Injection site reactions after subcutaneous oligonucleotide therapy.

Oligonucleotides (ONs) are short fragments of nucleic acids, currently being investigated as therapeutic agents. When administered subcutaneously (sc), ONs cause a specific local reaction originating around the injection site, such as erythema, itching, discomfort and pain, including more severe manifestations such as ulceration or necrosis. These injection site reactions (ISRs) are common, but rather poorly described in the literature. With this review, we aim to provide an overview on the extent of the problem of ISRs, based on reported incidence. A structured literature search was performed to identify reported incidence and clinical features of ISRs which yielded 70 manuscripts that contained information regarding ISRs. The data from literature was combined with data on file available at our institution. All sc administered ONs described in the literature lead to the occurrence of ISRs. The percentage of trial subjects that developed ISRs ranged from 22 to 100% depending on ON. The majority of ONs caused ISRs in more than 70% of the trial subjects. The severity of the observed reactions varied between different ONs. Occurrence rate as well as severity of ISRs increases with higher doses. For chemistry and target of the compounds, no clear association regarding ISR incidence or severity was identified. All ONs developed to date are associated with ISRs. Overcoming the problem of ISRs might add greatly to the potential success of sc-administered ONs. Knowledge of these skin reactions and their specific immunostimulatory properties should be increased in order to obtain ONs that are more suitable for long-term use and clinically applicable in a broader patient population.

Assessment of adverse events and predictors of neurological recovery after therapeutic hypothermia.

BACKGROUND: Therapeutic hypothermia improves neurological recovery after witnessed cardiac arrest from ventricular fibrillation or tachycardia. Its application is expanding despite associated adverse events. OBJECTIVE: To assess the occurrence of adverse events and predictors of good versus poor neurological recovery after therapeutic hypothermia. METHODS: A single-center, retrospective review of medical records of 91 patients who received therapeutic hypothermia for ≥6 hours. Adverse events included laboratory abnormalities, shivering, acute kidney injury, or infection. Cerebral performance categories (CPC) scores delineated good (CPC of 1-3) or poor (CPC of 4 or 5) neurological outcomes. Groups were compared and parameters evaluated for effect on neurological recovery using backward logistic regression analysis. RESULTS: Therapeutic hypothermia was used for several indications, and 42 patients (46.2%) had good neurological recovery. Demographic parameters were similar between groups. Common adverse events were hypoglycemia (98.9%), shivering (84.6%), bradycardia (58.2%), electrolyte abnormalities (26.4%-91.2%), acute kidney injury (52.8%), infection (48.4%), and coagulopathy (40.7%). Characteristics independently associated with neurological recovery included faster return of spontaneous circulation (ROSC), quicker initiation of cooling, and the occurrence of infections. Pulseless electrical activity, faster achievement of goal cooling temperature, seizure, and the administration of insulin or epinephrine were inversely related to neurological recovery. CONCLUSIONS: Adverse events of therapeutic hypothermia were numerous and frequent, necessitating monitoring. Neurological recovery is primarily driven by the type of arrest, the rapidity of ROSC, the time needed to provide and achieve therapeutic hypothermia, the development of seizures or infection, and the use of insulin or epinephrine.

Management of Severe and Critical COVID-19 Infection with Immunotherapies.

Following the reduction in mortality demonstrated by dexamethasone treatment in severe COVID-19, many targeted immunotherapies have been investigated. Thus far, inhibition of IL-6 and JAK pathways have the most robust data and have been granted Emergency Use Authorization for treatment of severe disease. However, it must be noted that critically ill patients comprised a relatively small proportion of most of the trials of COVID-19 therapeutics, despite bearing a disproportionate burden of morbidity and mortality. Furthermore, the rapidity and fluidity with which clinical trials have been conducted in the pandemic setting have contributed to difficulty in extrapolating available trial data to critically ill patients. The exclusion of many patients requiring invasive mechanical ventilation, preponderance of ordinal scale based endpoints, and frequent lack of blinding are particular challenges. More data is needed to identify beneficial treatments in the complex milieu of critical illness from COVID-19 infection.

Pharmacologic Issues in Liver Disease.

This article describes key concepts for drug dosing considerations in liver disease. Included in this article is a review of pharmacokinetic changes that are known to occur in patients with liver disease that can aide in drug dosing. Although limited, the currently available pharmacokinetic data for medications that are commonly used in the critical care setting are also included.