The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock.

BACKGROUND: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock. METHODS: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events. DISCUSSION: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.

Incidence and onset of delayed seizures after overdoses of extended-release bupropion.

BACKGROUND: Delayed seizures have been reported with overdoses of bupropion extended-release (XL). This study systematically evaluates the frequency and timing of seizures and an association between other toxic effects (ie, agitation, tremors, and hallucinations) and seizures. METHODS: A 3-year multi-poison center observational study of hospitalized patients with ingestion of bupropion XL >or=600 mg in adults and >or=4 mg/kg in children was performed. Patients with coingestants or a medical history that could affect seizure occurrence were excluded. Data collection forms captured onset time of seizure(s), other symptoms, and treatment. RESULTS: One hundred seventeen patients met inclusion criteria: median age of 22 years (range, 1.3-65 years) with 16 children 8 hours. Subsequent seizures occurred in 49%. Children ages 1.3, 3, and 7 years, developed seizures. In patients >or= 13 years of age, median dose with seizures was 4350 mg (range, 600-54 000) compared to 2400 mg (range, 600-9000) in patients without seizures. Agitation, tremors, and hallucinations occurred in 29.7%, 40.5%, and 18.9% of patients with seizures, respectively, compared with 12.5 %, 17.5%, and 10% in patients without seizures. The neurologic effects agitation (P = .045) and tremors (P = .005) occurred more frequently. CONCLUSION: Delayed seizure onset suggests a minimum observation period of 24 hours after bupropion XL overdose. Although patients experiencing agitation or tremors may be at greater risk, seizures can occur without preceding central nervous system toxicity.

Toxicity from a clonidine suspension.

BACKGROUND: Clonidine is frequently prescribed to children. Clonidine overdose in children has resulted in major clinical effects and deaths. CASE REPORT: A 3.5-year-old male with a history of a seizure disorder and night terrors presented following difficulty walking, excessive sleeping, agitation when awake, and possible seizure activity. Chronic medications were valproic acid (VPA) and clonidine. On presentation, he alternated between poor responsiveness and agitation, with initial vitals: blood pressure, BP 144/76 mmHg; heart rate, 65 bpm; respiratory rate, 18 bpm; temperature 99.5 degrees F; and pulse oximetry 96% on room air. VPA level was 35 microg/mL. A toxicology consult the next day noted a dry mouth, 2-mm pupils, intermittent gasping, and central nervous system (CNS) depression, with a diagnostic impression of clonidine overdose. The caregiver had been giving 1 mL (0.1 mg) qd of a pharmacy-compounded clonidine suspension by a provided syringe. The pharmacy procedure record agreed with the physicians order. The amount dispensed was a 30-day supply but the bottle was empty on day 19, leading us to suspect a possible accelerated dosing error. The concentration in the bottle thus could not be confirmed. The child slowly returned to his baseline state over 48 hours. A serum clonidine level drawn approximately 18 hours after his last dose later returned at 300 ng/mL (reference range = 0.5-4.5 ng/mL). CASE DISCUSSION: Compounding and liquid dosing errors are common in children and may result in massive overdoses. There was an accelerated dosing error, but whether a compounding or suspension error or even an acute overdose occurred as well is unknown. CONCLUSION: Particular care should be taken with medications that have low therapeutic indices, that are extemporaneously compounded, and are prepared as liquids, where medication errors are more likely.