📘 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 very much, 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 fat stores and 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, presence of ketone bodies (in blood and urine) and metabolic acidosis [1].

This state is dangerous because it affects several organs simultaneously. 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, kidneys and brain. Without timely treatment, ketoacidosis can lead to shock, coma and death. It is often the first sign that the pancreas has stopped insulin production. You should know that early recognition of symptoms and rapid presentation to the hospital completely change the evolution of the disease [1].

Worldwide, ketoacidosis occurs at the onset of type 1 diabetes in approximately three out of ten children and adolescents. Frequency varies greatly by country, from values below 13–20% in some high-income countries, up to over 60–80% in many low- and middle-income countries. The difference is explained by access to medical care, the level of public awareness about warning signs and the readiness of family doctors to recognize diabetes at the first visit [2].

Ketoacidosis at onset is much more frequent in young children, especially under 5 years and particularly under 2 years. At this age, the classic symptoms (excessive thirst, frequent urination) are difficult to observe in a child who still wears a diaper or does not yet talk. In addition, in young children the disease evolves faster, and dehydration and acidosis appear within a few days. The frequency of ketoacidosis at onset is higher 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 see the classic signs of high blood glucose: intense thirst, frequent urination (including at night), unintentional weight loss, marked fatigue and sometimes blurred vision. In children, bedwetting at night often appears, after a period in which they were already toilet-trained. As ketone bodies accumulate, nausea, repeated vomiting, abdominal pain, Kussmaul breathing (rapid and deep) and a characteristic odor of the breath, similar to ripe fruit or acetone, appear [3].

In advanced stages, the acid in the blood begins to interfere with proper brain function. Confusion, drowsiness, difficulty waking up appear, and finally coma. In young children these symptoms can be confused with flu, gastroenteritis or pneumonia, especially when vomiting and rapid breathing are in the foreground. If you or someone in your family has thirst much greater than usual, combined with frequent urination and weight loss, it is important to go quickly to a doctor for a check with the glucometer. A single measurement can prevent missing a serious situation [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 by venous pH below 7.3 or serum bicarbonate below 18 mEq/L (mmol/L). The third criterion is the presence of ketone bodies, measured either in blood (beta-hydroxybutyrate above 3 mmol/L), or in urine (at least two pluses on the rapid test). These analyses are done quickly in the emergency department, from a sample of venous blood and a urine test [1].

The severity of ketoacidosis is established based on 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 analyses are obtained in less than one hour in any hospital with an emergency department. If you have suggestive symptoms, rapid presentation to the hospital allows confirmation of the diagnosis and the start of treatment in the first hours, before the condition worsens [1].

At the onset of type 1 diabetes mellitus, the main cause of ketoacidosis is the lack of diagnosis and, consequently, of insulin treatment. The immune system has already destroyed the majority of 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 confused with other more common conditions, such as a urinary infection, gastroenteritis or flu. The lack of awareness in the family and sometimes among doctors regarding the warning signs (thirst, frequent urination, weight loss) is a major cause of missing an early diagnosis [5].

In addition to 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 symptoms are difficult to observe. The lack of a close relative with type 1 diabetes also matters, because families without experience caring for this disease recognize warning signs more slowly. A low socioeconomic status, reduced access to medical care and living in areas where type 1 diabetes is rare also increase the risk of a delayed diagnosis. Concurrent infections can accelerate the appearance 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, cardiac rhythm disturbances related to potassium changes and the collapse of blood pressure through reduction of blood volume (hypovolemic shock). The imbalance of salts in the blood, especially the drop in potassium after starting insulin treatment, requires careful monitoring [6].

In countries with good access to pediatric care and intensive therapy, mortality from ketoacidosis in children and adolescents is very low, close to zero. In regions with access limited to hospital, mortality remains higher and is due to late presentation or to the inability to ensure continuous monitoring. Cerebral edema is the main cause of death and can leave neurological sequelae in some of those who survive. The message you can keep in mind is that prompt treatment, with careful monitoring and a well-prepared medical team, maximizes your chances for full recovery [6].

Cerebral edema means swelling of the brain due to the accumulation of water in and between nerve cells. It is the most feared complication of diabetic ketoacidosis and appears especially in children (especially under 5 years) and the elderly. The mechanism involves changes that are too rapid in blood glucose and, implicitly, in blood osmolality. For this reason, rebalancing is done slowly, in a controlled manner, and insulin is administered so as to avoid too rapid a drop in blood glucose [6].

Cerebral edema usually appears in the first 4 to 12 hours from the start of treatment, but sometimes it can appear later. Warning signs include intense headaches, vomiting that returns after the condition seemed to be improving, behavioral changes, drowsiness, decrease in heart rate and increase in blood pressure. Medical staff carefully watch for the appearance of these signs. If they appear, treatment includes hypertonic saline solutions or mannitol, raising the head of the bed and reassessment in intensive care. Currently adherence to the slow rebalancing protocol has greatly reduced the risk of this complication [6].

The treatment of ketoacidosis is based on four pillars. The first pillar is volemic rebalancing, with fluids administered intravenously, usually with normal saline (0.9% sodium chloride). The water deficit is replaced gradually over 24–48 hours. The second pillar is insulin administered intravenously continuously, at a rate of usually 0.05–0.1 units/kg/hour, using regular human insulin. The third pillar is potassium replacement, which is added to the infusion solutions, 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), of electrolytes, pH and bicarbonate (every 2–4 hours) [1].

Sodium bicarbonate is not administered routinely (only at pH below 7), because it is associated with a higher risk of cerebral edema. Ketoacidosis is considered resolved when the pH is above 7.3, bicarbonate above 18 mmol/L, ketone bodies drop below 1 mmol/L and the patient tolerates oral feeding. At this moment the transition to insulin administered subcutaneously is made. Long-acting basal insulin (glargine or degludec) can be added early to the rapid one (even before the complete resolution of ketoacidosis), to shorten the time to resolution and to reduce the total need for insulin and fluids [7].

Hospitalization for ketoacidosis at the onset of type 1 diabetes mellitus generally lasts between 3 and 10 days, depending on the severity of the ketoacidosis and the education program of the center. In some centers with structured programs, the admission can reach 14 days, in order to integrate complete therapeutic education. Hospitalization has two phases. The first phase, of 12–36 hours, is dedicated to correction of the ketoacidosis, careful monitoring and specific intensive care. Ketoacidosis usually resolves biochemically in the first 12–24 hours. The second phase, of several days, is dedicated to initiation of subcutaneous insulin treatment and the start of therapeutic education [4].

Family education is just as important as the treatment itself. You will learn, together with your loved ones, what type 1 diabetes is, how insulin is administered with a pen or syringe, how injection sites are rotated, how blood glucose is monitored (capillary or with a continuous monitoring system), how you recognize and treat hypoglycemia, how you count carbohydrates and adjust doses. You will receive rules for sick days, instructions for using glucagon and possibly a written plan for school or workplace. The team is multidisciplinary (specialist doctor, educator nurse, dietitian, psychologist), and after discharge regular visits follow every 3 months [4].

The brothers and sisters of a patient with type 1 diabetes mellitus have an increased risk of developing the disease, compared to the general population. Type 1 diabetes begins long before the appearance of symptoms, through autoimmune destruction of beta cells. This phase can be detected by searching the blood for specific autoantibodies (GAD, IAA, IA-2, ZnT8). If a person has two or more such autoantibodies, the risk of developing clinical diabetes in the following years is very high. Screening through autoantibodies is recommended for first-degree relatives of any patient with type 1 diabetes. There are international programs that 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 increase in HbA1c), but without symptoms. Stage 3 is the clinical disease, when symptoms appear and insulin treatment is necessary. Identifying patients in stage 1 or 2 allows periodic monitoring, education about warning signs and an action plan, so that the diagnosis of stage 3 is made before the onset of ketoacidosis. The discussion with your diabetes doctor about screening, monitoring and therapeutic options for your first-degree relatives is the most effective step to protect your brothers and sisters [10].