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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
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50 Anticoagulation Therapy
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TABLE 3-10: Target Anti-factor Xa Activity Level Considerations
for Selected Indications Using UFH
Indication Target Anti-Factor Xa Activity Level
VTE prophylaxis 0.1–0.3 units/mL
VTE treatment 0.3–0.7 units/mL
ACS Target values vary. 0.35–0.7 units/mL as well as 0.3–0.55 units/mL
Pregnancy 0.35–0.7 units/mL can be considered; however, the target may
a
Note: These values have not been validated for changes in heparin requirements, bleeding, or
thrombosis outcomes in clinical observations or trials. Anti-Xa activity values over 0.7 units/mL
have been associated with increased bleeding events.
ACS: acute coronary syndrome, mL: milliliters, VTE: venous thromboembolism
have been proposed (not validated) and may depend on concurrent
therapies (i.e., thrombolytics) used.
depend on the setting such as during pregnancy, during delivery and
use of spinal catheters, and the post-partum period.
24,a
• Data on the optimal approach to heparin
management are limited. Some data describe
using a weight-based approach or a set minimal
dose or having aPTT in target range within 24
hours as factors associated with a reduced risk
for thrombosis (Table 3-11).
•
Most trials comparing UFH to LMWH for VTE
treatment used set aPTT ratios for heparin.
Given the more sensitive heparin assays now in
use, underdosing of UFH may have been present
compared to current doses derived from aPTT
ranges determined by anti-factor Xa activity
titration. This may have created a bias favoring
LMWH in clinical trials that compared LWMH
to UFH targeting a predetermined aPTT (60–80
sec) vs. more sensitive assays to heparin (e.g.,
aPTT target 80–110 sec for anti-factor Xa
activity of 0.3–0.7 units/mL).
28
• Studies establishing the aPTT range for many
devices may not have accounted for different assay
reagent sensitivities.
• Examples of heparin dosing using aPTT or antiXa in VTE treatment are described in Tables
3-12, 3-13, 3-14.
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TABLE 3-11: Trials Achieving a Therapeutic aPTT in the First
24–48 Hours after Initiating UFH Lower Risk of Recurrent
a
VTE
Studies UFH Dose VTE Recurrence
Raschke R
8
1992
Hull 1997
Weight-based vs.
5,000 unit-bolus and
24,000 units/24 hr
25
See Table 3-4
Weight-based had a fivefold lower incidence of
recurrent VTE at 3 months.
aPTT over therapeutic range at 24 hr: 23.3%
incidence
The incidence of recurrent VTE is significantly lower
with aPTT in the therapeutic range at 24 hr.
Outlines importance of aPTT reaching target range
early.
Anand 1996
Five Trials
30,000 units/24 hr aPTT subtherapeutic 24 hr: 6.3%
26
aPTT over lower therapeutic limit: 7%
Outlines that if 30,000 units/day are provided, no
evidence of improved efficacy observed with earlier
aPTT in range.
Anand 1997
Three Trials
5,000 bolus + ≥1,250
27
units/hr
Low aPTT: odds 1.3 vs. therapeutic aPTT (at 24 and
48 hr) p = 0.56
Suggests the value of infusing at least 1,250 units/hr.
a
Controversy: It is unclear if an aPTT value within the target range at 24–48 hours or if daily doses
24,000–30,000 units are used lead to different outcomes. Lower daily doses and subtherapeutic
aPTT values in the setting of acute thromboembolism may be associated with increased recurrent
thromboembolism.
aPTT: activated partial thromboplastin time, hr: hours, VTE: venous thromboembolism
52 Anticoagulation Therapy
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TABLE 3-12: Adjusted Dosing Nomogram Example for
Continuous Heparin Infusions Using the aPTT in VTE
Treatment
APTT (sec) Dose Adjustment Comments
a
b
Weight-Based Non-Weight
Based
<35 Bolus 40–80 units/kg
Increase by 3 units/
kg/hr
35–49 Bolus 20–40 units/kg
Increase by
2 units/kg/hr
Bolus 2,500–5,000
units
Increase by 200–250
units/hr
Bolus 1,000–2,500
units
Increase by
Consider bolus
option if emergent
anticoagulation is
necessary.
100–200 units/hr
50–59 (50–70; see
Clinical Pearl below)
c
(70–90; see
60–90
Clinical Pearl below)
91–105 Decrease by
106–125 Decrease by
>125 Decrease by
a
Each nomogram should consider the reagent range used in each lab specific to the test and
Increase by
1 unit/kg/hr
No change No change
c
1 unit/kg/hr
2 units/kg/hr
3 units/kg/hr
Increase by
50–100 units/hr
Decrease by
50–100 units/hr
Decrease by
100–200 units/hr
Decrease by
200 units/hr
Option: Hold 30–60
minutes
Option: Hold 1–2 hr
reagent lot. This sample nomogram assumes an aPTT treatment range of 60–90 seconds based
on anti-factor Xa activity titration of 0.3–0.7 units/mL for VTE treatment. The aPTT range has to be
calibrated by each laboratory and will vary between lots of even the same reagent (see Chapter
21). The final nomogram for order sets should have specific numbers instead of a range. Smaller
bolus dosing may be an option.
b
Dose increase of 50–100 units/hr may depend on the patient weight.
c
Institution-specific therapeutic aPTT range of 60–90 seconds is equivalent to a plasma heparin
concentration of 0.3–0.7 anti-factor Xa activity units/mL or 0.2–0.4 units/mL by protamine
titration. Range may vary depending on the assay sensitivity to heparin for a particular reagent
and adjusted as reagent sensitivity to heparin changes. Repeat aPTT 4–8 hours post-rate change;
4 hours if no bolus; 6–8 hours if a bolus is administered (see Figure 3-1).
Note: In patients very sensitive to heparin and on very low doses, the titration scale may need
to be for smaller quantities for titrating to avoid large % changes in the dose with adjustments
(e.g., rate at 400 units/hr and adjustment of 100 and 200 units/hr is a 25–50% change. Consider
adjusting to 50–100 units/hr if not using a weight-based approach).
aPTT: activated partial thromboplastin time, hr: hour, kg: kilogram, VTE: venous
thromboembolism
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TABLE 3-13: Adjusted Weight-Based Dosing Nomograms for
Continuous Heparin Infusions Using the Anti-Factor Xa Activity
in VTE Treatment
Anti-Factor Xa
Activity (units/mL)
a,29
Dose Adjustment Comment
≤0.2 Bolus 26–30 units/kg
0.21–0.29 Bolus 15 units/kg
0.3–0.7 No change Option: 0.3–0.55 if bleeding is a notable
0.71–0.8 Decrease 1 unit/kg/hr
0.81–0.99 Decrease 2 units/kg/hr Option: Hold 30–60 min if notable
≥1 Hold infusion 1–2 hr
a
Repeat anti-factor Xa activity 4–8 hours after infusion rate change. Earlier draw (4–6 hours) can be
done if no bolus (see Figure 3-1). Once two consecutive anti-factor Xa activity levels are 0.3–0.7
units/mL, draw every 24 hours.
hr: hours, kg: kilograms, VTE: venous thromboembolism
Increase rate 3–4 units/kg/hr
Increase rate 2 units/kg/hr
Decrease 3 units/kg/hr
Option: Consider bolus if emergent
anticoagulation is necessary.
Option: Consider bolus if emergent
anticoagulation is necessary; option 0.21–
0.39 if higher levels of anticoagulation
desired where target range started at a
higher value such as 0.4 units/mL.
concern.
bleeding risks present.
• The upper end of the titration curve may be
selected for the aPTT range to ensure adequate
anticoagulation in acute VTE treatment (in this
example, 70–90 sec).
Timing of aPTT or Anti-Factor Xa Draw During Continuous
Infusion Heparin after a Bolus Dose of Heparin
•
The bolus dose may influence measured aPTT/anti-factor Xa values up to 8 hours
depending on the amount administered.
•
aPTT or anti-Xa activity assessments shortly after a bolus may suggest a higher
degree of anti-coagulation than provided by the continuous infusion alone.
•
Depending on the amount of a bolus (dashed line in Figure 3-1) administered,
the aPTT/anti-factor Xa will rise to a point higher than achieved by the continuous
infusion (dotted line in
in this situation will then drop over time to a value reflective of the infusion rate.
•
In patients who are at high risk for bleeding and
lower risk for thrombosis, the aPTT or anti-Xa
target range can be set at the lower part of the
target range (e.g., anti-Xa of 0.3 to 0.5 units/mL).
Figure 3-1). The measured value (solid line in Figure 3-1)
54 Anticoagulation Therapy
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TABLE 3-14: Sample Adjusted Dosing Nomogram for
Subcutaneous Heparin in VTE Treatment
aPTT (seconds) Dosing Adjustment Next aPTT
Below 40 Increase by 36–48 units/kg q 12 hr 6–8 hr post dose
40–59 Increase by 24–36 units/kg q 12 hr 6–8 hr post dose
60–90 No change Next morning, then daily (less
91–103 Decrease by 6–12 units/kg q 12 hr 6–8 hr post dose
104–124 Decrease by 12–24 units/kg q
Over 124 Decrease by 24–36 units/kg q
aPTT: activated partial thromboplastin time, hr: hours, kg: kilograms, q: every
•
Initial dose is 250 units/kg subcutaneous administered every 12 hr (or 17,500 units
every 12 hr).
• For change from IV to subcutaneous administration, see Table 3-6.
aPTT should be drawn at 6–8 hr (mid-interval) after dose.
•
•
In pregnancy, an 8- or 12-hr aPTT can be considered to determine if the dosing interval
needs to be changed to every 8 hr dosing (if on every 12 hr dosing) or every 12 hours
dosing (if on every 8 hour dosing) is feasible; institution-specific therapeutic range of
60–90 sec is equivalent to anti-factor Xa activity titration of 0.3–0.7 anti-factor Xa activity
units/mL or 0.2–0.4 units/mL by protamine titration.
12 hr
12 hr
frequent monitoring may be
required with long-term use)
6–8 hr post dose
6–8 hr post dose
• Figure 3-1 describes the influence of the bolus
dose on measured aPTT (or anti-factor Xa
activity) and subsequent dosing adjustments.
Early aPTT/anti-factor Xa measures after a
bolus dose may be higher than observed should
no bolus have been administered. This may
lead to no dosing adjustment or a downward
adjustment. The subsequent aPTT (or antifactor Xa activity) may then be below the target
range, creating a delay in reaching target values.
Checking aPTT values earlier than 6 hours after
initiating the UFH infusion may be requested to
determine if an adequate infusion rate is present
(aPTT value close to baseline). UFH bolus doses
of >5,000 units can also have an effect on aPTT
values drawn up to 8 hours later.
80
aPTT
Time
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60
UNFRACTIONATED HEPARIN 55
Bolus
Measured aPTT
40
2 hr 4 hr 6 hr 8 hr
Infusion
FIGURE 3-1. Bolus Dosing and Impact on Timing Laboratory
Values for Adjusting a Continuous Infusion
Heparin Resistance
•
Lack of a measurable heparin response in the absence of administering an
antidote can occur secondary to reduced antithrombin (benefit of the aPTT
assay), excessive factor VIII, or fibrinogen (benefit of anti-factor Xa activity assay).
Consider checking that the dose is being infused correctly into the patient as
ordered (one trick is to check the volume administered during the shift prior
to the lab draw and if it matches the prescribed administration rate). Consider
checking an alternative assay (anti-factor Xa if using aPTT), antithrombin, factor
VIII, and fibrinogen with infusion rates above 25 units/kg/hr and subtherapeutic
assay measurements. If additional clarification is required, consider a low range
ACT or sending samples to an outside lab for validation.
•
Patients with acute thrombosis may frequently need higher UFH dose requirements to attain therapeutic effect as these patients have been noted to eliminate UFH more rapidly, possibly because of increased binding to acute phase
reactants.
Lower aPTT and anti-factor Xa activity values may occur during
Although saline is commonly used during hemodialysis, heparin or sodium
citrate may be used to prevent thrombosis formation in the circuit. See Table
3-15 as an example for using heparin in continuous renal replacement therapy
(CRRT). Dosing approaches may vary between different approaches to CRRT.
1
awake periods compared to when asleep.
30
56 Anticoagulation Therapy
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TABLE 3-15: UFH Dosing Adjustments in Continuous Renal
Replacement Therapy
APTT (sec) Dose Adjustments
<35 Bolus 1,000–2,500 units
35–49 Bolus 1,000 units
c
50–65
66–75 Decrease by 50–100 units/hr
76–90 Decrease by 100–200 units/hr
>90 Decrease by 200 units/hr
a
Each nomogram should consider the reagent range used in each laboratory. The aPTT range
has to be calibrated by each laboratory and will vary between lots of even the same reagent (see
Chapter 18). Initial bolus doses of 25 units/kg (range 10–30 units/kg) followed by an infusion of
5–10 units/kg/hr (range 5–25 units/kg/hr) is one approach.Target aPTT should be a minimum of
1.5 times control or as established within the 0.3–0.7 units/mL anti-factor Xa activity calibrations.
Variations may exist between dialysis therapies.
b
Dose increases or decreases of 50–100 units/hr may depend on the patient weight and
sensitivity to heparin.
c
Institution-specific therapeutic aPTT range of 45–75 seconds is equivalent to a plasma heparin
concentration of 0.3–0.7 anti-factor Xa activity units/mL or 0.2–0.4 units/mL by protamine
titration. Range described is within (but more narrow) than the 0.3 to 0.7 units/mL, but may vary
depending on the assay sensitivity to heparin for a particular reagent.
hr: hour, min: minutes
Increase by 200 units/hr
Increase by 50–100 units/hr
No change
Option: Hold 30–60 min
Option: Hold 1–2 hr
a,31
b
b
•
Repeat aPTT 4–8 hours post-rate change; 4 hours if no bolus; 6–8 hours if a
bolus has been administered.
•
Survival of filter and heparin requirements may depend on the material (filter)
used.
•
Auto-anticoagulated patients at high risk of bleeding may not undergo anticoagulation of the circuit.
•
Regional heparin (patients with high bleeding risk and filter life span is too short
to accept): continuous UFH (500 units/mL) into arterial line (i.e., 9 × blood flow
[mL/min]). Continuous infusion protamine (5 mg/mL) into venous line starting
at a 1:100 (protamine 1 mg/100 units UFH). Check circuit aPTT (arterial line
post-UFH) and patient aPTT (arterial line pre-heparin). Target circuit aPTT is >55
seconds, and patient aPTT <45 seconds.
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• aPTT or anti-factor Xa activity values can vary
during a 24-hour period secondary to a potential
pharmacokinetic effect. Values can be higher
during sleeping periods (early a.m.) compared
to during awake hours.
30
Dosing increases and
decreases may subsequently occur. For prolonged
infusions and frequent daily dosing adjustments,
the infusions ordered may be modified (i.e.,
measuring the aPTT or anti-factor Xa
activity at the same time each day) to simplify
management.
• If resistance to UFH is suspected, check an
aPTT value shortly after a bolus dose to see
if a measure response occurs. If no response
(increase in aPTT or anti-factor Xa activity) is
noted, for example 15–30 minutes after an IV
bolus dose, the assay may need to be checked
(run anti-factor Xa activity off the aPTT, ACT)
or an alternative approach to anticoagulation
considered. If the patient is antithrombin (AT)
deficient, consider a direct-acting anticoagulant.
Extracorporeal Membranous Oxygenation (ECMO) or
Extracorporeal Life Support (ECLS) (See Chapter 17)
•
Infusion rates may be center-specific. Initial infusion rates of 20 units/kg/hr
have been used.
•
Infusion rates over 60 units/kg/hr have been associated with diminished
outcomes.
•
Can lead to a drop in antithrombin (AT) level. Impact of replacing AT on heparin
requirements unknown, but a change in UFH doses is not commonly seen after
AT administration.
•
Dosing adjustments may be done by bedside ACT (typically every 1–2 hours).
•
Infusion rates and target goals may depend on the age of the patient, circuit,
bleeding concerns, and cannulation site.
•
Unclear if the aPTT/anti-factor Xa or ACT is the best test and may vary between
centers. Correlation between assays is not strong.
•
Monitoring should include visual inspection of the circuit for any signs of clot
formation (see Chapter 17).
58 Anticoagulation Therapy
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• During ECLS/ECMO, the measured ACT or
aPTT may vary without changes in the infusion
rate. If one is not corresponding to dosing
adjustments, consider adding the other for
conformation. For pediatric patients, small peditubes can be used to minimize blood loss. Make
sure the correct ACT test is used consistently.
Impella (See Chapter 17)
TABLE 3-16: Drug Incompatibilities with Heparin
Alteplase
Amikacin
Amobarbital
Amphotericin B Deoxychoate
Atropine
Chlordiazepoxide
Ciprofloxacin
Clarithromycin
Codeine
Cytarabine
Daunorubicin
Diazepam
Doxorubicin
Doxycycline
Droperidol
Ergonovine maleate
Erythromycin
Filgrastim
Gentamicin
Haloperidol deconate
Haloperidol lactate
Hyaluronidase
Hydrocortisone sodium
phosphate
Hydroxyzine HCl
Idarubicin HCl
Kanamycin sulfate
Levofloxacin
Levorphanol tartrate
Methylprednisolone
Mitoxantrone
Morphine sulfate
Nesiritide
Norepinephrine bitartrate
Orphenadrine citrate
Pentamidine
Phenytoin sodium
Polymyxin B sulfate
Prochlorperazine
Promethazine
Quinupristin/dalfopristin
SIDE EFFECTS, PRECAUTIONS, AND
CONTRAINDICATIONS
Side effects, precautions, and contraindications to UFH are listed in Table
3-17.
Adverse Effects—Clinical Considerations
•
Excessive aPTT or Anti-Xa Activity: Result could be a hemidiluted sample,
especially if the INR is unexpectedly elevated or hemoglobin or hematocrit
(Hgb/HCT) is lower. Consider repeating by peripheral phlebotomy.
•
Presence of an oral anti-Xa inhibitor may substantially elevate the measured
anti-Xa activity.
•
Continued unexpected values: Check the bag concentration used or vial concentration; verify that patient received it or cross-check using an alternative assay
such as a low range ACT, anti-factor Xa activity, aPTT, or INR. Some individuals
for unexplained circumstances may not respond to a particular assay.
UNFRACTIONATED HEPARIN 59
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TABLE 3-17: Side Effects, Precautions, and Contraindications to
UFH
Side Effects Precautions Contraindications
History (recent) of
•
heparin-induced
thrombocytopenia
•
Inability to obtain
blood coagulation
tests at appropriate
intervals
• Severe
thrombocytopenia
Suspected intracranial
•
hemorrhage
•
Uncontrolled active
bleeding except
when due to DIC (see
Appendix H)
•
Bleeding
•
Hypersensitivity
• Local irritation
Thrombocytopenia,
•
HAT, HIT, HITTS (see
Chapter 18)
•
Long-term use:
Alopecia
Elevated AST/ALT
Hyperkalemia
Osteoporosis
Priapism
• Drug interactions including
oral anticoagulants and
platelet inhibitors
•
Fatal medication errors
Hemorrhage:
•
Bleeding disorders
Subacute bacterial
endocarditis
Active ulcerative GI
diseases
Continuous GI tube
drainage
Severe HTN
History of hemorrhagic
stroke
Recent invasive
procedures, including
spinal anesthesia
Concomitant platelet
inhibitors
Recent GI bleeding
Severe liver disease
Age >60 yr
Heparin resistance (>25,000
•
units/24 hr)
•
Hypersensitivity
• Hyperkalemia
• Osteoporosis
• Thrombocytopenia, HAT, HIT,
HITTS
ALT: alanine aminotransferase, AST: aspartate aminotransferase, DIC: disseminated intravascular
coagulation, GI: gastrointestinal, HAT: heparin-associated thrombocytopenia, HIT: heparininduced thrombocytopenia, HITTS: heparin-induced thrombocytopenia thrombosis syndrome,
hr: hour, HTN: hypertension, yr: years
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