Guidelines for the determination of death by neurologic criteria (DNC) require an absence of confounding factors if clinical examination alone is to be used. Drugs that depress the central nervous ...system suppress neurologic responses and spontaneous breathing and must be excluded or reversed prior to proceeding. If these confounding factors cannot be eliminated, ancillary testing is required. These drugs may be present after being administered as part of the treatment of critically ill patients. While measurement of serum drug concentrations can help guide the timing of assessments for DNC, they are not always available or feasible. In this article, we review sedative and opioid drugs that may confound DNC, along with pharmacokinetic factors that govern the duration of drug action. Pharmacokinetic parameters including a context-sensitive half-life of sedatives and opioids are highly variable in critically ill patients because of the multitude of clinical variables and conditions that can affect drug distribution and clearance. Patient-, disease-, and treatment-related factors that influence the distribution and clearance of these drugs are discussed including end organ function, age, obesity, hyperdynamic states, augmented renal clearance, fluid balance, hypothermia, and the role of prolonged drug infusions in critically ill patients. In these contexts, it is often difficult to predict how long after drug discontinuation the confounding effects will take to dissipate. We propose a conservative framework for evaluating when or if DNC can be determined by clinical criteria alone. When pharmacologic confounders cannot be reversed, or doing so is not feasible, ancillary testing to confirm the absence of brain blood flow should be obtained.
Background:
N-acetylcysteine (NAC) is an antioxidant which can regenerate glutathione and is primarily used for acetaminophen overdose. It is also a potential therapy to prevent iatrogenic acute ...kidney injury or slow the progression of chronic kidney disease. It has been considered in this context by many studies with mixed results. Notably, a biological-mechanism rationale for a protective effect of NAC has never been adequately reported. Among conflicting reports, there appears to be evidence that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, a systematic review of the literature will be conducted to determine whether there is an effect of NAC on kidney function measured with serum creatinine.
Objective:
To determine the effect of NAC on kidney function.
Design:
A systematic review and meta-analysis.
Settings:
Prospective studies, with administration of NAC, in the absence of any other change in kidney function (such as contrast administration or surgery).
Patients:
Adult humans aged 18 years old or more, either healthy volunteers or with chronic kidney disease, were administered with NAC. Populations having little to no kidney function such as in end-stage kidney disease will be excluded.
Measurements:
Serum creatinine and/or cystatin C measurements before and after NAC administration.
Methods:
An information specialist will assist in searching MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify all study types including randomized controlled trials, and prospective cohort studies reporting change in serum creatinine after NAC administration. Two reviewers will independently screen the titles and abstracts of the studies obtained from the search using predefined inclusion criteria and will then extract data from the full texts of selected studies. The weighted mean difference will be calculated for change in creatinine with NAC, using random-effects analysis. Quality assessment will be done with the Cochrane Risk of Bias tool for randomized trials and the Newcastle-Ottawa Scale for observational studies.
Results:
The outcome of interest is kidney function as reported by either change in serum creatinine and/or serum cystatin C measurement for randomized trials or comparing baseline (pre-NAC dose) values and those following the NAC dose.
Limitations:
Possible heterogeneity and publication bias and lack of mechanistic data.
Conclusions:
This systematic review will provide a synthesis of current evidence on the effect of NAC on serum creatinine measurement. These findings will provide clinicians with guidelines and serve as a strong research base for future studies in this field.
Systematic review registration:
This review is registered with PROSPERO, CRD42017055984
OBJECTIVE:Atrial fibrillation is a common problem associated with morbidity and mortality in critically ill patients; however, evidence-based treatment recommendations are lacking. The objective of ...this systematic review was to evaluate the efficacy of pharmacologic rhythm control of new-onset atrial fibrillation in noncardiac, critically ill adults.
DATA SOURCE:Citations identified from an electronic search of Medline, the Cochrane register of controlled trials, and Embase databases (1966 to August 2006) were independently reviewed by two investigators.
STUDY SELECTION:All prospective randomized controlled trials evaluating pharmacologic rhythm conversion regimens for new-onset atrial fibrillation in (noncardiac surgery) critically ill adult patients were included. The primary end point was atrial fibrillation resolution.
DATA EXTRACTION:Using a standardized data extraction form, data related to study design, population characteristics, pharmacologic intervention, and outcome measures were collected.
DATA SYNTHESIS:Four trials met inclusion criteria from 1995 citations screened. Of the 143 evaluable patients in these trials 89 (76%) had atrial fibrillation while the remaining ones had other atrial tachyarrhythmias. Drugs evaluated for rhythm conversion included amiodarone (n = 26), procainamide (n = 14), magnesium (n = 18), flecainide (n = 15), esmolol (n = 28), verapamil (n = 15), and diltiazem (n = 27). The definition of treatment success ranged from conversion within 1 hr to conversion within 24 hrs. No study evaluated maintenance of conversion, and one study included hemodynamically unstable patients. Lack of methodologic homogeneity prevented any pooled analysis.
CONCLUSIONS:Using the current published literature, we cannot recommend a standard treatment for atrial fibrillation in noncardiac critically ill adult patients. Clinical trials evaluating rhythm conversion in critically ill populations outside of cardiac surgery are lacking. Further trials that address goals of care in hemodynamically stable and unstable patients and utilize standardized definitions of successful cardioversion are required.
OBJECTIVE:To determine the effect of a low-calorie parenteral nutrition (PN) regimen on the incidence and severity of hyperglycemia and insulin requirements.
DESIGN:Prospective, randomized, clinical ...trial.
SETTING:Urban, university-affiliated, level-I trauma center.
PATIENTS:Consecutive surgical patients requiring PN.
INTERVENTIONS:Patients were randomized to receive either a low-calorie PN formulation (20 nonprotein kilocalories per kg per day) or a standard PN formulation (30 nonprotein kilocalories per kg per day). Lipid-derived calories were standardized to 1000 kilocalories three times weekly for all patients; consequently, the number of calories varied only by the amount of carbohydrate administered. Protein requirements were individualized on the basis of estimated metabolic stress. Hyperglycemia was defined as a blood glucose level ≥200 mg/dL.
MEASUREMENTS AND MAIN RESULTS:Forty patients were evaluated (low-calorie PN, n = 20; standard PN, n = 20). Demographics of the two groups were similar. The incidence of hyperglycemic events was significantly lower in the low-calorie group (0% 0–0.5 vs. 33.1% 0–58.4; p = .001. Additionally, the severity of hyperglycemia was also lower in the low-calorie group (mean glucose area under the curve = 118 ± 22 mg·hr/dL vs. 172 ± 44 mg·hr/dL; p < .001). This resulted in lower average daily insulin requirements (0 0–0 units vs. 10.9 0–25.6 units; p < .001.). The only predictor of hyperglycemia was a dextrose administration rate >4 mg/kg/min.
CONCLUSIONS:Administration of a low-calorie PN formulation resulted in fewer and less-severe hyperglycemic events and lower insulin requirements. PN regimens should not exceed a dextrose administration rate of 4 mg/kg/min to avoid hyperglycemic events.
Purpose
The incidence of febrile neutropenia (FN) in adults with castrate-resistant metastatic prostate cancer (mCRPC) receiving docetaxel in real-world settings has not been well studied since the ...expanded role of hormonal treatments. The study objective was to determine the incidence of FN and neutropenia among adults with mCRPC receiving docetaxel. Secondary objectives were to quantify outcomes of patients who develop FN and to identify predictors for FN in this population.
Methods
A single-center retrospective cohort study was conducted which included adults with mCRPC receiving docetaxel at the Ottawa Hospital over a 5-year period. Charts were reviewed to collect clinical data to determine the incidence of FN and neutropenia. A multiple logistic regression was used to identify predictors of FN.
Results
In patients receiving docetaxel for mCRPC, the incidence of FN and neutropenia was 34/137 (25%) and 45/137 (33%), respectively. Among 34 patients who developed FN, 94% required hospitalization for FN for a mean of 5 days (± 2.8) and 6% died. Following FN, 53% required at least 1 treatment delay and 71% had at least 1 dose reduction. Age category (OR 2.025, 95% CI 1.13–3.627) and presence of multiple comorbidities (OR 1.466, 95% CI 1.01–2.258) increased the risk of FN.
Conclusion
The incidence of FN and neutropenia in the clinical setting in patients receiving docetaxel for mCRPC is higher than previously reported and high enough to consider primary prophylaxis with granulocyte colony stimulating factors in high-risk groups. Age and multiple comorbidities were identified as risk factors.
Critically ill patients with sepsis admitted to the intensive care unit (ICU) often present with or develop renal dysfunction requiring renal replacement therapy (RRT) in addition to antimicrobial ...therapy. While early and appropriate antimicrobials for sepsis have been associated with an increased probability of survival, adequate dosing is also required in these patients. Adequate dosing of antimicrobials refers to dosing strategies that achieve serum drug levels at the site of infection that are able to provide a microbiological and/or clinical response while avoiding toxicity from excessive antibiotic exposure. Therapeutic drug monitoring (TDM) is the recommended strategy to achieve this goal, however, TDM is not routinely available in all ICUs and for all antimicrobials. In the absence of TDM, clinicians are therefore required to make dosing decisions based on the clinical condition of the patient, the causative organism, the characteristics of RRT, and an understanding of the physicochemical properties of the antimicrobial. Pharmacokinetics (PK) of antimicrobials can be highly variable between critically ill patients and also within the same patient over the course of their ICU stay. The initiation of RRT, which can be in the form of intermittent hemodialysis, continuous, or prolonged intermittent therapy, further complicates the predictability of drug disposition. This variability highlights the need for individualized dosing. This review highlights the practical considerations for the clinician for antimicrobial dosing in critically ill patients receiving RRT.
Allergic and hypersensitivity reactions in the intensive care unit Kanji, Salmaan; Chant, Clarence
Critical care medicine,
2010-June, Volume:
38 Suppl, Identification and Prevention of Common Adverse Drug Events in the Intensive Care Unit, Issue:
6 Suppl
Journal Article
Peer reviewed
Hypersensitivity reactions are defined as immunologically based adverse reactions to chemicals or medicinal agents. These reactions are common in the intensive care unit and can present as a simple, ...mildly symptomatic rash or as life-threatening anaphylactic reactions. Hypersensitivity reactions have traditionally been classified as types I to IV reactions based on the underlying immune mechanisms, although the clinical relevance of the classification is unclear, and new subtypes to this system have been recently proposed. Given the immunologic and often unpredictable nature of these reactions, avoidance or prevention is not a feasible option. Therefore, management has primarily consisted of withdrawal of potential offending agents, supportive therapy, symptomatic management, and, in some specific examples, targeted pharmacotherapy. This article outlines the background and types of hypersensitivity reactions and provides descriptions and management strategies when applicable to common types of hypersensitivity reactions encountered in the intensive care unit.
To determine the association between non-adherence to long term chronic obstructive pulmonary disease (COPD) medications and COPD related emergency department (ED) visits and hospitalizations in ...patients with incident COPD, utilizing time varying measures of adherence as well as accounting for time-varying confounding impacted by prior adherence.
We conducted a population-based retrospective cohort study between 2007–2017 among individuals aged 66 years and older with incident COPD using multiple linked administrative health databases from the province of Ontario, Canada. Adherence to COPD medications was measured using time varying proportion of days covered based on insurance claims for medications dispensed at community pharmacies. The parametric g-formula was used to assess the association between time-varying adherence (in the last 90-days) to COPD medications and risk of COPD related hospitalizations and ED visits while accounting for time varying confounding by COPD severity.
Overall, 60,251 individuals with incident COPD were included; mean age was 76 (SD 7) and 59% were male. Mean adherence over the entire follow-up was 23% (SD 0.3). There were 7248 (12%) COPD related ED visits (2.8 events per 100 person years PY) and 9188 (15%) COPD related hospitalizations (3.5 events per 100 PY). Compared to those with 0% 90-day adherence, those with adherence between 1–33% had a 19% decreased risk of COPD related ED visits (adjusted risk ratioaRR:0.81, 95% confidence interval CI:0.78–0.83), those with adherence between 34%−67% had a 18% decreased risk (aRR: 0.82, 95% CI: 0.77–0.85) while those with 68%−100% 90-day adherence had a 63% increased risk of COPD related ED visits (aRR: 1.63, 95% CI: 1.47–1.78). Nearly identical results were obtained for COPD specific hospitalizations.
After accounting for time varying confounding by COPD severity, the highest time varying 90-days adherence was associated with an increased risk of both COPD related ED visits and hospitalizations compared to the lowest adherence categories. Differences in COPD severity between adherence categories, perception of need for medication management in the higher adherence categories, and potential residual confounding makes it difficult to disentangle the independent effects of adherence from the severity of the condition itself.
Background
Recognition and management of adverse events (AEs) associated with immune checkpoint inhibitor (ICI) use by cancer patients requires expertise from multiple disciplines. Greater awareness ...of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.
Objective
The primary objective of this overview of systematic reviews was to synthesize and consolidate systematic review evidence describing the incidence proportion and severity of AEs associated with various ICI therapies across different cancers.
Methods
A systematic literature search of four databases was conducted to identify systematic reviews that describe the incidence proportion and severity of AEs related to ICI therapy in cancer patients. A systematic review was eligible if it included adults with cancer; on ICI alone or in combination with another ICI, chemotherapy, or targeted therapy; severity (graded according to the Common Terminology Criteria for Adverse Events) and incidence proportion of AEs and whether it reported its eligibility criteria. AEs of interest were identified through an iterative ranking exercise by key stakeholders and knowledge users. Extraction of PICOTTS elements and quality indicators (AMSTAR-2) were used to manage overlap of primary studies across systematic reviews at the outcome level. Cancer subtypes were mapped to drug class and AE severity.
Results
Overall, 129 systematic reviews met the inclusion criteria for data mapping. Systematic reviews reported incidence proportions for more than 76 AEs, of which 34 were identified as AEs of interest. After overlap assessment, 65 systematic reviews were chosen for data extraction. The three AEs with the highest median incidence were fatigue (18.3%, interquartile range IQR 15.0–28.0%), diarrhea (15.3%, IQR 9.7–29.2%) and rash (14.4%, IQR 10.3–19.2%). The three AEs (high-grade) with the highest median incidence were diarrhea (1.5%, IQR 1.2–6.0%), colitis (1.3%, IQR 0.6–6.1%) and neutropenia (1.2%, IQR 0.4–3.3%). Incidence proportions of high-grade AEs were often considerably lower than all-grade AEs and combination therapy (ICI combinations or combinations of ICI with chemotherapy or targeted therapy) was responsible for some of the highest incidence proportions regardless of AE. Rare AEs and certain cancer subtypes were not well reported.
Conclusions
Early recognition of AEs associated with ICIs requires expertise from diverse specialists, not just oncologists. Greater awareness of potential AEs may result in earlier recognition, appropriate management, and better patient outcomes.
PROSPERO Registration
CRD42021231593.
PDF
