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Case study- Diabetic ketoacidosis
A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is distinctive smell from her breath
What is the most likely diagnosis?
Causes- DKA occurs most frequently in knownDiabetics. It may also be the first presentation in patients who had not been previously diagnosed as diabetics. There is often a particular underlying problem that has led to DKA episode. This may be-
1) Inter current illness such as Pneumonia,Influenza, Gastroenteritis, Urinary tract infection or pregnancy.
2) Inadequate Insulin administration may be due to defective insulin pen device or in young patient intentional missing of dose due to fear of weight gain.
3) Associated myocardial infarction, stroke or use of cocaine
4) Inadequate food intake– may be due to anorexia associated with infective process or due to eating disorder in children.
Diabetic keto acidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity,strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labelled “ketosis-prone type 2 diabetes”.
DKA results from relative or absolute insulin deficiency combined with counter regulatory hormone excess (Glucagon, Catecholamines, cortisol, and growth hormone). The decreased ratio of insulin to Glucagon promotes Gluconeogenesis,glycogenolysis, and Ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver.
a) Cause of hyperglycemia Uncontrolled IDDM leads to increased hepatic glucose output.First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle,insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues.
Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism. In addition, the level of hepatic Glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin(primarily through covalent modifications). The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels.
b) Cause of kenosis One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipose storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids.
The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy.Free fatty acids are also taken up by the liver. Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyl Transferase I, the enzyme required for the transport of fatty acyl-CoA’s into the mitochondria where they are subject to oxidation for energy production.
Thus, in the absence of insulin,malonyl-CoA levels fall and transport of fatty acyl-CoA’s into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majorityof the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetoacetate and β-hydroxybutyrate. TCA cycle is in a state of suppression due to non availability of oxaloacetate which is channeled towards pathway of gluconeogenesis in the absence of Insulin.
These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of Acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.
c) Causes of Acidosis and hyperventilationThe ketone bodies, however, have a low pH and therefore turn the blood acidic(metabolic acidosis). The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration. Ketones, too,participate in osmotic diuresis and lead to further electrolyte losses. As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 ml/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/l or 250 mg/dl.
Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase triglyceride and VLDL production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Most commonly, DKA is precipitated by increased insulin requirements, as might occur during a concurrent illness. Occasionally, complete omission of insulin by the patient with type 1 DM precipitates DKA.
Clinical manifestations– The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst,excessive urine production and abdominal pain that may be severe.
Hyperglycemia is always present .In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as “Kussmaul respiration”). The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation.
Coffee ground vomiting(vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosions of the esophagus. In severe DKA, there may be confusion, lethargy, stupor or even coma(a marked decrease in the level of consciousness).
On physical examination -there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a “ketotic”odor is present, which is often described as “fruity”. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.
Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.7–1.0% of children with DKA, and has been described in young adults, but is very rare in adults. It carries 20–50% mortality.
Figure- showing causes and consequences of DKA
Investigations- Diabetic Ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated.
Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery.
In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes.
Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured.
Given the need to exclude infection, chest radiography and urinalysis are usually performed.If cerebral edema is suspected because of confusion, recurrent vomiting or other symptoms, computed tomography may be performed to assess its severity and to exclude other causes such as stroke.
The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin.
a) Fluid replacement The amount of fluid depends on the estimated degree of dehydration. If dehydration is sosevere, rapid infusion of saline is recommended to restore circulating volume.
b) Insulin is usually given continuously.
c) Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. Serum potassium levels are initially often mildly raised even though total body potassium is depleted. Hypokalemia often follows treatment. This increases the risk of irregularities in the heart rate. Therefore, continuous observation of the heart rate is recommended, as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l. If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia.
d) Bicarbonate- Sodium bicarbonate solution is administered to rapidly improve the acid levels in the blood.
Cerebral edema- administration of fluids is slowed; intravenous Mannitol and hypertonic saline (3%) are used.
With appropriate therapy, the mortality of DKA is low (<5%) and is related more to the underlying or precipitating event, such as infection or myocardial infarction. The major non metabolic complication of DKA therapy is cerebral edema,which most often develops in children as DKA is resolving.
The etiology of and optimal therapy for cerebral edema are not well established, but over replacement of free water should be avoided. The other known complications of DKA therapy are, Hypoglycemia, hypokalemia and hypophosphatemia. Venous thrombosis, upper gastrointestinal bleeding, and acute respiratory distress syndrome occasionally complicate DKA.
Prevention of DKA
Following treatment, the physician and patient should review the sequence of events that led to DKA to prevent future recurrences. Foremost is patient education about the symptoms of DKA, its precipitating factors, and the management of diabetes during a concurrent illness.
During illness or when oral intake is compromised, patients should:
(1) frequently measure the capillary blood glucose;
(2) measure urinary ketones when the serum glucose > 16.5 mmol/L (300 mg/dL);
(3) drink fluids to maintain hydration;
(4) continue or increase insulin; and
(5) seek medical attention if dehydration, persistent vomiting, or uncontrolled hyperglycemia develop. Using these strategies, early DKA can be prevented or detected and treated appropriately on an outpatient basis.
DKA IN PREGNANCY- DKA in pregnancy is of special concern. It tends to occur at lower plasma glucose levels and more rapidly than in non-pregnant patients and usually occurs in the second and third trimesters because of increasing insulin resistance. Fetal mortality rates have previously been reported as high as 30% rising to over 60% in DKA with coma. However with improvements in diabetic care the figure for fetal loss has been reported as low as 9% in some countries. Prevention, early recognition and aggressive management are vitally important to minimize fetal mortality.