Iman Al-Obari, Ms Pharm; Abdulrazaq Al-Jazairi, PharmD; Iman Zaghloul, PhD; Mahasen Saleh, MD Ali Sanei, MD; Aabdulrahman Al Mousa, MD; Zuhair Al-Halees, MD Department of Pharmacy Services, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia Evaluation of the Standard Paediatric Unfractionated Heparin Dosing Protocol in Middle-Eastern Patients  The hemostatic system of newborns and infants differ from adults.  The most recent international unfractionated heparin (UFH) dosing protocol in pediatrics was based on suggestions from a single clinical trial.  No single trial assessed the safety and efficacy of this suggested nomogram in pediatrics, including middle-eastern patients.  The main objective of this study falls into 2 folds:  To compare the efficacy of implementing CHEST nomogram- 2001, to conventional UFH dosing practice in KFSH & RC with regard to achieving therapeutic aPTT.  To assess the efficacy and safety of implementing standard pediatric UFH dosing protocol CHEST 2001, in patients less than 1 year of age compared to more than 1 year.  The safety of the CHEST dosing protocol and the conventional practice was monitored also by following the occurrence of major or minor bleeding, presence of rash or heparin-induced thrombocytopenia Statistical Analysis To estimate the study sample size, a sequential design was used, where 10 patients who required systemic UFH were recruited, and used to estimate . After recruiting 10 patients the calculated  was Therefore, the sample size was estimated using the following parameters [postulated  = 12 and estimated  =9.98,  =0.01,  =0.05], which was 25 in each arm. The patients of the prospective arm were compared to an equivalent randomly selected historical- controlled patients who used conventional method of UFH pediatric dosing. All continuous variables were compared using the Student t-test and discrete variables with Fischer exact test. These analyses were performed using SPSS 10.0 for windows, Introduction Materials and Methods Study Design: Prospective, historical-controlled study Inclusion Criteria: pediatric patients less than 14 yr who required treatment with systemic UFH [prospective arm]. Exclusion Criteria: patients undergoing cardiopulmonary bypass (CPB), angiographic procedures, bone marrow transplant, and patients who have antithrombin III deficiency, using any other anticoagulant, allergic or have contraindication to UFH use. This group of patients were compared to a historical control group [retrospective arm]. UFH Administration:  In the prospective arm UFH was administered for any eligible patient who required systemic anticoagulation following CHEST nomogram. It was initiated with a bolus of 75 U/kg administered over 10 min followed by maintenance therapy initiated at 28 U/kg for children less than one year and 20 U/kg for children over 1 year. UFH was adjusted according to aPTT values following the CHEST protocol.The aPTT therapeutic range was sec following our institutional reference range.  Each patient was followed from the day of starting systemic UFH till the day it was discontinued or a maximum of 8 days.  Patients in the retrospective arm were following conventional method, which is defined as dosing adjustments based on results of aPTT without using specific guidelines or protocol. Study Endpoints: Both groups were analyzed in a comparative fashion. The efficacy endpoints included:  The mean time needed to achieve target aPTT  The number of aPTT measurements needed to achieve the target  In the prospective arm, patients older than one year were compared to those less than one year of age with regard to same efficacy endpoints. Results  The indication for using systemic UFH in both arms were either post cardiac surgeries for pediatrics with congenital heart disease, deep vein thrombosis, or arterial thrombosis.  The baseline characteristics and laboratory measurements of both arms were generally similar except for aPTT. However most of the retrospective patients were less than 1 year of age and consequently had smaller total body weight than prospective patients.  Patients in the prospective arm [CHEST group, n= 25] needed less time to achieve target aPTT than did patients in the retrospective arm [Conventional group, n=25], 18.3 ± 10.0 vs ± 27.2 hrs, P <  Multiple linear regression model incorporated weight, age, and baseline aPTT, showed that time to therapeutic aPTT was maintained significant [P<0.001, 95% CI ( )].  The proportion of CHEST patients who reached therapeutic aPTT 12 hours after the start of UFH therapy was 44%, this increased to 72% at 24 hours, and to 96% at 36 hours. Whereas, the proportion of conventional patients who achieved a therapeutic aPTT at 12 hours was none, but increased to 20% at 24 hours, and reached only 40% after 36 hours. The difference between the CHEST and conventional groups was significant at all times, P< [Figure I].  Furthermore, patients in the conventional group needed more aPTT measurements to reach target aPTT (6  2.92) than CHEST group (2.96  1.67), P< [Figure II].  Within CHEST group, patients under one year of age (n=7) were compared to those over one year of age (n=18) with respect for both efficacy endpoints. Patients less than 1 yr needed more time to achieve target aPTT than patients ≥ 1 yr of age, 20.1  10.3 hrs, vs  5.3 hrs, P= [Figure III]. Discussion Conclusion Figure I: Cumulative Number of Patients Who Achieved Therapeutic aPTT in CHEST Group Compared to Conventional Group Figure III: Cumulative Percentage of Patients Who Achieved Therapeutic aPTT in CHEST Group Stratified by Age Group [ Patients < 1 yr compared to Patients ≥ 1 yr].  Our study showed that dosing unfractionated heparin in middle-eastern pediatric patients following CHEST nomogram, 2001, was effective, safe, and superior to conventional dosing method.  Pediatric patients who followed CHEST nomogram required less time, and less number of aPTT measurements to reach therapeutic range compared to conventional dosing method.  Compared to previous data by Andrew and her colleague, our patients needed less time to achieve therapeutic range, 18 hrs, compared to their study, 24 hours.  Although genetic variability between our population and western population was postulated, the differences, if it exists, seems minimal.  Infants less than 1 year of age required the largest number of adjustments and more time to reach target aPTT compared to children  1 year.  This finding is consistent with the previous findings, and can be explained by the decreased concentration and activity of prothrombin and other clotting, protease inhibitors, including ATIII, and to the rapid UFH clearance in this age group.  Although the sample size is small for safety outcomes, only one patient experienced minor bleeding in the CHEST group compared to 6 in the conventional group, 2 of them were major.  The main possible explanation may be the optimal dosing achieved by the CHEST nomogram that resulted in less supratherapeutic aPTT readings [data not shown].  Our study has several potential limitations, including the use of historical-controlled design, high risk group (post cardiac surgeries), the performance of the nomogram was not evaluated for the maintenance of therapeutic prolongation of the aPTT after it was first achieved. The performance of the UFH dosing nomogram, CHEST 2001, in our patients was excellent with regard to early achievement of target aPTT, with out increasing the risk of bleeding, as compared to conventional dosing method. Institutional implementation of this nomogram seems to be costly effective. The excellent performance of the current nomogram can not be extended for newborns and infants. Further studies are warranted for refining this nomogram for this age group of patients before global implementation.  The mean number of aPTT measurements need to reach therapeutic range was 4.4 ± 1.7 and 2.7  0.8, respectively, [P=0.017].  In the conventional arm, major bleeding was observed in two patients (8%) due to a significant drop in the hemoglobin > 3g/L, and minor bleeding in 4 (16%) characterized by increment chest tube draining of blood. However, only one patient (4%) had minor bleeding in CHEST group. Rash was observed in one patient (4%) in the conventional group. P < Adj. P < Figure II: Cumulative Number of Patients Who Achieved Target aPTT Per Number of aPTT Measurement Needed in CHEST Group Compared to Conventional Group P=0.036