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Ketones in type 1 diabetes

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Diabetic ketoacidosis (DKA) is the most common acute life-threatening complication of type 1 diabetes mellitus. DKA accounts for more than 100,000 hospital admissions per year in North America, and for four-to-nine per cent of all hospital discharges among patients with diabetes.

The prevalence of DKA at the time of diagnosis has been estimated to be approximately 30 – 40 per cent in children and 20 per cent in adult patients with type 1 diabetes mellitus. Unfortunately, despite the advances in the treatment of diabetes mellitus, the morbidity and mortality from DKA remains significant.


DKA is characterised by the triad of hyperglycaemia, metabolic acidosis and increased concentration of total body ketones. Hyperglycaemia occurs due to a combination of insulin deficiency and increased counter-regulatory hormones (glucagon, catecholamines, cortisol and growth hormone).

This leads to altered glucose homeostasis, i.e increased hepatic/renal gluconeogenesis and glycogenolysis, as well as impaired glucose utilisation in peripheral tissues. Ketoacidosis is secondary to the increased production of free fatty acids (FFA) from the liver and adipose tissues as a result of insulin insufficiency and increased counter-regulatory hormones; both these factors cause the activation of tissue lipase which breaks down triglycerides into glycerol and FFA. FFA are oxidised to ketone bodies in the liver, and becomes the hepatic precursors of the ketoacids.

Therefore, the key mechanisms that underlie the pathogenesis of DKA can occur during period of systemic stress (i.e. infections) or at the onset of diagnosis of type 1 diabetes mellitus, when the pancreatic beta-cell secretion of insulin becomes insufficient. In patients with established diabetes, precipitating factors for DKA include infections, intercurrent illnesses, psychological stress and poor compliance to therapy.

One study showed that young adults (< 25 years) were more likely to suffer DKA as a result of insulin omission, whereas older adults were more likely to have an underlying infective or other organic precipitant for ketoacidosis.

Several factors may contribute to the cause of insulin omission in younger patients; among them, fear of gaining weight with insulin, fear of hypoglycaemia, and psychological and social stresses. Psychological support is therefore important in many of these patients.

The cause of death in patients with DKA, especially in older adults, is usually secondary to the underlying illness that precipitated the metabolic derangement or co-morbid conditions. Therefore to reduce the related morbidity and mortality of DKA, it is important to promptly diagnose and treat the precipitating cause(s).


Symptoms and signs

The clinical presentation usually occurs acutely, in a period of less than 24 hours. Patients may have osmotic symptoms (polyuria and polydipsia), However, in nearly all reported studies the commonest presentation of DKA is nausea and vomiting (up to 80 per cent of cases).

Forty-70 per cent of patients may also present with abdominal pain, mimicking an acute abdomen. It is therefore important to have a low clinical threshold for suspecting DKA in this situation. Other symptoms would be related to the underlying manifestation of the precipitating factor, such as an  infection.

Physical examination would reveal signs of volume depletion and dehydration. Fever due to underlying infection can be present, as well as signs of ketoacidosis (Kussmaul respiration, acetone breath). The patient’s signs and mental status can vary, depending on their underlying illness (i.e infection, myocardial infarction, cerebrovascular event etc.) and the severity of the metabolic abnormalities. 

Biochemical and laboratory diagnosis

In DKA, plasma glucose is usually greater than 13 mmol/l. The level of hyperglycaemia per se does not solely determine the prognosis. Severe acidosis (pH<7.0) together with severe derangements of serum bicarbonate (<10 mEq/L) and electrolytes (sodium and potassium) can all lead to a poorer clinical outcome, particularly in older patients with co-morbid conditions. Each of these biochemical parameters therefore needs to be evaluated carefully.

Ketonaemia by the bedside can be assessed by measuring beta-hydroxybutyrate levels, which is the main ketoacid in DKA and can now be measured by the fingerstick method using certain measuring devices, which is more reliable than measuring urinary ketones. Metabolic acidosis is confirmed by an arterial pH value of less than 7.3 and a bicarbonate level of less than 17mmol/l.

Other abnormal laboratory findings in DKA include elevated liver enzymes. The cause of this is unclear, however if pancreatitis is suspected clinically, serum amylase must also be measured.

Leukocytosis  may point towards an infective precipitant but can sometimes occur in DKA without any evidence of an underlying infection. Therefore a full septic screen (blood cultures, MSU and CXR) is useful to exclude infection.

Common laboratory pitfalls and differential diagnosis

It is important to assess true serum sodium and water deficit on admission. In the presence of hyperglycaemia, serum sodium drops secondary to osmotic flux of water from the intracellular to extracellular space (translocational hyponatraemia). When serum glucose is corrected, rebound  hypernatramia may occur with occasional serious consequences.

Therefore, the corrected plasma sodium should be estimated in order to estimate the severity of the water deficit and guide appropriate fluid replacement to prevent rebound hypernatraemia. The state of insulin insufficiency and acidosis also causes the extracellular shift of potassium, with a subsequent sharp drop in serum potassium once insulin is initiated and the acidosis is corrected.

This should be anticipated and adequate potassium replacements are used. A source of laboratory assay interference is blood acetate levels, which can cause serum creatinine to be falsely elevated if measured by the colorimeteric method.

It is important to keep in mind causes of ketoacidosis other than DKA. In patients with ketoacidosis but without hyperglycaemia, alcoholic ketoacidosis is a possibility. Starvation (food intake less than 500 kcal/day) can also lead to ketosis. However, it is unusual for these patients to present with acidosis, as the renal secretion of ammonia is enhanced to compensate for the acidosis. 


Fluid therapy

Patients with DKA typically have a fluid deficit of 100 ml/kg of body weight. Fluid therapy is therefore aimed towards restoring this deficit, replacing intravascular volume and suppressing the levels of counter-regulatory hormones. Fluid replacement is crucial, as studies have shown that up to 80 per cent the of decline in blood glucose levels in the first four hours of DKA management is due to rehydration on its own.

The goal is to replace half of the estimated water deficit over (12–24) hours. Hourly urine output should be measured, and if necessary, a urinary catheter inserted. In patients who are in cardiogenic shock or exhibiting clinical signs of fluid overload, fluid replacement needs to be judiciously managed and the patient should be haemodynamically monitored in the  ICU/HDU.

Insulin therapy

Continuous intravenous insulin infusion is the treatment of choice to increase peripheral glucose uptake, decrease hepatic glucose production, and inhibit FFA release, thereby decreasing ketogenesis. Insulin actrapid is used, and an initial IV bolus of six units of actrapid is given.

This is followed by a continuous IV infusion at six units/hr via an infusion pump (see figure 1). Blood glucose will need to be monitored hourly while on the infusion pump. If the blood glucose remains unchanged after two hours on the infusion, the infusion rate will need to be doubled (after ensuring the IV line is patent).

In our unit, once the patient’s blood glucose reaches 12mmol/l or below, the insulin infusion is switched to a Glucose-Potassium-Insulin (GKI) solution. The GKI consists of a solution containing 10-15 mmol/l KCL and 10 units of actrapid in a 500mls bag of 10 per cent dextrose, infused over five hours. Blood glucose levels are checked every two hours and the infusion is adjusted accordingly.

The most common initial complication of managing patients with DKA is hypoglycaemia during insulin infusion. It is therefore important to frequently monitor blood glucose levels and to recognise for signs and symptoms of hypoglycaemia in the patient.

Potassium replacement

As mentioned above, once insulin treatment is started and the acidosis is reversed, hypokalaemia can occur as potassium is shifted intracellularly. Hypokalaemia is a potentially serious complication, leading to arrhythmias and cardiac arrest.

Therefore, it is important to monitor serum potassium once treatment is started, and replaced as necessary with potassium chloride (KCL) which can be infused in the fluid replacement bag. The amount of KCL added to each bag is dependent on the measured potassium level, and the aim is to maintain normokalaemia between four – five mmol/l (Figure 1).

Other management issues

In patients where infection is suspected, a septic screen should be performed (i.e blood culture, CXR and MSU). Once cultures are taken, a broad spectrum antibiotic as per local hospital guidelines should be given. In older patients, cardiac enzymes and a 12-lead ECG should always be performed, as these patients may not exhibit any typical cardiac symptoms.

It is advisable to have these patients on cardiac monitoring/telemetry as tachyarrythmias, either secondary to infections, cardiac events or electrolyte imbalance are common. Patients are also at increased risk of venous thrombo-embolic events due to their underlying volume-depleted state, hyperglycaemia, and increased period of immobility during their inpatient stay. Therefore prophylactic low molecular weight heparin should be given to these patients, unless there are specific contraindications.

Unless the patient is severely acidotic (pH < 6.9) and haemodynamically unstable, sodium bicarbonate therapy is to be avoided in DKA. There is no evidence that sodium bicarbonate is beneficial if given to patients with a pH level higher than 6.9.

In fact, rapid alkalinisation with sodium bicarbonate can result in hypokalaemia, paradoxical central nervous system acidosis, and worsened intracellular acidosis (due to increased carbon dioxide production), which can be life-threatening. If needed, it is only to be given under the supervision of a senior endocrinologist and the patient will need to be monitored in ICU/HDU.           

References available on request

Dr Hood Thabit, Specialist Registrar; and Dr Amar Agha, Consultant Endocrinologist, Beaumont Hospital, Dublin


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