Severe hypokalaemia in diabetic ketoacidosis: a contributor to central pontine myelinolysis?

Summary: Hypokalaemia at presentation of diabetic ketoacidosis is uncommon as insulin deficiency and metabolic acidosis shifts potassium extracellularly. However, hypokalaemia is a recognised complication of the management of diabetic ketoacidosis as insulin administration and correction of metabolic acidosis shifts potassium intracellularly. We describe the case of a 9-year-old girl with newly diagnosed type 1 diabetes mellitus presenting in diabetic ketoacidosis, with severe hypokalaemia at presentation due to severe and prolonged emesis. After commencing management for her diabetic ketoacidosis, her serum sodium and osmolality increased rapidly. However, despite maximal potassium concentrations running through peripheral access, and multiple intravenous potassium 'corrections', her hypokalaemia persisted. Seventy two hours after presentation, she became drowsy and confused, with imaging demonstrating central pontine myelinolysis ­ a rare entity seldom seen in diabetic ketoacidosis management in children despite rapid shifts in serum sodium and osmolality. We review the literature associating central pontine myelinolysis with hypokalaemia and hypothesise as to how the hypokalaemia may have contributed to the development of central pontine myelinolysis. We also recommend an approach to the management of a child in diabetic ketoacidosis with hypokalaemia at presentation. Learning Points: Hypokalaemia is a recognised complication of treatment of paediatric diabetic ketoacidosis that should be aggressively managed to prevent acute complications. Central pontine myelinolysis is rare in children, and usually observed in the presence of rapid correction of hyponatraemia. However, there is observational evidence of an association between hypokalaemia and central pontine myelinolysis, potentially by priming the endothelial cell membrane to injury by lesser fluctuations in osmotic pressure. Consider central pontine myelinolysis as a complication of the management of paediatric diabetic ketoacidosis in the presence of relevant symptoms with profound hypokalaemia and/or fluctuations in serum sodium levels. We have suggested an approach to the management strategies of hypokalaemia in paediatric diabetic ketoacidosis which includes oral potassium supplements if tolerated, minimising the duration and the rate of insulin infusion and increasing the concentration of potassium intravenously (via central line if necessary).

A pilot interventional study to evaluate the impact of cholecalciferol treatment on HbA1c in type 1 diabetes (T1D).

BACKGROUND: Higher 25(OH)D3 levels are associated with lower HbA1c, but there are limited UK interventional trials assessing the effect of cholecalciferol on HbA1c. AIMS: (1) To assess the baseline 25(OH)D3 status in a Manchester cohort of children with type 1 diabetes (T1D). (2) To determine the effect of cholecalciferol administration on HbA1c. METHODS: Children with T1D attending routine clinic appointments over three months in late winter/early spring had blood samples taken with consent. Participants with a 25(OH)D3 level <50 nmol/L were treated with a one-off cholecalciferol dose of 100,000 (2-10 years) or 160,000 (>10 years) units. HbA1c levels before and after treatment were recorded. RESULTS: Vitamin D levels were obtained from 51 children. 35 were Caucasian, 11 South Asian and 5 from other ethnic groups. 42 were vitamin D deficient, but 2 were excluded from the analysis. All South Asian children were vitamin D deficient, with mean 25(OH)D3 of 28 nmol/L. In Caucasians, there was a negative relationship between baseline 25(OH)D3 level and HbA1c (r = -0.484, P < 0.01). In treated participants, there was no significant difference in mean HbA1c at 3 months (t = 1.010, P = 0.328) or at 1 year (t = -1.173, P = 0.248) before and after treatment. One-way ANCOVA, controlling for age, gender, ethnicity, BMI and diabetes duration showed no difference in Δ HbA1c level. CONCLUSION: We report important findings at baseline, but in children treated with a stat dose of cholecalciferol, there was no effect on HbA1c. Further studies with larger sample sizes and using maintenance therapy are required.

Bordetella PlrSR regulatory system controls BvgAS activity and virulence in the lower respiratory tract.

Bacterial pathogens coordinate virulence using two-component regulatory systems (TCS). The Bordetella virulence gene (BvgAS) phosphorelay-type TCS controls expression of all known protein virulence factor-encoding genes and is considered the "master virulence regulator" in Bordetella pertussis, the causal agent of pertussis, and related organisms, including the broad host range pathogen Bordetella bronchiseptica We recently discovered an additional sensor kinase, PlrS [for persistence in the lower respiratory tract (LRT) sensor], which is required for B. bronchiseptica persistence in the LRT. Here, we show that PlrS is required for BvgAS to become and remain fully active in mouse lungs but not the nasal cavity, demonstrating that PlrS coordinates virulence specifically in the LRT. PlrS is required for LRT persistence even when BvgAS is rendered constitutively active, suggesting the presence of BvgAS-independent, PlrS-dependent virulence factors that are critical for bacterial survival in the LRT. We show that PlrS is also required for persistence of the human pathogen B. pertussis in the murine LRT and we provide evidence that PlrS most likely functions via the putative cognate response regulator PlrR. These data support a model in which PlrS senses conditions present in the LRT and activates PlrR, which controls expression of genes required for the maintenance of BvgAS activity and for essential BvgAS-independent functions. In addition to providing a major advance in our understanding of virulence regulation in Bordetella, which has served as a paradigm for several decades, these results indicate the existence of previously unknown virulence factors that may serve as new vaccine components and therapeutic or diagnostic targets.

The influence of the strength of bone on the deformation of acetabular shells: a laboratory experiment in cadavers.

Concerns have been raised that deformation of acetabular shells may disrupt the assembly process of modular prostheses. In this study we aimed to examine the effect that the strength of bone has on the amount of deformation of the acetabular shell. The hypothesis was that stronger bone would result in greater deformation. A total of 17 acetabular shells were inserted into the acetabula of eight cadavers, and deformation was measured using an optical measuring system. Cores of bone from the femoral head were taken from each cadaver and compressed using a materials testing machine. The highest peak modulus and yield stress for each cadaver were used to represent the strength of the bone and compared with the values for the deformation and the surgeon's subjective assessment of the hardness of the bone. The mean deformation of the shell was 129 µm (3 to 340). No correlation was found between deformation and either the maximum peak modulus (r² = 0.011, t = 0.426, p = 0.676) or the yield stress (r² = 0.024, t = 0.614, p = 0.549) of the bone. Although no correlation was found between the strength of the bone and deformation, the values for the deformation observed could be sufficient to disrupt the assembly process of modular acetabular components.

Guidance synthesis. Medical research for and with older people in Europe: proposed ethical guidance for good clinical practice: ethical considerations.

INTRODUCTION: In Europe the population is ageing rapidly. Older people are taking many medicinal products daily and these may not necessarily be suitable for them. Publications show that older patients are underrepresented in clinical trials, especially those over 75 years, with multiple co-morbidities, concomitant treatments and/or frailty. This document provides a summary of recommendations on ethical aspects of clinical trials with older people, who may in some cases be considered a vulnerable patient population. The EFGCP's Geriatric Medicine Working Party (GMWP) has developed this guidance to promote such research and to support health care professionals in their efforts. ETHICAL, SCOPE AND CONTEXT: The definition of a geriatric patient is reviewed. Frail and vulnerable patients, who are a minority of geriatric patients, should be included whenever it is relevant. The legal context is described. THE PROCESS OF INFORMED CONSENT: All adults should be presumed capable of consent, unless proven otherwise; informed consent must be sought for all older people who are able to consent. A simple, short and easy-to-understand information sheet and consent form will contribute to improving the readability and understanding of the older participant. A participant guide and the use of a simple tool to ensure decision making capacity, are recommended. Whenever older people are unable to consent, their assent should be sought systematically using adequate information, in addition to seeking the consent of their legal or authorised representative as appropriate. ETHICS COMMITTEES: Research ethics committees need internal and/or external geriatric expertise to balance the benefits and risks of research in older people and to appreciate and recognise their autonomy. DESIGN AND ANALYSES: Design and Analyses should be adapted to the objectives with appropriate outcomes and are not different from other clinical trials. CONCLUSIONS: The absence of proper recruitment or insufficient presence of older patients in clinical development plans for new medicinal products is detrimental; there is a need to improve evidence-based knowledge, understanding and management of their conditions and treatment. The aim of this guidance is to facilitate clinical research for and with the older patient population. The long version of the guidance will be available on the EFGCP's website: www.efgcp.be/.

Surface finish of the Exeter Trauma Stem: a cause for concern?

Recent guidance recommends the use of a well-proven cemented femoral stem for hemiarthroplasty in the management of fractures of the femoral neck, and the Exeter Trauma Stem (ETS) has been suggested as an example of such an implant. The design of this stem was based on the well-proven Exeter Total Hip Replacement stem (ETHRS). This study assessed the surface finish of the ETS in comparison with the ETHRS. Two ETSs and two ETHRSs were examined using a profilometer with a precision of 1 nm and compared with an explanted Exeter Matt stem. The mean roughness average (RA) of the ETSs was approximately ten times higher than that of the ETHRSs (0.235 µm (0.095 to 0.452) versus 0.025 µm (0.011 to 0.059); p < 0.001). The historical Exeter Matt stem roughness measured a mean RA of 0.973 µm (0.658 to 1.159). The change of the polished Exeter stem to a matt surface finish in 1976 resulted in a high stem failure rate. We do not yet know whether the surface differences between ETS and ETHRS will be clinically significant. We propose the inclusion of hemiarthroplasty stems in national joint registries.

Analysis of failed Van Straten LPM proximal interphalangeal prostheses.

The two-piece Van Straten Leuwen Poeschmann Metal (LPM) prosthesis was intended for the proximal interphalangeal joints. However, revision rates of 29% after 19 months were reported, as well as massive osteolysis. Five failed LPM titanium-niobium coated cobalt chromium components were obtained, three distal and two proximal, and subjected to a forensic retrieval analysis. Components were analyzed using a Talysurf contacting profilometer, ZYGO noncontacting profilometer, and environmental-scanning electron microscope. All components were heavily worn. In some regions the titanium-niobium coating had been scratched and penetrated. Elsewhere this coating had been removed where there was minimal scratching, which may have been due to corrosion between the coating and substrate. The osteolysis reported clinically was likely to be linked to the wear debris from the failed titanium-niobium coating and substrate.

A refined hemispheric model of normal human aortic valve and root geometry.

BACKGROUND: Better understanding of aortic root geometry could improve diagnosis and reconstruction of pathologic aortic valves. In this study, a previous model of hemispheric aortic valve leaflets nested within a cylindrical aorta was refined in humans with normal aortic valves. METHODS: Using 1-mm axial slices, high-resolution computed tomographic angiograms from 10 normal aortic roots were used to generate high-density X-, Y-, and Z-coordinates of valve structures using Mathematica software. Three-dimensional least squares regression analyses of leaflet and sinus coordinates were employed to compare multiple geometric models of aortic valve and root geometry. Shapes and dimensions of all root structures were evaluated and compared. RESULTS: Aortic valve geometry was roughly hemispherical, but the valve base was elliptical (minor-major diameter ratio = .66). Dimensional fits of the leaflet-sinus complexes also were better using ellipsoidal geometry, with taller leaflets than predicted by hemispheres. The commissure between the left and noncoronary cusps was located uniformly at the posterior junction of the base minor diameter and circumference, with the center of the right coronary cusp opposite. The subcommissural post areas flared outward by 5° to 10°, and the volume of the right coronary leaflet-sinus complex was 12.4% and 10.7% larger than the noncoronary cusps and left cusps, respectively. CONCLUSIONS: The normal human aortic valve is an elliptical structure, and ellipsoidal refinements improve representation of leaflet geometry. The left and noncoronary cusps commissure is located posteriorly; the right coronary cusp is located anteriorly. This model could be useful in quantifying pathologic geometry and in engineering devices for aortic valve reconstruction.

Low dose (0.05 units/kg/h) is comparable with standard dose (0.1 units/kg/h) intravenous insulin infusion for the initial treatment of diabetic ketoacidosis in children with type 1 diabetes-an observational study.

OBJECTIVE: To compare low dose (0.05 units/kg/h) with standard dose (0.1 units/kg/h) intravenous insulin infusion for the treatment of diabetic ketoacidosis (DKA) in children with type 1 diabetes. STUDY DESIGN: Data from five paediatric centres were compared in children who received 0.05 (41 episodes) or 0.1 units/kg/h (52 episodes). RESULTS: In the low vs. standard dose group, at 6 h following admission, the fall in blood glucose levels [11.3 (95% confidence interval 8.6 to 13.9) vs. 11.8 (8.4 to 15.2) mmol/L, p = 0.86] and rise in pH [0.13 (0.09 to 0.18) vs. 0.11 (0.07 to 0.15), p = 0.78] were similar. These changes were comparable between doses in relation to: severity of initial acidosis, children newly diagnosed with diabetes or aged less than 5 years. After adjustment for other clinical and biochemical covariates, insulin dose was unrelated to the change in pH and blood glucose levels at 6 h following admission. Comparisons of safety data, particularly in relation to abnormal Glasgow Coma Score, were inconclusive. CONCLUSION: In this observational study, low dose was as effective as standard dose intravenous insulin infusion in the initial treatment (less than 6 h) of DKA in children with type 1 diabetes. A randomised controlled trial is required to show true equivalence between doses and to evaluate potential safety benefits.

Hydatid cysts of the lung.

Cystic hydatid disease is a zoonosis caused by infection with the larval cysts of Echinococcus granulosus. Cysts commonly develop in the liver and lungs. Diagnosis in non-endemic regions is often delayed due to a failure to consider hydatidosis. This results from a non-specific presentation and a failure to record an accurate geographical history. The diagnosis requires integrating an appropriate index of suspicion with correct interpretation of imaging and serological tests. In our case, a 44-year-old woman of Yemeni origin presented to a UK hospital with chest pain, pruritus and weight loss. Following detection of pulmonary nodules, a CT-guided biopsy was carried out to exclude malignancy. Iatrogenic cyst rupture precipitated an acute eosinophilic pleurisy. Cystic hydatid disease was subsequently diagnosed following strongly positive hydatid serological tests. This case illustrates the importance of considering diagnoses appropriate to an individual's geographical history particularly in the context of rising immigration and foreign travel.

Neurologically presenting Whipple disease: case report and review of the literature.

A previously healthy male with subacute onset right leg weakness was suspected to have an astrocytoma as imaging showed a lesion. Subsequent biopsy showed the presence of foamy macrophages containing periodic acid-Schiff staining granules, suggesting Whipple disease as a possible diagnosis.

Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis.

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL(CR)) normalized by body surface area (ml/min/1.73 m(2)): mild (CL(CR), 60 to 80), moderate (30 to 50), and severe (/= 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng. h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing >/=60 kg: CL(CR) of >50 ml/min/1.73 m(2), 40 mg every 12 h; CL(CR) of 21 to 50 ml/min/1. 73 m(2), 20 mg every 12 h; and CL(CR) of 10 to 20 ml/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC(0-infinity), AUC(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.

Changes in cardiorespiratory fitness, psychological wellbeing, quality of life, and vocational status following a 12 month cardiac exercise rehabilitation programme.

OBJECTIVE: To examine and evaluate improvements in cardiorespiratory fitness, psychological wellbeing, quality of life, and vocational status in postmyocardial infarction patients during and after a comprehensive 12 month exercise rehabilitation programme. SUBJECTS: The sample population comprised 124 patients with a clinical diagnosis of myocardial infarction (122 men and two women). INTERVENTIONS: 62 patients were randomly allocated to a regular weekly aerobic training programme, three times a week for 12 months, and compared with 62 matched controls who did not receive any formal exercise training. A five year follow up questionnaire/interview was subsequently conducted on this population to determine selected vocational/lifestyle changes. RESULTS: Significant improvements in cardiorespiratory fitness (p < 0.01-0.001), psychological profiles (p < 0.05-0.001), and quality of life scores (p < 0.001) were recorded in the treatment population when compared with their matched controls. Although there were no significant differences in mortality, a larger percentage of the regular exercisers resumed full time employment and they returned to work earlier than the controls. Controls took lighter jobs, lost more time from work, and suffered more non-fatal reinfarctions (p < 0.05-0.01). CONCLUSIONS: Regularly supervised and prolonged aerobic exercise training improves cardiorespiratory fitness, psychological status, and quality of life. The trained population also had a reduction in morbidity following myocardial infarction, and significant improvement in vocational status over a five year follow up period.

Combined chemotherapy and radiotherapy for esophageal carcinoma in a hemodialyzed patient. Long-term survival.

The use of antimitotic chemotherapy in hemodialysis patients is not yet well codified, and each individual decision remains difficult. We report the case of a 68-year-old hemodialyzed man who developed a squamous cell carcinoma of the upper third of the esophagus. Necessarily disabling surgery was rejected, and three courses of combined radio- and chemotherapy with 5-fluorouracil and cis-platinum were performed without decreasing standard doses. The percentage of drugs removed during hemodialysis sessions was low; peak and residual platinum plasma concentrations were only slightly above those observed in normal renal function patients. The treatment was perfectly well tolerated, and tumor response was satisfactory without any relapse for 3 years. This observation suggests that hemodialysis patients could benefit from such 'full therapies', if necessary, without major adverse effects.