Central venous catheter sampling of low molecular heparin levels: an approach to increasing result reliability.

BACKGROUND: The low molecular weight heparin effect in children is monitored using the anti-factor Xa level. Venipuncture is recommended; however, central venous catheter blood sampling is often necessary. Heparin infused through central venous catheters may contaminate central venous catheter blood samples, preventing reliable anti-factor Xa level measurement. Simultaneous anti-factor Xa/partial thromboplastin time measurement with central venous catheter blood sampling may predict anti-factor Xa reliability. OBJECTIVES: To determine the prevalence of heparin contamination as measured by the partial thromboplastin time/anti-factor Xa in central venous catheter blood samples and whether careful sampling could minimize heparin contamination of anti-factor Xa levels from central venous catheter blood sampling. METHODS: Simultaneous partial thromboplastin time/anti-factor Xa measurements from central venous catheter blood sampling determined the prevalence of heparin contamination of central venous catheter blood samples. In phase II, children receiving low molecular weight heparin had routine central venous catheter blood sampling to measure the peak anti-factor Xa and the simultaneous partial thromboplastin time. Anti-factor Xa levels with a partial thromboplastin time of >40 secs (pair 1) were identified; there was no low molecular weight heparin dose change, and the paired sample was repeated using a careful sampling technique (pair 2). Pairs 1 and 2 were compared to determine the efficiency of the sampling technique in removing heparin from the central venous catheter blood samples. RESULTS: In phase I, 100 children had 485 paired anti-factor Xa/partial thromboplastin time central venous catheter blood samples with 29% ± 4.1% (95% confidence interval 25% to 33%) anti-factor Xa with partial thromboplastin times of >40 secs. In phase II, 43 children had 129 paired anti-factor Xa/partial thromboplastin time samples with partial thromboplastin times of >40 secs. The pair 1 mean partial thromboplastin times/anti-factor Xa levels were 109.8 secs (SD 53.1, range 34.0 to >200 secs) and 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL). Repeated partial thromboplastin times/anti-factor Xa levels (pair 2) were significantly decreased from those of pair 1 (p < .001) with means of 58.5 secs (SD 21.2, range 22-152 secs) vs. 109.8 secs (SD 53.1, range 34.0 to > 200 secs, p < .001) and 0.63 unit/mL (SD 0.30, range 0.02-1.77 units/mL) vs. 1.03 units/mL (SD 0.56, range 0.26-4.2 units/mL), respectively. CONCLUSIONS: Measurement of the partial thromboplastin time performed in combination with that of the anti-factor Xa level can be used to assist health practitioners to identify unfractionated heparin contamination of anti-factor Xa levels drawn from central venous catheters. A careful sampling technique may minimize heparin contamination in central venous catheter blood samples.

Online KidClot education for patients and families initiating warfarin therapy: The eKITE study.

Anticoagulation with Vitamin K antagonists (VKA) has always posed challenges in terms of monitoring requirements. These challenges were further exacerbated in the setting of the COVID-19 pandemic, with limited access to and/or avoidance of laboratory testing. The importance of utilizing point of care (POC) health technology for individualized patient management is salient. The foundation of effective home INR monitoring is establishing patient knowledge about their therapy and INR testing proficiency. The eKITE series was developed to support patients in establishing foundational knowledge required for VKA (warfarin) management and INR monitoring. The primary objectives were to evaluate eKITE, a patient-oriented innovative online education program for warfarin therapy, participant learning stress, and patient preference for online learning. This multi-center prospective study provided patients access to warfarin online education. Participants were required to complete written quizzes assessing warfarin knowledge of key concepts proficiency and identifying knowledge deficits. Patient preference, evaluating calm (lack of anxiety) while learning, and an INR on a home meter was completed. Participants performed INR tests at home and reported INRs by telephone. The analysis included 144 children and caregivers enrolled at five US and CDN sites. Most indications for anticoagulation were cardiac (congenital or acquired heart disease) with varied INR target ranges. Mean knowledge scores for warfarin and INR self-testing modules were 97%, with low anxiety with TTR of 84%. Patient preferred online learning. eKITE is an effective teaching modality for warfarin/home INR monitoring with safe INR testing and warfarin management that is appropriate for pediatrics and adults alike. PROLOGUE: The whir in the hallways is deafening. Lights bright, alarms are ringing in a chorus of unsynchronized beeps and screeches. It has been more than a week since I have slept. Snuggled beside me is my precious child, whining and equally irritated with the asynchronous symphony, further compounded by anxiety, procedures, and pain. The sun has broken. The staff smiles are welcoming and incessant, as one after one, they approach hurried, urgent, assiduous, their need to coach me for our upcoming departure to the warmth of home. Each provides essential information that I will require to keep my child, my treasure, safe and healthy. Yet, my eyes are heavy, blurred, and my brain foggy, trapped in a dark heavy cloud. How am I to follow? Comprehend? and retain anything? As they instruct, my precious child yearns for loving arms, compassion and love, whining, crying in disquiet. Overwhelmed does not adequately describe my ineffable exhaustion. Amidst this, how am I to learn about warfarin? Such a challenging medication, with so much to know. Concentrate, I tell myself, focus; now is my only opportunity to learn. I must be alert. It seems to be nonsensical.

Novel uses of insulin syringes to reduce dosing errors: a retrospective chart review of enoxaparin whole milligram dosing.

UNLABELLED: Enoxaparin is a low molecular weight heparin (LMWH) commonly used for thromboprophylaxis children. Enoxaparin dosing is based on patients' weight and results in decimal dosing. Due to the high concentration of enoxaparin the resultant decimal dose makes precise measurement difficult. Dilution is necessary and often results in ten-fold medication administration errors [Ghaleb MA, Barber N, Franklin BD, Yeung VWS, Khaki ZF, Wong ICK. Systematic review of medication errors in pediatric patients. Ann Pharmacother Oct 2006;40(10):1766-76, Raju TN, Kecskes S, Thornton JP, Perry M, Feldman S. Medication errors in neonatal and paediatric intensive-care units. Lancet Aug 12 1989;2(8659):374-6]. Enoxaparin may be administered in whole milligram doses via insulin syringe, where one milligram of enoxaparin equals one unit on the 100 unit graduated insulin syringe. STUDY DESIGN: A retrospective chart review of 514 children. Data was collected on underlying diagnosis, reason for anticoagulation, anti-Xa levels, hemorrhagic events, and medication errors identified. OUTCOME: to determine the occurrence rate of supra-therapeutic anticoagulation as indicated by anti-Xa levels >1.0 u/ml, when enoxaparin doses are rounded up to the whole milligram, and are administered using insulin syringes. The secondary objectives were to determine if the supra-therapeutic anti-Xa levels were associated with hemorrhagic events. To determine if children achieved and maintained therapeutic anti-Xa range using whole milligram dosing and to evaluate the impact of utilizing insulin syringes for administration on reducing dose measurement errors. RESULTS: All 514 patients were prescribed whole milligram enoxaparin dosing, and achieved therapeutic anti-Xa within a mean time of 2 days. No infant or child required decimal doses to achieve therapeutic levels. Five children achieved an initial supra-therapeutic anti-Xa level (1.04 -1.36 U/ml), requiring a single whole milligram dose decrease. There were no associated hemorrhagic events. CONCLUSION: Whole milligram enoxaparin dosing administered via an insulin syringe safely and effectively, achieved therapeutic levels in infants and children. The reduced incidence of enoxaparin dosing errors suggests that whole milligram enoxaparin dosing via an insulin syringe is a method that should be considered for standard of care.

KIDCLOT: the importance of validated educational intervention for optimal long term warfarin management in children.

BACKGROUND: Advances in medical and surgical therapy in children have resulted in increased survival in children with primary illnesses. However, thrombosis is a serious complication of this success and results in mortality and morbidity. Prevention or treatment of thrombosis using warfarin is challenging in children due to its narrow therapeutic index and the unique differences in children, including variable nutritional intake and the occurrence of common concomitant viral or bacterial illnesses which alter warfarin metabolism. The variable response to warfarin in children necessitates frequent International Normalized Ratio (INR) monitoring. Education may improve time in therapeutic range (TTR) a measure of warfarin effect, and a surrogate for patient adherence, safety and efficacy. METHODS: The Pediatric Anticoagulation program (Stollery Children's Hospital) developed a novel child-focused educational program KIDCLOT-POC about warfarin therapy and POC-INR meter use. A total of twenty eight children, and their caregivers, participated in KIDCLOT-POC. Questionnaire score comparisons and practical demonstrations assessed the learners' theoretical and practical knowledge of warfarin management. RESULTS: In caregivers, the median pre, post and knowledge retention questionnaire scores were 50 (IQR 27), 93 (IQR 6) (p<0.0001) and 96 (IQR 6) (p<0.0001), respectively. In the 18 children who were >or=6 years of age, post and knowledge retention questionnaire scores were 90 (IQR 16) and 92 (IQR 23) (p=0.44), respectively. The TTR for all children was 81.7% (SD 13.1). CONCLUSIONS: Implementation of KIDCLOT-POC program appears to promote high knowledge development and retention in children and caregivers and high TTR with no adverse events.

The journey for adolescents and young adults with chronic conditions transitioning to adult care with successful warfarin management.

UNLABELLED: Health transition of youth from a child-centered care model to the adult model has been recognized to be of critical importance due to the increasing numbers of children now surviving chronic conditions. A formalized transition process is required adequately assess the AYA's readiness for transition and to move towards adult care. Indefinite warfarin therapy poses challenges as warfarin is a narrow therapeutic index drug that requires frequent monitoring and attentiveness to warfarin interactions and affects. OBJECTIVE: The objective of this study was to evaluate transition to adult care for AYAs requiring indefinite warfarin therapy within a structured self-management program. OUTCOME MEASURES: Results were compared between Phase 1 (enrollment to patient self-management) and Phase 2 (independent warfarin management) 6months following confirmation of transition to adult care. There was no statistical difference between outcome measures except INR testing frequency, and no adverse events. CONCLUSIONS: This transition process resulted in successful transition as measured by TTR and other clinical end-points from pediatric to adult care. Implementing a formal transition process for young adults with chronic health conditions that considers patient preferences motivates and empowers them over time to develop autonomy with warfarin self-management, results in successful transition and warfarin management.

Antithrombotic therapy for ventricular assist devices in children: do we really know what to do?

The use of ventricular assist devices (VADs) in children is increasing. Stroke and device-related thromboembolism remain the most feared complications associated with VAD therapy in children. The presence of a VAD causes dysregulation of hemostasis due to the presence of foreign materials and sheer forces intrinsic to the device resulting in hypercoagulability and potentially life-threatening thrombosis. The use of antithrombotic therapy in adults with VADs modulates this disruption in hemostasis, decreasing the risk of thrombosis. Yet, differences in hemostasis in children (developmental hemostasis) may result in variances in dysregulation by these devices and preclude the use of adult guidelines. Consequently, pediatric device studies must include safety and efficacy estimates of device-specific antithrombotic therapy guidelines. This review will discuss mechanisms of hemostatic dysregulation as it pertains to VADs, goals of VAD antithrombotic therapy for children and adults, and emerging antithrombotic strategies for VAD use in children.

EMPoWARed: Edmonton pediatric warfarin self-management study.

BACKGROUND: Patient self-management (PSM) in adults is safer and more cost effective than conventional management. Warfarin is a narrow therapeutic index drug with individual patient response to changes and frequently a long-term therapy. Children and their families are proposed to be able to effectively manage their child's warfarin therapy. Increased health related quality of life is highly associated with effective therapy in patients with chronic conditions. OBJECTIVES: The aim of this study is to evaluate the safety and efficacy of PSM over time including HRQOL and variables that may influence PFU success at PSM. PATIENTS/METHODS: Children and their family units (PFUs) current performing patient self-testing/monitoring for ≥ 3 months were enrolled in this cohort study. PFUs participated in comprehensive education on warfarin testing and management followed by an apprenticeship. Socio-demographic, clinical, and laboratory data were collected to evaluate safety and efficacy and health related quality of life. Outcomes were compared between the first 6 months on PSM (phase 1) and the last 6 months data collected on PSM (phase 2). RESULTS: Forty-two patients performed PSM for a median of 2.7 years (range: 1.1-6.2 years). Time in therapeutic range was 90% and 92.9% (p=0.30) in phases 1 and 2 respectively. All measures were strongly associated with improved heath related quality of life. PFUs socio-demographic status did not influence success at PSM. All PFUs maintained warfarin knowledge and INR testing competency. Warfarin dosing decision errors median 0 (range: 0-5, p=0.73) and a median 0 (range 0-4, p=0.55) per patient in phases 1 and 2 respectively. There were no adverse hemorrhagic or thrombotic events. CONCLUSIONS: Empowering PFUs to self-manage warfarin results in increased knowledge and understanding of their health condition, improved commitment to their health care and adherence to medication regimens and is demonstrated to be sustainable over time.

Effect of sodium orthovanadate on the hepatobiliary clearance of rose bengal in streptozotocin-induced diabetic rats.

Sodium orthovanadate is known to promote glucose uptake in muscle and adipose tissues and has been suggested as a possible oral hypoglycemic agent. In addition, insulin-dependent diabetes has been shown to alter the hepatobiliary clearance of several drugs in rats. This study has determined whether orthovanadate, like insulin, can reverse diabetes-induced changes in the biliary excretion of endogenous bile acids and in the hepatobiliary clearance of rose bengal. Six groups of male Sprague-Dawley rats were used; normal, insulin-treated normal, vanadate-treated normal, diabetic, insulin-treated diabetic, and vanadate-treated diabetic. Diabetes was induced by injection of streptozotocin (45 mg/kg, i.v.). One week later, insulin (2-4 U/day, s.c.) and sodium orthovanadate (877 +/- 82 mumol/kg/day, p.o.) treatments were initiated. After 4 weeks, the clearance and biliary excretion of rose bengal (60 mumol/kg, i.v.) were determined for 3 hr. Bile flow rate, rose bengal excretion, and excretion of endogenous bile acids were unchanged in the two treated normal groups and in the insulin-treated diabetic rats. These parameters were increased in untreated diabetic and vanadate-treated diabetic rats as compared with normal. Pharmacokinetic analyses indicated that total and biliary clearances of rose bengal were increased in diabetic rats and that orthovanadate did not reverse these changes. However, liver weight and serum glucose concentrations were reduced by orthovanadate treatment. These data indicate that the oral insulinomimetic chemical sodium orthovanadate effectively reversed some, but not all, of the diabetes-induced alterations of hepatic function.

Cytopathology of papillary carcinoma of the thyroid with anaplastic transformation. A case report.

A case of papillary carcinoma of the thyroid with anaplastic transformation was diagnosed by fine needle aspiration. The atypical history and presentation of this case, the initially problematic cytologic and immunohistochemical findings, and the definitive cytologic and histologic features are described. The diagnostic problems posed by papillary carcinoma of the thyroid with anaplastic transformation are discussed. This diagnosis must be included in the differential diagnosis of poorly differentiated tumors of the neck.

Chylothorax in children with congenital heart disease: incidence of thrombosis.

Postoperative chylothorax is a frequently encountered pathology occurring in up to 4% of patients undergoing surgery for repair of congenital heart disease. Symptomatic thrombosis is associated with chylothorax and may contribute to its severity and duration. Furthermore, vessel thrombosis resulting in persistent vessel occlusion may impede future treatments, diagnostic studies and cardio-surgical interventions. The objective of this study was to determine the incidence of upper system thrombosis in pediatric congenital heart patients with confirmed chylothorax with ultrasound screening of all patients diagnosed with chylothorax. All pediatric patients with confirmed with chylothorax underwent doppler ultrasound of the upper venous system as per hospital standard. This retrospective cohort study enrolled all children between February 1, 2010-August 2012, post cardiac surgery with confirmed chylothorax to determine the incidence of all thrombosis. There were 1396 children who underwent 1396 cardiac surgical procedures during the study time with 760 undergoing cardiopulmonary bypass. Development of chylothorax occurred in 54 of 1396, 3.9% (95%CI 3.0;5.0) procedures in all children. In those children with chylothorax, 28 of 54 episodes, 51.8% (95%CI 38.9;64.6) had confirmed VTE. The 51.8% incidence in this study demonstrates a 2.6 fold increase in risk of thrombosis compared to 20% in children with heart disease and central venous lines and may result in serious clinical consequences. The contribution of upper venous system thrombosis to chylothorax is unknown. Often, clinical suspicion of chylothorax exists, however the lack of a standardized approach to objective diagnosis results in delayed confirmation. Approaches to therapy either treatment of confirmed thrombosis or prevention of thrombosis in patients with chylothorax require formal evaluation. Future studies are urgently needed.

Dynamic and structural formation of a thrombus: the inciting event of arterial ischemic stroke.

Arterial ischemic stroke occurs as a result of abnormal clinical circumstances that alter hemostasis and cause thrombosis, either within a vessel or as an embolic event. Understanding normal hemostasis, including differences between children (developmental hemostasis) and adults, will provide background for determining the pathophysiology of stroke and potential treatments.

Warfarin induced coagulopathy in children: assessment of a conservative approach.

BACKGROUND: Increasing numbers of children are being administered warfarin therapy as thromboprophylaxis. Warfarin has a narrow therapeutic window with a target international normalised ratio (INR) of 2-3.5, called the therapeutic range. The length of time a patient's INR remains within the therapeutic range is calculated as 'time in the therapeutic range'. Risk for haemorrhage in children receiving warfarin is 0.5%/patient-year and minor bleeding 2.3%/patient-year, which increases exponentially for INRs >5.0. Practice among non-bleeding adults with INRs ≥5 and ≤9 is to withhold warfarin and allow the INR to return to the therapeutic range. Faster warfarin clearance is correlated with younger age. METHODS AND RESULTS: The study objective was to determine the safety and effectiveness of a conservative approach for management of INRs >5 in children receiving warfarin. Children receiving warfarin with INRs ≥5 had warfarin withheld followed by a next day INR without vitamin K administration. Eighty-nine children (1-16 years) participated in the study with 2353 INRs performed. Twenty-six children had INRs ≥5, 5% of the total performed, with a mean INR of 5.9. The next day repeat mean INR after withholding one dose of warfarin was 3.3 (range 1.2-6.8) with 89% of INRs falling below 5. There were no overt bleeds or symptomatic thrombotic events in the month following the INR >5. Time in the therapeutic range for children with INRs ≥5 was 68%. CONCLUSIONS: Withholding warfarin alone for management of non-bleeding INRs ≥5 and ≤8 appears to be safe and effective.

Topical lidocaine and the effect on enoxaparin absorption in children: a pilot study.

UNLABELLED: Enoxaparin, a low molecular weight heparin (LMWH), is frequently used for the prevention and treatment of thromboembolic complications in infants and children (Sutor et al., 2004 [1]). Injection pain and the fear and anxiety associated with needle phobia in the pediatric population are well documented. Best practice pediatric pain management standards of care recommend mitigating the child's pain experience whenever possible. The use of topical anesthetics such as liposomal-lidocaine 4% results in a rapid onset of anesthesia, minimal blanching, without vasoconstriction (Koh et al., 2004 [2]) or risk of methemoglobinemia. Topical lidocaine has been used to reduce the injection pain of enoxaparin, but there is no data available examining whether it will interfere with the absorption of LMWH. OBJECTIVE: To determine if the topical lidocaine, Maxilene, interferes with enoxaparin absorption as measured by peak anti-Xa levels. METHODS: Infants and children clinically prescribed enoxaparin were eligible for this study. Children in group 1 were pre-treated with Maxilene prior to enoxaparin injection on day 1 with no Maxilene pre-treatment on day 2. For group 2, the order was reversed. Peak anti-Xa levels were measured following each enoxaparin dose and were compared between the groups. RESULTS: 26 children of ages 14d-16 y (median 6.7 months) were enrolled. Anti-Xa levels following topical lidocaine administration were 0.070 U/mL (95%CI 0.025; 0.114) lower than without prior topical lidocaine administration. Anti-Xa levels on the second day were on average 0.013 U/mL (95%CI -0.066; 0.040) higher compared to day one regardless of the order of topical lidocaine administration. There were no reported incidences of local reactions such as redness, hives or blanching. CONCLUSIONS: Topical lidocaine (Maxilene) administration before enoxaparin injection results in a small, clinically non-significant, reduction in anti-Xa levels.

EMPoWarMENT: Edmonton pediatric warfarin self-management pilot study in children with primarily cardiac disease.

UNLABELLED: Increasing numbers of children require warfarin thromboprophylaxis. Home INR testing by the patient (PST) has revolutionized warfarin management. However, the family/patient must contact the health team for guidance for warfarin dosing. Patient self management(PSM) prepares a patient performing PST to take an active role in warfarin dosing. Adult studies demonstrate that PSM is safe and effective with improved adherence and treatment satisfaction quality of life (QOL). OBJECTIVE: To estimate the safety and efficacy in children performing PSM or PST, to evaluate warfarin dose decision making in PSM, and warfarin related QOL. METHODS: Warfarinized children performing PST for >3m were randomized to PST or PSM. The PSM group underwent warfarin management education and assumed independent warfarin management. INRs were collected for a year prior to and for 1 year of study to determine TTR and warfarin decision making. QOL was assessed through inventory completion and interviews. RESULTS: 28 children were randomized and followed for 12 months. TTR was (83.9% pre/ post), and 77.7% pre to 83.0% post for PST and PSM (p=0.312). Appropriate warfarin decision making was 90% with no major bleeding episodes and no thromboembolic events. PSM was preferred by families. CONCLUSIONS: PSM for children may be a safe and effective management strategy for warfarinized children. Clinical studies with larger sample size are required.

Development and preliminary evaluation of the KIDCLOT PAC QL: a new health-related quality of life measure for pediatric long-term anticoagulation therapy.

UNLABELLED: Long term anticoagulation (LTA) is hypothesized to induce treatment dissatisfaction influence quality of life (QOL). QOL is measured by a tool developed specific to the patient condition. Pediatric QOL inventory for children on LTA should assess constructs salient for this population. Identification and evaluation of QOL constructs, critical to improve care, and is accepted as the "gold-standard" measurement for patient-centered outcomes in clinical research. OBJECTIVES: To develop and preliminarily validate a pediatric QOL inventory for children/families receiving LTA. Secondary objective was to determine how anticoagulation disrupts children's life. METHODS: Stage 1: Item/theme generation through focus groups and existing inventories, Stage 2: Item reduction, inventory generation and content validity. Stage 3: Inventory refinement, implementation and reliability testing. Responses were evaluated for variability, internal consistency, and scale structure. Item reduction was based on response rate, item variability, and clinical utility. RESULTS: Two inventories, KIDCLOT-PAC-Child -Tween QL and KIDCLOT-PAC Parent-proxy-QL were developed. Content and face validity was assessed by experts, parents, and patients. Internal consistency determined by Cronbach's alpha was good for parent-proxy(0.82) and child(0.89). Pearson correlation was acceptable with >0.5 for test-retest reliability (parent inventory). CONCLUSIONS: KIDCLOT-PAC-QL is the first preliminarily validated inventory to assess QOL in anticoagulated children. The inventory identifies barriers in care and areas for improvement in order to modify care to provide the "best" management (improved QOL associated with safety and efficacy) for children requiring LTA.