Chronic subdural haematoma: the role of peri-operative medicine in a common form of reversible brain injury.

Epidemiological studies project a significant rise in cases of chronic subdural haematoma over the next 20 years. Patients with this condition are frequently older and medically complex, with baseline characteristics that may increase peri-operative risk. The intra-operative period is only a small portion of a patient's total hospital stay, with a majority of patients in the United Kingdom transferred between institutions for their surgical and rehabilitative care. Definitive management remains surgical, but peri-operative challenges exist which resonate with other surgical cohorts where multidisciplinary working has become the gold standard. These include shared decision-making, medical optimisation, the management of peri-operative anticoagulation and the identification of key points of equipoise for examination in the future trials. In this narrative review, we use a stereotyped patient journey to provide context to the recent literature, highlighting where multidisciplinary expertise may be required to optimise patient care and maximise the benefits of surgical management. We discuss the triage, pre-operative optimisation, intra-operative management and immediate postoperative care of patients undergoing surgery for a chronic subdural haematoma. We also discuss where adjunctive medical management may be indicated. In so doing, we present the current and emerging evidence base for the role of an integrated peri-operative medicine team in the care of patients with a chronic subdural haematoma.

Incidence of chronic subdural haematoma: a single-centre exploration of the effects of an ageing population with a review of the literature.

BACKGROUND: Chronic subdural haematoma (cSDH) is a common neurosurgical pathology frequently occurring in older patients. The impact of population ageing on cSDH caseload has not been examined, despite relevance for health system planning. METHODS: This is a single-centre study from the UK. Operated cases of cSDH (n = 446) for 2015-2018 were identified. Crude and directly standardised incidence rates were calculated. Medline and EMBASE were systematically searched to identify studies reporting on the incidence of cSDH by year, so an estimate of rate of incidence change could be determined. Local incidence rates were then applied to population projections for local catchment area to estimate operated cSDH numbers at 5 yearly intervals due to shifting demographics. RESULTS: We identified nine studies presenting incidence estimates. Crude estimates for operative cases ranged from 1.3/100,000/year (1.4-2.2) to 5.3/100,000/year (4.3-6.6). When non-operated cases were included, incidence was higher: 8.2/100,000/year (6.0-11.2) to 48/100,000/year (37.7-61.1). Four pairs of studies demonstrated incidence rate increases of 200-600% over the last 50 years, but data was deemed too heterogeneous to generate formal estimate of incidence change. Local crude incidence of operated cSDH was 3.50/100,000/year (3.19-3.85). Directly standardised incidence was 1.58/100,000/year (1.26-1.90). After applying local incidence rates to population projections, case numbers were predicted to increase by 53% over the next 20 years. CONCLUSIONS: The incidence of cSDH is increasing. We project a 53% increase in operative caseload within our region by 2040. These are important findings for guiding future healthcare planning.

Qualitative grading of disc degeneration by magnetic resonance in the lumbar and cervical spine: lack of correlation with histology in surgical cases.

BACKGROUND: Clinically, magnetic resonance (MR) imaging is the most effective non-invasive tool for assessing IVD degeneration. Histological examination of the IVD provides a more detailed assessment of the pathological changes at a tissue level. However, very few reports have studied the relationship between these techniques. Identifying a relationship may allow more detailed staging of IVD degeneration, of importance in targeting future regenerative therapies. OBJECTIVES: To investigate the relationship between MR and histological grading of IVD degeneration in the cervical and lumbar spine in patients undergoing discectomy. METHODS: Lumbar (N = 99) and cervical (N = 106) IVD samples were obtained from adult patients undergoing discectomy surgery for symptomatic IVD herniation and graded to ascertain a histological grade of degeneration. The pre-operative MR images from these patients were graded for the degree of IVD (MR grade) and vertebral end-plate degeneration (Modic Changes, MC). The relationship between histological and MR grades of degeneration were studied. RESULTS: In lumbar and cervical IVD the majority of samples (93%) exhibited moderate levels of degeneration (ie MR grades 3-4) on pre-operative MR scans. Histologically, most specimens displayed moderate to severe grades of degeneration in lumbar (99%) and cervical spine (93%). MR grade was weakly correlated with patient age in lumbar and cervical study groups. MR and histological grades of IVD degeneration did not correlate in lumbar or cervical study groups. MC were more common in the lumbar than cervical spine (e.g. 39 versus 20% grade 2 changes; p < 0.05), but failed to correlate with MR or histological grades for degeneration. CONCLUSIONS: In this surgical series, the resected IVD tissue displayed moderate to severe degeneration, but there is no correlation between MR and histological grades using a qualitative classification system. There remains a need for a quantitative, non-invasive, pre-clinical measure of IVD degeneration that correlates with histological changes seen in the IVD.

Annual review of children with neurofibromatosis type 1.

We aim to provide a concise, evidence-based framework to assist secondary level, community and acute paediatricians during a 20-60 min annual review of children with neurofibromatosis type 1. This review does not cover all aspects of the disorder. We recognise the importance of an overview of the pathogenesis, molecular genetic testing, clinical manifestations and management; we shall cover some of this briefly, but this is not our focus here. We focus instead on the following areas: (A) what questions should be asked during annual review, (B) what should be included in a focused examination, (C) when to request further investigations and (D) when should a referral be made to tertiary specialists and other members of the multidisciplinary team. Ongoing debates regarding screening remain in certain areas, particularly regarding imaging and ophthalmology follow-up; here we summarise the differing opinions and make a recommendation based on the currently available evidence.

Major trauma care at a regional trauma centre during the COVID-19 lockdown in England.

INTRODUCTION: The COVID-19 pandemic has changed the presentation of many medical and surgical conditions, including major trauma. We aimed to assess how lockdown changed the presentation, severity and management of major trauma patients at our level 1 trauma centre in England. METHODS: Data were collected retrospectively from the Trauma Audit and Research Network's database between 23 March and 28 April 2020 and compared with the same period in 2019. Collected data included patient demographics, and the mechanism, severity and management of injuries. RESULTS: We experienced a 56.4% reduction in major trauma admissions during the lockdown period when compared with 2019. In 2020, more patients arrived in haemodynamic shock (25.3% vs 12.2%, p=0.02); however, Glasgow Coma Scale and Injury Severity Score were unchanged. A higher proportion of incidents occurred at home (37.2% vs 53.5%, p=0.018), with no difference in trauma secondary to substance abuse or assault. During lockdown, patients had a significantly shorter hospital (17 vs 10 days, p=0.029) and critical care stay (2 vs 1 day, p=0.033). A higher proportion of major trauma patients were assessed by specialty trainees in the emergency department in 2020 (12.8% vs 53.1%, p=0.0001) with a lower proportion assessed by a consultant (69.8% vs 46.7%, p=0.001). CONCLUSIONS: The COVID-19 pandemic and lockdown drastically changed human behaviour, as reflected in the change in presentation of major trauma. Changes in the management of these patients reflect adaptive measures to manage the pressures generated by the worldwide pandemic.

Low body mass index is associated with increased mortality in patients with pelvic and acetabular fractures.

AIMS: Fractures of the pelvis and acetabulum are often the consequence of high energy trauma in young individuals or fragility fractures in osteoporotic bone. They can be life-threatening or life changing injuries. No published data exists comparing body mass index (BMI) and mortality for this patient group. The aim of this study was to identify if low BMI (<18.5) was a predictor of morbidity and mortality for patients with these injuries. PATIENTS AND METHODS: Of the 1033 patients with pelvic or acetabular fractures referred to a single level 1 major trauma centre (MTC) over a 4.5-year period (August 2015 - January 2020); we retrospectively analysed data for all admitted patients. Data was collected on demographics, injury pattern, operative intervention and complications. Comparison was made between patients that were underweight (BMI<18.5) and patients that were not. Both in-hospital and post discharge complications were recorded including pulmonary embolus (PE), deep venous thrombosis (DVT), ileus, infection, loss of reduction and mortality at 6 months. RESULTS: 569 patients admitted to the MTC with a pelvic or acetabular fracture were included in our analysis. Underweight patients had a statistically significant increase in mortality both in-hospital (p = 0.019) and at 6 months post injury (p = 0.039) when compared to other BMI groups. No statistical significance was found between these BMI groups comparing morbidity: DVT (p = 0.712), PE (p = 0.736) nor ileus (p = 0.149). Covariate analysis showed that a low BMI was associated with triple the in-hospital mortality after correction for age and energy of injury (adjusted OR 3.028, 95% CI 1.059-8.659). CONCLUSION: This is the first published study that demonstrates a statistically significant increase in mortality in patients with pelvic or acetabular fractures who are underweight. Surgeons should carefully consider appropriate peri-operative optimisation for these patients. Further investigation into the effects of low BMI and response to trauma is required.

Chlorhexidine dressings could reduce external ventricular drain infections: results from a systematic review and meta-analysis.

The incidence of external ventricular drain (EVD) infections remains high. Chlorhexidine dressings have demonstrated efficacy in reducing infections associated with indwelling catheters at other body sites, although evidence for their use with EVDs is limited. The aim of this systematic review and meta-analysis was to evaluate the efficacy of chlorhexidine dressings in reducing EVD-associated cerebrospinal fluid infection (EVDAI). MEDLINE, EMBASE and the Cochrane library were queried for articles from inception. The primary outcome was the incidence of EVDAI. Secondary outcomes included device safety, microbiological outcomes and shunt-dependency. From 896 unique records, five studies were included of which four presented suitable data for quantitative analysis including three case series and one underpowered randomized controlled trial. There was a high risk of bias in all studies. A total of 880 patients were included with a mean age of 57.7 years (95% confidence interval (CI) 57.4-58.0 years). In primary outcome analysis, the chlorhexidine dressing group had a significantly lower incidence of EVDAI (1.7% vs 7.9%, risk difference (RD) = 0.07, 95% CI 0.00-0.13, P=0.04). In conclusion, chlorhexidine dressings may reduce the incidence of EVDAI but require future study in randomized trials to definitively determine efficacy.

Does chlorhexidine and povidone-iodine preoperative antisepsis reduce surgical site infection in cranial neurosurgery?

Introduction Surgical site infection (SSI) is a significant cause of postoperative morbidity and mortality. Effective preoperative antisepsis is a recognised prophylactic, with commonly used agents including chlorhexidine (CHG) and povidone-iodine (PVI). However, there is emerging evidence to suggest an additional benefit when they are used in combination. Methods We analysed data from our prospective SSI database on patients undergoing clean cranial neurosurgery between October 2011 and April 2014. We compared the case-mix adjusted odds of developing a SSI in patients undergoing skin preparation with CGH or PVI alone or in combination. Results SSIs were detected in 2.6% of 1146 cases. Antisepsis with PVI alone was performed in 654 (57%) procedures, while 276 (24%) had CHG alone and 216 (19%) CHG and PVI together. SSIs were associated with longer operating time (p<0.001) and younger age (p=0.03). Surgery type (p<0.001) and length of operation (p<0.001) were significantly different between antisepsis groups. In a binary logistic regression model, CHG and PVI was associated with a significant reduction in the likelihood of developing an SSI (adjusted odds ratio [AOR] 0.12, 95% confidence interval [CI] 0.02-0.63) than either agent alone. There was no difference in SSI rates between CHG and PVI alone (AOR 0.60, 95% CI 0.24-1.5). Conclusions Combination skin preparation with CHG and PVI significantly reduced SSI rates compared to CHG or PVI alone. A prospective, randomized study validating these findings is now warranted.

The dexamethasone suppression test and plasma dexamethasone in generalized anxiety disorder.

A Dexamethasone Suppression Test nonsuppression rate of 27% was found in a group of 30 generalized anxiety disorder patients before treatment. The dexamethasone concentrations in the eight nonsuppressors were significantly lower than in eight suppressors matched by sex and age, but were similar to those in five nonsuppressors from a matched normal control group. The dexamethasone concentrations in the generalized anxiety disorder suppressors and a matched group of eight normal control suppressors were similar. After successful nondrug behavioral treatment, all generalized anxiety disorder patients were suppressors. Posttreatment dexamethasone concentrations in the initial nonsuppressor patients remained significantly lower than in the initial suppressors. The results suggest that low plasma dexamethasone concentrations after 1 mg oral dexamethasone may confer a vulnerability to nonsuppression that may be expressed in the presence of high state anxiety.

Drug resistance following irradiation of RIF-1 tumors: influence of the interval between irradiation and drug treatment.

RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.

Radiation induction of drug resistance in RIF-1: correlation of tumor and cell culture results.

The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual. We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.

Dexamethasone kinetics in depressed patients before and after clinical response.

Dexamethasone pharmacokinetics were measured in 19 depressed patients, 10 dexamethasone suppression test (DST) nonsuppressors and nine suppressors, following a 1 mg oral dose in tablet form at 2300 h. Median dexamethasone concentrations were significantly lower in the nonsuppressors from 3-16 hr post-administration. Nonsuppressors had a significantly lower area under the curve than suppressors, and plasma clearance was significantly faster in the nonsuppressors than in the suppressors. Eleven patients, six nonsuppressors and five suppressors, agreed to a repeat DST after clinical improvement when all six nonsuppressors had normal DST responses. There were no significant differences between the median dexamethasone concentrations, or any of the pharmacokinetic parameters measured, of the "normalising" nonsuppressors and the suppressors. Dexamethasone kinetics were altered in depressed nonsuppressors but became normal with remission of depressive symptoms and normalisation of the DST response.

Plasma cortisol and 11-deoxycortisol activity in depressed patients and normal volunteers.

Plasma cortisol and 11-deoxycortisol were measured in 30 depressed patients and 110 normal volunteers before and after a 1.0 mg dexamethasone suppression test (DST). Post-dexamethasone plasma cortisol, 11-deoxycortisol and the cortisol/11-deoxycortisol ratio were significantly higher in the depressives compared to the controls, even when age and sex were taken into account. Pre-dexamethasone plasma cortisol, post-dexamethasone cortisol, 11-deoxycortisol and their ratio were significantly higher in the cortisol nonsuppressors than in the suppressors. The measurement of post-dexamethasone 11-deoxycortisol and the ratio did not differentiate between endogenous and reactive depression. Using the normative data, we explored several methods for determining a criterion value to define abnormal post-dexamethasone plasma 11-deoxycortisol and the cortisol/11-deoxycortisol ratio in depressed patients. All showed poor sensitivity and a low positive predictive value for depression. The measurement of 11-deoxycortisol thus does not enhance the clinical utility of the DST.

The dexamethasone suppression test: a study in a normal population.

One hundred healthy, non-depressed volunteers were given a standard dexamethasone suppression test (DST) to determine the appropriate criterion values of plasma cortisol to define suppression or nonsuppression. By radioimmunoassay (RIA) of cortisol, the criterion value for 5% nonsuppression was plasma cortisol greater than 187 nmol/l, and for suppression less than 153 nmol/l, with an indeterminate range between these values. Use of the widely accepted pre-determined criterion value of 138 nmol/l gave a significantly greater frequency of nonsuppression. Values of cortisol measured by two RIAs in a subset of 43 volunteers were not equivalent. With the experimentally determined criterion value, no significant differences between nonsuppressors and suppressors were found for any measured physical or psychological parameters. Women taking oral contraceptives had significantly higher plasma cortisol pre-dexamethasone and post-dexamethasone. Their exclusion did not alter the calculated criterion value for the remainder, but their separately estimated criterion value was significantly higher. Caution should be exercised when classifying the DST status of women on oral contraceptives, particularly when values are at the lower end of the nonsuppressor range. Determination of a separate normal range for them may be warranted.

Structural and functional effects of long-term lithium therapy.

To determine the effects of long-term lithium therapy, we have studied the renal histology and the renal function of 47 patients with affective disorders who were either currently receiving or had previously received maintenance lithium therapy (lithium patients), and we have compared the results with those of 32 other psychiatric patients with similar affective illnesses who had never taken lithium (prelithium patients). The renal biopsy samples, analyzed by a point-counting technique for interstitial fibrosis, were not different in degree between the lithium and the prelithium patients. Interstitial fibrosis was also not different between prelithium patients and age-matched transplant donor kidney controls, but it was greater in lithium patients when compared with the donor kidney controls (P less than 0.01). The specific distal tubular lesion associated with lithium therapy was present in all the biopsy samples of the patients who were currently receiving lithium therapy. Marked distal nephron dysfunction, as measured by urinary concentrating ability (P less than 0.0001) and urinary acidification (P less than 0.0001), was evident in lithium patients compared with the prelithium patients. These defects were correlated with the duration of lithium therapy. Serum creatinine estimations (P less than 0.01), serum beta-2 microglobulins (P less than 0.01), and 51Cr-EDTA clearances (P less than 0.01) suggested some impairment of GFR in lithium patients compared with prelithium patients. These defects did not correlate with the duration of lithium therapy. From these studies we concluded that the marked distal nephron dysfunction induced by lithium might produce prerenal impairment of GFR because the renal function abnormalities have no structural basis when the degree of interstitial fibrosis of other psychiatric patients is used as a control. Prospective studies are needed to answer the controversial question of whether stable maintenance lithium therapy produces chronic nephrotoxicity.

Viloxazine plasma concentrations and clinical response.

Eleven patients suffering from primary depressive illness were treated with 300 mg/d of viloxazine for 29 days. Blood samples were collected at weekly intervals and severity of depression assessed using the Hamilton depression rating scale. Mean plasma viloxazine level for all patients during the trial was 1.20 micrograms/ml and ranged from 0.40 to 2.70 micrograms/ml. No simple relationship between plasma concentration and amelioration score was observed at day (rs = -0.02), day 22 (rs = -0.29) or day 29 (rs = 0.09). No significant difference in plasma concentrations between responders and non-responders was observed at day 29. Side effects were not correlated with plasma concentrations.

Tyramine pressor response with moclobemide--a reversible monoamine oxidase inhibitor.

Moclobemide is a reversible, short-acting monoamine oxidase inhibitor (MAO1), specific for MAO A. To study moclobemide effects on the tyramine pressor response, we gave 12 depressed patients (2 males, 10 females; mean age 47, SD 11 years) an i.v. tyramine test after 7 days drug free. The mean (+/- SD) tyramine dose to raise systolic blood pressure 30 mmHg was 5.6 +/- 2.5 mg. Repeat tyramine testing after 2 weeks of treatment with moclobemide (280 +/- 90 mg/d) showed the tyramine dose required was reduced to 2.5 +/- 1.6 mg (n = 8). The mean (+/- SD) increase in sensitivity to tyramine was 2.9 +/- 1.8. Four patients did not have repeated tyramine tests as testing was discontinued because of tyramine-induced cardiac arrhythmias. Moclobemide seems an effective antidepressant with less tyramine sensitivity than MAOIs in current use.

Zimelidine: a placebo-controlled trial in depression.

Twenty-eight hospital inpatients with a primary major depressive disorder were treated with either zimelidine or placebo. Patients were matched for age, sex, and initial severity of depression and assigned double blind to the treatment regimen. An initial dosage of 150 mg/day was used for up to 6 weeks. Zimelidine was significantly more effective in alleviating the symptoms of depression than placebo, with 82% of zimelidine and 25% of placebo patients showing clinical improvement. There were few complaints of severe side effects in zimelidine-treated patients, and few effects on the cardiovascular system. Two zimelidine-treated patients were withdrawn for suspected drug-related adverse events. Zimelidine was a safe, effective antidepressant in this group of patients.

A series of four fractured Exeter™ stems in hip arthroplasty.

We describe the cases of four patients who presented with painful hips and were found to have fractured cemented Exeter™ V40™ stems. Failure was multifactorial. Fractured Exeter™ stems are rarely reported and this series raises a concern that a population of patients may be at risk of such morbidity.