Diabetic Ketoacidosis Dr. Osama Y Kentab, M.D,FAAP,FACEP Assistant Professor of Emergency Medicine - KSAU Clinical Assistant Professor Pediatrics – KSU Consultant Pediatric Emergency Medicine KAMC – KFH - Riyadh

Definition Diabetic Ketoacidosis is a stat of metabolic acidosis, hyperglycemia and ketonemia where: Acidosis: arterial ( or capillary) pH < 7.3 and/ or serum HCO3- OF < 15 mmol/L Hyperglycemia: Blood glucose of > 15 mmol/L Ketonemia: positive ketones in serum or urine

Pathophysiology Diabetic ketoacidosis is the result of complex metabolic derangements caused by insulinopenia and increased levels of counter regulatory hormones mainly glucagon. Metabolic consequences of DKA includes the following: Hyperglycemia Ketoacidosis Hypovolemia Electrolyte Disturbances

Hyperglycemia Two hormonal abnormalities appear to be necessary for expression of these abnormalities: insulin deficiency (and/or resistance) glucagon excess (which may be induced both by removal of the normal suppressive effect of insulin and by a concurrent defect in the pancreatic A cell). With hyperglycemia, for example, insulin deficiency impairs peripheral glucose utilization in skeletal muscle and increases both fat and muscle breakdown, leading to enhanced delivery of gluconeogenetic precursors (glycerol and alanine) to the liver . Both insulin deficiency and, more importantly, glucagon excess then promote hepatic gluconeogenesis

The genesis of ketoacidosis Insulin deficiency leads to enhanced lipolysis → ↑ free fatty acid delivery to the liver. Normal subjects, however, will convert these fatty acids primarily into triglycerides. The development of ketoacidosis requires a specific alteration in hepatic metabolism so that free fatty acyl CoA can enter the mitochondria, where conversion to ketones occurs . Mitochondrial entry is regulated by the enzyme carnitine palmitoyl transferase, the activity of which is low in the fed state but is markedly increased by glucagon excess.

Hypovolemia Osmotic diuresis due to hyperglycemia leads to renal free water loss. Hypovolemia will increase catecholamines level. 

Electrolyte Disturbances: Potassium Total body potassium is depleted due to renal loss. However , the intial serum potassium is either normal or increase due to acidosis. Once acidosis is corrected the serum level of potassium will decrease. Sodium Serum level is decreased due to dilution effect of hyperglycemia and partially due to renal loss. Sodium will decrease by 1.6 meq/L for every 100 mg/dL increment in blood glucose above 100mg/dL Phosphate, magnesium and calcium : Are always depleted due to renal loss. However, they usually do not present a problem unless they are very low. Phosphate therapy is not recommended because it precipitates with calcium, causing hypocalcemia.

Differential diagnosis DKA must be differentiated from other causes of coma and metabolic acidosis, these include: hypoglycemia uremia gastroenteritis with metabolic acidosis lactic acidosis salicylate intoxication encephalitis and other intracranial lesions Nonketotic hyperosmolar coma

DIAGNOSIS The diagnosis of DKA is usually suspected from the history and the presence of hyperglycemia with a high anion gap metabolic acidosis.   History: Polydipsia, polyuria and may have abdomial pain and/ or vomiting Clinical: Acidotic respiration, dehydration. Confirmation of the diagnosis requires the demonstration of hyperglucosemia plus ketonemia or ketonuria .

Investigations blood glucose urea and electrolytes venous blood gas except if patient is in coma or hemodynamically unstable urinalysis for glucose, ketones, protein ECG for hypo or hyperkalemia Others if indicated: CBC, Blood C/S, Urine for micro, culture and sensitivity , CXR.

TREATMENT Therapy in DKA include the administration of insulin and correction of each the fluid and electrolyte abnormalities that is present: hyperglycemia Hyperosmolality Hypovolemia metabolic acidosis potassium and phosphate depletion

TREATMENT Insulin Insulin acts to lower the plasma glucose concentration (primarily by decreasing hepatic glucose production rather than enhancing peripheral utilization) , to diminish ketone production (by reducing both lipolysis and glucagon secretion), and perhaps to augment ketone utilization . The net effect is a 65 to 125 mg/dL (3.6 to 7 mmol/L) per hour reduction in the plasma glucose concentration induced by insulin alone , with fluid repletion adding another 35 to 70 mg/dL (2 to 4 mmol/L) per hour

TREATMENT Insulin therapy may be withheld for 30 to 60 minutes in patients who are markedly hypovolemic to allow the initial administration of 1 to 2 liters of isotonic saline. Insulin alone drives glucose and, due to the ensuing fall in plasma osmolality, water into the cells, an effect that can exacerbate the extracellular volume depletion.

TREATMENT Hypovolemia The aim of therapy is to replete the extracellular fluid volume without inducing cerebral edema due to too rapid reduction in the plasma osmolality.

TREATMENT Potassium depletion Both renal and gastrointestinal losses can contribute to an often marked degree of potassium depletion. The plasma potassium concentration is usually normal or, in about one-third of cases, elevated at presentation due primarily to hyperosmolality and insulin deficiency . Careful monitoring is required, with potassium repletion being instituted once insulin and fluids have lowered to plasma potassium concentration to 4.5 meq/L.

TREATMENT Metabolic acidosis Insulin largely corrects the acidemia in DKA, as bicarbonate is generated from the metabolism of ketoacid anions. The major indications for bicarbonate supplementation are severe acidemia (arterial pH below 7.0 ), a relatively normal anion gap due to the urinary loss of the ketoacid anions, or severe hyperkalemia (since bicarbonate will drive some of the excess potassium into the cells).

TREATMENT Phosphate depletion Cellular phosphate depletion is another common problem in uncontrolled diabetes mellitus, although the plasma phosphate concentration may initially be normal or elevated due to movement of phosphate out of the cells . As with hyperkalemia, the phosphate depletion is rapidly unmasked following the institution of insulin therapy, frequently leading to hypophosphatemia. Most patients remain asymptomatic and prophylactic phosphate administration is more likely to be harmful than beneficial.

Management Full clinical assessment and observations: Assess and record in the notes, so that comparisons can be made by others later. Degree of Dehydration: Conscious Level: If alert or drowsy institute hourly neurological observations. If in coma on admission, or there is any subsequent deterioration, record Glasgow Coma Score transfer to ICU consider instituting cerebral oedema management Full Examination looking particularly for evidence of – cerebral oedema irritability, slow pulse, high blood pressure, papilloedema. N.B. Examine fundi but this a late sign.

Management Does the child need to be in ICU? YES if comatose, or >10% dehydrated with shock, or staffing levels on the wards are insufficient to allow adequate monitoring. Observations to be carried out: Ensure full instructions are given to the senior nursing staff emphasizing the need for: strict fluid balance and urine testing of every sample daily weight hourly or more frequent neuro observations initially reporting immediately to the medical staff, even at night, symptoms of headache or any change in either conscious level or behavior reporting any changes in the ECG trace, especially T wave changes.

Steps in Management of Diabetic Ketoacidosis ABCs Protect the airway Treat shock Determine underlying cause  

Steps in Management of Diabetic Ketoacidosis  Fluid Initial 10 mL/kg normal saline in 1 hr. (20 mL/kg rapidly if in shock) This may be repeated as necessary. Subsequently Assume 10% dehydration ,Fluid replacement should be gradual (24 hr) Maximum fluid administration 4 L/m2/day (including initial boluses) Normal saline used from 1 to 6 hr. then 50% normal saline D5 ½ N.S. if blood sugar < 18mmol/dl Continue intravenous fluids until oral fluids are well tolerated and the metabolic defects are corrected.

Steps in Management of Diabetic Ketoacidosis Insulin Initial IV: 0.1 unit/kg/hr by continuous infusion after 1st hour of fliud therapy Subsequent Double if no improvement in glucose or pH by 3 hr. Maximum glucose decline: 3 to 5 mmol/L/hr. At 15 mmol/L glucose, add dextrose to intravenous solutions (up to 12.5%) as needed to maintain plasma glucose at 12- 15 mmol/L Continue insulin regimen until the academia is corrected (pH >7.3 and/or HCO3 >18) Start subcutaneous insulin with a 1-hr overlap in the intravenous.

Steps in Management of Diabetic Ketoacidosis Potassium Monitor ECG If the K+ is <3.5 mEq/L, add 40 to 60 mEq/L; if 3.5 to 5, and 30 mEq/L; if >5.0, then hold K+ replacement After 3-5 hr. half of K+ replacement as K+ phosphate

Steps in Management of Diabetic Ketoacidosis Bicarbonate Only use bicarbonate (HCO3-) for pH <7.0 Increase pH to 7.1 or final bicarbonate to 12 mEq/L [mEq HCO3- = 12- measured HCO3- x 0.6 x body weight (in kg] Add HCO3- slowly maximum 50 mEq/500 mL IV solution (over 2-3 hr) Maximum HCO3- should be 50 mEq/500 mL IV solution

COMPLICATIONS OF DKA Hypoglycemia Hypophosphasemic muscle weakness during recovery from DKA Acute tubular necrosis from severe dehydration Hemolysis due to acidosis Myoglobinuria due to acidosis Pulmonary edema and adult respiratory distress syndrome secondary to fluid overload Cardiovascular complications ( seen more in adults than children) CNS complications: Thrombovascular phenomena (22 to dehydration and hypercoagulability of DKA) cerebral edema.

Cerebral edema may cause brain herniation and consequent severe brain damage or death. Occur after or during recovery from diabetic ketoacidosis Etiology: unknown seen mainly in children with DKA.

Cerebral edema hypothesis: hyponatermia leading to inappropriate regulation of vassopressin secreation. idiogenic osmoles

Cerebral edema Idiogenic osmoles Recovery from DKA: During DKA: Osmotic disequilibrium between brain and periphery is connected to intracerebrally by the generation of hypothetical osmotically active particles termed idiogenic osmoles that serve to maintain brain tissue isosmolar with the blood. Recovery from DKA: If rapid: dissipation of idiogenic osmoles may be inappropriately slow and influx of water into cerebral cells causes brain edema.

Cerebral edema-signs and symptoms headache that is often sudden and severe confusion irritability reduced conscious level fits (seizures) small pupils increasing BP, slowing pulse papilloedema (not always present acutely) possibly respiratory impairment

Cerebral edema-Management Exclude hypoglycemia The following measures should be taken: give Mannitol 0.5 g/kg stat (=2.5 ml/kg Mannitol 20% over 15 minutes). This needs to be given within 10 minutes. restrict IV fluids to 2/3 maintenance and replace deficit over 72 rather than 24 hours the child will need to be moved to ICU (if not there already) arrange for the child to be intubated and, hyperventilated to reduced blood pCO2 inform neurosurgeons exclude other diagnoses by CT scan – other intracerebral events may occur (thrombosis, hemorrhage or infarction) and present in the same way intracerebral pressure monitoring may be required repeated doses of Mannitol (above dose every 6 hours) should be used to control intracranial pressure.

Cerebral edema-Prognosis 50% die 50% survive but majority with severe brain damage

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