PAAD Reader Response: On choice of crystalloid during pediatric kidney transplantation
B. Dean Bruins, Justin L. Lockman, Ty Muhly, Ben Laskin, Matthew Pearsall, Matthew Levine, Sandra Amaral
We normally post reader responses on Fridays. I received this response from our regular readers and contributors from the Seattle Children’s Hospital. It was too important and too long to be part of the normal Friday postings. So, today I am posting this response as its own PAAD. Myron Yaster MD
Original article
Collins MG, Fahim MA, Pascoe EM, Hawley CM, Johnson DW, Varghese J, Hickey LE, Clayton PA, Dansie KB, McConnochie RC, Vergara LA, Kiriwandeniya C, Reidlinger D, Mount PF, Weinberg L, McArthur CJ, Coates PT, Endre ZH, Goodman D, Howard K, Howell M, Jamboti JS, Kanellis J, Laurence JM, Lim WH, McTaggart SJ, O'Connell PJ, Pilmore HL, Wong G, Chadban SJ; BEST-Fluids Investigators; Australasian Kidney Trials Network. Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial. Lancet. 2023 Jul 8;402(10396):105-117. doi: 10.1016/S0140-6736(23)00642-6. Epub 2023 Jun 18. Erratum in: Lancet. 2023 Jul 1;402(10395):26. PMID: 37343576.
We read with interest the recent Pediatric Anesthesia Article of the Day, “What’s the best solution to use during kidney transplantation?”1 The authors, in reviewing the original manuscript by Collins et al, concluded “Clearly, we should be using PlasmaLyte in cadaveric kidney transplants.”
We believe this is one of those times when it’s important to remember that children are NOT small adults. Some of us (JLL, WTM, MP) reached out to our nephrology colleagues at the Children’s Hospital of Philadelphia to discuss this paper and the PAAD and we think the resulting conversation is worth sharing with PAAD readers. In short: the jury is still out!
First, a review of the primary data shows that only 4 children were included in the BEST-Fluids study, and that only one of those children received balanced crystalloid.1 The study also excluded children under 20 kg; while 20 kg is the average weight of a 5-year-old based on CDC growth charts, renal failure patients often have failure to thrive meaning that many children older than 5 years would be excluded from the data.
Second, the primary outcome was delayed graft function (DGF), which occurred in 30% of the balanced crystalloid group vs. 40% of the saline group. While this is an impressive finding and we agree may warrant change in adult practice, DGF is far less common in children – less than 10% of recipients. (SRTR ADR PMID 37132350). The reasons for reduced DGF in children relate primarily to the high-quality donors received, including a preponderance of living donors. Among children who receive deceased donors, over 96 % of children receive organs from donors with Kidney Donor Profile Index (KDPI) < 35, and very few donors to children in the US undergo Donation after Circulatory Death (DCD) vs. Deceased after Brain Death (DBD). (SRTR report). In contrast, the deceased donors in the BEST-Fluids study were of older donor age, and the results were more robust among recipients of DCD kidneys. Thus, using DGF as a primary outcome in children is problematic.
Additional theoretical benefits of balanced crystalloid vs. normal saline include avoidance of saline-induced hyperchloremic metabolic acidosis, which may increase serum potassium levels. This is weighed against theoretical risks of increased hyperkalemia with potassium-containing fluids. The BEST-Fluids study found no differences in hyperkalemia, graft function within the first year, or length of hospital stay, but did note post-operative increases in urine output among the group receiving balanced crystalloid vs. the group receiving saline.1 Here, too, we see differences between adults and children. The most common etiology of kidney disease in children is Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), representing approximately 36% of incident pediatric kidney transplant recipients. (SRTR report). These children often have primarily tubular kidney disease with significant dyselectrolytemia and often polyuria, both atypical of adults with end-stage renal disease. Younger children may also require higher volumes of fluid to maintain renal perfusion and blood pressure.2
The literature is limited and mixed on “ideal” perioperative fluids for children, and the majority of published pediatric studies are from the United Kingdom. Williamson et al. conducted a retrospective, observational study of 50 children who underwent kidney transplantation and received 0.9% normal saline for urine output replacement with 10% dextrose for insensible losses.3 They noted hypernatremia in 15% of patients and hyponatremia in 4% of patients, hypokalemia in 36% of patients and hyperkalemia in 18% of children. They also noted hyperchloremia in 68% of children and acidosis (low plasma bicarbonate) in 88% of children. The vast majority of patients who developed hyperkalemia were deceased donor kidney transplant recipients. In another study, Hayes W, et al. (Plasma Electrolyte Imbalance in pediatric KT recipients, Ped Neph 2019: 23: e13411.) described dyselectrolytemia in 76 children receiving kidney transplants in the UK who received 0.45% sodium chloride with 5% glucose (D5 1/2NS).4 In that study, 59% developed acute hyponatremia, 30% hyperkalemia and 57% non-anion gap acidosis as well as hyperglycemia in 97% patients. Besides dyselectrolytemias, Wyatt et al. have described tremendous practice variation in perioperative fluid volumes.5
Recently, the PLUTO multi-center randomized controlled trial in children reported their results comparing Plasma-Lyte 148 with standard of care (which varied and included 0.45% and 0.9% sodium chloride solutions).2,6 For this study, which included both living and deceased donor kidney transplants, the primary outcome was hyponatremia, with numerous secondary outcomes including fluid overload, and other electrolyte derangements. The study analyzed results from 137 children across nine UK pediatric kidney transplant centers, with 68 in the Plasma-Lyte group and 69 in the standard fluids group. Hyponatremia occurred in 53% of the Plasma-Lyte group and 58% of the standard fluids group and these results were not statistically significant. The authors highlight that the hyponatremia was likely secondary to the high volumes of fluid administered (often exceeding 3 times usual maintenance amounts) compounded by impaired free water excretion, ADH response, in the immediate post-transplant setting. Interestingly, hypernatremia was more frequent in the Plasma-Lyte group, but there was significantly less hyperchloremia, acidosis and hypomagnesemia and no differences in potassium dysregulation.
What is quite clear is that more studies are desperately needed to inform safety and efficacy and to ensure that children get the best care for children. While we all want transplanted kidneys to survive, we believe it is premature to conclude that adult data about balanced fluids are applicable to pediatric recipients. We hope that by submitting this response, we can organize the SPA community to collaborate with our nephrology colleagues to form a multi-center collaborate to study this issue.
References
1. Collins MG, Fahim MA, Pascoe EM, Hawley CM, Johnson DW, Varghese J, Hickey LE, Clayton PA, Dansie KB, McConnochie RC, Vergara LA, Kiriwandeniya C, Reidlinger D, Mount PF, Weinberg L, McArthur CJ, Coates PT, Endre ZH, Goodman D, Howard K, Howell M, Jamboti JS, Kanellis J, Laurence JM, Lim WH, McTaggart SJ, O'Connell PJ, Pilmore HL, Wong G, Chadban SJ, Investigators BE-F, Australasian Kidney Trials N: Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial. Lancet 2023; 402: 105-117
2. Hayes WN, Laing E, Brown R, Silsby L, Smith L, Thomas H, Kaloyirou F, Sharma R, Griffiths J, Hume-Smith H, Marks SD, Kessaris N, Christian M, Dudley J, Shenoy M, Malina M, Muorah M, Ware N, Yadav P, Reynolds B, Bryant W, Spiridou A, Wray J, Peters MJ: A pragmatic, open-label, randomized controlled trial of Plasma-Lyte-148 versus standard intravenous fluids in children receiving kidney transplants (PLUTO). Kidney Int 2024; 105: 364-375
3. Williamson SJ, Plant ND, Shenoy M: Use of normal saline and incidence of dyselectrolytaemia in children following kidney transplantation. Pediatr Nephrol 2022; 37: 2127-2130
4. Hayes W, Longley C, Scanlon N, Bryant W, Stojanovic J, Kessaris N, Van't Hoff W, Bockenhauer D, Marks SD: Plasma electrolyte imbalance in pediatric kidney transplant recipients. Pediatr Transplant 2019; 23: e13411
5. Wyatt N, Norman K, Ryan K, Shenoy M, Malina M, Weerassoriya L, Merritt J, Balasubramanian R, Hayes W: Perioperative fluid management and associated complications in children receiving kidney transplants in the UK. Pediatr Nephrol 2023; 38: 1299-1307
6. Hayes W, Laing E, Foley C, Pankhurst L, Thomas H, Hume-Smith H, Marks S, Kessaris N, Bryant WA, Spiridou A, Wray J, Peters MJ: Multicentre randomised controlled trial: protocol for Plasma-Lyte Usage and Assessment of Kidney Transplant Outcomes in Children (PLUTO). BMJ Open 2022; 12: e055595