Ketoacidosis in the Emergency Department

Home , Alcoholic ketoacidosis, Lipoatrophic diabetes

Morton Adam (Orcid ID: 0000-0001-9887-714X)

Title : Ketoacidosis in the Emergency Department

Short running title: Ketoacidosis in the Emergency Department

Author: Adam Morton FRACP

Mater Health Services Brisbane and University of Queensland

Raymond Tce, South Brisbane, Brisbane QLD 4101.

No acknowledgements

Competing interests: None declared

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1742-6723.13503

Abstract

Diabetic ketoacidosis, a life-threatening complication of type 1 diabetes mellitus, is a common cause of presentation to Emergency Departments. Two new drug classes have been found to cause ketoacidosis with distinctive presentations. The sodium-glucose transport protein 2 inhibitors used in the management of type 2 diabetes mellitus may present with ketoacidosis with normal glucose levels. Ketoacidosis with these medications may be prolonged and recur after initial resolution. Checkpoint inhibitors may present with fulminant diabetic ketoacidosis in individuals with previously normal glucose tolerance. Ketoacidosis may also occur as a result of starvation and alcohol excess, as well as a number of rare causes. Other causes of metabolic acidosis with both high and normal anion gap need to be considered in the differential diagnosis of ketoacidosis. Diabetic ketoacidosis may also present with biochemical changes suggestive of myocardial infarction and pancreatitis in the absence of these pathologies. This paper reviews ketone body metabolism, ketone testing, and the causes and differential diagnosis of ketoacidosis with particular relevance to Emergency Medicine.

Keywords

Ketoacidosis

Ketosis-prone type 2 diabetes mellitus

Sodium-glucose transport protein 2 inhibitors

Starvation ketoacidosis

Introduction

Diabetic ketoacidosis (DKA) is a common cause of presentation to Emergency Departments. Between January 2000 and December 2013 DKA accounted for 1.1% of admissions to Australian Intensive Care units (ICU), with the population incidence of ICU admission with DKA progressively rising from 0.97/100 000 in 2000 to 5.3/100 000 in 2013.1 More than a quarter of these patients had no history of prior insulin therapy, and there is increasing recognition of the risk of DKA with type 2 diabetes mellitus (T2DM). In the last 6 years two new medication classes that may precipitate ketoacidosis, sodium-glucose transport protein 2 inhibitors (SGLT2i) and immune checkpoint inhibitors (CPI), have become available. Uncommon causes of ketoacidosis also need to be considered, as well as other conditions that may cause high anion gap and normal anion gap acidosis.(Table 1) Ketoacidosis may

Methods

A literature search was undertaken in Medline (OVID) and PubMed, using MeSH search terms “ketoacidosis”, “ketones”, “starvation”, “ketosis”, “pregnancy”, “lactation” and “child”. Full texts of relevant articles were obtained and reference lists screened for additional relevant articles. Ethics exemption was granted by the Mater Health Research Ethics Committee.

Ketone body metabolism

The 3 main ketone bodies are acetoacetate, β-hydroxybutyrate (BOHB) and acetone. They are fuels used for energy generation and supply in the setting of low glucose availability. Free fatty acids (FFA) derived from adipose tissue undergo β-oxidation in hepatic mitochondria resulting in the formation of acetyl-CoA. When the oxidative capacity of the Krebs cycle is exceeded acetyl-CoA is metabolised to acetoacetate. BOHB is formed from the reduction of acetoacetate by NADH. Glucagon and catecholamines increase FFA mobilisation, oxidation and ketogenesis. Insulin suppresses ketogenesis. Any process resulting in insulin deficiency or resistance may increase ketogenesis.

Ketone testing

Normal ketone levels can be defined as plasma BOHB less than 0.5mmol/L, and hyperketonemia as levels greater than 1 mmol/L.2 Plasma ketone levels are 2-3 times higher in healthy pregnancy than in non-pregnant individuals. Point- of- care testing (POCT) for capillary blood BOHB is superior to urinary acetone testing as the latter does not measure BOHB, is inaccurate regarding the resolution of ketonemia, and reflects the average acetone concentration since the last void.3 POCT BOHB levels of ≥ 3.0 mmol/L can be used to diagnose ketoacidosis in patients with diabetes mellitus with sensitivity of 95-100% and specificity of 78-94%.4 While a good correlation exists between POCT ketones and laboratory-measured plasma BOHB up to 3mmol/L, POCT measurements may be significantly lower than laboratory BOHB at higher levels.5, 6 Additionally acetoacetate is a potential interfering substance for POCT BOHB testing. Thus while POCT testing is useful in diagnosing DKA, it may not be useful to monitor response to therapy with BOHB greater than 5mmol/L.5 POCT ketone measurement may be affected by the use of ethyl chloride spray and vitamin C ingestion.7

Breath acetone sensors show good correlation with POCT BOHB levels, and have been used to monitor starvation and ketogenic diets, but their use has not been examined in ketoacidosis.

Type 1 Diabetes Mellitus

This article is protected by copyright. All rights reserved. The most common precipitants of DKA in T1DM are insulin omission (42%) and infection (30%).8 Other important precipitants include medications (glucocorticoids, antipsychotics, SGLT2i and immune CPI), myocardial infarction, eating disorders and unrecognised malfunction of continuous subcutaneous insulin infusion devices. Characteristics of young adults with multiple episodes of DKA include mental health issues, prior pregnancies, fewer clinic attendances and poor diabetic control.9

The role of illicit drug use is unclear. Cocaine stimulates cortisol and catecholamine release and may be associated with insulin omission and starvation, however no association was found between active cocaine use and hyperglycaemic crisis.10 Synthetic cannabinoids may be associated with prolonged acidosis and a tendency to hypokalemia.11 Conversely cannabis use in T1DM with DKA is associated with significantly higher bicarbonate and chronic alkalosis.

SGLT2i

Sodium-glucose transport protein 2 inhibitors (SGLT2i) were listed on the Pharmaceutical Benefits scheme in 2013. SGLT2i reduce the renal tubular reabsorption of filtered glucose by 30-50%. Benefits of SGLT2I including the absence of hypoglycaemia as monotherapy, weight loss, improved blood pressure, reduction in adverse cardiovascular outcomes and renal protection have led to this class being the second choice medication for T2DM after metformin. In mid-2015 a warning was issued regarding SGLT2i associated DKA after 167 cases were reported in Europe and the United States. The incidence of SGLT2i-DKA in randomised controlled trials has been reported to be 0.16-0.76 cases per 1000 patient years, versus 1.6 cases per 1000 person years in cohort studies.12 The duration of SGLT2i exposure preceding the development of DKA is extremely variable ranging from 0.3 to 420 days. Major precipitants includeded rapid reduction or discontinuation of insulin (40%), surgery (19%), infection (18%), low carbohydrate diets (10%), alcohol and glucocorticoid therapy. SGLT2i- DKA may be associated with euglycaemia - presenting glucose was less than 11.1mmol/L in 30% of cases. 13 Sixty-two per cent of cases occurred in individuals with T2DM, 27% in T1DM, and 4% in individuals with latent autoimmune diabetes. Postulated mechanisms in the generation of SGLT2i- DKA include increase in plasma glucagon levels due to a direct effect on pancreatic α-cells, reduced renal elimination of BOHB and acetoacetate, reduction in insulin doses, a net negative glucose balance promoting fatty acid oxidation and ketogenesis, and hypovolaemia. A study of 28 well patients taking SGLT2i found that 14% had serum BOHB levels greater than 2.8 mmol/L in the absence of acidosis.14 Patients taking SGLT2i who present to the Emergency Department should have the medication temporarily ceased and blood ketones checked every 4 hours regardless of glycaemia. Urine ketone testing is unreliable as SGLT2i reduce urine ketone excretion. If capillary or blood BOHB levels are greater than 1.5mmol/L, venous blood gases should be performed to exclude ketoacidosis. It is important to note that SGLT2i-DKA may be prolonged, ketonemia having been reported up to 12 days after cessation of SGLT2i, and that ketoacidosis may recur when insulin infusion rates are reduced.15 Instruction of patients in home capillary ketone testing is advisable

This article is protected by copyright. All rights reserved. prior to discharge. While current recommendations are for cessation of SGLT2i for 3 days prior to elective surgery, prolonged ketonemia with SGLT2i has led authors to recommend cessation at least 1 week prior to elective procedures.16 Trials of SGLT2i in non-diabetic individuals are underway, some health professionals already using SGLT2i “off-label” in the management of obesity, cardiac and renal disease.

Checkpoint inhibitors

The immune CPIs ipilimumab, nivolumab, pembrolizumab and atezolizumab are monoclonal antibodies have revolutionised the treatment of malignancies refractory to previous therapies. T1DM has been reported in 0.9% of patients exposed to CPIs.17 Presentation is usually fulminant, DKA being the first sign of DM in 86% of cases. Time from initiation of therapy to development of DKA ranges between 1 and 52 weeks, with a median time of 6 weeks. Ninety-three per cent of patients had low or undetectable c-peptide levels with low-glycated haemoglobin consistent with rapid beta-cell destruction and brief duration of hyperglycaemia. Patients should also be tested for cortisol deficiency and thyroid dysfunction.

Interferon

Interferon treatment of hepatitis C virus is associated with a 10-18 fold higher incidence of T1DM than in the general population. The clinical course is fulminant with abrupt severe hyperglycaemia and DKA, high titre of islet autoantibodies, and permanent insulin requirement.

Other drugs

Approximately 85 case reports have described ketoacidosis due to antipsychotic medications, particularly olanzapine and clozapine.18 Antipsychotic-induced hyperglycaemic emergencies are estimated to occur at approximately 1-2 events per 1000 patient years of exposure. In almost 90% of cases DKA was the first presentation of DM, and occurred in the first 6 months of drug therapy.18 Weight gain did not occur prior to 39% of cases of antipsychotic-induced DKA implying other mechanisms causing insulin resistance and/or deficiency.

Glucocorticoid therapy has been rarely reported to precipitate DKA in previously non-diabetic subjects. Glucocorticoids induce insulin resistance, and stimulate lipolysis and ketogenesis. This is particularly important to consider in women given corticosteroids for induction of fetal lung maturity during pregnancy, given the susceptibility of pregnant women to ketoacidosis, and the risk of ketonemia causing defects in intellectual development in children and potentially fetal demise. 19

Ketosis- Prone Diabetes

This article is protected by copyright. All rights reserved. Ketosis- prone diabetes (KPD) is a heterogeneous group of syndromes characterised by initial presentation with DKA in the absence of the classic phenotype of T1DM.20 KPD may be divided into 4 subgroups by the presence or absence of islet autoantibodies and the β cell functional reserve measured 6-8 weeks after presentation with DKA.20 It is important to consider as antibody negative patients with β cell functional reserve can usually cease insulin within 4-8 months of presentation with DKA, and be managed with oral hypoglycaemics in the long term without risk of recurrent DKA. The typical patient with this form of KPD will be male, middle-aged, obese and have a family history of T2DM. KPD was first recognised in patients of African heritage, though it is increasingly being recognised in Asian, Indian and Hispanic populations.

Starvation ketoacidosis

Fasting results in decreased insulin secretion, lipolysis and ketogenesis. In healthy individuals mild ketonemia may develop after 12 to 14 hours of starvation, with ketone levels rising above 1 mmol/L after fasting for 3 days.2 Ketoacidosis only occurs after 14 days of fasting in non-pregnant healthy adults, and is usually mild.21 Fasting or very low carbohydrate diets may be associated with serum ketone levels of 1-5 mmol/L without acidosis. Pregnancy, particular the third trimester is associated with significant insulin resistance resulting in an accelerated state of starvation. Additionally there is reduced buffering capacity for increased ketone production as the physiological respiratory alkalosis of pregnancy is compensated by increased renal excretion of bicarbonate. Ketoacidosis may occur in pregnant women with normal glucose tolerance after as little as 16 hours of starvation.22 Ketoacidosis has also been described in lactating women on low carbohydrate diets or while fasting.23 Starvation ketoacidosis has also been reported following bariatric surgery, with fruitarian and ketogenic diets, and the use of artificial sweeteners such as aspartame.

Children less than age 7 years develop fasting ketonemia more rapidly than older children and adults.24 After a 24 hour fast ketones of 2-5 mmol/L may be seen in young children. The delay of ketone body production in the fasting state with increasing age may be secondary to decrease in energy demands as a function of body weight, and increase in muscle mass providing a reserve for gluconeogenesis. Accelerated starvation of childhood (ASC) most frequently occurs in boys age less than 6 years with low body mass.25 ASC is associated with elevated ketones, glucagon, free fatty acids and cortisol and low levels of insulin. Ketonemia may precipitate worsening vomiting and abdominal pain, and be followed by the development of hypoglycaemia. It is recommended that capillary ketones be checked in any child who has been fasting for more than 24 hours, and carbohydrate replacement commenced where BOHB level is above 2.5mmol/L.

Alcoholic ketoacidosis

Alcoholic ketoacidosis (AKA) typically occurs as a combined lactic and ketoacidosis.26 Patients typically have a history of prolonged heavy alcohol misuse, with a recent bout of excessive intake terminated several days prior to presentation because of abdominal pain and vomiting. Examination

This article is protected by copyright. All rights reserved. reveals an alert patient with tachypnoea, tachycardia, hypotension, and epigastric tenderness. Investigations reveal a severe high anion gap metabolic acidosis with elevated lactate and hyperketonemia, normo- or hypoglycaemia, and often absent serum alcohol.27 Hyperketonemia may be missed on urine testing which does not detect BOHB. AKA occurs due to starvation, depleted hepatic glycogen stores, and catecholamine, cortisol, glucagon and growth hormone release in response to hypoglycaemia and volume depletion. Lactic acidosis occurs as a result of ethanol metabolism causing a high hepatic NADH:NAD ratio diverting pyruvate metabolism to lactate and inhibiting gluconeogenesis, and thiamine deficiency.

Rare Causes of Ketoacidosis

Ketoacidosis is rarely reported as the presenting feature in individuals with acromegaly, phaeochromocytoma and thyrotoxicosis in the absence of underlying autoimmune diabetes. Growth hormone excess causes insulin resistance and increased lipolysis. Catecholamine excess results in inhibition of pancreatic insulin release, increased hepatic glucose output and reduced skeletal muscle glucose uptake.28 Thyrotoxicosis is associated with adrenergic- driven increase in insulin resistance, increased insulin clearance, reduced skeletal muscle uptake of glucose, increased lipase activity and increased glycogenolysis.29

Sepsis may result in ketoacidosis through multiple mechanisms. Sepsis is associated with increased glucagon release, insulin resistance, increased lipolysis, increased carbohydrate demands, and inhibition of acetyl-CoA carboxylase by adrenaline, further exacerbated by cytokine- related effects. 30

Several cases of pancreatitis have been associated with non-diabetic ketoacidosis in pregnant and non-pregnant individuals, the authors postulating that ketoacidosis was not due to starvation alone, but the promotion of ketogenesis by high levels of lipase, as well as elevated counter-regulatory hormones to insulin.31, 32

Severe ketoacidosis may occur following brief periods of starvation in individuals with Duchenne muscular dystrophy and spinal muscular atrophy.33, 34 Glucose infusion results in rapid resolution of ketoacidosis. Contributing factors include low muscle mass, a mitochondrial β-oxidation abnormality in muscle and defective glucose metabolism.

Lipodystrophy may be complicated by DKA due to severe insulin resistance.35

Rare causes of non-diabetic ketoacidosis in children include organic acidaemias, glycogenic storage disease and disorders of gluconeogenesis. 36

Differential diagnosis of ketoacidosis

Glycogenic hepatopathy is an uncommon syndrome seen in poorly controlled T1DM, and is characterised by hepatomegaly, abnormal liver function tests, elevated lactate, nausea, vomiting

This article is protected by copyright. All rights reserved. and painful hepatomegaly. It may be associated with a persistent high anion gap acidosis which may be exacerbated by high dose insulin and dextrose therapy.37

Normal anion gap metabolic acidosis in subjects with diabetes mellitus may be mistaken for DKA. Hyperchloraemic normal anion gap acidosis is commonly seen following successful treatment of DKA, and may delay transition back to subcutaneous insulin if mistaken for persistent DKA. Type IV renal tubular acidosis may complicate diabetic nephropathy, and is characterised by a persistent normal anion gap hyperchloraemic, hyperkalaemic metabolic acidosis. Exposure to toluene with glue-sniffing may cause a type 1/distal renal tubular acidosis characterised by a hypokalaemic hyperchloraemic , normal anion gap acidosis.

Ketoacidosis also needs to be differentiated from other causes of high anion gap acidosis. These include lactic acidosis, toxic serum alcohols (methanol, ethylene glycol, propylene), drug toxicity, paraldehyde and renal failure.

Lactic acidosis is a common finding with DKA.38 In one study, 27 of 68 patients (40%) with DKA had a serum lactate greater than 4 mmol/L.39 Elevated lactate is not due solely inadequate tissue perfusion and oxygenation, but also to metabolic derangements. Deficiency of thiamine, an important co-factor in aerobic metabolism, may contribute to lactic acidosis. Thiamine deficiency has been demonstrated in 25-35% of individuals with DKA, with an inverse relationship between thiamine and lactate levels.40 41

Conditions imitated by ketoacidosis

Ketoacidosis may be associated with biochemical and electrocardiographic (ECG) changes consistent with myocardial ischaemia and pancreatitis in the absence of these pathologies. Acute myocardial infarction is estimated to be the precipitant in 1-4% of cases of DKA.42 Abnormal ECGs with markedly elevated cardiac troponin and CK-MB without echocardiographic evidence of infarction and normal coronary angiography have been described with DKA. 42, 43 Ten to 27% patients with DKA have an elevated troponin on presentation. 42, 44

Abdominal pain occurs in 45% of patients with DKA.45 Baseline assessment of more than 9000 T2DM in the LEADER trial found that 16.6% of well individuals had an elevated lipase.46 Elevated lipase and amylase occurs in 98% of cases of fulminant T1DM.47 The diagnosis of pancreatitis should therefore be based on imaging abnormalities in individuals with T1DM. Elevated lipase has also been reported in post-bariatric surgery starvation ketoacidosis in the absence of pancreatitis. 48 The amylase/creatinine clearance ratio has been suggested as a test to exclude acute pancreatitis in patients with DKA.49

Treatment of Ketoacidosis

This article is protected by copyright. All rights reserved. Management of ketoacidosis is directed to recognition and treatment of precipitating factors (including exclusion of pregnancy), correction of volume depletion, thiamine, dextrose and insulin therapy, and correction of electrolyte disorders. Individuals with alcoholic and starvation KA generally do not require insulin treatment. Phosphate and magnesium depletion is common with chronic alcoholism. In SGLT2i-DKA ketoacidosis may recur after initial therapy and capillary ketones should be closely monitored after cessation of insulin/dextrose infusion. There is no evidence for benefit with bicarbonate therapy which has potential harmful effects. Intravenous phosphate should only be considered in DKA where hypophosphataemia is severe (< 0.3mmol/L), particularly in the setting of cardiac dysfunction, respiratory depression or haemolysis.

Conclusion

A number of factors may predispose to increasing presentations with ketoacidosis to Australian Emergency Departments. These include increasing use of SGLT2i, starvation and ketogenic diets, greater use of continuous subcutaneous insulin infusion devices, as well as increasing obesity and migration of ethnic groups at higher risk of ketosis-prone diabetes. Awareness of the various causes of ketoacidosis is important, as is recognition of other causes of high-anion gap and normal anion gap acidosis. In particular it is important to cease SGLT2i in any patient presenting to the Emergency Department, and test blood ketone levels regularly regardless of glucose levels, given SGLT2i-DKA may be associated with normal glucose levels, and occur after cessation of the medication.

- Ketoacidosis may occur with conditions other than T1 diabetes mellitus - SGLT2i-DKA may be associated with normal glucose levels - SGLT2i may be associated with prolonged DKA which may recur after initial resolution of ketoacidosis - POCT ketones are inaccurate at BOHB levels > 3mmol/L, and may be misleading regarding response to therapy - DKA may present with biochemical / ECG changes suggestive of myocardial infarction and pancreatitis in the absence of these pathologies

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