Diabetic ketoacidosis

Abstract

Diabetic ketoacidosis is a potentially life-threatening condition that affects people with diabetes mellitus. It typically affects people with type 1 diabetes and can be a first presentation for people not yet diagnosed. It can also affect people with type 2 diabetes, although this is much more uncommon. This article aims to increase understanding of a condition where prompt recognition and rapid management by GPs is essential in preventing morbidity and mortality.

The GP curriculum and diabetic ketoacidosis

Clinical module 3.17: Care of people with metabolic problems states that the GP should be able to:

Recognise your central role as a primary care physician in managing diabetes mellitus and hypothyroidism

Understand the need for early recognition and monitoring of complications in diabetes mellitus

Intervene urgently when patients present with a metabolic emergency, e.g. hypoglycaemia and hyperglycaemic conditions

Demonstrate a logical, incremental approach to investigation and diagnosis of metabolic problems: Manage appropriately primary contact with patients who have a metabolic problem

Understand the use and main limitations of tests commonly used in primary care to investigate and monitor metabolic or endocrine disease, e.g. fasting blood glucose, HbA1c, urinalysis for glucose and protein, urine albumin: creatinine ratio, ‘near patient testing’ (point of care testing) for capillary glucose, lipid profile and thyroid function tests, and uric acid tests

Understand the systems of care for metabolic conditions including the roles of primary and secondary care, shared-care arrangements, multidisciplinary teams and patient involvement

What is diabetic ketoacidosis?

Diabetic ketoacidosis (DKA) is characterised by the biochemical triad of hyperglycaemia, ketonaemia and acidosis. This complex metabolic state usually results from either an absolute or a relative insulin deficiency coupled with an increase in counter-regulatory hormones (catecholamines, growth hormone, cortisol and glucagon) as demonstrated in Fig. 1 (English, 2004; Joint British Diabetes Societies Inpatient Care Group, 2013; Wolfsdorf, Glaser, & Sperling, 2006).

Figure 1.

Pathophysiology of diabetic ketoacidosis (FFA, free fatty acids). Source: Wolfsdorf, Glaser, & Sperling (2006).

These hormone changes increase hepatic gluconeogenesis and glycogenolysis, thus leading to increased glucose production. This is augmented by reduced glucose utilisation in peripheral tissues resulting in hyperglycaemia. As the blood glucose levels rise, the hyperglycaemia is exacerbated further, due to decreased renal perfusion that is caused by osmotic diuresis and dehydration, which in turn, reduces renal clearance of glucose (English, 2004; Wolfsdorf et al., 2006).

Simultaneously, there is an increase in lipolysis that provides increased free fatty acids. The oxidation of free fatty acids not only facilitates gluconeogenesis, but also generates ketones (β-hydroxybutyrate and acetoacetate) at a faster rate than the body can utilise them, resulting in ketonaemia. Ketones are strong organic acids and overwhelm the body’s buffering capacity, leading to metabolic acidosis (English, 2004; Kitabchi, Umpierrez, Miles, & Fisher, 2009; Wolfsdorf et al., 2006).

There are several mechanisms responsible for fluid depletion and electrolyte imbalance in DKA. The hyperglycaemia and ketonaemia cause an osmotic diuresis with dehydration and loss of electrolytes, particularly sodium, magnesium and potassium. Acidosis can lead to nausea and vomiting, which contributes to further fluid loss and electrolyte imbalance, particularly potassium loss. Hyperventilation, fever, and increased sweating all contribute to further fluid losses and the fluid deficit averages 6 L or more at presentation in adults (English, 2004; Joint British Diabetes Societies Inpatient Care Group, 2013).

Precipitating factors

The most common precipitant of DKA is infection (Alourfi & Homsi, 2015; Barski et al., 2012; English, 2004; Kitabchi et al., 2009). Another principal cause is inadequate insulin therapy, either through lack of knowledge about managing insulin during intercurrent illness or omission through non-concordance (Alourfi & Homsi, 2015; Barski et al., 2012; English, 2004; Kitabchi et al., 2009; Wolfsdorf et al., 2006). In children and adolescents with type 1 diabetes (T1DM) it is important to consider psychosocial reasons for omitting insulin. Factors include fear of weight gain through metabolic control, depression, psychiatric disorders (including eating disorders), fear of hypoglycaemia, rebellion against authority, and children with difficult or unstable home circumstances (Kitabchi et al., 2009; Wolfsdorf et al., 2006).

Other precipitating factors to consider are stressors such as pancreatitis, myocardial infarction, cerebrovascular events, pulmonary embolism and excessive alcohol consumption, all of which increase insulin demand. Drugs that increase carbohydrate metabolism, such as corticosteroids, thiazides, loop diuretics and sympathomimetic agents, can also precipitate the development of DKA. There are an increasing number of reported cases of DKA in type 2 diabetes with no obvious precipitant attributable (English, 2004; Kitabchi et al., 2009).

Clinical presentation

DKA usually presents over a short time frame (less than 24 hours) compared with another hyperglycaemic crisis called hyperglycaemic hyperosmolar state which usually evolves over days to weeks (English, 2004; Kitabchi et al., 2009). However, because the brain continues to have a plentiful supply of glucose, the onset of symptoms in DKA is more gradual when compared with hypoglycaemia. In hypoglycaemia, patients experience sudden onset of symptoms (minutes) due to depletion of glucose to the brain, this is in contrast with the accumulating effect of dehydration from osmotic diuresis and the build-up of acid from ketones in DKA.

History

An appropriate history should pick-up any precipitants for DKA as outlined above, with particular attention paid to infective illness or omission of medication. The classic clinical picture of symptoms is that of polyuria, polydipsia, weight loss, dehydration, weakness, abdominal pain and nausea and vomiting (Table 1). Altered mental status in the form of profound lethargy or drowsiness is also present in some cases (Lin, Lin, & Huang, 2005).

Table 1.

Clinical signs and symptoms of DKA.

Symptoms of DKA	Signs of DKA
Polyuria	Dehydration: Reduced skin turgor, dry mucous membranes
Polydipsia	Hypovolaemia: Tachycardia, hypotension, postural hypotension
Weight loss	Neurological: Restlessness, agitation, drowsiness, lethargy
Lethargy	Kussmaul breathing
Abdominal pain	Acetone breath
Nausea	Mild hypothermia
Vomiting	Visual disturbances
Dyspnoea

Examination

A full physical examination, including assessment of weight, blood pressure (BP), level of consciousness using the Glasgow Coma Scale (GCS) and degree of dehydration is important to confirm diagnosis and determine possible cause. The examination may reveal signs of dehydration, signs of hypovolaemia, Kussmaul respirations (rapid and deep breathing), acetone odour on the breath, neurological signs, visual disturbances or mild hypothermia (Table 1).

Investigations

The diagnostic criteria for DKA consist of (Joint British Diabetes Societies Inpatient Care Group, 2013):

Plasma glucose greater than 11 mmol/L or known diabetes mellitus

Urine ketostix reaction more than ++ or ketonaemia greater than or equal to 3 mmol/L

A metabolic acidosis (pH less than 7.3) and/or a plasma bicarbonate less than 15 mmol/L

After initial assessment, biochemical investigations include capillary blood glucose, capillary blood ketones, if available, and urinalysis to assess for glycosuria and ketonuria. Bedside urine dipstick and glucometer measurements are of exceptional value for both first diagnosis of T1DM and follow-up of patients with known T1DM. In children and adolescents, measurements can allow differentiation on a sick day between starvation ketones and DKA to guide initial management (Table 2) (Brink et al., 2009).

Table 2.

Interpretation of blood and urine analyses for ketones with suggestions for the initial management.

Ketones		Blood glucose (mmol/L)
Urinary	Blood (mmol/L)	Less than 5.5	5.5–10	10–14	14–22	Greater than 22
Negative or trace	Less than 0.6	Monitor for hypoglycaemia	No need to worry	Consider extra insulin	Extra insulin	Extra insulin
Trace or small	0.6–0.9	Starvation: Carbohydrates and fluids	Starvation: Carbohydrates and fluids	Extra insulin	Extra insulin	Extra insulin
Small or moderate	1.0–1.4	Starvation: Carbohydrates and fluids	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin
Moderate or large	1.5–2.9	Risk of developing ketoacidosis - Close monitoring of blood sugar level and ketones
		Starvation: Carbohydrates and fluids	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin	Starvation: Carbohydrates and fluids + extra insulin
Large	3.0 or greater	EMERGENCY: Immediate risk of ketoacidosis

Source: Brink et al. (2009) .

In any child or young person without known diabetes presenting with the clinical signs and symptoms suggestive of DKA as described above and with a capillary blood glucose of greater than 11 mmol/L, immediate transfer to a hospital with acute paediatric facilities is required. For any patient with known diabetes and symptoms of DKA, measure the blood ketones. If this is elevated, even in the presence of a normal capillary glucose, immediately transfer the patient to hospital. For a child or young person, a hospital with acute paediatric facilities is required (National Institute for Health and Care Excellence (NICE), 2015).

Other blood samples for laboratory measurement will include:

Plasma glucose

Full blood count

Electrolytes

Urea and creatinine

Arterial blood gases to assess for metabolic acidosis

Blood cultures

Troponin: If suspicion of myocardial ischaemia/infarction

Amylase/lipase: If pancreatitis is suspected

An electrocardiogram should be done to exclude a cardiac precipitant of DKA, and because of the increased potential for cardiac arrhythmias secondary to the large shifts in electrolytes, particularly potassium. Urine and sputum cultures and chest radiography should be performed because infection is a common precipitant and difficult to exclude.

Management

Specialist involvement

The diabetes team should be involved in the care of any patient admitted with DKA. It has been shown that involvement of the diabetes specialist team shortens hospital stay (Levetan, Salas, Wilets, & Zumoff, 1995). Ideally this referral should be done as early as possible during admission.

Resuscitation

A rapid ABC (Airway, Breathing, Circulation) assessment should be carried out. The airway must be assessed for patency and managed appropriately. In the patient with altered consciousness or vomiting, the airway should be secured and a nasogastric tube inserted to help prevent aspiration. Give oxygen to those with circulatory impairment or shock.

Obtain peripheral venous access with a large bore cannula, this is important, not only for intravenous therapy, but also for convenient and painless repeat blood sampling. If the systolic BP is below 90 mmHg, a fluid bolus of 500 ml NaCl 0.9% is given over a 10 to 15 minute time period and then the BP is reassessed (Joint British Diabetes Societies Inpatient Care Group, 2013). Antibiotics are given to febrile patients after obtaining blood cultures. Continuous cardiac monitoring should be used to assess for signs of hyper- or hypokalaemia and arrhythmias.

Assessment of severity

DKA is classified as mild, moderate or severe. If the patient exhibits any signs to indicate severe DKA (Box 1), discussion with intensive care and consideration of referral to a high-dependency unit is warranted.

Box 1.

Indicators of severe DKA.

The presence of one or more of the following may indicate severe DKA:

• Blood ketones greater than 6 mmol/L

• Bicarbonate level less than 5 mmol/L

• Venous/arterial pH below 7.0

• Hypokalaemia on admission (less than 3.5 mmol/L)

• GCS less than 12 or abnormal AVPU (alert, voice, pain, unresponsive) scale

• Oxygen saturation less than 92% on air (assuming normal baseline respiratory function)

• Systolic BP below 90 mmHg

• Pulse greater than 100 beats per minute or less than 60 beats per minute

• Anion gap above 16 [Anion Gap = (Na⁺+ K⁺) – (Cl⁻+ HCO3⁻)]

Joint British Diabetes Societies (JBDS), reproduced with permission.

Monitoring

Careful monitoring of the patient’s response to treatment is essential for the successful management of DKA. Clinical and biochemical markers should be reassessed frequently to allow timely adjustment of treatment where indicated. Generally, hourly blood glucose and ketone measurements should be performed along with potassium and bicarbonate levels measured at least every 2 hours for the first 6 hours. Hourly monitoring of clinical observations includes respiratory rate, oxygen saturations, heart rate, BP, temperature, fluid balance and GCS score.

Intravenous fluid therapy

An average adult patient weighing 70 kg with DKA will have a typical deficit of 7 L of water, 490–700 mmol of sodium, 210–350 mmol of chloride and 210–350 mmol of potassium. In adults, the main aims of fluid replacement are to restore the circulatory volume, clear ketones and correct electrolyte imbalance over 24 hours (Joint British Diabetes Societies Inpatient Care Group, 2013). In a previously well 70 kg adult with a systolic BP over 90 mmHg, a typical fluid regime might consist of 1000 ml of isotonic saline (NaCl 0.9%) infused over the first hour. Rates can be adjusted based on subsequent requirements (based on hydration status, electrolytes and urinary output) but will usually be in the region of 250–1000 ml/hour for the next 4 hours using NaCl 0.9% with potassium (English, 2004). Cardiovascular status should be reassessed at 12 hours. Special attention is required in the following patients as fluids should be replaced cautiously (Joint British Diabetes Societies Inpatient Care Group, 2013):

Young people aged 18–25 years

Elderly

Pregnant

Heart or kidney failure

Other serious co-morbidities

In paediatric patients, due to the risk of cerebral oedema associated with rapid fluid administration, intravenous fluid therapy in the management of DKA is different to that in adults. Fluid replacement is calculated by working out the fluid deficit (either 5% if mild/moderate DKA or 10% if severe DKA) and giving the total volume evenly over the next 48 hours along with maintenance fluids. Calculate the maintenance fluid requirement using the following ‘reduced volume' rules (NICE, 2015):

If they weigh less than 10 kg, give 2 ml/kg/hour

If they weigh between 10 and 40 kg, give 1 ml/kg/hour

If they weigh more than 40 kg, give a fixed volume of 40 ml/hour

During DKA, hyperglycaemia is corrected at a faster rate than ketoacidosis. Once the plasma glucose level is less than 14.0 mmol/L, then commence 10% glucose in addition to the 0.9% sodium chloride solution for adults and 5% glucose with 0.9% sodium chloride for children (Joint British Diabetes Societies Inpatient Care Group, 2013; NICE, 2015).

Insulin therapy

Insulin has many metabolic effects (Fisher, 2011). The mainstay of treatment of DKA involves administration of regular insulin to suppress ketogenesis, reduce hyperglycaemia and correct electrolyte imbalances. Insulin therapy is usually by a fixed rate intravenous insulin infusion (FRIII). This infusion consists of 50 units of human soluble insulin made up to 50 ml with NaCl 0.9%. A fixed rate infusion calculated at 0.1units/kg/hour is recommended. If the patient usually takes long-acting insulin, in the form of Lantus™, Levemir™ or Tresiba™ subcutaneously, this should be continued at the usual dose and time (Joint British Diabetes Societies Inpatient Care Group, 2013).

The recommended targets are a reduction of the blood ketone concentration by 0.5 mmol/L/hour, a venous bicarbonate increase of 3.0 mmol/L/hour, a reduction in capillary blood glucose by 3.0 mmol/L/hour and to maintain potassium between 4.0 and 5.5 mmol/L, FRIII rate should be increased if these targets are not met (Joint British Diabetes Societies Inpatient Care Group, 2013; NICE, 2015).

Potassium

Dehydration and osmotic diuresis cause large electrolyte shifts in cells and serum. Despite total body potassium depletion, mild-to-moderate hyperkalaemia is common at patient presentation with DKA. Both hypo- and hyperkalaemia are life-threatening conditions that are frequently seen in DKA. With the start of insulin therapy, the subsequent correction of acidosis and volume expansion, serum potassium falls precipitously. Potassium replacement of 40 mmol/L of infusion solution should commence as soon as hyperkalaemia (serum potassium greater than 5.5 mmol/L) has been excluded or resolved with treatment. Hypokalaema (serum potassium less than 3.5 mmol/L) on presentation needs special attention, as more potassium needs to be given (Joint British Diabetes Societies Inpatient Care Group, 2013). Regular monitoring is required.

Sodium

Hyponatraemia may be present on initial assessment; however, this is caused by a dilution effect of the hyperglycaemia. It does not usually require specific treatment and resolves with the correction of hyperglycaemia.

Bicarbonate

It has been shown that administration of bicarbonate in DKA is not justified, due to the lack of sustained benefits and possible harm. Bicarbonate has been linked with increased risk of cerebral oedema and prolonged hospital stays in children, paradoxical worsening and delay of resolution of ketosis, and an increase in the need for potassium supplementation (Chua, Schneider, & Bellomo, 2013; Glaser et al., 2001; Hale, Crase, & Nattrass, 1984). Adequate fluid and insulin therapy will resolve the acidosis in DKA.

Phosphate

DKA causes whole-body deficits of phosphate of approximately 1 mmol/kg body weight, although at presentation serum phosphate is often normal or raised. As with potassium and glucose, once insulin therapy is commenced the phosphate concentration will fall (American Diabetes Association, 2001; Kitabchi et al., 2009). Routine phosphate replacement has not been shown to have any benefit to the clinical outcome in DKA (Keller & Berger, 1980; Wilson, Keuer, Lea, Boyd, & Eknoyan, 1982). Complications related to hypophosphataemia are rare, but include respiratory, cardiac and skeletal muscle weakness. Those with cardiac dysfunction, anaemia or respiratory depression in the context of hypophosphataemia should be considered for phosphate replacement (American Diabetes Association, 2001; Wilson, Keuer, Lea, Boyd & Eknoyan, 1982).

Transition to subcutaneous insulin

Insulin therapy is by FRIII until the hyperglycaemic crisis has resolved. The criteria for resolution are for the patient to have: blood ketone levels of less than 0.6 mmol/L; a pH greater than 7.3; and for the patient to be able to eat and drink. The conversion from intravenous insulin to subcutaneous insulin should ideally be managed by the diabetes team. It is important to allow an overlap of 1–2 hours between administration of subcutaneous insulin and discontinuation of the intravenous insulin infusion to help prevent recurrence of hyperglycaemia or ketoacidosis (Joint British Diabetes Societies Inpatient Care Group, 2013; Kitabchi et al., 2009; Wolfsdorf et al., 2006). A convenient time for the conversion is just prior to a meal. In patients with established diabetes, their usual insulin regime may be restarted, as long as it was controlling glucose adequately as per their most recent HbA1c. For insulin-naive patients, a total daily dose of insulin is estimated and then a basal bolus or a twice daily regimen is calculated (Joint British Diabetes Societies Inpatient Care Group, 2013). Close supervision from the diabetes team is required.

Complications

Hypokalaemia and hypoglycaemia are probably the most common complications that arise from the management of DKA. However, the use of continuous low-dose insulin therapy and appropriate monitoring means that these complications occur less often. Hyperkalaemia is a potentially life-threatening complication of DKA. Due to dehydration, there is a risk of pre-renal acute kidney injury, and so potassium should not be prescribed with initial fluid resuscitation or if the serum concentration is greater than 5.5 mmol/L.

Cerebral oedema is an uncommon, but devastating, complication of DKA and is more common in children, occurring in approximately 0.3–1% of DKA episodes (Edge, Hawkins, Winter & Dunger, 2001; Kitabchi et al., 2009). It is associated with a high mortality rate (24–90%) and a significant proportion of survivors (35%) are left with severe disabilities (Edge et al., 2001; Hammond & Wallis, 1992). It usually presents with headache, incontinence and behavioural changes, followed by abrupt neurological deterioration with seizures, incontinence, pupillary changes, bradycardia, and respiratory arrest (American Diabetes Association, 2001; English, 2004). There is no consensus on the aetiology of cerebral oedema (American Diabetes Association, 2001; Hammond & Wallis, 1992; Joint British Diabetes Societies Inpatient Care Group, 2013). Treatment with mannitol or hypertonic normal saline is recommended (NICE, 2015; Roberts, Slover, & Chase, 2001).

Pulmonary oedema has only rarely been reported in DKA. Elderly patients and those with reduced cardiac function are at the highest risk, and should be monitored closely with appropriate non-invasive or invasive methods (Joint British Diabetes Societies Inpatient Care Group, 2013).

Prevention

Patients who are admitted with DKA should be seen by the diabetes team and counselled on precipitating factors and early warning signs. Improved education and good communication is essential in preventing future admissions with DKA. The individuals and their caregivers should be educated on sick day management. This includes when to contact a health care provider, the use of supplemental insulin during intercurrent illness, when to increase the frequency of blood glucose monitoring and initiating an easily digestible liquid diet containing carbohydrates and salts when not tolerating solid foods (English, 2004; Kitabchi et al., 2009). Provision of a written care plan and ongoing outpatient management by a multidisciplinary team consisting of diabetes specialists, dieticians, psychologists and GPs can help to prevent recurrence and reduce the impact of this serious and potentially life-threatening condition.

Key points

Recognition of DKA can be improved by increased awareness for early clinical signs and symptoms

The use of urinalysis, capillary blood glucose and blood ketone meters in patients suspected to have DKA is an integral part of early diagnosis

DKA requires intensive management, and patients should be transferred early to an appropriate unit for care

Detailed accounts of the pathophysiology of DKA and hospital management of DKA emphasise the significance and origin of early clinical signs and symptoms, the importance of prevention and the urgency of referral

Contact with the diabetes specialist team should be established early and continued throughout admission

Education for patients with diabetes, particularly sick day management, can help in the prevention of DKA

References

Alourfi, Z., & Homsi, H. (2015). Precipitating factors, outcomes, and recurrence of diabetic ketoacidosis at a university hospital in Damascus. Avicenna Journal of Medicine, 5(1), 11–15. doi: 10.4103/2231-0770.148503.

American Diabetes Association (2001) Hyperglycaemic crises in patients with diabetes mellitus. Clinical Diabetes 19(2): 82–90. doi: 10.2337/diaclin.19.2.82.

Barski, L., Nevzorov, R., Rabaev, E., Jotkowitz, A., Harman-Boehm, I., Zektser, M., … Almog, Y. (2012). Diabetic ketoacidosis: Clinical characteristics, precipitating factors and outcomes of care. Israel Medical Association Journal, 14(5), 299–303. Retrieved from www.ima.org.il/FilesUpload/IMAJ/0/38/19466.pdf.

Brink, S., Laffel, L., Likitmaskul, S., Liu, L., Maguire, A. M., Olsen, B., … Hanas, R. (2009). Sick day management in children and adolescents with diabetes. Pediatric Diabetes, 10, 146–153. doi: 10.1111/j.1399-5448.2009.00581.x.

Chua

Schneider

Bellomo

(2011) Bicarbonate in diabetic ketoacidosis - a systematic review. Annals of Intensive Care 1(1): 23, doi: 10.1186/2110-5820-1-23.

Edge, J. A., Hawkins, M. M., Winter, D. L., & Dunger, D. B. (2001). The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Archives of Disease in Childhood, 85(1), 16–22. doi: 10.1136/adc.85.1.16.

English

(2004) Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgraduate Medical Journal 80(943): 253–261. doi: 10.1136/pgmj.2002.004291.

Fisher, M. (2011). Drugs for diabetes: part 7 insulin. British Journal of Cardiology, 18(5/6), 224–228. doi: 10.5837/bjc.2011.003.

Glaser, N., Barnett, P., McCaslin, I., Nelson, D., Trainor, J., Louie, J., … Kuppermann, N. (2001). Risk factors for cerebral edema in children with diabetic ketoacidosis. New England Journal of Medicine, 344(4), 264–269. doi: 10.1056/nejm200101253440404.

10.

Hale

P. J.

Crase

Nattrass

(1984) Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. BMJ 289(6451): 1035–1038. doi: 10.1136/bmj.289.6451.1035.

11.

Hammond

Wallis

(1992) Cerebral oedema in diabetic ketoacidosis. BMJ 305(6847): 203–204. doi: 10.1136/bmj.305.6847.203.

12.

Joint British Diabetes Societies Inpatient Care Group. (2013). The management of diabetic ketoacidosis in adults. Retrieved from www.diabetes.org.uk/resources-s3/2017-09/Management-of-DKA-241013.pdf?_ga=2.158769599.468428599.1505127410-1295258485.1505127410.

13.

Keller

Berger

(1980) Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma. Diabetes 29(2): 87–95. doi: 10.2337/diab.29.2.87.

14.

Kitabchi

A. E.

Umpierrez

G. E.

Miles

J. M.

Fisher

J. N.

(2009) Hyperglycaemic crises in adult patients with diabetes. Diabetes Care 32(7): 1335–1343. doi: 10.2337/dc09-9032.

15.

Levetan

C. S.

Salas

J. R.

Wilets

I. F.

Zumoff

(1995) Impact of endocrine and diabetes team consultation on hospital length of stay for patients with diabetes. The American Journal of Medicine 99(1): 22–28. doi: 10.1016/s0002-9343(99)80100-4.

16.

Lin

S. F.

Lin

J. D.

Huang

Y. Y.

(2005) Diabetic ketoacidosis: Comparisons of patient characteristics, clinical presentations and outcomes today and 20 years ago. Chang Gung Medical Journal 28(1): 24–30. Retrieved from https://pdfs.semanticscholar.org/da77/2932df760f46e81a2a7936b5a2d82d23181d.pdf.

17.

Liu

P. Y.

Jeng

C. Y.

(2013) Severe hypophosphatemia in a patient with diabetic ketoacidosis and acute respiratory failure. Journal of the Chinese Medical Association 67(7): 355–359. Retrieved from http://homepage.vghtpe.gov.tw/∼jcma/67/7/355.pdf.

18.

NICE. (2015). Diabetes (type 1 and type 2) in children and young people: Diagnosis and management. Retrieved from www.nice.org.uk/guidance/ng18.

19.

RCGP. Clinical example 3.17: Care of people with metabolic problems. Retrieved from www.rcgp.org.uk/training-exams/gp-curriculum-overview/online-curriculum/applying-clinical-knowledge-section-2/3-17-metabolic-problems.aspx.

20.

Roberts

M. D.

Slover

R. H.

Chase

H. P.

(2001) Diabetic ketoacidosis with intracerebral complications. Pediatric Diabetes 2(3): 109–114. doi: 10.1034/j.1399-5448.2001.002003109.x.

21.

Wilson, H. K., Keuer, S. P., Lea, A. S., Boyd, A. E., & Eknoyan, G. (1982). Phosphate therapy in diabetic ketoacidosis. Archives of Internal Medicine, 142(3), 517–520. doi: 10.1001/archinte.142.3.517.

22.

Wolfsdorf

Glaser

Sperling

M. A.

(2006) Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 29(5): 1150–1159. doi: 10.2337/dc06-9909.