Hyperglycemic emergencies

Hyperglycemic crisis is a metabolic emergency associated with uncontrolled diabetes mellitus that may result in significant morbidity or death.

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History:

The first detailed clinical description of diabetic coma in an adult patient with severe polydipsia, polyuria, and a large amount of glucose in the urine followed by progressive decline in mental status and death was reported by August W. von Stosch in 1828. This publication was followed by several case reports describing young and adult patients, with newly diagnosed or with established diabetes, who presented with abrupt clinical course of excessive polyuria, glycosuria, coma and death. In 1874, The German physician Adolf Kussmaul reported that many cases of diabetic coma were preceded by deep and frequent respiration and severe dyspnea. Kussmaul breathing rapidly became one of the hallmarks of diabetic coma. Shortly after that, it was reported that in many of these patients, the urine contained large amounts of acetoacetic acid and β-hydroxybutyric acid. Dr. Julius Dreshfeld in 1886, was first to provide a comprehensive description of the two different categories of diabetic coma, one with Kussmaul breathing and positive ketones and the other, an unusual type of diabetic coma in older, well-nourished individuals, characterized by severe hyperglycemia and glycosuria but without Kussmaul breathing, fruity breath odor, or a positive urine acetone test.

Prior to the discovery of insulin in 1921, the mortality rate of patients with diabetic ketoacidosis was over 90%. The first successful case of DKA treated with insulin was reported by Banting and Best in a 14-year-old boy who presented with a blood glucose of 580 mg/dL and strongly positive urinary ketones at the Toronto General Hospital in 1923. They reported a dramatic improvement in glycosuria along with disappearance of acetone bodies in the urine after a few doses of pancreatic extract injections. Following the discovery of insulin, mortality rate associated with diabetic comas fell dramatically to 60% in 1923 and 25% by 1930’s, 7–10% in the 1970s and is currently less than 2% in patients for DKA and between 5–16% in patients with HHS.

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Etiology

Drug-induced hyperglycemia:

Several medications that altered carbohydrate metabolism may precipitate the development of DKA and HHS

• Glucocorticoids
• β-blockers
• Thiazide diuretics
• Certain chemotherapeutic agents
• Atypical antipsychotics
• Sodium glucose co-transporter 2 (SGLT2) inhibitors (newer oral antidiabetic agents): Associated with DKA in patients with T1D and T2D

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Pathophysiology

Insulin deficit with counter-regulatory hormone upregulation:

The two most important pathophysiologic mechanisms for DKA and HHS are significant insulin deficiency and increased concentration of counter-regulatory hormones such as glucagon, catecholamines, cortisol, and growth hormone.

Oxidative stress/Inflammation:

Development of hyperglycemia and ketoacidosis results in an inflammatory state characterized by an elevation of pro-inflammatory cytokines and increased oxidative stress markers. The increased inflammatory response, oxidative stress and generation of reactive oxygen species (ROS) can lead to capillary perturbation and cellular damage of lipids, membranes, proteins, and DNA

• Severe hyperglycemia-induced macrophage production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF α), interleukin (IL)-6 and IL-1β, and C-reactive protein, which in turn lead to impaired insulin secretion as well as reduced insulin sensitivity
• Elevation in FFAs also increases insulin resistance as well as impaired nitric oxide production in endothelial cells and endothelial dysfunction.

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Diabetic ketoacidosis (DKA):

Increased Ketone Bodies and ketoacidosis: Decrease in insulin levels combined with increased in counter-regulatory hormones, particularly epinephrine causes the activation of hormone sensitive lipase (HSL) in adipose tissue and breakdown of triglyceride into glycerol and free fatty acids (FFAs). In the liver, FFAs are oxidized to ketone bodies, a process predominantly stimulated by glucagon. The two major ketone bodies are β-hydroxybutyrate and acetoacetic acid. Accumulation of ketone bodies leads to a decrease in serum bicarbonate concentration and metabolic acidosis. Higher insulin levels present in HHS inhibit ketogenesis and limit metabolic acidosis.

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Hyperglycemic hyperosmolar state (HHS):

Increased Glucose Production in DKA and HHS: When insulin is deficient, hyperglycemia develops as a result of three processes: increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues. Hyperglycemia cause osmotic diuresis that lead to hypovolemia, decreased glomerular filtration rate and worsening hyperglycemia.

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Presentation

Euglycemic DKA (EDKA/euDKA):

Some patients exhibit only mild elevations in plasma glucose levels (termed ‘euglycemic DKA’). This phenomenon has been reported during pregnancy, in patients with prolonged starvation, alcohol intake, pregnancy, partially treated patients receiving insulin, and more recently in the setting of SGLT-2 inhibitor use.

Ketosis-Prone Diabetes (KPD) ‘Flatbush diabetes’:

The genotype looks like idiopathic T1D but phenotype looks like T2D. Usually a middle aged obese man presents with DKA at diagnosis of new onset diabetes. Initial aggressive insulin therapy settles the acute stage. Subsequently, diet alone or a combination with oral hypoglycaemics can achieve glycaemic without need of insulin

• Aβ KPD classification: Based on presence/absence of autoantibodies and the presence/absence of β-cell functional reserve
  1. A + β − (A: Autoantibodies presence; β: β-cell function)  
  2. A + β + 
  3. A − β −
  4. A − β + 

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Diagnosis

Nitroprusside reaction:

Provides a semi-quantitative estimation of acetoacetate and acetone levels. The test can however, underestimate the severity of ketoacidosis because this assay does not recognize the presence of β-hydroxybutyrate, the main metabolic product in ketoacidosis. Therefore, direct measurement of serum β-hydroxybutyrate is preferred for diagnosis.

Differential diagnosis:

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Management

American Diabetes Association algorithm for the management of hyperglycemic emergencies:

In general, treatment goals include correction of dehydration, hyperglycemia and hyperosmolality, electrolyte imbalance, increased ketonemia, and identification and treatment of precipitating event(s). The average time to resolution between 10–18 hours for DKA and 9–11 hours for HHS. During treatment, frequent monitoring of vital signs, volume and rate of fluid administration, insulin dosage, and urine output are needed to assess response to medical treatment. In addition, laboratory measurements of glucose and electrolytes, venous pH, bicarbonate, and anion gap should be repeated every 2–4 hours.

Fluid Therapy:

Intravenous (IV) fluids are a critical aspect of treatment of hyperglycemic emergencies. Treatment with IV fluids alone expands intravascular volume, restores renal perfusion and reduces insulin resistance by decreasing circulating counter-regulatory hormone levels. Adequate fluid resuscitation is of particular importance in management of HHS, as many of them, may see improvement in or resolution of mental status changes with correction of fluid deficits.

1. Isotonic saline (0.9% NaCl): Preferred solution and given at an initial rate of 500–1000 mL/hour during the first 2–4 hours. (time to correct hyperglycemia is significantly longer in the lactate ringers)
2. After volume depletion has been corrected: Rate of NS infusion reduced to 250 mL/h or changed to 0.45% saline (250–500 mL/h)
3. Once the plasma glucose level reaches ~200 mg/dL (11.1 mosm/L): 5–10% dextrose added to replacement fluids (allow continued insulin administration until ketonemia is corrected, while avoiding hypoglycemia)

Potassium:

Metabolic acidosis and insulin deficiency both lead to extracellular movement of potassium. Thus, although serum potassium levels may be normal or elevated in DKA, patients are actually total body depleted. Similarly, HHS is associated with total body potassium depletion due to lack of insulin and increased plasma osmolality. The total-body potassium deficit has been estimated to be ~3–5 mEq/kg. Potassium replacement should be started when the serum concentration is < 5.2 mEq/L to maintain a level of 4–5 mEq/L.

• Potassium replacement: 20–30 mEq potassium/L fluids sufficient for most patients (lower doses for acute/chronic renal failure)
• Among patients with admission hypokalemia, with serum potassium levels < 3.3 mEq/L, insulin administration may result in severe symptomatic hypokalemia with muscle weakness and increased risk of cardiac arrhythmias. In such patients, potassium replacement should begin at a rate of 10–20 mEq/h and insulin therapy should be delayed until the potassium level rises above 3.3 mEq/L.

Bicarbonate:

Recommended in patients with life threatening acidosis with pH <6.9. Bicarbonate therapy may increase the risk of hypokalemia and cerebral edema. In patients with mild DKA with pH >7.0 or with HHS, bicarbonate therapy is not indicated.

• Sodium bicarbonate: 50–100 mmol as an isotonic solution (in 400 mL of water) until pH is > 6.9.

Insulin:

Insulin administration is the mainstay of DKA therapy as it lowers the serum glucose by inhibiting endogenous glucose production and increasing peripheral utilization. Insulin also inhibits lipolysis, ketogenesis, and glucagon secretion, thereby decreasing the production of ketoacidosis.

• Continuous IV infusion of regular insulin (treatment of choice):
  • 0.1 unit/kg body weight bolus followed by continuous insulin infusion at 0.1 u/kg/hr
  • Dose reduced by half (0.05 u/kg/hr) when blood glucose is ~ 200 mg/dL and rate is adjusted between 0.02–0.05 u/kg/hr, along with the addition of 5% dextrose, to maintain glucose concentrations between 140 and 200 mg/dL until resolution of ketoacidosis

Resolution of crises:

• DKA resolution: Glucose < 250 mg/dl, venous pH > 7.30, normal anion gap, and serum bicarbonate ≥ 18 mEq/L
• HHS resolution: Serum osmolality < 310 mOsm/kg, glucose ≤ 250 mg/dL (13.8 mmol/l) with recovered mental alertness and regaining of mental status

Complications

Hypoglycemia (5–25% DKA cases):

M/C complication during treatment. Lack of frequent monitoring, and the failure to reduce insulin infusion rate and/or to use dextrose-containing solutions when blood glucose levels are < 200 mg/dL are the most important risk factors associated with hypoglycemia during insulin treatment.

• Hypoglycemia unawareness (initial feature): Loss of perception of warning symptoms of developing hypoglycemia
• Acute adverse outcomes: Seizures, arrhythmias and cardiovascular events

Hypokalemia:

#2 M/C complication during DKA & HHS treatment. During insulin treatment, plasma concentration of potassium will invariably decrease due increased cellular potassium uptake in peripheral tissues. to prevent hypokalemia, replacement with IV potassium is indicated.

• Serum K+ < 5.2 mEq/l: Replacement IV potassium indicated
• Serum K+ < 3.3 mEq/L: IV potassium replacement immediately and insulin therapy held until serum potassium is ≥ 3.3 mEq/L to avoid severe hypokalemia

Cerebral edema (rare):

Due disruption of the blood–brain barrier. The degree of edema formation during DKA in children correlates with the degree of dehydration and hyperventilation at presentation, but it does not correlate with initial osmolality, osmotic changes during treatment, or rate of fluid or sodium administration

• Clinical features:
  • Altered mentation or fluctuating level of consciousness
  • Abnormal motor or verbal response to pain
  • Decorticate or decerebrate posturing
  • Cranial nerve palsy (especially III, IV, and VI)
  • Abnormal neurogenic respiratory pattern (e.g., grunting, tachypnea, Cheyne–Stokes respiration.
• Treatment:
  • IV mannitol: 0.5–1 g/kg over 20 min (repeat if no initial response in 30 min)
  • Hypertonic saline (3%): 5–10 mL/kg over 30 min (alternative to mannitol)

Rhabdomyolysis:

May occur in DKA and more commonly with HHS resulting in increased risk of acute kidney failure.

• Classic symptom triad:
  • Myalgia
  • Weakness
  • Dark urine
• Monitoring creatine kinase every 2-3 h recommended for early detection