A Brief Review of Heparin-Induced Thrombocytopenia

Chris Brabant, perfusionist, Children's Hospital of Wisconsin.

Thrombocytompenia is one of the most common laboratory abnormalities among hospitalized patients. A low platelet count, less than 150,000 K/uL, can be caused by a variety of factors including septicemia, hypersplenism and hemodilution. Heparin-induced thrombocytopenia (HIT) is a rare and potentially severe condition that can cause substantial morbidity or mortality. As many as 28 percent of patients receiving heparin will develop HIT. It often is not recognized because the symptoms typically do not occur until five or more days after heparin is administered. Onset can be sooner if the patient had former heparin exposure.

Two clinical syndromes of heparin-induced thrombocytopenia are currently identified. HIT type I is characterized by a mild decrease in the platelet count. It most likely results from the proaggregatory effects of heparin on platelets. This is a nonimmunogenic mechanism that causes a direct, mild platelet activation. Conversely, HIT type II is considerably more severe. It is induced by immunologic mechanisms and is associated with clinical events that range from mild and asymptomatic to life threatening. The platelet count drops prodigiously and there is the potential for concomitant development of thromboembolic complications. HIT type I most commonly occurs in patients treated with intravenous high-dose heparin. However, HIT type II can occur in patients receiving heparin by any route and at any dose, including heparin flushes.

Before a few years ago, there was little explanation for thrombocytopenia and thrombosis in some patients receiving heparin therapy. Current evidence indicates the pathogenesis of HIT involves heparin binding to platelet factor 4. Together, these form an immune complex that is deposited on the platelet surface. Antibodies (IgG) against these immune complexes bind and activate the platelets. The activated platelets, in turn, release platelet micro particles, which have intensely pro-agulant activity. These micro particles explain the prothrombotic nature of HIT.

Paradoxically, patients who develop HIT are at a higher risk of thrombosis than bleeding, even when thrombocytopenia is severe. The presenting clinical manifestation of HIT often is thrombosis and can occur during the period of thrombocytopenia or platelet count recovery, despite the cessation of heparin. Most thrombotic events tend to be venous, although arterial thrombosis occurs as well. Typically, these events include deep vein thrombosis, disseminated intravascular coagulopathy (DIC), pulmonary embolism, cerebral thrombosis, myocardial infarction and ischemic injury to the legs or arms.

Heparin-induced thrombocytopenia differs from other immune-medicated drug-induced thrombocytopenias in that the antibodies associated with HIT often become undetectable several weeks after the drug is discontinued. Also, the clinical syndrome does not always recur on re-exposure to heparin, and sometimes resolves despite continued drug therapy. Finally, thrombosis and DIC develop only in some patients. It is interesting to note that most studies indicate that bovine lung heparin is five times more likely to cause an HIT episode than porcine mucosal heparin.

Demonstration of heparin-induced aggregation of platelets confirms the diagnosis of HIT type II. This can be accomplished with a heparin-induced serotonin release assay or a specific heparin-induced platelet activation assay.

Treatment of HIT should begin by immediately discontining heparin. This includes heparin flushes and vascular catheters that are heparin coated. Patients with HIT remain at high risk for thrombotic complications after cessation of heparin. Therefore, therapeutic-dose anticoagulation with thrombin inhibitors such as danaparoid, lepirudin or argatroban should be given. Therapy should not be delayed for the results of laboratory testing if the clinical suspicion of HIT is strong.

Although its occurrence is rare in adults and exceptionally rare in children, the presence of heparin-induced thrombocytopenia in a patient requiring cardiopulmonary bypass for the correction or palliation of cardiac disease may represent a formidable challenge for the surgical team. Fortunately, several clinical approaches are available. The approach should vary according to the presence or absence of active syndrome, the severity of the syndrome and the urgency of the surgical procedure. The simplest strategy is to postpone surgery for six to eight weeks, measure the level of antibodies and proceed with heparin if they are absent. If surgical intervention is determined to be more urgent, plasma pharesis, preoperative pharmacologic inactivation of platelets in preparation for intra-operative anticoagulation with heparin, or selection of an anticoagulant other than heparin have proven to be successful options.

Until recently, heparin-induced thrombocytopenia and associated thrombotic events was poorly understood. However, increasing consensus is emerging regarding its recognition and treatment options. Since heparin is being used for an ever expanding list of indications, it is essential that clinicians, as well as allied health personnel, familiarize themselves with this rare, potentially lethal complication.

Variables Influencing Lab Results Preanalytical Variation

Stanley F. Lo, PhD, technical director, Clinical Chemistry, Children's Hospital of Wisconsin

Abnormal test results usually are attributed to disease. Unfortunately, this is not always the case. Important considerations in interpreting laboratory results include preanalytical and biological variation.

Preanalytical variation is a variable influencing laboratory specimens prior to testing, and is primarily encountered during specimen collection and processing. Being aware of these variations and following proper procedures will minimize these effects, allowing for more reproducible and accurate results.

Biological variability can be classified as those that are controllable and less controllable. For example, biological variability can be controlled through proper patient preparation, as in the fasting requirement for lipid tests or the restricted diet for patients requesting catecholamine testing. Examples of less controllable biological variations include age, gender and genetic predisposition. Briefly described below are a few pre-analytical variables that occur in blood collection.

Venipuncture
Venipuncture is the most common method used for blood collection. In this process, a tourniquet is used to occlude the return of venous blood to the heart. The increased filtration pressure from the tourniquet can dramatically change the composition of the blood across the capillary wall. Tissue fluid and low molecular weight compounds are able to pass through, similar to the effects seen in the change in posture from lying to standing.

Typically, it is expected that the tourniquet be applied for less than one minute, within which changes in blood composition are minimal. However, more notable changes are observed after three minutes. Total protein, iron, total lipids and cholesterol increase from 5 to 7 percent, bilirubin increases 8 percent and AST 9 percent, while potassium decreases 6 percent when the occlusion is prolonged from one to three minutes. The blood drawn first is most representative of the circulating blood, an indication that specimens should be collected in a specific order. Therefore, the most critical medical decision-making tests should be collected from the first blood drawn.

For blood drawn later, consider the increase in protein and protein bound analytes. Occasionally, fist pumping is used to locate a vein. This practice should be avoided because it results in an increased potassium, phosphate and lactate levels. The increased lactate decreases the pH, resulting in release of protein-bound calcium or an increase in ionized calcium.

Blood Gases
Other considerations for blood collection are dependent on the test requested. For example, blood gas specimens require that all residual air (bubbles) be removed immediately to prevent changes in gas tension and subsequently sealed anaerobically. The temperature at which blood specimens are kept can affect the PO 2 result. When PO 2 levels are normal (100mmHg) and placed in an icewater slurry, PO 2 levels can increase by as much as 8 mmHg. However when levels are low, the PO 2 results are unaffected.

Samples kept at room temperature can be unaffected for up to 30 minutes as long as the specimen does not have an increased leukocyte or platelet count. Low hemoglobin levels may also affect PO 2 levels due to the decreased hemoglobin-oxygen buffering capacity. Specimens containing high PO 2 levels (>200mmHg) need to be measured in 10 minutes to minimize possible changes.

Occasionally, it is impossible to obtain an arterialized specimen. In these cases a capillary puncture may be used to collect an arterialized capillary blood specimen. A capillary specimen flowing freely from the puncture site, not squeezed out, mimics arterial blood well enough to allow clinical decision-making. The PCO 2 and H of capillary and arterial samples have excellent correlation. In contrast, levels for capillary PO 2 do not provide similar values to arterial blood, especially with capillary levels at 50 to 60 mmHg. Capillary PO2 levels should not be used for patients with peripheral vasoconstriction or vasodilation, reduced cardiac output, or hypotension.

The Comfort Zone: An Innovative Model for Improving Pain Management

Renee Ladwig, RN, MSN, CS, advanced practice nurse, Jane B. Pettit Pain Management Program, Children's Hospital of Wisconsin.

Creating change in clinical practice is always complex, especially when it involves multi-level changes in an organization. Due to new Joint Commission standards, health care organizations are challenged with developing processes to improve pain assessment and management. The Jane B. Pettit Pain Management Program at Children's Hospital of Wisconsin developed "The Comfort Zone" as a unique means of mobilizing institutional resources.

The Comfort Zone is a media and health system-wide campaign directed toward improving pain management for children during all phases of illness or injury.

Comfort Zone initiatives will impact on the care of all children undergoing cardiovascular surgery at Children's Hospital. The principles outlined above will help insure that all patients undergoing evaluation and treatment for cardiovascular disease will be afforded the highest level of comprehensive care available. Through regular pain assessment during procedures or after surgery, patients at Children's Hospital will be able to receive analgesic therapy targeted to their individual needs.

The Comfort Zone was based on the concept of "The Ouchless Place" developed at Saint Francis Hospital and Medical Center in Hartford, Connecticut. The Ouchless Place strategies were designed to address similar pain management problems in a 20-bed pediatric unit. For the first time, these strategies were applied on a larger scale to an entire institution here at Children's Hospital.

The Comfort Zone was adopted as a medical, fundraising and marketing priority that is supported by health system administration, nursing and medical staff, Public Relations and Children's Hospital Foundation.

Specific interventions include:

• The use of regular, developmentally-appropriate pain assessment.
• Quick response to reports of pain.
• The use of pain-free routes for giving medication.
• The use of topical anesthetics for IV placement or injection.
• Options for treating pain and ways parents can support their child

Successes
Designating our institution The Comfort Zone has led to significant improvement in the assessment of pain and the utilization of pain management resources for children. In the year following the implementation of The Comfort Zone:

• Consults to the Acute Pain Service increased by 21 percent and referral to the Chronic Pain Clinic more than doubled.
• Documentation of postoperative pain scores increased from an average of 1.7 to 5.5 pain scores during the first 24 hours post surgical.
• A Collaborative Practice Protocol for EMLA was approved.
• The use of procedural sedation increased.
• Requests for education about the use of nonpharmacological techniques during procedures increased.
• Child Life referrals increased by 88 percent.
• Children's Hospital Foundation focused on raising funds to support pain management in children. Several large endowments have resulted.

Blunt Cardiac Injury in Children

Anna Karpas, MD, and Kenneth Yen, MD, fellows, Pediatric Emergency Medicine, Children's Hospital of Wisconsin

Trauma is the leading cause of morbidity and mortality in children. Of all trauma deaths, 25 percent occur secondary to thoracic injuries and another 50 percent have thoracic injury as a significant contributing factor. Examples of thoracic injuries include pulmonary contusion, pneumothorax, hemothorax, aortic dissection and cardiac trauma. Blunt cardiac injury (BCI) is an important clinical entity due to the potential for lethal complications if not recognized promptly.

BCI (or myocardial trauma) is thought to be an infrequent injury in children, reported in approximately 5 percent of pediatric patients with blunt chest trauma. But it probably is under diagnosed, as this diagnosis often depends on the high degree of suspicion for the injury. Myocardial contusion has been called the most common unsuspected visceral injury after blunt trauma.

In children, BCI generally results from motor vehicle crashes (either as a pedestrian or passenger) and less commonly from falls, crush injuries or assaults. It most commonly is diagnosed in severely injured children with multi-system trauma.

In a recent retrospective review of 184 children with the diagnosis of BCI, 87.5 percent of patients presented with injuries to one or more additional other anatomic areas. Other thoracic injuries were present in approximately 50 percent of the patients, with pulmonary contusion being the most common. Associated non-thoracic injuries most often involved the extremities (52.2 percent), the brain (46.7 percent) and the abdominal organs (44.6 percent). Isolated cardiac injury represented only 12.5 percent of BCI.

BCI produces a range of injuries from an asymptomatic minor cardiac contusion to fatal cardiac rupture. In the largest retrospective review of 184 children with blunt cardiac injuries, 94.4 percent of the patients had myocardial contusion, 1.5 percent had myocardial concussion, and 2.1 percent suffered from cardiac laceration and/or rupture.

There are few signs and symptoms consistently present in patients with BCI. The initial clinical manifestations range from an absence of symptoms to severe hypotension, low cardiac output and death. In the largest retrospective review of children with BCI, external evidence of chest trauma was present infrequently and the initial cardiac exam was most often normal. BCI becomes more obvious with the development of early complications such as dysrhythmias and reduced cardiac output secondary to cardiac failure.

In patients presenting to the Emergency Department/Trauma Center with BCI associated with severe multi-system trauma, there is a significant risk the physician will be distracted by more obvious injuries and miss the BCI diagnosis. A high index of suspicion is essential to promptly recognize cardiac injury in the context of multi-system trauma.

Currently no "gold standard" for establishing the diagnosis of BCI has been identified. A 12-lead EKG, one of the commonly used tests, is abnormal in approximately half of the patients with BCI. Echocardiography, which allows evaluation of both anatomic and functional aspects of the heart, also is commonly performed. For practical purposes, significant myocardial contusion can be ruled out when findings on 12-lead EKG and echocardiography are normal.

Laboratory evidence of elevated cardiac enzymes can be useful in detecting cardiac injury. Specific markers of myocardial injury are available. A commonly used test is the CK-MB fraction. This enzyme also is present in skeletal muscle, however, CK-MB elevation may not be a sensitive indicator in the case of multi-system trauma. Recently troponin (cTnI) has proven to be a more accurate and reliable indicator of myocardial contusion. In BCI, elevated levels of troponin I (>2.0 ng/ml) correlated with the high likelihood of cardiac contusion. Troponin I also offers improved specificity because of the exclusive cardiac source.

In patients with myocardial contusion who are hemodynamically stable and without rhythm disturbances in the early posttraumatic period, clinical sequelae are uncommon (4.3 percent). However, hemodynamic compromise may not be apparent for at least 24-48 hours post trauma.

Patients who are hemodynamically stable and without evidence of dysrrhythmia after blunt chest trauma should be observed for at least 24-48 hours. Discharge is appropriate for patients who remain asymptomatic and where follow-up can be ensured.

Patients who present with hemodynamic instability/dysrrhythmia, or who develop signs of instability during the period of observation, should be admitted to the Pediatric Intensive Care Unit. The suggested diagnostic work-up for these patients should include a 12 lead EKG, echocardiography, CK-MB and troponin I level. If the patient remains symptomatic, serial echocardiography and cardiac catherterization should be considered.

We conclude that even though BCI is uncommon, it can be the consequence of seemingly mild blunt trauma and requires a high index of suspicion on the part of the treating physician. Initial BCI presentation may be overlooked, especially if the child is suffering from multi-system or unrecognized chest wall trauma. Physicians should utilize all available diagnostic modalities in cases where BCI is suspected. Close monitoring is important in order to identify the development of complications of BCI, such as dysrhythmias, traumatic VSD and ventricular wall aneurysms.

Update on Cardiac ECMO Usage

Jeanne Braby, RN, MSN, ECMO coordinator, Children's Hospital of Wisconsin

When ECMO (extracorporeal membrane oxygenation) first was started at Children's Hospital of Wisconsin in 1986, the majority of patients were neonates with pulmonary diagnoses. These included meconium aspiration, congenital diaphragmatic hernia, neonatal sepsis and persistent pulmonary hypertension of the newborn (PPHN). Newer non-invasive therapies, such as high frequency oscillating ventilation (HFOV) and inhaled nitric oxide (iNO) have decreased the need for ECMO in these neonatal populations.

Since 1995, the majority of ECMO patients at Children's Hospital have had a cardiac diagnosis. In 2000, nine of the 15 ECMOs were cardiac patients. Most cardiac ECMO patients go on after surgical repair of a cardiac defect. This is either due to an inability to wean from bypass, or due to acute deterioration in the Pediatric Intensive Care Unit (PICU) post-operatively. These patients may require ECMO to temporarily rest their hearts.

Some patients need ECMO to stabilize them prior to cardiac surgery. Patients with myocarditis or cardiomyopathy may need ECMO temporarily, or as a bridge to cardiac transplantation. In all cases, the need for cardiac ECMO results from an inability to maintain an adequate cardiac output.

The Extracorporeal Life Support Organization (ELSO) maintains an international registry of ECMO patients. They recently started reporting patients in a new category titled ECPR for those who go on ECMO during or immediately following cardiopulmonary resuscitation. This category is not used for all patients who have a cardiac arrest prior to ECMO, but is reserved for those whose primary reason for ECMO is cardiac arrest. For example, a post-op cardiac patient with low cardiac output may need CPR prior to cannulation for ECMO; however, they would be classified as a cardiac patient since ECMO is needed due to their low cardiac output condition. Although we have done patients who would fit into this new category, ECMO patients from Children's Hospital have not yet been entered into the ECPR category. According to the January 2001 International ELSO Summary, 175 patients underwent ECMO for ECPR and 59 (34 percent) survived to discharge from the hospital.

Another New Use
Recently, ECMO has been used at the University of Michigan when families have requested the option to donate organs on a terminally ill patient who has not been declared "brain dead." After consent is obtained, femoral venous and arterial catheters are placed prior to termination of the ventilator. After the patient is declared, they are placed on ECMO to continue to perfuse the organs until procurement occurs. This only is being done when families show a strong interest in organ donation