On Patient Safety: Concerns About Topical Tranexamic Acid in Spine Surgery

From the Column Editor: The goal of “On Patient Safety” column is to highlight key safety messages about clinically relevant topics. In this month’s guest column, Dr. Tian-qing Li and colleagues discuss the safety issues related to the off-label use of topical tranexamic acid (TXA) in spine surgery. TXA is an antifibrinolytic agent that is widely used around the world to reduce blood loss in joint replacement; its use has recently increased in spine surgery for the same indication. Their column highlights the safety concerns associated with the off-label use of any potent therapeutic agent; however, these concerns are heightened in this case by the serious risk of inadvertent intrathecal administration of TXA resulting from an intraoperative dural tear or other complication, which can lead to a truly catastrophic result. Their essay spotlights several components needed for the safe use of off-label drugs and medical devices. The authors discuss the increased need for appropriate informed consent for our patients whenever we use TXA off-label, and they also note serious knowledge gaps among surgeons who routinely use this product off-label. Additionally, the authors highlight the need for appropriate studies to confirm the safety profile of off-label uses of TXA. Many surgeons use drugs and devices off-label in ways that are safe. Addressing the concerns pointed out by Dr. Li and colleagues in off-label usage of TXA will increase patient safety for this drug, and doing so points the way for safer administration of other off-label therapeutics. — James Rickert MD Introduction Tranexamic acid (TXA) is used in numerous orthopaedic settings to minimize blood loss and reduce the usage of blood transfusions. In orthopaedics, TXA usage in hip and knee arthroplasty is now routine [3], but anecdotally, we are seeing an increase in the usage of TXA during spine surgery [8, 9, 21], where TXA applied topically before wound closure is considered an effective bleeding management option [8, 21]. We believe that this is a dangerous practice, and surgeons should not use topical TXA in routine spine surgery until or unless its safety has been demonstrated in studies large enough to provide precise estimates of its potential risks and harms. Case series and randomized trials will be too small to achieve that goal [13]. Complications of TXA in the Spine Are Underappreciated Although neurotoxicity to the central nervous system [12, 17, 21] has been reported due to inadvertent intraspinal use of TXA instead of local anesthetics, there are few reports of this occurrence when TXA is administered topically during spine surgery [8, 9, 21]. We believe these adverse events are happening, but they are underreported by researchers and underappreciated by orthopaedists and spine surgeons alike. We do not believe that researchers are doing enough to emphasize this very serious complication. Dural and arachnoid tears are common complications of spine surgery [5, 18]; they represent potential ports through which topical TXA can enter spinal fluid and the central nervous system. Currently, there is no FDA-approved (that is, on-label) indication for topical TXA [2, 20]. In fact, the FDA has warned that intrathecal TXA may result in potentially life-threatening problems, such as seizures, cardiac arrhythmias, paraplegia, permanent neurological injuries, and death [4]. But the prescribing information in China is less detailed, noting that intravenous TXA may pass through the blood-brain barrier and enter the cerebrospinal fluid, which in rare cases, can result in blurred vision, headaches, dizziness, and fatigue [20]. Seizures and death were not included in this prescribing information. Safety Concerns About Intrathecal TXA Extend Beyond Complications Beyond the potential complications associated with topical TXA in spine surgery, there have been several published reports of safety issues related to topical TXA. One 2019 report found that inadvertent intraspinal use of TXA instead of local anesthetics was the second most frequent medication error, behind only abbreviating “tPA” and “TXA,” which can lead to confusion between alteplase and tranexamic acid [11]. In 2020, the National Alert Network, which is comprised of members of the National Coordinating Council for Medication Error Reporting and Prevention, learned of three instances of accidental spinal injection of TXA instead of local anesthetics. All three patients experienced seizures and fell into a coma for several days [1, 10, 19]. Although one must be careful drawing broad inferences about efficacy from case reports, they are not a bad way to detect initial safety concerns. One reported that a patient was given 350 mg of intrathecal TXA instead of levobupivacaine; it took more than 2 months for the patient’s neurological status to improve [6]. Another case report described a 54-year-old woman who had revision lumbar decompression and instrumented fusion that was complicated by dural and arachnoid tears with a cerebrospinal fluid leak; despite that, the surgeon injected 1.0 g of TXA epidurally [7]. Within minutes of the conclusion of that procedure, the patient complained of urethral discomfort, hypoxia, and convulsions. Fortunately, that patient gradually improved after spinal fluid drainage, sedation, and treatment with antihistamines. A case series found that 20 of 21 patients who accidentally received spinal TXA administration experienced that medication error because surgeons confused the vials [17], and 20 of 21 experienced life-threatening neurological or cardiac complications resulting in resuscitation or intensive care; 10 patients died [17]. In all likelihood, published reports like these represent only a small portion; the real frequency of these serious complications likely is underreported (and so will be underestimated) [16]. For those reasons and others, spinal TXA has been called “a new killer” [15]. Results of This Peculiar Silence Despite these sporadic warnings, the relative silence on this topic seems peculiar—and dangerous—to us. The lack of coverage on this topic is reflected in the practice patterns in our country, which also strike us as potentially dangerous. One recent online survey of 9699 orthopaedic surgeons in China found that 88% of participants did not know about the potential complications that may occur if TXA finds its way into spinal fluid, 92% of participants did not realize that TXA used topically could reach the spinal fluid, and 95% of participants did not know how to treat the patient in the event TXA gets into spinal fluid [14]. Solutions Orthopaedic surgeons need to know that there are no FDA-approved indications for topical TXA, and that they should not use it unless there are some strong, specific indications to justify off-label use of this product in a particular patient's circumstances (such as much greater than expected blood loss, or patients with severe cardiovascular risk who might poorly tolerate acute postoperative anemia). We believe such circumstances are rare. If a surgeon wishes to use TXA (or is contemplating using it), that surgeon should get the patient’s specific informed consent. Certainly, all spine surgeons need to learn about the potential neurotoxicity of TXA. Given the medication errors that have been documented in association with topical TXA (including medication-vial errors, confusing intravenous with topical TXA, or inadvertently using TXA when local anesthetic was intended), if a drug is to be used intraspinally, we suggest surgeons consider following the four practice recommendations to prevent errors during spinal anesthesia as suggested by Patel et al. [16, 17] (Table 1). And, of course, it should never be used topically in the spine if a dural or arachnoid tear is seen or even suspected. Avoiding the use of topical TXA is no great loss, we believe, since intravenous administration of TXA is similarly effective to topical use in reducing perioperative blood loss [3, 8, 21]. Table 1. - Four practice recommendations to prevent adverse events during the administration of spinal anesthesia [17] 1. Careful reading of the label on any drug ampoule or syringe before the drug is drawn up or injected 2. Labeling all syringes 3. Checking labels with a second person or a device (such as a barcode reader linked to a computer) before the drug is drawn up or administered 4. Use of non-Luer connectors on all epidural/spinal/combined spinal-epidural devices Finally, we encourage spine surgeons worldwide to collect, report, and publish any complications and medication errors associated with topical TXA in the spine. Larger research efforts should use large-database settings to link the use of topical TXA with inpatient complications after spinal surgery to help us arrive at more precise estimates of event frequencies. Studies of that design are both possible and very important to perform.