Ketorolac use in neonates and young infants: Lots of anecdotes and opinions not a lot of data
Rita Agarwal MD, FAAP, FASA and Lynne G. Maxwell MD
Pharmacist: “Doctor, you wrote for 20 mg of ketorolac on this patient, did you mean 15mg?” “Me: “The patient is 40 mg, I wanted 0.5 mg/kg “
Pharmacist: “But our vials come in 15 mg vials, and 15 mg is just as good as 20 mg, can’t we use 15 mg instead”.
Me: “But the patient just had spine surgery, the studies in adults advocating for 15mg doses of ketorolac were done in the ED, I don’t know that they apply to post-operative pain in children.”
Pharmacist: silence……..
Me: “Whatever, fine, let’s go with 15mg.” (which was later increased back to 20 mg 2 days later because of difficult pain control)
Later that week, I was working with one of our excellent fellows doing a pyloric stenosis. As we discussed the anesthetic plan, I mentioned that I routinely administer a single dose of ketorolac in my babies undergoing pyloric stenosis. He was surprised and didn’t think many faculty did that and that he had learned in residency not to use ketorolac in infants less than 6 months. That conversation then morphed into a general conversation about dosing and safety of ketorolac..
Like any good fellow, he immediately did a quick PubMed search to look at both dosing strategies and lower age limit for safe use of ketorolac. We found several interesting recent reviews, which I am going to share for today’s PAAD. The first question “is ketorolac safe in young infants?” I found 3 recent reviews looking at this question.
Original articles
Nicole A McElroy, Anna Bustin, Sarah Gattoline. Evaluation of the Safety of Ketorolac in Postsurgical Infants Less Than Six Months of Age. Pediatr Pharmacol Ther. 2022;27(4):347-351.
PMID: 35558356 PMCID: PMC9088443
Stone SB. Ketorolac in Postoperative Neonates and Infants: A Systematic Review. J Pediatr Pharmacol Ther. 2021;26(3):240-247. PMID: 33833624; PMCID: PMC8021237
Ziesenitz VC, Welzel T, van Dyk M, Saur P, Gorenflo M, van den Anker JN. Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years. Paediatr Drugs. 2022 Nov;24(6):603-655. doi: 10.1007/s40272-022-00514-1. Epub 2022 Sep 2. PMID: 36053397; PMCID: PMC9592650
While the literature is not robust, and the total numbers of patients studied is small, the 1 retrospective safety study (McElroy) and 2 reviews seem to indicate that there are only minor adverse events when using ketorolac even in neonates and infants. McElroy and colleagues1 are pharmacists who retrospectively examined the use of ketorolac in children less than 6 months of age in the immediate postoperative period at their institution (CHOP). Patients with risk factors such renal disease, or coagulation issues, or those who didn’t receive ketorolac in the first 72 hours were excluded. There were 125 patients that met their criteria, mean age was 53 weeks post menstrual age (PMA) with a range of 47-59 weeks), mean weight 5.6 kg (range 4.3-6.9 kg). Their primary outcome was evidence of bleeding based on decreased Hb and/or clinical bleeding evidence, and renal complications. There was a 1.6 % incidence of decreased Hb by 2 gm and a 3.2% incidence of renal dysfunction (decreased UOP or decreased GFR). There were no clinical signs of bleeding noted in the medical records and no obvious renal injury documented. There is no discussion about other reasons why Hb or UOP could have decreased in these patients or why these particular parameters were picked as the markers of adverse events, although these were the outcomes most commonly reported in previous retrospective studies, with the renal function most commonly reported having been serum creatinine. They did not comment on any other possible adverse events or on the efficacy of pain management. They do not mention how long the patients received ketorolac. Their conclusion was that ketorolac appears to be safe in this patient population. The most frequent dose of ketorolac used was 0.5 mg/kg q 6 hours around the clock. “Based on our results and those previously reported, ketorolac appears to be associated with a low risk of renal injury or dysfunction.”1 The authors hedged their bets by saying “appears” because “larger prospective studies are needed to confirm the safety of ketorolac in this patient population.”1
The articles by Ziesenitz et al.2 and Stone3 are reviews of the literature and meta analysis with considerable overlap, although the Ziesenitz paper discussed all NSAIDS, not just ketorolac. There were a total of 8 studies that reviewed either pharmacokinetics (a minority of studies) or safety of ketorolac in doses of 0.5-1mg (early recommendations were for 1 mg/kg). Many of these reports were single dose administration and some were repeated dosing (most commonly q6h for 48 hours). There were only minor adverse events reported and the authors concluded that ketorolac 0.5mg/kg q 6 hrs was safe and effective in children who were at least 37 weeks post conceptual age and 21 days postnatal age.
PS from Myron: As you can see, the use of ketorolac in neonates and infants < 6 months has really not been studied well. How, or if to use it, is very physician and institution specific. So readers, “Do you use ketorolac in this age group?” “Do you limit the doses and duration of administration” “Do you routinely check renal function and if you do what measures do you use?” Let me know what you think and do and I will post in the Friday Reader Response.
References
1. McElroy NA, Bustin A, Gattoline S. Evaluation of the Safety of Ketorolac in Postsurgical Infants Less Than Six Months of Age. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2022;27(4):347-351. doi:10.5863/1551-6776-27.4.347
2. Ziesenitz VC, Welzel T, van Dyk M, Saur P, Gorenflo M, van den Anker JN. Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years. Paediatric drugs. Nov 2022;24(6):603-655. doi:10.1007/s40272-022-00514-1
3. Stone SB. Ketorolac in Postoperative Neonates and Infants: A Systematic Review. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG. 2021;26(3):240-247. doi:10.5863/1551-6776-26.3.240