Treatment of Hypoglycemia

Abstract

Hypoglycemia is an important condition that can be seen in everyone, more often in those with diabetes mellitus, and can sometimes be life-threatening. Hypoglycemia is a condition that can be prevented with simple precautions. It is a simple procedure that can be done mostly by ordinary people when the treatment is known. The most important step in the treatment is the education of those at risk of hypoglycemia and their relatives. The first step in treatment is to measure blood glucose, if possible. If blood sugar is below 70 mg/dl, hypoglycemia is diagnosed; if it is below 50 mg/dl, it is called severe hypoglycemia. The first approach in a conscious patient is to give the patient 15 mg of carbohydrate and measure the blood glucose again after 15 minutes. If the measured value is <70 mg/dl, the procedure should be repeated. If possible, glucagon should be administered to unconscious, out-of-hospital hypoglycemic patients until emergency help arrives. If glucagon is not available, glucose gel can be applied to the buccal mucosa. 50 ml of 50% glucose IV is administered to an unconscious hypoglycemic patient in the hospital. If the blood sugar does not rise above 70 mg/dl, the procedure is repeated.

1. Introduction

Hypoglycemia is generally considered to be a plasma blood glucose level of less than 4 mmol/L (70 mg/dL) in patients with diabetes mellitus. In general, the ‘Whipple triad’ (glycemia <50 mg/dL, symptoms suitable with low glycemia and these symptoms improve with a treatment that increases low glycemia) is sufficient for the diagnosis of hypoglycemia in persons with nondiabetics, although the plasma glucose level is above 50 mg/dL, most diabetic patients need treatment because of the symptoms of hypoglycemia [1].

2. Symptoms of acute hypoglycemia

It is divided into two main groups: adrenergic (neurogenic, autonomic) and neuroglycopenic [2]:

2.1 Adrenergic signs and symptoms

It develops due to the activation of the autonomic nervous system and the adrenal medulla.

• Shaking.

• Cold sweats.

• Anxiety.

• Nausea.

• Palpitations.

• Numbness.

2.2 Neuroglycopenic signs and symptoms

It develops due to decreased glucose delivery to the cerebral cortex.

• Dizziness.

• Headache.

• İnability to concentrate.

• Difficulty speaking.

• Fatigue.

• Confusion.

3. Classification of hypoglycemia

Dividing symptomatic hypoglycemia into three according to the following clinical criteria is beneficial in terms of managing hypoglycemia;

3.1 Mild hypoglycemia

A condition in which the patient can detect and treat hypoglycemia ownself. Blood glucose is less than 70 mg/dL but is 54 mg/dL or higher.

Symptoms:

Sweating.

Shaking.

Nausea.

Extreme hunger.

Nervousness.

Dizziness.

3.2 Moderate hypoglycemia

It is the situation when the patient has to go to someone else’s aid, but treatment is possible orally. Blood glucose is less than 54 mg/dL.

Symptoms:

Difficulty concentrating or speaking.

Confusion.

Weakness.

Vision changes.

Mood swings.

3.3 Severe hypoglycemia

When the patient is unconscious or unable to take oral glucose due to excessive disorientation and the treatment has to be administered parenterally as glucagon injection or intravenous glucose [3, 4].

Symptoms:

Confusion.

Dizziness.

Nausea or vomiting.

Shortness of breath.

Tremors or chills.

Extreme anxiety.

Irritability and changes in behavior.

Profuse sweating.

Pale, clammy skin.

Rapid heartbeat.

Extreme fatigue or sleepiness.

Loss of consciousness.

Seizures.

4. Treatment of hypoglycemia

4.1 Mild and moderate hypoglycemia

Mild hypoglycemic episodes can be prevented if a patient maintains a healthy diet and blood sugar levels are monitored regularly. For example, eating frequent small meals and having a few small snacks throughout the day will work in preventing hypoglycemia and keeping the patient’s blood sugar under control. A good general rule is to eat six small meals each day, enough to meet your total daily carbohydrate needs. You should also drink plenty of water throughout the day. Treatment of mild hypoglycemia usually involves taking glucose tablets and/or foods containing simple sugars in case of hypoglycemia. However, this type of treatment is usually only necessary when you have no other choice. If patients continue to experience hypoglycemia despite following appropriate treatment and a healthy lifestyle, they should talk to their physician to revisal of their treatment [5].

Studies have shown that the glycemic response to oral glucose is transient, typically less than 2 hours. It was concluded that in the case of persistent or recurrent hypoglycemia, although oral glucose is effective, this is a temporary measure and may require a more substantial snack or meal followed by a meal. There is a “rules of 15” that recommends treating blood sugar <70 mg/dL by eating or drinking, a popular treatment strategy for mild hypoglycemia. 15 g carbs and repeat this treatment if symptoms persist after 15 minutes [6].

4.2 Severe hypoglycemia

Out of hospital: It is recommended that immediate administration of glucagon, if available, for the treatment of hypoglycemia in an unconscious person and in whom IV treatment is not possible. Administration of glucagon (subcutaneous, intramuscular, or nasal) will usually result in recovery of consciousness within about 15 minutes, although this may be followed by marked nausea and even vomiting. Therefore, the dose of glucagon should be followed by oral intake of concentrated carbohydrates just before the patient regains consciousness and nausea develops [7]. In the absence of glucagon, there are no conclusive data to guide the management of severe hypoglycaemia in patients with impaired consciousness who do not have immediate access to glucagon or intravenously (IV) dextrose (while emergency personnel are waiting). In a study on normoglycemic volunteers, buccal absorption of glucose was shown to be minimal. However, due to the lack of other options for such patients, some authors suggest that while awaiting emergency personnel, family members may apply a glucose gel (e.g., teeth and buccal mucosa) with the patient’s head tilted slightly to the side [8]. If a glucose gel or pastry cream is not available There is some data showing that sprinkling table sugar under the tongue may be effective [9].

In hospital: Patients currently in the hospital can usually be treated quickly by administering 25 g of 50% glucose (dextrose) IV. Capillary blood glucose measurement must be repeated after 10 minutes. If it is still less than 70 mg/dL repeat IV glucose administration (Figure 1) [7].

Figure 1.

Treatment of Hypoglycemia.

5. Glucagon therapy

Glucagon exerts its hyperglycemic effects mainly by stimulating hepatic glycogenolysis. Unlike insulin, glucagon promotes catabolism and releases glucose [10]. Unlike other peptide hormones (e.g., insulin), glucagon does not show a clear dose-response relationship, suggesting that the glycemic response to glucagon is saturable. Increasing doses of glucagon do not result in a dose-dependent increase in glucose. Therefore, fixed doses are usually used. This situation has recently paved the way for the use of mini-doses of glucagon administered in doses of 100–150 μg instead of 1 mg to prevent or treat mild hypoglycemia [11].

5.1 Intranasal glucagon

Intranasal glucagon is a simple system that inserts the tip of the device into one nostril and empties the powder into the nostril. In a randomized trial comparing intranasal (3 mg) and intramuscular (1 mg) glucagon in patients with type 1 diabetes (T1DM) and hypoglycemia, hypoglycemia was successfully corrected in 98.7% and 100% of patients. The time taken for glucose values to rise above 70 mg/dL was 16 min for intranasal administration and 13 min for intramuscular administration [12].

5.2 Stable, liquid glucagon

Glucagon (or its glucagon analog) can be administered using a syringe kit as a pre-filled syringe containing a single-dose vial, all containing a fixed-dose, stable liquid glucagon preparation (dilution is not required) [13]. In studies in patients with type 1 diabetes, the improvement effects of hypoglycemia were similar in patients receiving 1 mg of stable liquid glucagon, 1 mg of reconstituted glucagon, or 0.6 mg of a glucagon receptor agonist (daciglucagon) [14].

5.3 Reconstituted glucagon

Glucagon lyophilized powder requires reconstitution just before use. It is administered subcutaneously or intramuscularly (1 mg). In an emergency, the dilution work may force the helpers into the environment [15].

6. Treatment of hypoglycemia in special cases

6.1 Strick glycemic control

In the treatment of diabetes, tight control is an important strategy in the prevention of microvascular complications. However, the morbidity and potential mortality of hypoglycemia are proven downsides of intensive glycemic management of diabetes [16]. There is strong evidence that tight glycemic control with insulin, sulfonylurea and glinide increases hypoglycemic morbidity and mortality in T1DM and type 2 diabetes (T2DM) [17, 18]. Therefore, alternative drugs with low hypoglycemic effect should be preferred if regulation can be achieved.

6.2 Lipohyperthyrophy at injection sites

Lipohyperthyrophy is an area of thickened subcutaneous fat tissue which is become due to the administering of continuous injection of insulin to the same area and incorrect rotation. When injecting insulin into the lipohypertrophic area, absorption is irregular, the rate of absorption is unpredictable and may cause glycemic fluctuations such as hypoglycemia [19]. Development of lipohypertrophy is preventable by changing the injection site (rotation) and not using insulin needles more than once [20].

6.3 Hypoglycaemia unawareness

Hypoglycemia unawareness (HU) refers to the occurrence of neuroglycopenia before the onset of warning symptoms in response to hypoglycemia. It is a condition that prevents strict diabetes regulation and reduces the quality of life, occurs in approximately 40% of people with T1DM and less frequently in T2DM [21]. Blood glucose monitoring, individualized goals and educational programs are important for the prevention and management of HU. Glycemic targets should be individualized, targeting less stringent regulation, especially for patients with long-standing diabetes, patients at high risk of HU and severe hypoglycemia, and/or patients with multiple comorbidities [22].

6.4 Severe hepatic dysfunctions

Hypoglycemia occurs when gluconeogenesis fails, especially in severe conditions such as liver failure where liver glycogen stores are reduced. The liver is one of the most important organs of glucose balance. Any disorders of its metabolism, structural integrity, or cellular functioning may impair the liver’s ability to maintain normal glucose homeostasis. If such a disruption affects hepatic glucose output and gluconeogenesis, hypoglycemia may be occurred [23]. For patients with active liver disease, restrictive diets can often worsen protein-calorie malnutrition [24]. Most oral antidiabetic drugs are metabolized in the liver, and decreased glycogen stores are a risk factor for insulin-induced hypoglycemia, therefore strict monitoring of blood glucose levels should be performed during treatment in diabetic patients [25].

6.5 Impaired renal functions

Chronic kidney disease (CKD) can increase the risk of hypoglycemia. Decreased GFR is associated with decreased renal gluconeogenesis and clearance of insulin and other glucose-lowering drugs, and attenuation of the efficacy of regulatory mechanisms against hypoglycemia. Therefore, an individualized approach to diabetes management is essential, especially for patients with advanced CKD [26].

7. Prevention of hypoglycemia

Patient education, appropriate diet and exercise regimens, blood glucose monitoring, appropriate antidiabetic drug selection, and close clinical follow-up are necessary to prevent hypoglycemia [7].

7.1 Patient education

Patients and those around them should be educated about recognizing the symptoms of hypoglycemia and giving appropriate treatment for hypoglycemia as soon as possible. It is important to explain to patients the potential dangers of hypoglycemia and how it should be treated in patients treated with insulin, a sulfonylurea or glinide. Any documented hypoglycemia should be investigated with the patient to try to identify the causes, e.g., skipped meals/prolonged fasting, physical exertion, alcohol consumption, and injection of high insulin dose.

Diabetic patients at high risk of hypoglycemia are instructed to always carry glucagon with them. Family members and people around the patients with diabetes should be educated about the administration of glucagon to the patient; they also need to know where the glucagon is being held. There are subcutaneous, intramuscular injections, and intranasal forms of glucagon in the market.

7.2 Diet regulation

Dietary adjustment includes information about the amount of carbohydrates in meals and its effect on blood sugar concentration, and creating a personalized regular meal plan. The importance of administering insulin with the appropriate dose and timing regarding meals should be emphasized in patients receiving insulin therapy. Patients at risk of hypoglycemia should be advised to keep foods containing glucose or carbohydrates with them or in an accessible place. In some patients, especially those with T1DM or at high risk of nocturnal hypoglycemia, a bedtime snack may be recommended to prevent nocturnal hypoglycemia.

7.3 Recommendations on physical exercise

Physical exercise increases the risk of hypoglycemia by increasing glucose consumption. If necessary, early action can be taken to prevent hypoglycemia by measuring blood glucose before and after physical exercise. If there is a decrease in glucose level to the level of hypoglycemia, small meals should be eaten before physical exercise. Patients should be carried fast-acting carbohydrates with them during physical exercise. When planning physical exercise, it is important to adjust the insulin dose according to the exercise. Insulin doses should be reduced, more in heavy exercise and less in light exercise.

7.4 Medication adjustment

In patients receiving diabetes treatment, episodes of hypoglycemia may be associated with the treatment itself; therefore, it is important to use drugs with the low risk of hypoglycemia in such patients. Metformin, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and pioglitazone are drugs with a low risk of hypoglycemia. In contrast, sulfonylureas and glinides are associated with a higher risk of hypoglycemia; Therefore, if treatment-related hypoglycemia occurs, it is recommended to consider reducing or discontinuing the dose of these drugs and switching to a different treatment [27].

With the transition to the use of long-acting basal insulin analogues (such as Detemir and Glargine U100), a significant reduction in nocturnal hypoglycemia attacks was achieved compared to Neutral Protamine Hagedorn (NPH) insulin [28]. The new ultra-long basal insulins Glargine U300 and Degludec have recently led to a significant additional reduction in the rate of nocturnal hypoglycemia [29]. The use of short-acting insulin analogs has resulted in a significant reduction in the rates of severe hypoglycemia compared to conventional human insulin [30].