Developing Parametric and Nonparametric Models for Model-Informed Precision Dosing: A Quality Improvement Effort in Vancomycin for Patients With Obesity.

BACKGROUND: Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity. METHODS: Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using metrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset. RESULTS: In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m2 (range: 40-70.3 kg/m2). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to c clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients). CONCLUSIONS: Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.

A Retrospective Study of Early vs Delayed Home Dose Basal Insulin in the Acute Management of Diabetic Ketoacidosis.

BACKGROUND: Insulin via continuous intravenous infusion (ICII) is a standard of care for treating patients with diabetic ketoacidosis (DKA). Once DKA is resolved, ICII is transitioned to subcutaneous therapy. However, recent guidelines recommend continuation of home dose subcutaneous basal insulin (HDBI) in patients with DKA. The objective of this study was to evaluate outcomes in patients who received early vs delayed HDBI. METHODS: This is a retrospective cohort study of patients ≥16 years old admitted to the medical intensive care unit between 1 July 2012 and 30 June 2015 with a primary diagnosis of DKA who received ICII and HDBI. Patients were stratified into early or delayed groups if they received HDBI before or after resolution of DKA, respectively. The primary outcome was incidence of transitional failure, defined as resumption of ICII or recurrence of DKA after initial ICII discontinuation. RESULTS: A total of 106 admissions were included for analysis; 33 (31.1%) received early HDBI. The incidence of transitional failure was similar between the early and delayed groups (OR, 0.60; 95% CI, 0.26 to 1.44; P = 0.72). In the early group, ICII duration was shorter at 13.8 hours [interquartile range (IQR), 10.1 to 16.5] vs 17.1 hours (IQR, 12.6 to 21.1; P = 0.04), with a trend toward lower rates of hypoglycemia (OR, 0.41; 95% CI, 0.16 to 1.05; P = 0.058). CONCLUSION: There was no significant difference in incidence of transitional failure between early and delayed HDBI. Early HDBI was associated with a shorter duration of ICII and a trend toward less hypoglycemia. A prospective analysis is needed to confirm these findings.

Management of Acute Alcohol Withdrawal Syndrome in Critically Ill Patients.

Approximately 16-31% of patients in the intensive care unit (ICU) have an alcohol use disorder and are at risk for developing alcohol withdrawal syndrome (AWS). Patients admitted to the ICU with AWS have an increased hospital and ICU length of stay, longer duration of mechanical ventilation, higher costs, and increased mortality compared with those admitted without an alcohol-related disorder. Despite the high prevalence of AWS among ICU patients, no guidelines for the recognition or management of AWS or delirium tremens in the critically ill currently exist, leading to tremendous variability in clinical practice. Goals of care should include immediate management of dehydration, nutritional deficits, and electrolyte derangements; relief of withdrawal symptoms; prevention of progression of symptoms; and treatment of comorbid illnesses. Symptom-triggered treatment of AWS with γ-aminobutyric acid receptor agonists is the cornerstone of therapy. Benzodiazepines (BZDs) are most studied and are often the preferred first-line agents due to their efficacy and safety profile. However, controversy still exists as to who should receive treatment, how to administer BZDs, and which BZD to use. Although most patients with AWS respond to usual doses of BZDs, ICU clinicians are challenged with managing BZD-resistant patients. Recent literature has shown that using an early multimodal approach to managing BZD-resistant patients appears beneficial in rapidly improving symptoms. This review highlights the results of recent promising studies published between 2011 and 2015 evaluating adjunctive therapies for BZD-resistant alcohol withdrawal such as antiepileptics, baclofen, dexmedetomidine, ethanol, ketamine, phenobarbital, propofol, and ketamine. We provide guidance on the places in therapy for select agents for management of critically ill patients in the presence of AWS.

A Retrospective Study on the Protective Effects of Topical Vancomycin in Patients Undergoing Multilevel Spinal Fusion.

BACKGROUND: Topical vancomycin may be an effective intervention to decrease the risk of postoperative surgical site infections (SSIs). The primary objective of this study was to evaluate the impact of topical vancomycin with intravenous (IV) cefazolin compared with IV cefazolin alone on the incidence of SSI in instrumented multilevel spinal fusion (MLSF) surgery. METHODS: This was a retrospective cohort study of patients 18 years and older who underwent instrumented MLSF surgery between January 1, 2010, and July 31, 2014. Patients who underwent anterior cervical diskectomy and fusion, had spine surgery within 3 months prior to index case, received antibiotics other than IV cefazolin prior to surgery, or had preoperative length of stay longer than 5 days were excluded. SSIs were identified using Centers for Disease Control and Prevention National Healthcare Safety Network definitions. Summary statistics were computed. Variables found to be associated with increased risk of SSI through univariate analysis were included in a multivariate analysis. RESULTS: Among 326 patients, 29 (8.9%) developed an SSI. Univariate analysis showed a trend toward decreased SSI incidence in the cohort receiving topical vancomycin with IV cefazolin compared with IV cefazolin alone, although this was not statistically significant ([6/116] 5.2% vs [23/210] 11.0%, p = 0.08). Topical vancomycin was associated with a protective effect against SSI in the multivariate analysis (odds ratio [OR] 0.26, p = 0.02). Significant risk factors for the development of SSI included female sex (OR 3.3, p = 0.01), increasing invasiveness score (p < 0.01), and diabetes mellitus (OR 5.1, p < 0.01). CONCLUSION: Topical vancomycin administered in addition to IV cefazolin was associated with a decreased risk of SSI in high-risk MLSF patients. Female patients and those with diabetes mellitus were at higher risk of developing postsurgical infection. Further prospective studies are needed to confirm these results and to define the most clinically effective dose of topical vancomycin in this patient population.