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Drug dosing in the critically ill obese patient: a focus on medications for hemodynamic support and prophylaxis

Abstract

Medications used for supportive care or prophylaxis constitute a significant portion of drug utilization in the intensive care unit. Evidence-based guidelines are available for many aspects of supportive care but drug doses listed are typically for patients with normal body habitus and not morbid obesity. Failure to account for the pharmacokinetic changes that occur with obesity can lead to an incorrect dose and treatment failure or toxicity. This paper is intended to help clinicians design initial dosing regimens in critically ill obese patients for medications commonly used for hemodynamic support or prophylaxis. A detailed literature search of medications used for supportive care or prophylaxis listed in practice guidelines was conducted with an emphasis on obesity, pharmacokinetics and dosing. Relevant manuscripts were reviewed and strategies for dosing are provided. For medications used for hemodynamic support, a similar strategy can be used as in non-obese patients. Similarly, medications for stress ulcer prophylaxis do not need to be adjusted. Anticoagulants for venous thromboembolism prophylaxis, on the other hand, require an individualized approach where higher doses are necessary.

Introduction

Medications for supportive care and prophylaxis constitute a large proportion of drug use in the intensive care unit (ICU). In fact, evidence-based guidelines exist for many of the therapies considered “routine care” and form the basis for checklists and standardization of therapy. The drug doses that are included, however, are often formulated for patients with normal body habitus and do not account for the pharmacokinetic variability encountered with obesity. This is concerning because clinical trials that provide efficacy and safety data for the ICU rarely include obese individuals thereby presenting a unique challenge for bedside clinicians when designing a dosing regimen. Most data in this area are from studies that utilize pharmacokinetic variables, surrogate markers for efficacy or physicochemical characteristics. Nevertheless, clinicians must still make important dosing decisions at the bedside despite the limited amount of data that are available.

Recent data from the CDC indicate the prevalence of obesity (BMI ≥ 30 kg/m2) among US adults is 42.4% [1]. Furthermore, there is an alarming increase in the prevalence of severe obesity (BMI ≥ 40 kg/m2) which has risen from 4.7% in 1999 to 9.2% in 2018. Unfortunately, this trend has not been recognized with regard to the availability of obesity-specific dosing information in product labeling. One study, published in 2020, stated only 30% of medications evaluated had some reference to a weight descriptor in the dosing information compared to 27% reported in a similar study conducted about 10 years prior [2, 3]. This is problematic because the use of an incorrect weight metric, for weight-based dosing, could lead to treatment failure (in the event of subtherapeutic levels) or drug toxicity (caused by supratherapeutic levels) (Fig. 1). Knowledge of the most appropriate weight-metric for each medication is essential to optimize outcomes with drug therapy in the critically ill obese patient.

Fig. 1
figure1

Consequences of using an incorrect weight metric when dosing weight-based medications in obese patients

The weight metric used to characterize weight status is body mass index (BMI). Body mass index, however, is not commonly used for drug dosing. The weight metrics most commonly referenced when dosing medications in the ICU are total body weight or some alternative, such as ideal body weight (IBW), lean body weight (LBW) or adjusted body weight (Table 1). Ideal body weight characterizes weight based on height and gender. It was formulated more than 60 years ago using actuarial data based on the premise that for a given height, there was an ideal weight [4]. Ideal body weight does not account for differences in body composition or the increases in absolute lean mass that typically accompany obesity. Thus, it is inherently flawed as a surrogate for fat-free mass. Lean body weight appears to be the best representation of fat-free mass [5]. These equations, however, are prone to calculation errors so software programs are recommended. Adjusted body weight using a correction factor (i.e., a fraction of the difference between total and ideal body weight) is commonly used for drug dosing, and these equations are well known by most practitioners. Adjusted body weight is roughly equivalent to LBW and for the purposes of this paper will be considered a surrogate (for LBW) because of familiarity and ease of calculation.

Table 1 Common weight measures used to estimate size when dosing medications in obese patients

Designing dosing regimens in the critically ill obese patient requires a detailed understanding of the physicochemistry of the medication, and the impact obesity has (coupled with critical illness) on physiology and drug pharmacokinetics [6]. Because of the tremendous variability observed, an individualized dosing approach is preferred [7]. Generalized clinical pearls exist to assist with dosing in this challenging population (Table 2) but specific dosing recommendations to guide clinicians are limited. The purpose of this paper is to assist clinicians with dosing regimens for medications commonly used as part of the supportive care and prophylaxis in critically ill obese patients.

Table 2 Generalized clinical pearls for crafting medication doses in the setting of extreme obesity

Methodology

The medications reviewed for evaluation consisted of those used for supportive care or prophylaxis mentioned in evidence-based guidelines. Published guidelines from the following therapeutic domains were screened: pain, agitation, delirium, neuromuscular blockade, hemodynamic support in sepsis, stress ulcer prophylaxis and venous thromboembolism prophylaxis [8,9,10,11,12]. Antimicrobials were not included given the overarching theme of this manuscript coupled with the availability of other manuscripts providing dosing recommendations in this area [13,14,15]. Furthermore, thorough reviews providing recommendations for medications used for pain, agitation, delirium and neuromuscular blockade are also available and the reader is referred to these texts [16, 17]. Thus, the remaining areas included were medications for hemodynamic support in shock (i.e., vasopressors and corticosteroids), stress ulcer prophylaxis and venous thromboembolism.

A detailed literature search was performed using PubMed from inception to July 2020, using search terms from the following three categories: (1) obesity: "Obesity"[Mesh] OR "Overweight"[Mesh] OR "body composition"[MeSH Terms] OR "extreme obesity" OR "body weight change*" OR "body size" OR "body fat" OR "body fatness" (2) pharmacokinetics and dosing: "Drug Monitoring"[Mesh] OR "Dose–Response Relationship, Drug"[Mesh] OR "pharmacokinetic" OR "pharmacokinetic considerations " OR "drug dosing" OR "drug dose" OR "therapeutic drug monitoring" OR "drug monitoring" and (3) the specific drug in question. The results from the primary literature search were reviewed and pertinent articles were retained. Bibliographies were reviewed for any articles that may have been missed by the primary literature search. Non-English articles and animal studies were not included. The focus will be on adult patients with more severe forms of obesity (i.e., BMI ≥ 40 kg/m2), since such patients are typically limited in numbers in the studies used to formulate product labeling information. A comprehensive, online database was consulted for drug physicochemical properties (e.g., octanol–water partition coefficient (log P)) [18]. This database provides detailed drug data (e.g., chemical, pharmacological and pharmaceutical) and comprehensive drug target information (e.g., sequence, structure and pathway) with more than 14,000 drug entries. Suggestions were then formed using the available data based on the following prioritization strategy: studies evaluating clinical outcomes, pharmacokinetics, adverse effect profiles and physicochemical properties. Because of the heterogeneity of study outcomes (i.e., pharmacokinetic-related, clinical outcome, etc.) and the expected lack of information for many of the medications included, advanced statistical techniques such as meta-analysis were not performed.

Vasopressors

All of the commonly used vasopressors are hydrophilic as indicated by negative log P values, so distribution is typically limited at most to the extracellular fluid compartment. Small volumes of distribution combined with rapid clearance values results in short half-lives for these agents typically necessitating their administration as continuous intravenous infusions. Irrespective of obesity, there is substantial variability in the pharmacokinetics and pharmacodynamics of vasoactive agents (dopamine, dobutamine, epinephrine, norepinephrine and angiotensin II) when used in critically ill patients [19,20,21,22,23]. These physicochemical, pharmacokinetic and pharmacodynamic characteristics argue for the use of non-weight-based dosing regimens, or for weight-based dosing regimens with the use of an IBW or lean body mass descriptor.

In multicenter, retrospective studies evaluating the outcomes of patients with severe infections including septic shock, obese patients received significantly lower weight-based doses of fluids, norepinephrine and other vasopressors compared to normal-weight patients with either no change or lower overall mortality [24,25,26]. Further, data from single-center, retrospective evaluations investigating weight descriptors for dosing vasopressor medications in critically ill, obese patients demonstrate substantial inter-patient variability in response to vasopressor administration with no consistent weight-based, dose–response relationship [27,28,29,30,31].

Summary: For vasopressors administered as continuous infusions, either a non-weight-based dosing regimen, or a weight-based dosing regimen using an ideal or adjusted body weight is suggested for initial doses in obese patients. If a weight-based method is chosen, seek consistency between using ideal or adjusted body weight across different vasopressor agents (e.g., norepinephrine and dopamine) to minimize error risk.

Corticosteroids

The majority of studies published to date evaluating relationships between corticosteroids and obesity concern hypothalamic–pituitary–adrenal axis regulation and cortisol activity [32]. In one of the few pharmacokinetic studies involving corticosteroids and obese subjects, methylprednisolone pharmacokinetics were compared in 6 obese and 6 non-obese males [33]. Obese patients received a dose of 0.6 mg/kg while non-obese subjects received a fixed dosage of 40 mg (approximately 0.5 mg/kg based on reported total body weight). Volume of distribution was closely related to IBW suggesting limited distribution into adipose tissue. The authors concluded doses based on IBW and not total body weight were recommended. In a second study prednisolone disposition was assessed in 8 obese and 4 normal-weight (i.e., actual weight equaled IBW) men after a single intravenous injection of 33 mg [34]. The obese compared to the normal-weight subjects had proportional increases in volume of distribution (approximately 20%) and clearance (approximately 35%) which were less than the proportional differences in actual body weight in the obese subjects (62% above IBW). The differences in the pharmacokinetic parameters in the obese subjects are more consistent with those expected from hydrophilic medications that primarily distribute into lean tissue, rather than the dose proportional increases expected with more lipophilic agents (e.g., log P values between 1 and 2) like corticosteroids. Additionally, corticosteroids easily pass through cell membranes to bind to cytosolic glucocorticoid receptors that are present in almost all body cells, so the relationship between pharmacokinetic and pharmacodynamics effects is complex [35]. All of these issues complicate the choice of an appropriate size descriptor when considering weight-based dosing regimens. In adult critically ill patients, current guidelines recommend intravenous doses of hydrocortisone equivalents of less than 400 mg daily for hospitalized patients with community-acquired pneumonia or septic shock unresponsive to fluids and vasopressors, and intravenous doses of methylprednisolone of 1 mg/kg daily for patients with early moderate to severe acute respiratory distress syndrome (ARDS) [9, 11]. These doses result in supraphysiological levels of corticosteroid in terms of cortisol equivalents [36].

Summary: For non-weight-based dosing of hydrocortisone in patients with community-acquired pneumonia or septic shock unresponsive to fluids and vasopressors, intravenous doses of hydrocortisone in obese patients should be the same as those used in non-obese patients. For weight-based dosing of methylprednisolone for patients with ARDS, the use of an ideal or adjusted body weight is suggested for weight-based dosing in obese patients, particularly in patients with more severe forms of obesity (e.g., BMI of 40 kg/m2 or greater).

Stress ulcer prophylaxis

Acid suppressive therapy is routinely administered to critically ill patients for the prevention of clinically important gastrointestinal bleeding (CIB) due to stress ulcers. The agents most commonly chosen for stress ulcer prophylaxis (SUP) are the proton pump inhibitors (PPI) followed by histamine-2-receptor-antagonists (H2RA) [37]. Unfortunately, clinical trials comparing effectiveness in obese patients are lacking. In the most recent prospective trials evaluating SUP, weight is not reported, making the impact of obesity on outcomes difficult to determine [38,39,40].

The PPIs and H2RA’s are both considered acceptable therapy for the provision of SUP but there are some differences in their pharmacokinetic profiles that could be affected by obesity. Proton pump inhibitors are highly lipophilic as prodrugs, which promote distribution into adipose tissue. The H2RA’s, on the other hand, are hydrophilic compounds and poorly distribute into fat. Pantoprazole, lansoprazole, omeprazole and esomeprazole are metabolized through the cytochrome P-450 (CYP) system. (Rabeprazole is metabolized by a non-enzymatic process.) Both animal and human studies have shown a correlation between increased liver fat content and decreased CYP activity [41]. This relationship has not been quantified across varying degrees of obesity; thus, the clinical significance remains unknown. Body mass index has been associated with nonalcoholic fatty liver disease in a near-linear relationship [42]. Histamine-2-receptor antagonists are metabolized through non-CYP pathways and primarily eliminated renally [43].

There are limited studies evaluating the pharmacokinetics of acid suppressive medications in obesity and none are specific to ICU patients for the provision of SUP. Most data originate from pharmacokinetic studies conducted in healthy volunteers or symptom-related outcomes in patients with gastroesophageal reflux disease (GERD). Furthermore, few patients in these studies had more extreme forms of obesity (e.g., BMI > 40 kg/m2). Extrapolation of these results to the ICU population can be difficult due to the differences in pathophysiological features (between CIB due to stress ulceration and GERD) and alterations that occur in critical illness. One study evaluated the effect of obesity on intragastric pH following a single dose of PPI (pantoprazole or rabeprazole) in patients with GERD [44]. There was no correlation between BMI and the total time with pH > 4. Other studies have evaluated outcomes in GERD patients such as esophageal pH, heartburn symptoms and healing of erosive esophagitis [45,46,47]. Overall, these studies have demonstrated no differences based on BMI. Weight-based dosing of PPI’s has been evaluated in the pediatric population. These studies have revealed PPI exposure correlates best with lean body weight dosing as opposed to actual body weight [48, 49]. Collectively, these data reveal that despite some of the theoretical pharmacokinetic concerns with PPI’s in obesity, obesity has minimal impact on PPI-related pharmacodynamics.

Similar to PPI’s, the pharmacokinetic parameters of H2RA’s are not largely affected by obesity [50,51,52]. In one study of surgical patients with BMI ≥ 35 kg/m2, preoperative ranitidine was effective in increasing gastric pH (6.1 ± 1.2) compared to unmedicated controls (3.5 ± 1.6) [53]. Standard doses of H2RA’s therefore seem to be adequate.

Summary: Standard, non-weight-based doses for both H2RA’s and PPI’s are appropriate for stress ulcer prophylaxis in obese critically ill patients.

Venous thromboembolism prophylaxis

Obesity is a well-known risk factor for venous thromboembolism (VTE) in both critically ill and non-critically ill patients. In a risk factor analysis using data from a large randomized thromboprophylaxis trial, each 10-point increase in BMI was associated with a significant increase in both proximal deep vein thrombosis [HR (95% CI) 1.25 (1.06–1.46)] and pulmonary embolism [HR (95% CI) 1.37 (1.02–1.83)] [54]. Prophylaxis in the ICU is typically provided with low molecular weight heparin or unfractionated heparin using a fixed dosing strategy as recommended by the package insert. Standard dosing strategies, however, may be inadequate as several studies have demonstrated an inverse linear relationship between total body weight and anti-Xa activity [55, 56]. Unfortunately, the majority of the data are in the bariatric surgery population, so do not necessarily account for the pharmacokinetic variability observed in the critically ill that results from a variety of factors including the use of vasopressors and tissue edema [57, 58]. Furthermore, there are few studies focused on clinical outcomes such as VTE incidence; instead, most endpoints were directed toward surrogate markers (e.g., anti-Xa levels) [59,60,61,62,63,64,65,66,67,68,69]. One retrospective, before-after study compared VTE rates using two enoxaparin dosing regimens (30 mg or 40 mg subcutaneous twice daily) in a cohort of bariatric surgical patients [67]. Postoperative VTE was significantly lower with the higher dosing regimen (5.4% vs. 0.6%, p < 0.01). There was no difference in the incidence of hemorrhage. A second retrospective study evaluated the efficacy and safety of enoxaparin and heparin in patients who weighed at least 100 kg [69]. In this study, patients were stratified according to receipt of a standard or high dose of anticoagulant (80 mg/day of enoxaparin or 22,500 units/day of unfractionated heparin). In the cohort of patients with a BMI of at least 40 kg/m2, the VTE rate was 1.48% with standard dosing compared to 0.77% in the high-dose group [OR (95% CI) 0.52 (0.27–1.00);p = 0.05]. Similar to the previous study, no difference in hemorrhage was noted.

In light of the evidence surrounding low molecular weight heparin dosing in obesity, several alternative approaches have been evaluated based on anti-Xa levels. There is wide disparity in the doses of low molecular weight heparin utilized, the patient populations studied and the degree of obesity present among the patients. In one study specific to critically ill patients, 23 surgical ICU patients with a mean BMI of 46.4 ± 11.7 kg/m2 and weight of 137 ± 37 kg reported anti-Xa levels following a 0.5 mg/kg twice daily enoxaparin regimen [62]. Initial anti-Xa levels were in the appropriate range (0.2–0.5 IU/ml) in 91% of patients and none experienced major bleeding. A second retrospective study evaluated weight-based dosing of enoxaparin (0.5 mg/kg twice daily) in obese trauma patients [59]. In this study, the median BMI and weight was 35.3 kg/m2 and 113 kg, respectively. Target anti-Xa levels (0.2–0.6 IU/ml) were achieved in 86% of patients and no patients experienced a bleeding event. A third trial randomized hospitalized medical patients to receive enoxaparin 40 mg daily, 0.4 mg/kg daily or 0.5 mg/kg daily [61]. The average BMI in each of the study cohorts exceeded 60 kg/m2 while weight was greater than 170 kg (range 115–256 kg). The primary outcome was achievement of target anti-Xa level (0.2–0.5 IU/ml), which was reached significantly more often in the 0.5 mg/kg/day group compared to the other regimens. The incidence of subtherapeutic anti-Xa levels was 87%, 36% and 18% for the fixed (non-weight-based), 0.4 mg/kg and 0.5 mg/kg regimens, respectively. Finally, one prospective trial evaluated a BMI-stratified dosing approach in a cohort of bariatric surgery patients [60]. Patients with a BMI ≤ 50 kg/m2 received an enoxaparin dosage of 40 mg twice daily while patients in excess of 50 kg/m2 received 60 mg twice daily. The average BMI in each of the groups was 44.9 ± 3.7 kg/m2 and 57.4 ± 6.4 kg/m2 while weight was 126 ± 19 kg and 161 ± 27 kg, respectively. Subtherapeutic anti-Xa levels were observed in 21% of the patients who received a 40 mg dose and 14% of patients who received a 60 mg dose. There were no patients in the 40 mg cohort who were supratherapeutic but 17% were supratherapeutic in the 60 mg group. Bleeding was not associated with a high Xa-level. For a descriptive evaluation of these and other studies, the reader is referred to Additional file 1.

Summary: Critically ill obese patients who receive low molecular weight heparin require a higher dosage for VTE prophylaxis than patients who are not obese. Most data are with enoxaparin and the only dosing regimen associated with a reduction in VTE rate is 40 mg twice daily. In patients with more extreme forms of obesity (i.e., BMI ≥ 50 kg/m2), higher doses may be necessary. There is wide disparity in the dosing regimens suggested for these patients including a BMI-stratified approach (60 mg twice daily, equivalent to approximately 0.4 mg/kg/dose based on reported weights) to a weight-based approach ranging from 0.5 mg/kg once daily to 0.5 mg/kg twice daily. For patients with a BMI exceeding 40 kg/m2, enoxaparin 40 mg twice daily is appropriate. For patients with a BMI ≥ 50 kg/m2, a weight-based approach of 0.4–0.5 mg/kg twice daily based on total body weight is suggested. Given the lack of consistency with dosing suggestions across pharmacokinetic studies, anti-Xa monitoring seems reasonable in this population.

Unfractionated heparin dosing has also been evaluated in obese hospitalized patients (Additional file 1) [70,71,72]. Patanwala, et al. compared VTE rates in obese (BMI ≥ 30 kg/m2) and non-obese (BMI < 30 kg/m2) populations who received heparin 5000 units three times daily [71]. There were 5110 patients assessed (approximately 26% were critically ill) and no difference in VTE rate was noted (obese, 0.7% vs. non-obese, 0.6%; p = 0.7). Joy, et al. compared heparin doses of 7500 units with 5000 units every 8 h in patients who weighed more than 100 kg [70]. Approximately 37% were admitted to an ICU. Overall, there was no difference in VTE rate between the high-dose and low-dose groups (3% vs. 1.5%, p = 0.14). Furthermore, in the patients with a BMI ≥ 40 kg/m2, VTE rates were 3% (high-dose) and 2% (low-dose), p = 0.43. Next, unfractionated heparin dosing was evaluated in a retrospective study of neurocritical care patients [72]. Patients who weighed over 100 kg were stratified based on receipt of a traditional (5000 units every 8 h) or high (7500 units every 8 h) heparin dose. There were 398 patients included with an average weight of 116 kg (traditional dose) and 123 kg (high dose). The incidence of VTE was 9.3% and 5.7% (p = 0.2) for the traditional and high heparin doses, respectively. There was no difference in major bleeding events (11% vs. 14%, p = 0.33). Finally, high-dose unfractionated heparin (7500 units every 8 h) was compared to enoxaparin 40 mg every 12 h in a retrospective study of obese hospitalized patients (mean BMI = 49.5 ± 8.9 kg/m2) [73]. No difference in VTE rate was reported but major bleeding events were higher with unfractionated heparin [OR(95% CI) 1.85 (1.07–3.13)].

Summary: Critically ill obese patients who receive unfractionated heparin for VTE prophylaxis appear to have equal benefit with traditional and high-dosing regimens. When unfractionated heparin is utilized in this population, 5000 units every 8 h is appropriate. In patients with more extreme forms of obesity (BMI ≥ 50 kg/m2), 7500 units every 8 h can be considered.

Conclusion

High-level evidence describing dosing of supportive care medications in obesity is lacking. Many of the medications used for supportive care can be dosed using a similar strategy to that observed in non-obese patients (e.g., vasopressors, corticosteroids and acid-suppressants). Anticoagulants for VTE prophylaxis, on the other hand, require an individualized approach. Therapeutic drug monitoring should be used where available. Further research is necessary to guide medication dosing in obese, critically ill patients.

Availability of data and materials

Not applicable.

Abbreviations

BMI:

Body mass index

CIB:

Clinically important bleeding

GERD:

Gastroesophageal reflux disease

H2RA:

Histamine 2 receptor antagonist

IBW:

Ideal body weight

ICU:

Intensive care unit

LBW:

Lean body weight

PPI:

Proton pump inhibitor

SUP:

Stress ulcer prophylaxis

VTE:

Venous thromboembolism

References

  1. 1.

    Hales CM, Carroll MD, Fryar CD, Ogden CL. Prevalence of obesity and severe obesity among adults: United States, 2017–2018. NCHS Data Brief. 2020;360:1–8.

    Google Scholar 

  2. 2.

    Eastman C, Erstad BL. Availability of information for dosing ocmmonly used medications in special ICU populations. Am J Health Syst Pharm. 2020;77(7):529–34.

    PubMed  Article  Google Scholar 

  3. 3.

    Jacques KA, Erstad BL. Availability of information for dosing injectable medications in underweight or obese patients. Am J Health Syst Pharm. 2010;67(22):1948–50.

    PubMed  Article  Google Scholar 

  4. 4.

    Pai MP, Paloucek FP. The origin of the “ideal” body weight equations. Ann Pharmacother. 2000;34(9):1066–9.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(10):1051–65.

    PubMed  Article  Google Scholar 

  6. 6.

    Schetz M, De Jong A, Deane AM, Druml W, Hemelaar P, Pelosi P, et al. Obesity in the critically ill: a narrative review. Intensive Care Med. 2019;45(6):757–69.

    PubMed  Article  Google Scholar 

  7. 7.

    Erstad BL. Designing drug regimens for special intensive care unit populations. World J Crit Care Med. 2015;4(2):139–51.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    ASHP Therapeutic Guidelines on Stress Ulcer Prophylaxis. ASHP Commission on Therapeutics and approved by the ASHP Board of Directors on November 14, 1998. Am J Health Syst Pharm. 1999;56(4):347–79.

    Article  Google Scholar 

  9. 9.

    Annane D, Pastores SM, Rochwerg B, Arlt W, Balk RA, Beishuizen A, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2017;45(12):2078–88.

    PubMed  Article  Google Scholar 

  10. 10.

    Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e195S-e226S.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Pastores SM, Annane D, Rochwerg B. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (part II): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Crit Care Med. 2018;46(1):146–8.

    PubMed  Article  Google Scholar 

  12. 12.

    Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017;45(3):486–552.

    PubMed  Article  Google Scholar 

  13. 13.

    Meng L, Mui E, Holubar MK, Deresinski SC. Comprehensive guidance for antibiotic dosing in obese adults. Pharmacotherapy. 2017;37(11):1415–31.

    PubMed  Article  Google Scholar 

  14. 14.

    Pai MP, Bearden DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy. 2007;27(8):1081–91.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Polso AK, Lassiter JL, Nagel JL. Impact of hospital guideline for weight-based antimicrobial dosing in morbidly obese adults and comprehensive literature review. J Clin Pharm Ther. 2014;39(6):584–608.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Erstad BL, Barletta JF. Drug dosing in the critically ill obese patient-a focus on sedation, analgesia, and delirium. Crit Care. 2020;24(1):315.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Erstad BL, Barletta JF. Dosing of neuromuscular blocking agents in patients with obesity: a narrative review. Anaesth Intensive Care (in press).

  18. 18.

    Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074–82.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Giapreza (angiotensin II) [package insert]. San Diego, CA: LaJolla Pharmaceutical Company; 12/2017.

  20. 20.

    Abboud I, Lerolle N, Urien S, Tadie JM, Leviel F, Fagon JY, et al. Pharmacokinetics of epinephrine in patients with septic shock: modelization and interaction with endogenous neurohormonal status. Crit Care. 2009;13(4):R120.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Beloeil H, Mazoit JX, Benhamou D, Duranteau J. Norepinephrine kinetics and dynamics in septic shock and trauma patients. Br J Anaesth. 2005;95(6):782–8.

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Johnston AJ, Steiner LA, O’Connell M, Chatfield DA, Gupta AK, Menon DK. Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients. Intensive Care Med. 2004;30(1):45–50.

    PubMed  Article  Google Scholar 

  23. 23.

    Klem C, Dasta JF, Reilley TE, Flancbaum LJ. Variability in dobutamine pharmacokinetics in unstable critically ill surgical patients. Crit Care Med. 1994;22(12):1926–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  24. 24.

    Adams C, Tucker C, Allen B, McRae A, Balazh J, Horst S, et al. Disparities in hemodynamic resuscitation of the obese critically ill septic shock patient. J Crit Care. 2017;37:219–23.

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Arabi YM, Dara SI, Tamim HM, Rishu AH, Bouchama A, Khedr MK, et al. Clinical characteristics, sepsis interventions and outcomes in the obese patients with septic shock: an international multicenter cohort study. Crit Care. 2013;17(2):R72.

    PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Wacharasint P, Boyd JH, Russell JA, Walley KR. One size does not fit all in severe infection: obesity alters outcome, susceptibility, treatment, and inflammatory response. Crit Care. 2013;17(3):R122.

    PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Hodge EK, Hughes DW, Attridge RL. Effect of body weight on hemodynamic response in patients receiving fixed-dose vasopressin for septic shock. Ann Pharmacother. 2016;50(10):816–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Lam SW, Bauer SR, Cha SS, Oyen LJ. Lack of an effect of body mass on the hemodynamic response to arginine vasopressin during septic shock. Pharmacotherapy. 2008;28(5):591–9.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Miller JT, Welage LS, Kraft MD, Alaniz C. Does body weight impact the efficacy of vasopressin therapy in the management of septic shock? J Crit Care. 2012;27(3):289–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Radosevich JJ, Patanwala AE, Erstad BL. Norepinephrine dosing in obese and nonobese patients with septic shock. Am J Crit Care. 2016;25(1):27–32.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Wong PJ, Pandya KA, Flannery AH. Evaluating the impact of obesity on safety and efficacy of weight-based norepinephrine dosing in septic shock: a single-center, retrospective study. Intensive Crit Care Nurs. 2017;41:104–8.

    PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Incollingo Rodriguez AC, Epel ES, White ML, Standen EC, Seckl JR, Tomiyama AJ. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: a systematic review. Psychoneuroendocrinology. 2015;62:301–18.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Dunn TE, Ludwig EA, Slaughter RL, Camara DS, Jusko WJ. Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity. Clin Pharmacol Ther. 1991;49(5):536–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Milsap RL, Plaisance KI, Jusko WJ. Prednisolone disposition in obese men. Clin Pharmacol Ther. 1984;36(6):824–31.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Strehl C, Buttgereit F. Optimized glucocorticoid therapy: teaching old drugs new tricks. Mol Cell Endocrinol. 2013;380(1–2):32–40.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Venkatesh B, Cohen J, Cooper M. Ten false beliefs about cortisol in critically ill patients. Intensive Care Med. 2015;41(10):1817–9.

    PubMed  Article  Google Scholar 

  37. 37.

    Barletta JF, Kanji S, MacLaren R, Lat I, Erstad BL. Pharmacoepidemiology of stress ulcer prophylaxis in the United States and Canada. J Crit Care. 2014;29(6):955–60.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Alhazzani W, Guyatt G, Alshahrani M, Deane AM, Marshall JC, Hall R, et al. Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: a pilot randomized clinical trial and meta-analysis. Crit Care Med. 2017;45(7):1121–9.

    PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU. N Engl J Med. 2018;379(23):2199–208.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Selvanderan SP, Summers MJ, Finnis ME, Plummer MP, Ali Abdelhamid Y, Anderson MB, et al. Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): randomized double-blind exploratory study. Crit Care Med. 2016;44(10):1842–50.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Morrish GA, Pai MP, Green B. The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol. 2011;7(6):697–706.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Loomis AK, Kabadi S, Preiss D, Hyde C, Bonato V, St Louis M, et al. Body mass index and risk of nonalcoholic fatty liver disease: two electronic health record prospective studies. J Clin Endocrinol Metab. 2016;101(3):945–52.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Lipsy RJ, Fennerty B, Fagan TC. Clinical review of histamine2 receptor antagonists. Arch Intern Med. 1990;150(4):745–51.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Bruley des Varannes S, Coudsy B, Waechter S, Delemos B, Xiang J, Lococo J, et al. On-demand proton pump inhibitory treatment in overweight/obese patients with gastroesophageal reflux disease: are there pharmacodynamic arguments for using higher doses? Digestion. 2013;88(1):56–63.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Pace F, Coudsy B, DeLemos B, Sun Y, Xiang J, LoCoco J, et al. Does BMI affect the clinical efficacy of proton pump inhibitor therapy in GERD? The case for rabeprazole. Eur J Gastroenterol Hepatol. 2011;23(10):845–51.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Shah SL, Lacy BE, DiBaise JK, Vela MF, Crowell MD. The impact of obesity on oesophageal acid exposure time on and off proton pump inhibitor therapy. Aliment Pharmacol Ther. 2015;42(9):1093–100.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Sharma P, Vakil N, Monyak JT, Silberg DG. Obesity does not affect treatment outcomes with proton pump inhibitors. J Clin Gastroenterol. 2013;47(8):672–7.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Shakhnovich V, Abdel-Rahman S, Friesen CA, Weigel J, Pearce RE, Gaedigk A, et al. Lean body weight dosing avoids excessive systemic exposure to proton pump inhibitors for children with obesity. Pediatr Obes. 2019;14(1):e12459.

    Article  Google Scholar 

  49. 49.

    Shakhnovich V, Smith PB, Guptill JT, James LP, Collier DN, Wu H, et al. Obese children require lower doses of pantoprazole than nonobese peers to achieve equal systemic drug exposures. J Pediatr. 2018;193(102–8):e1.

    Google Scholar 

  50. 50.

    Abernethy DR, Greenblatt DJ, Matlis R, Gugler R. Cimetidine disposition in obesity. Am J Gastroenterol. 1984;79(2):91–4.

    CAS  PubMed  Google Scholar 

  51. 51.

    Bauer LA, Wareing-Tran C, Edwards WA, Raisys V, Ferreri L, Jack R, et al. Cimetidine clearance in the obese. Clin Pharmacol Ther. 1985;37(4):425–30.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Davis RL, Quenzer RW, Bozigian HP, Warner CW. Pharmacokinetics of ranitidine in morbidly obese women. Dicp. 1990;24(11):1040–3.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Mahajan V, Hashmi J, Singh R, Samra T, Aneja S. Comparative evaluation of gastric pH and volume in morbidly obese and lean patients undergoing elective surgery and effect of aspiration prophylaxis. J Clin Anesth. 2015;27(5):396–400.

    PubMed  Article  Google Scholar 

  54. 54.

    Lim W, Meade M, Lauzier F, Zarychanski R, Mehta S, Lamontagne F, et al. Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*. Crit Care Med. 2015;43(2):401–10.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e24S-e43S.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Frederiksen SG, Hedenbro JL, Norgren L. Enoxaparin effect depends on body-weight and current doses may be inadequate in obese patients. Br J Surg. 2003;90(5):547–8.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, et al. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005;33(7):1565–71.

    PubMed  Article  Google Scholar 

  58. 58.

    Roberts JA, Taccone FS, Lipman J. Understanding PK/PD. Intensive Care Med. 2016;42(11):1797–800.

    PubMed  Article  Google Scholar 

  59. 59.

    Bickford A, Majercik S, Bledsoe J, Smith K, Johnston R, Dickerson J, et al. Weight-based enoxaparin dosing for venous thromboembolism prophylaxis in the obese trauma patient. Am J Surg. 2013;206(6):847–51.

    PubMed  Article  Google Scholar 

  60. 60.

    Borkgren-Okonek MJ, Hart RW, Pantano JE, Rantis PC Jr, Guske PJ, Kane JM Jr, et al. Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity. Surg Obes Relat Dis. 2008;4(5):625–31.

    PubMed  Article  Google Scholar 

  61. 61.

    Freeman A, Horner T, Pendleton RC, Rondina MT. Prospective comparison of three enoxaparin dosing regimens to achieve target anti-factor Xa levels in hospitalized, medically ill patients with extreme obesity. Am J Hematol. 2012;87(7):740–3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Ludwig KP, Simons HJ, Mone M, Barton RG, Kimball EJ. Implementation of an enoxaparin protocol for venous thromboembolism prophylaxis in obese surgical intensive care unit patients. Ann Pharmacother. 2011;45(11):1356–62.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Miranda S, Le Cam-Duchez V, Benichou J, Donnadieu N, Barbay V, Le Besnerais M, et al. Adjusted value of thromboprophylaxis in hospitalized obese patients: a comparative study of two regimens of enoxaparin: the ITOHENOX study. Thromb Res. 2017;155:1–5.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Parikh S, Jakeman B, Walsh E, Townsend K, Burnett A. Adjusted-dose enoxaparin for VTE prevention in the morbidly obese. J Pharm Technol. 2015;31(6):282–8.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  65. 65.

    Rondina MT, Wheeler M, Rodgers GM, Draper L, Pendleton RC. Weight-based dosing of enoxaparin for VTE prophylaxis in morbidly obese, medically-Ill patients. Thromb Res. 2010;125(3):220–3.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Rowan BO, Kuhl DA, Lee MD, Tichansky DS, Madan AK. Anti-Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg. 2008;18(2):162–6.

    PubMed  Article  Google Scholar 

  67. 67.

    Scholten DJ, Hoedema RM, Scholten SE. A comparison of two different prophylactic dose regimens of low molecular weight heparin in bariatric surgery. Obes Surg. 2002;12(1):19–24.

    PubMed  Article  Google Scholar 

  68. 68.

    Simone EP, Madan AK, Tichansky DS, Kuhl DA, Lee MD. Comparison of two low-molecular-weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc. 2008;22(11):2392–5.

    PubMed  Article  PubMed Central  Google Scholar 

  69. 69.

    Wang TF, Milligan PE, Wong CA, Deal EN, Thoelke MS, Gage BF. Efficacy and safety of high-dose thromboprophylaxis in morbidly obese inpatients. Thromb Haemost. 2014;111(1):88–93.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70.

    Joy M, Tharp E, Hartman H, Schepcoff S, Cortes J, Sieg A, et al. Safety and efficacy of high-dose unfractionated heparin for prevention of venous thromboembolism in overweight and obese patients. Pharmacotherapy. 2016;36(7):740–8.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Patanwala AE, Seaman SM, Kopp BJ, Erstad BL. Heparin dosing for venous thromboembolism prophylaxis in obese hospitalized patients: an observational study. Thromb Res. 2018;169:152–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Samuel S, Iluonakhamhe EK, Adair E, Macdonald N, Lee K, Allison TA, et al. High dose subcutaneous unfractionated heparin for prevention of venous thromboembolism in overweight neurocritical care patients. J Thromb Thrombolysis. 2015;40(3):302–7.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Mason SW, Barber A, Jones E, Chen SL, Moll S, Northam K. Safety and efficacy of high-dose unfractionated heparin versus high-dose enoxaparin for venous thromboembolism prevention in morbidly obese hospitalized patients. Am J Med. 2020;133(6):e249–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Devine BJ. Case number 25: gentamicin therapy. Drug Intell Clin Pharm. 1974;8:650–5.

    Article  Google Scholar 

  75. 75.

    Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA. Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol. 1983;24(5):643–7.

    CAS  PubMed  Article  Google Scholar 

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BLE and JFB contributed to development of manuscript outline, literature search, literature evaluation, crafting of recommendations, manuscript preparation and critical review. Both authors read and approved the final manuscript.

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Additional file 1:

 Pharmacokinetic and clinical trials involving low molecular weight heparin and unfractionated heparin.

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Erstad, B.L., Barletta, J.F. Drug dosing in the critically ill obese patient: a focus on medications for hemodynamic support and prophylaxis. Crit Care 25, 77 (2021). https://doi.org/10.1186/s13054-021-03495-8

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Keywords

  • Critical illness
  • Obesity
  • Pharmacokinetics
  • Drug dosing