Right Median Nerve Electrical Stimulation for Acute Traumatic Coma Patients

Abstract

The right median nerve as a peripheral portal to the central nervous system can be electrically stimulated to help coma arousal after traumatic brain injury (TBI). The present study set out to examine the efficacy and safety of right median nerve electrical stimulation (RMNS) in a cohort of 437 comatose patients after severe TBI from August 2005 to December 2011. The patients were enrolled 2 weeks after their injury and assigned to the RMNS group (n=221) receiving electrical stimulation for 2 weeks or the control group (n=216) treated by standard management according to the date of birth in the month. The baseline data were similar. After the 2-week treatment, the RMNS-treated patients demonstrated a more rapid increase of the mean Glasgow Coma Score, although statistical significance was not reached (8.43±4.98 vs. 7.47±5.37, p=0.0532). The follow-up data at 6-month post-injury showed a significantly higher proportion of patients who regained consciousness (59.8% vs. 46.2%, p=0.0073). There was a lower proportion of vegetative persons in the RMNS group than in the control group (17.6% vs. 22.0%, p=0.0012). For persons regaining consciousness, the functional independence measurement (FIM) score was higher among the RMNS group patients (91.45±8.65 vs. 76.23±11.02, p<0.001). There were no unique complications associated with the RMNS treatment. The current study, although with some limitations, showed that RMNS may serve as an easy, effective, and noninvasive technique to promote the recovery of traumatic coma in the early phase.

Introduction

Traumatic brain injury (TBI) is a major health and socioeconomic problem worldwide, which affects persons of all ages along with a high risk of death and severe disability.¹ Apart from the devastating effect on victims and their families, brain injury also causes a huge economic burden to society. In the United States alone, it was estimated that the cost on treatment and rehabilitation of patients with TBI exceeds US$ 60 billion per year.^2,3 The outcome of severe TBI is generally poor. Approximately 10–15% of patients are discharged in a prolonged coma or a vegetative state.⁴ A potent intervention in the acute phase to speed recovery from coma with the aim of gaining a more favorable outcome is expected by family and caregivers of the patients.

The use of right median nerve electrical stimulation (RMNS) for coma arousal was developed more than two decades ago. Experts from the United States and Japan reported that electrical stimulation of the right median nerve had the effect of hastening the awakening of coma patients.^5
–7 The right median nerve was stimulated based on its role as a peripheral portal to the central nervous system. The electrical currents transdermally (converted to nerve impulses) applied may reach the brainstem, thalamus, and the cerebrum. The neuroendocrine system is activated to improve the level of consciousness.^8,9 The spinorecticular component of the median nerve pathway synapses with neurons of the ascending reticular activating system (ARAS) where the state of wakefulness is maintained. Some new mechanisms were also identified recently: the increase of cerebral blood flow.^10
–12

The recently published systematic reviews have identified three clinical studies investigating the efficacy of RMNS in promoting emergence from coma. These include two randomized controlled trials and one case series.^6,9,11 Although all of them suggested benefits associated with electrical stimulation, significant limitations were found including small sample sizes, less robust methodology, and negative side effects. This presents a challenge to make substantial conclusions regarding whether or not RMNS effectively and safely results in significant coma arousal after TBI.^13,14

In the present study, we intend to assess the efficacy and safety of right median nerve electrical stimulation in promoting recovery from coma after TBI with a larger sample size and a prospective controlled design.

Methods

Patients

From August 2005 through December 2011, a total of 437 comatose patients that were 2 weeks after severe TBI were recruited from the neurosurgical intensive care unit (NICU) in Renji Hospital, Shanghai Jiaotong University School of Medicine. Patients were eligible for the study if they were 6 to 65 years of age without sex restriction, had a confirmed history of severe TB2and a score on the Glasgow Coma Scale (GCS) of 8 or less on admission. In addition, the subjects had GCS scores remaining below or equal to 8 despite two weeks of intensive treatment, had a stabilized condition regarding vital signs and intracranial image on head CT scan. We excluded patients who had a history of severe cardiac arrhythmias or implanted pacemaker, as well as patients with uncontrolled seizures or pregnancy. The study was approved by the Ethics Committee of the hospital. In all cases, the patients' legal representatives provided written informed consent.

This is a prospective, follow-up study performed in a single center. Patients in the coma state 2 weeks post brain injury were initially assessed and assigned into the RMNS group or the control group based on the date of birth in the month. Persons with uneven numbers in their date of birth in the month (e.g., 1, 3, 5, 7, etc.) were assigned into the RMNS group, and patients with even numbers were placed into the control group.

Treatment protocol

The patients in RMNS group received RMNS in addition to standard neurosurgical management. Rational and methods of RMNS technique have been described in detail elsewehere.⁷ In brief, the electrical treatment was delivered via a pair of lubricated 1-inch square rubber surface electrodes pasted on the volar aspect of the right distal forearm over the median nerve. An electrical neuromuscular stimulator (Verity Medical Ltd., UK) supplied trains of asymmetric biphasic pluses at an amplitude of 10–20 milliamps (10–15 mA for children and adolescents less than 18 years and 15–20 mA for adult patients) with a pulse width of 300 microseconds at 40 Hz for 20 sec/min. The RMNS treatment continued 8 h per day for 2 weeks. These electrical settings have been well tolerated for two decades when used by the senior co-author without pain or skin irritation.

Patients in the control group received standard neurosurgical treatment alone in accordance with the current guidelines.^15,16 Large intracranial hematomas and hemorrhagic contusions were evacuated with emergency surgery once detected. All patients were treated in the NICU. The goal of treatment was to avoid hypotension, hypoxia, intracranial hypertension, and a disturbed internal environment. Serum glucose, blood gases, and serum electrolytes were regularly evaluated and supplemented if needed.

Data collection and follow-up

Demographic data were obtained from the patients' medical records and their family reports. Physiological parameters were recorded hourly by the NICU nurses. The level of consciousness during the 2-week treatment was evaluated daily on the Glasgow Coma Scale by a fixed physician. The complications during the course of study were documented, including seizures, gastrointestinal bleeding, pneumonia, or increased sympathetic activity.

All patients were followed up for 6 months by means of outpatient visits, questionnaires, or telephone interview. If the patients or their relatives could not be contacted after multiple attempts, then those patients were recorded as lost to follow-up. The state of consciousness of the patients 6 months post-injury was determined as conscious, minimally conscious state (MCS), or vegetative state (VS). These categories were diagnosed based on widely accepted criteria.^17,18 The definition of consciousness includes complete wakefulness and awareness of self and environment, precise comprehension and interaction, correct orientation of figures, time, and location, a high level of obeying to commands, and intact light and deep reflexes. MCS is characterized by global impaired responsiveness but limited evidence of awareness including following simple commands, gestural or verbal responses to yes/no questions, intelligible verbalization, or presence of purposeful behavior. The diagnosis of VS was made when patients showed completed unawareness of self and environment accompanied by sleep-wake cycles, incapability of interaction with others and no language comprehension or expression, and no purposeful voluntary behavioral response to visual, auditory, tactile, or noxious stimuli.

For those patients who were conscious, the functional independence measurement (FIM) instrument was used to assess the recovery of functional ability.¹⁹ The FIM assessment is composed of 18 items to measure functional independence in self-care, sphincter control, transferring, locomotion, communication, social interaction, and cognition. Each item is rated on a seven-point scale (1–7), and the total score is summated. The ranges are from 18 to 126, with a higher score indicating a greater level of independence.

Statistical analysis

All analyses were performed with the use of SPSS 16.0 software (SPSS Inc., Chicago, IL). Continuous data were expressed as mean and standard deviation and compared with the Student t test or Mann-Whitney U test, if appropriate. Categorical variables were described as numbers, percentages, and analyzed with the chi-square test. The comparison of GCS score between groups during the 2-week treatment period was conducted using repeated measures analysis of variance (ANOVA). If significant difference exhibited, then the Tukey test would be used for the post hoc analysis. Values of p<0.05 were considered significant.

Results

Baseline characteristics

From August 2005 through December 2011, a total of 437 comatose patients with severe TBI participated in the study. Subjects had their injury 2 weeks before the study. Of the 437 patients, 221 were assigned to RMNS treatment and 216 to standard therapy. After 6 months, there are 386 (88.3%) patients who had complete follow-up data—204 (92.3%) patients in the RMNS group and 182 (84.2%) patients in the control group. Baseline characteristics of the patients who were enrolled in the study are presented in Table 1. The baseline demographic and clinical characteristics were similar between the two groups. No significant difference was found in age, sex, cause of injury, baseline GCS score, and surgery between the two groups.

Table 1.

Baseline Characteristics in 437 Comatose Patients with Severe Traumatic Brain Injury Who Underwent Right Median Nerve Electrical Stimulation or Standard Treatment

Variables	RMNS group (n=221)	Control group (n=216)	p value
Age (year-old)	41.31±10.0	43.21±9.2	0.0694
Sex ratio (M/F)	154/67	145/71	0.5658
Cause of injury (%)			0.5435
Traffic accident	177 (80.1)	165 (76.4)
Fall	39 (17.6)	47 (21.8)
Others	5 (2.3)	4 (1.8)
GCS before treatment	6.27±4.32	6.31±4.13	0.2934
CT findings (%)			0.5252
Intracranial hematomas	190 (86.0)	181 (83.8)
Diffuse brain injury	31 (14.0)	35 (16.2)
Pupillary responses in ED (%)			0.7411
Normal	153 (69.2)	151 (69.9)
Unilaterally dilated	54 (24.4)	48 (22.2)
Bilaterally dilated	14 (6.4)	17 (7.9)
Surgery (%)			0.0904
Yes	215 (97.3)	203 (94.0)
No	6 (2.7)	13 (6.0)

RMNS, right median nerve electrical stimulation; GCS, Glasgow Coma Scale score; CT, computed tomography; ED, emergency department.

Data are expressed as means±SD. The table shows that the baseline data were well balanced.

Patient responses to RMNS treatment

All patients in the RMNS group demonstrated good tolerance to the transdermal electrical stimulation. Nonpurposeful right limb movements, together with obvious contractions of right thumb were noted in the first few days of treatment. Sometimes minor bodily movements of the upper trunk occurred. All these movements did not affect the location of intensive monitoring tubes or wires around the patient's body. There was no major change in heart rate, respiration, or blood pressure during the electrical treatment.

Alteration of GCS score during the 2-week treatment

The daily GCS score alteration during the study course was illustrated in Figure 1. There were 216 patients in the RMNS group and 210 in control group who completed the 2-week assessment. Before initiation of the electrical treatment, the baseline GCS score was similar between the two groups (6.27±4.32 vs. 6.31±4.13, p=0.2934). During the 2-week treatment/observation period, the mean GCS score increased in both groups. The RMNS-treated patients, however, demonstrated a more rapid increase. The repeated measures ANOVA analysis showed no significant difference between the two groups during the 2 weeks (p=0.1472). On Day 14, the mean GCS score of the RMNS group patients was higher, although not significant, than that of the control group patients (8.43±4.98 vs. 7.47±5.37, p=0.0532); however, a score trending above 8 is considered to be coming out of coma (the RMNS group).

FIG. 1.

Mean Glasgow Coma Scale score during the 2-week treatment period, according to study groups (I bars denote standard error). RMNS, right median nerve electrical stimulation.

Follow-up data on 6 months post-injury

Although we tried every means to contact the patients, only 386 (88.3%) patients responded. The follow-up data are illustrated in Table 2. Of the 204 patients who received the RMNS treatment and had complete data, 122 (59.8%) regained consciousness and 46 (22.6%) remained in MCS, 36 (17.6%) in VS. In the control group, 84 of the 182 (46.2%) patients became conscious and 40 (22.0%) were in MCS, 58 (31.8%) in VS. Comparison of the two groups showed significantly more persons in the RMNS group regained consciousness than in the control group (59.8% vs. 46.2%, p=0.0073). It is also important that the RMNS group had fewer persons in VS (17.6% vs. 22.0%, p=0.0012).

Table 2.

Follow-Up Data at 6 m=Months Post-Injury

	RMNS group (n=204)	Control group (n=182)	p value
Regain consciousness (%)	122 (59.8)	84 (46.2)	0.0073
Remain in MCS (%)	46 (22.6)	40 (22.0)	0.8929
Remain in VS (%)	36 (17.6)	58 (31.8)	0.0012
FIM score of conscious patients	91.45±8.65	76.23±11.02	<0.0001

RMNS, right median nerve electrical stimulation; MCS, minimally conscious state; VS, vegetative state; FIM, functional dependence measurement.

This table shows that there are a higher proportion of patients regaining consciousness and a lower proportion of patients who remained in VS in the RMNS group when assessed at 6 months post-injury. For persons in consciousness, the FIM score was calculated, and results show that the FIM is higher among patients in the RMNS group.

For persons in the state of consciousness, the FIM score was calculated. The results showed that the FIM was higher among patients in the RMNS group than the control group (91.45±8.65 vs. 76.23±11.02, p<0.001).

Adverse effect

Possible complications during the treatment period are listed in Table 3. Complications such as seizures, gastrointestinal bleeding, pneumonia, or increased sympathetic activity were recorded. Those effects were not unique to the RMNS treatment because of the similar proportions of the two groups.

Table 3.

Complications during the 2-Week Treatment Period

	RMNS group (n=221)	Control group (n=216)	p value
Seizures (%)	2 (0.9)	4 (1.8)	0.6604
Gastrointestinal bleeding (%)	12 (5.4)	9 (4.2)	0.5371
Pneumonia (%)	35 (15.8)	41 (19.0)	0.3859
Increased sympathetic activity (%)	11 (5.0)	16 (7.4)	0.2915

RMNS, right median nerve electrical stimulation.

Discussion

Historically, disorders of consciousness are very common among patients who sustain severe TBIs. Approximately one third of those patients remain in coma after becoming medically stable.^20
–22 The report from the Traumatic Coma Data Bank suggested that 41% of the prolonged comatose patients were expected to regain consciousness within 6 months after the events of injury and 52% could become conscious by 1 year.⁴ Therefore, speeding recovery, by the use of currently available effective interventions, is a priority to improve the prognosis and functional outcomes.

The therapeutic options developed to date for coma arousal have been multiple and promising. Direct approaches using pharmacological agents, surgical treatment, physical stimulation or indirect pathways (sensory stimulation, music therapy, and electrical stimulation) have been used.^13,23 Although a number of studies have been conducted in this area, no strong evidence was found for any of these measures. The common problems with most studies include lack of robust study design, a small number of participants enrolled, the lack of properly defined inclusion and exclusion criteria, and not using standardized assessment tests. Those limitations preclude definitive conclusions of the efficacy of new treatments.²⁴

RMNS has drawn growing attention from many intensivists, rehabilitationists, and clinical researchers over the past two decades. The first published article about median nerve electrical stimulation for acute coma was in 1999.⁶ The theory of peripheral nerve stimulation to awaken a severely injured brain was based on an earlier project a decade before. In 1987 at the Duke University Biomedical Engineering Department (Durham, NC), there was a unique research project using forearm electrical stimulation to induce gripping under voice control in paralyzed hands of C5 quadriplegic subjects.²⁵ Researchers surprisingly found that not only the partially innervated ipsilateral upper arm muscles became stronger because of the repeated afferent signals from the transdermal neuromuscular stimulator, but also the contralateral unstimulated proximal arm muscles became stronger as well. That crossover effect was not mediated at the cervical spinal cord level. The transfer of the electrochemical pulses required a pathway through the cervical cord, brainstem, thalamus, and cerebral cortex, then crossover of impulse within the corpus callosum to the opposite cerebral hemisphere. Next was the efferent pathway to the unstimulated arm to produce silent exercise whose source was the electrical stimulator on the other forearm.

Some pilot studies were performed thereafter at the medical centers of East Carolina University (Greenville, NC) and the University of Virginia (Charlottesville, VA), as well as in Japan in the early and middle 1990s.^5,6,7,9,11 The right median nerve was selected to be a portal to the reticular activating system, the thalamus, and the cortex of the dominant left cerebral hemisphere. The right median nerve was selected, not only because of its large cortical representation, but also because most humans are left hemisphere dominant whether the person is right- or left-handed.²⁶ The transdermal stimulation at a frequency of 40 Hz 20 sec on and 40 sec off was performed 8 h a day for 2 weeks. Usually the GCS scores rose steadily.

Importantly, these pilot research studies include two randomized trials. In the first randomized, double-blind study conducted by Cooper and colleagues⁶ in 1999, a group of six comatose patients with TBI randomized to receive the RMNS treatment or sham stimulation were followed up. The included patients had a post-resuscitation GCS score of 4 to 8, and RMNS was initiated within 1 week post-injury. The RMNS group recovered more quickly, showed an improved GCS and Glasgow Outcome Scores and a shorted intensive care unit stay compared with the control group. Another trial was reported by Peri and associates⁹ in 2001 with six RMNS-treated patients and four controls. They concluded that treatment with RMNS led to faster emergence from coma and a higher mean FIM score. Although the data were not statistically significant, a definite tendency favoring earlier emergence from coma in the stimulated subjects was observed. The review by Cooper and coworkers²⁷ summarized the past experience with RMNS and potential limitations in the existing evidence. They encouraged further investigation with larger samples and robust methodology within this topic.

With this in mind, we undertook the present study with a larger sample size and a prospective, controlled design from the year 2005 to 2011. A total of 437 patients were recruited with well-balanced baseline characteristics. Except for 51 (11.7%) patients lost to follow-up, our study demonstrated that electrical stimulation of the right median nerve could help the recovery process of comatose patients with TBI. The RMNS group had an improved GCS score (although not statistically significant) during the 2-week electrical treatment. The electrically treated patients had an increased level of consciousness and functional independence 6 months post-injury. Moreover, there was no evidence of adverse effects derived from this technique. The fact that there was no significant difference between groups of the GCS scores during the 2 weeks suggests that the efficacy of RMNS may be more obvious in the long-term follow-up.

The mechanisms of the electrical stimulation effect in comatose patients were not totally understood. The past studies have raised several possible explanations. One rationale is that RMNS enhances the activity of the ARAS through stimulation of the locus coeruleus and dorsal raphe nucleus, the origins of the noradrenergic and serotonergic neurotransmitter systems, respectively.²⁸ The second mechanism is related to neruotrophic factors including nerve growth factor and brain-derived neurotrophic factor, which play an important role in neuroplasticity. Possibly silent or injured synapses are transformed into functional ones.²⁹ The third theory is the increased cerebral blood flow and enhancement of neurotransmitter metabolism in brain cells during stimulation of the median nerve, which facilitated the emergence from coma.¹¹ The fourth potential mechanism, which was identified in the recent decade, is that RMNS may activate the projections between the thalamus and the cortex.³⁰

The current study has several limitations. First, the allocation was based on the date of the patient's birth instead of a randomized method. Selection bias is likely to exist. The study, however, was conducted with a large sample of 437 patients and a prospective controlled design with the baseline characteristics well balanced; the impact of selection bias on study results may be small. Second, whether the patients received other rehabilitation interventions such as hyperbaric oxygen therapy after discharge was unknown. From the perspective of scientific evidence, however, the effect of rehabilitation interventions including hyperbaric oxygen therapy for TBI is still not clear.^31,32 Third, there were 51 of 437 (11.7%) participants lost to follow-up. Four, neuromuscular disorder—e.g.—neuropathy, is a common complication among comatose patients after an acute brain injury, which prevents effective electrical stimulation and prolongs the recovery of unconscious patients.³³ The presence of neuropathy and the effect on outcomes have not been evaluated in our study. As the above biases could not be ruled out, the validity of the study may be challenged. We suggest the findings be interpreted with caution as well. In the future, a large randomized, double-blinded, sham-controlled study is needed.

Conclusion

The present study, with a sample size of 437 patients, showed that RMNS efficaciously and safely promoted the recovery of acute comatose patients who had sustained severe TBI. Although the strength of evidence was limited, RMNS is a simple, inexpensive, noninvasive technique with a good safety profile. RMNS could be considered as one option in clinical practice for treating coma patients. A randomized, double-blinded, sham-controlled study with an adequate sample size is therefore warranted.

Footnotes

Acknowledgments

This work was supported by grants from National Key Basic Research Project (No. 2012CB518100), National Natural Scientific grants (No. 81271381), and Program for Shanghai Outstanding Medical Academic Leader.

Author Disclosure Statement

No competing financial interests exist.

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