BSA-BASED HEPARIN PROTOCOL EXCERPT
The purpose of this document is to outline a proposal to utilize a
new heparin dosing protocol at Lakeland Regional Medical Center.
DISCUSSION:
The dosing of heparin, despite the drug's long history of use in
many conditions, is largely based on empirical regimens that have
not been fully consistent with the known pharmacology of the drug.
The aim of heparin therapy is to prevent the initiation of thrombus
formation and also to prevent the extension of existing thrombi.
The dosing strategy employed must strive toward this goal while
minimizing the possible complications of therapy, most notably
hemorrhage.
The pharmacology of heparin is complex. Heparin is a
mucopolysaccharide anticoagulant derived from mast cells of animal
tissues. The onset of action is immediate after intravenous
administration. The volume of distribution of the drug
corresponds to plasma volume in both lean and obese individuals.
The therapeutic half-life of heparin ranges from 0.63 to 2.13 hours
in adult humans, and is prolonged in obese subjects. Plasma half-
life is also prolonged in obese subjects.
The ideal dosing strategy for heparin would be a regimen that will
rapidly attain therapeutic effect without undue risk of iatrogenic
complications. To date, there is no widely accepted standard
dosing regimen for heparin. Many clinicians employ an empiric
regimen that is not adjusted according to physiologic parameters,
but is titrated according to response as indicated by the activated
partial thromboplastin time (APTT). Some regimens have been
developed to overcome this deficiency. Currently there are weight
based regimens in use at various institutions around the country
that have been proved superior to empiric (non-adjusted) regimens.
Such a regimen is used at Lakeland Regional Medical Center. The
problem with currently available weight based regimens is that they
are based either on total body weight (TBW) or ideal body weight
(IBW) which limits their utility in obese subjects. TBW based
regimens will tend to overdose an obese subject while IBW based
regimens will underdose the obese subject. This phenomenon occurs
because the distribution of heparin mirrors the plasma volume.
Adipose tissue contains less plasma per unit weight than does
muscle or visceral tissues. In the obese subject the higher
percentage of adipose tissue will mean that a TBW regimen will give
a higher dose that is warranted by the blood volume while an IBW
regimen will underdose because the plasma present in the adipose
tissue will not be accounted for. The ideal regimen would be one
that has the initial dose calculated by a measurement or estimation
of plasma volume.
Various methods have been described for estimating the plasma
volume in man. Plasma volume can be most easily estimated from
height, weight, and body surface area measurements. The most
accurate method is calculation of plasma volume by utilizing weight
and the cube of the height, but the complexity of the calculation
limits the use in a clinical setting. Of the easily measured and
calculated physiologic parameters (height, weight, and BSA) the
estimated body surface area most closely correlates with actual
plasma volume. The estimated plasma volume is 1536ml per square
meter of BSA for men, and 1414ml per square meter of BSA for
women.
The therapeutic plasma concentration of heparin is usually
described as 0.6 units/ml. With a known therapeutic target, and
a reliable estimation of the volume of distribution and the
elimination half-life of heparin, it is simple to calculate the
initial loading dose and maintenance infusion rate for any subject.
The loading dose for heparin therapy is given by tradition.
Empirically, the current protocol uses 80 units/kg TBW. This is
equal to approximately 3000 units per square meter BSA in a 68"
70kg patient. The expected plasma level from such a dose is
approximately 1.9 units/ml, or about 3 times the desired
concentration of 0.6 units/ml. The loading dose is probably not
important in heparin therapy, however. With an elimination half-
life of one hour, the majority of the loading dose is eliminated by
the time the first APTT is drawn at 6 hours (over 98% of the
loading dose will have been eliminated at 6 hours past
administration) so the APTT seen at 6 hours is due almost entirely
to the maintenance infusions. A bolus may hasten the development
of therapeutic APTT's, but a dose of 0.6 u/ml plasma volume (or 920
units/sq meter for men, 850 units/sq meter for women) would be
adequate. (This would be approximately 23 units/kg TBW in a 70kg
68" male.) If a dose equivalent to 80 units/kg IBW was desired,
then 3000 units/sq meter could be used. This would provide a
safety margin in obese persons since TBW would not be used to
calculate the loading dose. In any instance, the loading dose is
not of primary concern as long as it is not any higher than the
current dose or any lower than that sufficient to provide a plasma
level of 0.6 units/ml.
To determine the initial maintenance infusion rate, the desired
plasma concentration is multiplied by the expected plasma volume,
with the resultant concentration multiplied by the first order
elimination rate constant. For heparin the plasma volume can be
estimated by utilizing the Dubois surface area nomogram to first
find BSA (from measured height and weight) and then multiplying by
the appropriate factor (1536ml/sq m for men, 1414ml/sq m for
women). The estimated plasma volume is then multiplied by 0.6
units/ml to determine the desired total body store of heparin. The
infusion rate required to maintain this plasma level (0.6 units/ml)
is then calculated by multiplying the desired total body store by
the first order elimination rate constant for heparin which is
0.693/hr (assuming a one hour therapeutic half-life).
Adjustments to the initial dose should be made by measurements of
the APTT. If the APTT is <38 seconds (or <1.2 X control) the
infusion should be increased by 150 units/sq meter/hr with an
additional bolus of 1000 units/sq meter. If the APTT is 38 to 47
seconds (1.2 to 1.5 X control) the infusion should be increased by
75 units/sq meter/hr with an additional bolus of 750 units/sq
meter. No change is made if the APTT is 48 to 74 seconds (1.5 to
2.3 X control). If the APTT is 75 to 96 seconds (2.3 to 3 X
control) the infusion rate is decreased by 75 units/sq meter/hr.
If the APTT is 97 to 120 seconds, the infusion is held for one hour
and the rate decreased by 120 units/sq meter/hr when restarted. If
the APTT is 121 to 200 seconds, the infusion is held for 90 minutes
and restarted at a rate decreased by 150 units/sq meter/hr. If the
APTT is greater than 200 seconds, the infusion is held for 2 hours
and restarted at a rate reduced by 190 units/sq meter/hr. Note that
the rate adjustments made through APTTs of 120 seconds correlate
with the adjustments made in the weight based dosing regimen by
Raschke when the patient is of average size (5'8", 70kg). As
adiposity increases, the change in dose per kg of TBW is decreased,
but the absolute change in dose is increased to compensate for the
plasma volume of the adipose tissue. Intermittent bolusing is
selected at approximately the same as the initial bolus for APTTs
< 38 seconds, and reduced to 75% of the initial bolus for APTTs
>from 38 to 47 seconds.
PROPOSAL:
It is proposed that a study be undertaken to validate this new
heparin dosing protocol. Patients will be assigned to either a
weight-based protocol as proposed by Raschke or the protocol
described in this document on a random basis (with physician
agreement) and data collected. After approximately one hundred
patients have been treated with each protocol, data will be
analyzed to compare efficacy and safety of the different protocols.
The study will be started if this proposal is accepted and approved
by the appropriate medical staff committees and the LRMC
institutional review board. It is anticipated that the dosage
calculations will be performed by the nursing staff with all
calculations double-checked by the clinical pharmacist.
METHODOLOGY:
The new heparin dosing strategy outlined in this document will be
tested for efficacy and safety in a randomized trial at Lakeland
Regional Medical Center. One hundred patients will be assigned, on
a random basis, to both the new protocol and the Raschke weight-
based protocol (total of 200 patients). The Raschke protocol
utilizes weight-adjusted bolus (using TBW for calculations) and
infusion rate adjustments as determined by the measured APTT.
Randomization will occur when a participating physician enters a
patient into the study. Sealed envelopes, containing one of the
two appropriate protocols, will be selected by the RN responsible
for the patient's care. The envelopes will be identical in all
aspects in regards to external appearance and thickness (number of
sheets of paper contained) and sealed with a tamper-proof seal in
order to insure random distribution of the protocols by preventing
any purposeful selection by a caregiver. Blinding of caregivers
between the protocols is not possible because they must see the
nomograms in order to perform dosage calculations. Patients will
be blinded - they may be informed that they are to receive heparin,
but they will not be told of the method used to determine the dose.
The protocol will be numbered and will contain all relevant
instructions and forms for data documentation. Only the specific
heparin dosing protocol will be a part of the permanent medical
record (along with expected monitoring data such as APTT and the
physician's progress notes). Additional data collected for the
sole purpose of this study will be excluded from the patient's
chart. All relevant forms and documents excluded from the chart
will be kept in a secure location on the nursing unit until it is
collected (on a daily basis) by a designated member of the study
team.
The intent of the study will be to compare aspects of the two
heparin dosing strategies with regards to safety and efficacy.
Specifically, the study will seek to elucidate any difference in
the following parameters:
1. Time elapsed until the first therapeutic APTT and until
a steady-state therapeutic APTT is achieved.
2. Number of required dosage adjustments until the first
therapeutic APTT and number of adjustments until a
therapeutic steady-state APTT is achieved.
3. Total number of subtherapeutic APTT measurements.
4. Total number of supratherapeutic APTT measurements.
5. Total number of clinically detectable thrombotic events.
6. Total number of clinically detectable bleeding events.
7. Total number of dosage adjustments made in the course of
therapy normalized to number of treatment days.
8. Total number of dosage adjustments required to
reestablish a therapeutic APTT when an initial
therapeutic APTT had been achieved and a subsequent APTT
indicated the need for further dosage adjustment.
9. Time elapsed to achieve a therapeutic APTT when a
therapeutic APTT had been achieved and a subsequent APTT
indicated the need for further dosage adjustment.
10. Number of subtherapeutic and supratherapeutic APTT
measurements until initial therapeutic APTT and until
therapeutic steady-state APTT achieved.
11. Platelet counts pre and post therapy.