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Figure.  Mannitol Use in Partial Nephrectomy Over Time
Mannitol Use in Partial Nephrectomy Over Time

Mannitol use by month is represented by dots; pre- and postpublication linear regression models are represented by lines. A dissemination period spanning from online publication to 1 month after print publication is shown with the blue bar.

Table.  Multiple Mixed-Effect Logistic Regression Analysis Modifiers of Trial Association With Mannitol Use
Multiple Mixed-Effect Logistic Regression Analysis Modifiers of Trial Association With Mannitol Use
1.
Behnia  R, Koushanpour  E, Brunner  EA.  Effects of hyperosmotic mannitol infusion on hemodynamics of dog kidney.   Anesth Analg. 1996;82(5):902-908.PubMedGoogle Scholar
2.
Johnston  PA, Bernard  DB, Perrin  NS, Levinsky  NG.  Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney.   J Clin Invest. 1981;68(1):127-133. doi:10.1172/JCI110227PubMedGoogle ScholarCrossref
3.
Berman  LB, Smith  LL, Chisholm  GD, Weston  RE.  Mannitol and renal function in cardiovascular surgery.   Arch Surg. 1964;88:239-243. doi:10.1001/archsurg.1964.01310200077017PubMedGoogle ScholarCrossref
4.
Spaliviero  M, Power  NE, Murray  KS,  et al.  Intravenous mannitol versus placebo during partial nephrectomy in patients with normal kidney function: a double-blind, clinically-integrated, randomized trial.   Eur Urol. 2018;73(1):53-59. doi:10.1016/j.eururo.2017.07.038PubMedGoogle ScholarCrossref
5.
Shah  PH, Leibovich  BC, Lyon  TD.  Should urologists abandon the use of mannitol during partial nephrectomy?   Eur Urol. 2018;73(1):60-61. doi:10.1016/j.eururo.2017.09.017PubMedGoogle ScholarCrossref
6.
Campbell  S, Uzzo  RG, Allaf  ME,  et al.  Renal mass and localized renal cancer: AUA guideline.   J Urol. 2017;198(3):520-529. doi:10.1016/j.juro.2017.04.100PubMedGoogle ScholarCrossref
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    Research Letter
    August 11, 2021

    Response to a Randomized Trial on Mannitol Use During Partial Nephrectomy

    Author Affiliations
    • 1Department of Urology, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York
    • 2Department of Healthcare Policy and Research, Weill Cornell Medicine, New York, New York
    • 3Department of Urology, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
    JAMA Surg. 2021;156(11):1064-1066. doi:10.1001/jamasurg.2021.3598

    The merits of mannitol for kidney function preservation following iatrogenic ischemia during partial nephrectomy, kidney transplant, and cardiac surgery requiring bypass have been the subject of study and controversy for decades.1-3 To that end, a randomized clinical trial (RCT) investigating the impact of intraoperative mannitol on kidney function following partial nephrectomy, published in January 2018, found no advantage to mannitol vs placebo, concluding that its routine use for this indication should cease.4 Study criticisms include favorable baseline kidney function among the study cohort, administration of low-dose (12.5 g vs 25 g) mannitol, and absent coadministration of furosemide.5

    In light of these results and criticisms, and absent professional society guidelines, the extent to which surgeons discontinued mannitol use in response to this study is uncertain.6 Here, we use a large, national sample capturing medication administration to estimate real-world surgical practice response to a prominent surgical RCT.

    Methods

    Premier Healthcare Database (Premier) captured 22 320 partial nephrectomies at 510 centers in the United States between January 2016 and December 2019. International Classification of Diseases, Current Procedural Terminology, and Premier billing codes identified procedure, approach, comorbidities, chronic kidney disease (CKD) stage, mannitol administration and dosage, furosemide administration, and patient and hospital demographics (eMethods in the Supplement). Mannitol use was calculated as the proportion of partial nephrectomies during which mannitol was administered and was compared pre- and postpublication, allowing for a 6-month dissemination period (spanning from online to 1 month following print publication [August 2017-February 2018]). University Hospital’s Institutional Review Board certified that the study methodology did not constitute human subjects research, so approval and informed consent were not required. Regression models were constructed to identify the association of trial publication with mannitol use and to identify modifiers of this association. Analysis was conducted using R version 4.0.3, with 2-sided significance set at α = .05.

    Results

    Mannitol use decreased postpublication (Figure). Prepublication, 51.3% of patients received mannitol, compared with 33.7% postpublication. In a regression model adjusting for patient age, sex, race, comorbidities, CKD stage, surgical approach, and center academic affiliation and operative volume, patients undergoing surgery postpublication were 61% less likely to receive mannitol (odds ratio [OR], 0.39; 95% CI, 0.36-0.42; P < .001).

    Academic affiliation (OR, 0.33; 95% CI, 0.3-0.37; P < .001), higher center partial nephrectomy volume (OR, 0.31; 95% CI, 0.28-0.34; P < .001), and minimally invasive surgical (laparoscopic or robotic assisted) approach (OR, 0.37; 95% CI, 0.34-0.4; P < .001) were associated with a greater decrease in mannitol use vs nonacademic affiliation, lower volume, and open approach, where postpublication decreases were observed but were significantly smaller in magnitude (Table). Coadministration of furosemide during surgery was associated with a smaller postpublication decrease in odds of mannitol receipt (OR, 0.6; 95% CI, 0.45-0.8; P < .001) vs no coadministration (OR, 0.38; 95% CI, 0.35-0.41; P < .001). Similarly, surgery performed by a surgeon who used high-dose mannitol prepublication was also associated with a smaller decrease in the odds of mannitol administration (OR, 0.43; 95% CI, 0.39-0.47; P < .001) vs surgeons who used low-dose mannitol (OR, 0.29; 95% CI, 0.26-0.33; P < .001). No temporal changes were observed in the overall use of minimally invasive surgery, rate of partial vs radical nephrectomy, and use of intraoperative ultrasonography.

    Discussion

    Following RCT publication, there was a rapid decrease in mannitol use for partial nephrectomy. This suggests an eagerness (particularly among academic, high-volume surgeons) to practice evidence-based medicine. Surgeons whose practice did not align with study protocols were less likely to change, perhaps reflecting the generalizability of the trial’s design. Whether the publication was associated with use of mannitol in kidney transplant or cardiac surgery, where therapeutic benefits may differ, is an area of interest.

    As a limitation, distinction cannot be made between surgeons who were not aware of the RCT vs those who disagreed with its conclusions. Given absence of detailed information on kidney function, assessment of the trial’s association with individual patient outcomes is limited. That considered, surgical RCTs are rare, and few studies have estimated their association with nationwide practice. Here we show the broad, rapid real-world surgical practice response to a prominent surgical RCT.

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    Article Information

    Accepted for Publication: May 12, 2021.

    Published Online: August 11, 2021. doi:10.1001/jamasurg.2021.3598

    Corresponding Author: Jonathan E. Shoag, MD, Case Western Reserve University School of Medicine, 2103 Cornell Rd, Wolstein Research Bldg 4541, Cleveland, OH 44106 (jxs218@case.edu).

    Author Contributions: Dr Shoag had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Lewicki, Basourakos, Scherr, Ponsky, Shoag.

    Acquisition, analysis, or interpretation of data: Lewicki, Basourakos, Qiu, Arenas Gallo, Shoag.

    Drafting of the manuscript: Lewicki, Basourakos, Arenas Gallo, Scherr, Shoag.

    Critical revision of the manuscript for important intellectual content: Lewicki, Basourakos, Qiu, Ponsky, Shoag.

    Statistical analysis: Lewicki, Basourakos, Qiu.

    Administrative, technical, or material support: Scherr, Shoag.

    Supervision: Arenas Gallo, Scherr, Ponsky, Shoag.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: Dr Shoag is supported by the Frederick J. and Theresa Dow Foundation of the New York Community Trust, Vinney Scholars Award, and a Damon Runyon Cancer Research Foundation Physician Scientist Training Award.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Behnia  R, Koushanpour  E, Brunner  EA.  Effects of hyperosmotic mannitol infusion on hemodynamics of dog kidney.   Anesth Analg. 1996;82(5):902-908.PubMedGoogle Scholar
    2.
    Johnston  PA, Bernard  DB, Perrin  NS, Levinsky  NG.  Prostaglandins mediate the vasodilatory effect of mannitol in the hypoperfused rat kidney.   J Clin Invest. 1981;68(1):127-133. doi:10.1172/JCI110227PubMedGoogle ScholarCrossref
    3.
    Berman  LB, Smith  LL, Chisholm  GD, Weston  RE.  Mannitol and renal function in cardiovascular surgery.   Arch Surg. 1964;88:239-243. doi:10.1001/archsurg.1964.01310200077017PubMedGoogle ScholarCrossref
    4.
    Spaliviero  M, Power  NE, Murray  KS,  et al.  Intravenous mannitol versus placebo during partial nephrectomy in patients with normal kidney function: a double-blind, clinically-integrated, randomized trial.   Eur Urol. 2018;73(1):53-59. doi:10.1016/j.eururo.2017.07.038PubMedGoogle ScholarCrossref
    5.
    Shah  PH, Leibovich  BC, Lyon  TD.  Should urologists abandon the use of mannitol during partial nephrectomy?   Eur Urol. 2018;73(1):60-61. doi:10.1016/j.eururo.2017.09.017PubMedGoogle ScholarCrossref
    6.
    Campbell  S, Uzzo  RG, Allaf  ME,  et al.  Renal mass and localized renal cancer: AUA guideline.   J Urol. 2017;198(3):520-529. doi:10.1016/j.juro.2017.04.100PubMedGoogle ScholarCrossref
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