Dantrolene for Control of Refractory Shivering in Severe Traumatic Brain Injury: A Case Study

Introduction

Traumatic brain injury (TBI) is the leading cause of death and disability worldwide [1,2]. TBI can be classified into primary brain injury, which occurs at the time of the incident, and secondary brain injury, which is exacerbated by various post-injury factors, such as hypoxia, anemia, hyperthermia, shivering, and epilepsy. Limiting secondary brain injury is the primary goal of critical care for patients with TBI.

Fever is linked to poorer outcomes following TBI, likely due to exacerbation of secondary brain injury [3]. Fever can worsen intracranial pressure (ICP) control by increasing metabolic demand, blood flow, and blood volume [3]. In severe TBI, defined as a Glasgow coma scale (GCS) score ≤8, the shivering and abnormally high body temperature are often intractable and can increase metabolic demand and worsen brain tissue oxygenation, resulting in difficult ICP management [4,5]. However, no effective treatment for intractable shivering has been established or standardized in clinical practice [6].

This case report describes the successful management of refractory shivering using dantrolene sodium hydrate in a patient with severe TBI, contributing to a better understanding of the potential treatment pathways for similar cases.

Case Report

A 28-year-old healthy, inebriated male pedestrian was injured during a collision with a car. The car windshield was severely damaged. Upon admission, his measurements were as follows: height, 175 cm; body weight, 66 kg; and body mass index, 21.6. Initial assessments revealed a GCS of E1V1M1, blood pressure of 150/80 mm Hg, heart rate of 90 beats/min, respiratory rate of 30 breaths/min, and SpO2 of 99% on 10 L/min of oxygen. His body temperature was 36.2°C, and he exhibited anisocoria, with pupil diameters of 6 mm (right) and 3 mm (left), both with blunted light reflexes. He sustained a fracture of the right tibia and fibula, but no chest, abdominal, or pelvic trauma. Blood tests results revealed a white blood cell count of 14 670/µL, C-reactive protein level of 0.39 mg/dL, D-dimer level of 38.68 μg/mL, creatine kinase level of 323 IU/L, and a blood alcohol concentration of 219 mg/dL. Computed tomography revealed a right acute subdural hematoma, with midline shift, occipital bone fracture, and pneumocephalus (Figure 1).

Once the patient’s respiratory and circulatory statuses stabilized, percutaneous hematoma drainage and ICP sensor insertion were performed (Figure 2). This was followed by red blood cell transfusion and the administration of fresh frozen plasma. After correcting for coagulation, decompressive craniectomy and bilateral ventricular drainage were performed in the operating room. General anesthesia with propofol and fentanyl was continued for ICP management. An intravascular cooling device (Thermogard XP system, Asahi Kasei ZOLL Medical Corporation, Japan) initiated targeted temperature management (TTM), with a set point of 35°C. On the second day after injury, generalized shivering occurred, prompting continuous administration of midazolam and rocuronium, increasing the target temperature to 36°C, which subsequently controlled the shivering and regulated the body temperature and ICP.

By day 7, the body temperature and ICP stabilized, allowing for the removal of ventricular drainage and cessation of the cooling device. However, shivering recurred on day 9 and was accompanied by hyperthermia. Although a systemic examination ruled out meningitis or other infectious diseases, cefazolin, gentamicin, and tazobactam/piperacillin were administered. We speculated that the hyperthermia might be due to hypothalamic damage or malignant syndrome, leading to the resumption of TTM at 36°C. Despite the use of antipyretic analgesics (propofol, midazolam, and fentanyl), the shivering persisted. Even after the administration of magnesium sulfate, the shivering remained uncontrolled. Consequently, a single dose of intravenous dantrolene 40 mg was added to the treatment regimen, which effectively eliminated the shivering and stabilized the body temperature. The dosages of the other drugs were as follows: propofol 5.1 µg/kg/min, midazolam 1.5 µg/kg/min, and dexmedetomidine 0.6 µg/kg/min. By day 13, the ICP was well managed, allowing us to conclude TTM. Sedative medications were discontinued on day 18, and the patient quickly became responsive. Cranioplasty was performed on day 32. After substantial recovery, the patient was transferred to a rehabilitation hospital on day 70, without any neurological deficits, achieving a GCS score of E4V5M6 and a modified Rankin scale score of 1.

Discussion

In this report, we present the case of a 28-year-old healthy male who experienced refractory shivering after severe TBI. After conventional methods failed, we successfully managed shivering and the associated hyperthermia by introducing dantrolene. This intervention highlights the potential of dantrolene as an effective treatment for controlling complications in patients with severe TBI.

Shivering is a physiological response caused by a discrepancy between the set point of body temperature control and the peripheral body temperature [7]. Refractory shivering can more than double the basal metabolic rate, due to systemic muscle contractions, thereby increasing systemic oxygen demand. Moreover, a rise in deep body temperature can increase the basal metabolic rate by approximately 0.5°C per hour [7,8]. Elevated body temperatures above 37.5°C have been shown to exacerbate ICP, thus complicating management [9–11]. Thus, suppression is critical, as it aids in temperature and ICP control, thereby preventing secondary brain injury. In the present case, we speculated that the most likely causes of shivering were hypothalamic disorders, abnormalities in the temperature regulatory center, and catecholamine surges.

Anesthetics, such as propofol, opioids, alpha agonists, 5-hydroxytryptamine uptake inhibitors, cholinesterase inhibitors, and N-methyl-D-aspartate antagonists, target the temperature control center and suppress shivering by minimizing the temperature differential. Non-pharmacological interventions, such as percutaneous counter-warming, also contribute effectively, although they may not always eliminate shivering [12].

Previous studies have used assessment scales and stage-based treatments to evaluate and manage shivering [13–16]. For instance, the Bedside Shivering Assessment Score (BSAS) by Norisue et al [13], designed to gauge and sequentially treat shivering, was applied in the present case but failed to halt the symptoms. We assessed and treated the patient using the BSAS; however, conventional treatment methods failed to stop the shivering effectively.

Dantrolene is commonly used to treat malignant hyperthermia; however, it has also been reported to be effective in managing shivering [8,15–17]. Lin et al [8] reported that dantrolene significantly reduced the shivering threshold by influencing central thermoregulation and diminishing peripheral muscle contractility, which can be associated with shivering. Additionally, by reducing peripheral muscle contractility, dantrolene decreases the thermogenic response to shivering by 30 kcal/h, thereby aiding thermoregulation. This indicates that dantrolene may be effective in treating refractory shivering through a mechanism distinct from that of traditional anesthetics. However, the evidence supporting this theory is limited. Nevertheless, in our experience with a patient with TBI, a single dose of dantrolene effectively prevented shivering. This case highlights the potential of dantrolene as an effective treatment for controlling refractory shivering, because the patient did not experience shivering after a single dose of dantrolene, without any changes to other medications.

Hyperthermia following severe head injury is believed to be linked to abnormalities in body temperature regulation centers [16–18]. Conversely, most drugs used in the BSAS protocol are designed to target body temperature regulation centers. Conversely, dantrolene, which modulates peripheral muscle contractility, may be an effective alternative for preventing shivering following severe head injury through a different mechanism. However, the therapeutic efficacy of dantrolene in treating disorders related to temperature regulation centers, such as postcardiac arrest syndrome, has not been established. Consequently, the use of dantrolene is limited to specific conditions. More clinical experience and data accumulation are necessary to expand approved applications.

Conclusions

This case demonstrates the potential effectiveness of dantrolene in managing refractory shivering and hyperthermia after severe TBI. However, further research is required to confirm its broader efficacy in treating thermoregulatory disorders.