Nadroparin use in critically ill patients on the ICU ward: safe and steady form of coagulation?

Critically ill patients on intensive care ward (ICU) have a higher chance to
develop venous thromboembolism (VTE). Without prophylaxis the incidence of VTE
varies between 22% and 80% in different patient categories. Use of
low-molecular-weight heparin (LMWH) decreases risk to develop VTE with 50%.
Advantage of LMHW is that it is easy to use. Studies in non critically ill
patients have demonstrated a stable dose response curve. Therefore, daily
monitoring of anti-Xa activity is not necessary. However, there are a few
studies demonstrating a higher bleeding incidence in dialysis patients who were
given LMHW. Reason for bleeding is a higher anti-Xa activity due to
accumulation of LMHW in patients with renal insufficiency. Therefore, authors
advise to be alert and even perhaps to monitor anti-Xa activity.
In intensive care patients regulations for prophylaxis of VTE are not totally
clear. There is a necessity for VTE prophylaxis although the risk factors for
bleeding are not concrete yet. Therefore, it is advised to choose prophylaxis
individually for each patient taking safety and activity of prophylaxis into
account. However, in ICU patients choice and dosage of drugs for VTE
prophylaxis is difficult because of variable pharmacokinetics. Especially in
the acute phase circulation is compromised and kidney function fluctuates every
hour. For example, Dörffler-Melly et al have demonstrated that vasoactive
drugs, which are used to optimise circulation, influence anti-Xa activity. At
the same time critically ill patients have a significantly lower anti-Xa
activity after one dose enoxaparin subcutaneously in comparison to non
critically ill patients. It is not clear if a change in glomerular filtration
rate (GFR) in critically ill patients affects the anti-Xa activity. However, it
is clear that intensive care patients have a higher risk of VTE and bleeding
diathesis and accumulation of LMWH is not desirable.

We want to investigate if in critically ill patients use of LMWH is associated
with stable plasma levels of anti-Xa activity. Furthermore, we want to
investigate if GFR and circulation influence anti-Xa activity and which
complications can occur. Hopefully, at the end of the study we will be able to
advise about the need to monitor anti-Xa activity in critically ill patients
which use LMWH.

Study design: It is a prospective observational cohort study. All patients who
are admitted to ICU and fulfil inclusion and exclusion criteria will be
enrolled.
Patients stay enrolled in the study as long as they are on the ICU ward. Renal
insufficiency will be defined as glomerular filtration rate of <= 30 mL/min.

Inclusion
criteria:

1. Patient with minimum age of 18 years and expected admission time on the ICU
of minimum of 48 hours
2. Patient with prophylactic or therapeutic dosage of nadroparin daily

Exclusion
criteria:

1. thrombocytopenia (<
30)

2. heparin induced trombocytopenia and trombosis
(HITT)
3. bleeding diathesis in which the use of nadroparin is
contraindicated
4. use of unfractioned heparin exept during
dialysis
5. pregnancy

Data
collection:

Following data of patients will be noted on inclusion:
1. patient characteristics (age, gender, length,
weight)
2. medical
history

3. indication for
admittance

4. APACHE
score

5. medication use at
admittance

6. physical examination and vital parameters (hart frequency, blood pressure,
temperature)

7. laboratory tests: Hb/Ht, T, APTT, PTT, fibrinogen, d-dimer, anti-Xa
activity, creatinine, urea, GFR, bilirubin, albumin, IG#, Neut X, IPF, FEP/ZPP
Following data will be noted daily after inclusion:
1. medication use especially
inotropy

2. physical examination: delta weight, bleeding diathesis (nosebleed, blood
loss from central lines, haematomas, haematuria, gastrointestinal (GI)
bleeding, blood loss with tracheobronchial aspiration). Recurrence of VTE (deep
vein thrombosis, lung embolism, clotted central
lines)
3. laboratory tests: Hb/Ht, T,
APTT, PTT, fibrinogen, d-dimer, anti-Xa activity, creatinine, urea, GFR,
bilirubin, albumin, IG#, Neut X, IPF,
FEP/ZPP

4. amount of blood- and thrombocytic transfusions and
FFP*s
5. dialysis (CVVH, IHD and with or without use of fragmin or
heparin)
6. SOFA score


Medication:

Nadroparin is a low molecular heparin with a weak anti-IIa activity and a
stronger anti-Xa activity. Indications for use are prophylactic to prevent VTE
or therapeutic for lung embolism, rhythm disorders or angina pectoris.

Standard dosage of nadroparin:
1. Prophylactic: < 80 kg: 1 dd 2850 IE sc
>= 80 kg: 1 dd 3800 IE sc
2. Therapeutic: <= 50 kg: 2 dd 3800 IE sc
50-80 kg: 2 dd 5700 IE sc
>= 80 kg: 2 dd 7600 IE sc

Standard values of anti-Xa activity:
Peak anti-Xa activity on Cmax (Tmax = 4 uur) between 0.2 - 0.4 IU/ml is
considered effective and safe. Therefore, definition of a stable form of
anticoagulation is peak anti-Xa activity between 0,2 - 0.4 IU/ml.
Therapeutic use (2 times daily) Cmin (Tmin = 12 uur) of <= 0.1 IU/ml is
considered non therapeutic and >= 0.4 IU/ml accumulation.
Area under the curve (AUC) is 4 - 6 IU/h/ml in prophylactic use and 7-9
IU/h/ml in therapeutic use.

Anti-Xa activity:
Anti-Xa activity will be assessed daily. In prophylactic use nadroparin will be
given at 18.00. On day one and three 2,4,6,8,12,16,24 hours after the
nadroparin dose anti-Xa activity will be measured and also just before the
first nadroparin dose on day one. On all other days it will be measured 4,12,24
hours after dosing. In therapeutic use nadroparin will be given 2 times daily
at 6.00 and 18.00 hours.On day one and day three 2,4,6,8,12,16,24 hours after
the evening dose anti-Xa activity will be measured and just before the first
dose. On the other days samples will be taken after 4,12,24 hours after the
evening dose.

Method of
assessment:

Samples will be frozen and anti-Xa activity will be determined once a week.

Statistical
analysis:

It will be a prospective cohort study with 30 patients with a diminished GFR
and 90 patients with normal GFR. On average there will be 5 blood samples taken
per patient. After first 60 patients an interim analysis will be undertaken to
search for statistical significance.

Further statistical analysis:
Nominal variables concerning subgroups will be analysed with Chi-square test.
Ordinal variables concerning subgroups will be analysed with Mann-Whitney-test
or Kruskall-Wallis-test. Interval/ ratio variables concerning subgroups will be
analysed with T-test or ANOVA. Comparison of variables (depending on scale
level) will be done with Chi-square test, paired T-test, Wilcoxon test,
Friedman test and Pearson and Spearman correlation coefficient. Logistic and/
or linear regression will be used as multivariate technique to relate outcome
variables and background variables. Nominal and ordinal variables will be
described with use of frequency tables, modus and median. Interval/ ratio
variables will be described in terms of average, standard deviation and
confidence intervals. If necessary Odd*s ratio and relative risk will be used.

Anti-Xa activity will be assessed daily. In prophylactic use nadroparin will be
given at 18.00. On day one and three 2,4,6,8,12,16,24 hours after the
nadroparin dose anti-Xa activity will be measured and also just before the
first nadroparin dose on day one. On all other days it will be measured 4,12,24
hours after dosing. In therapeutic use nadroparin will be given 2 times daily
at 6.00 and 18.00 hours. On day one and day three 2,4,6,8,12,16,24 hours after
the evening dose anti-Xa activity will be measured and just before the first
dose. On the other days samples will be taken after 4,12,24 hours after the
evening dose. In total 67 ml of blood out of the arterial line will be drawn
seperated over 24 times.