Determining the Risk of Elevated Digoxin Concentrations Following Loading Dose in Patients With Acute and Chronic Kidney Disease.

BACKGROUND: The optimal loading dose of digoxin in patients with reduced kidney function is unknown. Tertiary references recommend reduced loading doses; however, these recommendations are based on immunoassays that are falsely elevated by the presence of digoxin-like immunoreactive substances, a problem that is minimized in modern assays. OBJECTIVE: To determine whether chronic kidney disease (CKD) or acute kidney injury (AKI) is associated with supratherapeutic digoxin concentrations after a digoxin loading dose. METHODS: A retrospective analysis on patients who received an intravenous loading dose of digoxin with a digoxin concentration collected 6 to 24 hours after the end of the dose. Patients were stratified into 3 groups: AKI, CKD, and non-AKI/CKD (NKI) based on glomerular filtration rate and serum creatinine. The primary outcome was frequency of supratherapeutic digoxin concentrations (>2 ng/mL) and secondary outcomes included frequency of adverse events. RESULTS: A total of 146 digoxin concentrations were included (AKI = 59, CKD = 16, NKI = 71). Frequencies of supratherapeutic concentrations were similar between groups (AKI: 10.2%, CKD: 18.8%, NKI: 11.3%; P = 0.61). Pre-planned logistic regression demonstrated no significant relationship between kidney function group and the development of a supratherapeutic concentration (AKI: odds ratio [OR]: 1.3, 95% confidence interval [CI]: 0.4-4.5; CKD: OR 4.3, 95% CI: 0.7-23). CONCLUSION AND RELEVANCE: This is the first study in routine clinical practice evaluating the relationship between kidney function and digoxin peak concentrations that differentiates AKI from CKD. We did not find a relationship between kidney function and peak concentrations; however, the group with CKD was underpowered.

Reversal of Advanced Directives in Neurologic Emergencies.

Objective: Patients with advanced directives or Medical Orders for Life-Sustaining Treatment (MOLST), including "Do Not Resuscitate" (DNR) and/or "Do Not Intubate" (DNI), may be candidates for procedural interventions when presenting with acute neurologic emergencies. Such interventions may limit morbidity and mortality, but typically they require MOLST reversal. We investigated outcomes of patients with MOLST reversal for treatment of neurologic emergencies. Methods: We conducted a retrospective chart review from July 1, 2019 to April 30, 2021 of patients with MOLST reversal treated in our NeuroMedicine Intensive Care Unit. Variables collected include neurologic disease, MOLST reversal decision maker, procedural interventions, and outcomes. Results: Twenty-seven patients (18 female, median age 78 years (IQR 73-85 years), median baseline modified Rankin score 1 [IQR 0-2.5] were identified with MOLST reversal. The most common pre-procedural MOLST was DNR/DNI (n=22, 81%), and 93% (n=25) pre-procedural MOLSTs were completed by the patient. MOLSTs were reversed by surrogates in n=23 cases (85%). The median time from MOLST completion to MOLST reversal was 603 days (IQR 45 days to 4 years). The most common neurologic emergency was ischemic stroke (n=14, 52%). Most patients died (n=14, 52%), 26% (n=7) were discharged to skilled nursing, and 22% (n=6) returned to home or assisted living. Conclusions: In neurologic emergencies, urgent shared decision making is needed to ensure goal-concordant care, which may result in reversal of existing advanced directives. Outcomes of patients with MOLST reversal were heterogeneous, emphasizing the importance of deliberate patient-centered care weighing the risks and benefits of each intervention.

Acid-base effects of continuous infusion furosemide in clinically stable surgical ICU patients: an analysis based on the Stewart model.

OBJECTIVES: We sought to test the strength of correlation between predicted and observed systemic acid-base status based on the Stewart model equations during continuous infusion (CI) furosemide therapy. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center, observational study conducted in the Surgical ICU of a large academic medical center. Ten critically ill patients who received CI furosemide were included. MAIN OUTCOMES AND MEASURES: The primary purpose was to characterize the relationship between changes in serum electrolyte and acid-base status and the excretion of electrolytes in the urine during infusion of CI furosemide in critically ill patients. As a secondary endpoint, we sought to evaluate the predictive application of the Stewart model. Over 72-h, intake and output volumes, electrolyte content of fluids administered, plasma and urine electrolytes, urine pH, and venous blood gases were collected. Predicted and observed changes in acid-based status were compared for each day of diuretic therapy using Spearman's correlation coefficient. RESULTS: The mean (SD) strong ion difference (SID) increased from 45.2 (3.2) at baseline to 49.6 (4.0) after 72 h of continuous infusion furosemide. At Day 1, the mean SID (observed) (SD) was 47.5 (3.5) and the predicted SID was 49.5 (5.8). Day 1 observed plasma SID was positively correlated with the predicted SID (rs = 0.80, p = 0.01). By Days 2 and 3, the correlations of observed and predicted SID were no longer statistically significant. CONCLUSIONS AND RELEVANCE: Using the Stewart model, increases in SID as an indicator of metabolic alkalosis due to the chloruretic effects of furosemide were observed. Predicted and observed SID correlated well over the first 24 h of treatment.

Hydrochloric Acid Infusion for the Treatment of Metabolic Alkalosis in Surgical Intensive Care Unit Patients.

BACKGROUND: Older reports of use of hydrochloric acid (HCl) infusions for treatment of metabolic alkalosis document variable dosing strategies and risk. OBJECTIVES: This study sought to characterize use of HCl infusions in surgical intensive care unit patients for the treatment of metabolic alkalosis. METHODS: This retrospective review included patients who received a HCl infusion for >8 hours. The primary end point was to evaluate the utility of common acid-base equations for predicting HCl dose requirements. Secondary end points evaluated adverse effects, efficacy, duration of therapy, and total HCl dose needed to correct metabolic alkalosis. Data on demographics, potential causes of metabolic alkalosis, fluid volume, and duration of diuretics as well as laboratory data were collected. RESULTS: A total of 30 patients were included, and the average HCl infusion rate was 10.5 ± 3.7 mEq/h for an average of 29 ± 14.6 hours. Metabolic alkalosis was primarily diuretic-induced (n = 26). Efficacy was characterized by reduction in the median total serum CO2 from 34 to 27 mM/L ( P < 0.001). The change in chloride ion deficit and change in apparent strong ion difference (SIDa) were not correlated with total HCl administered. There were no documented serious adverse effects related to HCl infusions. CONCLUSION: HCl was effective for treating metabolic alkalosis, and no serious adverse events were seen. In this clinical setting, the baseline chloride ion deficit and SIDa were not useful for prediction of total HCl dose requirement, and serial monitoring of response is recommended.

Relative bioavailability of orally administered fosphenytoin sodium injection compared with phenytoin sodium injection in healthy volunteers.

STUDY OBJECTIVE: To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL ) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN: Open-label, randomized, single-dose, two-period, two-sequence crossover study. SETTING: University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7-14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS: The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07-1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax ) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0-19.4) mg/L versus 5.0 (3.2-8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5-2.0) hours versus 6.0 (2.0-24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported. CONCLUSION: FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted.

Guidelines for intensive care unit design.

OBJECTIVE: To develop a guideline to help guide healthcare professionals participate effectively in the design, construction, and occupancy of a new or renovated intensive care unit. PARTICIPANTS: A group of multidisciplinary professionals, designers, and architects with expertise in critical care, under the direction of the American College of Critical Care Medicine, met over several years, reviewed the available literature, and collated their expert opinions on recommendations for the optimal design of an intensive care unit. SCOPE: The design of a new or renovated intensive care unit is frequently a once- or twice-in-a-lifetime occurrence for most critical care professionals. Healthcare architects have experience in this process that most healthcare professionals do not. While there are regulatory documents, such as the Guidelines for the Design and Construction of Health Care Facilities, these represent minimal guidelines. The intent was to develop recommendations for a more optimal approach for a healing environment. DATA SOURCES AND SYNTHESIS: Relevant literature was accessed and reviewed, and expert opinion was sought from the committee members and outside experts. Evidence-based architecture is just in its beginning, which made the grading of literature difficult, and so it was not attempted. The previous designs of the winners of the American Institute of Architects, American Association of Critical Care Nurses, and Society of Critical Care Medicine Intensive Care Unit Design Award were used as a reference. Collaboratively and meeting repeatedly, both in person and by teleconference, the task force met to construct these recommendations. CONCLUSIONS: Recommendations for the design of intensive care units, expanding on regulatory guidelines and providing the best possible healing environment, and an efficient and cost-effective workplace.

A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients.

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.

Recommendations for end-of-life care in the intensive care unit: a consensus statement by the American College [corrected] of Critical Care Medicine.

BACKGROUND: These recommendations have been developed to improve the care of intensive care unit (ICU) patients during the dying process. The recommendations build on those published in 2003 and highlight recent developments in the field from a U.S. perspective. They do not use an evidence grading system because most of the recommendations are based on ethical and legal principles that are not derived from empirically based evidence. PRINCIPAL FINDINGS: Family-centered care, which emphasizes the importance of the social structure within which patients are embedded, has emerged as a comprehensive ideal for managing end-of-life care in the ICU. ICU clinicians should be competent in all aspects of this care, including the practical and ethical aspects of withdrawing different modalities of life-sustaining treatment and the use of sedatives, analgesics, and nonpharmacologic approaches to easing the suffering of the dying process. Several key ethical concepts play a foundational role in guiding end-of-life care, including the distinctions between withholding and withdrawing treatments, between actions of killing and allowing to die, and between consequences that are intended vs. those that are merely foreseen (the doctrine of double effect). Improved communication with the family has been shown to improve patient care and family outcomes. Other knowledge unique to end-of-life care includes principles for notifying families of a patient's death and compassionate approaches to discussing options for organ donation. End-of-life care continues even after the death of the patient, and ICUs should consider developing comprehensive bereavement programs to support both families and the needs of the clinical staff. Finally, a comprehensive agenda for improving end-of-life care in the ICU has been developed to guide research, quality improvement efforts, and educational curricula. CONCLUSIONS: End-of-life care is emerging as a comprehensive area of expertise in the ICU and demands the same high level of knowledge and competence as all other areas of ICU practice.

Cytochrome P450 3A4 activity after surgical stress.

OBJECTIVE: To evaluate the relationship between the acute inflammatory response after surgical trauma and changes in hepatic cytochrome P450 3A4 activity, compare changes in cytochrome P450 3A4 activity after procedures with varying degrees of surgical stress, and to explore the time course of any potential drug-cytokine interaction after surgery. DESIGN: Prospective, open-label study with each patient serving as his or her own control. SETTING: University-affiliated, acute care, general hospital. PATIENTS: A total of 16 patients scheduled for elective repair of an abdominal aortic aneurysm (n = 5), complete or partial colectomy (n = 6), or peripheral vascular surgery with graft (n = 5). INTERVENTIONS: Cytochrome P450 3A4 activity was estimated using the carbon-14 [14C]erythromycin breath test (ERMBT) before surgery and 24, 48, and 72 hrs after surgery. Abdominal aortic aneurysm and colectomy patients also had an ERMBT performed at discharge. Blood samples were obtained before surgery, immediately after surgery, and 6, 24, 32, 48, and 72 hrs after surgery for determination of plasma concentrations of interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha. Clinical markers of surgical stress that were collected included duration of surgery, estimated blood loss, and volume of fluids administered in the operating room. MEASUREMENTS AND MAIN RESULTS: ERMBT results significantly declined in all three surgical groups, with the lowest value at the time of the 72-hr study in all three groups. There was a trend toward differences in ERMBT results among groups that did not reach statistical significance (p =.06). The nadir ERMBT result was significantly and negatively correlated with both peak interleukin-6 concentration (r(s) = -.541, p =.03) and log interleukin-6 area under the curve from 0 to 72 hrs (r(s) = -.597, p =.014). Subjects with a peak interleukin-6 of >100 pg/mL had a significantly lower nadir ERMBT compared with subjects with a peak interleukin-6 of <100 pg/mL (35.5% +/- 5.2% vs. 74.7% +/- 5.1%, p <.001). CONCLUSIONS: Acute inflammation after elective surgery was associated with a significant decline in cytochrome P450 3A4 activity, which is predictive of clinically important changes in the metabolism of commonly used drugs that are substrates for this enzyme.