Xigris was studied in an international, multi-center, randomized, double-blind, placebo-controlled trial (PROWESS) of 1690 patients with severe sepsis. Inclusion criteria was a systemic inflammatory response presumed due to infection and at least one associated acute organ dysfunction. Xigris was administered as a 96 hour infusion. After 28 days from Xigris administration, an efficacy end point was conducted. The study found a significantly lower mortality in patients who received Xigris (210 [25%] of 850) vs. placebo (259 [31%] of 840).2 Therefore, the study was terminated early.

APACHE II scores were used to measure the risk of death in the PROWESS study. Those with the lowest APACHE II scores had a 12% mortality rate, while those in the 2nd, 3rd, and 4th APACHE quartiles had mortality rates of 26%, 36% and 49% respectively. The observed mortality difference with Xigris and placebo was noted in the half of the patients who had a higher risk of death (3rd and 4th quartile). Xigris has not been established to be effective in patients with a lower APACHE II score (or 1st and 2nd quartiles or < 25).

Adverse Effects

The major adverse affect of Xigris is bleeding. It is contraindicated in active internal bleeding; hemorrhagic stroke within 3 months; intracranial or intraspinal surgery or severe head trauma within 2 months; trauma with an increased risk of life-threatening bleeding; presence of an epidural catheter; and intracranial neoplasm or mass lesion or evidence of cerebral herniation.

Xigris therapy may not be appropriate for patients with the following conditions and may lead to bleeding with Xigris therapy: concurrent heparin therapy (= 15 units/kg/hr); platelet count < 30,000 x 106/L, even if the platelet count is increased after transfusions; prothrombin time-INR > 3.0; gastrointestinal bleeding within 6 weeks; thrombolytic therapy within 3 days; oral anticoagulants or glycoprotein IIb/IIIa inhibitors within 7 days; aspirin > 650 mg per day or other platelet inhibitors within 7 days; intracranial arteriovenous malformation or aneurysm; chronic severe hepatic disease; any other condition where bleeding my be a significant hazard, or would be particularly hard to manage because of its location.

Should any clinically important bleeding occur during Xigris administration, the infusion should be stopped immediately. Once adequate homeostasis has been achieved, continued use of Xigris may be reconsidered. Xigris should be discontinued 2 hours before any invasive surgical procedure or any procedure with risk of bleeding. It may be reinstituted 12 hours after surgery and immediately after uncomplicated less invasive procedures such as line placement.

Xigris may prolong the APTT, therefore it is not a reliable measurement for coagulopathy measurements. Monitor the PT as Xigris has minimal effect on the PT. Drug interactions have not been studied with Xigris. Use in children has not been clinically studied. However, no dose adjustment is required in geriatric use as over 50% of the population was > 65 years old in the PROWESS study. There is no known antidote to Xigris. If overdose occurs, stop the infusion immediately and monitor closely for hemorrhagic complications.

Dosage and Administration

Xigris should be administered intravenously at an infusion rate of 24 mcg/kg/hr for a total duration of infusion of 96 hours through a dedicated line. The ONLY other solutions that can be administered through the same line are 0.9% Sodium Chloride, Lactated Ringer's, Dextrose, or Dextrose and Saline mixtures. If the infusion is interrupted, Xigris should be restarted at 24 mcg/kg/hr. Do not bolus or escalate.

Xigris contains no antibacterial preservatives and should be prepared immediately upon reconstitution. Intravenous administration must be completed within 12 hours after the intravenous solution is prepared. Avoid exposure to heat and/or direct sunlight. Xigris is supplied in 5 mg and 20 mg vials.

To read more about this drug, please visit www.lilly.com

1. Eli Lilly and Company. Xigris Drotrecogin alfa (activated). PV3420 AMP. 2001. www.lilly.com.

2. Bernard, GR, et al. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis. N Engl J Med. 2001;344:699-709.

Q - What specific ECG changes are you looking for on a right sided ECG?

A - If a patient has an inferior wall myocardial infarction, they are at risk for a right ventricular infarction. Therefore, cardiologists may request a right sided ECG to look for right ventricular infarction. It is typically present in 19% to 51% of patients with acute inferior MI's.1

Lead V4R is the most useful lead in evaluation of right ventricular infarction. The diagnostic criteria in lead V4R is ST segment elevation = 1 mm. In patients who have an inferior infarction, lead V4R has a high sensitivity and specificity for detecting right ventricular infarction, identifying the site of occlusion in the proximal RCA, and pinpointing patients at high risk for development of AV block.1

Right ventricular infarction occurs in patients who have had a transmural infarction of the inferior-posterior wall of the left ventricle. The MI extends into the right ventricle due to an occlusion of the proximal right coronary artery (RCA).

Hemodynamic symptoms occur in only 5 to 10% of patients with right ventricular infarction. If the patient develops cardiogenic shock, mortality rates as high as 35% exist. Thrombolytics do not seem to have an impact on end mortality. Hypotension and cardiogenic shock occur when the ischemia is enough to decrease the compliance and cause volume (pressure) overload in the right ventricle. The increased pressure causes a shift in the curvature of the septum, which impinges left ventricular function, thereby decreasing left ventricular preload and producing a hemodynamic situation consistent with left ventricular tamponade.` Patients with altered hemodynamics caused by right ventricular infarction have elevated jugular venous pressure, a positive Kussmaul's sign and clear lung fields. AV blocks are common. Third degree AV block development causes hypotension and the mortality is quite high. Pacing these individuals is important to remove preload from the ventricles.

Treatment of these individuals should include early diagnosis to prevent mismanagement. Response to reperfusion is good and RV function returns rapidly. Diuretics, nitroglycerin, and morphine should be avoided in right ventricular infarctions because they decrease preload.

Reference 1. Conover, Mary Boudreau (1996). Understanding Electrocardiology. (7th Edition). St. Louis, MO: Mosby. Pp. 415-417.

Q - Where are the leads placed for a right-sided ECG?

A - Normal placement of the precordial leads V1-V6 on the chest wall will give a look at the electrical conduction of the left ventricle and assess for changes in the anterior or posterior walls.

When doing a right-sided ECG, you leave V1 and V2 in place. The right chest leads are V3R, V4R, V5R and V6R. These leads are placed in the same position on the right side of the chest as you would place them on the left side.

Reference Conover, Mary Boudreau (1996). Understanding Electrocardiology. (7th Edition). St. Louis, MO: Mosby. Pp. 8.

Q - Does aggressive treatment of hyperglycemia in the critically ill patient improve outcomes?

A - Critically ill patients often have hyperglycemia even without any previous history of diabetes mellitus. Stress, increased release of glucose counter regulatory hormones, enteral and parental feedings, and medications, such as glucocorticoids can elevate a patient's serum glucose. Hyperglycemia in the critically ill clients place them at risk for fluid and electrolyte disturbances, ketoacidosis, poor wound healing, sepsis and other infections. Clients with acute myocardial infarctions and stroke have poorer outcomes with elevated serum blood glucoses.

For many years it has been known that hyperglycemia can increase risk in the critically ill client. However aggressive treatment of blood sugar has not been addressed. Often values under 200 mg/dL are not even treated.

A recent study done by Van den Berghe et al1 (NEJM, Nov 8, 2001) showed a 32% reduction in mortality from multisystem organ failure for patients treated with intensive insulin therapy. This prospective, randomized, controlled study involved adults admitted to a surgical intensive care unit who were receiving mechanical ventilation. The patients were randomly assigned on admission to receive intensive insulin therapy (using IV insulin therapy to maintain blood glucoses between 80 and 110 mg per deciliter), or conventional therapy (IV insulin only if the blood glucose exceeded 215 mg per deciliter and SQ insulin to keep blood glucose between 180 and 200 mg per deciliter).

The study planned on enrolling 2,500 patients, but was stopped after 12 months and 1,548 patients due to the significant reduction in mortality. Mortality occurred 8.0% with conventional insulin therapy vs. 4.6% (P<0.04) with intensive insulin therapy. The most noticeable benefit was to patients who remained in the ICU longer than five days. These patients had a 20.2% mortality with conventional treatment as compared to 10.6% with intensive insulin therapy (P=0.005). Deaths due to multiple-organ failure with a proven septic focus were significantly reduced. Patients receiving intensive insulin therapy were less likely to require prolonged mechanical ventilation and intensive care. The use of intensive insulin therapy noted overall reductions in mortality by category: in overall in-hospital mortality (34%), bloodstream infection (46%), acute renal failure requiring dialysis (41%), median red-blood cell transfusions (50%), and critical-illness polyneuropathy (44%).

Impact on Practice

This study was well designed, but it should be noted the study population was surgical intensive care patients without histories of diabetes mellitus. The results may not be transferable to a medical intensive care unit. However, intensive insulin therapy proved to be effective in reducing the number of deaths from multiple-organ failure with sepsis, regardless if a history of diabetes or hyperglycemia existed. Studies in populations of medical intensive care should replicate this design to prove effectiveness in medical populations. Glycemic control can be a preventive measure to reduce mortality in intensive care populations.

Glycemic control reduces the risks for septicemia, prolonged antibiotic therapy, prolonged mechanical ventilation, acute renal failure and multisystem organ failure. As patient advocates, we should monitor all critically ill patients and strive for glycemic control to reduce patient morbidity and mortality. Changing our practice to effectively monitor blood glucoses in all patients and treat aggressively blood sugars outside the normal range can have an impact in many outcomes for our clients.

References Van den Berghe, Greet, Wouters, Pieter, Weekers, Frank, Verwaest, Charles, Bruyninckx, Frans, Schetz, Miet, Vlasselaers, Dirk, Ferdinande, Patrick, Lauwers, Peter, and Bouillon, Roger. (2001). Intensive Insulin Therapy In Critically Ill Patients. The New England Journal of Medicine. 345, (19). 1359-1367.

Q - How do the different treatments of hyperkalemia work on the cellular level?

A - Hyperkalemia can be a serious and life threatening condition. The most serious consequence is the slowing of the electrical conduction of the heart which can lead to asystole. A normal serum potassium level is a concentration between 3.5 to 5.5 mEq/L. Hyperkalemia is defined as a serum K+ > 5.5 mEq/L. Potassium is a major intracellular cation which is maintained in proper balance between the intracellular and extracellular fluid.

Normal Physiology of Potassium Uptake and Excretion by the Kidney

Potassium is located predominantly inside the cell in skeletal muscle. The sodium-potassium pump regulates the amount of sodium able to enter the cell, by removing it intracellularly and keeping most of the potassium inside the cell. Predominately, potassium balance depends on dietary intake and renal excretion. Osmolar properties and insulin levels outside the cell (extracellular) regulate cellular uptake of potassium. Aldosterone levels regulate the excretion of excessive potassium based on the sodium-potassium balance. The proximal tubule of the kidney actively reabsorbs potassium. It is both actively and passively secreted into the distal tubule of the kidney so the body will maintain homeostasis. About 10-15% of filtered potassium is excreted in the urine. In comparison about 1-2% of filtered sodium is excreted.

Pathophysiology of Hyperkalemia

Three factors influence the development of hyperkalemia. These factors include: decreased excretion of serum potassium by the kidneys, such as acute or chronic renal failure; movement of potassium from the intracellular area which causes an osmolarity increase in the extracellular space, such as hyperglycemia or hypernatremia; and acidosis which leads to hydrogen ions entering the cell and causing potassium to move to the extracellular area.

An elevation in serum potassium level directly stimulates the release of aldosterone. The exchange of sodium and potassium ions occurs in the distal tubule and the collecting duct. Sodium is reabsorbed and potassium is excreted in the presence of the aldosterone. An inverse relationship exists between hydrogen ion concentrations and the potassium ion. When there is an increase in hydrogen ions (such as acidemia), potassium and hydrogen ions exchange across the cell membrane. Potassium is shifted from the intracellular fluid into the extracellular fluid, thereby increasing serum potassium levels. Normal renal mechanisms (explained earlier) will insure the excess potassium is excreted via the urine. But in the case of renal failure, potassium ions accumulate leading to hyperkalemia. In alkolitic states, the kidney responds by returning the potassium ions to the circulation, but unless the alkalosis is severe, the serum potassium levels will not drop below normal limits. Thus, normal urine output plays a role in maintaining homeostatis.

Causes of Hyperkalemia

• Acidosis due to renal failure (acute or chronic types) Myonecrosis (any type of muscle tissue death)
• Drugs (i.e. ACE inhibitors, ß-blockers, Cyclosporine, Digitalis, K+ Sparing Diuretics, Heparin, NSAID's, Pentamidine, Potassium penicillin, TMP- SMX, Succinylcholine, THAM)
• Renal insufficiency
• Adrenal insufficiency
• Massive blood transfusion

Medical Management of Hyperkalemia

The main goal of medical management of hyperkalemia is to avoid electrical slowing of the heart and eliminate potassium from the extracellular space. Management with calcium gluconate, calcium chloride, glucose-insulin, sodium bicarbonate all cause a membrane antagonism or transcellular shift of the potassium into the cell, they do not remove the potassium from the body, therefore, they only buy time for more effective measures to be in place.

Cardiac muscle cells typically have a resting membrane potential of -85 to -95 milivolts (mV). An increase in extracellular potassium tends to depolarize the cell (make less negative). The degree of polarization is important in determining the ease with which an action potential can be initiated. It is easier to reach threshold and initiate an action potential when the membrane is already partially depolarized. In hyperkalemia, this threshold is raised causing a prolonged action potential through phases 0-4 and the cell does not have time to rest.

In a normal action potential, sodium rapidly enters the cell in phase 0 through the voltage gated "fast" sodium channels. In phase 1, the "fast" sodium channels close and potassium is leaving the cell. The interior of the cell is more positively charged which causes potassium to leave. In phase 2, calcium ions move into the cell, offsetting potassium. In phase 3 is the return to resting membrane potential where the slow calcium channels close and more potassium is removed from the cell. Phase 4 is the resting phase between action potentials. Here the Na+/K+ pump and Ca+ pump work continuously throughout the phases to maintain internal and external concentrations of sodium, potassium and calcium ions.

By giving calcium (whether in gluconate or chloride form) we are directly antagonizing the membrane actions of potassium on the cell. With more calcium outside the cell it lowers threshold due to the polarity. Its effects last about 20-30 minutes, so other therapies should be initiated.

Combining insulin and dextrose together in a therapy will drive potassium into the muscle cell and decrease the serum potassium level by about 1 mEq/L. How this works is the extra glucose and insulin work together to create glycogen which is taken to the liver for deposit. Potassium is deposited with the glycogen in the liver.

ß2-adrenergic stimulation can also cause transcellular shifts of potassium. Albuterol, a nebulized ß2 agonist, is effective in decreasing serum potassium in patients on hemodialysis. It can reduce K+ by 0.5 mEq/L within 30 minutes and sustain it for 2 hours.

Sodium bicarbonate can shift potassium into the cells. The increase in pH results in a shift of potassium into the cells. Insulin-dextrose has proven to be much more effective in lowering the serum potassium level than bicarbonate in renal failure. Furthermore, bicarbonate binds with calcium and should not be given after calcium has been administered.

Combining the use of measures to enhance removal of potassium from the body should be utilitized since calcium and insulin-dextrose only displace potassium from the extracellular space, they do not remove it from the body.

Polystyrene sulfonate (Kayexalate) is a cation exchange resin that can enhance potassium clearance across the gastrointestinal mucosa. It acts like a gastrointestinal dialysis. Kayexalate can be given orally or by retention enema. It is mixed with 20% sorbitol to prevent its excretion. Considerations about sorbital are for every mEq of potassium that is removed, 2 to 3 mEq of sodium are added. This increase of sodium can be easily eliminated by the use of furosedmide to enhance natriuresis.

Loop diuretics such as furosemide (Lasix) enhance urinary excretion of potassium, sodium, chloride, and water. Loop diuretics inhibit sodium and chloride reabsorption in the proximal part of the ascending loop of Henle, promoting the excretion of sodium, water, chloride, and potassium. This can be used as a follow-up measure to calcium and insulin-dextrose. However it is ineffective in renal failure.

Hemodialysis is the most effective method for lowering the serum potassium in patients with renal failure.

References

Banasik, Jacquelyn L. (1995). Chapter 16: Cardiac Function. In Copstead, Lee-Ellen C. Perspectives on Pathophysiology. Philadelphia, PA: W.B. Saunders pp. 360-361.

Logan, Paul. (1999). Principles of Practice for the Acute Care Nurse Practitioner. Stamford, CT: Appleton & Lange. Pp. 228-229.

Marino, Paul L. (1998). The ICU Book. 2nd Edition. Baltimore, MD: Williams & Wilkins. Pp. 652-658.

Papadakis, Maxine A. (1997). Fluid and Electrolyte Disorders. In Tierney, Lawrence M., McPhee, Stephen J. and Papadakis, Maxine A. (36th Edition). Current Medical Diagnosis & Treatment. Stamford, CT: Appleton & Lange. Pp. 806-809.

Wright, Jonell E. & Shelton, Brenda K. (1993). Desk Reference for Critical Care Nursing. Boston, MA: Jones and Bartlett Publishers. Pp. 756-758.