Coma, ketoacidotic E87.2

From the year 1711, records of Valentini are found in which he described an apple or violet-like pervasive odor of the body and urine in a patient suffering from diabetes mellitus, which most closely corresponds to the smell of acetone. Joseph Kaulich (1830 - 1886) confirmed this observation in 1860 and named the clinical picture "acetonemia".

In 1842, William Prout (1785 - 1850) was the first to record all the symptoms of diabetic coma(Schadewaldt 1975).

Adolf Kußmaul (1822 - 1902) was the first to describe the special breathing in coma diabeticum in 1874, which was later named after him and is known as Kußmaul respiration (Kluge 2003).

Howard Root described in 1945 that the mortality rate of diabetic ketoacidosis, which existed until 1940, could be reduced from 12% to 1.6% by high insulin doses (Dhatariya 2017).

Ketoacidotic coma is a life-threatening metabolic complication of diabetes mellitus caused by absolute insulin deficiency and characterized by:

• hyperglycemia
• metabolic acidosis
• Increase in circulating ketone bodies in the blood (Meyhöfer 2020).

Another form of ketoacidotic coma shows metabolic acidosis and an increase in ketone bodies, but the blood glucose level is < 200 mg / dl. This defines euglycemic ketoacidosis (EDKA).

[Modi 201])

Ketoacidotic coma (DKA = diabetic ketoacidosis [Kasper 2015]), together with hyperosmolar coma (HHS = hyperglycemic hyperosmolar state [Kasper 2015]), belongs to the group of hyperglycemic comas(Herold 2020).

Ketoacidotic coma itself is divided into a:

• hyperglycemic diabetic ketoacidosis
• euglycemic diabetic ketoacidosis

(Karslioglu 2019)

Diabetic ketoacidosis is differentiated between different degrees of severity:

• mild: pH < 7.3 bicarbonate < 15 mmol / l
• moderate: pH < 7.2 bicarbonate < 10 mmol / l
• severe: pH < 7.1 bicarbonate < 5 mmol / l

(Herold 2020)

In the last 10 years, the incidence of diabetic ketoacidosis has increased (Karslioglu 2019). However, ketoacidosis rarely progresses to coma (Lohr 2002).

DKA is the most common coma, accounting for 80-90% (Waldhäusl 2013).

The incidence is estimated at 6.4 - 14 cases per 100,000 population or 4.6 - 8 cases per 1,000 diabetics. In 20 - 30 % it is the first manifestation of DM (Mehnert 2003).

DKA occurs preferentially in type 1 DM but can also occur in type 2 DM, then predominantly in patients who are of the ketosis-prone type, also referred to as "flatbush" (Evans 2019), such as individuals:

• Hispanic, African American (Kasper 2015), or of Caribbean descent (Evans 2019).

In addition to hyperglycemic ketoacidotic coma, increasing attention is being paid to euglycemic diabetic ketoacidosis (EDKA), which also occurs in both type 1 DM and type 2 DM (Nasa 2021).

The most common cause of diabetic ketoacidosis is acute infection (increased insulin requirement) with approximately 45%, followed by insufficient exogenous insulin intake with approximately 20%, initial diagnosis of DM, and alcohol or drug problems (Karslioglu 2019).

• Infections of the:
  • Respiratory
  • Gastrointestinal tract
  • Genitourinary tract (Adeyinka 2021).
• insufficient exogenous insulin supply due to e.g:
  • inadequate prescription of insulin
  • Technical errors in measurement or injection (Herold 2020).
  • fear of hypoglycaemia
  • fear of weight gain (Karslioglu 2019)
• lack of exogenous insulin supply:
  • Initial manifestation of previously unknown diabetes mellitus
  • Interruption of insulin administration with insulin pumps
  • Incorrect storage of insulin (too hot or too cold)
  • inadequate treatment (tablets instead of insulin when insulin is needed)
  • omitted injection
  • defects of the pen (Herold 2020)
• increased insulin requirement:
  • accident
  • operation
  • gastrointestinal diseases
  • infections (see above)
  • dietary errors
  • Gravidity
  • Hyperthyroidism (Herold 2020)
  • Treatment with corticosteroids, saluretics (Herold 2020), beta blockers (Ellinger 2007)
  • Acute myocardial infarction (Herold 2020)
  • stress (Ellinger 2007)
  • pancreatitis (Haak 2018)

Euglycemic ketoacidosis:

EDKA can be caused by:

• Treatment with SGLT2- inhibitors (Karslioglu 2019).
• Suspected genetic factors in type 2 DM, so-called flatbush (see "Occurrence") (Evans 2019).

Discussed as possible etiologies are:

• Pregnancy (pathophysiology unclear)
• recent use of insulin
• significant alcohol consumption
• decreased caloric intake
• disorders of glycogen stores
• chronic liver disease (Modi 2017)
• cocaine abuse (Abdin 2016)

In DKA, both a relative and an absolute insulin deficiency are present.

This leads to hepatic gluconeogenesis and lipolysis despite the increased BG values.

In the latter, ketone bodies such as acetone, acetoacetic acid and beta-hydroxybutyric acid are formed. The acids cause a drop in pH, increase the anion gap and lead to a consumption of bicarbonate (Reitgruber 2021).

Both hyperglycemia and the high concentration of ketone bodies result in osmotic diuresis associated with losses of chloride, potassium, calcium, magnesium, sodium, and phosphate.

Osmotic diuresis also leads to hypovolemia with decrease in glomerular filtration rate (Karslioglu 2019).

Diabetic decompensation is differentiated into three different clinical forms:

• 1. cardiovascular form:

Here there is, for example, a volume deficiency, shock, etc.

• 2. pseudoperitonitis form:

In this form, there are peritoneal irritation symptoms with gastric and intestinal atony (danger of gastric hyperinflation!).

• 3. renal form:

This leads to acute renal failure.

(Herold 2020)

Ketoacidotic coma develops very suddenly, within hours or a few days (Lohr 2002) - in contrast to hyperosmolar coma, which shows an insidious onset (Herold 2020).

In DKA, the spectrum of symptoms ranges from mild ketoacidotic metabolic derailment to life-threatening diabetic coma, with the severity of symptoms correlating with the severity of ketoacidosis (Haak 2018).

In the prodromal stage of DKA, there is usually polyuria (primary; due to osmotic diuresis [Berndt 2015]), polydipsia, and diffuse abdominal pain with nausea (Lohr 2002).

The following symptoms may be added:

• Dyspnea
• Tachypnea (Reitgruber 2021)
• Vomiting (caused by a ketosis [Berndt 2015]
• abdominal pain up to the so-called "pseudoperitonitis diabeticum".

This is triggered by hypokalemia and acidosis (Berndt 2015).

• lack of appetite
• weight loss (due to diuresis, catabolism [Berndt 2015])
• reduced AZ
• general weakness
• Signs of dehydration such as:
  • detachable, standing skin folds
  • dry oral cavity (dehydration caused by osmotic diuresis [Berndt 2015])
  • muscle cramps (caused by fluid and electrolyte loss [Berndt 2015])
  • Blood pressure drop (also caused by fluid and electrolyte loss [Berndt 2015])
  • Oligo-anuria (secondary).
• Kussmaul respiration to compensate for acidosis
• Acetone odor of exhaled air
• Failure of reflexes
• Gastroparesis (caused by the hyperglycemia [Berndt 2015]).

In the moderate severity of DKA, general drowsiness is added, which is accompanied by loss of consciousness in severe forms(Haak 2018).

In patients with euglycemic ketoacidosis, polyuria and polydipsia are usually not as pronounced. Here, tachycardia and tachypnea with or without fever are more prominent (Karslioglu 2019).

Since the clinical symptoms are sometimes not always clear, sometimes the precipitating clinical picture such as infection, apoplexy, myocardial infarction, etc., is clinically leading (Haak 2018).

Physical examination

• Evidence of exsiccosis
• Tachypnea
• Kussmaul respiration
• Tachycardia
• Acetone odor
• pseudoperitonitis symptoms

(Reitgruber 2021)

Glasgow- Coma- Scale: The severity of the disturbance of consciousness is determined with the Glasgow- Coma- Scale , where the score can range from 3 to 15 points (Herold 2020).

DKA is defined biochemically as:

• Blood glucose > 250 mg / dl (13.9 mmol / l)

plus

• Ketonemia

and / or

• Ketonuria

and / or

• arterial pH < 7.35

or

• venous pH < 7.3
• Serum bicarbonate < 270 mg / dl (15 mmol / l)

(Haak 2018)

Suspicious for DKA are:

• Ketone bodies in the urine or blood
• Hyperglycemia

If these values are pathological, it is recommended to determine the following values for further diagnosis:

• arterial and venous blood gas analysis
• blood count
• potassium
• serum creatinine
• CRP (Haak 2018).

The American Diabetes Association (ADA), the Joint British Diabetes Societies for Inpatient Care, and the American Association of Clinical Endocrinologists recommend direct measurement of acetoacetate in urine or β-hydroxybutyrate in blood (Karslioglu 2019).

Blood cultures should also be taken in cases of v. a. infections (Haak 2018).

• acute abdomen with signs of peritonitis (Herold 2020)
• euglycemic diabetic coma
• hyperosmolar coma (no Kussmaul's respiration, no acetone odor of exhaled air, blood sugar > 600 mg / dl, etc. [Plewa 2021]).

In the case of sudden unconsciousness, differential diagnosis include:

• Cardiovascular e.g:
  • Shock
  • collapse
  • Adam- Stokes- seizure
  • Circulatory arrest (Herold 2020)
• Cerebral disorders e. g.:
  • subarachnoid haemorrhage
  • subdural / epidural hematoma
  • hypertonic mass hemorrhage
  • sinus thrombosis
  • Meningitis
  • encephalitis
  • encephalomalacia
  • Craniocerebral trauma
  • Epilepsy
  • generalized seizure (Herold 2020)
• Endocrine disorders e. g.:
  • hypoglycemic shock see hypoglycemic coma (hypertonic muscles, skin moist, respiration normal etc. [Herold 2020])
  • Addison's crisis (see Addison's disease)
  • diabetes insipidus
  • pituitary coma
  • hypercalcemic crisis
  • thyrotoxic crisis
  • myxedematous coma (Herold 2020)
• Toxic e. g.:
  • exogenous poisoning by
  • Alcohol (the clinical picture of alcoholic ketoacidosis [AKA] is very similar [Plewa 2021].
  • Drugs, especially heroin
  • Psychotropic drugs
  • Sedatives
  • endogenous poisoning by
  • coma hepaticum
  • uremia (Herold 2020)
• Anoxemic e. g.:
  • hypercapnia in respiratory global insufficiency
  • asphyxia (Herold 2020)
• Lactic acidotic coma e. g.:
  • severe hypoxia
  • Leigh encephalopathy (rare [Danne 2016])
  • NW of a therapy with biguanides
  • Infusion with fructose in case of fructose intolerance
• Mental e. g.:
  • Hysteria (Herold 2020)

• venous thrombi
• acute respiratory distress syndrome
• cerebral edema (often develops in children as DKA subsides; both the etiology and treatment of cerebral edema have not yet been clearly established)
• upper gastrointestinal hemorrhage (Kasper 2015)
• hyperchloremic acidosis (due to excessive amounts of NaCl solution [Berndt 2015])
• Hypokalemia (predominantly the result of delayed supplementation of potassium)
• hyperkalemia (rare, mostly affecting patients with renal dysfunction)
• Myocardial infarction
• Pulmonary edema (Karslioglu 2019).

The rate of complications is increased in patients with ketoacidosis even after hospitalization, e.g. apoplexy is 1.55 times more frequent than in patients without previous ketoacidosis (Karslioglu 2019).

In the event of a clinical indication of moderate or severe DKA, patients should be admitted to hospital immediately for intensive care treatment. In the case of a mild form, outpatient treatment may be possible (Haak 2018).

For intensive medical therapy, it may be necessary to:

• bladder catheter for balancing
• central venous catheter for ZVD measurement
• Gastric tube for the pseudoperitonitis form (Herold 2020).

The following should be monitored:

• half-hourly:
  • Blood pressure
  • Heart rate (Haak 2018)
• hourly:
  • Blood glucose
• every 2 h:
  • Base excess
  • Bicarbona
  • Sodium
  • Potassium
  • Glasgow Coma Scale
  • Blood gas analysis with pH- value (Herold 2020 / Haak 2018)

Prophylaxis required regarding:

• Thromboembolism (see thrombosis prophylaxis)
• Decubitus
• Pneumonia (Herold 2020)

The following therapeutic principles are recommended for DKA:

• Initial volume administration of 1 l isotonic solution (e.g., 0.9% NaCl) within the first hour to stabilize the circulation. Subsequently, fluids and electrolytesshould be administered depending on concomitant diseases, age, height, and weight (the supply of 6 l / 24 h may be required in the process [Haak 2018]).

In patients with known heart failure, there is a risk of pulmonary edema due to too rapid an infusion rate. In this case, infusion should therefore be slow (Herold 2020).

• Potassium:

Hypokalemia must be compensated before insulin treatment, since insulin shifts potassium to intracellular levels, posing a risk of hypoglycemic ventricular fibrillation (Herold 2020).

• Substitution of potassium at a pH of > 7.1:
  • for potassium > 4 - 5 mmol /l substitution of 10 - 15 mmol / l
  • with potassium 3 - 4 mmol / l substitution of 15 - 20 mmol / l
  • for potassium < 3 mmol / l substitution of 20 - 25 mmol / l (Herold 2020)

A maximum of 40 mmol of potassium chloride should be infused per 1,000 ml of NaCl 0.9% at a time (Haak 2018). Contraindication to potassium administration is anuria (Herold 2020).

If hypokalemia of < 3 mmol / l occurs during insulin therapy, insulin administration should be interrupted - if possible (Herold 2020).

The target value of serum potassium should be > 3.5 mmol / l (Kasper 2015).

• Insulin

Insulin delivery should be via a perfusor.

In exsiccosis, insulin can act poorly, so primary volume administration is required to achieve a good effect of insulin (Reitgruber 2021).

In shock, patients should be treated with normal ins ulin only; the duration of action is 20-40 min, and the half-life is <10 min (Herold 2020).

Blood glucose concentration should be reduced by 50 mg / dl / h (2.8 mmol / l), but not lower than 250 mg / dl during the first 24 h to avoid cerebral edema and retinal damage (Herold 2020).

From a blood glucose concentration of 300 mg / dl (16.7 mmol / l), an infusion with 10% glucose should run in parallel to avoid

- a too rapid drop in blood glucose (Haak 2018)

- of lipolysis with an increase in free fatty acids (Herold 2020).

"Low-dose" insulin therapy is recommended in most patients, i.e.:

- initial bolus of 0.10 - 0.15 IU / kg bw i. v. and subsequently about 5 IU normal insulin / h i. v. via the dosing pump (Herold 2020).

If blood glucose does not drop within 2 h, the patient requires higher doses of insulin due to insulin resistance. To break this resistance, the insulin dose should be doubled. In rare cases, an even higher amount of insulin may be needed beyond that (Herold 2020).

• Bicarbonate:

Bicarbonate should only be substituted from a pH- value < 7.0 and only until correction to pH 7.1 (Haak 2018), since lipolysis is inhibited under insulin therapy anyway. The dosage should be only 25% of the calculated requirement to avoid hypokalemia (Herold 2020). Too high a dose of bicarbonate also increases the risk of cerebral edema (Kasper 2015).

• Sodium:

Sodium is substituted as part of infusion therapy (Herold 2020).

• Phosphate:

Phosphate is usually within the normal range. If the value is < 0.5 mmol / l, substitution of about 50 mmol / 24 h may be recommended. However, phosphate is contraindicated in renal insufficiency (Herold 2020).

• Magnesium:

Magnesium deficiency may occur under treatment of DKA, which requires appropriate substitution (Kasper 2015).

• specific therapy such as.
  • Antibiotics, etc.

• Causal research (Haak 2018).

The complication rate can be reduced by:

• low-dose insulin therapy
• slow compensation of the metabolic derailments (Herold 2020).

The CNS needs some time to normalize the water shifts triggered by the coma. Therefore, the patient may remain unconscious despite normalization of blood glucose, electrolytes, pH and volume balance. This disturbance usually disappears with a delay (Herold 2020).

The diet should start with a light diet. A small amount of normal insulin s. c. should be injected before each meal. Subsequently, readjustment of DM is required (Herold 2020).

With appropriate, early therapy, the lethality of DKA is low and is < 1 %. It is more likely to be related to the triggering causes(myocardial infarction, infection, etc.) than to the DKA itself (Kasper 2015).

In diabetic children, however, DKA remains the most common cause of death (Waldhäusl 2013).

Type 1 diabetics are recommended to perform regular test strip measurements for the detection of ketone bodies in the urine for the prophylaxis of diabetic ketoacidotic coma (Haak 2018).

It is essential to clarify the cause of ketoacidotic coma and educate the patient accordingly to prevent recurrence (Karslioglu 2019).

Diabetic patients should also be educated about the symptoms and precipitating factors of DKA, as well as behavior regarding diabetes mellitus. During a disease or even when oral food intake is impaired, the patient should:

• measure blood glucose frequently
• measure ketones in the urine as soon as the BG is > 300 mg / dl (16.5 mmol / l)
• drink plenty of fluids
• Continue insulin administration
• consult a doctor as soon as
  • uncontrolled hyperglycaemia occurs
  • persistent vomiting occurs
  • in the case of dehydration

(Kasper 2015)

Euglycemic ketoacidosis:

Regarding euglycemic ketoacidosis, patients should be educated about the following behaviors:

• Discontinuation of SGLT2- inhibitors:
  • before planned surgery
  • during acute disease processes
• avoid dehydration at all costs
• excessive alcohol consumption as well (Karslioglu 2019).

In case of elevated concentrations of ketones, further progression may be avoided with the following strategy:

• DiscontinueSGLT2 inhibitors immediately.
• Inject bolus insulin
• Add approx. 30 g of carbohydrates
• Hydration with water
• Check ketone levels every 3 - 4 hours (Karslioglu 2019).

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