Retrospective Audit of a Factor VIII Continuous Infusion Protocol to Examine Inhibitor Formation, Complications and Product Use.
Authors: Walsh Meghan , Mulcahy Rebecca , Scully Mary-Frances 
Published: October 2019

Abstract
Continuous infusion (CI) of factor concentrates has been suggested to decrease both the risk of bleeding and cost in the treatment of bleeding disorders. However, concerns have been raised with regards to the stability and sterility of products administered by CI and the risk of local thrombophlebitis. Most recently, there has been a concern about a potential association between the use of CI and the development of an inhibitor in mild hemophilia. A retrospective chart review was conducted to determine the effectiveness, safety, product use and risk of inhibitor formation of a continuous infusion protocol in the management of hemophilia A. Currently 248 patients are registered with the Provincial Hemophilia Program for Newfoundland and Labrador. These patients include 104 with mild hemophilia A, 3 with moderate hemophilia A and 5 with severe hemophilia A. The charts of twelve hemophilia A patients who received factor VIII (FVIII) by CI a total of 18 times between April 1998 and September 2003 were reviewed. All patients were affected by hemophilia A; 8 patients were diagnosed as mild, 1 as moderate and 3 as severe. The mean age of the cohort was 36.1 years and the patients’ ages ranged from 4 months to 75 years. Continuous infusion was used as treatment for severe bleeds in 12 cases and as prophylaxis for surgical procedures in 6 cases. All patients received recombinant FVIII. Recommended devices such as a syringe pump and mini-pump were unavailable therefore all infusions were carried out by diluting the reconstituted concentrate in saline and delivering via IV infusion. The CI protocol followed required a bolus of 50 U/kg of FVIII followed by CI at an initial rate of 4 U/kg/hr. Based on daily FVIII levels, this maintenance dose could be adjusted, with an initial targeted FVIII level of 1.0 U/L. The maximum initial infusion rate was 6.7 U/kg/hr and the minimum was 3.2 U/kg/hr (mean 4.3 U/kg/hr). The infusion rate was reduced in 8 cases to a minimum of 1.2 U/kg/hr. Adequate FVIII levels were maintained after the reduction of the infusion rate in all cases. The mean low and high FVIII levels were 0.79 U/L and 1.23 U/L, respectively (range 0.05 to 1.82 U/L). Excluding the patient who developed an inhibitor, the FVIII level remained above the minimum acceptable level of 0.3 U/L for the duration of CI in all but one case (low 0.29 U/L). Patients required an average dose of 53,163 units (range 2651–299,137 units) of factor concentrate delivered by continuous infusion over a mean period of 8.1 days (range 2–21 days). FVIII infusion was well tolerated in all cases; there were no documented cases of significant bleeding, adverse reactions, thrombophlebitis or infection. One patient was documented to have a minor bleed from an NG tube despite adequate FVIII levels throughout the period of infusion. One patient with mild hemophilia developed a low titer inhibitor (0.8 BU) approximately 2 years after receiving FVIII by continuous infusion for 8 days. Another mild hemophilia patient was discovered to have a low titer inhibitor (1.3 BU) on the eighth day after the third infusion had begun. It is possible that CI contributed to the development of an inhibitor in this patient. CI was not found to significantly reduce product use. More rapid downward adjustment of infusion rates in response to high FVIII levels might improve product utilization.