Endocrinology
A 37 year old man presents to the Emergency Department with abdominal pain and drowsiness. He has a past medical history of type 1 diabetes. His blood results show a metabolic acidosis with a raised blood glucose, you diagnose diabetic ketoacidosis. Regarding the management of diabetic ketoacidosis, glucose should be given in addition to insulin once the blood glucose concentration falls below what level?
Answer:
- Glucose
- Once blood-glucose concentration falls below 14 mmol/litre, glucose 10% should be given by intravenous infusion (into a large vein through a large-gauge needle) at a rate of 125 mL/hour, in addition to the sodium chloride 0.9% infusion.
- Consider reducing the rate of intravenous insulin infusion to 0.05 units/ kg/hour when glucose falls below 14 mmol/L.
Diabetic Ketoacidosis
Endocrinology
Last Updated: 19th May 2023
Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterised by hyperglycaemia, acidosis, and ketonaemia. DKA has been considered to be indicative, or even diagnostic, of type 1 diabetes, but increasingly there are cases of ketone-prone type 2 diabetes being recognised. However, the initial treatment is the same.
Diagnostic criteria (all three must be present):
- Capillary blood glucose > 11 mmol/L
- Ketonaemia > 3 mmol/L or Ketonuria > ++
- Bicarbonate (HCO3-) < 15 mmol/L and/or venous pH < 7.3
Pathophysiology
DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter regulatory hormones (i.e. glucagon, cortisol, growth hormone, catecholamines). This hormonal imbalance enhances hepatic gluconeogenesis and glycogenolysis resulting in severe hyperglycaemia. Enhanced lipolysis increases serum free fatty acids that are then metabolised as an alternative energy source in the process of ketogenesis. This results in accumulation of large quantities of ketone bodies and subsequent metabolic acidosis. There is initial compensation for the metabolic acidosis by hyperventilation and a respiratory alkalosis but as the condition progresses, the combination of acidosis, hyperosmolality and dehydration leads to coma. There are several mechanisms responsible for fluid depletion in DKA. These include osmotic diuresis due to hyperglycaemia, vomiting and eventually, inability to take in fluid due to a diminished level of consciousness. Electrolyte shifts and depletion are in part related to the osmotic diuresis. Hyperkalaemia and hypokalaemia need particular attention.
Precipitating factors
- Infection (for example pneumonia or a urinary tract infection)
- Physiological stress (such as trauma or surgery)
- Non-adherence to insulin treatment regimen or intentional insulin omission in order to lose weight (diabulimia)
- Other medical conditions (such as hypothyroidism or pancreatitis)
- Drug treatment (such as corticosteroids, diuretics, and sympathomimetic drugs
Clinical features
Suspect diabetic ketoacidosis (DKA) in a person with known diabetes or significant hyperglycaemia (finger-prick blood glucose level greater than 11 mmol/L) and the following clinical features:
- Increased thirst and urinary frequency
- Weight loss
- Inability to tolerate fluids
- Persistent vomiting and/or diarrhoea
- Abdominal pain
- Visual disturbance
- Lethargy and/or confusion
- Fruity smell of acetone on the breath
- Acidotic breathing — deep sighing (Kussmaul) respiration
- Dehydration, which can be classified as:
- Mild — only just clinically detectable.
- Moderate — dry skin and mucous membranes, and reduced skin turgor.
- Severe — sunken eyes and prolonged capillary refill time.
- Shock (resulting from severe dehydration). The person is severely ill with:
- Tachycardia, poor peripheral perfusion, and (as a late sign) hypotension (indicating decreased cardiac output)
- Lethargy, drowsiness, or decreased level of consciousness (indicating decreased cerebral perfusion)
- Reduced urine output (indicating decreased renal perfusion)
Complications
- Cerebral oedema (more common in children)
- Cardiac dysrhythmias, usually secondary to electrolyte disturbance
- Pulmonary oedema
- Acute renal failure
- Severe hypokalaemia
- Acute respiratory distress syndrome (ARDS)
- Comorbid states e.g. pneumonia, acute myocardial infarction, sepsis
Investigations
- Blood tests:
- Capillary and laboratory glucose
- Ketones
- Venous blood gas
- U&Es
- Urine dipstick for glucose and ketones
- ECG and continuous cardiac monitoring (and pulse oximetry)
- Infection screen if indicated:
- FBC, CRP
- Blood cultures
- Chest x-ray
- Urinalysis, culture and sensitivities
- Throat swab
- Lumbar puncture
- Pregnancy test if appropriate
Management in adults
- Intravenous fluids
- Initial fluids:
- Systolic BP < 90 mmHg on admission
- 500 mL 0.9% sodium chloride should be given intravenously over 10 – 15 minutes and repeated if blood pressure remains < 90 mmHg whilst awaiting senior input. Most people require 500-1000 mL given rapidly.
- Consider involving the ITU/critical care team.
- Once systolic BP > 90 mmHg, 1 L 0.9% sodium chloride should be given over the next 60 minutes. The addition of potassium is likely to be required in this second litre of fluid.
- Systolic BP ≥ 90 mmHg on admission.
- 1 L 0.9% sodium chloride should be given over the first 60 minutes.
- Systolic BP < 90 mmHg on admission
- Continuing fluids:
- Regime:
- 0.9% sodium chloride 1L with potassium chloride over next 2 hours
- 0.9% sodium chloride 1L with potassium chloride over next 2 hours
- 0.9% sodium chloride 1L with potassium chloride over next 4 hours
- More cautious fluid replacement in young people aged 18-25 years, elderly, pregnant, heart or renal failure. (Consider HDU and/or central line).
- Accurate fluid balance chart, minimum urine output 0.5 ml/kg/hr.
- Regime:
- Potassium replacement:
- Potassium chloride should be included in the fluids unless anuria is suspected, and adjusted according to plasma-potassium concentration (measured at 60 minutes, 2 hours, and 2 hourly thereafter; and hourly if outside the normal range).
- Potassium levels:
- K+ Level >5.5 = nil replacement
- K+ level 3.5 - 5.5 = 40 mmol/L replacement
- K+ level <3.5 = senior review
- Other electrolytes:
- Venous blood gas for pH and bicarbonate should be checked at 60 minutes, 2 hours and 2 hourly thereafter.
- Plasma electrolytes should be checked 4 hourly.
- Initial fluids:
- Insulin
- An intravenous insulin infusion should be started at a concentration of 1 unit/mL, infused at a fixed rate of 0.1 units/kg/hour using 50 units human soluble insulin (Actrapid® or Humulin S®) made up to 50 ml with 0.9% sodium chloride solution.
- Established subcutaneous long-acting insulin therapy should be continued during the treatment of DKA at usual dose and time.
- Blood ketone and blood glucose concentrations should be checked hourly and the insulin infusion rate adjusted accordingly. Blood ketone concentration should fall by at least 0.5 mmol/litre/hour OR bicarbonate should rise by at least 3 mmol/L/hour and blood glucose concentration should fall by at least 3 mmol/litre/hour.
- The insulin infusion should be continued until blood ketone concentration is below 0.6 mmol/litre, blood pH is above 7.3 and/or venous bicarbonate is over 18 mmol/L and the patient is able to eat and drink; ideally the insulin infusion should be stopped about an hour after giving subcutaneous fast-acting insulin and a meal.
- Glucose
- Once blood-glucose concentration falls below 14 mmol/litre, glucose 10% should be given by intravenous infusion (into a large vein through a large-gauge needle) at a rate of 125 mL/hour, in addition to the sodium chloride 0.9% infusion.
- Consider reducing the rate of intravenous insulin infusion to 0.05 units/ kg/hour when glucose falls below 14 mmol/L.
Management in children
N.B. *For 16-18 year olds, use the following guidelines if managed by the paediatric diabetes team but if managed by the adult team follow the guidelines above.
Severity:
- Mild DKA – venous pH 7.2- 7.29 or bicarbonate < 15 mmol/l. Assume 5% dehydration.
- Moderate DKA – venous pH 7.1-7.19 or bicarbonate < 10 mmol/l. Assume 5% dehydration.
- Severe DKA – venous pH less than 7.1 or serum bicarbonate < 5 mmol/l. Assume 10% dehydration.
Children who are alert, not clinically dehydrated, not nauseated or vomiting, do not always require IV fluids, even if their ketone levels are high. They usually tolerate oral rehydration and subcutaneous insulin but do require monitoring regularly to ensure that they are improving and their ketone levels are falling. For those who do not respond, or are clinically unwell, or are dehydrated by more than 5%, insulin and replacement fluids are best given by intravenous infusion.
- Intravenous fluids:
- Initial fluid bolus
- All patients presenting WITH SHOCK should receive an initial 10 ml/kg bolus of isotonic crystalloid over 15 minutes. Following the initial 10 ml/kg bolus, shocked patients should be reassessed and further boluses of 10 ml/kg may be given if required to restore adequate circulation up to a total of 40 ml/kg at which stage inotropes should be considered.
- All patients with DKA (mild, moderate or severe) in whom intravenous fluids are felt to be indicated AND WHO ARE NOT IN SHOCK should receive an initial 10 ml/kg 0.9% saline bolus over 30 minutes. Shocked patients do NOT need this extra bolus.
- N.B. Boluses given to treat shock SHOULD NOT be subtracted from the calculated fluid deficit. The initial 10 ml/kg bolus given to all non-shocked patients requiring IV fluids SHOULD be subtracted from total calculated fluid deficit.
- Calculating fluid deficit
- It is not possible to accurately clinically assess the degree of dehydration to work out the deficit thus estimation of the fluid deficit should be based on the initial blood pH as described above - assume 5% dehydration for mild and moderate DKA or 10% dehydration for severe DKA.
- To calculate the fluid deficit, use 5%/10% x body weight (kg) x 10. This gives the calculated fluid deficit to be replaced over 48 hrs.
- Calculating fluid maintenance
- Maintenance fluid volumes should be calculated using the Holliday – Segar formula (the traditional method of calculating fluid volume in children in the UK):
- 100 ml/kg/day (4 ml/kg/hr) for the first 10 kg body weight PLUS
- 50 ml/kg/day (2 ml/kg/hr) for the next 10 to 20 kg PLUS
- 20 ml/kg/day (1 ml/kg/hr) for each additional kilogram above 20 kg.
- Maintenance fluid volumes should be calculated using the Holliday – Segar formula (the traditional method of calculating fluid volume in children in the UK):
- Total fluid requirement calculation
- Calculate the fluid deficit as described above. Subtract the initial 10 ml/kg bolus then divide this over 48 hours to give an hourly rate.
- Calculate the maintenance fluids as described above. If calculated using ml/kg/day, divide this over 24 hours to give an hourly rate.
- Add these volumes together i.e. Hourly rate = ({Deficit – initial bolus} / 48hr) + Maintenance per hour. Give the total volume evenly over the next 48 hours.
- N.B. Wherever possible the patient’s actual weight on admission should be used rather than an estimated weight or approximation. A maximum weight of 75 kg should be used for the calculation of fluid replacement and deficit as this ensures that excessive volumes of fluids are not given.
- Initial fluid bolus
- Potassium
- Ensure that all fluids (except any initial boluses given) contain 40 mmol/l potassium chloride, unless there is evidence of renal failure.
- Where potassium is above the upper limit of the normal range at presentation it is recommended that potassium is only added to intravenous fluids after the patient has passed urine or until after the potassium has fallen to within the upper limit of the normal range.
- Insulin
- Once rehydration fluids and potassium are running, blood glucose levels will start to fall. There is some evidence that cerebral oedema is more likely if insulin is started early. Therefore start an intravenous insulin infusion 1-2 hours after beginning intravenous fluid therapy. Do not give bolus doses of intravenous insulin.
- Insulin rates of 0.05 Units/kg/hr and 0.1 Units/kg/hr are typically suggested.
- An infusion rate of 0.05 Units/kg/hr is likely to be sufficient in most cases, and may have a lower incidence of subsequent hypoglycaemia, though in severe DKA an infusion rate of 0.1 Units/kg/hr may be needed.
- The recommendation of the BSPED working group was that a starting dose of 0.05 Units/kg/hr should be used unless severe DKA or in adolescents. In children younger than 5 years 0.05 Units/kg/hr was suggested (consensus recommendation) to reduce the incidence of subsequent hypoglycaemia.
- Once the blood glucose has fallen to 14 mmol/l add glucose to the fluid and think about the insulin infusion rate, as follows:
- Change the fluid to contain 5% glucose
- Reduce insulin infusion rate to 0.05 units/kg/hr from 0.1 Units/kg/hour (or maintain at that rate if patient initiated on 0.05 units/kg/hr)
- Once ketones are < 1.0 mmol/l, consider switching from intravenous to subcutaneous insulin
Treating cerebral oedema:
Immediately assess a child or young person with DKA for suspected cerebral oedema and treat as necessary if they have any of these early manifestations:
- headache
- agitation or irritability
- unexpected fall in heart rate
- increased blood pressure
Immediately treat for cerebral oedema if a child or young person develops any of these signs:
- deterioration in level of consciousness
- abnormalities of breathing pattern, for example respiratory pauses &/or drop in SaO2.
- oculomotor palsies
- abnormal posturing
- pupillary inequality or dilatation
Treat immediately with the most readily available of
- hypertonic saline (2.7% or 3% 2.5-5 ml/kg over 10-15 minutes) or
- mannitol (20% 0.5-1 g/kg over 10-15 minutes)
Many intensivists prefer hypertonic saline to mannitol but the key point is that treatment should not be delayed sourcing either – so give what is available.
In addition fluids should be restricted to ½ maintenance rates and senior staff informed immediately.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
