Tyree H. Kiser

Management of Extravasation Injuries: A Focused Evaluation of Noncytotoxic Medications

Extravasations are common manifestations of iatrogenic injury that occur in patients requiring intravenous delivery of known vesicants. These injuries can contribute substantially to patient morbidity, cost of therapy, and length of stay. Many different mechanisms are behind the tissue damage during extravasation injuries. In general, extravasations consist of four different subtypes of tissue injury: vasoconstriction, osmotic, pH related, and cytotoxic. Recognition of high‐risk patients, appropriate cannulation technique, and monitoring of higher risk materials remain the standard of care for the prevention of extravasation injury. Prompt interdisciplinary action is often necessary for the treatment of extravasation injuries. Knowledge of the mechanism of extravasation‐induced tissue injury, agents for reversal, and appropriate nonpharmacologic treatment methods is essential. The best therapeutic agent for treatment of vasopressor extravasation is intradermal phentolamine. Topical vasodilators and intradermal terbutaline may provide relief. Intradermal hyaluronidase has been effective for hyperosmotic extravasations, although its use largely depends on the risk of tissue injury and the severity of extravasation. Among the hyperosmotic agents, calcium extravasation is distinctive because it may present as an acute tissue injury or may possess delayed clinical manifestations. Extravasation of acidic or basic materials can produce significant tissue damage. Phenytoin is the prototypical basic drug that causes a clinical manifestation known as purple glove syndrome (PGS). This syndrome is largely managed through preventive and conservative treatment measures. Promethazine is acidic and can cause a devastating extravasation, particularly if administered inadvertently through the arteriolar route. Systemic heparin therapy remains the accepted treatment option for intraarteriolar administration of promethazine. Overall, the evidence for managing extravasations due to noncytotoxic medications is nonexistent or limited to case reports. More research is needed to improve knowledge of patient risk, prompt recognition of the extravasation, and time course for tissue injury, and to develop prevention and treatment strategies for extravasation injuries.

Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy

IntroductionIntravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50xa0ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.MethodsThis prospective, open-label pharmacokinetic study enrolled patients >18xa0years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5xa0days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.ResultsTen patients (meanu2009±u2009standard deviation (SD)) 53u2009±u200911xa0years old, 50% male, 81u2009±u200914xa0kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5u2009±u20093.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Meanu2009±u2009SD voriconazole and SBECD dosages administered were 8.1u2009±u20092.1xa0mg/kg/day and 129u2009±u200933xa0mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1xa0mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12xa0hours (AUC0-12) (4,484u2009±u20094,368 to 4,553u2009±u20092,880xa0mg*hr/L; Pu2009=u20090.97) were observed after study day 1.ConclusionsCVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.Trial registrationClinicalTrials.gov NCT01101386. Registered 6 April 2010.

A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes.

Introduction: Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD). Methods: This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD. Results: A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients (P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD (P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium (P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients (P = .069). Conclusions: Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the development of delirium and facilitate remembrance of ICU experiences but may lead to manifestations of ASD. Monitoring hypotension is required for both the sedatives. Additional comparative studies focusing on the long-term impact of ICU recall and psychological outcomes are needed.

The impact of genetic polymorphisms, diltiazem, and demographic variables on everolimus trough concentrations in lung transplant recipients

Everolimus (EVR) has inter‐individual pharmacokinetic (PK) variability and a narrow therapeutic index. The study objective was to determine whether genetic polymorphisms, co‐medications, and/or demographic variables accounted for inter‐individual variability in EVR PK in lung transplant recipients (LTxR). LTxR were genotyped for ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T, CYP3A4*1B, CYP3A5*3, CYP2C8*2/*3/*4, and pregnane X receptor (NR1I2) c.44477T>C, c.63396C>T, c.69789A>G polymorphisms. The primary outcome was the difference in dose‐adjusted EVR levels (EVR L/D) between ABCB1 diplotype groups (2 vs. 1 vs. 0 copies of the 1236C/2677G/3435C haplotype). Sixty‐five LTxR were included. There was no significant difference in EVR L/D between ABCB1 CGC diplotype groups (CGC/CGC = 2.4 ± 1.1 [n = 9] vs. CGC/XXX = 2.5 ± 1.7 [n = 36] vs. XXX/XXX = 2.7 ± 1.7 ng/mL per mg/d [n = 20]; p = 0.9). CYP3A5*3, CYP3A4*1B, CYP2C8*3/*4, and NR1I2 polymorphisms were not associated with EVR L/D. EVR L/D was 3.4 ± 1.7 in LTxR receiving diltiazem (DILT) vs. 1.8 ± 1.1 ng/mL per mg/d in LTxR not receiving DILT (p <0.001). Demographic variables, including cystic fibrosis, were not associated with EVR PK. DILT use increased EVR L/D, but selected polymorphisms in ABCB1, CYP3A5, CYP3A4, CYP2C8, and NR1I2 did not affect EVR L/D in LTxR. Genotyping LTxR for these polymorphisms is unlikely to aid clinicians in optimizing EVR therapy.

Evaluation of Early Dexmedetomidine Addition to the Standard of Care for Severe Alcohol Withdrawal in the ICU: A Retrospective Controlled Cohort Study

Purpose: This study evaluated the impact of dexmedetomidine (DEX) administration on benzodiazepine (BZD) requirements in intensive care unit (ICU) patients experiencing alcohol withdrawal syndrome (AWS). Methods: This trial included adults admitted to the ICU for >24 hours for AWS. Early DEX was defined as receiving DEX within 60 hours of hospital admission. The primary outcome was 12-hour BZD requirement from the inflection point or DEX initiation. Secondary outcomes included 24-hour BZD requirements, symptom control, ICU and hospital length of stay, and incidence and duration of mechanical ventilation. Safety outcomes included incidence of bradycardia and hypotension. Results: Twenty patients receiving DEX were matched to 22 control patients. The mean 12-hour change in BZD requirement was significantly different for DEX versus control (−20 vs −8.3 mg, P = .0455) with a trend toward significance at 24 hours (−29.6 vs −11 mg, P = .06). No significant differences were noted in other secondary outcomes. Patients receiving DEX experienced significantly more bradycardia than controls (35% vs 0%, P < .01) but not hypotension. Conclusions: This study suggests DEX is associated with a reduction in BZD requirement when utilized as adjunctive therapy for AWS. A larger prospective trial is needed to evaluate the clinical impact of DEX for AWS.

Intraventricular Daptomycin and Intravenous Linezolid for the Treatment of External Ventricular-Drain—Associated Ventriculitis Due to Vancomycin-Resistant Enterococcus faecium

Objective: To report the successful treatment of external ventricular-drain (EVD)– associated infection due to vancomycin-resistant Enterococcus faecium (VRE) with intraventricular daptomycin and intravenous linezolid. Case Summary: A 64-year-old white male with a complicated medical history was admitted to the neurosurgical unit with Scedosporium apiospermum meningitis and hydrocephalus requiring management with a right and left EVD. On day 28, cerebrospinal fluid cultures from the right EVD grew VRE. Despite initiation of intravenous linezolid, cultures from the right EVD remained positive. Intraventricular daptomycin 5 mg daily was initiated and administered into the right EVD for 7 days. Cerebrospinal fluid was collected from EVD outputs and analyzed for daptomycin concentrations. VRE in cultures from the EVD cleared after 1 day of therapy and no adverse effects were noted. Right and left EVD daptomycin concentrations were discordant throughout therapy by at least a 3-fold difference. First-dose peak and trough daptomycin concentrations in the cerebrospinal fluid were 112.2 and 1.34 μg/mL, respectively, for the right EVD and 37.4 and 0.37 μg/mL, respectively, for the left EVD. Daptomycin accumulation was evident after 3 days of therapy. Discussion: Varying doses and frequencies of intraventricular daptomycin have been reported effective for VRE ventriculitis. Intraventricular drug distribution may not be homogeneous throughout the central nervous system. Therefore, daptomycin minimum inhibitory concentration for VRE, cerebrospinal fluid communication throughout the central nervous system, EVD output, and the potential for drug accumulation should be considered when selecting a dose and frequency. Conclusions: Intraventricular daptomycin may be an option for EVD-associated VRE infections that do not respond to conventional therapy. Intraventricular daptomycin 5 mg is a reasonable initial dose in adults with VRE ventriculitis, based on our experience in this patient.

Evaluation of a Heparin-Calibrated Antifactor Xa Assay for Measuring the Anticoagulant Effect of Oral Direct Xa Inhibitors

The introduction of oral direct anti-Xa anticoagulants apixaban and rivaroxaban has significantly impacted the treatment and prevention of thromboembolic disease. Clinical scenarios exist in which a quantitative assessment for degree of anticoagulation due to these agents would aid management. The purpose of this work was to evaluate the chromogenic antifactor Xa assay calibrated with heparin standards at our institution for assessment of intensity of anticoagulation with rivaroxaban or apixaban in addition to its current use for unfractionated heparin or low-molecular-weight heparin. We also aimed to propose expected steady state peak and trough antifactor Xa activities for these agents based upon dosing regimens approved for nonvalvular atrial fibrillation. Antifactor Xa activity correlated very strongly with apixaban and rivaroxaban concentration in both spiked samples and treated patient plasma samples (r 2 = .99, P < .001). This correlation was observed over a broad range (20-500 ng/mL) of drug concentrations, as sample dilution with pooled normal plasma significantly extended the range of quantitative assessment. Based on drug concentrations previously published in pharmacokinetic studies, the expected steady state peak and trough antifactor Xa activity ranges for apixaban are 1.80 to 2.20 IU/mL and 0.70 to 1.10 IU/mL, respectively. For rivaroxaban, these ranges are 3.80 to 6.20 IU/mL and 0.60 to 1.00 IU/mL, respectively. In conclusion, our findings demonstrate that heparin-calibrated antifactor Xa activity correlates strongly with apixaban and rivaroxaban concentration. The dilution of samples allowed for this correlation to be extended over the majority of on-therapy drug concentrations.

Antithrombotic Therapy in Patients With Thrombocytopenic Cancer: Outcomes Associated With Reduced-Dose, Low-Molecular-Weight Heparin During Hospitalization

Background: Guidelines are discordant concerning management of patients having thrombocytopenia with cancer-associated thrombosis (CAT). Methods: Hospitalized adults with CAT and platelets ≤50 × 109 cells/L were managed with dalteparin 100 units/kg subcutaneously once daily. Comparator patients with CAT and platelets >50 × 109 cells/L were managed with dalteparin 200 units/kg/d. Results: Outcomes of 35 patients with thrombocytopenia (mean platelet count 26 ± 8.3 × 109 cells/L) and 58 comparator patients (mean platelet count 155 ± 75 × 109 cells/L) were evaluated. In all, 2 (5.7%) patients in the thrombocytopenia group and 1 patient (1.9%) in the comparator group experienced new-onset venous thromboembolism (odds ratio 3.31, 95% confidence interval [CI] 0.29-37.90, P = .556). The incidence of bleeding in patients with thrombocytopenia (8.6%) was similar to that in comparator patients (9.4%; risk ratio 0.94, 95% CI 0.37-2.39, P = .607). Conclusion: In hospitalized patients having thrombocytopenia with CAT, reduced-dose low-molecular-weight heparin was generally efficacious.

Weight-based versus set dosing of vancomycin for coronary artery bypass grafting or aortic valve surgery

OBJECTIVESnThis study was undertaken to identify a preferred dosing strategy for patients undergoing coronary artery bypass grafting or valve replacement procedures with cardiopulmonary bypass.nnnMETHODSnPatients undergoing coronary artery bypass grafting, valve replacement surgery, or both were randomly assigned to receive either standard 1-g dosing with vancomycin before and after cardiopulmonary bypass or a single weight-based 20-mg/kg dose before surgery. The primary outcome was the percentage of time plasma concentrations were greater than 15 μg/mL during cardiopulmonary bypass and at surgical closure. Secondary outcomes included concentration of vancomycin in endothoracic tissue after vancomycin infusion, average time patients had vancomycin concentrations greater than 15 μg/mL, and vancomycin plasma and tissue pharmacokinetic parameters.nnnRESULTSnBaseline characteristics were similar between the study dosing group (n = 10) and the standard dosing group (n = 10). From postinfusion to end of bypass, the median percentage of time vancomycin concentrations remained greater than 15 μg/mL was 100% (interquartile range [IQR], 72.6%-100%) for weight-based dosing versus 43.7% (IQR, 28.7%-53.4%) for standard dosing (P = .0005). From postinfusion to surgical closure, the percentage of time vancomycin concentrations remained greater than 15 μg/mL was significantly higher in the weight-based group (100% [IQR, 58.3%-100%] vs 34.6% [IQR, 25.3%-41.6%]; P = .0005). Weight-based dosing increased calculated time with vancomycin concentrations greater than 15 μg/mL and resulted in higher endothoracic tissue vancomycin concentrations.nnnCONCLUSIONSnWeight-based vancomycin dosing before coronary artery bypass grafting or valve replacement results in vancomycin concentrations greater than 15 μg/mL consistently more than does standard 1-g dosing.

A survey of prescriber perceptions about the prevention of stress‐related mucosal bleeding in the intensive care unit

Practices vary between institutions and amongst prescribers regarding when to initiate stress ulcer prophylaxis (SUP), which agent to choose (including doses and frequencies) and rationale, and decisions about escalation or discontinuation of therapy. The purpose of this survey is to evaluate the perceptions of prescribers about risk assessment of stress‐related mucosal bleeding (SRMB) and practice patterns of SUP.