Research Spotlight

Squiers, J. J. (2019). “Patient Safety under Flexible and Standard Duty-Hour Rules.” N Engl J Med 380(24): 2380.

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Silber and colleagues report that in their trial, 30-day mortality and other measures of patient safety were not adversely affected by flexible duty hours, as compared with standard duty hours, for internal-medicine residents. Similarly, in the Flexibility in Duty Hour Requirements for Surgical Trainees (FIRST) Trial, Bilimoria and colleagues1 reported that flexible duty hours for general surgical residents were associated with noninferior rates of postoperative death or complications. However, previously reported results of these trials showed that residents’ satisfaction with the quality of their education varied: internal-medicine interns with standard duty hours had greater satisfaction than those with flexible duty hours, but among general surgical residents, there was no difference in satisfaction between those in the standard-duty group and those in the flexible-duty group. In another trial, pediatrics residents who were randomly assigned to shifts with standard duty hours were less satisfied with their education than residents assigned to shifts with flexible duty hours. Although the Accreditation Council for Graduate Medical Education (ACGME) recently relaxed duty-hour regulations for all specialties, these findings suggest that the “one-size-fits-all” approach affects resident education differently across specialties, without any improvement in patient outcomes. Instead, each specialty should determine how best to regulate resident schedules in compliance with the ACGME 80-hour workweek. (Text of letter concerning the article, Silber JH, Bellini LM, Shea JA, et al. Patient safety outcomes under flexible and standard resident duty-hour rules. N Engl J Med 2019; 380: 905-914.)

Ward, M. A., C. M. Dunst, M. E. Glasgow, E. N. Teitelbaum, W. F. Abdelmoaty, K. M. Reavis, L. L. Swanstrm and S. R. DeMeester (2019). “Can Impedance-pH Testing on Medications Reliably Identify Patients with GERD as Defined by Pathologic Esophageal Acid Exposure off Medications?” J Gastrointest Surg 23(7): 1301-1308.

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INTRODUCTION: Impedance-pH testing (MII-pH) while patients are on acid suppression medications is frequently used to evaluate persistent reflux symptoms. The aim of this study was to determine whether MII-pH on medications can reliably identify patients with gastroesophageal reflux disease (GERD) as defined by pathologic esophageal acid exposure off medications, and to determine if there is a threshold of total reflux episodes on medications where pH testing off medications may be unnecessary. METHODS: A retrospective review identified all patients between 1/2010 and 4/2017 who underwent MII-pH testing on PPI medications and subsequently had pH testing off medications. GERD was defined on pH testing off medications by an abnormal DeMeester Score (DMS) and on MII-pH on medications by >/= 48 total reflux episodes. Patients with an abnormal DMS by MII-pH on medications were excluded. RESULTS: There were 71 patients, (22 males; 49 females), with a median age of 52 years. Based on >/= 48 total reflux episodes by MII-pH testing on medications, 42 patients (59%) had GERD. When tested off medications, an abnormal DMS was present in 44 patients (62%). Among those with GERD based on impedance testing on medications, 31% did not have GERD based on pH testing off medications. Further, in the 29 patients with 73 reflux events with MII-pH on medications, all 15 patients in our series had pathologic acid exposure on pH testing off medications. CONCLUSION: MII-pH testing on medications in patients with refractory GERD symptoms does not reliably correlate with a diagnosis of GERD as defined by pathologic esophageal acid exposure off medications. The commonly used abnormal MII-pH test value of >/= 48 total reflux episodes is not validated and should not be used. However, in our series, patients with > 73 total reflux episodes had a high likelihood of having pathologic acid exposure off medications. Overall, the preferred strategy to evaluate patients with persistent GERD symptoms on acid suppression therapy should be pH testing off medications.

Szerlip, M., A. Zajarias, S. Vemalapalli, M. Brennan, D. Dai, H. Maniar, B. R. Lindman, R. Brindis, J. D. Carroll, M. Hamandi, F. H. Edwards, F. Grover, S. O’Brien, E. Peterson, J. S. Rumsfeld, D. Shahian, E. M. Tuzcu, D. Holmes, V. H. Thourani and M. Mack (2019). “Transcatheter Aortic Valve Replacement in Patients With End-Stage Renal Disease.” J Am Coll Cardiol 73(22): 2806-2815.

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BACKGROUND: In patients with end-stage renal disease (ESRD), surgical aortic valve replacement is associated with higher early and late mortality, and adverse outcomes compared with patients without renal disease. Transcatheter aortic valve replacement (TAVR) offers another alternative, but there are limited reported outcomes. OBJECTIVES: The purpose of this study was to determine the outcomes of TAVR in patients with ESRD. METHODS: Among the first 72,631 patients with severe aortic stenosis (AS) treated with TAVR enrolled in the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC) TVT (Transcatheter Valve Therapies) registry, 3,053 (4.2%) patients had ESRD and were compared with patients who were not on dialysis for demographics, risk factors, and outcomes. RESULTS: Compared with the nondialysis patients, ESRD patients were younger (76 years vs. 83 years; p < 0.01) and had higher rates of comorbidities leading to a higher STS predicted risk of mortality (median 13.5% vs. 6.2%; p < 0.01). ESRD patients had a higher in-hospital mortality (5.1% vs. 3.4%; p < 0.01), although the observed to expected ratio was lower (0.32 vs. 0.44; p < 0.01). ESRD patients also had a similar rate of major vascular complications (4.5% vs. 4.6%; p = 0.86), but a higher rate of major bleeding (1.4% vs. 1.0%; p = 0.03). The 1-year mortality was significantly higher in dialysis patients (36.8% vs. 18.7%; p < 0.01). CONCLUSIONS: Patients undergoing TAVR with ESRD are at higher risk and had higher in-hospital mortality and bleeding, but similar vascular complications, when compared with those who are not dialysis dependent. The 1-year survival raises concerns regarding diminished benefit in this population. TAVR should be used judiciously after full discussion of the risk-benefit ratio in patients on dialysis.

Spinowitz, B. S., S. Fishbane, P. E. Pergola, S. D. Roger, E. V. Lerma, J. Butler, S. von Haehling, S. H. Adler, J. Zhao, B. Singh, P. T. Lavin, P. A. McCullough, M. Kosiborod and D. K. Packham (2019). “Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.” Clin J Am Soc Nephrol 14(6): 798-809.

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Background and objectives: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate–associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. Design, setting, participants, & measurements: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24–72 hours until normokalemic (potassium =3.5–5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5–5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. Results: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3–12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor–naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0–3.4 mmol/L, respectively. Conclusions: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

Smith, A. G., S. Pereira, A. Jaramillo, S. T. Stoll, F. M. Khan, N. Berka, A. A. Mostafa, M. J. Pando, C. Y. Usenko, M. P. Bettinotti, C. W. Pyo, W. C. Nelson, A. Willis, M. Askar and D. E. Geraghty (2019). “Comparison of SSOP versus NGS for HLA-A, B, C, DRB1, DRB3/B4/B5, DQA1, DQB1, DPA1, and DPB1 typing: toward single pass high resolution HLA typing in support of solid organ and hematopoietic cell transplant programs.” HLA Jun 24. [Epub ahead of print].

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Many clinical laboratories supporting solid organ transplant programs employ multiple HLA genotyping technologies, depending on individual laboratory needs. Sequence specific primers and quantitative PCR serve the rapid turnaround necessary for deceased donor workup, while sequence specific oligonucleotide probe (SSOP) technology is widely employed for higher volumes. When clinical need mandates high resolution data, Sanger sequencing-based typing (SBT) has been the “gold standard”. However, all those methods commonly yield ambiguous typing results that utilize valuable laboratory resources when resolution is required. In solid organ transplantation, high resolution typing may provide critical information for highly sensitized patients with donor specific anti-HLA antibodies (DSA), particularly when DSA involve HLA alleles not discriminated by SSOP typing. Arguments against routine use of SBT include assay complexity, long turnaround times (TAT) and increased costs. Here we compare a next generation sequencing (NGS) technology with SSOP for accuracy, effort, turnaround time and level of resolution for genotyping of 11 HLA loci among 289 specimens from five clinical laboratories. Results were concordant except for SSOP mis-assignments in 8 specimens and 21 novel sequences uniquely identified by NGS. With few exceptions, SSOP generated ambiguous results while NGS provided unambiguous 3-field allele assignments. For complete HLA genotyping of up to 24 samples by either SSOP or NGS, bench work was completed on day 1 and typing results were available on day 2. This study provides compelling evidence that, although not viable for STAT typing of deceased donors, a single pass NGS HLA typing method has direct application for solid organ transplantation.