A Comparison of Dilute Versus Concentrated Heparin for CRRT Anticoagulation

Our study will compare two protocols using heparin for anticoagulation of the extra-corporeal
circuit during CRRT. Study subjects will be recruited from patients started on continuous
venovenous hemodialysis (CVVHD) in all intensive care units at Vanderbilt University Medical
Center (VUMC). Once enrolled, patients will be pragmatic cluster-randomized (by month of
entry) into one of two study arms. Arm A will receive dilute heparin and arm B will receive
standard concentrated heparin as both approaches are standard practices at VUMC. Heparin will
be delivered as an intravenous infusion proximal to the dialysis filter in both groups.
Replacement of the extra-corporeal circuit, including the dialysis filter, is performed under
several circumstances: stopping of CRRT when the subject is transported out of the ICU for a
procedure or study, machine malfunction, and clotting of the filter. All CRRT circuits and
filters, regardless of patency, are replaced at 72 hours per our dialysis unit protocol. Only
data from the first filter used for CVVHD will be used and the study subject's enrollment
will end with replacement of the extracorporeal circuit and filter.

Study subjects will receive standard care for the duration of the study and the inpatient
Nephrology team will control all aspects of the dialysis treatment. Changes to the heparin
infusion rates will be made based on the heparin nomogram for this study and it applies to
either arm. A copy of this nomogram will be provided to the inpatient Nephrology team who
will make adjustments to the heparin infusion as required to maintain blood anticoagulation
levels at goal. The principle investigators (PIs) will be available at all times by pager and
phone to address questions regarding proper adjustment of the heparin infusion and will
monitor each heparin dosing change to ensure consistency in implementation of the study
protocol.

The following is a summary for the two interventions (arms):

Treatment Algorithm Dilute heparin: Patients in the dilute heparin arm (enrolled in odd
calendar months) will receive a systemic loading dose of heparin of 15 units per kilogram of
weight (all heparin doses will be rounded to the nearest 100 units) by rapid (< 10 seconds)
intravenous bolus. The heparin concentration for the rapid intravenous loading bolus is 1000
units per mL. Then a maintenance rate of heparin of 7.5 U/Kg per hour will be started.
Heparin will be delivered as a solution of 2 units/mL and the infusion will be prepared with
2,000 units of heparin in 1,000 mL of 0.9% NaCl and delivered intravenously proximal to the
dialysis filter.

Standard concentrated heparin: Patients in the concentrated heparin arm (enrolled in even
calendar months) will receive a systemic loading dose of heparin of 15 units per kilogram of
weight* by rapid (< 10 seconds) intravenous bolus. The heparin concentration for the rapid
intravenous loading bolus for this arm is also 1000 units per mL. Then a maintenance rate of
heparin of 7.5 U/Kg per hour will be started and delivered via a syringe on the Prismaflex®
proximal to the dialysis filter. The concentration of heparin used will be 1,000 units of
heparin per mL of 0.9% NaCl.

Dose monitoring and adjustment: aPTT tests will be measured at baseline and at regular
intervals thereafter. Adjustment of the heparin dose will be made using a heparin nomogram
(see below) if the aPTT is not at the target level of greater than 35 seconds and less than
50 seconds. aPTT levels will be monitored every six hours routinely. If a significant change
is made to the heparin infusion rate due to a prolonged aPTT, the aPTT will be checked at a
shorter interval of three hours to ensure that aPTT is not persistently at a supratherapeutic
level as this could increase risk for bleeding complications.

Nomogram for heparin infusion:

aPTT (in seconds)< 35, infusion (continue), infusion rate change (increase 10%), repeat aPTT
(in 6 hours);

aPTT (in seconds) 35 to 50, infusion (continue), infusion rate change (no change), repeat
aPTT (in 6 hours);

aPTT (in seconds) 51 to 60, infusion (stop for 1/2 hour), infusion rate change (decrease
10%), repeat aPTT (in 3 hours);

aPTT (in seconds) 61 to 70, infusion (stop for 1 hour), infusion rate change (decrease 20%),
repeat aPTT (in 3 hours);

aPTT (in seconds) 71 to 80, infusion (stop for 1.5 hours), infusion rate change (decrease
20%), repeat aPTT (in 3 hours);

aPTT (in seconds) >80, infusion (stop for 2 hours), infusion rate change (decrease 20%),
repeat aPTT (in 3 hours);

For the purposes of this study, data will only be collected from the first filter used during
the CVVHD treatment. Following the end of the study enrollment period patients will continue
on CVVHD and heparin infusions at the discretion of their treating physicians. Heparin
infusions will continue to be adjusted based on the heparin nomogram.

Inclusion Criteria:

- Age greater than 18 years

- Renal failure, electrolyte disturbance, or volume overload requiring continuous
venovenous hemodialysis (CVVHD) as determined by the Nephrology consult service

Exclusion Criteria:

- Age less than 18 years

- Active bleeding

- Coagulopathy as defined by baseline INR > 1.8, aPTT > 45 seconds, or platelet count <
50 thousand/μL

- Active administration of systemic anticoagulation (such as warfarin, therapeutic
unfractionated heparin, or therapeutic enoxaparin)

- Contraindication to heparin (allergy, thrombocytopenia with platelet count < 50, known
or suspected heparin induced thrombocytopenia [HIT])

- Contraindication to systemic anticoagulation (recent surgical or other invasive
procedure, significant bleeding disorder, concern for intracranial bleeding, or other
contraindication as determined by treating physician)

- Administration of drotrecogin (Xigris™)

- Anticipated surgical or other invasive procedure that would necessitate withdrawal of
anticoagulation within 72 hours

- Expected termination of continuous renal replacement therapy (CRRT) or death in < 24
hours

- The need for more than 500 cc an hour of IV fluids delivered proximal to the filter
for the purpose of performing continuous venovenous hemofiltration (CVVH) or
continuous venovenous hemodiafiltration (CVVHDF)