# Drug dosing in obese surgical patients

Hussain, Z ORCID: 0000-0003-0819-3380 2019 , 'Drug dosing in obese surgical patients', PhD thesis, University of Tasmania.

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## Abstract

Obesity has become a global health problem, reaching epidemic proportions in developed countries. Nearly 13% of the world’s population is considered obese. Obesity contributes to the development of numerous health issues, including type 2 diabetes, coronary heart disease, osteoarthritis, respiratory problems such as obstructive sleep apnoea, and certain forms of cancer. Obesity is also linked with several physiological alterations, such as increased adipose tissue mass, increased cardiac output, elevated liver enzymes and renal hyperfiltration. These physiological changes contribute to alterations in the pharmacokinetic parameters of various drugs, including their volume of distribution and clearance. Despite the increasing prevalence of obesity and its associated drug dosing challenges, obese subjects are usually not included in clinical trials during the process of drug development. Therefore, the dosing information available in current monographs of medications may not be generalisable to the obese patient population. The situation is further worsened by the lack of universally accepted dosing guidelines for obese patients.
The overall aim of the thesis was to determine current drug dosing practices in obese elective surgical patients and examine clinical outcomes in relation to dosing in this patient group. Owing to the challenges of evaluating drug dosing in some real-life obese patient settings, such as limited documentation of weight and height, presence of acute illnesses and lack of follow-up information in out-patients, intensive care unit patients and general medical patients, the author chose to study elective surgical patients, who generally have better documentation, follow-up and no acute illness. Four studies using different methodologies, including a systematic review of the published literature, two retrospective studies and a cross-sectional survey, were performed to address the overall aim of the thesis.
In the first part of the thesis, the author identified the current level of published evidence for drug doses used in obese elective surgical patients. Clinical studies of drug dosing in this patient group were selected if they had a non-obese control or comparative dosing scalar group. Thirty-three studies of six surgically related drug classes were identified: antibiotics (n=5), anticoagulants (n=7), anaesthetics (n=6), muscle relaxants (n=10), neuromuscular reversal agents (n=3) and analgesics (n=2). A variety of dose scalars and/or recommendations was observed for the different drugs. The standard 2g intravenous dose of cefazolin appeared effective in the prevention of surgical site infection (SSI) in obese individuals. Stratified dosing of enoxaparin, using body mass index (BMI), was effective for venous thromboembolism prevention. Lean body weight was proposed as a suitable weight scalar for induction of anaesthesia with propofol, whereas total body weight was suggested for maintenance of anaesthesia with propofol and the depolarizing muscle relaxants. Ideal body weight was reported as an appropriate dosing scalar for the non-depolarizing muscle relaxants and neuromuscular reversal agents. Ideal body weight and ideal body weight plus a correction factor of 40% were reported as suitable weight scalars for post-operative analgesia with morphine. However, no drug dosing recommendation achieved an “Excellent” (level 1) rating for quality of evidence. Methodologically strong clinical outcome studies are needed to provide empirical evidence for current dosing recommendations of these drugs.
The American Society of Health System Pharmacists’ guidelines and the Australian Medicines Handbook recommend an increased 3g intravenous dose of cefazolin for surgical patients ≥ 120kg as antibiotic prophylaxis. Therefore, in the second part of the thesis, the author aimed to compare the prevalence of SSIs in obese and non-obese patients (BMI ≥ 30kg/m$$^2$$ and < 30kg/m$$^2$$), and those weighing ≥ 120kg and < 120kg, who received the standard 2g dose of cefazolin preoperatively. A 5-year retrospective 1:1 case control study of cefazolin dosing was conducted in patients who underwent elective surgical procedures (general, gynaecological and orthopaedic) from 2012 to 2016 at the Royal Hobart Hospital. The 90-day prevalence of SSI was investigated. At the study site, in contrast to the aforementioned guidelines, the standard antibiotic prophylaxis practice was 2g cefazolin administered at the induction of anaesthesia. One hundred and fifty-two obese patients met the inclusion criteria and were matched with non-obese controls. Baseline characteristics were similar between groups, except for an increased prevalence of diabetes in the obese group (35.5% vs 13.2%; p<0.001), as well as an American Society of Anaesthesiologists Score of 3 (61.8% vs 17.1%; p<0.001). The prevalence of SSI in the obese group was almost double that of the non-obese group (8.6% vs 4.6%; p=0.25), and in patients weighing ≥ 120kg (n=102) compared to those weighing < 120kg (n=202) (9.8% vs 5.0%; p=0.17). With the sample size studied, the prevalence of SSI was not significantly increased in obese patients, or those weighing ≥ 120kg, who received cefazolin 2g prophylactically; however, trends toward an increase prevalence were evident. There is a clear need for large scale randomised controlled trials to examine whether a 2g or 3g cefazolin dose is adequate to prevent SSI in obese individuals. In the interim, changing local practice to use the higher dose, in line with the guidelines above, might be advisable.
Guidelines such as those of the American Society for Metabolic and Bariatric Surgery, the American College of Chest Physicians and, the National Institute for Health and Care Excellence have suggested the use of chemoprophylaxis for venous thromboembolism (VTE), but no information on type, dose and duration was provided. In the third part of the thesis, the author performed a retrospective clinical study of enoxaparin use in obese surgical patients undergoing weight loss procedures (primary and revisional laparoscopic adjustable gastric banding), from 2013 to 2017 at the Royal Hobart Hospital and Hobart Private Hospital. The incidence of VTE and major bleeding was investigated during a 90-day follow-up period. The study included 112 and 100 patients who had undergone primary and revisional (24 band procedures and 76 port procedures) laparoscopic adjustable gastric band surgery, respectively. The majority of patients (97%) had a mild risk of VTE development according to an assessment tool from the Cleveland Clinic, USA. Despite the low VTE risk, the majority of patients received enoxaparin. All primary procedure patients received prophylactic enoxaparin, compared to 79% and 20% of revisional patients who underwent band and port procedures, respectively (p<0.001). Most of these patients received 40mg enoxaparin once daily. The overall VTE incidence after 90 days was 0.9% (2/212), and no major bleeding events were observed. With no procedure-specific thromboprophylaxis guidelines for bariatric surgery, and with its use based solely on the discretion of the surgeon, thromboprophylaxis may not always achieve such low VTE and bleeding incidences. Further research to provide procedure and technique-specific thromboprophylaxis evidence may improve outcomes.
The Association of Anaesthetists of Great Britain and Ireland and the Society for Obesity and Bariatric Anaesthesia’s combined guidelines have suggested the use of dosing scalars other than total body weight specific for every anaesthetic drug, to improve anaesthesia outcomes. However, these dosing recommendations are based on small-scale pharmacokinetic studies and no level 1 evidence is available to support these recommendations. In the final part of the thesis, the author conducted a cross-sectional survey to determine anaesthetists’ drug dosing practices for class-III obese (BMI ≥ 40 kg/m$$^2$$) surgical patients, explore if they had experienced increased incidences of adverse events related to drug dosing with these patients, and assess which resources they consulted for dosing advice in this population. After validation, an invitation and web link to an electronic survey was emailed to 1000 randomly selected members of the Australian and New Zealand College of Anaesthetists. There were 230 completed responses (response rate 23%). Anaesthetists frequently reported dosing class-III obese patients in keeping with current recommendations, but substantial heterogeneity in dosing practices between respondents was observed. Lean body weight was most frequently used for dosing propofol, non-depolarising muscle relaxants, sugammadex and opioids; whereas, total body weight was most frequently used for suxamethonium. Increased incidences of adverse events related to drug dosing in class-III obese patients were commonly reported. Many anaesthetists did not use any published drug dosing resources. Until higher level drug dosing evidence is available for class-III obese patients, anaesthetists should consider current recommendations as well as exercising increased attention with dosing and clinical observation of patients.
In conclusion, it was observed that obese patients were dosed mainly based on the clinical judgment of surgeons and anaesthetists. Dosing based on clinicians’ experience and personal judgement may not always achieve optimal patient outcomes. Therefore, there is a need for more evidence to guide dosing for this patient group. Obese patients are not yet identified as a special population, unlike geriatric patients, paediatric patients and pregnant women. However, the extent of physiological and associated pharmacokinetic changes are similar to these groups. There is a need for large-scale clinical studies and randomised clinical trials to identify optimal doses of drugs commonly used in these patients. Results of the studies in this thesis may serve as baseline information in the development of more robust and widely acceptable obesity-specific drug dosing guidelines.