Onset with ketoacidosis in type 1 diabetes

Diabetic ketoacidosis is an acute complication of diabetes mellitus, with the status of a medical emergency. It occurs when the insulin level drops sharply, beyond a personal threshold. Initially, the drop in insulin reduces glucose utilization and raises blood glucose. Unable to use glucose efficiently, the body breaks down its fat stores, and the free fatty acids are converted by the liver into ketone bodies. These are acidic and consume the bicarbonate in the blood. Ketoacidosis is thus defined by the combination of hyperglycemia, the presence of ketone bodies (in blood and urine) and metabolic acidosis [1].

This state is dangerous because it affects several organs at the same time. You lose a lot of water and salts through frequent urination, you become dehydrated rapidly, and potassium becomes unstable. The increased acidity disturbs the function of the heart, the kidneys and the brain. Without timely treatment, ketoacidosis can lead to shock, coma and death. It is often the first sign that the pancreas has stopped producing insulin. Recognizing the symptoms early and getting to hospital quickly completely changes how the disease unfolds [1].

Worldwide, ketoacidosis occurs at the onset of type 1 diabetes in roughly three out of ten children and adolescents. The frequency varies greatly from country to country. In some high-income countries it drops to 13–20%. In many low- and middle-income countries it reaches 60–80%. The difference is explained by access to medical care and by how well the public is informed about the warning signs. How prepared family doctors are to recognize diabetes at the first visit also matters [2].

Ketoacidosis at onset is much more common in young children, especially under 5 years and particularly under 2 years. At this age the classic symptoms (excessive thirst, frequent urination) are hard to spot in a child who still wears a nappy or cannot yet talk. In addition, in young children the disease progresses faster, and dehydration and acidosis can appear within a few days. Ketoacidosis at onset is also more frequent in areas where type 1 diabetes is rarer, because families and doctors are less likely to think of this condition [3].

Symptoms appear gradually, over the course of a few days. At first you notice the classic signs of high blood glucose: intense thirst, frequent urination (including at night), unintentional weight loss, marked tiredness and sometimes blurred vision. In children, bedwetting at night often appears, after a period in which they had already learned to use the potty. As the ketone bodies build up, nausea, repeated vomiting, abdominal pain, Kussmaul breathing (rapid and deep) and a characteristic odour on the breath, similar to ripe fruit or acetone, appear [3].

In advanced stages, the increased acidity of the blood impairs the way the brain works. Confusion, drowsiness, difficulty waking and finally coma set in. In young children these symptoms can be mistaken for flu, gastroenteritis or pneumonia, especially when vomiting and rapid breathing are to the fore. Thirst far greater than usual, together with frequent urination and weight loss, is a warning sign. If it appears in you or in someone in your family, go to the emergency room straight away. Ketoacidosis does not resolve at home and cannot wait for an appointment. A single blood glucose measurement can reveal a serious situation in time [4].

Diabetic ketoacidosis is defined by three criteria that must be present together. The first is blood glucose above 200 mg/dL (11.1 mmol/L) or an already known diagnosis of diabetes. The second is increased acidity of the blood, expressed as a venous pH below 7.3 or a serum bicarbonate (the substance that neutralizes the acids in the blood) below 18 mEq/L, that is, below 18 mmol/L. The third criterion is the presence of ketone bodies, measured either in the blood (beta-hydroxybutyrate above 3 mmol/L) or in the urine (at least two pluses, written as "++", on the rapid test strip). These tests are done quickly in the emergency department, from a sample of venous blood and a urine test [1].

The severity of ketoacidosis is graded by the blood pH. The mild form corresponds to a pH between 7.2 and 7.3, the moderate form to a pH between 7.1 and 7.2, and the severe form to a pH below 7.1. The lower the pH, the greater the dehydration and the risk of complications. These tests are obtained in under an hour in any hospital with an emergency department. If you have suggestive symptoms, getting to hospital quickly allows the diagnosis to be confirmed and treatment to be started within the first hours, before the condition worsens, as the figure below shows [1].

At the onset of type 1 diabetes, the main cause of ketoacidosis is the lack of a diagnosis and, as a result, of insulin treatment. The immune system has already destroyed most of the pancreatic beta cells, but the disease has not yet been recognized. Without insulin, blood glucose rises, the body burns fat and ketone bodies appear. In many situations the initial symptoms are mistaken for other, more common conditions, such as a urinary infection, gastroenteritis or flu. Families, and sometimes doctors, are not aware of the warning signs (thirst, frequent urination, weight loss). This lack of awareness is a major reason an early diagnosis is missed [5].

Alongside the delay in diagnosis, there are also factors that increase the risk of ketoacidosis at onset. Younger age is the most important factor, especially under 2 years, when the symptoms are hard to spot. Not having a close relative with type 1 diabetes also matters, because families with no experience of caring for this disease recognize the warning signs more slowly. A low socioeconomic status, limited access to medical care and living in areas where type 1 diabetes is rare also raise the risk of a delayed diagnosis. Concurrent infections can speed up the onset of ketoacidosis in a person who already has undiagnosed diabetes [3].

Diabetic ketoacidosis is a serious medical condition, an emergency that must be treated in hospital. The lower the pH and the more severe the dehydration, the higher the risk of complications. The most important complications are cerebral edema (especially in children under 5 years), acute kidney failure due to dehydration, heart rhythm disturbances linked to potassium changes and a collapse in blood pressure from the reduced blood volume (hypovolaemic shock). The imbalance of salts in the blood, especially the drop in potassium after insulin treatment is started, needs careful monitoring [6].

In countries with good access to pediatric care and intensive care, mortality from ketoacidosis in children and adolescents is very low, close to zero. In regions with limited access to hospital, mortality remains higher and is due to late presentation or to the inability to provide continuous monitoring. Cerebral edema is the main cause of death and can leave neurological after-effects in some of those who survive. Prompt treatment, with careful monitoring and a well-prepared medical team, offers the best chances of a full recovery [6].

Cerebral edema means swelling of the brain caused by water building up in and between the nerve cells. It is the most feared complication of diabetic ketoacidosis and occurs above all in children, especially those under 5 years. The mechanism involves too rapid a change in blood glucose, and therefore in blood osmolality (the concentration of particles dissolved in the blood). For this reason, rebalancing is carried out slowly and in a controlled way, and insulin is given so as to avoid too rapid a fall in blood glucose [6].

Cerebral edema usually appears in the first 4 to 12 hours after treatment is started, but it can sometimes appear later. Warning signs include severe headache, vomiting that returns after the condition seemed to be improving, behavioral changes, drowsiness, a slowing heart rate and a rise in blood pressure. Medical staff watch carefully for these signs. If they appear, treatment includes hypertonic saline or mannitol (a solution that draws water out of the swollen tissue), raising the head of the bed and reassessment in intensive care. Today, following the slow rebalancing protocol has greatly reduced the risk of this complication [6].

Ketoacidosis is treated only in hospital, by a medical team. The doses, thresholds and procedures described below show what doctors do; they are not instructions to follow at home. The treatment rests on four pillars. The first pillar is fluid resuscitation (restoring the fluid that has been lost), with fluids given intravenously, usually as normal saline (0.9% sodium chloride). The water deficit is replaced gradually over 24–48 hours. The second pillar is insulin given as a continuous intravenous infusion, usually at a rate of 0.05–0.1 units/kg/hour, using regular human insulin (a short-acting insulin). The third pillar is potassium replacement, added to the infusion fluids, because insulin and the change in blood acidity push potassium from the blood into the cells. The fourth pillar is monitoring of blood glucose (every 1–2 hours) and of electrolytes, pH and bicarbonate (every 2–4 hours) [1].

Sodium bicarbonate is not given routinely. It is considered only in severe acidosis with impaired cardiac contractility or in life-threatening hyperkalemia, because giving it is associated with a higher risk of cerebral edema in children [1]. Ketoacidosis is considered resolved when the pH is above 7.3, bicarbonate is above 18 mmol/L, ketone bodies drop below 1 mmol/L and the patient can tolerate eating. At this point the switch to insulin given under the skin is made. Long-acting basal insulin (glargine or degludec) can be added early to the rapid-acting one, even before ketoacidosis has fully resolved. This shortens the time to resolution and reduces the total need for insulin and fluids [7].

The hospital stay for ketoacidosis at the onset of type 1 diabetes usually lasts between 3 and 10 days. The length depends on the severity of the ketoacidosis and on the education program of the center. In some centers with structured programs, the stay can reach 14 days, in order to include complete therapeutic education. The stay has two phases. The first phase, of 12–36 hours, is dedicated to correcting the ketoacidosis, careful monitoring and specialized intensive care. Ketoacidosis usually resolves biochemically within the first 12–24 hours. The second phase, of several days, is dedicated to starting subcutaneous insulin treatment and beginning therapeutic education [4].

Educating the family is just as important as the treatment itself. Together with your loved ones, you will learn:

• what type 1 diabetes is;
• how insulin is given with a pen or syringe;
• how injection sites are rotated;
• how blood glucose is monitored (by finger-prick or with a continuous monitoring system);
• how to recognize and treat hypoglycemia;
• how to count carbohydrates and adjust doses.

You will be given sick-day rules, instructions for using glucagon and, possibly, a written plan for school or work. The team is multidisciplinary (specialist doctor, diabetes educator nurse, dietitian, psychologist), and after discharge follow-up visits take place every 3 months [4].

The brothers and sisters of a patient with type 1 diabetes have a higher risk of developing the disease than the general population. Type 1 diabetes begins long before symptoms appear, through the autoimmune destruction of the beta cells. This phase can be detected by looking in the blood for specific autoantibodies (GAD, IAA, IA-2, ZnT8). If a person has two or more of these autoantibodies, the risk of developing clinical diabetes in the following years is very high. Screening with autoantibodies is recommended for first-degree relatives of any patient with type 1 diabetes. International programs offer this screening, such as TrialNet, Fr1da, ASK, GPPAD and ELSA [8]. The disease is today divided into three stages. Stage 1 means the presence of at least two autoantibodies with normal blood glucose.

Stage 2 adds blood glucose disturbances (impaired fasting glucose, impaired glucose tolerance or a prediabetic rise in HbA1c), but without symptoms. Stage 3 is the clinical disease, when symptoms appear and insulin treatment becomes necessary. Identifying patients in stage 1 or 2 allows regular monitoring, education about the warning signs and an action plan. In this way, a stage 3 diagnosis can be made before ketoacidosis sets in. As part of the action plan, blood ketones (beta-hydroxybutyrate) can also be measured at home. To detect ketoacidosis early you can use portable meters or, more recently, continuous ketone monitoring systems [9]. Talk to your diabetes doctor about screening, monitoring and the treatment options for your first-degree relatives. This is the most effective step you can take to protect your brothers and sisters [10].