Nutritional ketosis as treatment for alcohol withdrawal symptoms in female C57BL/6J mice.

Upon both acute and prolonged alcohol intake, the brain undergoes a metabolic shift associated with increased acetate metabolism and reduced glucose metabolism, which persists during abstinence, putatively leading to energy depletion in the brain. This study evaluates the efficacy of ketogenic treatments to rescue psychiatric and neurochemical alterations during long-term alcohol withdrawal. Female mice were intermittently exposed to alcohol vapor or air for three weeks, during which mice were introduced to either a ketogenic diet (KD), control diet supplemented with ketone ester (KE) or remained on control diet (CD). Withdrawal symptoms were assessed over a period of four weeks followed by re-exposure using several behavioral and biochemical tests. Alcohol-exposed mice fed CD displayed long-lasting depressive-like symptoms measured by saccharin preference and tail suspension, as well as decreased norepinephrine levels and serotonin turnover in the hippocampus. Both KD and KE rescued anhedonia for up to three weeks of abstinence. KD mice showed higher latency to first immobility in the tail suspension test, as well as lower plasma cholesterol levels. Our findings show promising effects of nutritional ketosis in ameliorating alcohol withdrawal symptoms in mice. KD seemed to better rescue these symptoms compared to KE.

Eu- or hypoglycemic ketosis and ketoacidosis in children: a review.

The last decade has been characterized by exciting findings on eu- or hypoglycemic ketosis and ketoacidosis. This review emphasizes the following five key points: 1. Since the traditional nitroprusside-glycine dipstick test for urinary ketones is often falsely negative, the blood determination of ß-hydroxybutyrate, the predominant ketone body, is currently advised for a comprehensive assessment of ketone body status; 2. Fasting and infections predispose to relevant ketosis and ketoacidosis especially in newborns, infants, children 7 years or less of age, and pregnant, parturient, or lactating women; 3. Several forms of carbohydrate restriction (typically less than 20% of the daily caloric intake) are employed to induce ketosis. These ketogenic diets have achieved great interest as antiepileptic treatment, in the management of excessive body weight, diabetes mellitus, and in sport training; 4. Intermittent fasting is more and more popular because it might benefit against cardiovascular diseases, cancers, neurologic disorders, and aging; 5. Gliflozins, a new group of oral antidiabetics inhibiting the renal sodium-glucose transporter 2, are an emerging cause of eu- or hypoglycemic ketosis and ketoacidosis. In conclusion, the role of ketone bodies is increasingly recognized in several clinical conditions. In the context of acid-base balance evaluation, it is advisable to routinely integrate both the assessment of lactic acid and ß-hydroxybutyrate.

Alcoholic ketoacidosis evaluated with a point-of-care capillary beta-hydroxybutyrate measurement device.

BACKGROUND: The diagnosis of alcoholic ketoacidosis (AKA) has traditionally been made based only on clinical history and the presence of severe metabolic acidosis with a high anion gap (AG); however, the concentration of beta-hydroxybutyrate (BOHB), a pivotal ketone body in AKA, is not evaluated in most cases. The aim of this study was to clarify the clinical spectrum of AKA in terms of the severity of ketoacidosis by using a point-of-care capillary BOHB measurement device. METHODS: This retrospective case series was conducted at a Japanese private teaching hospital. Patients with suspected AKA, based on their clinical history, who underwent BOHB measurement using a point-of-care capillary measurement device in the emergency department, were included. Data on their clinical presentations, blood tests, and treatments were collected, described, and compared between patients with a BOHB concentration higher than 3.0 mmol/L (H-BOHB) and those with a concentration less than 3.0 mmol/L (L-BOHB). RESULTS: A total of 83 patients were included in this study. Sixty-eight patients were categorized as having H-BOHB and 15 as having L-BOHB. Nausea (71%), vomiting (71%), tachycardia (76%), and tachypnea (46%) were commonly observed at presentation. Hyponatremia (46%), hypokalemia (34%), hypomagnesemia (42%), and hyperphosphatemia (41%) were frequent electrolyte abnormalities upon presentation. Rehydration with balanced crystalloids and glucose-containing intravenous fluids, electrolyte supplementation, and thiamine replacement were the major treatments. The mean length of stay in the ICU and hospital were 4.4 and 7.0 days, respectively, with low overall mortality (1%). The H-BOHB and L-BOHB groups did not differ in terms of clinical data. Seventy percent of patients with L-BOHB had severe metabolic acidosis with a high AG due to hyperlactatemia (mean lactate concentration: 8.5 mmol/L). CONCLUSIONS: We described the clinical features of AKA measured by using a point-of-care capillary BOHB measurement device. Although certain patients diagnosed with AKA based only on their clinical history had predominant lactic acidosis with minor elevations in BOHB concentration, the BOHB concentration had no effect on the clinical spectrum of AKA in this study.

Relationship Between Time in Range, Glycemic Variability, HbA1c, and Complications in Adults With Type 1 Diabetes Mellitus.

PURPOSE: Real-time continuous glucose monitoring (RT-CGM) provides information on glycemic variability (GV), time in range (TIR), and guidance to avoid hypoglycemia, thereby complimenting HbA1c for diabetes management. We investigated whether GV and TIR were independently associated with chronic and acute diabetes complications. METHODS: Between September 2014 and January 2017, 515 subjects with type 1 diabetes using sensor-augmented pump therapy were followed for 24 months. The link between baseline HbA1c and CGM-derived glucometrics (TIR [70-180 mg/dL], coefficient of variation [CV], and SD) obtained from the first 2 weeks of RT-CGM use and the presence of complications was investigated. Complications were defined as: composite microvascular complications (presence of neuropathy, retinopathy, or nephropathy), macrovascular complications, and hospitalization for hypoglycemia and/or ketoacidosis. RESULTS: Individuals with microvascular complications were older (P < 0.001), had a longer diabetes duration (P < 0.001), a higher HbA1c (7.8 ± 0.9 vs 7.5 ± 0.9%, P < 0.001), and spent less time in range (60.4 ± 12.2 vs 63.9 ± 13.8%, P = 0.022) compared with those without microvascular complication. Diabetes duration (odds ratio [OR] = 1.12 [1.09-1.15], P < 0.001) and TIR (OR = 0.97 [0.95-0.99], P = 0.005) were independent risk factors for composite microvascular complications, whereas SD and CV were not. Age (OR = 1.08 [1.03-1.14], P = 0.003) and HbA1c (OR = 1.80 [1.02-3.14], P = 0.044) were risk factors for macrovascular complications. TIR (OR = 0.97 [0.95-0.99], P = 0.021) was the only independent risk factor for hospitalizations for hypoglycemia or ketoacidosis. CONCLUSIONS: Lower TIR was associated with the presence of composite microvascular complications and with hospitalization for hypoglycemia or ketoacidosis. TIR, SD, and CV were not associated with macrovascular complications.

CRRT-associated ketoacidosis: A series of 5 cases.

Continuous renal replacement therapy (CRRT) is a dialysis modality used in critically ill patients with acute kidney injury (AKI). Although most dialysate and replacement fluids are dextrose-containing, CRRT-associated hypophosphatemia sometimes warrants the use of phosphorus-containing solutions which are dextrose free. The other less commonly used dextrose-free dialysate solutions are certain formulations of Prismasol and Prismasate. As glucose is a small molecule, which is readily cleared with dialysis, use of these solutions can result in increased caloric loss, net glucose deficit, and shifting of the metabolic pathway towards gluconeogenesis and ketogenesis. Starvation ketosis is usually a benign entity, however when combined with factors such as stress of critical illness, can produce metabolic acidosis which at times can be severe. We describe five patients who developed worsening metabolic acidosis despite adequate clearance from CRRT and were diagnosed with CRRT-associated ketoacidosis. Administration of dextrose-containing fluids or tube feeds promptly resulted in resolution of ketonemia and acidosis. Recognition of this entity is of great importance as the reflexive reaction to increase the prescribed dose of CRRT to improve the acidosis, in fact worsens the problem.

Therapeutic ketosis decreases methacholine hyperresponsiveness in mouse models of inherent obese asthma.

Obese asthmatics tend to have severe, poorly controlled disease and exhibit methacholine hyperresponsiveness manifesting in proximal airway narrowing and distal lung tissue collapsibility. Substantial weight loss in obese asthmatics or in mouse models of the condition decreases methacholine hyperresponsiveness. Ketone bodies are rapidly elevated during weight loss, coinciding with or preceding relief from asthma-related comorbidities. As ketone bodies may exert numerous potentially therapeutic effects, augmenting their systemic concentrations is being targeted for the treatment of several conditions. Circulating ketone body levels can be increased by feeding a ketogenic diet or by providing a ketone ester dietary supplement, which we hypothesized would exert protective effects in mouse models of inherent obese asthma. Weight loss induced by feeding a low-fat diet to mice previously fed a high-fat diet was preceded by increased urine and blood levels of the ketone body ß-hydroxybutyrate (BHB). Feeding a ketogenic diet for 3 wk to high-fat diet-fed obese mice or genetically obese db/db mice increased BHB concentrations and decreased methacholine hyperresponsiveness without substantially decreasing body weight. Acute ketone ester administration decreased methacholine responsiveness of normal mice, and dietary ketone ester supplementation of high-fat diet-fed mice decreased methacholine hyperresponsiveness. Ketone ester supplementation also transiently induced an "antiobesogenic" gut microbiome with a decreased Fermicutes/Bacteroidetes ratio. Dietary interventions to increase systemic BHB concentrations could provide symptom relief for obese asthmatics without the need for the substantial weight loss required of patients to elicit benefits to their asthma through bariatric surgery or other diet or lifestyle alterations.

Alcoholic Ketoacidosis: Etiologies, Evaluation, and Management.

BACKGROUND: Alcoholic ketoacidosis (AKA) is defined by metabolic acidosis and ketosis in a patient with alcohol use. This is a common presentation in the emergency department (ED) and requires targeted therapies. OBJECTIVE: This narrative review evaluates the pathogenesis, diagnosis, and management of AKA for emergency clinicians. DISCUSSION: AKA is frequently evaluated and managed in the ED. The underlying pathophysiology is related to poor glycogen stores and elevated nicotinamide adenine dinucleotide and hydrogen. This results in metabolic acidosis with elevated beta-hydroxybutyrate levels. Patients with AKA most commonly present with a history of alcohol use (acute or chronic), poor oral intake, gastrointestinal symptoms, and ketoacidosis on laboratory assessment. Patients are generally dehydrated, and serum glucose can be low, normal, or mildly elevated. An anion gap metabolic acidosis with ketosis and electrolyte abnormalities are usually present on laboratory evaluation. Management includes fluid resuscitation, glucose and vitamin supplementation, electrolyte repletion, and evaluation for other conditions. CONCLUSIONS: Emergency clinician knowledge of the evaluation and management of AKA is essential in caring for these patients.

Euglycaemic ketoacidosis in pregnant women with COVID-19: two case reports.

BACKGROUND: Euglycaemic ketoacidosis (EKA) is an infrequent but serious condition which usually follows a period of starvation, severe vomiting or illness in individuals with or without diabetes. Ketoacidosis is associated with materno-fetal morbidity and mortality necessitating prompt diagnosis and management. Physiological increases in insulin resistance render pregnancy a diabetogenic state with increased susceptibility to ketosis. COVID-19 is associated with worse clinical outcomes in patients with diabetes and is an independent risk factor for ketoacidosis in normoglycaemic individuals. CASE PRESENTATIONS: We describe two cases of SARS-CoV-2 positive pregnant women presenting with normoglycaemic metabolic ketoacidosis. Both cases were associated with maternal and fetal compromise, requiring aggressive fluid and insulin resuscitation and early delivery. CONCLUSION: We discuss possible physiology and propose a management strategy for euglycaemic ketoacidosis in pregnancy.

Euglycemic Ketoacidosis as a Complication of SGLT2 Inhibitor Therapy.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are drugs designed to lower plasma glucose concentration by inhibiting Na+-glucose-coupled transport in the proximal tubule. Clinical trials demonstrate these drugs have favorable effects on cardiovascular outcomes to include slowing the progression of CKD. Although most patients tolerate these drugs, a potential complication is development of ketoacidosis, often with a normal or only a minimally elevated plasma glucose concentration. Inhibition of sodium-glucose cotransporter-2 in the proximal tubule alters kidney ATP turnover so that filtered ketoacids are preferentially excreted as Na+ or K+ salts, leading to indirect loss of bicarbonate from the body and systemic acidosis under conditions of increased ketogenesis. Risk factors include reductions in insulin dose, increased insulin demand, metabolic stress, low carbohydrate intake, women, and latent autoimmune diabetes of adulthood. The lack of hyperglycemia and nonspecific symptoms of ketoacidosis can lead to delays in diagnosis. Treatment strategies and various precautions are discussed that can decrease the likelihood of this complication.

Euglycemic Ketosis During Continuous Kidney Replacement Therapy With Glucose-Free Solution: A Report of 8 Cases.

In this report, we describe 8 patients with critical illness and diabetes mellitus who developed euglycemic ketosis during continuous kidney replacement therapy (CKRT) with a glucose-free CKRT solution. Two patients had chronic kidney disease stage 5, while the rest had acute kidney injury. The patients had improvement in all metabolic parameters following CKRT commencement, except for a worsening high anion gap metabolic acidosis, in spite of improvement in serum lactate. This led to detection of elevated serum ß-hydroxybutyrate in the setting of normoglycemia. Following diagnosis of ketosis, the patients' caloric intake was increased from a median of 15 (IQR, 10-20) to 25 (IQR, 20-29) kcal/kg/d by adding a dextrose infusion. This allowed for a corresponding increase in the insulin administered, from a median of 0.2 (IQR, 0-0.2) to 3.0 (IQR, 2.3-3.9) U/h. These contributed to a complete resolution of ketosis. This report of 8 cases demonstrates that critically ill patients are at risk of developing euglycemic ketosis during CKRT, which can be mitigated by providing adequate caloric intake and using glucose-containing CKRT solutions with appropriate insulin therapy. We recommend vigilance in evaluating for euglycemic ketosis in patients who have a persistent metabolic acidosis despite improvements in solute control during CKRT.

Cetoacidosis normoglicémica en paciente embarazada con neumonía por COVID-19. Reporte de un caso clínico / Euglycaemic ketoacidosis in a pregnant woman with COVID-19 pneumonia. A case report

RESUMEN Introducción: La cetoacidosis en el embarazo es una emergencia médica que requiere tratamiento en Unidad de Cuidados Intensivos debido a su asociación con morbimortalidad maternofetal. Las gestantes pueden presentar una forma atípica del cuadro llamada cetoacidosis normoglicémica, siendo muy infrecuente en pacientes sin antecedente de diabetes. Caso Clínico: Se presenta una gestante cursando tercer trimestre de embarazo, sin antecedente de diabetes, ingresada en Unidad de Paciente Crítico debido a neumonía por COVID-19 y acidosis metabólica con anión gap aumentado. Se realizó diagnóstico de cetoacidosis normoglicémica posterior al ingreso, iniciándose tratamiento intensivo de trastorno ácido-base con buena evolución. Conclusión: La infección por SARS-CoV-2 puede causar cetoacidosis normoglicémicas en embarazadas no diabéticas; se requiere una alta sospecha clínica para realizar el diagnóstico y tratamiento oportuno.

ABSTRACT Introduction: Ketoacidosis in pregnancy is a medical emergency that requires treatment in an intensive care unit due to its association with maternal-fetal morbimortality. Pregnant women may present an atypical form of the condition called normoglycemic ketoacidosis, being very rare in patients with no history of diabetes. Clinical Case: We present a pregnant woman in the third trimester of pregnancy, without history of diabetes, admitted to a critical patient unit due to COVID-19 pneumonia and metabolic acidosis with an increased anion gap. A diagnosis of normoglycemic ketoacidosis was made after admission, and intensive treatment of acid-base disorder was initiated, with good evolution. Conclusion: SARS-CoV-2 infection can cause normoglycemic ketoacidosis in non-diabetic pregnant women; is required a high clinical suspicion to make the diagnosis and appropriate treatment.

Exogenous Ketone Supplements Improved Motor Performance in Preclinical Rodent Models.

Nutritional ketosis has been proven effective for neurometabolic conditions and disorders linked to metabolic dysregulation. While inducing nutritional ketosis, ketogenic diet (KD) can improve motor performance in the context of certain disease states, but it is unknown whether exogenous ketone supplements-alternatives to KDs-may have similar effects. Therefore, we investigated the effect of ketone supplements on motor performance, using accelerating rotarod test and on postexercise blood glucose and R-beta-hydroxybutyrate (R-ßHB) levels in rodent models with and without pathology. The effect of KD, butanediol (BD), ketone-ester (KE), ketone-salt (KS), and their combination (KE + KS: KEKS) or mixtures with medium chain triglyceride (MCT) (KE + MCT: KEMCT; KS + MCT: KSMCT) was tested in Sprague-Dawley (SPD) and WAG/Rij (WR) rats and in GLUT-1 Deficiency Syndrome (G1D) mice. Motor performance was enhanced by KEMCT acutely, KE and KS subchronically in SPD rats, by KEKS and KEMCT groups in WR rats, and by KE chronically in G1D mice. We demonstrated that exogenous ketone supplementation improved motor performance to various degrees in rodent models, while effectively elevated R-ßHB and in some cases offsets postexercise blood glucose elevations. Our results suggest that improvement of motor performance varies depending on the strain of rodents, specific ketone formulation, age, and exposure frequency.

Ketoacidosis associated with ketogenic diet in a non-diabetic lactating woman.

A 37-year-old woman who had 8 weeks post partum, breast feeding and on a low carbohydrate and high protein (ketogenic) diet, was admitted to the hospital with acute onset of nausea, vomiting and abdominal pain of 1-day duration. On admission, she was found to have high anion gap metabolic acidosis, elevated beta-hydroxybutyric acid level, normal glucose level and evidence of ketoacidosis. She was treated with lactated Ringer solution, along with dextrose 5% solution with the resolution of symptoms and metabolic derangement.

[Starvation ketoacidosis during prolonged fasting of 26 days]. / Hypercétose dans un contexte de jeûne prolongé de 26 jours.

Ketosis is a metabolic situation involving an increase in blood and urine concentrations of ketones that, when prolonged, leads to acidosis. Moderate ketosis usually appears after a fast of a few hours, but its prolongation exposes to hyperketosis. Observation: A 25-year-old woman presented to the emergency department for cohercitive vomiting. She was fasting for a long time in a spiritual setting and had a restricted diet limited to water and vitamin supplements. Clinical and biological assessment was in favour of fasting ketoacidosis. Evolution was favorable with intravenous hydration, poly-ionic and micronutrient supplementation and a gradual resumption of oral feeding. Conclusion: We report the case of a patient with fasting ketoacidosis. Besides consequences of this ketoacidosis, the challenge was also in resuming oral feeding in order to avoid a potentially fatal inappropriate renutrition syndrome.

Development, diagnosis and therapy of ketosis in non-gravid and non-lactating Guinea pigs.

BACKGROUND: Ketosis is a metabolic disorder often triggered by anorexia in animals fed on high energy diets. Although mostly described in pregnant female guinea pigs, under the name of pregnancy toxicosis; there is limited information on ketosis in males and non-pregnant females, often presented to clinics with anorexia or inappetence. The objective of this study was to observe progression of ketosis in guinea pigs, document the changes and evaluate diagnostic methods and a therapeutic approach. RESULTS: Twenty eight adult guinea pigs (Cavia porcellus), castrated males and intact females of obese and slim body condition were fasted for 3 days and refed afterwards. The slim animals served as control group for body condition. Either slim and fat animals were divided into two treatment groups: half of them received fluid replacements with glucose subcutaneously, the other half did not receive any injection and served as treatment control. Serum beta-hydroxybutyrate, and urine acetoacetate and acetone were measured during and after fasting. Serum ALT, bile acids and liver histology were also analyzed after 7 days of refeeding (and therapy). Females and obese guinea pigs showed a significantly higher increase in ketone bodies in serum and urine. Obese, female, or animals not receiving therapy needed more time to regulate ketone bodies to normal levels than slim animals, males or animals receiving therapy. Liver histology revealed increased hepatocyte degeneration and higher glycogen content in obese animals and animals receiving therapy, and additionally more glycogen content in males. Only minor hepatic fat accumulation was documented. Bile acids showed good correlation to histological liver changes whereas ALT did not. CONCLUSIONS: Female and obese animals react more intensively to fasting. As preventive management, animals should be kept in adequate body condition, fasting should be avoided, and anorexia should be treated immediately. In such a case, urinary dip sticks to detect ketone bodies are a useful diagnostic tool. Glucose therapy leads to faster cessation of ketogenesis and should be recommended in cases of ketosis. However, it needs to be adjusted to avoid hepatocyte glycogen overload and degeneration. Measuring bile acids presents a valuable indicator of liver damage.

Symposium review: Big data, big predictions: Utilizing milk Fourier-transform infrared and genomics to improve hyperketonemia management.

Negative animal health and performance outcomes are associated with disease incidences that can be labor-intensive, costly, and cumbersome for many farms. Amelioration of unfavorable outcomes through early detection and treatment of disease has emphasized the value of improving health monitoring. Although the value is recognized, detecting hyperketonemia (HYK) is still difficult for many farms to do practically and efficiently. Increasing data streams available to farms presents opportunities to use data to better monitor cow and herd health; however, challenges remain with regard to validating, integrating, and interpreting data. During the transition to lactation period, useful data are presented in the form of milk production and composition, milk Fourier-transform infrared (FTIR) wavelength absorbance, cow management records, and genomics, which have been employed to monitor postpartum onset of HYK. Attempts to predict postpartum HYK from test-day milk and performance variables incorporated into multiple linear regression models have demonstrated sufficient accuracy to monitor monthly herd prevalence; however, they lacked the sensitivity and specificity for individual cow diagnostics. Subsequent artificial neural network prediction models employing FTIR data and milk composition variables achieved 83 and 81% sensitivity and specificity for individual cow diagnostics. Although these results fail to reach the diagnostic goals of 90%, they are achieved without individual cow blood samples, which may justify acceptance of lower performance. The caveat is that these models depend on milk analysis, which is traditionally done every 4 weeks. This infrequent sampling allows for a single diagnostic sample for about half of the fresh cows. Benefits to farms are greatly improved if postpartum cows can be milk-tested weekly. Additionally, this allows for close monitoring of somatic cell count and may open the door for use of other herd health monitoring tools. Future improvements in these models may be achievable by maximizing sensitivity at the expense of specificity and may be most economical in disorders for which the cost of treatment is less than that of mistreating (e.g., HYK). Genomic predictions for HYK may be improved by incorporating genome-wide associated SNP and further utilized for precision management of HYK risk groups. Development and validation of HYK prediction models may provide producers with individual cow and herd-level management tools.