Research Spotlight

Colbert, G. B. and H. M. Szerlip (2018). “Euvolemia-A critical target in the management of acute kidney injury.” Semin Dial Nov 9. [Epub ahead of print].

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It has been clearly established that critically ill patients with sepsis require prompt fluid resuscitation. The optimal amount of fluid and when to taper this resuscitation is less clear. There is a growing evidence that fluid overload leads to acute kidney injury, and increased morbidity and mortality. A clinician’s best intentions in resuscitating a patient can lead to too much of a good thing. Currently, there are several bedside tools to aid in determining a patient’s response to a fluid challenge as well as in the assessment of the current volume status. Guidelines are not available on the exact rate of fluid overload removal and what medicinal or mechanical modality is most favorable. We discuss our experience and an examination of the literature on the problems with fluid overload, and how a patient may benefit from forced fluid removal.

Chiruvolu, A., K. K. Miklis, E. Chen, B. Petrey and S. Desai (2018). “Delivery Room Management of Meconium-Stained Newborns and Respiratory Support.” Pediatrics 142(6) Epub Nov 6.

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Video Abstract: media-1vid110.1542/5839992674001PEDS-VA_2018-1485 BACKGROUND AND OBJECTIVES: Recently, the Neonatal Resuscitation Program (NRP) recommended against routine endotracheal suctioning of meconium-stained nonvigorous newborns but suggested resuscitation with positive pressure ventilation. Our purpose is to study the effects of this change in management. METHODS: In this multicenter cohort study, we compare 130 nonvigorous newborns born during the retrospective 1-year period before the implementation of new NRP guidelines (October 1, 2015, to September 30, 2016) to 101 infants born during the 1-year prospective period after implementation (October 1, 2016, to September 30, 2017). RESULTS: Endotracheal suctioning was performed predominantly in the retrospective group compared with the prospective group (70% vs 2%), indicating the change in practice. A significantly higher proportion of newborns were admitted to the NICU for respiratory issues in the prospective group compared with the retrospective group (40% vs 22%) with an odds ratio (OR) of 2.2 (95% confidence interval [CI]: 1.2-3.9). Similarly, a significantly higher proportion of infants needed oxygen therapy (37% vs 19%) with an OR of 2.5 (95% CI: 1.2-4.5), mechanical ventilation (19% vs 9%) with an OR of 2.6 (95% CI: 1.1-5.8), and surfactant therapy (10% vs 2%) with an OR of 5.8 (95% CI: 1.5-21.8). There were no differences in the incidence of other outcomes, including meconium aspiration syndrome. CONCLUSIONS: The recent NRP guideline change was not associated with an increased incidence of meconium aspiration syndrome but was associated with an increased incidence of NICU admissions for respiratory issues. Also, the need for mechanical ventilation, oxygen, and surfactant therapy increased.

Appiah, G. D., J. R. Chung, B. Flannery, F. Havers, R. K. Zimmerman, M. P. Nowalk, A. S. Monto, E. T. Martin, M. Gaglani, K. Murthy, L. A. Jackson, M. L. Jackson, H. Q. McLean, E. A. Belongia and A. M. Fry (2018). “Hospitalization following Outpatient Medical Care for Influenza: US Influenza Vaccine Effectiveness Network, 2011-12-2015-16.” Influenza Other Respir Viruses Nov 8. [Epub ahead of print].

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Over five seasons, we determined the proportion of outpatients with laboratory-confirmed, influenza-associated illness who were hospitalized within 30 days following the outpatient visit. Overall, 136 (1.7%) of 7,813 influenza-positive patients were hospitalized a median of 4 days after an outpatient visit. Patients aged >/=65 years and those with high-risk conditions were at increased risk of hospitalization. After controlling for age and high-risk conditions, vaccination status and infecting influenza virus type were not associated with hospitalization risk among adults.

Adams, S., P. Schmid, H. S. Rugo, E. P. Winer, D. Loirat, A. Awada, D. W. Cescon, H. Iwata, M. Campone, R. Nanda, R. Hui, G. Curigliano, D. Toppmeyer, J. O’Shaughnessy, S. Loi, S. Paluch-Shimon, A. R. Tan, D. Card, J. Zhao, V. Karantza and J. Cortes (2018). “Pembrolizumab Monotherapy for Previously Treated Metastatic Triple-Negative Breast Cancer: Cohort A of the Phase 2 KEYNOTE-086 Study.” Ann Oncol Nov 26. [Epub ahead of print].

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Background: Treatment options for previously treated metastatic triple-negative breast cancer (mTNBC) are limited. In cohort A of the phase 2 KEYNOTE-086 study, we evaluated pembrolizumab as second or later line of treatment for patients with mTNBC. Patients and methods: Eligible patients had centrally confirmed mTNBC, >/=1 systemic therapy for metastatic disease, prior treatment with anthracycline and taxane in any disease setting, and progression on or after the most recent therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. Primary endpoints were objective response rate (ORR) in the total and PD-L1-positive populations, and safety. Secondary endpoints included duration of response, disease control rate (DCR; percentage of patients with complete or partial response or stable disease for >/=24 weeks), progression-free survival (PFS), and overall survival (OS). Results: All enrolled patients (N=170) were women, 61.8% had PD-L1-positive tumors, and 43.5% had received >/=3 previous lines of therapy for metastatic disease. ORR (95% CI) was 5.3% (2.7-9.9) in the total and 5.7% (2.4-12.2) in the PD-L1-positive populations. DCR (95% CI) was 7.6% (4.4-12.7) and 9.5% (5.1-16.8), respectively. Median duration of response was not reached in the total (range, 1.2+-21.5+) and in the PD-L1-positive (range, 6.3-21.5+) populations. Median PFS was 2.0 months (95% CI, 1.9-2.0), and the 6-month rate was 14.9%. Median OS was 9.0 months (95% CI, 7.7-11.2), and the 6-month rate was 69.1%. Treatment-related adverse events (AEs) occurred in 103 (60.6%) patients, including 22 (12.9%) with grade 3 or 4 AEs. There were no deaths due to AEs. Conclusions: Pembrolizumab monotherapy demonstrated durable antitumor activity in a subset of patients with previously treated mTNBC and had a manageable safety profile. Clinical trial registration: ClinicalTrials.gov, NCT02447003.

Girard, T. D., M. C. Exline, S. S. Carson, C. L. Hough, P. Rock, M. N. Gong, I. S. Douglas, A. Malhotra, R. L. Owens, D. J. Feinstein, B. Khan, M. A. Pisani, R. C. Hyzy, G. A. Schmidt, W. D. Schweickert, R. D. Hite, D. L. Bowton, A. L. Masica, J. L. Thompson, R. Chandrasekhar, B. T. Pun, C. Strength, L. M. Boehm, J. C. Jackson, P. P. Pandharipande, N. E. Brummel, C. G. Hughes, M. B. Patel, J. L. Stollings, G. R. Bernard, R. S. Dittus and E. W. Ely (2018). “Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.” N Engl J Med Oct 22. [Epub ahead of print].

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BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522.)