UNDERSTANDING THE CAREER OPPORTUNITIES OF CLINICAL PHARMACY IN INDIA

http://www.pharmatutorjournal.com/index.php/pt/article/view/understanding-the-career-opportunities-of-clinical-pharmacy-in-india 

FIRST AID MEASURES IN POISONING

FIRST AID MEASURES IN POISONING from Dr. Abhimanyu Parashar

Cells and organisation of body from Dr. Abhimanyu Parashar

Cell division (Mitosis and Meiosis) from Dr. Abhimanyu Parashar

Digestive System from Dr. Abhimanyu Parashar

Endocrine system from Dr. Abhimanyu Parashar

Pi specialist, Roles & Responsibilities from Dr. Abhimanyu Parashar

Systematic approach to answer Poison Information Query from Dr. Abhimanyu Parashar

Poison information center (Structural Organization and functions) from Dr. Abhimanyu Parashar

Case on Heart failure with Type 2 Diabetes mellitus from Dr. Abhimanyu Parashar

Endocrine system from Dr. Abhimanyu Parashar

Medication Errors in General Medicine wards of a tertiary care teaching Hospital - Abhimanyu from JSS University

Electroconvulsive therapy from JSS University

Oculomotor palsy from JSS University

TYPE 1 DM Facts

Type 1 Diabetes Facts

About T1D

Type 1 diabetes (T1D) is an autoimmune disease in which a person’s pancreas stops producing insulin, a hormone that enables people to get energy from food. It occurs when the body’s immune system attacks and destroys the insulin-producing cells in the pancreas, called beta cells. While its causes are not yet entirely understood, scientists believe that both genetic factors and environmental triggers are involved. Its onset has nothing to do with diet or lifestyle. There is nothing you can do to prevent T1D, and—at present—nothing you can do to get rid of it.

Whom T1D Affects

Type 1 diabetes strikes both children and adults at any age. It comes on suddenly, causes dependence on injected or pumped insulin for life, and carries the constant threat of devastating complications.

How T1D Is Managed

Living with T1D is a constant challenge. People with the disease must carefully balance insulin doses (either by injections multiple times a day or continuous infusion through a pump) with eating and other activities throughout the day and night. They must also measure their blood-glucose level by pricking their fingers for blood six or more times a day. Despite this constant attention, people with T1D still run the risk of dangerous high or low blood-glucose levels, both of which can be life threatening. People with T1D overcome these challenges on a daily basis.

Insulin Is Not a Cure

While insulin injections or infusion allow a person with T1D to stay alive, they do not cure the disease, nor do they necessarily prevent the possibility of the disease’s serious effects, which may include: kidney failure, blindness, nerve damage, heart attack, stroke, and pregnancy complications.

The Outlook for Treatments and a Cure

Although T1D is a serious and difficult disease, treatment options are improving all the time, and people with T1D can lead full and active lives. JDRF is driving research to progressively remove the impact of the disease from people’s lives until we ultimately achieve a world without T1D.

Statistics

• As many as three million Americans may have T1D.¹

• Each year, more than 15,000 children and 15,000 adults—approximately 80 people per day—are diagnosed with T1D in the U.S.²

• Approximately 85 percent of people living with T1D are adults, and 15 percent of people living with T1D are children.¹

• The prevalence of T1D in Americans under age 20 rose by 23 percent between 2001 and 2009.³

• The rate of T1D incidence among children under age 14 is estimated to increase by three percent annually worldwide.⁴

• T1D accounts for $14.9 billion in healthcare costs in the U.S. each year.⁵

Warning Signs

Warning signs of T1D may occur suddenly and can include:

• Extreme thirst

• Frequent urination

• Drowsiness or lethargy

• Increased appetite

• Sudden weight loss

• Sudden vision changes

• Sugar in the urine

• Fruity odor on the breath

• Heavy or labored breathing

• Stupor or unconsciousness

What Is It Like to Have T1D?

Ask people who have T1D, and they will tell you: it’s difficult. It’s upsetting. It’s life threatening. It never goes away. But at the same time, people with T1D serve as an inspiration by facing the disease’s challenges with courage and perseverance, and they don’t let it stand in the way of achieving their goals.

“Both children and adults who live with type 1 diabetes need to be mathematicians, physicians, personal trainers, and dietitians all rolled into one. We need to be constantly factoring and adjusting, making frequent finger sticks to check blood sugars, and giving ourselves multiple daily insulin injections just to stay alive.”
— JDRF International Chairman
Mary Tyler Moore

“It is a 24/7/365 job. We never get to relax and forget about food, whether we’ve exercised too much or too little, insulin injections, blood-sugar testing, or the impact of stress, a cold, a sunburn, and on and on. So many things make each day a risky venture when you live with T1D.”
— Mary Vonnegut, adult, Rhode Island

“Unlike other kids, I have to check my blood sugar 8 to 10 times a day; everything I eat is measured and every carbohydrate counted. My kit goes with me everywhere I go … Too much exercise or not eating all my food can be dangerous. I think I’m too young to have to worry about all this stuff.”
— Jonathan Platt, 8, California

“It controls your life in ways that someone without it doesn’t even see. For me, the worst part of living with T1D is the fear that my three children or their children might develop the disease.”

Endocrine organs and secreted hormones

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Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is an acute, major, life-threatening complication of diabetes that mainly occurs in patients with type 1 diabetes, but it is not uncommon in some patients with type 2 diabetes. This condition is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria.

Signs and symptoms

The most common early symptoms of DKA are the insidious increase in polydipsia and polyuria. The following are other signs and symptoms of DKA:

• Malaise, generalized weakness, and fatigability
• Nausea and vomiting; may be associated with diffuse abdominal pain, decreased appetite, and anorexia
• Rapid weight loss in patients newly diagnosed with type 1 diabetes
• History of failure to comply with insulin therapy or missed insulin injections due to vomiting or psychological reasons
• Decreased perspiration
• Altered consciousness (eg, mild disorientation, confusion); frank coma is uncommon but may occur when the condition is neglected or with severe dehydration/acidosis

Signs and symptoms of DKA associated with possible intercurrent infection are as follows:

• Fever
• Coughing
• Chills
• Chest pain
• Dyspnea
• Arthralgia

Diagnosis

On examination, general findings of DKA may include the following:

• Ill appearance
• Dry skin
• Labored respiration
• Dry mucous membranes
• Decreased skin turgor
• Decreased reflexes
• Characteristic acetone (ketotic) breath odor
• Tachycardia
• Hypotension
• Tachypnea
• Hypothermia

In addition, evaluate patients for signs of possible intercurrent illnesses such as MI, UTI, pneumonia, and perinephric abscess. Search for signs of infection is mandatory in all cases.

Testing

Initial and repeat laboratory studies for patients with DKA include the following:

• Serum glucose levels
• Serum electrolyte levels (eg, potassium, sodium, chloride, magnesium, calcium, phosphorus)
• Amylase levels
• Urine dipstick
• Ketone levels
• Serum or capillary beta-hydroxybutyrate levels
• ABG measurements
• Bicarbonate levels
• CBC count
• BUN and creatinine levels
• Urine and blood cultures if intercurrent infection is suspected
• ECG (or telemetry in patients with comorbidities)

Note that high serum glucose levels may lead to dilutional hyponatremia; high triglyceride levels may lead to factitious low glucose levels; and high levels of ketone bodies may lead to factitious elevation of creatinine levels.

Imaging tests

Radiologic studies that may be helpful in patients with DKA include the following:

• Chest radiography: To rule out pulmonary infection such as pneumonia
• Head CT scanning: To detect early cerebral edema; use low threshold in children with DKA and altered mental status
• Head MRI: To detect early cerebral edema (order only if altered consciousness is present
  
  

  Management

  Goals

  Treatment of ketoacidosis should aim for the following:

  • Fluid resuscitation
  • Reversal of the acidosis and ketosis
  • Reduction in the plasma glucose concentration to normal
  • Replenishment of electrolyte and volume losses
  • Identification the underlying cause

  Pharmacotherapy

  Regular and analog human insulins are used for correction of hyperglycemia, unless bovine or pork insulin is the only available insulin.

  Medications used in the management of DKA include the following:

  • Rapid-acting insulins (eg, insulin aspart, insulin glulisine, insulin lispro)
  • Short-acting insulins (eg, regular insulin)
  • Electrolyte supplements (eg, potassium chloride)
  • Alkalinizing agents (eg, sodium bicarbonate)
    
    

    Pathophysiology

    Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycemia, ketoacidosis, and ketonuria. DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by an increase in counter-regulatory hormones (ie, glucagon, cortisol, growth hormone, epinephrine). This type of hormonal imbalance enhances hepatic gluconeogenesis, glycogenolysis, and lipolysis.

    Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Hepatic metabolism of free fatty acids as an alternative energy source (ie, ketogenesis) results in accumulation of acidic intermediate and end metabolites (ie, ketones, ketoacids). Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.

    Hepatic gluconeogenesis, glycogenolysis secondary to insulin deficiency, and counter-regulatory hormone excess result in severe hyperglycemia, while lipolysis increases serum free fatty acids. Ketone bodies are produced from acetyl coenzyme A mainly in the mitochondria within hepatocytes when carbohydrate utilization is impaired because of relative or absolute insulin deficiency, such that energy must be obtained from fatty acid metabolism. High levels of acetyl coenzyme A present in the cell inhibit the pyruvate dehydrogenase complex, but pyruvate carboxylase is activated. Thus, the oxaloacetate generated enters gluconeogenesis rather than the citric acid cycle, as the latter is also inhibited by the elevated level of nicotinamide adenine dinucleotide (NADH) resulting from excessive beta-oxidation of fatty acids, another consequence of insulin resistance/insulin deficiency. The excess acetyl coenzyme A is therefore rerouted to ketogenesis. Ketones include acetone, beta-hydroxybutyrate, and acetoacetate.

    Progressive rise of blood concentration of these acidic organic substances initially leads to a state of ketonemia, although extracellular and intracellular body buffers can limit ketonemia in its early stages, as reflected by a normal arterial pH associated with a base deficit and a mild anion gap.

    When the accumulated ketones exceed the body's capacity to extract them, they overflow into urine (ie, ketonuria). If the situation is not treated promptly, a greater accumulation of organic acids leads to frank clinical metabolic acidosis (ie, ketoacidosis), with a drop in pH and bicarbonate^[5] serum levels. Respiratory compensation for this acidotic condition results in rapid shallow breathing (Kussmaul respirations).

    Ketones—in particular, beta-hydroxybutyrate—induce nausea and vomiting that consequently aggravate fluid and electrolyte loss already existing in DKA. Moreover, acetone produces the fruity breath odor that is characteristic of ketotic patients.

    Hyperglycemia, osmotic diuresis, serum hyperosmolarity, and metabolic acidosis result in severe electrolyte disturbances. The most characteristic disturbance is total body potassium loss. This loss is not mirrored in serum potassium levels, which may be low, within the reference range, or even high.

    Potassium loss is caused by a shift of potassium from the intracellular to the extracellular space in an exchange with hydrogen ions that accumulate extracellularly in acidosis. Much of the shifted extracellular potassium is lost in urine because of osmotic diuresis.

    Patients with initial hypokalemia are considered to have severe and serious total body potassium depletion. High serum osmolarity also drives water from intracellular to extracellular space, causing dilutional hyponatremia. Sodium also is lost in the urine during the osmotic diuresis.

    Typical overall electrolyte loss includes 200-500 mEq/L of potassium, 300-700 mEq/L of sodium, and 350-500 mEq/L of chloride. The combined effects of serum hyperosmolarity, dehydration, and acidosis result in increased osmolarity in brain cells that clinically manifests as an alteration in the level of consciousness.

    Many of the underlying pathophysiologic disturbances in DKA are directly measurable by the clinician and need to be monitored throughout the course of treatment. Close attention to clinical laboratory data allows for tracking of the underlying acidosis and hyperglycemia, as well as prevention of common potentially lethal complications such as hypoglycemia, hyponatremia, and hypokalemia.

    Complications Associated with DKA

    Complications associated with DKA include sepsis and diffuse ischemic processes. Other associated complications include the following:

    • CVT
    • Myocardial infarction
    • DVT
    • Acute gastric dilatation
    • Erosive gastritis
    • Late hypoglycemia
    • Respiratory distress
    • Infection (most commonly, urinary tract infections)
    • Hypophosphatemia
    • Mucormycosis
    • Cerebrovascular accident
    • Complicated pregnancy
    • Trauma
    • Stress
    • Cocaine
    • Surgery
    • Heavy use of concentrated carbohydrate beverages (eg, sodas, sports drinks)
    • Acromegaly
    • Idiopathic condition (20-30%)
    • Dental abscess
      
      

      Approach Considerations

      Diabetic ketoacidosis is typically characterized by hyperglycemia over 300 mg/dL, a bicarbonate level less than 15 mEq/L, and a pH less than 7.30, with ketonemia and ketonuria.

      While definitions vary, moderate DKA can be categorized by a pH less than 7.2 and a serum bicarbonate less than 10 mEq/L, whereas severe DKA has a pH less than 7.1 and bicarbonate less than 5 mEq/L.

      Laboratory studies for diabetic ketoacidosis (DKA) should be scheduled as follows:

      • Blood tests for glucose every 1-2 h until patient is stable, then every 6 h
      • Serum electrolyte determinations every 1-2 h until patient is stable, then every 4-6 h
      • Initial blood urea nitrogen (BUN)
      • Initial arterial blood gas (ABG) measurements, followed with bicarbonate as necessary

      Repeat laboratory tests are critical, including potassium, glucose, electrolytes, and, if necessary, phosphorus. Initial workup should include aggressive volume, glucose, and electrolyte management.

      It is important to be aware that high serum glucose levels may lead to dilutional hyponatremia; high triglyceride levels may lead to factitious low glucose levels; and high levels of ketone bodies may lead to factitious elevation of creatinine levels.

      Treatment & Management

      Managing diabetic ketoacidosis (DKA) in an intensive care unit during the first 24-48 hours always is advisable. When treating patients with DKA, the following points must be considered and closely monitored:

      • Correction of fluid loss with intravenous fluids
      • Correction of hyperglycemia with insulin
      • Correction of electrolyte disturbances, particularly potassium loss
      • Correction of acid-base balance
      • Treatment of concurrent infection, if present

      It is essential to maintain extreme vigilance for any concomitant process, such as infection, cerebrovascular accident, myocardial infarction, sepsis, or deep venous thrombosis.

      It is important to pay close attention to the correction of fluid and electrolyte loss during the first hour of treatment. This always should be followed by gradual correction of hyperglycemia and acidosis. Correction of fluid loss makes the clinical picture clearer and may be sufficient to correct acidosis. The presence of even mild signs of dehydration indicates that at least 3 L of fluid has already been lost.

      Patients usually are not discharged from the hospital unless they have been able to switch back to their daily insulin regimen without a recurrence of ketosis. When the condition is stable, pH exceeds 7.3, and bicarbonate is greater than 18 mEq/L, the patient is allowed to eat a meal preceded by a subcutaneous (SC) dose of regular insulin.

      Insulin infusion can be discontinued 30 minutes later. If the patient is still nauseated and cannot eat, dextrose infusion should be continued and regular or ultra–short-acting insulin should be administered SC every 4 hours, according to blood glucose level, while trying to maintain blood glucose values at 100-180 mg/dL.

      The 2011 JBDS guideline recommends the intravenous infusion of insulin at a weight-based fixed rate until ketosis has subsided. Should blood glucose fall below 14 mmol/L (250 mg/dL), 10% glucose should be added to allow for the continuation of fixed-rate insulin infusion.^{[15, 16]}

      In established patients with diabetes, SC long-acting insulin (eg, insulin glargine, Detemir, Ultralente) should be initiated at the dose that was used prior to the manifestation of DKA. If neutral protamine Hagedorn (NPH) insulin was used previously, however, start back at the usual dose only when the patient eats well and is able to retain meals without vomiting; otherwise, the dose should be reduced to avoid hypoglycemia during its peak efficacy period.

      In newly diagnosed patients with type 1 diabetes, a careful estimate of the long-acting insulin dose should be considered. Starting with smaller doses generally is recommended to avoid hypoglycemia.

      Correction of Fluid Loss

      Fluid resuscitation is a critical part of treating patients with DKA. Intravenous solutions replace extravascular and intravascular fluids and electrolyte losses. They also dilute both the glucose level and the levels of circulating counterregulatory hormones. Insulin is needed to help switch from a catabolic state to an anabolic state, with uptake of glucose in tissues and the reduction of gluconeogenesis as well as free fatty acid and ketone production.

      Initial correction of fluid loss is either by isotonic sodium chloride solution or by lactated Ringer solution. The recommended schedule for restoring fluids is as follows:

      • Administer 1-3 L during the first hour.
      • Administer 1 L during the second hour.
      • Administer 1 L during the following 2 hours
      • Administer 1 L every 4 hours, depending on the degree of dehydration and central venous pressure readings

      When the patient becomes euvolemic, the physician may switch to half the isotonic sodium chloride solution, particularly if hypernatremia exists. Isotonic saline should be administered at a rate appropriate to maintain adequate blood pressure and pulse, urinary output, and mental status.

      If a patient is severely dehydrated and significant fluid resuscitation is needed, switching to a balanced electrolyte solution (eg, Normosol-R, in which some of the chloride in isotonic saline is replaced with acetate) may help to avoid the development of a hyperchloremic acidosis.

      When blood sugar decreases to less than 180 mg/dL, isotonic sodium chloride solution is replaced with 5-10% dextrose with half isotonic sodium chloride solution.

      After initial stabilization with isotonic saline, switch to half-normal saline at 200-1000 mL/h (half-normal saline matches losses due to osmotic diuresis).

      Insulin should be started about an hour after IV fluid replacement is started to allow for checking potassium levels and because insulin may be more dangerous and less effective before some fluid replacement has been obtained.

      Although the incidence of life-threatening hypokalemia due to aggressive insulin administration is very low, there is little to no advantage in starting insulin prior to rehydration and evaluation of serum potassium levels. Initial bolus of insulin does not change overall management of DKA.^[20]

      Pediatric protocols to minimize the risk of cerebral edema by reducing the rate of fluid repletion vary. The International Society for Pediatric and Adolescent Diabetes (ISPAD) Clinical Practice Consensus Guidelines suggest initial fluid repletion in pediatric patients should be 10-20 mL/kg of normal saline (0.9%) solution during the first 1-2 hours without initial bolus, and then, after 1-2 hours, insulin should be started to avoid pediatric cerebral edema.^[21]

      ISPAD provides detailed fluid administration guidelines. Total volume over the first 4 hours should not exceed 40-50 mL/kg. Fluid administration is as vital in children as in adults.

      Insulin Therapy

      When insulin treatment is started in patients with DKA, several points must be considered. A low-dose insulin regimen has the advantage of not inducing the severe hypoglycemia or hypokalemia that may be observed with a high-dose insulin regimen.

      Only short-acting insulin is used for correction of hyperglycemia. Subcutaneous absorption of insulin is reduced in DKA because of dehydration; therefore, using intravenous or intramuscular routes is traditionally preferable.

      SC use of the fast-acting insulin analog (lispro) has been tried in pediatric DKA (0.15 U/kg q2h). The results were shown to be comparable to IV insulin, but ketosis took 6 additional hours to resolve. Such technically simplified methods may be cost-effective and may preclude admissions to intensive care units in patients with mild cases.

      The initial insulin dose is a continuous IV insulin infusion using an infusion pump, if available, at a rate of 0.1 U/kg/h. A mix of 24 units of regular insulin in 60 mL of isotonic sodium chloride solution usually is infused at a rate of 15 mL/h (6 U/h) until the blood glucose level drops to less than 180 mg/dL; the rate of infusion then decreases to 5-7.5 mL/h (2-3 U/h) until the ketoacidotic state abates.

      Larger volumes of an insulin and isotonic sodium chloride solution mixture can be used, providing that the infusion dose of insulin is similar. Larger volumes may be easier in the absence of an IV infusion pump (eg, 60 U of insulin in 500 mL of isotonic sodium chloride solution at a rate of 50 mL/h).

      The optimal rate of glucose decline is 100 mg/dL/h. Do not allow the blood glucose level to fall below 200 mg/dL during the first 4-5 hours of treatment. Hypoglycemia may develop rapidly with correction of ketoacidosis.

      Allowing blood glucose to drop to hypoglycemic levels is a common mistake that usually results in a rebound ketosis derived by counter-regulatory hormones. Rebound ketosis necessitates a longer duration of treatment. The other hazard is that rapid correction of hyperglycemia and hyperosmolarity may shift water rapidly to the hyperosmolar intracellular space and may induce cerebral edema.

      Although DKA was a common problem in patients with diabetes who were treated with continuous subcutaneous insulin infusion through insulin infusion pumps, the incidence of DKA was reduced with the introduction of pumps equipped with sensitive electronic alarm systems that alert users when the infusion catheter is blocked.

      Electrolyte Correction

      If the potassium level is greater than 6 mEq/L, do not administer potassium supplement. If the potassium level is 4.5-6 mEq/L, administer 10 mEq/h of potassium chloride. If the potassium level is 3-4.5 mEq/L, administer 20 mEq/h of potassium chloride.

      Monitor serum potassium levels hourly, and the infusion must be stopped if the potassium level is greater than 5 mEq/L. The monitoring of serum potassium must continue even after potassium infusion is stopped in the case of (expected) recurrence of hypokalemia.

      In severe hypokalemia, not starting insulin therapy is advisable unless potassium replacement is under way; this is to avert potentially serious cardiac dysrhythmia that may result from hypokalemia.

      Potassium replacement should be started with initial fluid replacement if potassium levels are normal or low. Add 20-40 mEq/L of potassium chloride to each liter of fluid once the potassium level is less than 5.5 mEq/L. Potassium can be given as follows: two thirds as KCl, one third as KPO4.

      Correction of Acid-Base Balance

      Sodium bicarbonate only is infused if decompensated acidosis starts to threaten the patient's life, especially when associated with either sepsis or lactic acidosis. If sodium bicarbonate is indicated, 100-150 mL of 1.4% concentration is infused initially. This may be repeated every half hour if necessary. Rapid and early correction of acidosis with sodium bicarbonate may worsen hypokalemia and cause paradoxical cellular acidosis.

      Bicarbonate typically is not replaced as acidosis will improve with the above treatments alone. Administration of bicarbonate has been correlated with cerebral edema in children.

      Management of Treatment-Related Complications

      Cerebral edema

      Cerebral edema is a serious, major complication that may evolve at any time during treatment of DKA and primarily affects children. It is the leading cause of DKA mortality in children.

      Be extremely cautious to avoid cerebral edema during initiation of therapy. Deterioration of the level of consciousness in spite of improved metabolic state usually indicates the occurrence of cerebral edema. MRI usually is used to confirm the diagnosis.

      Cerebral edema that occurs at initiation of therapy tends to worsen during the course of treatment. Mannitol or hypertonic saline should be available if cerebral edema is suspected.

      According to Wolfsdorf et al, 0.5-1 g/kg intravenous mannitol may be given over the course of 20 minutes and repeated if no response is seen in 30-120 minutes.^[21]Also, if no response to mannitol occurs, hypertonic saline (3%) may be given at 5-10 mg/kg over the course of 30 minutes.

      Clinical cerebral edema is rare and carries the highest mortality rate. Although mannitol (0.25-1 g/kg IV) and dexamethasone (2-4 mg q6-12h) frequently are used in this situation, no specific medication has proven useful in such instances.

      Recent research by Glaser et al indicated that cerebral edema occurs in 1% of children with DKA, with a mortality rate of 21% and neurologic sequelae in another 21% of patients. Glaser et al suggested that up to half of children with DKA have subtle brain MRI findings, particularly with respect to narrowing of the lateral ventricles.^[22]

      Muir et al have identified diagnostic criteria for cerebral edema that include abnormal response to pain, decorticate and decerebrate posturing, cranial nerve palsies, abnormal central nervous system respiratory patterns, fluctuating level of consciousness, sustained heart rate deceleration, incontinence, and more nonspecific criteria such as vomiting, headache, lethargy, and elevated diastolic blood pressure.^[23]

      Cerebral edema begins with mental status changes and is believed to be due partially to idiogenic osmoles, which have stabilized brain cells from shrinking while the diabetic ketoacidosis was developing.

      The risk of cerebral edema is related to the severity and duration of DKA. It is often associated with ongoing hyponatremia. Cerebral edema is correlated with the administration of bicarbonate. Concerns about the role of overaggressive or overly hypotonic fluid resuscitation as a cause of the edema that have been raised in the past correlate more closely with disease severity than with rapid administration of fluids.^[24]

      Cardiac dysrhythmia

      Cardiac dysrhythmia may occur secondary to severe hypokalemia and/or acidosis either initially or as a result of therapy in patients with DKA. Usually, correction of the cause is sufficient to treat cardiac dysrhythmia, but if it persists, consultation with a cardiologist is mandatory. Performing cardiac monitoring on patients with DKA during correction of electrolytes always is advisable.

      Pulmonary edema

      Pulmonary edema may occur for the same reasons as cerebral edema in patients with diabetic ketoacidosis. Be cautious of possible overcorrection of fluid loss, though it occurs only rarely.

      Although initial aggressive fluid replacement is necessary in all patients, particular care must be taken in those with comorbidities such as renal failure or congestive heart failure. Diuretics and oxygen therapy often suffice for the management of pulmonary edema.

      Myocardial injury

      Nonspecific myocardial injury may occur in severe DKA, which is associated with minute elevations of myocardial biomarkers (troponin T and CK-MB) and initial ECG changes compatible with myocardial infarction (MI).

      Acidosis and very high levels of free fatty acids could cause membrane instability and biomarker leakage. Coronary arteriography usually is normal, and patients tend to recover fully without further evidence of ischemic heart disease. Regardless of the pathogenesis, the presence of minute biomarker elevations and ECG changes do not necessarily signify MI in DKA.

      Diabetic retinopathy

      Microvascular changes consistent with diabetic retinopathy have been reported prior to and after treatment of diabetic ketoacidosis; the blood-retinal barrier does not experience the same degree of perturbation as the blood-brain barrier does, however.

      See Diabetic Retinopathy for more complete information on this topic.

      Hypoglycemia

      In patients with diabetic ketoacidosis, hypoglycemia may result from inadequate monitoring of glucose levels during insulin therapy.

      Hypokalemia

      Hypokalemia is a complication that is precipitated by failing to rapidly address the total body potassium deficit brought out by rehydration and insulin treatment, which not only reduces acidosis but directly facilitates potassium reentry into the cell.

      
      

low molecular heparin

Low-Molecular-Weight Heparin in Preventing and Treating DVT

ERIC J. RYDBERG, M.D., JOHN M. WESTFALL, M.D., M.P.H., and RICHARD A. NICHOLAS, M.D., University of Colorado Health Sciences Center, Denver, Colorado

Low-molecular-weight heparin is a relatively recent addition to the list of therapies for prophylaxis and treatment of deep venous thrombosis (DVT). As a prophylactic, low-molecular-weight heparin is as effective as standard heparin or warfarin and does not require monitoring of the activated partial thromboplastin time or the International Normalized Ratio. Traditionally, treatment for DVT required patients to be hospitalized for administration of intravenous heparin. With subcutaneous injections of low-molecular-weight heparin, treatment of DVT can be initiated or completed in the outpatient setting with no increased risk of recurrent thromboembolism or bleeding complications. Low-molecular-weight heparin is an attractive option for use in patients with a first episode of DVT, no risk factors for bleeding and the ability to administer injections with or without the help of a visiting nurse or family member

Deep venous thrombosis (DVT) is a relatively common disease that is often encountered by family physicians. Epidemiologic data suggest that the annual incidence of a first episode of DVT ranges from 60 to 180 cases per 100,000 people, or more than 300,000 new cases annually in the United States.¹ The cost burden of this disease is quite high, since most patients with DVT require one or more diagnostic tests, treatment with intravenous heparin and a three- to seven-day hospital stay.² Low-molecular-weight heparin, which is administered by subcutaneous injection, offers the option of treatment on an outpatient basis for patients with DVT. Low-molecular-weight heparin can also be used effectively in patients requiring prophylaxis for DVT after general or orthopedic surgery.

Advantages of Low-Molecular-Weight Heparin

The clinical advantages of low-molecular-weight heparin include predictability, dose-dependent plasma levels, a long half-life and less bleeding for a given antithrombotic effect.³ Furthermore, immune-mediated thrombocytopenia is not associated with short-term use of low-molecular-weight heparin,³ and the risk of heparin-induced osteoporosis may be lower than the risk with the use of standard heparin. Low-molecular-weight heparin is administered according to body weight once or twice daily, both during the high-risk period when prophylaxis for DVT is recommended and also when waiting for oral anticoagulation to take effect in the treatment of DVT. The activated partial thromboplastin time (aPTT) does not need to be monitored, and the dosage does not need to be adjusted. Since low-molecular-weight heparin is given subcutaneously, outpatient administration by the patient, with or without the assistance of a visiting nurse or family member, is both possible and cost-effective.

Properties of Low-Molecular-Weight Heparin

Low-molecular-weight heparin is a relatively new class of anticoagulant that has been used in Europe and is now being used more often in the United States following reports of randomized, controlled trials demonstrating its efficacy and safety.

Low-molecular-weight heparin is derived from standard heparin through either chemical or enzymatic depolymerization. Whereas standard heparin has a molecular weight of 5,000 to 30,000 daltons, low-molecular-weight heparin ranges from 1,000 to 10,000 daltons, resulting in properties that are distinct from those of traditional heparin. Low-molecular-weight heparin binds less strongly to protein, has enhanced bioavailability, interacts less with platelets and yields a very predictable dose response, eliminating the need to monitor the aPPT. Low-molecular-weight heparin, like standard heparin, binds to antithrombin III; however, low-molecular-weight heparin inhibits thrombin to a lesser degree (and Factor Xa to a greater degree) than standard heparin.⁴

Prophylaxis of DVT

The symptoms, signs, risk factors and diagnosis of DVT are reviewed elsewhere.⁵ Low-molecular-weight heparin helps prevent DVT in a variety of clinical situations, including patients undergoing general surgery, or hip or knee replacements. Given the high incidence of DVT after such procedures, prophylaxis is strongly recommended. Although a surgeon often consults in such cases, family physicians should be aware of the need for prophylaxis for DVT and should ensure that adequate therapy is provided, when appropriate. The Fourth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy has recently published a review of the complex data on prophylactic treatment for DVT, which is summarized below.⁶

PROPHYLAXIS FOR GENERAL SURGERY

Patients undergoing general surgery have a 16 percent risk of DVT and a 1.6 percent incidence of pulmonary embolus when they do not receive prophylactic treatment for DVT.⁶ Low-molecular-weight heparin is as effective as low-dose subcutaneous heparin, decreasing the incidence of DVT to 5 to 8 percent following general surgery, and slightly reducing bleeding complications. Although low-molecular-weight heparin costs approximately 10 times more per dose than low-dose subcutaneous heparin, it can be given once daily, which may offset some of the higher cost. While noninvasive methods of preventing DVT (i.e., use of elastic compression stockings or intermittent pneumatic stockings) are adequate in low- and moderate-risk surgical patients, low-molecular-weight heparin is an excellent therapeutic choice in high-risk patients (i.e., patients over 40 years of age, patients undergoing major surgery, patients with concurrent risk factors for DVT).⁶ Prophylactic low-molecular-weight heparin should be given subcutaneously once or twice daily until the patient is ambulating well.

PROPHYLAXIS FOR ORTHOPEDIC SURGERY

In patients not receiving prophylaxis for DVT who are undergoing elective hip or knee replacement or hip fracture surgery, the risk of postoperative DVT is at least 40 percent, and the risk of pulmonary embolus ranges from 1.8 to 30 percent.⁶ Low-molecular-weight heparin is safe and effective following surgery for hip replacement. It has been shown in a recent meta-analysis⁷ to be superior to low-dose subcutaneous heparin, and its use resulted in significantly fewer hemorrhagic complications.⁸

Studies comparing low-molecular-weight heparin with low-dose warfarin (Coumadin) therapy (maintaining an International Normalized Ratio [INR] between 2.0 and 3.0) showed that low-molecular-weight heparin is slightly more effective, although the difference is quite small.^9,10 Thus, the decision to use low-molecular-weight heparin or warfarin should be based on convenience and cost. Low-molecular-weight heparin is given subcutaneously twice daily, and laboratory monitoring is not required. Treatment with either warfarin or low-molecular-weight heparin should be continued for a minimum of seven days postoperatively.

DVT is especially hard to prevent following knee replacement surgery, and low-dose standard heparin provides marginal benefit.¹¹ Again, low-molecular-weight heparin is safe and effective. Five studies comparing low-molecular-weight heparin with low-dose warfarin demonstrate better efficacy with low-molecular-weight heparin.⁶ Intermittent pneumatic compression stockings are also quite effective in preventing DVT following knee replacement surgery¹²; however, the number of patients studied in this trial was small compared with the number of patients in the low-molecular-weight heparin trials. No trials to date have compared the use of intermittent pneumatic compression stockings with low-molecular-weight heparin therapy and, currently, either offers adequate prophylaxis. In high-risk patients, low-molecular-weight heparin and compression stockings may be used simultaneously.

Treatment of DVT

Traditionally, a patient diagnosed with DVT has been hospitalized for treatment, which includes intravenous heparin and monitoring of the aPTT. The patient remains hospitalized until warfarin is administered to achieve an INR between 2.0 and 3.0. Such management usually results in a three- to seven-day hospital stay.²

Recent randomized, controlled trials demonstrate the efficacy of low-molecular-weight heparin in the treatment of DVT, both in the hospital^13–16 and in an outpatient setting.^17,18  Results of each of these studies demonstrated no advantage to standard intravenous heparin over low-molecular-weight heparin in terms of recurrent thromboembolism or major bleeding complications (Table 1). Patients who received twice-daily injections of low-molecular-weight heparin spent fewer days in the hospital and, in the studies where low-molecular-weight heparin was administered in the outpatient setting, many patients did not require hospitalization at all.^17,18 Furthermore, social functioning and physical activity were better in the group receiving low-molecular-weight heparin.¹⁸  The dosage of low-molecular-weight heparin depends on the specific agent used (Table 2).

TABLE 1
Controlled Trials Comparing Intravenous Heparin with Subcutaneous LMW Heparin in Proximal DVT

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Study	Number of patients	Outcome
Prandoni, et al.13	170	No difference in rates of symptomatic extension, recurrence, pulmonary embolus or severe bleeding
Hull, et al.14	432	No difference in rates of recurrence, pulmonary embolus, or major or minor bleeding
Simonneau, et al.15	134	Less enlargement of thrombus in patients Treated with LMW heparin, fewer thromboembolic events in patients treated with LMW heparin, no difference in rates of major bleeding
Lindmarker, et al.16	204	No difference in Marder score (venographic assessment of clot size)
Levine, et al.17	400	No difference in rates of recurrent thromboembolism or major bleeding
Koopman, et al.18	400	No difference in rates of recurrent thromboembolism or major bleeding

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LMW = low-molecular-weight; DVT = deep venous thrombosis.

Information from references 13 through 18.

TABLE 2
Low-Molecular-Weight Heparins

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Heparin	Availability	Prophylactic dosing
Ardeparin (Normiflo)	5,000 U in 0.5 mL; 10,000 U in 0.5 mL	50 U per kg SC on the evening of the day of surgery or the following morning, then every 12 hours for 14 days or until ambulatory
Dalteparin (Fragmin)	16 mg per 0.2 mL; 32 mg per 0.2 mL	2,500 IU SC 1 to 2 hours before surgery, then 2,500 IU every day for 5 to 10 days
		High-risk patients: 5,000 IU SC the evening before surgery, then 5,000 IU every day for 5 to 10 days
Danaparoid (Orgaran)	750 U per 0.6 mL	750 U SC 1 to 4 hours before surgery, then 750 U every 12 hours for 7 to 10 days
Enoxaparin (Lovenox)	30 mg per 0.3 mL; 40 mg per 0.4 mL	30 mg SC every 12 hours or 40 mg every day for 7 to 10 days, depending on the type of surgery (hip, knee, abdomen); therapy should begin postoperatively (see prescribing information for more details)

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SC = subcutaneously.

Cost analysis was incomplete in these trials; however, elimination of even a single hospital day by use of low-molecular-weight heparin would be likely to yield a savings. In our community, the cost of low-molecular-weight heparin ranges from approximately $100 to $150 per day. The average cost of treating a patient with uncomplicated DVT is reduced by approximately $5,000 to $8,000 when using low-molecular-weight heparin instead of standard heparin therapy. It is likely that additional studies will yield important information on the cost savings of treatment with low-molecular-weight heparin.

Patients with a first episode of proximal DVT and no risk factors for bleeding complications (e.g., active peptic ulcer disease, thrombocytopenia, liver disease, other coagulopathy) are good candidates for initial therapy with low-molecular-weight heparin. The Physicians' Desk Reference¹⁹  does not yet list low-molecular-weight heparin as an indicated use in the treatment of DVT; hence, this suggested treatment represents an off-label use. Because several subsets of patients were excluded from the low-molecular-weight heparin trials, treatment with low-molecular-weight heparin in these patients cannot be recommended at this time (Table 3).

TABLE 3
Subsets of Patients Excluded from Controlled Trials of LMW Heparin in DVT*

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Previous history of DVT:
	Ipsilaterally15
	Ipsilaterally in the past two years12
	Two or more episodes, either extremity16
	Any venous thromboembolism in the past two years17
Pregnancy12–17
Renal or hepatic insufficiency13,15
Active bleeding13–16
Surgery in the previous five15 to seven14 days
Protein C,13,16 antithrombin III or protein S deficiency16 (hypercoagulable state)
Inability to undergo outpatient treatment16
Noncompliance16
Other relative contraindications:
	Thrombocytopenia
	Coagulopathy
	Active peptic ulcer disease

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LMW = low-molecular-weight; DVT = deep venous thrombosis.

*—Currently evidence is insufficient to support the routine use of low-molecular-weight heparin in the treatment of DVT in these patients.

Information from references 12 through 17.

Several recent articles have reported the safety and efficacy of low-molecular-weight heparin in the treatment of pulmonary embolism.^20,21 Because pulmonary embolism is sometimes suspected in patients with DVT, appropriate treatment is essential. Treatment with low-molecular-weight heparin may still be considered in patients with DVT and suspected pulmonary embolus. Physicians should become familiar with the absolute and relative contraindications of the specific brand of low-molecular-weight heparin they choose to use.

Appropriate patients may be taught to self-administer low-molecular-weight heparin or, if needed, a visiting nurse or a family member can give the injections. Warfarin is started on the first or second day of therapy with low-molecular-weight heparin and, once the INR is between 2.0 and 3.0, the low-molecular-weight heparin is discontinued