Reader response
Myron Yaster
From Lynn Martin MD MBA retired Seattle Children’s Hospital commenting on intraoperative dexmedetomidine and acute kidney injury:
This is a truly spectacular PAAD! The adage “association does not prove causation” may be relevant to this study as variables like surgical complexity, selection bias from clinician assessment of risk and other unknown confounders may blur the study findings, despite advanced statistical measures which attempt to control for these biases. However, this study does fulfill several criteria for causality. While admittedly oversimplistic, the Causal Criteria by Hill4 include the following: 1) strength, 2) consistency, 3) specificity, 4) temporality, 5) biologic gradient, 6) plausibility, 7) coherence, 8) experimental evidence, and 9) analogy. The strength of the association between intraoperative dexmedetomidine and postoperative AKI is rather strong, with the higher bounds of the 95% CI of the OR falling quite short of 1. Further, the multiple sensitivity analyses indicate robustness of these findings. The findings are consistent with those of adult studies3 and consistent with findings in studies of children having cardiac surgery.5 The temporality criterion is fulfilled as the dexmedetomidine exposure occurred before the development of AKI and the biologic gradient criteria is fulfilled by evidence of a dose response. Plausibility is demonstrated by the known effects of dexmedetomidine- enhanced renal blood flow and diuresis by inhibition of renin release and increased glomerular filtration, possible anti-inflammatory effects and reduced apoptosis, etc.6 Lastly, a word regarding the E-value analysis, which may be foreign to many readers. “The E-value is defined as the minimum strength of association, on the risk ratio scale, that an unmeasured confounder would need to have with both the treatment and the outcome to fully explain away a specific treatment- outcome association, conditional on the measured covariates. A large E-value implies that considerable unmeasured confounding would be needed to explain away an effect estimate.”7 The E-value analysis offers some measure of how likely or unlikely unmeasured/unknown confounders are actually causing the measured association.
An important limitation of this study was the inclusion of confounders such as fluid administration and vasopressor use in the multivariable regression models. These were included because they remained imbalanced between the groups after propensity score matching. However, these variables are potential mediators between dexmedetomidine and AKI, as dexmedetomidine may cause hypotension leading to fluid or vasopressor use. Adjusting for these confounders thus may attenuate the true effect.
How do observational studies change your practice? Should maintenance of anesthesia with volatile alone become a vestige of the past? Send your thoughts to Myron (myasterster@gmail.com)!
References:
1. Schacham NY, Chhabada S, Efune PN, et al. Intraoperative Hypotension and Acute Kidney Injury after Noncardiac Surgery in Infants and Children: A Retrospective Cohort Analysis. Anesthesiology. 2022;136(1):93-103. doi:10.1097/ALN.0000000000004057
2. Wingert T, Grogan T, Cannesson M, Sapru A, Ren W, Hofer I. Acute Kidney Injury and Outcomes in Children Undergoing Noncardiac Surgery: A Propensity-Matched Analysis. Anesth Analg. 2021;132(2):332-340. doi:10.1213/ANE.0000000000005069
3. Zhuang K, Yang HT, Long YQ, Liu H, Ji FH, Peng K. Dexmedetomidine and acute kidney injury after non-cardiac surgery: A meta-analysis with trial sequential analysis. Anaesth Crit Care Pain Med. 2024;43(3):101359. doi:10.1016/j.accpm.2024.101359
4. Hill AB. The Environment and Disease: Association or Causation?. Proc R Soc Med. 1965;58(5):295-300. doi:10.1177/003591576505800503
5. Jo, Youn Yi MDa; Kim, Ji Young MDb; Lee, Ji Yeon MDa; Choi, Chang Hu MDc; Chang, Young Jin MDa; Kwak, Hyun Jeong MDa,*. The effect of intraoperative dexmedetomidine on acute kidney injury after pediatric congenital heart surgery: A prospective randomized trial. Medicine 96(28):p e7480, July 2017. | DOI: 10.1097/MD.0000000000007480
6. Gao X, Wu Y. Perioperative acute kidney injury: The renoprotective effect and mechanism of dexmedetomidine. Biochem Biophys Res Commun. 2024;695:149402. doi:10.1016/j.bbrc.2023.149402
7. VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017;167(4):268-274. doi:10.7326/M16-2607