Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Characterization of the Clinical Evidence Supporting Repository Corticotropin Injection for FDA-Approved Indications: A Scoping Review.

IMPORTANCE: Repository corticotropin injection is an expensive medication that was approved in 1952 for the treatment of many inflammatory conditions. The clinical evidence supporting the use of repository corticotropin (hereinafter referred to as corticotropin) has been weak, perhaps because its approval predated the modern review standards of the US Food and Drug Administration (FDA). OBJECTIVE: To characterize the clinical evidence supporting the use of corticotropin for its FDA-approved indications. EVIDENCE REVIEW: Studies were identified via electronic searches of Ovid MEDLINE, the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and the Cochrane Central Register of Controlled Trials (CENTRAL) from database inception to May 12, 2021 (the MEDLINE search was updated on June 8, 2021). Bibliographies of retrieved articles were also reviewed through ClinicalTrials.gov, FDA documents, and the manufacturer's website. Search terms included HP Acthar, ACTH gel, repository corticotropin, and terms for specific diseases, such as multiple sclerosis, nephrotic syndrome, rheumatoid arthritis, and West syndrome (or spasms, infantile). The review included randomized clinical trials (RCTs), nonrandomized and single-arm clinical trials, and prospective cohort studies that compared corticotropin with an active comparator, placebo, or no treatment. Data were extracted by 1 reviewer and verified by a second. Disagreements were resolved through discussion. Studies were qualitatively synthesized by indication to summarize important design features and results. FINDINGS: Of 1059 records screened, 203 full-text articles were assessed for eligibility. A total of 41 studies involving 2235 participants met inclusion criteria; of those, 11 involved infantile spasms, 10 involved multiple sclerosis (MS), 11 involved rheumatological conditions, 7 involved nephrotic syndrome, 1 involved ocular conditions, and 1 involved sarcoidosis. Overall, 19 studies either included a single arm or exclusively compared different corticotropin dosing strategies. The evidence was most robust for the treatment of infantile spasms and MS. The largest number of studies comparing corticotropin with an active agent (n = 4) or placebo (n = 5) pertained to MS, with almost all studies finding that corticotropin performed better than placebo but no different than corticosteroids. For the treatment of infantile spasms, 8 controlled studies were identified (6 were randomized); of those, only 1 small RCT found corticotropin to be significantly superior to corticosteroids. Studies of patients with other conditions (n = 20) frequently lacked a control group (n = 12), were placebo-controlled (n = 5), or exclusively examined different corticotropin dosing strategies (n = 2). Placebo-controlled RCTs of rheumatoid arthritis, ankylosing spondylitis, optic neuritis, systemic lupus erythematosus, and nephrotic syndrome were generally small and did not consistently demonstrate that corticotropin was superior to placebo. Blinded RCTs showed a similar or greater number of adverse effects with corticotropin relative to corticosteroids. CONCLUSIONS AND RELEVANCE: In this scoping review, few RCTs supported the clinical benefit of corticotropin for most FDA-approved indications. Most RCTs found that corticotropin was not superior to corticosteroids for treating relapses of MS or infantile spasms.

Heritability and individuality of the plasma sodium concentration: a twin study in the United States veteran population.

Little is known about the population genetics of water balance. A recent meta-genome-wide association study on plasma sodium concentration identified novel loci of high biological plausibility, yet heritability of the phenotype has never been convincingly shown in European ancestry. The present study linked the Vietnam Era Twin Registry with the Department of Veterans Affairs VistA patient care clinical database. Participants (n = 2,370, 59.6% monozygotic twins and 40.4% dizygotic twins) had a median of seven (interquartile range: 3-14) plasma sodium determinations between October 1999 and March 2017. Heritability of the mean plasma sodium concentration among all twins was 0.41 (95% confidence interval: 0.35-0.46) and 0.49 (95% confidence interval: 0.43-0.54) after exclusion of 514 twins with only a single plasma sodium determination. Heritability among Caucasian (n = 1,958) and African-American (n = 268) twins was 0.41 (95% confidence interval: 0.34-0.47) and 0.36 (95% confidence interval: 0.17-0.52), respectively. Exclusion of data from twins who had been prescribed medications known to impact systemic water balance had no effect. The ability of the present study to newly detect substantial heritability across multiple racial groups was potentially a function of the cohort size and relatedness, exclusion of sodium determinations confounded by elevated plasma glucose and/or reduced glomerular filtration rate, transformation of plasma sodium for the independent osmotic effect of plasma glucose, and use of multiple laboratory determinations per individual over a period of years. Individual-level plasma sodium concentration exhibited longitudinal stability (i.e., individuality); the degree to which individual-level means differed from the population mean was substantial, irrespective of the number of determinations. In aggregate, these data establish the heritability of plasma sodium concentration in European ancestry and corroborate its individuality.

Repository Corticotropin Versus Glucocorticoid for Nephrotic Syndrome: When Will We See the Evidence?

Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for repository corticotropin (rACTH) injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications.

Risk Factors for New-Onset Atrial Fibrillation in Patients With Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVE: Atrial fibrillation frequently develops in patients with sepsis and is associated with increased morbidity and mortality. Unfortunately, risk factors for new-onset atrial fibrillation in sepsis have not been clearly elucidated. Clarification of the risk factors for atrial fibrillation during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice. DATA SOURCES: Medline, Embase, Web of Science, and Cochrane CENTRAL. STUDY SELECTION: We conducted a systematic review and meta-analysis to identify risk factors for new-onset atrial fibrillation during sepsis. DATA EXTRACTION: We extracted the adjusted odds ratio for each risk factor associated with new-onset atrial fibrillation during sepsis. For risk factors present in more than one study, we calculated pooled odds ratios (meta-analysis). We classified risk factors according to type and quantified the factor effect sizes. We then compared sepsis-associated atrial fibrillation risk factors with risk factors for community-associated atrial fibrillation. DATA SYNTHESIS: Forty-four factors were examined as possible risk factors for new-onset atrial fibrillation in sepsis, 18 of which were included in meta-analyses. Risk factors for new-onset atrial fibrillation included demographic factors, comorbid conditions, and most strongly, sepsis-related factors. Sepsis-related factors with a greater than 50% change in odds of new-onset atrial fibrillation included corticosteroid use, right heart catheterization, fungal infection, vasopressor use, and a mean arterial pressure target of 80-85 mm Hg. Several cardiovascular conditions that are known risk factors for community-associated atrial fibrillation were not identified as risk factors for new-onset atrial fibrillation in sepsis. CONCLUSIONS: Our study shows that risk factors for new-onset atrial fibrillation during sepsis are mainly factors that are associated with the acute sepsis event and are not synonymous with risk factors for community-associated atrial fibrillation. Our results provide targets for future studies focused on atrial fibrillation prevention and have implications for several key areas in the management of patients with sepsis such as glucocorticoid administration, vasopressor selection, and blood pressure targets.

Echocardiogram in the Evaluation of Hemodynamically Stable Acute Pulmonary Embolism: National Practices and Clinical Outcomes.

RATIONALE: Societal guideline recommendations vary with regard to the role of routine trans-thoracic echocardiography to screen for right ventricular strain in patients with hemodynamically stable acute pulmonary embolism. OBJECTIVE: To characterize national patterns in use of early trans-thoracic echocardiography for the evaluation of patients with hemodynamically stable acute pulmonary embolism and determine associations between trans-thoracic echocardiography use and patient outcomes. METHODS: Retrospective cohort study using Premier, Inc. database of approximately 20% of patients hospitalized in the United States with hemodynamically stable acute pulmonary embolism between 2008 and 2011. Multivariable, risk-adjusted hierarchical regression models were used to evaluate hospital variation in use of trans-thoracic echocardiography for pulmonary embolism and associations between hospital trans-thoracic echocardiography rates and patient outcomes. Patient-level trans-thoracic echocardiography exposure was used in sensitivity analyses. RESULTS: We identified 64,037 patients (mean age, 61.7 years; 54% women; 68% white) hospitalized at 363 U.S. hospitals. Trans-thoracic echocardiography rates for hemodynamically stable acute pulmonary embolism varied widely among hospitals (median trans-thoracic echocardiography rate, 41.4%; range, 0-89%; interquartile range, 32.7-51.7%). Hospital rates of trans-thoracic echocardiography were not associated with significant differences in risk-adjusted mortality (trans-thoracic echocardiography rate quartile 4 vs. quartile 1: odds ratio, 0.88; 95% confidence interval, 0.69-1.13) or use of thrombolytics (odds ratio, 1.28; 95% confidence interval, 0.84-1.96), but rates of intensive care unit admission (odds ratio, 1.57; 95% confidence interval, 1.18-2.07), hospital length of stay (relative risk, 1.08; 95% confidence interval, 1.03-1.15), and costs (relative risk, 1.15; 95% confidence interval, 1.07-1.23) were significantly higher at hospitals with high trans-thoracic echocardiography rates. Analyses of patient-level trans-thoracic echocardiography exposure produced similar results, except with higher rates of thrombolysis (odds ratio, 5.58; 95% confidence interval, 4.40-7.09) and bleeding (odds ratio, 1.37; 95% confidence interval, 1.24-1.51) among patients receiving trans-thoracic echocardiography. CONCLUSIONS: Trans-thoracic echocardiography use in the evaluation of patients with hemodynamically stable acute pulmonary embolism varied widely between hospitals. Hospitals with high rates of pulmonary embolism-associated trans-thoracic echocardiography use did not achieve different patient mortality outcomes but had higher resource use and costs. Our findings support the 2016 American College of Chest Physicians guidelines for management of pulmonary embolism, which recommend selective, rather than routine, use of trans-thoracic echocardiography to risk stratify patients with hemodynamically stable pulmonary embolism.

Industry Payments to Physician Specialists Who Prescribe Repository Corticotropin.

Importance: Despite great expense and little evidence supporting use over corticosteroids, prescriptions for repository corticotropin (H. P. Acthar Gel; Mallinckrodt Pharmaceuticals) have increased markedly. Aggressive sales tactics and payments from the manufacturer may influence prescribing behavior for this expensive medication. Objective: To characterize industry payments to physician specialists who prescribe corticotropin in the Medicare program. Design, Setting, and Participants: This study was a cross-sectional analysis of Centers for Medicare & Medicaid Services 2015 Part D prescribing data linked to 2015 Open Payments data. Nephrologists, neurologists, and rheumatologists with more than 10 corticotropin prescriptions (frequent prescribers) in 2015 were included. Exposures: Frequency, category, and magnitude of corticotropin-related payments from Mallinckrodt recorded in the Open Payments database. Main Outcomes and Measures: Frequency, category, and magnitude of corticotropin-related payments from Mallinckrodt, as well as corticotropin prescriptions and expenditures for Medicare beneficiaries. Results: Of the 235 included physicians, 65 were nephrologists; 59, neurologists; and 111, rheumatologists. A majority of frequent corticotropin prescribers (207 [88%]) received corticotropin-related payments from Mallinckrodt. The median (range) total payment for 2015 was $189 ($11-$138 321), with the highest payments ranging from $56 549 to $138 321 across the specialties. More than 20% of frequent prescribers received more than $10 000 and the top quartile of recipients received a median (range) of $33 190 ($9934-$138 321) in total payments per prescriber. Payments for compensation for services other than consulting contributed the most to the total amount. Mallinckrodt payments were positively associated with greater Medicare spending on corticotropin (ß = 1.079; 95% CI, 1.044-1.115; P < .001), with every $10 000 in payments associated with a 7.9% increase (approximately $53 000) in Medicare spending on corticotropin. There was no association between corticotropin-related payments and spending on prescriptions for synthetic corticosteroids. Conclusions and Relevance: In this study, most nephrologists, neurologists, and rheumatologists who frequently prescribe corticotropin received corticotropin-related payments from Mallinckrodt. These findings suggest that financial conflicts of interest may be driving use of corticotropin in the Medicare program.

The cumulative effects of intravenous antibiotic treatments on hearing in patients with cystic fibrosis.

BACKGROUND: Aminoglycosides (AGs) and glycopeptides are antibiotics essential for treating life-threatening respiratory infections in patients with cystic fibrosis (CF). The goal of this study was to examine the effects of cumulative intravenous (IV)-AG (amikacin and/or tobramycin) and/or glycopeptide (vancomycin) dosing on hearing status in patients with CF. METHODS: Hearing thresholds were measured from 0.25 to 16.0kHz, in 81 participants with CF. Participants were categorized into two groups: normal hearing in both ears (≤25dB HL for all frequency bands) or hearing loss (>25dB HL for any frequency band in either ear). Participants were also characterized into quartiles by their cumulative IV-AG (with or without vancomycin) exposure. Dosing was calculated using two strategies: (i) total number of lifetime doses, and (ii) total number of lifetime doses while accounting for the total doses per day. This was referred to as the "weighted" method. RESULTS: Participants in the hearing loss group were significantly older than those in the normal-hearing group. After adjusting for gender and age at the time of hearing test, participants in the two highest-quartile exposure groups were almost 5 X more likely to have permanent sensorineural hearing loss than those in the two lowest-quartile exposure groups. There was a small group of CF patients who had normal hearing despite high exposure to IV-antibiotics. CONCLUSIONS: Cumulative IV-antibiotic dosing has a significant negative effect on hearing sensitivity in patients with CF, when controlling for age and gender effects. A trend for increasing odds of hearing loss was associated with increasing cumulative IV-antibiotic dosing.

Arterial Catheter Use in the ICU: A National Survey of Antiseptic Technique and Perceived Infectious Risk.

OBJECTIVES: Recent studies have shown that the occurrence rate of bloodstream infections associated with arterial catheters is 0.9-3.4/1,000 catheter-days, which is comparable to that of central venous catheters. In 2011, the Centers for Disease Control and Prevention published new guidelines recommending the use of limited barrier precautions during arterial catheter insertion, consisting of sterile gloves, a surgical cap, a surgical mask, and a small sterile drape. The goal of this study was to assess the attitudes and current infection prevention practices used by clinicians during insertion of arterial catheters in ICUs in the United States. DESIGN: An anonymous, 22-question web-based survey of infection prevention practices during arterial catheter insertion. SETTING: Clinician members of the Society of Critical Care Medicine. SUBJECTS: Eleven thousand three hundred sixty-one physicians, nurse practitioners, physician assistants, respiratory therapists, and registered nurses who elect to receive e-mails from the Society of Critical Care Medicine. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1,265 responses (11% response rate), with 1,029 eligible participants after exclusions were applied. Only 44% of participants reported using the Centers for Disease Control and Prevention-recommended barrier precautions during arterial catheter insertion, and only 15% reported using full barrier precautions. The mean and median estimates of the incidence density of bloodstream infections associated with arterial catheters were 0.3/1,000 catheter-days and 0.1/1,000 catheter-days, respectively. Thirty-nine percent of participants reported that they would support mandatory use of full barrier precautions during arterial catheter insertion. CONCLUSIONS: Barrier precautions are used inconsistently by critical care clinicians during arterial catheter insertion in the ICU setting. Less than half of clinicians surveyed were in compliance with current Centers for Disease Control and Prevention guidelines. Clinicians significantly underestimated the infectious risk posed by arterial catheters, and support for mandatory use of full barrier precautions was low. Further studies are warranted to determine the optimal preventive strategies for reducing bloodstream infections associated with arterial catheters.

Potassium modulates electrolyte balance and blood pressure through effects on distal cell voltage and chloride.

Dietary potassium deficiency, common in modern diets, raises blood pressure and enhances salt sensitivity. Potassium homeostasis requires a molecular switch in the distal convoluted tubule (DCT), which fails in familial hyperkalemic hypertension (pseudohypoaldosteronism type 2), activating the thiazide-sensitive NaCl cotransporter, NCC. Here, we show that dietary potassium deficiency activates NCC, even in the setting of high salt intake, thereby causing sodium retention and a rise in blood pressure. The effect is dependent on plasma potassium, which modulates DCT cell membrane voltage and, in turn, intracellular chloride. Low intracellular chloride stimulates WNK kinases to activate NCC, limiting potassium losses, even at the expense of increased blood pressure. These data show that DCT cells, like adrenal cells, sense potassium via membrane voltage. In the DCT, hyperpolarization activates NCC via WNK kinases, whereas in the adrenal gland, it inhibits aldosterone secretion. These effects work in concert to maintain potassium homeostasis.

Transcriptome-based analysis of kidney gene expression changes associated with diabetes in OVE26 mice, in the presence and absence of losartan treatment.

Diabetes is among the most common causes of end-stage renal disease, although its pathophysiology is incompletely understood. We performed next-generation sequencing-based transcriptome analysis of renal gene expression changes in the OVE26 murine model of diabetes (age 15 weeks), relative to non-diabetic control, in the presence and absence of short-term (seven-day) treatment with the angiotensin receptor blocker, losartan (n = 3-6 biological replicates per condition). We detected 1438 statistically significant changes in gene expression across conditions. Of the 638 genes dysregulated in diabetes relative to the non-diabetic state, >70% were downregulation events. Unbiased functional annotation of genes up- and down-regulated by diabetes strongly associated (p<1 × 10(-8)) with terms for oxidative stress and for endoplasmic reticulum stress/protein folding. Most of the individual gene products up- or down-regulated with diabetes were unaffected by losartan treatment; however, of the gene products dysregulated in diabetes and influenced by losartan treatment, the vast majority of changes were in the direction of amelioration rather than exacerbation of the diabetic dysregulation. This group of losartan-protected genes associated strongly with annotation terms for endoplasmic reticulum stress, heat shock proteins, and chaperone function, but not oxidative stress; therefore, the losartan-unaffected genes suggest avenues for additional therapeutic opportunity in diabetes. Interestingly, the gene product most highly upregulated by diabetes (>52-fold), encoded by the cationic amino acid transporter Slc7a12, and the gene product most highly downregulated by diabetes (>99%)--encoded by the "pseudogene" Gm6300--are adjacent in the murine genome, are members of the SLC7 gene family, and are likely paralogous. Therefore, diabetes activates a near-total genetic switch between these two paralogs. Other individual-level changes in gene expression are potentially relevant to diabetic pathophysiology, and novel pathways are suggested. Genes unaffected by diabetes alone but exhibiting increased renal expression with losartan produced a signature consistent with malignant potential.

Individuality of the plasma sodium concentration.

Older literature has suggested that the plasma sodium concentration is not individual, that it is neither intrinsic to an individual nor reproducible, longitudinally. We recently observed that the plasma sodium concentration is heritable. Because demonstrable heritability requires individuality of the relevant phenotype, we hypothesized that the plasma sodium concentration was substantially individual. In two large health plan-based cohorts, we demonstrated individuality of the plasma sodium concentration over a 10-yr interval; the intraclass correlation coefficient (ICC) averaged 0.4-0.5. The individuality of plasma sodium increased significantly with age. Plasma sodium individuality was equal to or only slightly less than that for plasma glucose but was less than the individuality for creatinine. The individuality of plasma sodium was further confirmed by comparing the Pearson correlation coefficient for within-individual versus between-individual pairs of sodium determinations and via application of the agreement index. Furthermore, the distribution of all sodium determinations for all participants within a population was similar to the distribution for the mean sodium concentration for individuals within that population. Therefore, the near-normal distribution of plasma sodium measurements within a population is likely not attributable to assay-specific factors but rather to genuine and durable biological variability in the osmotic set point. In aggregate, these data strongly support the individuality of the plasma sodium concentration. They further indicate that serial plasma sodium values for any given individual tend to cluster around a patient-specific set point and that these set points vary among individuals.

Hourly oral sodium chloride for the rapid and predictable treatment of hyponatremia.

Hypertonic NaCl is first-line therapy for acute, severe and symptomatic hyponatremia; however, its use is often restricted to the intensive care unit (ICU). A 35-year-old female inpatient with an optic chiasm glioma and ventriculoperitoneal shunt for hydrocephalus developed acute hyponatremia (sodium 122 mEq/l) perhaps coinciding with haloperidol treatment. The sum of her urinary sodium and potassium concentrations was markedly hypertonic vis-à-vis plasma; it was inferred that serum sodium concentration would continue to fall even in the complete absence of fluid intake. Intravenous (i.v.) 3% NaCl was recommended; however, a city-wide public health emergency precluded her transfer to the ICU. She was treated with hourly oral NaCl tablets in a dose calculated to deliver the equivalent of 0.5 ml/kg/h of 3% NaCl with an objective of increasing the serum sodium concentration by 6 mEq/l. She experienced a graded and predictable increase in serum sodium concentration. A slight overshoot to 129 mEq/l was rapidly corrected with 0.25 l of D5W, and she stabilized at 127 mEq/l. We conclude that hourly oral NaCl, in conjunction with careful monitoring of the serum sodium concentration, may provide an attractive alternative to i.v. 3% NaCl for selected patients with severe hyponatremia.

A reversible cause of 'end-stage renal disease': discrepant findings in serial duplex ultrasonograms in a suspected occlusion of a renal arterial bypass graft.

Duplex ultrasonography may be inaccurate due to a number of variables in operator and patient characteristics. We describe a 40-year-old woman who presented with acute kidney injury after prior complex abdominal aortic surgery that had left her with an essentially solitary functional kidney. On the basis of normal Doppler findings, she was started on dialysis. Owing to high clinical suspicion and a failure of renal function to return, a second Doppler study was performed 3 weeks after the first, revealing the characteristic tardus-parvus waveform of renal artery stenosis. The patient underwent urgent renal arterial angioplasty and stent placement. She experienced an immediate increase in urinary output, required no further dialysis, and the creatinine improved to 1.7 mg/dL (her prior renal baseline). The case illustrates an important complication of abdominal aortic aneurysm repair, draws attention to a potential source of error in the Doppler measurement, and underscores the limitations of duplex ultrasonography for excluding renal artery stenosis in the presence of high pretest probability.