Rat middle cerebral artery vasoreactivity in controls, sham operative controls, and following acute subarachnoid haemorrhage by arterial rupture without craniotomy

The principle hypothesis of the current study is that events associated with the acute ictus of acute subaraclmoid haemorrhage (SAH) elicit changes in cerebrovascular physio-pharmacology that are independent of any subsequent effects of chronic clot lysis. As a result, such changes might interact with the effects of chronic clot lysis in a way that may, in consequence, ultimately explain why currently favoured 'clot-VSM' fail to adequately explain delayed VSM and DCI. The principle aim of the current thesis was to formally categorize cerebrovascular physio-pharmacological properties in sham and non-operative controls, and to compare these with those obtained in the acute period after SAH in a model more representative of the true clinical scenario. Clearly, the most ideal SAH model would be one in which arterial rupture is created inside a closed skull, since only here will the acute intracranial pressure changes be faithfully recreated. Ironically, the earliest SAH models came close to such an ideal: nevertheless, all utilized a prior craniotomy. More recently, endovascular filament (EF) models have instead gained credence. Because, in such models, intracranial arterial rupture is created in small animals by EF advancement through the intracranial internal carotid artery from an extracranial source in the neck, the potential disadvantages associated with a prior craniotomy are avoided. However, to date no EF-SAH model has yet been used to study cerebrovascular reactivity: this thesis is the first to do so. Hypothetically, however, two sources of 'side bias' potentially thwart the application of EF-SAH cerebrovascular study. One source relates to the manipulation and temporary ischaemia suffered during EF insertion (in particular, with prolonged carotid clamping). Another relates to relative uncertainty regarding the precise site of intracranial rupture. A secondary aim of the thesis, then, was to formally assess the hypothesis that EF-SAH introduce procedural 'side bias' by comparing cerebrovascular responses ipsilateral and contralateral to EF insertion using a range of constrictory and dilatory agonists-conceivably all relevant to SAH. The successful exclusion of 'side bias' would be important to any future study of delayed (i.e. chronic) VSM because, should any side differences be subsequently found in such delayed studies, then these could be attributable to focal factors-such as thickened clot lateralization-with somewhat greater confidence. Another potential flaw with current 'clot-VSM' models, however, resides not in their design but in their application. Thus, many do not use as substrate for cerebrovascular study vessels from the anterior cerebral circulation-where both VSM and DCI are most frequently apparent. Instead, most choose vessels from the posterior circulation: in particular, the basilar artery. Furthermore, many do not appear to restrict study to particular segments of specific arteries, and thus potentially thwart 'like-wit-like' comparisons. Most studies also do not quote vessel diameters in relation to subgroups and their responses: in this regard, most assume that randomisation for vessel side would make up for any 'size effects' on vessel responses. And finally, most ignore a principle implied by Brandt, that variation in vasoreactivity in individual arteries might be discontinuous-and not continuous-and so therefore not amenable to routine statistical analysis. It was therefore considered critical in this thesis to assess and limit such potentially confounding factors by fully reviewing what is already known about cerebral vessels before and after SAH, by critically reviewing all experimental models used to derive such data, and by assiduously analyzing normal vessel responses in a standard small vessel study model before progressing to their ultimate study post-SAH. To this end, middle cerebral arteries (MCA) medial to the olfactory tract were analyzed by 'wire myography'. Whilst the ultimate aim of all DCI research must clearly be in the effects of delayed VSM on a post-ictal brain, it is a scientific duty to delineate cerebrovascular reactivity at all stages prior to this. Unfortunately, it is not possible to apply the methodology of this current thesis to assess all of the 192 hours that pass between the acute ictus and the typically delayed start of VSM: instead, restriction of study to a shorter time interval would only be possible in one thesis. As a result, the current thesis was restricted to an analysis of the first three hours of EF-SAH for the following reasons: 1. To assess the principle hypothesis that events associated with acute SAH elicit changes in MCA physio-pharmacology that are independent of any subsequent effects of chronic clot lysis 2. To assess the secondary hypothesis that EF-SAH models introduce a procedural 'side bias' by comparing constrictory and dilatory MCA responses ipsilateral and contralateral to EF insertion. (Abstract shortened by ProQuest.)

Cushing's variant response (acute hypertension) following subarachnoid haemorrhage: association with moderate intracranial tensions and subacute cardiovascular collapse in rats

Background and Purpose: Hypertension is considered common and appropriate with subarachnoid hemorrhage (SAH), maintaining cerebral perfusion. Hypotension, in contrast, is considered rare and detrimental. This study was designed to assess the frequency of each in both acute and subacute phases of primary SAH.\ud \ud Methods: SAH was created by arterial rupture in spontaneously breathing rats under urethane anesthesia without craniotomy (n=32). Arterial pressure and intracranial pressure (ICP) were monitored invasively.\ud \ud Results: After extensive extravasation, the mean ICP rose acutely from 8±1 to 53±4 mm Hg over 2.4±0.3 minutes. Acute pressor changes occurred transiently in 71%. The most common acute response was hypotension (63%). Hypertension, in contrast, was rare (6%); the remainder was invariant (29%). Hypertension was associated with significantly lower maximum ICP values (39±4 versus 69±4 mm Hg, P<.001) with a negative correlation between hypotension and ΔICP (r=−.7, P<.01). Distinct and independent of acute responses, hypotension also occurred subacutely as a cardiovascular collapse (38%).\ud \ud Conclusions: In contrast to popular belief, the most common acute response with SAH is hypotension; hypertension is rare. This, in fact, is in full agreement with Cushing: hypertension was seen only with gradual ΔICPs. In contrast, a "variant" to the classic response (hypotension) occurred with sudden ΔICPs. In the present study, hypotension stanched SAH at lower maximum ICP values, and thus with less cerebral compression. Despite this, cardiovascular collapse developed in a large proportion irrespective of acute change. Such collapse without prior hypertension (94%) implies a nonadrenergic etiology

Sex life and the Oswestry Disability Index

Background context\ud \ud Despite the option to not answer, there is widespread anecdotal belief that the Oswestry Disability Index (ODI) Section 8 (ODI-8/sex life) is answered inaccurately (ie, in relation to psychosocial factors, not pain) or that it repels ODI participation. Oswestry Disability Index versions have therefore been created that omit ODI-8; however, no evidence base justifies this. Interestingly, one recent study reported an ODI-8 response rate (RR) of 97%.\ud \ud Purpose\ud \ud The aims of this study were to measure RR to sex life questions in patients with chronic low back pain (CLBP) and to validate that ODI-8 is answered appropriately and represents a specific measure of CLBP-mediated sexual inactivity.\ud \ud Study design\ud \ud Original.\ud \ud Patient sample\ud \ud Eighty-eight patients.\ud \ud Outcome measures\ud \ud The outcome measures used in this study were the ODI, the Sexual Quality of Life Scale–version 2 (SQOL-2), the Short Form-12 version 2 (mental and physical), the Depression Anxiety and Stress Scale, the Coping Strategies Questionnaire, the Short-Form McGill Pain Questionnaire–version 2, the Opioid Risk Tool, and the Fear-Avoidance Beliefs Questionnaire (work and physical).\ud \ud Method\ud \ud Chronic low back pain patients older than 18 years attending a multicultural Western spinal clinic were prospectively offered the aforementioned questionnaires. Sex life disability questions—pain dependent (ODI-8) and pain independent (SQOL-2)—appeared first and fifth in every sequence.\ud \ud Results\ud \ud Results were obtained in 65 patients (male 29, female 36). Despite expected response attrition with battery progression (RRs for the first and eighth questionnaires were 100% and 64.61%, respectively), RRs for ODI-8 (52.31%) and SQOL-2 (52.31%) were equal and significantly lower than others (p<.001). Nonresponders to ODI-8 (60.57±13.3 years) and SQOL-2 (59.68±13.34 years) were significantly older than responders (ODI-8: 47.82±12.17 years, p<.001; SQOL-2: 48.27±12.76 years, p=.001). Among ODI-8 or SQOL-2 responders, ODI-8 and SQOL-2 were not correlated (r=−0.340, p=.104). Although ODI-8 significantly correlated with prospectively identified pain-correlated questionnaires, ODI-8 did not correlate significantly with non–pain-correlated questionnaires.\ud \ud Conclusion\ud \ud Contrary to previous findings, 47.69% of CLBP patients specifically ignored ODI-8; however, 100% completed the ODI remainder. Among "responders," ODI-8 was validated as having measured CLBP-mediated sexual inactivity. The ODI-8 was therefore treated consistently, as directed: It was either answered appropriately (ie, in relation to pain) or it was ignored (respecting the clause "if applicable"). No ODI modification therefore appears required for adults older than 18 years attending a multicultural Western CLBP clinic: One standard form including ODI-8 appears to yield appropriate ODI-8 response-treatment, with unaffected ODI participation. Multiple ODIs circumventing ODI-8 appear unnecessary and redundant in this population

Gabapentin superadded to a pre-existent regime containing amytriptyline for chronic sciatica

Setting. There is currently a gross lack of evidence base guiding the medical management of chronic sciatica (CS). Only scant previous studies have assessed gabapentin (GBP) in CS. Extrapolating NICE-UK guidelines, prescribing authorities often insist on trialling anti-depressants (e.g., amytriptyline, AMP) as a first line for neuropathic pain states such as CS. When super-adding second-line agents, such as GBP, NICE-UK encourages overlap with first-line agents to avoid decreased pain-control. No study has reflected this practice. Objective. Evaluate efficacy and side effects (SE) of GBP superadded to a pre-existent regime containing AMP for CS. Subjects and Methods. Prospective cohort of patients with unilateral CS attending a specialist spine clinic. Eligible patients had experienced partial benefit to a pre-existent regime containing AMP: none had significant SE. No drugs other than GBP were added or discontinued (the latter was considered inequitable) for 3 months. Visual analog pain score (VAS), Oswestry disability index (ODI), and SE were recorded. Results. Efficacy: in 56% (43/77) there were reductions in VAS (5.3 +/- 3.6 -> 2.8 +/- 2.7, P 30.7 +/- 25.2, P=0.008). SE: Eightytwo SE (23 types) were reported in 53% (41/77). Efficacy was less in those with SE: a trend existed for a lesser reduction in VAS (2.0 +/- 2.4 v 3.0 +/- 2.7, P=0.08), which proved significant for ODI (8.1 +/- 11.4 v 16.7 +/- 18.2, P=0.01). Thirty-four percent (26/77) discontinued GBP all within 1 week (i.e., during titration). Conclusion. This is the first prospective cohort study of GBP super-added to a pre-existent regime containing AMP for CS, as per routine clinical practice and NICE-UK principles. Super-added GBP demonstrated further efficacy over the previous regime in 56%; however, SE were frequent (53%) and diverse (23 types), and 34% abruptly discarded GBP. Although SE were associated with decreased efficacy, 37% nevertheless tolerated GBP despite SE

Long-term survival after chronic subdural haematoma

Outcome after chronic subdural haematoma (CSDH) is invariably assumed favourable: however, little data regarding long term survival (LTS) exists. One study reported excess mortality restricted to year 1, but with expected actuarial rates thereafter. We aimed to determine LTS after CSDH in a retrospective analysis relative to actuarial data from age-matched controls. Data was obtained in n = 155, (M:F 97:58, 69.3 +/- 2.3 years). Follow-up maxima was 14.19 years (mean: 4.02 +/- 3.07 years, median: 5.2 years). Mortality in-hospital, at 6 months, 1 year, 2 years and 5 years was n = 13 (8.39%), n = 22 (14.19%), n = 31 (20.35%), n = 42 (27.1%) and n = 54 (34.84%). LTS was significantly worse than controls (5.29 +/- 0.59 years vs. 17.74 +/- 1.8 years, hazard ratio [HR]: 3.52, P < 0.0001). Death most frequently related to pneumonia/sepsis and ischemic heart disease (IHD). Median modified Rankin score (mRS) in those discharged home (n = 94, 60.65%) was 2 [IQR: 1-3]. Discharge mRS in those who died at 6 months, 1 year, 2 years and 5 years was 5 [IQR: 3-6], 5 [IQR: 4-6], 3 [IQR: 1-3], 4 [IQR: 2-5]. Discharge mRS was significantly worse with year 1 mortality (P = 0.014). LTS related to discharge mRS (HR: 37.006, P < 0.001), post-operative motor-score (HR: 0.581, P = 0.0026), IHD (HR: 5.186, P = 0.005), warfarin-use (HR: 5.93, P= 0.036) and dementia (HR: 5.39, P= 0.031). No long term recurrences (LTR) were recorded. Although most were discharged home with mRS = 2, LTS was markedly less than previously reported: peers lived 12.4 years longer. Although greater in year 1, excess mortality was not restricted to year 1, but continued throughout prolonged follow-up. LTS related to discharge disability and dependence, and co-morbid risk factors for cerebral atrophy. No LTR suggests that, once ultimately closed, the 'subdural space' remains closed. CSDH patients represent a vulnerable group who require continued long-term medical surveillance

Anterograde amnesia and disorientation are associated with in-patients without traumatic brain injury taking opioids. Retrograde amnesia (RA) is absent. RA assessment should be integral to post-traumatic amnesia testing.

The Glasgow Coma Scale (GCS) only assesses orientation after traumatic brain injury (TBI). ‘Post-traumatic amnesia’ (PTA) comprises orientation, anterograde amnesia (AA) and retrograde amnesia (RA). However, RA is often disregarded in formalized PTA assessment. Drugs can potentially confound PTA assessment: e.g. midazolam can cause AA. However, potential drug confounders are also often disregarded in formalized PTA testing. One study of medium-stay elective-surgery orthopaedic patients (without TBI) demonstrated AA in 80% taking opiates after general anesthesia. However, RA was not assessed. Opiates/opioids are frequently administered after TBI. We compared AA and RA in short-stay orthopaedic surgery in-patients (without TBI) taking post-operative opioids after opiate/opioid/benzodiazepine-free spinal anesthesia. In a prospective cohort, the Westmead PTA Scale (WPTAS) was used to assess AA (WPTAS < 12), whilst RA was assessed using the Galveston Orientation and Amnesia Test RA item. Results were obtained in n = 25 (60 ± 14 yrs, M:F 17:8). Surgery was uncomplicated: all were discharged by Day-4. All were taking regular oxycodone as a new post-operative prescription. Only one co-administered non-opioid was potentially confounding (temezepam, n = 4). Of 25, 14 (56%) demonstrated AA: five (20%) were simultaneously disorientated. Mean WPTAS was 11.08 ± 1.22. RA occurred in 0%. Conclusions: AA and disorientation, but not RA, were associated with in-patients (without TBI) taking opioids. Caution should therefore be applied in assessing AA/orientation in TBI in-patients taking opioids. By contrast, retrograde memory was robust and more reliable: even in older patients with iatrogenic AA and disorientation. RA assessment should therefore be integral to assessing TBI severity in all formalized PTA and GCS testing

Membrane surface area to volume ratio in chronic subdural hematomas: critical size and potential postoperative target

Background: It is unknown why some chronic subdural hematomas (CSDHs) grow and require surgery, whereas others spontaneously resolve. Although a relatively small CSDH volume (V) reduction may induce resolution, V percent reduction is often unreliable in predicting resolution. Although CSDHs evolve distinctive inner neomembranes and outer neomembranes (OMs), the OM likely dominates the dynamic growth-resorption equilibrium. If other factors remain constant, one previous hypothesis is that resorption could fail as the surface area (SA) to V ratio decreases when CSDHs exceed a critical size. We aimed to identify a critical size and an ideal target, which implies resolution without recurrence. Methods: Three-dimensional computed tomography CSDH SA to V ratios were obtained using computer software to compare CSDH SA to V between cases requiring surgery (surgical) and cases managed conservatively with spontaneous resolution (nonsurgical). Results: Data were obtained in 45 patients (surgical: n = 28; nonsurgical: n = 17). CSDH risk factors did not significantly differ between surgical and nonsurgical cases. Surgical V was 2.5× the nonsurgical V (119.9 ± 33.1 mL vs. 48.4 ± 27.4 mL, respectively; P < 0.0001). Surgical total SA was 1.4× nonsurgical SA (256.63 ± 70.65 cm 2 vs. 187.67 ± 77.72 cm 2 , respectively; P = 0.004). Surgical total SA to V ratio was approximately one half that of nonsurgical SA to V ratio (2.14 ± 0.90 mL −1 vs. 3.88±1.22 mL −1 , respectively; P < 0.0001). Surgical OM SA (SA OM ) was 120.63 ± 52 cm 2 , and nonsurgical SA OM was 94.10 ± 41 cm 2 (P < 0.0001). Nonsurgical SA OM to V ratio was 1.94 mL −1 , whereas surgical SA OM to V ratio was 1.005 mL −1 (i.e., surgical SA OM ≈ V). Conclusions: Because surgical total SA to V ratio was ≈2:1, one neomembrane may indeed dominate the dynamic growth-resorption equilibrium. CSDH critical size therefore appears to be when SA OM ≈ V, which is intuitive. Practically, subtotal CSDH evacuation which approximately doubles total SA to V ratio or SA OM to V ratio implies CSDH resolution without recurrence. This could guide subdural drain removal timing, discharge, or transfer. Prospective validation studies are required

Long-term survival after chronic subdural haematoma

Outcome after chronic subdural haematoma (CSDH) is invariably assumed favourable: however, little data regarding long term survival (LTS) exists. One study reported excess mortality restricted to year 1, but with expected actuarial rates thereafter. We aimed to determine LTS after CSDH in a retrospective analysis relative to actuarial data from age-matched controls. Data was obtained in n = 155, (M:F 97:58, 69.3 +/- 2.3 years). Follow-up maxima was 14.19 years (mean: 4.02 +/- 3.07 years, median: 5.2 years). Mortality in-hospital, at 6 months, 1 year, 2 years and 5 years was n = 13 (8.39%), n = 22 (14.19%), n = 31 (20.35%), n = 42 (27.1%) and n = 54 (34.84%). LTS was significantly worse than controls (5.29 +/- 0.59 years vs. 17.74 +/- 1.8 years, hazard ratio [HR]: 3.52, P < 0.0001). Death most frequently related to pneumonia/sepsis and ischemic heart disease (IHD). Median modified Rankin score (mRS) in those discharged home (n = 94, 60.65%) was 2 [IQR: 1-3]. Discharge mRS in those who died at 6 months, 1 year, 2 years and 5 years was 5 [IQR: 3-6], 5 [IQR: 4-6], 3 [IQR: 1-3], 4 [IQR: 2-5]. Discharge mRS was significantly worse with year 1 mortality (P = 0.014). LTS related to discharge mRS (HR: 37.006, P < 0.001), post-operative motor-score (HR: 0.581, P = 0.0026), IHD (HR: 5.186, P = 0.005), warfarin-use (HR: 5.93, P= 0.036) and dementia (HR: 5.39, P= 0.031). No long term recurrences (LTR) were recorded. Although most were discharged home with mRS = 2, LTS was markedly less than previously reported: peers lived 12.4 years longer. Although greater in year 1, excess mortality was not restricted to year 1, but continued throughout prolonged follow-up. LTS related to discharge disability and dependence, and co-morbid risk factors for cerebral atrophy. No LTR suggests that, once ultimately closed, the 'subdural space' remains closed. CSDH patients represent a vulnerable group who require continued long-term medical surveillance

Pregabalin and gabapentin for the treatment of sciatica

Whilst pregabalin (PGB) and gabapentin (GBP) are both used to treat neuropathic pain, their relative role in sciatica is unclear. Our aim was to extensively review the roles of PGB and GBP in treating sciatica. The efficacy, side effects (SE) profile and cost of PGB and GBP in neuropathic pain states were reviewed with special reference to sciatica. Eleven articles matched the criteria: seven systematic reviews, one retrospective cross-sectional study, one placebo-controlled-crossover study, one randomized placebocontrolled double-blind study and one case report. GBP and PGB appeared to demonstrate comparable efficacy and SE. However, the amount and quality of evidence was low, and only indirect comparisons were available. Importantly, no direct "head-to-head" study existed. Globally, costs varied widely (by up to 31 times) and unpredictably (PGB cheaper than GBP, or vice versa). Formulary regulator rulings were globally disparate; however, many exclusively favoured the more expensive drug (whether GBP or PGB). No studies assessed PGB-GBP interchange. Weak evidence suggests that efficacy and SE with GBP and PGB are probably similar; however, firm conclusions are precluded. Despite weak data, and having cited minor titration, but definite cost, advantages, UK National Institute for Health and Clinical Excellence favoured PGB over GBP. Given that no evidence supports unhindered PGB-GBP interchange, neither drug should probably be favoured. Prospective "head-to-head" studies are are urgently required to provide robust evidence-based knowledge of GBP or PGB in sciatica