What Is Ketoacidosis?
Ketoacidosis is a medical condition that is mainly characterized by the 3 following abnormalities :
- High blood concentration of glucose
- High blood and urine concentration of ketone bodies
- High blood acid levels
The most common type of ketoacidosis occurs as a complication of diabetes. In diabetic ketoacidosis, the low level of insulin and the excess of its opposing hormones cause the buildup of glucose in the blood and the breakdown of fatty molecules into ketone bodies in the liver .
Although diabetic ketoacidosis is more common in patients with type 1 diabetes, it can also occur in those with type 2 diabetes. Its frequency is higher in those of African, African-American, or Hispanic origin .
Other types of ketoacidosis include:
- Starvation ketoacidosis: Caused by prolonged fasting periods 
- Alcoholic ketoacidosis: Caused by long-term alcohol abuse 
- Salicylate ketoacidosis: Caused by intoxication with salicylate (found in painkillers) 
- Inborn ketoacidosis: Caused by genetic changes in proteins used for ketone body production and breakdown 
- Lactation ketoacidosis: May spontaneously appear in breastfeeding women 
The 3 main factors that cause ketoacidosis are :
- Infections, such as pneumonia and urinary tract infections (30 to 50% of cases)
- Inadequate treatment of diabetes (20 to 40%)
- Undiagnosed diabetes (20 to 30%)
Additional, less frequent causes include :
- Heart attack
- Blockage of lung vessels
- Pancreas inflammation
- Bowel obstruction
- Kidney failure
- Alcohol abuse
- Severe burns
- Use of certain medications
In 2 to 10% of cases, no cause can be identified .
Mechanism of Ketoacidosis
Diabetic patients have low blood insulin levels, while neurotransmitters (catecholamines) and the following insulin-opposing hormones are found at high concentrations :
In normal conditions, insulin prevents sugar production and fat breakdown. An imbalance between insulin and its opposing hormones triggers the mechanisms of diabetic ketoacidosis .
1) Glucose Buildup
The low blood insulin levels, as well as the high concentration of glucagon, cortisol, and neurotransmitters (catecholamines), activate 2 types of sugar (glucose) production pathways :
- Breakdown of sugar stores in the liver (glycogenolysis)
- Production of sugar from non-sugar compounds (gluconeogenesis)
2) Ketone Buildup and Acidosis
The resulting fatty acids build up in the liver, where they are transformed into the following ketone bodies :
Ketone bodies raise blood acid levels and exhaust the molecules (e.g., bicarbonate) used to neutralize them, making the condition worse .
Alternatively, the lactate produced by sugar store breakdown also contributes to blood acidosis .
3) Water and Electrolyte Imbalance
High glucose levels in bodily fluids cause the movement of water and ions (electrolytes) out of cells .
The kidney cannot absorb too much glucose, which is found in the urine when concentrations get too high. This causes more frequent urination, which can lead to a deficiency in water and the following electrolytes :
4) Other Types of Ketoacidosis
In starvation ketoacidosis, prolonged fasting :
- Exhausts sugar stores in the liver
- Decreases insulin levels
- Increases the levels of insulin-opposing hormones
- Increases use of ketone bodies for energy
In alcoholic ketoacidosis, long-term alcohol abuse is normally accompanied by malnutrition. The exhaustion of sugar and protein stores increases ketone bodies .
Salicylate intoxication can cause acidosis by :
- Stimulating lactate production (which is used to produce sugar)
- Increasing fatty acid breakdown and decreasing blood sugar levels (which causes the build-up of ketone bodies)
- Increasing blood acid levels
Inborn ketoacidosis is caused by genetic defects in enzymes involved in the production and breakdown of ketone bodies .
Symptoms of Ketoacidosis
- Dehydration and excessive thirst
- Excessive urine production
- Excessive appetite
- Weight loss
- Nausea and vomiting, ‘coffee-ground’ vomiting
- Stomach pain, upper bowel, and stomach bleeding
- Nail polish- or fruity-smelling breath
- Rapid and deep breathing
- Dry mucosae and rougher skin
- High heart rate and low blood pressure
- Normal to low body temperature
- Sleepiness, confusion, or coma
- Blurred vision
- Leg cramps
If emergency nurses detect several of the symptoms listed in the previous section, they must conduct quick bedside testing for blood glucose and blood or urine ketones .
The blood chemistry is analyzed to determine :
- Glucose concentration
- Ketone concentration
- Blood osmolality (electrolyte-water balance)
- C-reactive protein count to detect inflammation
- Troponin T concentration to detect heart failure
- Full blood count
- Coagulation profile to confirm normal blood clotting function
- Kidney and liver function
- Toxicology screen for harmful chemicals (e.g., salicylate)
Additionally, urine tests must be performed to analyze :
- Ketone concentration
- Nitrite presence to detect infections
- Presence of a specific hormone (β-human chorionic gonadotropin) to detect pregnancy
- White blood cell levels to detect infections, stress, and dehydration
The subsequent laboratory evaluation must include :
- Blood gases to assess blood acidosis
- Chest X-ray to detect infections and breathing complications
- Electrocardiogram to identify signs of heart disease, especially in patients with ion imbalance
- Bacterial samples of blood, urine, and sputum to identify infectious organisms and test for the presence of ketone bodies
Diabetic ketoacidosis is diagnosed in the presence of :
- High urine ketone concentration (above 3 mmol/l)
- High blood glucose concentration (above 250 mg/dl) or presence of type 1 diabetes
- Low blood bicarbonate concentration (below 18 mmol/l) or high acidosis (pH below 7.3) in the veins
Additionally, the following conditions confirm the diagnosis :
- Low sodium levels (below 149 mmol/l)
- High blood creatinine concentration (above 0.12 mmol/l)
- High blood osmolality (above 320 mmol/kg)
The consequences for children can be serious. In juvenile cases, 1 to 2% of children with diabetic ketoacidosis suffer from dangerous fluid buildup in the brain.
- In a study of 8 children and adolescents, those with diabetic ketoacidosis performed worse in some types of intelligence tests .
- Children with sudden brain damage caused by diabetic ketoacidosis all suffered from brain stroke (a study of 5 children) .
- A 5-year-old child with diabetic ketoacidosis developed thrombosis in the brain .
- In 2 studies on children and adolescents with severe diabetic ketoacidosis, all of them had signs of fluid buildup in the lungs [35, 36].
Diabetic ketoacidosis can lead to serious complications in adults too.
- Approximately 20% of patients with severe ketoacidosis are admitted in a coma .
- Ketoacidosis can also cause the irritation of the protective layers of the brain (meningeal syndrome) .
- A 50-year-old patient with recurrent diabetic ketoacidosis episodes lost vision in one eye due to nerve damage .
- On very rare occasions, diabetic ketoacidosis can cause the obstructive buildup of fluid in the brain (hydrocephalus) .
- Ketoacidosis increases the risk of patients developing thrombosis since it causes dehydration, reduced blood vessel volume, heart problems, and increased blood thickness [40, 41].
Diabetic ketoacidosis can damage the muscles, kidneys, stomach, and other vital organs.
- Several case studies described the rapid breakdown of damaged muscles (rhabdomyolysis) in patients with diabetic ketoacidosis. In some cases, it was accompanied by a severe reaction that causes fever, muscle stiffness, and fast heart rate (malignant hyperthermia) [42, 43, 44].
- In a study of 284 patients with diabetic ketoacidosis, 26 had bleeding in the stomach and upper bowels .
- Severe diabetic ketoacidosis can cause kidney failure [46, 47].
- In a study of 21 patients with severe diabetic ketoacidosis, most non-survivors had developed multiple organ failures .
The successful treatment of ketoacidosis depends on adequately :
- Providing fluids to restore blood circulation and correct dehydration
- Giving insulin to stop the generation of ketone bodies
- Replacing electrolytes
- Treating any causes
- Monitoring complications during therapy
1) Fluid Therapy
Fluid therapy has the following positive effects :
- It increases the amount of fluids inside and outside the vessels, increasing volume, which improves blood circulation into the kidneys
- It increases glucose elimination in the urine
- It reduces the concentration of insulin-opposing hormones
The goal of this therapy is to replace 50% of the total water loss during the first 8 hours and the rest over the next 16 to 24 hours .
2) Insulin Therapy
Ketoacidosis was fatal before the discovery of insulin in the 1920s. Thanks to insulin therapy, its death rate has been reduced to less than 1% in developed countries .
Some patients with diabetic ketoacidosis have potassium deficits. Because insulin therapy may further decrease the blood levels of this ion, it is important to make sure that its concentration is not too low (at least 3.3 mmol/l) before starting the treatment .
In a study on 48 patients with diabetic ketoacidosis, low doses of insulin were as efficient as high-dose therapies at reducing blood glucose levels. The low-dose treatment showed a lower risk of glucose and potassium deficits .
A study (RCT) on 40 patients found that insulin injections into the veins and muscles are equally safe, but the former acts faster to reduce glucose and ketone levels .
Insulin (initial dose of 0.1 U per kg an hour) is infused during the treatment until the blood glucose concentration reaches a normal level (250 mg/dl) .
At this point, the insulin dose may be reduced by half and supplemented with glucose (5%). The treatment is continued until acidosis is resolved (blood bicarbonate level over 18 mmol/l and pH exceeding 7.3) .
3) Potassium Therapy
Patients with ketoacidosis may have low blood potassium levels, especially if they have been vomiting or taking diuretics .
Generally, potassium is infused to ensure that its blood concentration is within the normal range (4-5 mmol/l) .
In patients with severe potassium deficits, it is important to monitor heart function .
4) Bicarbonate Therapy
The use of bicarbonate to correct acidosis remains controversial. Several studies have failed to demonstrate any benefits of its use except in extreme acidosis (pH below 6.9) .
A systematic review of 44 articles did not find any effects of bicarbonate therapy on ketoacidosis symptoms. Its intake was associated with increased risk of fluid buildup in the brain .
However, it is important to note that none of these studies included patients with a blood pH below 6.9. In this situation, patients may be given bicarbonate to prevent the negative impacts of severe acidosis on the heart, brain, and liver .
5) Phosphate Therapy
During insulin therapy, the entry of phosphate into the cells decreases its concentration in the blood. Although it occurs very rarely, phosphate deficit in the blood can cause the following complications :
- Muscle weakness
- Poor heart performance
- Limited oxygen delivery into tissues
A study (DB-RCT) of 44 patients with diabetic ketoacidosis did not find any beneficial effects of phosphate therapy on treatment duration, insulin dose required, muscle function, glucose levels, health status, or death risk .
Additionally, another study (DB-RCT) on 30 patients with diabetic ketoacidosis found an increased risk of calcium deficit in patients treated with phosphate .
Therefore, it is only recommended to apply phosphate therapy to patients with very low blood phosphate levels (below 1 mg/dl), or suffering from conditions such as heart failure, anemia, or breathing abnormality .
6) Magnesium Therapy
Blood magnesium deficits usually occur in patients with diabetic ketoacidosis. Symptoms of magnesium deficiency include :
- Pins and needles
- Muscle contractions
- Irregular heart rates
Treatment with magnesium sulfate is an option if the blood magnesium concentration is below normal (0.74 mmol/l) and symptoms are present .
7) Sodium Therapy
In patients with diabetic ketoacidosis, blood sodium deficits can occur. High blood glucose levels cause a decrease in sodium levels, and sodium therapy can be considered if it gets too low .
8) Treatment of Causes
The causes of ketoacidosis must be identified immediately to facilitate the management process. In case of infections, they must be appropriately treated .
It is important to recognize other factors that might be masked by the symptoms of diabetic ketoacidosis, such as :
- Heart attack
- Stomach and bowel bleeding
- Pancreas inflammation
- Blockage of lung vessels
The treatment of ketoacidosis can lead to the following complications:
1) Fluid Buildup in the Brain
During the first 24 hours of therapy, 0.5 to 2% of patients experience fluid buildup in the brain. This complication is most frequent in children .
The main early signs of this complication are :
- A Headache
- Behavioral changes
Other, less frequent symptoms include :
- Eye swelling
- High blood tension
- High body temperature
- Increased thirst and diluted urine (diabetes insipidus)
In severe cases, the patient can experience :
- Changes in pupils
- Breathing cessation
- Slow heart rate
Fluid buildup in the brain is the main cause of death in children with ketoacidosis, accounting for 31% of the deaths associated with this condition and 20% of the overall deaths in diabetic children .
Possible causes of this fluid buildup as a result of the treatment include :
- Increased water entry into brain tissues due to ion therapy
- Entry of electrolytes into brain tissues due to insulin therapy
- Restoring sodium levels too quickly
- Gradually correcting water and sodium deficits
- Minimizing glucose loss
- Adding glucose to therapy fluids once the blood concentration of this sugar has reached normal values (250 mg/dl)
- Avoiding bicarbonate therapy unless absolutely necessary
2) Adult Respiratory Distress Syndrome (ARDS)
This is when there is fluid buildup in the lung tissues. ARDS reduces lung function and dramatically decreases oxygen levels in the blood. The mechanisms and treatment of this condition are similar to those for fluid buildup in the brain .
3) Hyperchloremic Acidosis
This complication consists of blood acidosis with high chloride and low bicarbonate concentrations .
- Loss of ketone bodies, which are necessary to regenerate bicarbonate
- Infusion of fluid therapy containing high concentrations of chloride
- Infusion of bicarbonate-free solutions during fluid therapy
- Sodium bicarbonate entry into the cells during fluid therapy
The acidosis is normally temporary and is not a health concern, except in patients with kidney failure .
4) Glucose and Potassium Deficits
These complications are the most common ones due to :
- Excessive insulin intake (glucose deficit)
- Insulin intake combined with treatment against acidosis (potassium deficit)
Fluid therapy must correct the potassium deficit and 5% glucose added as soon as blood glucose levels reach normal values (250 mg/dl) to prevent deficits in this sugar .
It is also important not to interrupt insulin therapy too soon to prevent blood sugar levels from rising again .
1) Individual Factors
In two studies on 135 and 121 patients, the second member of the family affected by type 1 diabetes was less likely to present diabetic ketoacidosis due to the increased awareness of this condition by their families [81, 82].
2) Socio-economic Factors
The frequency of diabetic ketoacidosis is higher in ethnic minority groups. This is usually due to socio-economic factors like language barriers and difficulties in accessing health care [83, 84, 85, 86].
In 2 studies conducted in the US, the lack of private healthcare insurance increased the risk of children to present diabetic ketoacidosis, since their parents tended to avoid seeking medical care until the condition was severe [84, 90].
Two studies failed to find a negative correlation between family income and ketoacidosis incidence. However, another study on 735 patients showed that children from families with very low income had an almost 2-fold risk of developing this condition [89, 91, 92].
A study on 401 Swedish and 286 Lithuanian children assessed the correlation between the work status of the parents and the child incidence of diabetic ketoacidosis. While this factor was irrelevant in Lithuania, Swedish children with unemployed mothers had an almost 5-fold risk of developing this condition .
3) Medical Factors
- Undetected defects in the insulin pump
- Lack of education
- Eating disorders (especially frequent in adolescent girls)
- Not adhering to diabetes management guidelines (especially frequent in adolescent and elderly patients)
- Lack of adequate healthcare insurance (in adolescents and adults)
- Psychological or psychiatric disorders (in adolescents and adults)
Diabetic ketoacidosis was also more frequent if there was a delay of more than 24 hours between diabetes diagnosis and treatment start or if the hospital did not have a structured diabetic team [95, 98].
4) High-Risk Patients
- Diabetes may remain undiagnosed
- They are more prone to infections that mask the symptoms
- Ketosis and acidosis develop faster below this age
Children below this age are also more prone to complications such as fluid buildup in the brain 
Pregnant women have an increased risk of developing ketoacidosis since they have :
- Decreased sensitivity to insulin
- Increased sensitivity to starvation (accelerated starvation)
- Frequent nausea and vomiting
- Increased levels of insulin-opposing hormones
- Lower bicarbonate levels
Ketoacidosis can severely damage the fetus and must be carefully managed in pregnant women .
Older patients typically require more insulin to treat ketoacidosis, have a longer length of hospital stay, and higher death rates .
In patients suffering a stroke, fluid replenishment is slower. As a result, the effect of insulin may be reduced .
Patients with kidney failure are less efficient at eliminating excess glucose and ketone bodies as well as maintaining their water and ion balances. When treating them against ketoacidosis, it is important to note that these patients are more prone to:
- Extremely high sugar and ketone levels 
- Excessive potassium levels 
- Fluid overload 
- Changes in blood acid level 
- Blood acidosis with high chloride and low bicarbonate concentrations (hyperchloremic acidosis) 
Patients with a history of heart failure must be carefully monitored because the ion imbalance resulting from ketoacidosis can reduce heart function .
Additionally, heart failure stimulates the production of ketone bodies, which can make the ketoacidosis worse .
Prevention & Management
Patients with diagnosed type 1 diabetes and their social environment (parents, spouses, colleagues) must receive proper education on all the aspects of diabetes care, such as :
- Importance of adhering to insulin therapy
- The frequency of insulin use
- Insulin pump functioning
- Monitoring of main parameters (blood glucose, urine ketones)
- Blood glucose goals
- Sick-day management
- Use of a liquid diet containing sugars and salts when sick
- Guidelines for high-risk patients
- Early symptoms of ketoacidosis
- When to contact their healthcare providers
Young patients with recurrent ketoacidosis episodes must undergo a psychological evaluation to identify disorders that may contribute to it, such as :
- Eating disorders
- Sexual or physical abuse
SGLT2 blockers are medications for diabetic patients that lower blood glucose levels. They also reduce insulin blood levels and increase those of glucagon, which can worsen ketoacidosis. High-risk patients should avoid these types of drugs [115, 116].
Ketoacidosis vs. Nutritional Ketosis
Ketogenic diets are defined by low carbohydrate (typically below 50 g/day) and high fat intake and lead to the increased production of ketone bodies and fatty acids .
It is important to note that eating a ketogenic diet or fasting for a controlled time period will lead to ketosis but not to ketoacidosis:
- Blood glucose levels remain normal during ketosis because the liver starts producing this sugar from other sources like lactate, pyruvate, and amino acids after the carbohydrate stores have been exhausted 
- Because ketone bodies can inhibit their own production, blood ketone levels never exceed 8 mmol/l, which is a safe value during nutritional ketosis [120, 121]
- As opposed to the ketone concentrations reached during ketoacidosis (approximately 20 mmol/l), those of nutritional ketosis do not cause blood acidification 
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