Gaps in our knowledge of managing inpatient dysglycaemia and diabetes in non-critically ill adults: A call for further research.

AIMS: To describe the gaps in knowledge for the care of people in the hospital who have dysglycaemia or diabetes. METHODS: A review of the current literature and the authors' knowledge of the subject. RESULTS: Recent data has suggested that the prevalence of hospitalised people with diabetes is approximately three times the prevalence in the general population and is growing annually. A wealth of observational data over the last 4 decades has shown that people with hyperglycaemia, severe hypoglycaemia or diabetes, all experience more harm whilst in the hospital than those who do not have the condition. This often equates to a longer length of stay and thus higher costs. To date, the proportion of federal funding aimed at addressing the harms that people with dysglycaemia experience in hospitals has been very small compared to outpatient studies. National organisations, such as the Joint British Diabetes Societies for Inpatient Care, the American Diabetes Association and the Endocrine Society have produced guidelines or consensus statements on the management of various aspects of inpatient care. However, whilst a lot of these have been based on evidence, much remains based on expert opinion and thus low-quality evidence. CONCLUSIONS: This review highlights that inpatient diabetes is an underfunded and under-researched area.

Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from the Joint British Diabetes Societies (JBDS) for Inpatient Care Group.

Hyperosmolar Hyperglycaemic State (HHS) is a medical emergency associated with high mortality. It occurs less frequently than diabetic ketoacidosis (DKA), affects those with pre-existing/new type 2 diabetes mellitus and increasingly affecting children/younger adults. Mixed DKA/HHS may occur. The JBDS HHS care pathway consists of 3 themes (clinical assessment and monitoring, interventions, assessments and prevention of harm) and 5 phases of therapy (0-60 min, 1-6, 6-12, 12-24 and 24-72 h). Clinical features of HHS include marked hypovolaemia, osmolality ≥320 mOsm/kg using [(2×Na+ ) + glucose+urea], marked hyperglycaemia ≥30 mmol/L, without significant ketonaemia (≤3.0 mmol/L), without significant acidosis (pH >7.3) and bicarbonate ≥15 mmol/L. Aims of the therapy are to improve clinical status/replace fluid losses by 24 h, gradual decline in osmolality (3.0-8.0 mOsm/kg/h to minimise the risk of neurological complications), blood glucose 10-15 mmol/L in the first 24 h, prevent hypoglycaemia/hypokalaemia and prevent harm (VTE, osmotic demyelination, fluid overload, foot ulceration). Underlying precipitants must be identified and treated. Interventions include: (1) intravenous (IV) 0.9% sodium chloride to restore circulating volume (fluid losses 100-220 ml/kg, caution in elderly), (2) fixed rate intravenous insulin infusion (FRIII) should be commenced once osmolality stops falling with fluid replacement unless there is ketonaemia (FRIII should be commenced at the same time as IV fluids). (3) glucose infusion (5% or 10%) should be started once glucose <14 mmol/L and (4) potassium replacement according to potassium levels. HHS resolution criteria are: osmolality <300 mOsm/kg, hypovolaemia corrected (urine output ≥0.5 ml/kg/h), cognitive status returned to pre-morbid state and blood glucose <15 mmol/L.

The Association Between Glycaemic Control, Renal Function and Post-operative Ophthalmic Complications in People With Diabetes Undergoing Cataract Surgery-A Single-Centre Retrospective Analysis.

INTRODUCTION: In general surgery, it has been shown that poor peri-operative diabetes control, as measured by glycated haemoglobin (HbA1c), is associated with adverse post-operative outcomes. National data for the UK suggest that the post-operative complication rate for cataract surgery is 2.8%. It is unknown whether people with diabetes who undergo cataract surgery are also at increased risk. METHODS: This single-centre retrospective study looked at the association of peri-operative HbA1c and estimated glomerular filtration rate (eGFR) with the risk of post-operative complications in people undergoing phacoemulsification and intraocular lens implantation under local anaesthesia during 2016. RESULTS: 4401 individuals had cataract surgery. Of these, 34.6% (1525) had diabetes. Of those with diabetes, 114 (7.5%) developed a post-operative ophthalmological complication (as defined by the Royal College of Ophthalmologists) necessitating at least one eye clinic appointment. Mean HbA1c did not differ between those who did and those who did not develop complications (52 vs 50 mmol/mol, p = 0.12). After adjustment, HbA1c was not a significant risk (OR 1.00; 95% CI: 0.99-1.05; p = 0.85). However, eGFR had a small but statistically significant effect on outcome (OR 0.99; 95% CI: 0.98-1.00; p = 0.02). CONCLUSIONS: This study has shown that more people who undergo cataract surgery have diabetes than previously reported. Also, people with diabetes are at higher risk of developing complications than previously reported. HbA1c concentration was not a factor in these adverse post-operative outcomes. However, eGFR was a predictor of risk. More focus should be placed on pre-operatively optimising co-morbidities than diabetes control in those undergoing cataract surgery.

People with suboptimally controlled diabetes (as measured by glycated haemoglobin, HbA_1c) who have an operation are at increased risk of post-operative complications. However, whether this risk extends to cataract surgery is unknown. Our single-centre study showed that 34.6% of all cataract operations during the calendar year 2016 were performed on someone with diabetes­a number far higher than previously reported. In addition, we looked at the post-operative outcomes of the 1525 people with diabetes who had a cataract operation. We showed that, overall, more people with diabetes had complications than previously reported: 7.5%. However, in the whole cohort, HbA_1c did not differ between those who did and those who did not develop complications. The factors that were associated with differences in the risk of developing complications were whether the person was looked after in secondary care for their diabetes and whether they had any kidney disease.

The management of diabetic ketoacidosis in adults-An updated guideline from the Joint British Diabetes Society for Inpatient Care.

This article summarises the Joint British Diabetes Societies for Inpatient Care guidelines on the management of ketoacidosis; available at https://abcd.care/resource/management-diabetic-ketoacidosis-dka-adults. The document explicitly states that when a person aged 16-18 is under the care of the paediatric team, then the paediatric guideline should be used, and if they are cared for by an adult team, then this guideline should be used. The guideline takes into account new evidence on the use of the previous version of this document, particularly the high prevalence of hypoglycaemia and hypokalaemia, and recommends that when the glucose concentration drops below 14 mmol/L, that de-escalating the insulin infusion rate from 0.1 to 0.05 units/kg/h should be considered. Furthermore, a section has been added to address the recognition that use of sodium glucose co-transporter 2 inhibitors is associated with an increased risk of euglycaemic ketoacidosis. The management of ketoacidosis in people with end-stage renal failure or on dialysis is also mentioned. Finally, the algorithms to illustrate the guideline have been updated.

Bilateral Charcot Neuroarthropathy in Pregnancy: A Case Report and Review of the Influence of Pregnancy Hormones on Ligament Laxity.

OBJECTIVE: To describe the case of a woman with long-standing poorly controlled type 1 diabetes mellitus who developed bilateral Charcot foot while pregnant. To the best of our knowledge, this is the first reported case of this condition in pregnancy. METHODS: We performed a retrospective review of physical paper medical records; electronically held laboratory results, including glycated hemoglobin; and imaging reports, including plain radiographs and magnetic resonance imaging. RESULTS: The Charcot feet were treated by standard offloading in total-contact casts or below-knee removable walking boots. As 1 side resolved, the patient was stepped down into normal footwear on one side and a below-knee walking boot on the other. A review of the literature suggests that the increase in ligamentous laxity associated with a rise in circulating hormones, such as relaxin, increases the risk of developing Charcot neuroarthropathy. CONCLUSION: Bilateral concurrent Charcot neuroarthropathic foot is uncommon, and to our knowledge, this is the first reported case in pregnancy. We present a possible explanation for why there is an increased risk for the development of Charcot neuroarthropathy in pregnancy.

AMIODARONE-INDUCED THYROTOXICOSIS AFTER TOTAL THYROIDECTOMY FOR METASTATIC FOLLICULAR THYROID CANCER.

OBJECTIVE: To describe the case of a man who developed amiodarone-induced thyrotoxicosis (AIT) after a total thyroidectomy for metastatic follicular thyroid cancer because of the effect of the drug on metastasis. To the best of our knowledge this is the first reported case of this condition. METHODS: We completed a retrospective review of medical records and laboratory results including thyroid function tests as well as imaging reports including plain radiographs, positron emission tomographs, computed tomographs, and histology reports. RESULTS: A 78-year-old man had undergone a total thyroidectomy for follicular thyroid cancer. He had meta-static disease in his chest and vertebrae, and after the operation he was started on suppressive levothyroxine treatment prior to ablative radioactive iodine treatment. Prior to thyroidectomy, his thyroid-stimulating hormone (TSH) concentration was 3.21 mU/L (reference range is 0.35 to 3.50 mU/L). On suppressive thyroxine replacement, his TSH concentration was 0.02 mU/L, his free thyroxine was 13 pmol/L (reference range is 8 to 12 pmol/L), and free triiodothyronine was 5.8 pmol/L (reference range is 3.8 to 6.0 pmol/L). He subsequently had a myocardial infarction and required antiarrhythmic treatment with amiodarone. Eleven days later he developed the clinical and biochemical features of thyrotoxicosis (TSH <0.01 mU/L, free thyroxine of 41 pmol/L, and free triiodothyronine of 14.7 pmol/L). His thyroxine dose was reduced and then discontinued 3 days later. AIT was the principal differential diagnosis, but before being able to determine the nature of the condition he died 18 days after his myocardial infarction. CONCLUSION: AIT can still occur after total thyroidectomy if metastatic tissue is present.

Diabetic ketoacidosis.

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present - 'D', either elevated blood glucose levels or a family history of diabetes mellitus; 'K', the presence of high urinary or blood ketoacids; and 'A', a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children.

Mitochondrial dysfunction is the cause of one of the earliest changes seen on magnetic resonance imaging in Charcot neuroarthopathy - Oedema of the small muscles in the foot.

The hypothesis laid out in this thesis states that the early changes seen on an MR imaging in those with early Charcot neuroarthopathy may be due to mitochondrial dysfunction. In a Charcot foot, there is movement between bones. In an attempt to prevent this movement, the small muscles of the foot contract continuously when the foot is weight bearing. This contraction takes energy in the form of ATP. However, the reduction of glucose transport into the muscle cells due to insulin resistance / insufficiency, leads to reduction in the ATP producing capacity of the mitochondria. The ATP depletion affects the cell membrane gradient leading to mitochondrial and cellular swelling. These early cellular changes could then be picked up with MR imaging as muscle oedema.

Myositis ossificans in the diabetic foot: a review of the literature with an illustrative case series.

OBJECTIVE: Myositis ossificans is a rare non-neoplastic form of heterotopic ossification most commonly described after trauma or surgery, in the diabetic foot. DESIGN: We provide a review of the literature including three illustrative cases. PARTICIPANTS: Individuals presenting to the foot clinic. SETTING: Single centre, tertiary multidisciplinary specialist diabetes foot clinic. RESULTS: We review the literature surrounding Myositis ossificans, and describe three cases of Myositis ossificans following foot surgery in people with diabetes. All of the imaging was consistent with the descriptions of Myositis ossificans reported elsewhere in large muscle groups. These are the first reports of Myositis ossificans occurring in the feet of people with diabetes. CONCLUSIONS: Myositis ossificans has only very rarely been described in the foot and, as far as we are aware, never in people with diabetes. Given that the prevalence of diabetes is increasing, and the foot problems requiring surgery are also rising, we suggest that clinicians should be more aware of this condition because it may occur more frequently.

The endocrine management of intractable masturbation after epilepsy surgery: a case report and literature review.

Intractable masturbation has been reported after epilepsy surgery and can be difficult to control, we present a case treated with cyproterone acetate and haloperidol to achieve an endocrine based resolution of symptoms.

Defining and characterising diabetic ketoacidosis in adults.

AIMS: Diabetic ketoacidosis (DKA) remains one of the most frequently encountered diabetes related emergencies, and despite updates in management and increasing standardisation of care, still has an appreciable morbidity and mortality. This review focusses on the pathophysiology and epidemiology of DKA, but also on the importance of having a standardised definition. METHODS: Relevant data were reviewed where there was available basic science or clinical papers published in peer-reviewed international journals on DKA. These included consensus documents and national or international guidelines. RESULTS: The prevalence of DKA varies around the world, but part of this could be down to the way the condition is defined. Examples of this difference include the recent studies on sodium glucose co-transporter inhibitors in people with type 1 and type 2 diabetes which have all been associated with increased rates of DKA, but have highlighted how differences in definitions can make comparisons between agents very difficult. CONCLUSIONS: DKA should only be diagnosed when all three components are present - the 'D', the 'K' and the 'A'. In addition, the definitions used to diagnose DKA should be standardised - in particular for clinical trials.

BILATERAL NEUROARTHROPATHY 11 YEARS AFTER SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANT FOR TYPE 1 DIABETES MELLITUS.

OBJECTIVE: To report a case of a man who developed bilateral Charcot arthropathic feet 11 years after a simultaneous pancreas-kidney transplant (SPKT) for type 1 diabetes mellitus (DM). The patient had remained normoglycemic after surgery. METHODS: We present a retrospective review of the case notes and serial imaging. RESULTS: The patient developed dense peripheral diabetic neuropathy due to poor glycemic control. His biochemical markers of DM all normalized following SPKT, and he was discharged by his primary and secondary care diabetes services. Eleven years later, he developed Charcot arthropathy in one foot and, within a month, the other foot as well. CONCLUSION: Individuals with DM who had preoperative end organ diabetes-related damage who went into biochemical remission after SPKT may be at risk for future complications. They should not be discharged from specialist diabetes services, and they need continued education about foot care.

Discordance in glycemic categories and regression to normality at baseline in 10,000 people in a Type 2 diabetes prevention trial.

The world diabetes population quadrupled between 1980 and 2014 to 422 million and the enormous impact of Type 2 diabetes is recognised by the recent creation of national Type 2 diabetes prevention programmes. There is uncertainty about how to correctly risk stratify people for entry into prevention programmes, how combinations of multiple 'at high risk' glycemic categories predict outcome, and how the large recently defined 'at risk' population based on an elevated glycosylated haemoglobin (HbA1c) should be managed. We identified all 141,973 people at highest risk of diabetes in our population, and screened 10,000 of these with paired fasting plasma glucose and HbA1c for randomisation into a very large Type 2 diabetes prevention trial. Baseline discordance rate between highest risk categories was 45.6%, and 21.3-37.0% of highest risk glycaemic categories regressed to normality between paired baseline measurements (median 40 days apart). Accurate risk stratification using both fasting plasma glucose and HbA1c data, the use of paired baseline data, and awareness of diagnostic imprecision at diagnostic thresholds would avoid substantial overestimation of the true risk of Type 2 diabetes and the potential benefits (or otherwise) of intervention, in high risk subjects entering prevention trials and programmes.

Assessing the Effect of Piperacillin/Tazobactam on Hematological Parameters in Patients Admitted with Moderate or Severe Foot Infections.

INTRODUCTION: Piperacillin/tazobactam is a commonly used antibiotic for the empirical treatment of severe diabetic foot infections. One of the most feared complications of this drug is the development of pancytopenia. The aim of this study was to determine whether the use of piperacillin/tazobactam caused any hematological changes in patients admitted with severe diabetes-related foot infections from a specialist multidisciplinary foot clinic. Specifically, looking at whether it caused anemia, leukopenia, neutropenia, or thrombocytopenia. METHODS: A 1-year retrospective analysis of patients admitted to a tertiary care center for treatment of diabetes-related foot infection using piperacillin/tazobactam. Hematological indices, urea and electrolytes, and C-reactive protein (CRP) were recorded pretreatment, during treatment, and posttreatment. HbA1c, vitamin B12, folate, thyroid-stimulating hormone, and free thyroxin were also analyzed to exclude any potential confounders as a cause of pancytopenia. RESULTS: A total of 154 patients were admitted between 1 January 2016 and 31 December 2016 who received piperacillin/tazobactam for severe diabetes-related foot infection. On admission, white cell count and CRP were raised and fell significantly within the first 48 h. Other hematological factors did not change. Five patients developed a mild pancytopenia, of which three were unexplained. CONCLUSION: In this relatively small cohort, pancytopenia did not occur. As such, piperacillin/tazobactam appeared to have a low risk of adverse hematological outcomes and remains the treatment of choice for severe diabetes-related foot infections.

The impact of glycaemic variability on wound healing in the diabetic foot - A retrospective study of new ulcers presenting to a specialist multidisciplinary foot clinic.

AIMS: Glycaemic variability - the visit-to-visit variation in HbA1c - plays a possible role in the development of micro and macrovascular disease in patients with diabetes. Whether HbA1c variability is a factor determining wound healing in diabetic foot ulcers remains unknown. We aimed to determine whether HbA1c variability is associated with foot ulcer healing time. METHODS: A retrospective analysis of patients presenting to our specialist multidisciplinary foot clinic between July 2013 and March 2015, with at least three HbA1c measurements within five years of presentation and more than two follow-up reviews. HbA1c variation was measured by magnitude of standard deviation. RESULTS: 629 new referrals were seen between July 2013 and March 2015. Of these, 172 patients had their number of days to healing recorded and sufficient numbers of HbA1c values to determine variability. The overall geometric mean days to heal was 91.1 days (SD 80.8-102.7). In the low HbA1c variability group the geometric mean days to heal was 78.0 days (60.2-101.2) vs 126.9 days (102.0-158.0) in the high Hb1Ac variability group (p = .032). Those with low HbA1c (<58 mmol/mol) and low variability healed faster than those with high HbA1c and high variability (73.5 days [59.5-90.8] vs 111.0 days [92.0-134.0], p = .007). Additionally, our results show that time to healing is more dependent on the mean HbA1c than the variability in HbA1c (p = .007). CONCLUSIONS/INTERPRETATION: Our data suggest that there was a significant association between HbA1c variability and healing time in diabetic foot ulcers.

Treatment of Diabetic Ketoacidosis (DKA)/Hyperglycemic Hyperosmolar State (HHS): Novel Advances in the Management of Hyperglycemic Crises (UK Versus USA).

PURPOSE OF REVIEW: Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are diabetic emergencies that cause high morbidity and mortality. Their treatment differs in the UK and USA. This review delineates the differences in diagnosis and treatment between the two countries. RECENT FINDINGS: Large-scale studies to determine optimal management of DKA and HHS are lacking. The diagnosis of DKA is based on disease severity in the USA, which differs from the UK. The diagnosis of HHS in the USA is based on total rather than effective osmolality. Unlike the USA, the UK has separate guidelines for DKA and HHS. Treatment of DKA and HHS also differs with respect to timing of fluid and insulin initiation. There is considerable overlap but important differences between the UK and USA guidelines for the management of DKA and HHS. Further research needs to be done to delineate a unifying diagnostic and treatment protocol.