Right median nerve electrical stimulation for acute traumatic coma (the Asia Coma Electrical Stimulation trial): study protocol for a randomised controlled trial

The incidence of traumatic brain injury (TBI), which is the most common cause of death and disability in persons between 15 and 30 years of age, has increased as a result of heavy traffic [1, 2]. Approximately 10–15% of patients with severe TBI end up in a coma or vegetative state [1, 3, 4]. It is now believed that coma is a self-limiting state that typically evolves within 2–4 weeks into a vegetative state (VS), minimally conscious state (MCS), or conscious state (CS) [5]. A VS is a condition of wakeful unconsciousness in which patients can open their eyes spontaneously but cannot understand, communicate or behave purposefully. An MCS is a condition of severely altered consciousness characterised by minimal but definite behavioural evidence of self-awareness or environmental awareness. The examiner may elicit clear evidence of volitional behaviour on one examination, but fail to do so during a subsequent examination conducted hours or even minutes later [6, 7]. Coma and its unfavourable successions, VS and MCS, have become a heavy burden for families and society.

Neuroscientists are working on how to speed recovery and improve the functional outcomes and prognosis of these patients. Treatments including pharmacological interventions, right median nerve stimulation (RMNS), sensory stimulation, dorsal column stimulation, transcranial magnetic stimulation, deep brain stimulation and hyperbaric oxygen therapy have all been used to better achieve rehabilitation goals [3, 8‐12]. No treatment has been proven robustly to alter the pace of recovery or improve the neurological outcomes of comatose patients following TBI.

As a simple, inexpensive, non-invasive technique, RMNS for coma arousal has a history of more than two decades. The application of electrical current to the extremities to treat central nervous system injury was first introduced in 1972 at the University of Virginia [13]. Radio-linked electrodes were surgically implanted on the bilateral femoral and sciatic nerves of a paraplegic patient to produce a semblance of walking using an external switch. Unexpectedly, in the mid-1980s researchers at Duke Biomedical Engineering not only noted a significant improvement in motor responses to electrical pulses in the stimulated arm of a quadriplegic subject, but also discovered a crossover effect of improvement in the strength of the proximal muscles of the unstimulated arm [14, 15]. This observation of intracerebral transfer led to the development of median nerve electrical stimulation for coma arousal. The first article about median nerve electrical stimulation for acute coma was published in 1999 [16]. Since then, RMNS has drawn increasing attention from many intensivists, rehabilitationists and clinical researchers [3, 5, 14, 17‐23].

Among the articles published on RMNS, three randomised trials give some clues about the efficacy of this treatment. In the first randomised, double-blind study, a group of six comatose patients with TBI were randomised to receive RMNS treatment or sham stimulation. The RMNS group recovered more quickly, with a shorter intensive care unit (ICU) stay and improved Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) scores 1 month after the injury [16]. In a double-blind randomised controlled trial with six RMNS-treated patients and four controls, the RMNS group emerged from coma 2 days earlier and scored higher in the Functional Independence Measure/Functional Assessment Measure (FIM/FAM) 3 months post injury [19]. In a third double-blind randomised controlled trial conducted by Lei and colleagues, 437 comatose patients with severe TBI were enrolled 2 weeks after their injury and assigned to the RMNS group or the control group according to their date of birth. The RMNS-treated patients had a more rapid increase in mean GCS, a significantly higher proportion of them regained consciousness and a lower proportion ended in VS. For those patients who regained consciousness, the FIM score was higher among the RMNS group [24].

Non-randomised controlled trial studies and reviews, although not as convincing, also indicate that RMNS may play a role in the emergence from coma following severe brain injury. For example, Liu and colleagues used RMNS on six comatose patients for 3 months. Four patients regained consciousness within 35 days, and brain perfusion increased in all six cases assessed by single-photon emission computed tomography (SPECT) scans after stimulation [20]. A review by Cooper and colleagues concluded that RMNS is a promising therapy for the neuroresuscitation of comatose patients, and time in the ICU may be shortened and the quality of the final outcome enhanced when the stimulation is applied early in the coma [18].

The trials selected had limitations due to the small number of cases analysed in most studies, inappropriate methods of randomisation in some cases, the diversity in coma length and coma severity, the heterogeneity of outcome measures, the different timing of intervention and follow-up and the lack of multicentre studies. We designed the ACES trial with an adequate sample size and a standardised protocol to obtain convincing evidence about the efficacy and safety of RMNS in both accelerating emergence from coma and promoting long-term outcomes.

Right median nerve electrical stimulation has been adopted as a safe, inexpensive, non-invasive therapy for the neuroresuscitation of coma patients for more than two decades. There are several advantages to stimulating the right median nerve instead of other parts of body. First, the right median nerve is a peripheral portal to the central nervous system, and the sensory representation of the hand in the cortex is disproportionately large compared to other parts of the body. Second, Broca’s motor/speech planning area is in the left frontotemporal region in most individuals. Several possible mechanisms may underlie the effects of this treatment.

The first is that the spinoreticular component of the median nerve pathway synapses with neurons of the ascending reticular activating system (ARAS) [14]. The ARAS is a complex neural network connecting the reticular formation of the brain stem to the cerebral cortex via excitatory relays in the intralaminar nuclei of the thalamus. Therefore, the ARAS plays an important role in maintaining a state of wakefulness [26‐29]. Studies have shown that the ARAS is activated by RMNS applied with a painful intensity [30], which may be a pathway for the therapeutic function of electrical stimulation.

A second mechanism is related to neurotrophins such as nerve growth factor and brain-derived neurotrophic factor (BDNF). Neurotrophic factors, which play an important role in neuroplasticity, may promote synaptic remodelling and changes in receptor expression or activation [31]. Previous studies have found that BDNF might enhance the survival of neurons after a hypoglycaemic coma [32]. Studies have also shown that BDNF levels increase in environmental enrichment animals compared to those housed in standard conditions [33]. RMNS, serving as a type of environmental enrichment, may raise the concentration of neurotrophins, leading to the survival of more neurons and hastening the recovery of comatose patients.

Increases in cerebral blood flow may be another pathway through which RMNS functions. In a research project conducted by Liu and colleagues, six comatose patients underwent SPECT scans for cerebral perfusion evaluation before and after the stimulation, and brain perfusion was found to have increased in all cases [20]. Other mechanisms include RMNS-induced changes in neurotransmitters such as dopamine and glutamate [34, 35] and improved electroencephalogram activity [16].

Over the years, a great number of researchers have focused on this treatment. However, because of the limitations of the studies mentioned above, its efficacy in accelerating recovery and improving overall outcomes has not been well established. Our ACES trial addresses right median nerve electrical stimulation therapy applied at an early phase (7–14 days post injury), with a standard stimulation protocol continuing for 14 days and with follow-up for 6 months.

This trial has some novel features compared with other major RMNS trials. First, it is an Asian multicentre randomised controlled trial. The previous trials only focused on one region or even a single hospital. This trial is the first to widen the scope to a whole continent, reducing selection bias to a great extent. Second, in this trial, the RMNS therapy starts at an early stage, 7–14 days after the injury. Research shows that the later the application of electrical stimulation, the longer the duration needed to obtain a similar outcome [14]. Earlier commencement of neuroresuscitation treatment can show more efficacy, as long as the patient is stable. Third, the ACES trial uses various kinds of assessment scales to evaluate the condition of participants. The assessments fall into two groups: recovery pace parameters and long-term outcome parameters. The former group includes the GCS, GMS and FOUR. The GCS includes eye opening, verbal and motor responses. It has been used ubiquitously in acute care databases and in studies of acute neurologic injury. However, the GCS has been deficient in measuring key components of neurologic examination used for prognostication and most conspicuously lacks assessment of the brainstem reflexes. The FOUR score has been developed to overcome these inadequacies. It consists of four components that evaluate eye responses, motor responses, brainstem reflexes and respiration patterns. Because of its greater neurologic detail, the FOUR score is of more benefit than the GCS in predicting mortality in the ICU. A recent large multicentre prospective study in critically ill patients found an excellent inter-rater agreement between paired clinicians [36‐38]. The long-term outcome parameters are the CRS-R, DRS and GOSE. The CRS-R is a standardised neurobehavioural assessment tool comprising six hierarchically organised subscales (auditory, visual, motor, oromotor–verbal, communication and arousal). Scores range from 0 to 23, with higher scores indicating a higher level of neurobehavioural function [1]. The DRS, a measure of functional outcome, includes measures of eye opening, verbalisation and motor response; cognitive understanding of feeding, dressing and grooming; degree of assistance and supervision required; and employability. Scores range from 0 to 29, with higher values indicating greater disability [1, 39]. The GOSE has eight ordered categories: death, vegetative state, lower severe disability, upper severe disability, lower moderate disability, upper moderate disability, lower good recovery and upper good recovery. It was developed as an extended version of the GOS in response to the perceived lack of sensitivity of the latter. It is now the primary outcome measure in trials of TBI [40]. Using all these scales, we hope to evaluate the condition of the coma patients as thoroughly as possible.

TBI-related coma remains an important topic for today’s neuroscientists owing to its high incidence, poor outcomes and the heavy burden it places on families and society. RMNS therapy is promising. It is hoped that the ACES trial will provide valuable information regarding the question: Is right median nerve electrical stimulation able to facilitate a faster awakening and a better long-term outcome in TBI comatose patients? and lead to optimal use of median nerve electrical treatment.

The study is currently recruiting participants.