per patient was 124 mg/dL. Six patients had a total of 10 events of BG <70 mg/dL (0.9% of BG measurements), and no patients experienced BG level <40 mg/dL. The total estimated duration of BG <70 mg/dL was 3 h (0.2% of the total CGGM time). In conclusion, our study demonstrates that stringent BG control in HCT patients using CGGM is feasible.

Selective pulmonary vasodilation improves ventriculovascular coupling and gas exchange in a patient with unrepaired single-ventricle physiology.

We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology.

Should magnetic resonance imaging or computed tomography be the primary brain imaging modality in the transient ischemic attack clinic?

OBJECTIVE: The Royal College of Physicians and National Institute of Clinical Excellence have recommended that magnetic resonance imaging should be the modality of choice for cerebral imaging in transient ischemic attack patients. However, implementation of this is often difficult. Therefore, it is important to know whether magnetic resonance imaging contributes significantly to early clinical management in transient ischemic attack patients. DESIGN: A retrospective case-notes review of 65 consecutive patients seen by one neurology trainee (with consultant review), in a neurovascular service where computed tomography has been the primary cerebral imaging modality. SETTING: Outpatient TIA/Neurovascular clinic at Imperial College hospital. PARTICIPANTS: 65 consecutive patients seen by one neurology trainee (with consultant review). MAIN OUTCOME MEASURE: We recorded the preliminary clinical diagnosis, details of investigations performed and whether or not patients had a magnetic resonance imaging brain scan subsequently, the number followed up in clinic and the final diagnosis. RESULTS: Of the 65 cases seen, 55% were classified initially as transient ischemic attack/stroke mimics. Of the 29 cases (45%) that were classified as transient ischemic attack, all had computed tomography scans, 12 had magnetic resonance imaging scans subsequently and 14 were followed up several weeks later. Of the 36 cases classified as stroke mimics, 27 had computed tomography scans immediately and 31 had carotid Dopplers, six subsequently had magnetic resonance imaging scans and 14 were followed up in clinic. Only two patients had their diagnosis revised on the basis of the magnetic resonance imaging. CONCLUSIONS: Our study suggests that magnetic resonance imaging brain changes the diagnosis in a relatively small percentage of cases. A good history and examination remain paramount in the assessment of patients presenting to the transient ischemic attack clinic, particularly when more than 50% of cases referred are transient ischemic attack/stroke mimics.

Running out of brain.

Stroke is the third most common cause of death after coronary artery disease and cancer in the UK, and running is a popular form of exercise, and increasingly, people are participating in large scale endurance events such as marathons and half-marathons. We describe here two cases of young men suffering a stroke after running a marathon and who were subsequently found to have a patent foramen ovale (PFO). We have reviewed the existing literature concerning stroke in those undertaking long-distance running, and suggest why PFO may have been important etiologically in our two patients. We tentatively suggest that individuals with a PFO who engage in long distance running may be at increased risk of stroke, independent of other cerebrovascular risk factors.

The role of the right inferior frontal gyrus in the pathogenesis of post-stroke psychosis.

Psychotic symptoms have previously been reported following right hemisphere brain injury. We sought to identify the specific neuroanatomical basis of delusions following stroke by studying a series of patients with post-stroke psychosis. Lesion overlap analysis was conducted on three individuals with delusions following right hemisphere stroke. These cases were compared with a control group of patients with similar anatomical damage. The main outcome measures were presence of delusions and presence of behavioural susceptibility. The right inferior frontal gyrus and underlying white matter, including the superior longitudinal fasciculus and anterior corona radiata, were involved in all three cases. All three had a preexisting untreated psychiatric disorder. In contrast, only one of nine control cases with equivalent lesions had evidence of previous psychiatric disorder (p = 0.0182, Fisher's exact test), and this was being treated at the time of stroke. We provide clinical evidence from patients with structural brain lesions implicating damage to the right inferior frontal lobe in the generation of persistent psychosis following stroke. We suggest that preexisting psychiatric disease provided a behavioural susceptibility to develop delusions in these individuals.

Intra-abdominal pressure measurements in lateral decubitus versus supine position.

OBJECTIVE: Intra-abdominal pressure (IAP) has traditionally been measured in the supine position, however, measuring the pressure in lateral semi-recumbent position has not been studied. DESIGN: A single centre prospective 1-day study. PATIENTS: 10 patients admitted for more then 24 hours who were mechanically ventilated and had an indwelling urinary catheter. METHODS: Inclusion criteria included were age > 18 years, sedated to a RASS score of -5 and mechanically ventilated. The pressures were measured via the bladder with the mid-axillary line as zero reference point. When patients were nursed in lateral decubitus, pressures were measured and compared immediately to the supine position. RESULTS: 10 patients were included with a total of 60 measurements.The male/female ratio was 9:1 with a mean APACHE Pi score of 11.5 [95% CI 4.8-22.4], SAPS 2 of 31.5 [95% CI 8.9-35.8] and SOFA score of 4.0 [95% CI 1.8-7.2]. Four patients were medical and 6 were surgical. The mean IAP at different time intervals (morning, afternoon and evening) in lateral and supine position were 10.9 +/- 2.0 (in mmHg) vs 6.6 +/- 3.2 (SD with p < 0.001); 11.0 +/- 4.0 vs 5.4 +/- 2.2 (p < 0.0005) and 11.6 +/- 3.8 vs 7.8 +/- 3.0 (p< 0.001). Overall, the LSP did not change significantly (p= 0.76), but the SP did (p=0.006) with the afternoon reading being significantly lower than the evening measurement. However, the trend in the difference (LSP minus SP) was not significant (p=0.43). CONCLUSION: There was a significant statistical difference in the pressures measured in LSP versus SP.The LSP position should not be used to measure IAP.

Symptomatic late recanalization of an occluded internal carotid artery: a case report and review of the literature.

The natural history of patients with carotid artery occlusion is poorly understood, and patients are usually offered conservative treatment as the difficulty and risks of surgical intervention are thought to outweigh the natural history of the condition. The case of a 71-year-old male patient with symptomatic internal carotid artery stenosis in a previously occluded vessel is presented. This case suggests that symptomatic recanalization of an occluded carotid artery may occur and long-term duplex surveillance may be a justifiable strategy in this patient group.

Sedation and delirium in the intensive care unit: an Australian and New Zealand perspective.

A survey was conducted to determine sedation and delirium practices in Australian and New Zealand intensive care units. The survey was in two parts, comprising an online survey of reported sedation and delirium management (unit survey) and a collection of de-identified data about each patient in a unit at a given time on a specified day (patient snapshot survey). All intensive care units throughout Australia and New Zealand were invited by email to participate in the survey. Twenty-three predominantly metropolitan, level III Australian and New Zealand intensive care units treating adult patients participated. Written sedation policies were in place in 48% of units, while an additional 44% of units reported having informal sedation policies. Seventy percent of units routinely used a sedation scale. In contrast, only 9% of units routinely used a delirium scale. Continuous intravenous infusion is the primary means of patient sedation (74% of units). While 30% of units reported routinely interrupting sedation, only 10% of sedated patients in the snapshot survey had had their sedation interrupted in the preceding 12 hours. Oversedation appears to be common (46% of patients with completed sedation scales). Use of neuromuscular blockade is low (10%) compared to other published studies. Midazolam and propofol were the most frequently used sedatives. The proportion of patients developing delirium was 21% of assessable patients. Failed and self-extubation rates were low: 3.2% and 0.5% respectively. In Australian and New Zealand intensive care units, routine use of sedation scales is common but not universal, while routine delirium assessment is rare. The use of a sedation protocol is valuable and should be encouraged.

Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia.

BACKGROUND: Brain abscesses and ischaemic strokes complicate pulmonary arteriovenous malformations (PAVMs). At risk individuals are poorly recognised. Stroke/abscess risk factors have not been defined. METHODS: A cohort study of 323 consecutive individuals with PAVMs (n = 219) and/or the commonly associated condition hereditary haemorrhagic telangiectasia (HHT, n = 305) was performed. Most of the 201 individuals with PAVMs and HHT had no respiratory symptoms, and were unaware they had HHT. Anderson-Gill models assessed constant and time dependent potential predictive variables for stroke/abscess, and rate reduction by PAVM embolisation. RESULTS: 57 individuals with PAVMs and HHT experienced brain abscess or ischaemic stroke, usually prior to the diagnosis of underlying PAVMs/HHT. The primary determinants of stroke and abscess risks were unrelated to severity of PAVMs. Males had higher brain abscess rates (hazard ratio 3.61 (95% CI 1.58, 8.25), p = 0.0024); interventional histories and bacteriological isolates suggested dental sources. Once adjusted for gender, there was a marginal association between brain abscess and low oxygen saturation. For ischaemic stroke, there was no association with any marker of PAVM severity, or with conventional neurovascular risk factors. Surprisingly, low mean pulmonary artery pressure was strongly associated with ischaemic stroke (hazard ratio 0.89 (95% CI 0.83, 0.95) per mm Hg increase; p = 6.2x10(-5)). PAVM embolisation significantly reduced ischaemic stroke rate (p = 0.028); no strokes/abscesses occurred following obliteration of all angiographically visible PAVMs. The mean PAVM diagnosis-treatment interval was longer, however, when neurological risks were unrecognised. CONCLUSIONS: Ischaemic strokes and brain abscesses occur commonly in undiagnosed HHT patients with PAVMs. Risk reduction could be improved.

Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability.

Clonidine is used for analgesia and sedation in paediatric anaesthesia, but there are no data on its sedative properties and side effects in critically ill children. We studied 30 ventilated children aged 10 yr and under to determine an effective i.v. dosing range and to assess its cardiovascular effects. Twenty non-paralysed, ventilated children were given a background infusion of midazolam 50 micrograms kg-1 h-1 combined with a variable clonidine infusion (0.1-2 micrograms kg-1 h-1) to maintain optimal sedation. The effects of clonidine 1 microgram kg-1 h-1 on cardiac index were measured in 10 postoperative cardiac patients using a reverse Fick method. Dose-dependent sedation was achievable (713 out of 861 h) without cardiovascular side effects, but an infusion limit of clonidine 1 microgram kg-1 h-1 was inadequate in two patients. An increased dose limit of 2 micrograms kg-1 h-1 combined with midazolam 50 micrograms kg-1 h-1 achieved satisfactory sedation scores for 602 out of a total of 672 h studied with no failures. Clonidine in combination with midazolam at 1 microgram kg-1 h-1 was not associated with significant changes in heart rate arterial pressure or cardiac index.

Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: a comparison of different fentanyl doses.

High-dose opioids are advocated for paediatric cardiac surgery to suppress stress responses but they can produce unwanted side effects. There are no data on the dose-dependent effects of opioids on the stress response on which to base rational opioid administration. We conducted a dose ranging study on 40 children less than 4 yr undergoing elective open heart surgery using one of five fentanyl doses: 2, 25, 50, 100 or 150 micrograms kg-1 before surgery. The standardized anaesthetic also included pancuronium and isoflurane. Blood samples were taken at induction, before incision, after sternotomy, immediately before, and at the end of cardiopulmonary bypass. Patients in the 2 micrograms kg-1 group had significant rises in prebypass glucose (P < 0.01), pre- and post-bypass cortisol (P < 0.01), and pre- and post-bypass norepinephrine (P < 0.01). No significant rise occurred in glucose, cortisol and catecholamines in any of the higher dosage groups. Patients in the 2 micrograms kg-1 group had significantly higher mean systolic blood pressure (P < 0.02) and heart rate (P < 0.04). A balanced anaesthetic containing fentanyl 25-50 micrograms kg-1 is sufficient to obtund haemodynamic and stress responses to the pre-bypass phase of surgery. Higher doses of fentanyl (100 and 150 micrograms kg-1) offer little advantage over 50 micrograms kg-1, and can necessitate intervention to prevent hypotension.