Importance of Endotoxin Clearance in Endotoxemic Septic Shock: An Analysis From the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized Controlled Trial of Adults Treated for Endotoxemic Septic Shock (EUPHRATES) Trial.

To investigate the relationship between survival and treatment-related reduction in endotoxin activity for patients in the Evaluating Use of PolymyxinB Hemoperfusion in a Randomized controlled trial of Adults Treated for Endotoxemia and Septic shock trial with baseline endotoxin activity assay greater than or equal to 0.60 to less than 0.90 units. DESIGN: Post hoc analysis of a multicenter randomized controlled clinical trial. SETTING: Fifty-five tertiary hospitals in North America. PATIENTS: Patients with septic shock and endotoxin activity assay level greater than or equal to 0.60 to less than 0.90 and multiple organ dysfunction syndrome greater than 9. INTERVENTIONS: Two polymyxin B hemoperfusion treatments or Sham. MEASUREMENTS AND MAIN RESULTS: One-hundred ninety-four patients were included (88 polymyxin B and 106 Sham). We evaluated the impact of changes in endotoxin activity assay based on comparison to the median reduction from baseline to day 3 and a second method where a target post-treatment endotoxin activity assay level (day 3) was established. The population median reduction in endotoxin activity assay level was 10.4%. In patients with a greater than median reduction, there was trend toward lower mortality with polymyxin B (17.1% vs 33.3%; p = 0.07) and a significant increase in mechanical ventilation-free days (20 vs 13.5; p = 0.04). The pressure adjusted heart rate showed a significant improvement in the polymyxin B group (p = 0.02). For patients who achieved an endotoxin activity assay of less than 0.65 at day 3, the polymyxin B treated group had a trend toward a mortality reduction compared to Sham (16% vs 33%;p = 0.06) and a significant increase in ventilation-free day (20 vs 16; p = 0.05). Kaplan-Meier analysis showed a 17% reduction in mortality with polymyxin B (p = 0.04). CONCLUSIONS: These findings suggest that reducing endotoxin activity assay levels with polymyxin B as measured by comparison to a median reduction or when a treatment target is established, may result in improvements in mortality and organ function outcomes. This article is the first to report endotoxin activity assay measurements in response to polymyxin B use versus Sham in patients with septic shock and elevated endotoxin activity assay. These findings are considered to be hypothesis generating and will need to be prospectively validated.

Renal Replacement Therapy in the ICU.

OBJECTIVES: The incidence of acute kidney injury in critically ill patients is increasing steeply. Acute kidney injury in this setting is associated with high morbidity and mortality. There is no doubt that renal replacement therapy for the most severe forms of acute kidney injury can be life saving, but there are a number of uncertainties about the optimal application of renal replacement therapy for patients with acute kidney injury. The objective of this synthetic review is to present current evidence supporting best practices in renal replacement therapy for critically ill patients with acute kidney injury. DATA SOURCES: We reviewed literature regarding timing of initiation of renal replacement therapy, optimal vascular access for renal replacement therapy in acute kidney injury, modality selection and dose or intensity of renal replacement therapy, and anticoagulation during renal replacement therapy, using the following databases: MEDLINE and PubMed. We also reviewed bibliographic citations of retrieved articles. STUDY SELECTION: We reviewed only English language articles. CONCLUSIONS: Current evidence sheds light on many areas of controversy regarding renal replacement therapy in acute kidney injury, providing a foundation for best practices. Nonetheless, important questions remain to be answered by ongoing and future investigation.

Effect of Targeted Polymyxin B Hemoperfusion on 28-Day Mortality in Patients With Septic Shock and Elevated Endotoxin Level: The EUPHRATES Randomized Clinical Trial.

Importance: Polymyxin B hemoperfusion reduces blood endotoxin levels in sepsis. Endotoxin activity can be measured in blood with a rapid assay. Treating patients with septic shock and elevated endotoxin activity using polymyxin B hemoperfusion may improve clinical outcomes. Objective: To test whether adding polymyxin B hemoperfusion to conventional medical therapy improves survival compared with conventional therapy alone among patients with septic shock and high endotoxin activity. Design, Setting, and Participants: Multicenter, randomized clinical trial involving 450 adult critically ill patients with septic shock and an endotoxin activity assay level of 0.60 or higher enrolled between September 2010 and June 2016 at 55 tertiary hospitals in North America. Last follow-up was June 2017. Interventions: Two polymyxin B hemoperfusion treatments (90-120 minutes) plus standard therapy completed within 24 hours of enrollment (n = 224 patients) or sham hemoperfusion plus standard therapy (n = 226 patients). Main Outcomes and Measures: The primary outcome was mortality at 28 days among all patients randomized (all participants) and among patients randomized with a multiple organ dysfunction score (MODS) of more than 9. Results: Among 450 eligible enrolled patients (mean age, 59.8 years; 177 [39.3%] women; mean APACHE II score 29.4 [range, 0-71 with higher scores indicating greater severity), 449 (99.8%) completed the study. Polymyxin B hemoperfusion was not associated with a significant difference in mortality at 28 days among all participants (treatment group, 84 of 223 [37.7%] vs sham group 78 of 226 [34.5%]; risk difference [RD], 3.2%; 95% CI, -5.7% to 12.0%; relative risk [RR], 1.09; 95% CI, 0.85-1.39; P = .49) or in the population with a MODS of more than 9 (treatment group, 65 of 146 [44.5%] vs sham, 65 of 148 [43.9%]; RD, 0.6%; 95% CI, -10.8% to 11.9%; RR, 1.01; 95% CI, 0.78-1.31; P = .92). Overall, 264 serious adverse events were reported (65.1% treatment group vs 57.3% sham group). The most frequent serious adverse events were worsening of sepsis (10.8% treatment group vs 9.1% sham group) and worsening of septic shock (6.6% treatment group vs 7.7% sham group). Conclusions and Relevance: Among patients with septic shock and high endotoxin activity, polymyxin B hemoperfusion treatment plus conventional medical therapy compared with sham treatment plus conventional medical therapy did not reduce mortality at 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT01046669.

Plasma oxalate levels in prevalent hemodialysis patients and potential implications for ascorbic acid supplementation.

OBJECTIVES: Ascorbic acid (AA) supplementation may increase hemoglobin levels and decrease erythropoiesis-stimulating agent dose requirement in patients with end stage renal disease (ESRD). While plasma AA levels >100µM may be supratherapeutic, levels of at least 30µM may be needed to improve wound healing and levels may need to reach 70µM to optimize erythropoiesis. Of concern, oxalate (Ox), an AA metabolite, can accumulate in ESRD. Historically, if plasma Ox levels remain ≥30µM, oxalosis was of concern. Contemporary hemodialysis (HD) efficiencies may decrease the risk of oxalosis by maintaining pre-HD Ox levels <30µM. This study focuses on the plasma Ox levels in HD patients. DESIGN AND METHODS: A prospective, observational study of 197 HD patients with pre-HD AA levels and pre-HD and post-HD Ox levels. RESULTS: Mean plasma Ox levels decreased 71% during the intradialytic period (22.3±11.1µM to 6.4±3.2µM, P<0.001). In regression analysis, pre-HD plasma AA levels ≤100µM were not associated with a pre-HD plasma Ox level≥30µM, even if ferritin levels were increased. Pre-HD plasma Ox levels ≥20 or ≥30µM were not associated with lower cumulative 4-year survival. CONCLUSIONS: Pre-HD plasma AA levels up to 100µM in HD patients do not appear to be associated with an increased risk of developing secondary oxalosis, as the corresponding pre-HD plasma Ox level appears to be maintained at tolerable levels.

Lactic Acidosis in a Patient with Type 2 Diabetes Mellitus.

Lactic acidosis occurs when lactate production exceeds its metabolism. There are many possible causes of lactic acidosis, and in any given patient, several causes may coexist. This Attending Rounds presents a case in point. Metformin's role in the pathogenesis of lactic acidosis in patients with diabetes mellitus is complex, as the present case illustrates. The treatment of lactic acidosis is controversial, except for the imperative to remedy its underlying cause. The use of sodium bicarbonate to treat the often alarming metabolic derangements may be quite efficacious in that regard but is of questionable benefit to patients. Renal replacement therapies (RRTs) have particular appeal in this setting for a variety of reasons, but their effect on clinical outcomes is untested.

Plasma ascorbic acid concentrations in prevalent patients with end-stage renal disease on hemodialysis.

OBJECTIVE: To determine the prevalence of vitamin C (ascorbic acid [AA]) deficiency in patients with end-stage renal disease, the effect of supplemental AA on plasma AA concentrations, and the extrinsic and intrinsic factors that affect plasma AA concentrations in this patient population. DESIGN: In study 1, we compared the effect of hemodialysis (HD) on plasma AA concentrations between patients with low and high pre-HD AA concentrations. In study 2, we analyzed kinetic and nonkinetic factors for their association with increased plasma AA concentrations in patients on maintenance HD. Study 1 was performed in a single outpatient HD clinic in Cherry Hill, New Jersey. Study 2 was performed in 4 outpatient HD clinics in Southern New Jersey. SUBJECTS AND INTERVENTION: In study 1, we collected plasma samples from 8 adult patients on maintenance HD at various time points around their HD treatment and assayed them for AA concentration. In study 2, we enrolled 203 adult patients and measured pre-HD plasma AA concentrations. We ascertained supplemental AA use and assessed dietary AA intake. MAIN OUTCOME MEASURE: In study 1, plasma AA concentrations were compared during the intradialytic and interdialytic period. In study 2, pre-HD plasma AA concentrations were correlated with supplement use and demographic factors. RESULTS: Study 1 showed that over the course of a single HD treatment, the plasma AA concentration decreased by a mean (±standard deviation) of 60% (±6.6). In study 2, the median pre-HD plasma AA concentration was 15.7 µM (interquartile range, 8.7-66.8) in patients who did not take a supplement and 50.6 µM (interquartile range, 25.1-88.8) in patients who did take a supplement (P < .001). Supplement use, increasing age, and diabetes mellitus were associated with a pre-HD plasma AA concentration ≥30 µM. CONCLUSION: HD depletes plasma AA concentrations, and AA supplementation allows patients to achieve higher plasma AA concentrations.

Pseudo-blood leak? A hemodialysis mystery.

Hydroxocobalamin is a treatment for cyanide toxicity with few side effects. We report a case of a hemodialysis patient whose treatment was compromised by hydroxocobalamin interference with the blood leak detector.

The fallacy of the BUN:creatinine ratio in critically ill patients.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is common in critically ill patients and is associated with a high mortality rate. Pre-renal azotemia, suggested by a high blood urea nitrogen to serum creatinine (BUN:Cr) ratio (BCR), has traditionally been associated with a better prognosis than other forms of AKI. Whether this pertains to critically ill patients is unknown. METHODS: We conducted a retrospective observational study of two cohorts of critically ill patients admitted to a single center: a derivation cohort, in which AKI was diagnosed, and a larger validation cohort. We analyzed associations between BCR and clinical outcomes: mortality and renal replacement therapy (RRT). RESULTS: Patients in the derivation cohort (N = 1010) with BCR >20 were older, predominantly female and white, and more severely ill. A BCR >20 was significantly associated with increased mortality and a lower likelihood of RRT in all patients, patients with AKI and patients at risk for AKI. Patients in the validation cohort (N = 10 228) with a BCR >20 were older, predominantly female and white, and more severely ill. A BCR >20 was associated with increased mortality and a lower likelihood of RRT in all patients and in those at risk for AKI, BUN correlated with age and severity of illness. CONCLUSIONS: A BCR >20 is associated with increased mortality in critically ill patients. It is also associated with a lower likelihood of RRT, perhaps because of misinterpretation of the BCR. Clinicians should not use a BCR >20 to classify AKI in critically ill patients.

The patient-centered medical home and the nephrologist.

The patient-centered medical home (PCMH) is a model of practice that has been proposed to address the many ills of our current health care delivery and financing systems. At its heart is a primary care practice that provides comprehensive, coordinated, high-quality, personalized care. Integral to the success of the PCMH model is a "neighborhood" of specialists who subscribe to the principles of the PCMH. Nephrologists will have an opportunity to practice within this framework, either as the PCMH itself or, more likely, as "neighbors" to the "home." The effective and enthusiastic participation of nephrologists and other specialists will depend on the details of the model, not the least important of which is the financial structure. Dozens of demonstration projects around the country are currently testing the model. If the PCMH model proves to be workable and is widely adopted, nephrologists could be uniquely positioned to participate, given our long experience providing coordinated care for complex patients in a quality-conscious environment.

Minerals in dialysis therapy: an introduction.

The 180 l of glomerular filtrate formed each day contain some 1100 g (2.5 pounds) of sodium chloride, of which only 5-10 g are excreted in the urine--95% is reabsorbed by the tubules. Some 425 g (nearly a pound) of sodium bicarbonate and 145 g of glucose are filtered, and more than 99% of both are reabsorbed. Also filtered, only to be reabsorbed, are substantial quantities of potassium, calcium, magnesium, phosphate, sulfate, amino acids, vitamins, and many other substances valuable to the body. It is no exaggeration to say that the composition of the blood is determined not by what the mouth takes in but by what the kidneys keep: they are the master chemists of our internal environment, which, so to speak, they manufacture in reverse by working it over completely some fifteen times a day…Our bones, muscles, glands, even our brains are called upon to do only one kind of physiological work, but our kidneys are called upon to perform an innumerable variety of operations. Bones can break, muscles can atrophy, glands can loaf, even the brain can go to sleep, without immediately endangering our survival; but should the kidneys fail to manufacture the proper kind of blood neither bone, muscle, gland nor brain could carry on (1).

The safety of low-potassium dialysis.

Patients with kidney failure depend on dialysis to maintain neutral potassium balance. The amount of potassium removed during a hemodialysis treatment is inversely proportional to the potassium concentration in the dialysis bath. Nephrologists adjust the dialysis bath potassium to account for individual variation in potassium intake among their patients. This management strategy is remarkably successful, because most patients on maintenance hemodialysis have a normal predialysis serum potassium concentration. But the serum potassium concentration of patients on maintenance hemodialysis is not constant over time; it follows a sawtooth pattern. It is this instability--especially the acute fall during dialysis--that has concerned nephrologists for decades, particularly in view of the crucial role of potassium in cardiac electrophysiology. This concern is amplified by the extraordinarily high rate of sudden death among patients on maintenance hemodialysis. In this paper, we review the safety of low-potassium dialysis and make recommendations for managing patients whose serum potassium concentration falls outside the target range.

Treatment of lactic acidosis: appropriate confusion.

BACKGROUND: Lactic acidosis (LA) is common in hospitalized patients and is associated with poor clinical outcomes. There have been major recent advances in our understanding of lactate generation and physiology. However, treatment of LA is an area of controversy and uncertainty, and the use of agents to raise pH is not clearly beneficial. AIM AND METHODS: We reviewed animal and human studies on the pathogenesis, impact, and treatment of LA, published in the English language and available through the PubMed/MEDLINE database. Our aim was to clarify the physiology of the generation of LA, its impact on outcomes, and the different treatment modalities available. We also examined relevant data regarding LA induced by medications commonly prescribed by hospitalists: biguanides, nucleoside analog reverse-transcriptase inhibitors (NRTIs), linezolid, and lorazepam. RESULTS/CONCLUSIONS: Lactic acid is a marker of tissue ischemia but it also may accumulate without tissue hypoperfusion. In the latter circumstance, lactic acid accumulation may be an adaptive mechanism-a novel possibility quite in contrast to the traditional view of lactic acid as only a marker of tissue ischemia. Studies on the treatment of LA with sodium bicarbonate or other buffers fail to show consistent clinical benefit. Severe acidemia in the setting of LA is a particularly poorly studied area. In the settings of medication-induced LA, optimal treatment, apart from prompt cessation of the offending agent, is still unclear.

Management of severe hyperkalemia.

BACKGROUND AND OBJECTIVES: Hyperkalemia is one of the few potentially lethal electrolyte disturbances. Prompt recognition and expeditious treatment of severe hyperkalemia are expected to save lives. This review is intended to provide intensivists and other interested clinicians with an understanding of the pathophysiology that underlies hyperkalemia, and a rational approach to its management. METHODS: This article reviews and analyzes literature relevant to the pathophysiology and management of severe hyperkalemia. Methods include search of MEDLINE, and bibliographic search of current textbooks and journal articles. RESULTS AND CONCLUSIONS: A more complete understanding of potassium homeostasis in recent years has led to new approaches to the management of severe hyperkalemia. The physiologically based sequential approach still applies. The efficacy, pitfalls, and risks of the agents available for use at each step in the sequence are critically reviewed. Rational use of the available tools will allow clinicians to successfully treat severe hyperkalemia.

Night and day proteinuria in patients with sleep apnea.

BACKGROUND: Previous studies have suggested an association between obstructive sleep apnea (OSA) and heavy proteinuria. Two recent studies cast doubt on the association between OSA and proteinuria, but neither studied the effect of disordered sleep per se on urinary protein excretion. METHODS: We prospectively studied 75 patients undergoing polysomnography for suspected OSA. We excluded patients with renal insufficiency, diabetes mellitus, and systemic lupus erythematosus and those administered angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Urine protein-creatinine (P/C) ratio was measured on the date of the polysomnography before sleep (awake P/C ratio) and on awakening (asleep P/C ratio). Severity of OSA was stratified by means of the apnea-hypopnea index (AHI). RESULTS: Twenty-six patients (35%) did not have OSA, 25 patients (33%) had mild OSA, 9 patients (12%) had moderate OSA, and 15 patients (20%) had severe OSA. Asleep P/C ratio was less than 0.2 in 96% of patients, and awake P/C ratio was less than 0.2 in 89% of patients. No patient had an asleep P/C ratio greater than 1.0. There was no correlation between log asleep P/C ratio and log AHI ( r = -0.042; P = 0.73) or log awake P/C ratio and log AHI (r = 0.004; P = 0.97). No significant differences could be shown between mean log P/C ratio for either the asleep or awake urine collection across any of the 4 OSA severity strata. CONCLUSION: We found clinically significant proteinuria to be absent in stable outpatients with OSA. Proteinuria in patients with OSA should not be attributed to sleep apnea and warrants further evaluation.