Abstract
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Convulsions are a neurological illness that has complexity. In clinical treatment, drug-induced convulsions appear from time to time. Drug-induced convulsions often begin as isolated acute seizures but may progress to persistent seizures. In orthopedics, topical administration of tranexamic acid is commonly used in conjunction with intravenous drip to achieve hemostasis during artificial joint replacement surgery. However, side effects induced by tranexamic acid accidental spinal administration should be taken seriously.
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We report a case of a middle-aged male treated with tranexamic acid locally in combination with intravenous drip for intraoperative hemostasis when undergoing spinal surgery. The patient had involuntary convulsions in both lower limbs after the operation. After symptomatic administration, the symptoms of convulsions gradually resolved. During the follow-up, the convulsions never occurred again. We reviewed the literature on cases with side effects of local tranexamic acid application in spinal surgery and discussed the mechanism of tranexamic acid-induced convulsions.
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Tranexamic acid is associated with an increased incidence of postoperative seizures. However, many clinicians are unaware that tranexamic acid causes seizures. This rare case summarized the risk factors and clinical features of these seizures. Moreover, it highlights several clinical and preclinical studies that offer mechanistic insights into the potential causes and treatments for tranexamic acid-associated seizures. A clear understanding of tranexamic acid-induced convulsions-related adverse reactions can help the first-line clinical screening of causes and adjustment of drug treatment. This review will aid the medical community by increasing awareness about tranexamic acid-associated seizures and translating scientific findings into therapeutic interventions for patients.
Introduction
Seizures refer to involuntary convulsion or intense contraction of groups of skeletal muscles in the whole body or parts that can be convulsed to cause joint movement and ankylosis (1). The onset of convulsions may be associated with various factors, including brain disease, systemic disease, and neurosis. In clinical treatment, the symptoms of an epileptic seizure, referred to as drug-induced seizures caused by improper medication, appear occasionally. Drug-induced convulsion is the main form of adverse reactions, such as brain toxicity. Drug-induced seizures often begin as isolated acute seizures but may potentially progress to persistent seizures.
Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine-binding sites on plasminogen molecules (2). TXA decreases hemorrhage-related mortality in trauma patients and is increasingly used during obstetric and orthopedic surgeries. Systemic TXA administered at the outset of surgery reduces intraoperative blood loss and blood loss from drained spaces such as the knee or mediastinum but may be contraindicated in patients with intravascular stents or thrombophilia (3). Topical application of TXA to the bleeding surface can inhibit local fibrinolysis at the bleeding site, reducing bleeding with minimal systemic effects. The effects of topical TXA have been evaluated primarily during not only orthopedic surgery (4) but also head and neck surgery (5) and cardiac surgery (6, 7). A systematic review identified 28 trials that compared topical TXA in surgical patients (cardiac, thoracic, spinal, knee, or head and neck surgery) with no TXA or placebo (8). Blood loss was significantly reduced in those who received TXA (pooled ratio: 0.71, 95% CI: 0.69–0.72), which decreased the need for blood transfusion.
Local administration of TXA is common in orthopedics, especially in joint surgery in combination with intravenous drip for intraoperative hemostasis during artificial joint replacement surgery. However, there is no unified standard on the route of administration, dose, timing, and way to improve the safety of TXA. Even if the drug is given locally, it should only be used in the subcutaneous and muscle around the incision. What happens if TXA enters the spinal canal or the cerebrospinal fluid?
Recently, we used TXA local combined with intravenous administration in a patient with lumbar spine surgery for intraoperative hemostasis. Four hours after the operation, the patient had an attack of involuntary convulsions in both lower limbs. To further clarify the pathophysiological mechanism and incidence of convulsion induced by TXA, a literature review of the side effects of topically-used TXA was done.
Case report
A 43-year-old male with good health without an extraordinary drug history record suffered recurrent backache for 3 years without apparent incentives, relieved after rest and aggravated after activity. The patient's backache aggravated in the past 3 months, accompanied by radiating pain in the left lower extremity (buttock, back of the left calf). The MRI showed lumbar 5/sacral 1 (L5/S1) intervertebral disc herniation (Fig. 1A and B). The pain has not been relieved after conservative treatment for 3 months. The patient underwent ‘transforaminal lumbar interbody fusion’ on March 25, 2021. The patient received cefazolin and anesthetic drugs for infection prevention and analgesia. General anesthesia with endotracheal intubation, intraoperative exposure of the superior articular process of the L5/S1, and two pedicle screws were placed into the superior joints on both sides, respectively. The disc space was exposed on both sides by removing the facet joints and protecting the nerve roots. It was seen that the bilateral L5/S1 intervertebral disc herniation on the left side was mainly noticeable herniation, which compressed the S1 nerve root, resulting in edema of the left S1 nerve root.
MRI performed with T2-weighted shows L5/S1 intervertebral disc herniation (A: sagittal; B: axial). Repeat CT shows the screw in L5 vertebrae (C) and S1 (D).
Citation: EFORT Open Reviews 8, 6; 10.1530/EOR-23-0016
The disc space was entered, and the disc material was removed. An interbody cage filled with bone graft was placed into the disc space to maintain the disc height. Intraoperative exploration showed that the dural sac was filled, the outer membrane was intact, and no clear liquid was educated. During the operation, TXA was administered intravenously and locally through the incision before suture, 1 g each. Moreover, two indwelling drainage tubes were placed. Intraoperative neurophysiological monitoring showed no abnormality, and intraoperative blood loss was about 150 mL. (The operation ended at 16:25.) At 20:18, the patient had occasional involuntary convulsions of both lower extremities, and the lower back drainage tube was opened. When the patient attached convulsions, arterial blood gas analysis and electroencephalograph (EEG) were performed. Electrolyte levels were in the normal range. No abnormality was found in the EEG (as shown in Fig. 2), which ruled out hypocalcemia causing convulsions, and epileptic seizures were not considered. At 20:30, the convulsions of both lower extremities were more frequent, and diazepam 5 mg was given intravenously. At 23:30, the patient's oxygen saturation dropped, the patient presented with pyrexia and tachycardia. Hence, tracheal intubation was performed, and the patient was transferred to ICU for further treatment. The patient was given symptomatic treatment during the ICU, such as mechanical ventilation, propofol sedation, and sufentanil analgesia. The patient's lower extremity convulsions improved the next day, and the vital signs were stable. The tracheal intubation was removed.
The result of electroencephalograph.
Citation: EFORT Open Reviews 8, 6; 10.1530/EOR-23-0016
On the 27th, there were occasional convulsions. On the 28th, there were still convulsions in the lower limbs, but they were better than before; on the 29th, there were no convulsions. Repeat CT showed that the screw did not cause nerve root injury (Fig. 1C and D). On March 31, the drainage volume was relatively negligible, so the drainage tubes on both sides were removed (the drainage fluid of the patients every day after surgery was blood-red, and the drainage flow was less than 60 mL). The patient's test indicators gradually improved, and finally, he was discharged from the hospital. During a year follow-up, the patient did not experience convulsions of both lower extremities again and currently has no symptoms of low back pain, and the convulsions never occurred again.
Discussion
We conducted a comprehensive review and analysis of the treatment process. Convulsions caused by cephalosporins and anesthetic drugs were more likely to present as generalized convulsions. However, the patient's convulsions were limited to both lower extremities. Thus, the possibility that these two drugs caused the convulsions was ruled out.
During the operation, it was observed that the patient had bilateral L5/S1 intervertebral disc herniation. However, the left side was mainly noticeable herniation, which compressed the S1 nerve root, resulting in edema of the left S1 nerve root. However, the patient only presented radiating pain and numbness in the left lower limb without any convulsion symptoms before surgery. The patient's nerve compression symptoms were relieved through surgery, and the postoperative review showed that the screw did not contact the nerve. In addition, the convulsions caused by disc herniation were mainly confined to specific lower limb areas. Based on the patient's condition, the L5/S1 disc herniation was more likely to be a simple spasm behind the left calf, but he presented with a spasm in both lower limbs. Therefore, we conceive that the possibility of disc or screw compression can be ruled out.
Inadvertent intrathecal injection of TXA is a rare, potentially lethal event leading to dose-dependent cardiotoxicity and neurotoxicity. The literature about systemic side effects or complications of TXA accidental spinal administration is not comprehensive, and most are case reports. We found that survivors of intraspinal TXA often experience seizures, permanent neurological injury, and paraplegia (9). Further, we collated relevant case reports (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36). Details are shown in Table 1.
Summary of clinical features and sequelae of tranexamic acid.
| Reference | Dose | Sex | Age | Symptoms | Treatment | Outcome |
|---|---|---|---|---|---|---|
| Wong et al. (35) | 75 mg | M | 18 | Motor and sensory block of both lower extremities, urinary incontinence, tonic–clonic convulsions, hyperthermia | Diazepam, diclofenac | Full recovery |
| De Leede-van der Maarl et al. (14) | 50 mg | M | 68 | Immediate status epilepticus | Midazolam, phenytoin, thiopental infusion | Multiorgan dysfunction, critical illness polyneuropathy; bilateral peroneal palsy and cognitive deficits persisting |
| Yeh et al. (36) | 500 mg | F | 49 | Severe pain in back and gluteal region, hypertension, generalized convulsions, VF | Diazepam, CPR, tracheal intubation and ventilation, lidocaine, adrenaline, atropine, amiodarone | Death within hours |
| Garcha et al. (15) | 300 mg | F | 55 | Severe burning pain in lower limbs, myoclonic facial contractions, VF | Tracheal intubation and ventilation | Death within hours |
| Mohseni et al. (25) | 350 mg | M | 57 | Perianal burning, hypertension, myoclonic movements in lower extremities, metabolic acidosis, hypotension | Midazolam, fentanyl, atracrium, phenytoin, diazepam, dexamethasone, sodium valproate, thiopental infusion, sodium bicarbonate, dopamine infusion | Full neurological recovery |
| Sabzi et al. (28) | NR | F | 30 | Severe low back pain, convulsions, tachycardia, hypotension, VF | General anesthesia, diazepam, defibrillation, lidocaine, amiodarone, amrinone, adrenaline | Death |
| Veisi et al. (34) | NR | F | 21 | Severe pain in lower extremities, dizziness, severe jerks leading to seizures, tachyarryhthmias, VT, VF, asystole | General anesthesia, lidocaine, cardioversion, CPR | Death within a few hours |
| Kaabachi et al. (21) | 80 mg | M | 30 | Severe pain in back and gluteal region, myoclonic movements in extremities, hypertension, tachycardia, convulsions | Midazolam, fentanyl, general anesthesia, propofol infusion, clonazepam, thiopental infusion, oral phenobarbital, prophylactic amiodarone infusion | Full recovery |
| Butala et al. (13) | 300 mg | F | 37 | Severe pain in legs, back and gluteal region, myoclonic seizures in legs, severe hypertension, severe tachycardia with premature ventricular contractions | Tracheal intubation and ventilation. Fentanyl, propofol, thiopental, diazepam, phenytoin, dexamethasone, sodium valproate, mannitol, lidocaine, levetiracetam, sodium bicarbonate. Midazolam, thiopental, atracurium and nitroglycerin infusions. CSF lavage | Full recovery |
| Mahmoud & Ammay (24) | 300 mg | M | 54 | Severe pain in back and gluteal region, hypertension, tachycardia, generalized myoclonic seizures, feverish, VF | Fentanyl, midazolam, propofol, lidocaine, mannitol, propranolol, amidoarone, suxamethonium | Full recovery |
| Srivastava et al. (32) | 350 mg | F | 33 | Severe pain in back and lower limbs, restless, hypertension, tachycardia, myoclonic movements, generalized convulsions, cardiac arrest | Midazolam, fentanyl, diazepam, adrenaline, noradrenaline, vasopressin, lidocaine, amiodarone, CPR, tracheal intubation and ventilation | Death within a few hours |
| Antwi-Kusi et al. (12) | NR | F | 27 | Myoclonic seizures limited to the lower limbs and the abdomen, hypertension, cardiac arrest, VT, VF | General anesthesia, anticonvulsants, thiopental | Death |
| Goyal et al. (17) | 250 mg | M | 36 | Pain in the back and lower limbs, tonic deviation of all limbs, uprolling of his eyeballs, hypertension, tachycardia, tonic clonic seizures, status epilepticus | Fentanyl, midazolam, lorazepam, phenytoin, propofol, tracheal intubation and ventilation | Full recovery |
| Roy et al. (27) | 200 mg | F | 26 | Restlessness, severe tachycardia and hypertension, myoclonic contractions in legs, hypoxemia, status epilepticus, pulseless VT | Midazolam, phenytoin, thiopental, amiodarone and noradrenaline infusions, CPR and defibrillation | Full recovery |
| Hatch et al. (20) | 200 mg | F | 31 | Severe back pain, muscle spasm and tetany, severe tachycardia and hypertension, multiple episodes VT | General anesthesia, thiopentone, vecuronium, fentanyl, amiodarone, midazolamand mannitol infusions, dexamethasone, diazepam, labetalol, and phenytoin boluses | Death |
| ElKhateeb & Kamel (22) | NR | F | 21 | Severe pain in buttocks and legs, myoclonus in legs and generalized seizures, severe tachycardia and hypertension, VF, cardiac arrest | General anesthesia, tracheal intubation and ventilation, clonazepam, phenobarbital, midazolam, thiopental, CPR | Death within a few hours |
| Grissinger (18) | NR | F | 68 | Myoclonus of lower extremities and seizures and recurrent VT | Tracheal intubation and ventilated, fosphenytoin | Rehabilitation in community |
| Koch et al. (23) | 200 mg | M | 63 | Full-body myoclonic jerking motions, tachyarrhythmias, hypertension | General anesthesia, midazolam | Full recovery |
| van Lanschot Hubrecht et al. (33) (case 1) | NR | M | 78 | Pain, myoclonic jerks, seizures, hypercapnia, hypertension | General anesthesia | Death after 3 weeks for pneumonia |
| van Lanschot Hubrecht et al. (33) (case 2) | NR | F | 53 | Myoclonus, hemodynamically unstable | CSF lavage | Residual neurological deficits |
| Prior et al. (26) | NR | F | 78 | Generalized myoclonic seizures | Anticonvulsants, pentobarbital, fosphenytoin | Mild cognitive impairment |
| Akodjenou et al. (10) (case 1) | 300 mg | F | 25 | Convulsions of lower limbs, refractory status epilepticus, pulmonary edema | Tracheal intubation and mechanical ventilation, diazepam, midazolam, and thiopentone | Death |
| Akodjenou et al. (10) (case 2) | 300 mg | F | 35 | Similar to case 1 | Similar to case 1 | Death |
| Akodjenou et al. (10) (case 3) | 300 mg | F | 41 | Similar to case 1 | Similar to case 1 | Death |
| Akodjenou et al. (10) (case 4) | 200 mg | F | 46 | Seizures, rhabdomyolysis, multiorgan failure and paraplegia, hemodialysis | Transferred to ICU in another hospital | Full recovery |
| Al-Taei et al. (11) | NR | M | 76 | Myoclonic seizures, hypertension, polypnea | Levetiracetam, midazolam, endotracheal intubation | Death |
| Shah et al. (30) (case 1) | 250 mg | M | 21 | Burning sensation and pain in gluteal region and lower extremities, hypertension, tachyarrhythmias | Midazolam, fentanyl | Full recovery |
| Shah et al. (30) (case 2) | 200 mg | F | 23 | Pain from waist to lower extremity followed by dysphoric dizziness, tachyarrhythmias, VT, VF, asystole | Lignocaine, CPR | Death |
| Serrazina et al. (29) (case 1) | NR | M | 73 | Severe burning pain in perineal region and lower limbs, hemodynamic instability, myoclonus and spinal segmental myoclonus | General anesthesia, midazolam and levetiracetam | Full recovery |
| Serrazina et al. (29) (case 2) | 250 mg | M | 19 | Perianal burning pain, exuberant propriospinal myoclonus | General anaesthesia, midazolam, levetiracetam, valproate, diazepam and morphine | Full recovery |
| Sy Su (31) | 300 mg | M | 14 | Lower limbs and back pain, tachycardia, hypertension | Midazolam, propofol, labetalol, general anesthesia, CSF lavage and spinal drainage | Full recovery |
| Godec et al. (16) | 350 mg | M | 51 | Severe burning pain in the gluteal region and both thighs, myoclonic jerks, diffuse brain swelling, bilateral facial nerve palsy, cauda equina syndrome and spontaneous pathological activity at multiple root levels | General anesthesia, levetiracetam, lacosamide, dexamethasone, propofol, midazolam, fentanyl, and thiopental, magnesium sulfate, right lateral ventricle infusion and lumbar drainage | Neurological status improved. lost to follow-up after 4 months |
| Harby & Kohaf (19) | 400 mg | M | 31 | Back and gluteal pain, myoclonus of the lower limbs, agitation, widespread convulsions | Midazolam, fentanyl, phenytoin, general anesthesia, CSF lavage and spinal drainage | Full recovery |
CPR, cardiopulmonary resuscitation; CSF, cerebrospinal fluid; F, female; M, male; NR, not reported; VF, ventricular fibrillation; VT, ventricular tachycardia.
Through literature, we consider that the reasons for this case of convulsions may be associated with TXA. The mechanism may be that TXA penetrates the cerebrospinal fluid. Intrathecal administration of 1 g of TXA was evenly distributed in 150 mL of normal cerebrospinal fluid, and the concentration reached 6600 μg/mL, which was about 7000 times higher than that after intravenous administration (30). When given intraspinal, TXAinjection is a potent neurotoxin with a mortality rate of about 50% (37). Survivors of intraspinal TXA often experience seizures, permanent neurological injury, and paraplegia (9). Combined with literature and case reports, TXA can cause adverse reactions related to convulsions. Therefore, by analyzing the possible causes, we considered that the possibility of TXA inducing lower limb convulsions could not be ruled out in this case. The drainage volume was small, and the fluid was light-blooded, so the possibility of dural sac rupture was low. The patient's articular processes were destroyed during the operation, and TXA penetrated the intervertebral foramen. The convulsions in the patient may have been caused by increased permeability due to surgical procedures that resulted in dural capillary filling and local damage. This could have allowed tranexamic acid to enter the intrathecal space and trigger convulsions. For this reason, we considered that TXA induced the patient's lower extremity convulsions. The mechanism of TXA-induced epilepsy and muscle spasms mainly directly inhibits γ-aminobutyric acid and glycine receptors located on the postsynaptic site of neurons in the dorsal horn of the spinal cord through TXA, thereby increasing excitability (38). This can be the cause of immediate pain in the back and buttocks as well as myoclonus in the legs, which most patients experience. Treatment remains symptomatic and supportive. Even with a variety of conventional anticonvulsants, seizures could not be terminated (39). However, early cerebrospinal fluid lavage to reduce the concentration of TXA in the cerebrospinal fluid is an effective treatment (19, 31). Unlike previous studies, the spinal surgeons in our case wanted to reduce bleeding around the surgery by applying TXA topically, rather than ampoule error. TXA penetrates into the cerebrospinal fluid, causing convulsions in both lower extremities. Through this case, we realized that the use of TXA around the dura has great safety risks and should be avoided as much as possible in the clinic.
Limitations and enlightenments
We acknowledge the limitations of our study. This paper summarizes our shortcomings and previous literature reports, expecting to deduce a more feasible and scientific conclusion and provide references for aiding the medical community by increasing awareness about TXA-associated seizures. During the diagnosis and treatment process of this case, we identified certain deficiencies in our intervention measures. Specifically, when the patient exhibited lower extremity twitches, an increased heart rate, and shortness of breath, our response was inadequate. After the MDT discussion, diazepam was given according to the advice of the neural department. Reviewing the whole treatment process, we reflected that the severe limitation of this case was lack of experience. Certain defects in intervention measures and treatment decisions failed to confirm this conjecture in multiple dimensions. Although the whole treatment process is not perfect and the clinical decision is not excellent, this paper will bring warnings and lessons for the subsequent research and the decision of clinical workers.
Here, we have some recommendations for spine surgeons (including those in orthopedics and brain or neurosurgery). Any intraspinal misuse of TXA into the cerebrospinal fluid or topical application of TXA during spinal surgery is likely to result in seriously adverse consequences once TXA has been introduced into the spinal canal. When combined with local anesthetics or in the surgical field, local hemostasis with TXA is avoided during spinal surgery. There is no absolute guarantee that tranexamic acid will not inadvertently enter the spinal canal during surgical procedures. If this happens, tranexamic acid can potentially enter the cerebrospinal fluid, which surrounds the spinal cord and brain, and cause adverse effects.
It is suggested that hospitals with similar cases report them as adverse drug reactions of TXA to attract the attention of the corresponding departments. We call on clinicians to publish more case reports of such severe surgical complications, with the seemingly increasing trend of topical use of TXA, with catastrophic consequences. It is called for clinicians to have enough understanding and attention to the harm of TXA entering the spinal canal.
Conclusion
The safety profile of topical TXA after spinal surgery is low. Even if it is clear that the dural tear did not occur, TXA may enter the cerebrospinal fluid through osmosis and induce serious adverse effects. Combined with the above literature and the situation we encountered in clinical practice, we considered the neurological adverse effect induced by TXA as not negligible. Research on TXA's neurological adverse effects needs to be further in depth. Topical TXA in spinal surgery should be avoided in the absence of appropriate evidence-based medical evidence.
ICMJE conflict of interest statement
The authors declare that no conflict of interest could be perceived as prejudicing the impartiality of the research reported..
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
Informed consent statement
Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Author contribution statement
TYQ and HL conceived and designed the project. CJS performed the literature retrieval. YR and HL drafted the article. YS and LC conceived the project and provided suggestions to improve it, HL developed the idea for the study and finally revised the paper.
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