Article, Cardiology

Error in body weight estimation leads to inadequate parenteral anticoagulation

Original Contribution

Error in body weight estimation leads to inadequate parenteral anticoagulation?

Leon Gustavo dos Reis Macedo MD a, Luciana de Oliveira MDb, Maria Carolina Pintao MD, PhD b,

Andrea Aparecida Garcia MD, PhD b, Antonio Pazin-Filho MD, MBA, PhD c,?

aCardiology Division of Clinical Hospital of the University of Sao Paulo, Ribeirao Preto School of Medicine, 14015-030 Ribeirao PretoSP Brazil

bHaemostasis Division of Clinical Hospital of the University of Sao Paulo, Ribeirao Preto School of Medicine, 14015-030 Ribeirao PretoSP Brazil

cDepartament of Internal Medicine of the University of Sao Paulo, Ribeirao Preto School of Medicine, 14015-030 Ribeirao PretoSP Brazil

Received 21 November 2009; revised 11 January 2010; accepted 11 January 2010

Abstract Parenteral anticoagulation is a cornerstone in the management of venous and arterial thrombosis. unfractionated heparin has a wide dose/response relationship, requiring frequent and troublesome laboratorial follow-up. Because of all these factors, low-molecular-weight heparin use has been increasing. Inadequate dosage has been pointed out as a potential problem because the use of subjectively estimated weight instead of real measured weight is common practice in the emergency department (ED). To evaluate the impact of inadequate weight estimation on enoxaparin dosage, we investigated the adequacy of anticoagulation of patients in a Tertiary ED where subjective weight estimation is common practice. We obtained the estimated, informed, and measured weight of 28 patients in need of parenteral anticoagulation. Basal and steady-state (after the second subcutaneous shot of enoxaparin) anti-Xa activity was obtained as a measure of adequate anticoagulation. The patients were divided into 2 groups according the anticoagulation adequacy. From the 28 patients enrolled, 75% (group 1, n = 21) received at least 0.9 mg/kg per dose BID and 25% (group 2, n = 7) received less than

0.9 mg/kg per dose BID of enoxaparin. Only 4 (14.3%) of all patients had anti-Xa activity less than the inferior limit of the therapeutic range (b0.5 UI/mL), all of them from group 2. In conclusion, when weight estimation was used to determine the enoxaparin dosage, 25% of the patients were inadequately anticoagulated (anti-Xa activity b0.5 UI/mL) during the initial crucial phase of treatment.

(C) 2011

Introduction

? The authors have no disclosure to make.

* Corresponding author. Departamento de Clinica Medica, Faculdade de Medicina de Ribeirao Preto-Universidade de Sao Paulo. Centro de Estudos de Emergencias em Saude-CEES, R. Bernardino de Campos, 1000, 14015-030 Ribeirao Preto-SP Brazil.

E-mail address: [email protected] (A. Pazin-Filho).

Parenteral anticoagulation is a cornerstone in the emergency management of venous and arterial thrombosis [1]. Unfractionated heparin (UH) has a wide dose/response relationship, requiring frequent and troublesome laboratorial follow-up [2]. Even with this frequent follow-up, keeping the patient within the recommended therapeutic range is

0735-6757/$ – see front matter (C) 2011 doi:10.1016/j.ajem.2010.01.006

difficult. Recent problems with the international UH manufacturer have complicated the matter even further, with a lot of adverse events being reported, including death and severe bleeding [3]. Because of all these factors, low- molecular-weight heparin (LMWH) use has been increasing. Nevertheless, a recent study involving acute coronary syndrome patients using LMWH (enoxaparin) has dem- onstrated increased mortality and 30-day myocardial infarction Incidence rates among those with anti-Xa less than 0.5 UI/mL 4 to 6 hours after the second shot of the medication [4]. Inadequate dosage has been pointed out as one of the possibilities to explain this finding because subjectively estimated weight instead of real measured weight is common practice in the emergency department (ED) [5]. This error could be maximized because of the lack of anti-Xa monitoring in ED laboratories, which is

very expensive.

To evaluate the impact of inadequate weight estimation on enoxaparin dosage, we investigated the adequacy of anticoagulation of patients with venous or arterial thrombosis in a tertiary ED where subjective weight estimation is common practice, using anti-Xa activity as criterion standard.

Methods

Study population

Twenty-eight patients in need of parenteral anticoagula- tion were enrolled in this prospective observational study conducted from May to November 2006 in a tertiary Brazilian ED. The study was approved by the local ethics committee (protocol 0278.0.004.000-03), and all the patients were enrolled only after informed consent was obtained. Patients from both sexes, between 18 and 80 years old, started on subcutaneous enoxaparin who could be reeval- uated 24 hours after enrollment were included. Any patient with values of international normalized ratio (INR; pro- thrombin time) greater than 1.3 and/or activated partial thromboplastin time greater than 1.2 or pregnancy was excluded from the study.

Estimated weight

We defined the patients’ estimated weight for the study purpose using the inverse relationship of the enoxaparin prescribed dose recommendation. So if a patient was using

57.5 mg BID, we admitted 57.5 kg as his estimated weight.

Informed weight

We took note if the patient was asked for his weight on ED admission by the attending physician; and we also asked for his weight on the second day, when the measure of

weight was obtained. Only the second was taken into consideration for analysis.

Measured weight

In the second day of treatment, the patients’ weight was obtained, in the morning, with the patient still fasting and after emptying the bladder. The weight was obtained with hospital garments and without shoes for those who could stand using a Filizola, Sao Paulo-SP/Brazil digital platform scale. If the patient could not leave the hospital bed, an appropriate digital scale was used (Slingscale 2002, Instrucom/Hill-Rom series, Hillenbrand Industries Battes- ville, Indiana, USA). All the measures were obtained in kilograms, and the 2 scales provided similar results.

Because there is no consensus of the weight error level of clinical significance, we took into consideration previous work conducted in our institution that showed that weight error of 10% up or down the therapeutic level could be present in 30% in a group of intensive care patients [6]. Based on that, when we obtained the measured weight, we divided our patients into 2 groups: group 1–enoxaparin of at least 0.9 mg/kg per dose BID (no weight error or weight error less than 10% below the therapeutic range) and group 2

–enoxaparin less than 0.9 mg/kg per dose BID (weight error 10% below the therapeutic range).

Anti-Xa activity

Before the first subcutaneous shot of enoxaparin, a laboratorial profile including INR, aPTT, anti-Xa activity, hemogram, and creatinine was obtained; and the enoxaparin dosage prescribed at this moment was recorded for the study purposes. creatinine clearance was calculated according Cockcroft-Gault formula. This laboratorial profile was repeated 4 to 6 hours after the second shot of enoxaparin (anti-Xa steady state) [4].

The methodology for anti-Xa measure was similar to that described elsewhere [4], using a specific chromogenic substrate (AMAX ACCUCOLOR Heparin, Trinity Sigma, St Louis, MO).

Anti-Xa activity levels between 0.5 and 1.2 UI/mL were considered normal [7]. Patients with anti-Xa activity less than

0.5 UI/mL were considered bellow the therapeutic range. Based on the anti-Xa obtained values, we further subdivided group 2 (b0.9 mg/kg per dose BID) into subgroup 2T (therapeutic) and subgroup 2UT (under therapeutic) for comparison.

Statistical analysis

Categorical variables were expressed as percentage, and continuous variables were expressed as mean and standard deviation. Fisher exact test, ?2 test, or nonparametric Mann- Whitney or Spearman test was used as applicable. For all

tests, a P b .05 was considered significant. All analyses were performed using Intercool Stata version 9.2 [8].

Results

From the 28 patients enrolled, 75% (group 1, n = 21) received at least 0.9 mg/kg per dose BID and 25% (group 2, n = 7) received less than 0.9 mg/kg per dose BID of enoxaparin (error greater than 10% below the therapeutic range). Table 1 compares the demographic characteristics of the 2 groups showing that only weight (group 1: 67.1 +- 14.0 kg vs group 2: 86.1 +- 18.8 kg, P = .04) and body

mass index (group 1: 25.2 +- 4.3 kg/m2 vs group 2: 30.2 +- 4.2 kg/m2, P = .04) were significantly different. Only 4 (14.3%) of all patients had anti-Xa activity less than the inferior limit of the therapeutic range (b0.5 UI/mL), all of them from group 2. No patient had anti-Xa activity values greater than the therapeutic range.

Group 1 parted from initial values of anti-Xa activity of

0.03 UI/mL, with a steady state of 1.0 +- 0.1 UI/mL (mean dose, 1.1 mg/kg), whereas group 2 parted from 0.03 UI/mL, reaching 0.6 +- 0.4 UI/mL of anti-Xa activity (mean dose, 0.8 +- 0.1 mg/kg) (Fig. 1).

Within group 2, there were significant differences (P b .05) between subgroups 2T and 2UT, respectively, considering age (63.6 +- 9.0 vs 57.5 +- 5.3 years), estimated weight (63.3 +- 12.01 vs 75.0 +- 5.0 kg), and measured weight (76.2 +- 10.3 vs 95.6 +- 4.6 kg). Fig. 2 shows the comparison of estimated and measured weight among groups 1, 2T, and 2UT.

Only 8 patients (28.5%) were asked about their actual weight at hospital admission by the attending emergency physician. When the patients were asked by the researcher, only 4 (14.3%) were not aware of their actual weight. Of those 24 patients aware of their weight, 2 (8.3%) underestimated it with an error greater than 10%, 4 (16.6%) overestimated it with an error greater than 10%, whereas the remaining 18 patients (75%) provided their weight with an acceptable error. There was a good correlation (r = 0.92) between the informed and measured weight.

Discussion

There are clinical conditions where the Therapeutic effect of medications can be monitored by clinical signs, such as heart rate when using intravenous ?-blockers, or by laboratorial follow-up, such as measuring aPTT when using UH. In these situations, subjective weight estimation for dose calculation is safe because we can easily adjust the dosage if needed. Relatively new medications, such as LMWH, can be a challenge in this regard because laboratorial follow-up can be expensive, at least for Developing countries. More importantly, because the phar- macokinetic and pharmacodynamic properties are supposed to be very predictable, laboratory monitoring is considered unnecessary [9,10].

Nevertheless, in the case of enoxaparin, it is important to point out that the evidence for its prognostic efficacy in the regular prescribed dosage (1 mg/kg per BID) was obtained in groups that excluded those with advanced age, pregnancy, renal failure (creatinine clearance b30 mL/min), and level III obesity (body mass index N40 kg/m2) in whom the enoxaparin pharmacokinetic was less predictable. When this subgroup of patients was excluded, the pharmacokinetic was very predictable; and monitoring anti-Xa activity was considered unnecessary [11]. Extrapolating this recommen- dation for all patients can be dangerous.

Lack of objective weight measure in ED and critical care units is common. A 1999 survey of 20 critical care units in England has shown that only 2 of them obtained objective weight measure of their patients, whereas subjective estimation was common practice in all the others [12]. This can be very dangerous because it is known that subjective weight estimation can be very inaccurate, with at least 10% error in up to 47% of the observations [5,12,13].

Thrombolysis in Myocardial Infarction 11A was the main study for enoxaparin dose determination after the excess of bleeding observed with the initial 1.25 mg/kg per dose BID recommended [14]. The actual usual 1.0 mg/kg per dose BID was established after this, which kept the prognostic value with less bleeding risk. Nevertheless, lower doses were not tested after that also.

Table 1 Clinical features and laboratory baseline of patients included in the study

Parameters

All patients

Weight estimation error

No significant error Dose

>=0.9 mg/kg (group 1, n= 21)

Error N10% below therapeutic range Dose b0.9 mg/kg (group 2, n= 7)

Age (y; mean +- standard deviation)

59.3 +- 13.9

59.3 +- 14.2

59.2 +- 14.2

Sex (% female)

48

50

40

Weight (kg; mean +- standard deviation)

71.2 +- 16.7

67.1 +- 14.0 ?

86.1 +- 18.8 ?

BMI (kg/m2)

26.3 +- 4.7

25.2 +- 4.3 ?

30.2 +- 4.2 ?

Creatinine clearance (mL/min)

65.9 +- 22.9

63.0 +- 22.5

76.4 +- 23.4

PT (INR)

1.1 +- 0.2

1.1 +- 0.2

1.1 +- 0.1

* P b .05.

Fig. 1 Anti-Xa activity values before and after the steady state of enoxaparin (4 to 6 hours after the second dose of enoxaparin) divided into group 1 (patients received enoxaparin >=0.9 mg/kg per dose) and group 2 (enoxaparin b0.9 mg/kg per dose).

The present study has demonstrated that error greater than 10% on the recommended enoxaparin dose (1 mg/kg per dose BID) was present in 25% of the patients. Patients with greater body weight had an increased risk of receiving a lower enoxaparin dose than recommended and, consequently, of being inadequately anticoagulated (anti-Xa activity b0.5 UI/mL). The fact that the 2 groups were not different regarding other potential confounders such as age and creatinine clearance reinforces the impact of weight underestimation as very important problem and a causal effect in undercoagulation.

The fact that the attending emergency physician did not inquire about the patients’ weight at ED admission is another interesting finding of our study. When the patient was asked by the authors, the great majority was able to provide an accurate value, which was a better estimate than that of the attending physician when prescribing enoxaparin. A median of 5.6 kg was found out in our work for weight underestimation, in concordance with the published literature. In a review of 34 studies of self- referred weight, underestimation was the rule, with a mean varying from 0.2 to 3.54 kg and standard deviation from 0.8 to 5.9 kg [15]. These errors would mean a less than 10% error in enoxaparin dosage because the vast majority of patients in need of parenteral anticoagulation weighs greater than 50 kg, which means that when faced with the impossibility of objectively weighing the patient, a self-referred weight can be accurate in more than 90% of the situations.

Some important limitation should be pointed out. First, it is very common for the emergency physician to round the enoxaparin dosage to accommodate the commercial

presentation. The fact that 78% of our patients received a round dosage emphasizes that this has happened in most of cases, and it is impossible to separate the impact of weight underestimation and rounding the dosage. Nevertheless, because there are several commercial presentations (20, 40, 60, 80, and 100 mg) and the rounding is a secondary error

Fig. 2 Box plot for representation of the subjective estimate of the initial weight of patients (estimated weight) and actual weight (measured weight) in the groups: group 1, patients who received enoxaparin dose of at least 0.9 mg/kg per dose; group 2T, patients who received enoxaparin dose of less than 0.9 mg/kg per dose and dosing showed therapeutic anti-Xa activity at the steady state of enoxaparin (anti-Xa >=0.5 IU/mL); group 2UT, patients who received enoxaparin dose of less than 0.9 mg/kg per dose and showed less than therapeutic anti-Xa activity at the steady state of enoxaparin (anti-Xa b0.5 IU/mL).

depending on the initial estimation, we assume that this error would be minor in consideration to weight underes- timation. It should be stressed that in ED where the availability of the several commercial presentations is not completely available, this could lead to a maximization of the initial error of weight underestimation. Second, we did not measure clinical events, but only surrogate events (anti-Xa activity), to express the inadequacy of antic- oagulation. To do so would require a greater sample size and a multicenter study. Third, our sample size could be a limitation, especially regarding the number of events (ie, number of out-of-range anti-Xa values) observed. Never- theless, considering that our inclusion criteria represent the majority of patients who could benefit from monitoring anti-Xa, we considered that it was not a major flaw.

In conclusion, when weight estimation was used to determine the enoxaparin dosage, 25% of the patients were inadequately anticoagulated (anti-Xa activity b0.5 UI/mL) during the initial crucial phase of treatment. Patients should have their weight obtained at ED admission to guarantee safety.

Acknowledgments

The authors thank the staff of Hematology (especially Marcia Baggio) and Emergency (especially Maria Jose da Silva Leite) laboratories and participants of the study for their important contributions.

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