Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF).

BACKGROUND: Therapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates. METHODS: This was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations. RESULTS: A total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs-Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L. CONCLUSIONS: PTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties.

BACKGROUND: Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking. OBJECTIVE: To assess novel metrics of e-consult appropriateness and utility. DESIGN: Retrospective cohort study. SETTING: Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system. PARTICIPANTS: Patients with e-consult requests to 5 specialties-hematology, infectious disease, dermatology, rheumatology, and psychiatry-between October 2017 and November 2018. MEASUREMENTS: The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources ("point-of-care resource test"), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days. RESULTS: Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%). LIMITATION: Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record. CONCLUSION: Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care. PRIMARY FUNDING SOURCE: None.

Vascular access for renal replacement therapy in acute kidney injury: Are nontunneled catheters the right choice?

Renal replacement therapy (RRT) in the setting of acute kidney injury (AKI) is generally provided by either tunneled or nontunneled dialysis catheters (TDCs or NTDCs), used immediately after insertion. Current consensus guidelines suggest using NTDCs rather than TDCs for vascular access in AKI primarily for logistical reasons, including ease of insertion and timeliness. However, there is increasing evidence that, compared to NTDCs, TDCs are associated with fewer complications (mechanical and infectious) and better dialysis delivery. Nevertheless, this evidence must be balanced by the feasibility and practicality of implementing a "TDC-first approach." In this paper, we assess the current evidence base for vascular access choice for AKI requiring RRT. We make the case for increased use of TDCs as first-line vascular access given growing observational evidence for improved patient outcomes; including decreased risk of infection and thrombosis, increased blood flow rates and decreased treatment interruptions, compared to NDTCs. We advocate for further research to test the feasibility and outcomes associated with a TDC-first approach to AKI-RRT access. A TDC-first approach has the potential to improve RRT clinical outcomes and reduce resource utilization and cost.

When to stop renal replacement therapy in anticipation of renal recovery in AKI: The need for consensus guidelines.

There is wide variation in clinical practice regarding timing of discontinuation of renal replacement therapy (RRT) in patients with acute kidney injury (AKI). Prolonged, unnecessary RRT treatment can contribute to length of stay, overall hospital costs, and risk of complications associated with RRT. In addition, prolonged RRT can paradoxically lengthen the time for which the patient remains dialysis-dependent. Well-designed, randomized clinical trials have utilized varied discontinuation criteria specifically related to urine output and creatinine clearance, which impedes the comparison of outcomes from such studies. Other observational studies have attempted to assess the sensitivity and specificity of various criteria for discontinuation of RRT. Whether diuretics influence renal recovery has not been fully elucidated as well. In this article, we propose a starting framework for RRT discontinuation criteria to guide clinicians and clinical researchers. We emphasize the importance of frequent clinical assessment while considering discontinuation of RRT for AKI patients with a creatinine clearance >15 mL/min on a timed urine collection and/or a urine output >400 mL/24 h without diuretics, or >2000 mL/24 h with diuretics. We also discuss newer biomarkers, methods of GFR estimation, and imaging techniques that may play a greater role in the future. Clinical trials objectively comparing the success of RRT discontinuation criteria will be required to provide high-quality evidence for our proposed guidelines.

Outcomes of kidney transplantation in Alport syndrome compared with other forms of renal disease.

INTRODUCTION: Alport syndrome is an inherited renal disease characterized by hematuria, renal failure, hearing loss and a lamellated glomerular basement membrane. Patients with Alport syndrome who undergo renal transplantation have been shown to have patient and graft survival rates similar to or better than those of patients with other renal diseases. METHODS: In this national case series, based in Beaumont Hospital Dublin, we studied the cohort of patients who underwent renal transplantation over the past 33 years, recorded prospectively in the Irish Renal Transplant Registry, and categorized them according to the presence or absence of Alport syndrome. The main outcomes assessed were patient and renal allograft survival. RESULTS: Fifty-one patients diagnosed with Alport syndrome in Beaumont Hospital received 62 transplants between 1982 and 2014. The comparison group of non-Alport patients comprised 3430 patients for 3865 transplants. Twenty-year Alport patient survival rate was 70.2%, compared to 44.8% for patients with other renal diseases (p = .01). Factors associated with patient survival included younger age at transplantation as well as differences in recipient sex, donor age, cold ischemia time, and episodes of acute rejection. Twenty-year graft survival was 46.8% for patients with Alport syndrome compared to 30.2% for those with non-Alport disease (p = .11). CONCLUSIONS: Adjusting for baseline differences between the groups, patients with end-stage kidney disease (ESKD) due to Alport syndrome have similar patient and graft survival to those with other causes of ESKD. This indicates that early diagnosis and management can lead to favorable outcomes for this patient cohort.

Zonisamide-induced distal renal tubular acidosis and critical hypokalaemia.

A woman in her 20s presented with rapidly progressive muscle weakness and a 1-month preceding history of fatigability, nausea and vomiting. She was found to have critical hypokalaemia (K+ 1.8 mmol/L), a prolonged corrected QT interval (581 ms) and a normal anion gap metabolic acidosis (pH 7.15) due to zonisamide-induced distal (type 1) renal tubular acidosis. She was admitted to the intensive care unit for potassium replacement and alkali therapy. Clinical and biochemical improvement ensued, and she was discharged after a 27-day inpatient stay.

Post-Intensive Care COVID Survivorship Clinic: A Single-Center Experience.

Patients discharged from the ICU post-COVID-19 pneumonitis may experience long-term morbidity related to their critical illness, the treatment for this and the ICU environment. The aim of this study was to characterize the cognitive, psychologic, and physical consequences of COVID-19 in patients admitted to the ICU and discharged alive. DESIGN: Prospective cohort study. SETTING: Post-intensive care syndrome (PICS) follow-up clinic at Tallaght University Hospital, a tertiary referral center with a 16-bed mixed medical-surgical ICU, including critical care physicians, a psychologist, a physiotherapist, and a research nurse. PATIENTS: Patients who had been admitted to the ICU in our tertiary referral center with COVID-19 pneumonitis 6 months earlier. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 22 patients attended the 6-month PICS follow-up clinic following admission to ICU with COVID-19 pneumonitis. Mean grip strength was low at the 6-month follow-up at 24.1 pounds (sd 9.8) with a minimally active median metabolic equivalent (MET) of 970 METs/wk (interquartile range, 0-7,794 METs/wk). Only 59% of patients were independent with regard to their activities of daily living. Eight of 14 patients (57%) had returned to work by 6 months post-ICU discharge. Their mean Intensive Care Psychological Assessment Tool (IPAT) score was 6.6 (sd 4.6) with a Post-Traumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5th Edition (PCL-5) score of 21.1 (sd 17.5) and a mean Montreal Cognitive Assessment (MoCA) score of 24 (sd 8.4); suggestive of mild cognitive impairment. In a multivariable regression model, only Acute Physiology and Chronic Health Evaluation II score was significantly independently associated with MoCA score as a cognitive PICS outcome (beta-coefficient, -1.6; se, 0.6; p = 0.04). None of the predictor variables were significantly independently associated with IPAT and PCL-5 as psychologic outcomes, nor with International Physical Activity Questionnaire-Short Form as a physical PICS outcome. CONCLUSIONS: In this single-center prospective cohort study, we found that patients have a high burden of physical and psychologic impairment at 6 months following ICU discharge post-COVID-19 pneumonitis; in many cases requiring specialist referrals for long-term input. We advocate for increased resources for this much needed follow-up multidisciplinary intervention for an ever-growing population of patients.

Comparison of hemodynamic instability among continuous, intermittent and hybrid renal replacement therapy in acute kidney injury: A systematic review of randomized clinical trials.

PURPOSE: To compare hemodynamic instability during continuous, intermittent and hybrid renal replacement therapy (RRT) in critically ill patients, and its association with renal recovery and mortality. MATERIALS AND METHODS: The search was conducted in accordance with the PRISMA guidelines which was registered at the PROSPERO Database (CRD42018086504). Randomized clinical trials (RCTs) involving critically ill patients with acute kidney injury (AKI) treated with continuous, intermittent or hybrid RRT were included. The search was performed using PubMed, Embase and Cochrane databases. RESULTS: Out of 3442 citations retrieved, 12 RCTs were included in the systematic analysis, representing 1419 patients. Most studies (n = 8) did not report differences in hemodynamic parameters across different RTT modalities. The incidence of hypotensive episodes varied from 5 to 60% among the studies. Punctual differences on heart rate and blood pressure were observed among studies. However, studies presented high heterogeneity in terms of outcome definitions and measurement, thus making the conduction of meta-analysis impossible. CONCLUSIONS: There is very few information available regarding hemodynamic tolerance of renal replacement therapy methods. A better standardization of hemodynamic tolerance and further reports are needed before conclusions can be drawn.

Controlled Study of Decision-Making Algorithms for Kidney Replacement Therapy Initiation in Acute Kidney Injury.

BACKGROUND AND OBJECTIVES: AKI requiring KRT is associated with high mortality and utilization. We evaluated the use of an AKI Standardized Clinical Assessment and Management Plan (SCAMP) on patient outcomes, including mortality, hospital length of stay, and intensive care unit length of stay. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a 12-month controlled study in the intensive care units of a large academic tertiary medical center. We alternated use of the AKI-SCAMP with use of a "sham" control form in 4- to 6-week blocks. The primary outcome was risk of inpatient mortality. Prespecified secondary outcomes included 30- and 60-day mortality, hospital length of stay, and intensive care unit length of stay. Generalized estimating equations were used to estimate the effect of the AKI-SCAMP on mortality and length of stay. RESULTS: There were 122 patients in the AKI-SCAMP group and 102 patients in the control group. There was no significant difference in inpatient mortality associated with AKI-SCAMP use (41% versus 47% control). AKI-SCAMP use was associated with significantly reduced intensive care unit length of stay (mean, 8; 95% confidence interval, 8 to 9 days versus mean, 12; 95% confidence interval, 10 to 13 days; P<0.001) and hospital length of stay (mean, 25; 95% confidence interval, 22 to 29 days versus mean, 30; 95% confidence interval, 27 to 34 days; P=0.02). Patients in the AKI-SCAMP group were less likely to receive KRT in the context of physician-perceived treatment futility than those in the control group (2% versus 7%; P=0.003). CONCLUSIONS: Use of the AKI-SCAMP tool for AKI KRT was not significantly associated with inpatient mortality, but was associated with reduced intensive care unit length of stay, hospital length of stay, and use of KRT in cases of physician-perceived treatment futility. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Acute Kidney Injury Standardized Clinical Assessment and Management Plan for Renal Replacement Initiation, NCT03368183. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_02_07_CJN02060221.mp3.

Hypokalaemic paralysis as the initial clinical presentation of Sjogren's syndrome induced distal renal tubular acidosis.

A 41-year-old woman presented by ambulance with a 1-day history of new-onset paralysis and nausea and vomiting ongoing for 48 hours. She had no history of any similar episodes. Biochemical analysis showed profound hypokalaemia with a non-anion gap metabolic acidosis. Her initial serum chloride was within the normal range. She had significant electrocardiographic changes on admission with ST depression, U waves and a prolonged QT interval. Urinary anion gap supported the diagnosis of a distal renal tubular acidosis. Subsequent connective tissue disease serology confirmed previously undiagnosed Sjogren's syndrome. Successful recovery for this patient required multidisciplinary input from the intensive care, nephrology and neurology teams.

Hypocalcemia is associated with hypotension during CRRT: A secondary analysis of the Acute Renal Failure Trial Network Study.

PURPOSE: We investigated the effect of potentially modifiable continuous renal replacement therapy (CRRT)-related treatment factors on the risk of severe hypotension. MATERIALS AND METHODS: We carried out a secondary statistical analysis of the Acute Renal Failure Trial Network (ATN) trial. The primary exposures of interest were CRRT treatment dose, ultrafiltration rate, blood flow rate, ionized calcium level and type of anti-coagulation used. The primary outcome was severe hypotension, defined as vasopressor-inotropic score > 18 and calculated based on treatment doses of vasopressor and inotropic agents. RESULTS: Of 1124 individuals enrolled in the ATN Trial, 786 were managed with CRRT. 265/786 (33.7%) patients experienced severe hypotension during the trial. A serum ionized calcium <1.02 mmol/l was associated with a higher risk of severe hypotension compared to a serum calcium >1.02 mmol/l (hazard ratio 2.9; 95% CI 1.5-5.7). There was no significant difference in the risk of hypotension associated with other CRRT treatment factors. CONCLUSIONS: Of the CRRT treatment factors studied, hypocalcemia with a serum ionized calcium <1.02 mmol/l was associated with a significantly increased risk of treatment-associated hypotension. Further studies will be required to assess whether treatment targets for serum calcium improve the risk of hypotension during CRRT.

The Impact of Outpatient Laboratory Alerting Mechanisms in Patients with AKI.

Background: AKI is an abrupt decrease in kidney function associated with significant morbidity and mortality. Electronic notifications of AKI have been utilized in patients who are hospitalized, but their efficacy in the outpatient setting is unclear. Methods: We evaluated the effect of two outpatient interventions: an automated comment on increasing creatinine results (intervention I; 6 months; n=159) along with an email to the provider (intervention II; 3 months; n=105), compared with a control (baseline; 6 months; n=176). A comment was generated if a patient's creatinine increased by >0.5 mg/dl (previous creatinine ≤2.0 mg/dl) or by 50% (previous creatinine >2.0 mg/dl) within 180 days. Process measures included documentation of AKI and clinical actions. Clinical outcomes were defined as recovery from AKI within 7 days, prolonged AKI from 8 to 89 days, and progression to CKD with in 120 days. Results: Providers were more likely to document AKI in interventions I (P=0.004; OR, 2.80; 95% CI, 1.38 to 5.67) and II (P=0.01; OR, 2.66; 95% CI, 1.21 to 5.81). Providers were also more likely to discontinue nephrotoxins in intervention II (P<0.001; OR, 4.88; 95% CI, 2.27 to 10.50). The median time to follow-up creatinine trended shorter among patients with AKI documented (21 versus 42 days; P=0.11). There were no significant differences in clinical outcomes. Conclusions: An automated comment was associated with improved documented recognition of AKI and the additive intervention of an email alert was associated with increased discontinuation of nephrotoxins, but neither improved clinical outcomes. Translation of these findings into improved outcomes may require corresponding standardization of clinical practice protocols for managing AKI.

Intensity of Renal Replacement Therapy and Duration of Mechanical Ventilation: Secondary Analysis of the Acute Renal Failure Trial Network Study.

BACKGROUND: Randomized clinical trials have failed to show benefit from increasing intensity of renal replacement therapy (RRT) for acute kidney injury, but continue to be frequently used. In addition, intensive RRT is associated with an increase in adverse events potentially secondary to small solute losses, such as phosphate. We hypothesized that, compared with less-intensive RRT, intensive RRT would lead to longer duration of mechanical ventilation. RESEARCH QUESTION: Does more-intensive renal replacement therapy in critically ill patients with acute kidney injury increase time to extubation from mechanical ventilation when compared with less-intensive therapy? STUDY DESIGN AND METHODS: The Acute Renal Failure Trial Network study was a randomized multicenter trial of more-intensive (hemodialysis or sustained low-efficiency dialysis six times per week or continuous venovenous hemodiafiltration at 35 mL/kg per hour) vs less-intensive (hemodialysis or sustained low-efficiency dialysis three times per week or continuous venovenous hemodiafiltration at 20 mL/kg per hour) RRT in critically ill patients with acute kidney injury. Of 1124 patients, 907 who were supported by mechanical ventilation on study initiation were included in this Cox-proportional hazards analysis. The primary outcome was the time to first successful extubation off mechanical ventilation. RESULTS: Patients who were assigned randomly to more-intensive RRT had a 33.3% lower hazard rate of successful extubation (hazard ratio, 0.67; 95% CI, 0.52-0.88; P < .001) when compared with patients who were assigned to less-intensive RRT. Patients who were assigned to more-intensive RRT had, on average, 2.07 ventilator-free days, compared with 3.08 days in those who were assigned to less-intensive RRT (P < .001) over 14 days from start of the study. INTERPRETATION: Critically ill mechanically ventilated patients who were assigned randomly to more-intensive RRT had longer duration of mechanical ventilation compared with those who were assigned to less-intensive RRT. The reasons for this, such as excessive phosphate loss from more-intensive RRT, deserve further study to optimize the safety and effectiveness of CRRT delivery. This was a post hoc analysis of the Acute Renal Failure Trial Network study; clinical trial registration of the original trial is NCT00076219.

Accelerated Oxalosis Contributing to Delayed Graft Function after Renal Transplantation.

Hyperoxaluria is an important and underrecognized cause for allograft dysfunction and loss after transplantation. It is potentially treatable if recognized in a timely fashion. Research is ongoing to expand the array of therapeutic options available to treat this. We present a case of a 59-year-old gentleman who underwent deceased donor renal transplantation that was complicated by delayed graft function necessitating continuation of renal replacement therapy. His initial biopsy showed extensive acute tubular necrosis with associated peritubular capillaritis and interstitial nephritis and oxalate crystals in several tubules. Despite receiving methylprednisolone to treat moderate acute cellular rejection, he remained dialysis dependent with minimal urine output. An interval renal allograft biopsy revealed residual acute tubular necrosis with extensive oxalate crystals now visible in many tubules. His plasma oxalate level was concurrently elevated to 19.3 µmol/L (reference range ≤ 1.9 µmol/L). He commenced calcium citrate to manage his hyperoxaluria and ultimately became dialysis independent at 3 weeks after transplantation. This case provides an important example of accelerated oxalate nephropathy as an underappreciated contributor to delayed graft function after renal transplantation. Our accompanying discussion provides an update on current therapeutic measures for managing this challenging condition.