Prescribing appropriate doses of drugs requiring weight-based dosing is challenging in overweight patients due to a lack of data. With 68% of the US population considered overweight and these patients being at an increased risk for hospitalization, clinicians need guidance on dosing weight-based drugs. The purpose of this study was to identify “real-world” dose ranges of high-risk medications administered via continuous infusion requiring weight-based dosing and determine the reasons for dosing changes (ineffectiveness or adverse drug reactions). A prospective, multicenter, observational study was conducted in four intensive care units at three institutions. A total of 857 medication orders representing 11 different high-risk medications in 173 patients were reviewed. It was noted that dosing did not increase in proportion to weight classification. Overall, 14 adverse drug reactions occurred in nine patients with more in overweight patients (9 of 14). A total of 75% of orders were discontinued due to ineffectiveness in groups with higher body mass indexes. Ineffectiveness leads to dosing adjustments resulting in the opportunity for medication errors. Also, the frequent dosing changes further demonstrate our lack of knowledge of appropriate dosing for this population. Given the medications’ increased propensity to cause harm, institutions should aggressively monitor these medications in overweight patients.
The 2008 National Health and Nutrition Examination Survey indicates that 68% of the US adult population is overweight [
Clinicians, in particular pharmacists, rely on interpreting the pharmacokinetic properties of drugs requiring weight-based dosing to estimate the correct dosages when specific dosage recommendations are lacking [
The purpose of this evaluation was to identify “real-world” dose ranges of high-risk medications administered via continuous infusion requiring weight-based dosing used in overweight populations and establish a foundation for standardized, institution-specific dosing guidelines for these patients.
This was a prospective, multicenter, observational study. Participating sites were the Cardiac Intensive Care Unit (CICU) and Medical Intensive Care Unit (MICU) of the University of Pittsburgh Medical Center (UPMC) Presbyterian Hospital (Pittsburgh, PA); the MICU of Kingsbrook Jewish Medical Center (Brooklyn, NY); and the CICU of Banner Good Samaritan Medical Center (Phoenix, AZ). UPMC Presbyterian is an adult tertiary academic medical center with over 800 licensed inpatient beds, including a 10-bed CICU and 24-bed MICU. Banner Good Samaritan is a quaternary care, teaching hospital with over 650 licensed inpatient beds, including a 16-bed CICU. Kingsbrook Jewish Medical Center is a teaching, nonprofit, private community institution with over 300 licensed inpatient beds, including a 10-bed MICU.
Data were collected for a continuous sample of patients >18 years of age admitted to any of the designated units during a 6-week period who received one or more high-risk medication, as defined by the Institute for Safe Medication Practices List of High-Alert Medications [
After IRB approval at the three institutions data were collected. Every day during the 6-week period, new medication orders, change in rate orders, and discontinued orders for the target high-risk medications were evaluated. Orders on the weekends were evaluated on Monday. All information was obtained from the patient’s electronic medical chart. Identifiable information was not collected to ensure compliance with Health Insurance Portability and Accountability Act (HIPPA) regulations. Patient data included sex, age, race, height, weight, dialysis use, liver panel, and serum creatinine. Drug data were obtained daily for new medication orders and changes in doses including drug name, dose, concentration, route, and rate. Discontinued orders were evaluated daily for reasons of discontinuation by reviewing clinician notes (physician and nurses) and communication with clinicians. Reasons of interest for discontinuation were ineffective dose, weaning from drug, or potential ADR and undeterminable. When a potential ADR was identified as a reason for drug discontinuation, then these potential ADRs were evaluated and classified using three published, objective causality assessment tools (modified-Kramer, Naranjo et al., and Jones) [
From the collected data, additional values were calculated for each patient including CrCl via Cockcroft and Gault, Child’s Pugh, and body mass index (BMI) [
Data compiled from all three sites were grouped together and divided by drug. Descriptive statistics were analyzed using SPSS v. 18. (Chicago, IL). For drugs with multiple rate changes identified in the daily data collection, data were recorded for the last dose received in the previous 24-hour period. Medications with the most orders (>15) were assessed. Our analysis included vasoactive drugs (dobutamine, dopamine, milrinone, nitroglycerin, and phenylephrine), heparin, sedatives (propofol, midazolam, and fentanyl), and rocuronium. Medication dosing identified in this real-world evaluation was compared to recommendations in the package insert for each drug.
A total of 857 medication orders representing 11 different high-risk medications in 173 patients were reviewed (underweight = 4, normal = 41, overweight = 60, obese = 60, and extremely obese = 31).
The dosing results for vasoactive agents are provided in Table
Dosing results for vasoactive drugs by weight category compared to recommendations in the literature.
Drugs | Weight category | Patients evaluated | Doses | Mean dose (mcg/kg/min) | Median Dose (mcg/kg/min) | Minimum (mcg/kg/min) | Maximum (mcg/kg/min) | Literature dose recommendation [ |
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Dobutamine | Underweight | 1 | 1 | 2.50 | 2.50 | 2.50 | 2.50 |
|
Normal weight | 4 | 7 | 4.11 | 2.76 | 2.29 | 10.05 | ||
Overweight | 1 | 1 | 2.52 | 2.52 | 2.52 | 2.52 | ||
Obese | 1 | 2 | 7.50 | 7.50 | 5.00 | 5.00 | ||
Extremely obese | 3 | 6 | 3.26 | 3.00 | 2.50 | 5.00 | ||
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Dopamine | Underweight | 1 | 4 | 6.75 | 7.50 | 4.00 | 8.01 |
|
Normal weight | 3 | 20 | 7.78 | 7.01 | 1.04 | 15.69 | ||
Overweight | 9 | 21 | 4.80 | 5.00 | 1.00 | 10.00 | ||
Obese | 4 | 12 | 7.45 | 5.00 | 2.49 | 20.00 | ||
Extremely obese | 3 | 17 | 5.09 | 5.00 | 1.00 | 13.87 | ||
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Underweight | 0 | 0 | — | — | — | — |
|
|
Normal weight | 3 | 11 | 0.36 | 0.37 | 0.19 | 0.50 | ||
Milrinone | Overweight | 2 | 3 | 0.43 | 0.50 | 0.30 | 0.50 | |
Obese | 1 | 4 | 0.27 | 0.25 | 0.20 | 0.38 | ||
Extremely obese | 2 | 3 | 0.77 | 0.78 | 0.51 | 1.04 | ||
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Nitroglycerin | Underweight | 0 | 0 | — | — | — | — |
|
Normal weight | 2 | 4 | 0.28 | 0.24 | 0.17 | 0.47 | ||
Overweight | 8 | 15 | 0.34 | 0.26 | 0.06 | 0.85 | ||
Obese | 4 | 4 | 0.26 | 0.24 | 0.07 | 0.47 | ||
Extremely obese | 1 | 1 | 0.36 | 0.36 | 0.36 | 0.36 | ||
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Norepinephrine | Underweight | 1 | 5 | 0.19 | 0.22 | 0.06 | 0.33 |
|
Normal weight | 3 | 12 | 0.10 | 0.10 | 0.07 | 0.14 | ||
Overweight | 4 | 4 | 0.14 | 0.15 | 0.06 | 0.14 | ||
Obese | 5 | 30 | 0.06 | 0.04 | 0.01 | 0.30 | ||
Extremely obese | 2 | 10 | 0.05 | 0.04 | 0.02 | 0.07 | ||
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Phenylephrine | Underweight | 0 | 0 | — | — | — | — |
|
Normal weight | 2 | 23 | 0.66 | 0.69 | 0.14 | 1.10 | ||
Overweight | 4 | 6 | 0.84 | 0.59 | 0.45 | 2.00 | ||
Obese | 0 | 0 | NA | NA | NA | NA | ||
Extremely obese | 2 | 2 | 0.83 | 0.83 | 0.10 | 1.56 |
There were 162 doses evaluated for heparin in 43 patients. The dose range, across all weight categories, was 3.93–26 units/kg/hr. Maximum doses in each weight category met or exceeded the normal dosing range and/or recommended maximum dose as defined by package insert or clinical recommendation as shown in Table
Dosing results for heparin by weight category compared to recommendations in the literature.
Drugs | Weight category | Patients evaluated | Doses | Average dose | Median dose | Minimum | Maximum | Literature dose recommendation [ |
---|---|---|---|---|---|---|---|---|
Underweight | 0 | 0 | — | — | — | — |
| |
Normal weight | 11 | 52 | 17.61 | 17.41 | 9.29 | 26.00 | ||
Heparin (units/kg/hr) | Overweight | 17 | 39 | 12.23 | 11.97 | 6.00 | 18.00 | |
Obese | 9 | 34 | 12.87 | 11.67 | 3.93 | 22.00 | ||
Extremely obese | 6 | 37 | 11.77 | 10.00 | 4.50 | 21.80 |
There were 209 doses evaluated for three different sedatives (fentanyl, midazolam, and propofol) and one neuromuscular blocker (rocuronium) in 53 unique patients. Across all weight categories, dose ranges again greatly varied for each drug and were as follows: fentanyl 0.0011–0.04 mcg/kg/min, midazolam 0.02–20 mcg/kg/min, propofol 5–101.67 mcg/kg/min, and rocuronium 3–12 mcg/kg/min. The maximum doses for propofol, midazolam, and rocuronium, regardless of weight category, exceeded the normal dosing range and/or the maximum dose as defined by package insert or clinical recommendation (Table
Dosing results for sedatives and neuromuscular blocker by weight category compared to recommendations in the literature.
Drugs | Weight category | Patients evaluated | Doses | Average dose | Median dose | Minimum | Maximum | Literature dose recommendation [ |
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Propofol (mcg/kg/min) | Underweight | 1 | 4 | 17.50 | 20.00 | 10.00 | 20.00 |
|
Normal weight | 5 | 14 | 36.67 | 35.50 | 10.00 | 85.50 | ||
Overweight | 6 | 44 | 45.83 | 50.00 | 6.50 | 75.00 | ||
Obese | 4 | 50 | 36.67 | 37.50 | 5.00 | 60.00 | ||
Extremely obese | 7 | 20 | 21.17 | 10.17 | 8.39 | 101.67 | ||
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Midazolam (mcg/kg/min) | Underweight | 0 | 0 | — | — | — | — | Loading dose: 0.17–0.83 mcg/kg/min |
Normal weight | 3 | 3 | 0.26 | 0.06 | 0.02 | 0.69 | ||
Overweight | 1 | 1 | 0.06 | 0.06 | 0.06 | 0.06 | ||
Obese | 3 | 28 | 8.81 | 7.50 | 0.14 | 20.00 | ||
Extremely obese | 1 | 6 | 0.24 | 0.26 | 0.06 | 0.41 | ||
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Fentanyl (mcg/kg/min) | Underweight | 0 | 0 | — | — | — | — | Mechanically-ventilated patients: 0.01–0.17 mcg/kg/min |
Normal weight | 5 | 8 | <0.01 | <0.01 | <0.01 | 0.01 | ||
Overweight | 8 | 15 | 0.01 | 0.01 | <0.01 | 0.01 | ||
Obese | 5 | 9 | 0.02 | 0.02 | 0.02 | 0.02 | ||
Extremely obese | 4 | 7 | 0.03 | 0.03 | 0.02 | 0.04 | ||
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Rocuronium (mcg/kg/min) | Underweight | 0 | 0 | — | — | — | — |
|
Normal weight | 0 | 0 | — | — | — | — | ||
Overweight | 0 | 0 | — | — | — | — | ||
Obese | 1 | 35 | 7.51 | 7.00 | 3.00 | 12.00 | ||
Extremely obese | 0 | 0 | — | — | — | — |
Overall, 14 ADRs occurred in nine patients as shown in Table
Adverse drug reactions reported.
Drug | ADR ( |
Weight category | Dosage | Weight-based dosage |
---|---|---|---|---|
Midazolam | Slightly responsive to noxious stimuli | Overweight | 685.00 mcg/min | 5.00 mcg/kg/min |
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Midazolam | Unresponsive to noxious stimuli | Overweight | 2740.00 mcg/min | 20.00 mcg/kg/min |
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Dobutamine | Ventricular tachycardia/implantable cardioverter-defibrillator firing | Underweight | 386.77 mcg/min | 5.00 mcg/kg/min |
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Dobutamine | Sinus tachycardia/implantable cardioverter-defibrillator fired | Morbidly obese | 805.33 mcg/min | 5.00 mcg/kg/min |
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Heparin | Bleeding | Normal weight | 876.00 units/hr | 11.20 units/kg/hr |
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Heparin | aPTT > 200 | Overweight | 3000.00 units/hr | 25 units/kg/hr |
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Heparin | Bleeding | Obese | 1150.00 units/hr | 7.67 units/kg/hr |
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Heparin | Bleeding | Obese | 1150.00 units/hr | 7.67 units/kg/hr |
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Heparin | Bleeding | Overweight | 2200.00 units/hr | 18.33 units/kg/hr |
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Norepinephrine | Sinus bradycardia | Overweight | 2.00 mcg/min | 0.01 mcg/kg/min |
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Rocuronium | Peripheral nerve stimulation = 0 | Overweight | 27.33 mcg/min | 0.20 mcg/kg/min |
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Rocuronium | Peripheral nerve stimulation = 0 | Overweight | 18.33 mcg/min | 0.13 mcg/kg/min |
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Rocuronium | Peripheral nerve stimulation = 0 | Overweight | 16.00 mcg/min | 0.12 mcg/kg/min |
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Rocuronium | Peripheral nerve stimulation = 0 | Overweight | 22.83 mcg/min | 0.17 mcg/kg/min |
The concern for inappropriate dosing of weight-based medications in overweight patients is truly a patient safety concern, leading to therapeutic failures or ADRs [
Fourteen ADRs in 9 patients related to five different medications were identified. There was a tendency for the ADRs to occur in overweight patients (12/14), but this does not necessarily appear to be a result of higher doses used in this population. It could be explained by more overweight patients included in this evaluation. Several other factors, such as severity of illness and concomitant drug therapy, could have contributed in part to these ADRs [
Weight-based dosing strategies for vasoactive medications have been suggested based on the drugs’ pharmacokinetics. Since all inotropes and vasopressors, with the exception of milrinone, have short half-lives, fast onsets, and low volumes of distribution, the use of ideal body-weight (IBW) has been suggested for all weight-based vasoactive drugs [
Heparin was another “high-risk” medication associated with variable and inappropriate dosing strategies. In our study, heparin was dosed outside the recommendations in the package insert for all weight categories except in “underweight” patients [
It is important to emphasize that the American College of Chest Physicians (ACCP) recommends an initial IV bolus dose of 80 units/kg or 5,000 units with an initial continuous infusion of 18 units/kg/hr or 1,300 units/hr for the treatment of VTE. For the treatment of ACS (NSTEMI, unstable angina, and STEMI), ACCP recommends an initial IV bolus dose of 60 units/kg (maximum 4,000 units) and an initial continuous IV infusion of 12 units/kg/hr (maximum 1,000 units/hr) [
As with the vasoactives, sedative dosing guidelines are not always applicable and may be titrated to a desired clinical endpoint based on a patient’s specific situation (mechanical ventilation, deep sedation). Much higher sedative doses are often seen in ICU patients compared to those in non-ICU patients [
Propofol, the other sedative reviewed in our study, is conjugated to inactive metabolites in the liver. The risk for prolonged sedation and CNS depression is less than that of midazolam, which is longer acting and has an active metabolite. Still, there is deeper anesthesia and concern for delayed awakenings by anesthesiologists for overweight patients [
Fentanyl, a synthetic narcotic analgesic, is the preferred agent for agitated critically ill patients [
Rocuronium, a neuromuscular blocking agent, is commonly dosed according to IBW in both obese and nonobese patients [
The goal of our evaluation was to provide specific dosing guidance and precautions about ADRs and therapeutic failures for an overweight population based on real-world application. Despite a multicenter approach to achieve an adequate sample, the wide variety in patients’ weights and variations in dosing preclude us from providing specific dosing recommendations. However, we did notice that patients with higher BMIs had a higher frequency of dose discontinuation due to ineffectiveness. The reason for more frequent dosing titration due to ineffectiveness in patients with higher BMIs despite the dosing being within the package insert recommendations may be due to clinicians using weight strategies such as IBW, LBM, or adjusted body weight that may not be reliable or using lower doses than TBW based on intuition to minimize the risk of toxicity. Notably, more dosing changes is an added patient safety concern with more opportunity for errors including calculation errors [
This study has several limitations. First, our sample size was small as we only looked at medications for 173 unique patients receiving 10 frequently used high-risk medications over a six-week period, despite our substantial efforts including four ICUs in three institutions. We did evaluate high-risk drugs according to the ISMP’s list; however we did not report the results for drugs such as diazepam, digoxin, enoxaparin, eptifibatide, or morphine. For these medications, less than 15 orders were available for analysis after the dosing exclusion criteria (scheduled regimens) were applied, thus making conclusions about dosing from such a small sample challenging. Second, because this was an observational study, it was difficult to control for confounding factors. While we did exclude certain patients from the study, such as those with renal and/or hepatic failure, we could not account for some other confounders. These factors include additional disease states, severity of illness, and concomitant medications. Third, we were unaware of the type of weight used for dosing the study patients. While we recorded the patients’ actual body weight during data collection, this may not always have been the weight used for dosing by the clinician. IBW, adjusted bodyweight, and total body weight are all used in clinical practice depending on a medication’s pharmacokinetic parameters. Given the various dosing weights, we attempted to standardize our data by recording the patients’ actual body weight and reporting recommended dosing regimens in terms of actual body weight. Finally, doses were difficult to record for some medications such as vasoactive drugs, which are constantly being titrated to a desired clinical effect. In order to control, in part, for these frequent dose changes, data were recorded for the last dose received by a patient in a 24-hour period. This precaution limited the amount of data recorded for each patient in order to avoid skewing the average dose and range. The emphasis of this study was assessment of dosing, so we did evaluate daily doses and their impact of ineffectiveness and ADRs, thus including more than one dose per patient.
A wide variance was seen in the doses provided by continuous infusion of high-risk medications used across different weight classifications in critically ill adult patients. The vasoactive drugs were within the dosing range provided in the package inserts, regardless of weight classification; while heparin and the sedatives were typically dosed outside the recommendations. The number of ADRs cannot be overlooked as there was a tendency for the ADRs to occur in overweight patients, but this does not necessarily appear to be a function of higher doses used based on weight. Still, the medications reviewed in this study are commonly associated with ADRs and have been labeled as high-risk drugs by the ISMP. The frequency of dosing changes due to ineffectiveness in patients with higher BMIs presents additional safety concerns. Given the medications’ increased propensity to cause harm, institutions should aggressively monitor these medications; especially in overweight patients. In order to advance the literature and provide specific dosing recommendations, we encourage the development of registries at individual institutions to track dosing and associated outcomes (ineffectiveness and ADRs) in overweight patients.
The authors declare there is no conflict of interests regarding publication of this paper.