Therapeutic Dosing of Unfractionated Heparin- Pediatric/Neonatal - Inpatient/Emergency Department Consensus Care Guideline Table of Contents Population/Problem: ...................................................................................................................... 3 Definitions: .................................................................................................................................... 3 Recommendations: ....................................................................................................................... 3 Conflicts of Interest ....................................................................................................................... 6 Methodology ................................................................................................................................. 6 Collateral Tools & Resources ....................................................................................................... 7 Appendix A. Heparin Dosing Tables ............................................................................................. 8 References .................................................................................................................................... 9 Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Content Expert(s): Name: Anne Rose, PharmD – Pharmacy: Anticoagulation Stewardship Email Address: arose@uwhealth.org Contact for Changes: Name: Philip Trapskin, PharmD, BCPS – Drug Policy Program Email Address: ptrapskin@uwhealth.org Guideline Author(s): Anne Rose, PharmD – Pharmacy Reviewer(s): Christina Amend, MD – Pediatrics - Oncology Hannah Garippo, RN – Nursing Practice Innovation Nicole Lubcke, PharmD – Pharmacy David Yang, MD – Pathology Committee Approval(s): Inpatient Anticoagulation Committee: November 2022 Pharmacy and Therapeutics: April 2023 Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Population/Problem: Unfractionated heparin (UFH) is used intravenously when therapeutic anticoagulation is needed, and low molecular weight heparin is not a suitable option. Intravenous UFH has an immediate onset of action but requires monitoring and infusion rate adjustments to achieve a targeted therapeutic range1. Neonates and pediatric patients differ in their pharmacologic response to UFH2-7. The following guideline provides recommendations for how to initiate, dose adjust and monitor a UFH infusion in a neonatal and pediatric patient. Definitions: UFH is a high alert medication. An additional double-check is required as specified in UW Health Clinical Policy 6.1.19 must be performed on all boluses, when IV pump programming is outside of the established IV pump decision support software (Alaris Guardrails®) limits, when a new bag of heparin is hung and at each shift change. Recommendations: UFH intravenous infusions with the intent for titration to a therapeutic goal must be ordered via the IP/ED Heparin Anticoagulation – Pediatric – Supplemental Order Set. Separate order sets are available for extracorporeal membrane oxygenation or ventricular assist devices. The standard heparin concentration is 25,000 units in 500 mL (50 units/mL). There is a higher concentration option for fluid restricted patients of 50,000 units in 500 mL (100 units/mL). 1. Baseline laboratory monitoring: prior to starting the UFH infusion, collect the following baseline labs if not already resulted in the previous 48 hours 1.1 PT/INR (UW Health low quality evidence, strong recommendation) 1.2 CBC with platelet (UW Health low quality evidence, strong recommendation) 1.3 Heparin anti-Xa level: only if an oral Xa inhibitor (e.g., apixaban, rivaroxaban) was taken 48 hours prior to starting the UFH infusion (UW Health low quality evidence, conditional recommendation) 1.4 Drug specific anti-Xa level: only if an oral Xa inhibitor (e.g., apixaban, rivaroxaban) was taken 48 hours prior to starting the UFH infusion (UW Health very low quality evidence, conditional recommendation) 1.5 Labs should be drawn from a fresh venipuncture site prior to initiating UFH infusion 2. Initiation of UFH infusion 2.1 Initial bolus dose of 75 units/kg will result in a therapeutic anti-Xa in 90% of children2 (UW Health low quality evidence, weak/conditional recommendation) 2.2 Bolus doses should be used with caution or avoided in patients with the following2 (UW Health low quality evidence, weak/conditional recommendation) 2.2.1 Neonate or premature neonates 2.2.2 Stroke 2.2.3 Active bleeding 2.2.4 High bleeding risk 2.3 Initial starting infusion rate is based on the age of the patient2-7 (UW Health moderate quality evidence, strong recommendation) 2.4 See Table 1 for recommendations on bolus and initial infusion rate recommendations Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Table 1. Initial Heparin Bolus Dose and Infusion Rate2-7 (UW Health moderate quality evidence, strong recommendation) Age Bolus Dose (units/kg) Maximum Bolus (units) Initial Infusion (units/kg/hr) Birth to 12 months 75 1,500 28 Children > 1 year 75 5,000 20 Children > 12 years 80 10,000 18 Initial boluses and infusion rates are based on actual body weight 3. Titration and monitoring of UFH infusion2,8-12 (UW Health moderate quality evidence, strong recommendation) 3.1 Check STAT anti-Xa after initiation of the infusion and every 6 hours after any rate change 3.2 Use the nomogram in Table 2 to guide UFH infusion rate adjustments 3.3 Once 3 consecutive anti-Xa levels are therapeutic it is recommended to check an anti- Xa level every 24 hours with the am labs 3.4 If a rate adjustment becomes necessary or the infusion is held for any reason and restarted, recheck anti-Xa level and repeat the above process 3.5 If a therapeutic goal is not reached within 24 hours with correct titration the patient may not be an appropriate candidate for adjustments based on the heparin algorithm. Recommend consultation with Pharmacy and/or Hematology for assistance with dosing. Table 2. Heparin Infusion Dose Adjustment Nomogram2,8-12(UW Health low quality evidence, weak/conditional recommendation) Heparin Level by Anti-Xa (IU/mL) Bolus/Hold Infusion Rate Change < 0.1 Bolus 50 units/kg  3 units/kg/hr 0.1 – 0.29 0  2 units/kg/hr 0.3 - 0.7 0 No Change; Therapeutic Range 0.71 - 0.9 0  by 2 unit/kg/hr 0.91 – 1.0 Hold infusion 30 min  by 2 units/kg/hr > 1.0 Hold infusion 1 hour  by 3 units/kg/hr • Inform physician of each anti-Xa result for heparin infusion rate adjustment 4. Additional monitoring1,2 (UW Health low quality evidence, strong recommendation) 4.1 Samples should not be drawn from an IV infusing UFH 4.2 Hemoglobin and platelets must be followed 24 hours after initiating UFH therapy and every other day thereafter for up to 14 days of until therapy is discontinued. 4.3 Every 8 hours inspect line/surgical or wound sites for bleeding and check patient for symptoms indicating bleeding such as: hematomas, bruising, and respiratory symptoms. Contact MD for any signs of bleeding 4.4 Physician should be notified for: 4.4.1 Each anti-Xa result and heparin infusion rate adjustment Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 4.4.2 Platelet count decrease > 50% from baseline or if count falls below 100 x 109/L 4.4.3 Hemoglobin decreases by > 2 g/dL from baseline 4.4.4 Patient has any deterioration in neurological status 4.4.5 Baseline anti-Xa > 0.1 unit/mL or baseline INR > 1.2 4.4.6 Anti-Xa level is < 0.1 IU/mL or > 0.9 IU/mL 5. Table 3. Transitioning between anticoagulants13,17(UW Health low quality evidence, weak/conditional recommendation) Heparin to Enoxaparin Stop heparin Administer enoxaparin 2-4 hours later Heparin to DOAC Stop heparin Give oral anticoagulant at the same time Heparin to Fondaparinux Stop heparin Administer fondaparinux 2-4 hours later 6. Heparin and Direct Xa Inhibitors (e.g., apixaban, rivaroxaban) (UW Health GRADE low quality evidence, conditional recommendation) 6.1 In the presence of a direct Xa inhibitor the measured anti-Xa level may be relatively high in proportion to the antithrombin activity. This may result in over estimation of the heparin activity by the assay. To account for this, a higher anti-Xa goal may be used for patients with recent use of direct Xa inhibitors. 6.2 Target a higher anti-Xa range (Table 4) in patients who received a direct Xa inhibitor in the previous 48 hours and if the baseline heparin anti-Xa level is elevated. 6.3 A drug specific anti-Xa level should be drawn prior to starting the heparin infusion: 6.3.1 If the drug specific anti-Xa level is within or elevated outside of the target range, then heparin infusion should not be started. 6.4 If unable to wait for the drug specific anti-Xa level to result, then patient risk/benefit for thrombotic and bleeding risks should be weighed prior to starting the heparin infusion. Table 4. Nomogram for Director Xa inhibitor in Previous 48 hours and Elevated Baseline Heparin Anti-Xa (UW Health GRADE very low quality evidence, conditional recommendation) Heparin Level by Anti-Xa (IU/mL) Bolus/Hold Infusion Rate Change < 0.1 Bolus 40 units/kg & inform MD (max 10,000 units) increase by 3 units/kg/hr 0.1 – 0.39 Bolus 20 units/kg & inform MD (max 5,000 units) increase by 2 units/kg/hr 0.4 – 0.69 increase by 1 unit/kg/hr 0.7 – 1.0 None NO CHANGE; Therapeutic Range 1.1 – 1.4 decrease by 1 unit/kg/hr 1.5 – 1.7 Hold infusion 1 hr decrease by 2 units/kg/hr > 1.7 Hold infusion 1½ hr & inform MD decrease by 3 units/kg/hr • Inform physician of each anti-Xa result for heparin infusion rate adjustment Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Disclaimer Consensus care models assist clinicians by providing a framework for the evaluation and treatment of patients. This guideline outlines the preferred approach for most patients. It is not intended to replace a clinician’s judgment or to establish a protocol for all patients. It is understood that some patients will not fit the clinical condition contemplated by a guideline and that a guideline will rarely establish the only appropriate approach to a problem. Conflicts of Interest All guideline workgroup members are expected to follow institutional policies and procedures around conflicts of interest. Actions in which a guideline member discloses a conflict of interest relevant to the guideline topic may include, but is not limited to, abstaining from voting, dismissal during comment and voting period, or recusal from requesting and/or participation in the decision-making process. Methodology Development Process Each guideline is reviewed and updated approximately every 3-5 years, but will vary in consideration of the primary literature and relevant practice changes. All guidelines are developed using the guiding principles, standard processes, and styling outlined in the UW Health Clinical Practice Guideline Resource Guide. This includes expectations for workgroup composition and recruitment strategies, disclosure and management of conflict of interest for participating workgroup members, literature review techniques, evidence grading resources, required approval bodies, and suggestions for communication and implementation. GRADE Methodology adapted by UW Health Rating Scheme for the Strength of the Evidence/Recommendations: GRADE Ranking of Evidence High We are confident that the effect in the study reflects the actual effect. Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different. Low The true effect may differ significantly from the estimate. Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Very Low The true effect is likely to be substantially different from the estimated effect. GRADE Ratings for Recommendations for or Against Practice Strong (S) Generally, should be performed (i.e., the net benefit of the treatment is clear, patient values and circumstances are unlikely to affect the decision.) Conditional (C) May be reasonable to perform (i.e., may be conditional upon patient values and preferences, the resources available, or the setting in which the intervention will be implemented.) Collateral Tools & Resources Metrics 1. VTE Performance Measure – VTE 4 – UFH with dosage and platelet monitored by protocol 2. Guideline adherence 3. Time to achieve a target Xa level 4. % of time with supra or sub-therapeutic Xa levels 5. Event rate for bleeding and thrombotic events during heparin management Order Sets & Smart Sets IP/ED Heparin Anticoagulant – Pediatric – Order Set Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 Appendix A. Heparin Dosing Tables The following tables provide guidance for the initiation and titration of heparin in neonatal/pediatric population. Table 1. Initial Heparin Bolus Dose and Infusion Rate2-7 (UW Health moderate quality evidence, strong recommendation) Age Bolus Dose (units/kg) Maximum Bolus (units) Initial Infusion (units/kg/hr) Birth to 12 months 75 1,500 28 Children > 1 year 75 5,000 20 Children > 12 years 80 10,000 18 Initial boluses and infusion rates are based on actual body weight Table 2. Heparin Infusion Dose Adjustment Nomogram2,8-12(UW Health low quality evidence, weak/conditional recommendation) Heparin Level by Anti-Xa (IU/mL) Bolus/Hold Infusion Rate Change < 0.1 Bolus 50 units/kg  3 units/kg/hr 0.1 – 0.29 0  2 units/kg/hr 0.3 - 0.7 0 No Change; Therapeutic Range 0.71 - 0.9 0  by 2 unit/kg/hr 0.91 – 1.0 Hold infusion 30 min  by 2 units/kg/hr > 1.0 Hold infusion 1 hour  by 3 units/kg/hr • Inform physician of each anti-Xa result for heparin infusion rate adjustment Table 4. Nomogram for Director Xa inhibitor in Previous 48 hours and Elevated Baseline Heparin Anti-Xa (UW Health GRADE very low quality evidence, conditional recommendation) Heparin Level by Anti-Xa (IU/mL) Bolus/Hold Infusion Rate Change < 0.1 Bolus 40 units/kg & inform MD (max 10,000 units) increase by 3 units/kg/hr 0.1 – 0.39 Bolus 20 units/kg & inform MD (max 5,000 units) increase by 2 units/kg/hr 0.4 – 0.69 increase by 1 unit/kg/hr 0.7 – 1.0 None NO CHANGE; Therapeutic Range 1.1 – 1.4 decrease by 1 unit/kg/hr 1.5 – 1.7 Hold infusion 1 hr decrease by 2 units/kg/hr > 1.7 Hold infusion 1½ hr & inform MD decrease by 3 units/kg/hr • Inform physician of each anti-Xa result for heparin infusion rate adjustment Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023 References 1. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence based clinical practice guidelines. CHEST 2012;141:24s-43s. 2. Monagle P, Chan A, Goldenberg N, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians evidence based clinical practice guidelines. CHEST. 2012; 141e737s-e801s. 3. Igniatovic V, Summerhayes R, Than J, et al. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost. 2006;4(10):2280-82. 4. Ignjatovic V, Furmedge J, Newall F, Chan A, Berry L, Fong C, et al. Age-related differences in heparin response. Thromb Res; 2006;118:741–5. 5. Andrew M, Marzinotto V, Massicotte P, et al. Heparin therapy in pediatric patients: a prospective cohort study. Pediatr Res; 1994:35:78-83. 6. Bhatt MD, Paes BA, Chan AK. How to use unfractionated heparin to treat neonatal thrombosis in clinical practice. Blood Coagul Fibrinolysis. 2016; 27(6):605-14 7. Dabbous MK, Sakr FR, Malaeb DN. Anticoagulant therapy in pediatrics. J Basic Clin Pharm. 2014; 5(2): 27-33 8. Newall F, Ignjatovic V, Summerhayes, et al. In vivo age dependency of unfractionated heparin in infants and children. Throm Res 2009; 123:710-14. 9. Newall F, Ignjatovic V, Johnston L, et al. Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin. Thromb Haemost. 2010; 103(5):1085-1090. 10. Igniatovic V, Summerhayes R, Than J, et al. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost. 2006;4(10):2280-82. 11. Schechter T, Finkelstein Y, Ali M, et al. Unfractionated heparin dosing in young infants: clinical outcomes in a cohort monitored with anti-factor Xa levels. J Thromb Haemost. 2012;10:368-74. 12. Igniatovic V, Summerhayes R, Gan A, et al. Monitoring unfractionated heparin (UFH) therapy: which antifactor Xa assay is appropriate? Thromb Res .2007;120(3): 347-351. 13. Enoxaparin. In: DRUGDEX® System (internet database). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at http://www.thomsonhc.com (cited March 24, 2014) 14. Eliquis [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 8/2014. 15. Pradaxa [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 12/2014 16. Xarelto [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 12/2014. 17. Fondaparinux. In: DRUGDEX® System (internet database). Thomson Micromedex, Greenwood Village, Colorado, USA. Available at http://www.thomsonhc.com (cited March 24, 2014) Effective 4/20/2023. Contact CCKM@uwhealth.org for previous versions Copyright © 2023 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 04/2023