Biomedical subjects
Publications and source records attributed to A D Mendelow.
The International Surgical Trial in Intracerebral haemorrhage has been set up to determine the role of surgery in spontaneous supratentorial intracerebral haemorrhage. This is an interim report as the results will remain blinded until all patients have been recruited and followed up.
Cerebral ischaemia and reperfusion injury may be exacerbated by leukocyte recruitment and activation. Adhesion molecules play a pivotal role in leukocyte recruitment. We report a prospective study of the potential role of the selectin family of adhesion molecules (E-, P- and L-selectin) in delayed cerebral ischaemia (DID) following aneurysmal subarachnoid haemorrhage. In patients with good grade SAH, we have compared serum concentrations of E-, P- and L-selectin, between patients who do, and do not develop delayed cerebral ischaemia. There was no difference in E-selectin concentration between the two groups (44.0 ng/ml vs. 37.4 ng/ml). Serum P-selectin concentration was significantly higher in patients with DID compared to those patients without DID (149.5 ng/ml vs. 112.9 ng/ml, p = 0.039). Serum L-selectin concentrations were significantly lower in patients with DID (633.8 ng/ml vs 897.9 ng/ml, p = 0.013). We conclude that P- and L-selectin are involved in the pathogenesis of DID following aneurysmal subarachnoid haemorrhage. The results of this study do not elucidate the exact role of each selectin in DID.
Oxidative damage to normal human brain tissue was induced following exposure to hydroxyl (OH.) or superoxide (O2-.) free radical species generated by CO60 irradiation in vitro. Both enzymic and cytoskeletal proteins showed substantial (dose dependent) oxidative damage following exposure to OH. or O2-., as quantified by SDS-polyacrylamide gel electrophoretic analysis. Extracts of Ginkgo biloba or Panax ginseng showed a remarkable capacity to protect brain tissue proteins from oxidative damage in vitro, even at extreme (2000 kRads) dosage levels of OH. or O2-.. We suggest, therefore, that the beneficial effect of these plant extracts in preventing brain tissue damage in vivo (e.g. following ischemia-reperfusion) may result from their action in protecting brain proteins from oxidative damage, in addition to their previously reported capacity to reduce free radical induced lipid peroxidation.
Although various neuroprotective and fibrinolytic drugs are currently under evaluation in the acute stages of ischaemic stroke, their therapeutic potential is likely to be limited by unwanted side effects and a narrow time window of opportunity for intervention. Proteolytic enzymes are involved in the catabolism of peptide neurotransmitters and structural cellular proteins in normal brain and have been implicated in the pathogenesis of neurodegenerative disorders. We hypothesised that activation of these enzymes might also play a crucial role in effecting ischaemic neuronal injury, thereby providing a potential site for therapeutic intervention in human stroke. Focal cerebral ischaemia was induced by thermocoagulation of the left middle cerebral artery in aged (30 month) male Wistar rats who were pre-treated with saline or the competitive N-methyl-D-Aspartate antagonist D-CPP-ene, which has been shown to be neuroprotective in young animal models of stroke. Major protease activities were analysed in the left (ischaemic) and right (non-ischaemic) hemispheres, following tissue homogenisation. Data have been analysed using Mann-Whitney tests and are presented as means +/- standard errors. Enzyme activity decreased in ischaemic brain; for example, the mean activity of dipeptidyl aminopeptidase I was 23 +/- 3 and 43 +/- 6 nmol substrate/hour/ml brain extract in the left and right hemispheres respectively (n = 10, p < 0.05). Ischaemic neuronal injury is not effected by the early activation of proteolytic enzymes and protease inhibitors are therefore unlikely to be of benefit in human stroke.
Sixty-two patients with a spontaneous supratentorial haemorrhage had continuous Intracranial Pressure (ICP) and Cerebral Perfusion Pressure (CPP) monitoring. In addition to the recordings of physiological data their past medical history, presenting neurological state, Computed Tomograph (CT) findings, daily Glasgow Coma Score (GCS) and outcome were noted. The mean age was 57.6 years (sd 13.3). Onset of recording, after ictus was at a mean of 32.6 hours (sd 26.0). Average length of recording was 62.0 hours (sd 39.8). Thirty-one patients had evacuation of haematoma, 6 insertion of External Ventricular Drain (EVD). Preoperative measures of ICP were significantly related to delayed neurological deterioration, death within three days and Glasgow Outcome Scale (GOS) at neurosurgical discharge. No such relationships existed with preoperative measures of CPP and neither ICP nor CPP was related to outcome at 6 months. Post-operative measures of both ICP and CPP demonstrated a significant relationship with death within three days of ictus and GOS at neurosurgical discharge. Again no relationship existed with these parameters and outcome at six months. Surgical evacuation of haematoma acted to significantly reduce ICP and improve CPP. Given that these factors seem to be related to deterioration, death and early outcome, it would seem that surgery could play a role in reducing mortality and improving outcome following Intra cerebral Haemorrhage (ICH).
We have investigated the comparative antioxidant capacity of a range of anaesthetics (inhaled and intravenous) and perioperative neurosurgical drugs (at clinically relevant concentrations) using different radical species and assay methods in vitro. The highest levels of antioxidant activity against the ABTS(.+) radical were obtained with propofol (100 mmol/LTE) and dopamine (1080 mmol/LTE), respectively. However, only dopamine (12 mmol/l) showed antioxidant activity in protecting proteins in normal brain tissue from oxidative damage (assessed via SDS-PAGE analysis) induced by OH(.) or O(2)(-.) generated radiolytically in vitro. Neither dopamine nor propofol showed antioxidant activity against O(2)(-.) generated chemically via reaction between xanthine and xanthine oxidase in vitro. From these data, together with data on the relative antioxidant properties of anaesthetics/drugs obtained by other research groups which we have reviewed, we conclude that the apparent antioxidant activity of a given compound may depend entirely on the free radical species and/or the method of generation or assay employed. Finally, we suggest that on the basis of data obtained showing protection of brain proteins from oxidative damage induced by OH(.), or O(2)(-.) in vitro, further investigation into the in vivo antioxidant therapeutic potential of dopamine (or its analogues) on neurosurgical patients may be warranted.
It is well established that nicotinic receptors in the mammalian striatum are involved in modulation of the release of several neurotransmitters, including dopamine. In addition, nicotinic receptors with high affinity for agonists have generally been found to be reduced in the striatum in Parkinson's disease. In the present study antibodies have been used to examine which subunits contribute to the striatal nicotinic receptor loss in Parkinson's disease, and whether the reduction in [(3)H]nicotine binding correlates with synaptic loss. Autopsy tissue from the putamen of 12 Parkinson's disease cases and 12 age-matched control subjects was analysed by immunoblotting using antibodies against recombinant peptides specific for alpha3, alpha4, alpha7, beta2 and beta4 nicotinic acetylcholine receptor (nAChR) subunits and the synaptic marker synaptophysin, in conjunction with assessment of [(3)H]nicotine binding by autoradiography. The data indicate that there is no loss of alpha3, alpha4, alpha7 and beta2 immunoreactivity in the putamen in Parkinson's disease, despite a highly significant reduction in [(3)H]nicotine binding. An intense signal of beta4 immunoreactivity was found in human dorsal root ganglia, but not in temporal cortex or putamen samples. Synaptophysin immunoreactivities were also similar in Parkinson's disease and control cases. These results suggest that the loss of nicotine binding in the putamen in Parkinson's disease may involve an nAChR subunit (e.g., alpha5 and/or alpha6) other than those investigated. Alternatively, the results could reflect impaired subunit assembly at the plasma membrane.
The cause and incidence of reductions in cerebral perfusion pressure, and rises in intracranial pressure have been examined in a series of patients with severe head injury defined as an initial Glasgow Coma Sum of less than or equal to 8. Two-hundred-and-seven adults (aged over 16 years) and 84 children admitted to Newcastle General Hospital, who had intracranial pressure monitoring as part of their routine management, were studied. Intracranial pressure (ICP), arterial pressure and cerebral perfusion pressure (CPP) were sampled and recorded every 2 min. Patients' CT findings were classified into distinct groups using the method described by Marshall. Secondary insults were defined using the Edinburgh University Secondary Insult Grades (EUSIG) and the incidence and cause (raised ICP, reduced CPP or a combination of the two) was established. Outcome was assessed at 6 months using the Glasgow Outcome Scale. In the majority of adults with head injury it is the combination of reduced arterial pressure and raised ICP that contributes to the reduction in cerebral perfusion pressure. This was not the case for Diffuse Injury Type I. In children similar characteristics were found across each of the CT classifications. The vast majority of falls in CPP down to 60 mmHg were caused by reduced arterial pressure. Reductions below 50 mmHg were almost always due to a combination of both reduced arterial pressure and raised ICP. The results in adults were similar, but not identical, to those of the paediatric cases. Diffuse Injury Type I stood out from all the other categories as the only one where reductions in perfusion pressure were almost exclusively due to reductions in arterial pressure and not to increases in ICP. The management of these patients should ensure the adequacy of perfusion pressure by maintaining arterial pressure at a satisfactory level. These results suggest that vigilant monitoring of both intracranial pressure and arterial pressure is required to lower the incidence of secondary insults.
The aim of this study was to determine the in vivo accuracy and reliability of intracranial pressure (ICP) measurement using the Codman MicroSensor by comparison with the Camino ICP transducer and associated clinical and radiological information. Paired ICP readings were recorded every minute in 17 patients. A total of 56,790 validated paired measurements were obtained over a wide range of ICP values (- 16 mm Hg to 114 mm Hg). Recording periods ranged from 3 hours to 6 days (median 41 hours). In 11 patients the MicroSensor and Camino readings were in good agreement. Paired readings were within 10 mmHg for 99% of the recording time and both readings were compatible with clinical intracranial events at all times (in one case it was not possible to verify the clinical information). In six patients large differences occurred between transducer readings (> 10 mm Hg apart for 41% of the recording period). In one case, either reading could have been compatible with intracranial clinical events. In two cases, although both readings were comparable, Camino readings were more consistent with clinical and radiological findings. In three cases, the MicroSensor readings were inconsistent with the clinical condition of the patients whereas the Camino readings were compatible. These results suggest that, during routine clinical use in our department, the MicroSensor provided misleading information in 18% of our patients and thus is not sufficiently reliable for routine use in the detection of adverse clinical events.
OBJECTIVES: (1) To establish the feasibility of myotatic reflex measurement in patients with head injury. (2) To test the hypothesis that cerebral dysfunction after head injury causes myotatic reflex abnormalities through disordered descending control. These objectives arise from a proposal to use reflex measurements in monitoring patients with head injury. METHODS: The phasic stretch reflex of biceps brachii was elicited by a servo-positioned tendon hammer. Antagonist inhibition was evoked by vibration to the triceps. Using surface EMG, the amplitude of the unconditioned biceps reflex and percentage antagonist inhibition were measured. After standardisation in 16 normal adult subjects, the technique was applied to 36 patients with head injury across the range of severity. Objective (1) was addressed by attempting a measurement on each patient without therapeutic paralysis; three patients were also measured under partial paralysis. Objective (2) was addressed by preceding each of the 36 unparalysed measurements with an assessment of cerebral function using the Glasgow coma scale (GCS); rank correlation was employed to test a null hypothesis that GCS and reflex indices are unrelated. RESULTS: In normal subjects, unconditioned reflex amplitude exhibited a positive skew requiring logarithmic transformation. Antagonist inhibition had a prolonged time course suggesting presynaptic mechanisms; subsequent measurements were standardised at 80 ms conditioning test interval (index termed "TI(80)"). Measurements were obtained on all patients, even under therapeutic paralysis (objective (1)). The unconditioned reflex was absent in most patients with GCS less than 5; otherwise it varied little across the patient group. TI(80) fell progressively with lower GCS, although patients' individual GCS could not be inferred from single measurements. Both reflex indices correlated with GCS (p<0.01), thereby dismissing the null hypothesis (objective (2)). CONCLUSION: Cerebral dysfunction in head injury is reflected in myotatic reflex abnormalities which can be measured at the bedside. With greater reproducibility, reflex measurements may assist monitoring of patients with head injury.
BACKGROUND AND PURPOSE: Primary intracerebral hemorrhage (ICH) accounts for 10% to 20% of stroke but carries the highest rates of mortality and morbidity of all stroke subtypes. Current treatment, however, is varied and haphazard. The most recent Cochrane systematic review refers to 4 prospective, randomized controlled trials. We present a further meta-analysis to include 3 new trials. In addition, we review the trials of Chen et al and McKissock et al and discuss aspects of their quality that, we believe, prevent their inclusion in modern day meta-analysis. METHODS: Literature databases and articles were searched from 1966 to October 1999. Using the end points of death and dependency, the results of the 7 identified randomized trials were expressed as odds ratios. All available data were then analyzed with meta-analysis techniques. Analysis of relevant subsets of trials was also carried out. RESULTS: Meta-analysis of all 7 trials shows a trend toward a higher chance of death and dependency after surgery (OR 1.20; 95% CI 0.83 to 1.74). Meta-analysis was also carried out after exclusion of the Chen and McKissock trials for reasons discussed in the text. This meta-analysis suggests a benefit from surgery, with a reduction in the chances of death and dependency after surgical treatment by a factor of 0.63 (OR 0.63; 95% CI 0.35 to 1.14). CONCLUSIONS: When meta-analysis is restricted to modern-day, post-CT, well-constructed, balanced trials, a trend for surgery to reduce the chances of death and dependency is found. Perhaps, then, in the modern era of CT, good neuroanesthesia, intensive care, and the operating microscope, surgery has a role in the treatment of supratentorial intracerebral hemorrhage. The results of a large, multicenter, randomized controlled trial are urgently needed, and the ongoing International Surgical Trial of Intracerebral Hemorrhage should fulfill this objective.
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There is at present no clear indication for surgical removal of intracerebral haemorrhage (ICH) in the majority of patients. With deterioration from an initially good level of consciousness, many surgeons would agree that removal is life saving. The question is whether or not surgical removal of clot improves the ultimate outcome in patients who are stable or even improving. Improvement in function is based on the concept of a penumbra around an ICH. There is now mounting evidence that there is a penumbra of functionally impaired, but potentially reversible, neuronal injury surrounding a haematoma. A pro-active approach must, therefore, be maintained in the management of these patients to salvage as much of this brain as possible. Alert patients with small (< 2 cm) haematomas and moribund patients with extensive haemorrhage may not require surgical evacuation. Indications for clot removal in patients between these extremes are controversial. Current practice favours surgical intervention in the following situations: (i) superficial haemorrhage; (ii) clot volume between 20-80 ml; (iii) worsening neurological status; (iv) relatively young patients; (v) haemorrhage causing midline shift/raised ICP; and (vi) cerebellar haematomas > 3 cm or causing hydrocephalus. A large multicentre prospective randomised controlled trial (International Surgical Trial in Intracerebral Haemorrhage) is currently underway to determine if early clot evacuation will lead to a better neurological outcome in patients with spontaneous supratentorial, non-aneurysmal ICH.
The optimal management, surgical or otherwise, of a patient following a spontaneous intracerebral haemorrhage (ICH) remains controversial. A survey of British neurosurgeons was carried out to assess current attitudes and practice. Patient management was most consistently influenced by the depth (71% agreement), dominance (74.3% agreement) and site (44.7%) of the haematoma. Almost half of neurosurgeons said they would evacuate an ICH in a deteriorating patient, but management choice was very varied in stable patients. However, 80% of the same respondents felt evacuation was helpful in reducing mortality, and 71.3% morbidity. Fifteen per cent of respondents were not influenced by the size of an ICH, but 31% would readily operate on haematomas with volumes of between 50 and 80 ml. Over 30% felt that there was no optimal time for surgical evacuation, but 66.9% felt delayed evacuation was helpful. Premorbid dependency was a stronger influence than age on management choice. Despite these variations, over half felt that they were consistent in their treatment of ICH. However, 81% expressed surgical uncertainty. Furthermore, respondents demonstrated a significant tendency to intervene surgically more readily in ICH related to aneurysm or AVM. Results from a prospective randomized controlled trial to assess the role of surgery are urgently needed.
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The aim of head injury management is to prevent secondary insults to the damaged brain. Raised intracranial pressure and low cerebral perfusion pressure are two secondary insults which are important determinants of outcome following severe head injury (SHI). Traditionally ICP is measured in the right frontal region in an attempt to minimise the effects and complications of transducer placement. This assumes that the brain acts like a fluid and that ICP is transmitted equally throughout the intracranial space. Experimental studies suggest that this is not the case: expanding mass lesions are associated with the development of ICP gradients. Ten patients with SHI who had an unilateral mass lesion confirmed on CT were studied. All had bilateral placement of intraparenchymal Camino ICP transducers in the frontal regions. Data from both transducers were recorded every two minutes and stored electronically. The volume of the mass lesion was calculated from the CT scan. Significant and lasting ICP gradients between hemispheres were found in all patients with an acute subdural haematoma (greater than 10 mmHg for longer than 10 minutes). Such differences were not found in patients with intracerebral haematoma or contusions. We would advocate that ICP is recorded IPSILATERAL to the lesion in patients with SHI due to acute subdural haematoma.
INTRODUCTION: The use of the Camino fibre-optic subdural device for measuring Intracranial Pressure (ICP) in patients, has been shown to correlate well with recordings from the "gold standard" intraventricular fluid filled catheter [1]. Following this work, its use has become standard in the clinical monitoring of patients. More recently, laboratory studies have demonstrated accuracy, acceptable drift and high fidelity for the new Codman Microsensor ICP Transducer, a miniature strain gauge mounted on a flexible nylon catheter [3]. Its performance in patients, however, has yet to be fully assessed, in comparative studies. METHODS: Eight patients (5 head injured, 3 with an Intracerebral haematoma) had a Codman Microsensor inserted. A Camino Transducer was fitted immediately adjacent to it. A computerised system was used to continuously record both ICP readings. RESULTS: In total 140,323 recordings were made over a wide range of ICP values. Study periods ranged from 0.5 to 116 hours. In one patient the Codman transducer tracing failed after several days, probably due to fracture of electrical cable close to the interface box. The readings from the two ICP transducers were compared on Time Series, logistic regression and Altman-Bland plots. Drift of the ICP recorded by the Codman microsensor, was noted in 2 patients, 1 in positive direction (maximum 30 mmHg), 1 negative (max. 20 mmHg). In both cases the Camino ICP recording was relatively stable. In 24% of the recordings the Codman microsensor recorded ICP as 5 or more mmHg greater than the Camino, this difference was 10 mmHg or greater in 9% of recordings. Conversely the Camino recording was 5 mmHg or more, than the Codman, in 5% of all recordings, and 10 mmHg or more in 3%. CONCLUSION: These differences could in the majority of cases (excepting the negative drift) be explained by a constant offset of the Codman transducer, as described previously [6]. Further examination of this device is required.