Douglas N. Fish

ISPD PERITONITIS RECOMMENDATIONS: 2016 UPDATE ON PREVENTION AND TREATMENT

Abstract Peritonitis is a common and serious complication of peritoneal dialysis (PD). Although less than 5% of peritonitis episodes result in death, peritonitis is the direct or major contributing cause of death in around 16% of PD patients (1-6). In addition, severe or prolonged peritonitis leads to structural and functional alterations of the peritoneal membrane, eventually leading to membrane failure. Peritonitis is a major cause of PD technique failure and conversion to long-term hemodialysis (1,5,7,8). Recommendations under the auspices of the International Society for Peritoneal Dialysis (ISPD) were first published in 1983 and revised in 1993, 1996, 2000, 2005, and 2010 (9-14). The present recommendations are organized into 5 sections: 1. Peritonitis rate 2. Prevention of peritonitis 3. Initial presentation and management of peritonitis 4. Subsequent management of peritonitis 5.

Patient-Level Medication Regimen Complexity Across Populations With Chronic Disease

BACKGROUNDnExpected treatment effectiveness from medications can be diminished due to suboptimal adherence. Medication nonadherence has been linked to pill burden from the quantity of medications; however, medication regimens with similar quantities of medications vary in complexity due to multiple dosage forms, frequency of dosing, and additional usage directions. Thus, a simple medication count ignores medication regimen complexity, especially as it pertains to a patient-level perspective that includes prescription and over-the-counter medications. A gap exists in the study of a patient-level medication regimen complexity metric across disease-specific populations.nnnOBJECTIVEnThe goal of this study was to implement the quantitative Medication Regimen Complexity Index (MRCI) at the patient level in defined populations with chronic disease (geriatric depression, HIV, diabetes mellitus, and hypertension). Patient-level medication regimen complexity included all prescribed medications and over-the-counter medications documented in the electronic medication list.nnnMETHODSnUsing electronic medical records at the University of Colorado Hospital ambulatory clinics, we sampled 4 retrospective cohorts of adult patients in active care in 2011 with a qualifying medical diagnosis and prescribed disease-specific medication. Samples were randomly selected from all qualifying patients; de-identified information was coded using the MRCI.nnnRESULTSnCohort-defining disease-specific prescription medications (eg, antidepressants for the depression-defined cohort) contributed <20% to the total patient-level complexity MRCI score; the MRCI score was dominated by complexity associated with all other prescription medications. Within disease-specific cohorts, MRCI scores differentiated patients with the highest and lowest medication counts, comorbidity counts, and the Charlson comorbidity index scores. For example, geriatric depression patients had a highest quartile mean MRCI score of 41 and a lowest quartile mean MRCI score of 13. Between disease-specific cohorts, high and low MRCI scores differed because each cohort had its own MRCI ranges. For example, highest quartile MRCI scores varied from a mean MRCI score of 41 (geriatric depression) to 30 (hypertension); lowest quartile scores ranged from a mean MRCI score of 7 (hypertension and HIV) to 13 (geriatric depression).nnnCONCLUSIONSnMRCI components of dosing frequency and prescribed medications outside of the cohort-defining disease medications contributed the most to the patient-level scores. Thus, chronic disease management programs may want to consider all medications that patients are taking and examine ways to reduce complexity, such as reducing multiple dosing frequencies when possible. MRCI scores differentiated high and low patient-level complexity measures, representing possible utility as a prospective tool to identify target patients for intervention. Future work includes simplifying the MRCI and enhancing the scores with medication risk factors, as well as explicitly linking to adherence and health services.

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.

Patient-Level Medication Regimen Complexity in Patients With HIV

Background: Patients with HIV often have multiple medications besides antiretrovirals (ARV). Medication regimen complexity—formulations, dosing frequencies, and additional directions—expands pill burden by considering self-care demands. Studies show an inverse association between ARV adherence and medication complexity for ARVs only. Patient-level medication regimen complexity beyond ARV complexity is unknown. Objective: To measure and characterize Patient-level Medication Regimen Complexity Index (pMRCI) and Antiretroviral Medication Regimen Complexity Index (ARCI) for patients in 2 HIV clinics. We hypothesized that an all-medication complexity metric will exceed disease-state-defined complexity metrics; for ARVs only, the pMRCI score will be smaller than the ARCI score by capturing fewer features of regimens. Associations between complexity and adherence were not assessed. Method: Electronic records supplied a retrospective, random sample of adult patients with HIV; medication lists were used to code the pMRCI (n=200). A random subsample (n=66) was coded using ARCI for ARV regimens only. Result: Medication counts ranged from 1 to 27; pMRCI scores ranged from 2 to 67.5. ARVs contributed roughly 25% to the pMRCI; other prescriptions contributed about 66%. Dosing frequency made the largest contribution of all components (62%) to the pMRCI. For ARVs, pMRCI and ARCI scores did not differ statistically. Conclusion: Unique dosing frequencies raised complexity and may provide opportunities for intervention. Other prescriptions drove pMRCI scores, suggesting that HIV management programs should review all medications. A patient-level approach added value to understanding the role of medications in patient complexity; future work can assess association of pMRCI with adherence and patient outcomes.

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.