Prompting Emergence from Coma

Consciousness is composed of two distinct dimensions: arousal (i.e., wakefulness or vigilance) and awareness (i.e., knowledge of self and environment) (Zeman 2006). Disorders of consciousness (DOC) are a spectrum of medical conditions that inhibit elements of consciousness (Schiff & Plum 2000), and include the following:

  • Coma: a state of complete unconsciousness, lacking both arousal and awareness (Posner & Plum 2007).
  • Vegetative state: a state of arousal without awareness, considered “persistent” when lasting longer than one month (Jennett 2002).
  • Minimally conscious state: a state of arousal with limited but discernable awareness (Giacino et al. 2002).

DOC present clinical challenges in both the diagnosis and treatment of patients following brain injury, and thus significantly impact outcomes in acute care (Nakase-Richardson et al. 2012).

Guideline Recommendations

The Royal College of Physicians (RCP) in the UK developed a set of guidelines for the diagnosis and management of DOC, in order to update and replace a previous report from 2003 ("Prolonged disorders of consciousness: National clinical guidelines"  2013). We have added these recommendations into our evaluation of each intervention, but our conclusions are based on our methodology and have not been influenced by the guidelines. The RCP provided descriptive guidelines but did not incorporate levels of evidence.

Non-Pharmacological interventions

Sensory Stimulation

It has been reported that one in eight patients with severe closed head injury suffers from prolonged coma and vegetative state following their injury (Levin et al. 1991). It has also been estimated that 50% of survivors from severe brain injuries who are in a vegetative state regain consciousness within one year of their injury, with up to 40% subsequently improving to a higher level on the Glasgow Outcome Scale (Multi-Society Task Force on PVS 1994). The notion that sensory stimulation could enhance the speed and degree of recovery from coma has gained popularity. Early studies employed single stimuli to a single sense (unimodal stimulation), whereas more current studies have focused on sensory stimulation to all the senses using various stimuli (multimodal stimulation). These studies have evaluated stimulation of several modalities: visual, auditory, tactile, olfactory, gustatory, kinesthetic, proprioceptive, and vestibular.

The RCP reported a lack of high-quality research regarding sensory stimulation programs for patients with DOC ("Prolonged disorders of consciousness: National clinical guidelines"  2013). However, the authors noted that such programs may provide the best opportunities to observe recovery in patients. It was recommended that stimulation focus on pleasurable and familiar sensations that are presented discretely, in order to detect individual effects and minimize overstimulation. 

Individual Studies

Table: Sensory Stimulation for Recovery of Consciousness Post ABI

Discussion

One of the major challenges for evaluating the efficacy of sensory stimulation in promoting recovery of consciousness is that outcome assessment measures are often qualitative and difficult to assess.  Several studies have reported improvements such as coma duration (Gorji et al. 2014; Mitchell et al. 1990; Pierce et al. 1990), physiology (Gruner & Terhaag 2000; Johnson et al. 1993), and behaviour (Wilson et al. 1996). Clinical assessment tools for measuring level of consciousness are preferred, including the GCS, Coma Recovery Scale, Coma/Near Coma Scale, and DOC Scale. These measures can be used in conjunction with the RLAS or Wessex Head Injury Matrix for the assessment of cognitive functioning. As well, tools such as the Western Neuro Sensory Stimulation Profile (WNSSP), Sensory Stimulation Assessment Measure, and Sensory Modality Assessment & Rehabilitation Technique were developed in order to better quantify the efficacy of sensory stimulation programs (Ansell & Keenan 1989; Gill-Thwaites 1997; Rader & Ellis 1994).

An early retrospective study found that a multisensory stimulation program over an extended period of time was not statistically different from standard care in terms of coma duration, recovery rate, or long-term outcomes (Pierce et al. 1990). However, two prospective trials described markedly different results. One study reported that patients receiving treatment had significantly shorter coma duration than those who received standard care (Mitchell et al. 1990). The other study noted that treated patients showed significantly greater improvement on the RLAS (Kater 1989). It also found that patients with moderate or severe coma (GCS≤10) showed greater benefit from the treatment. More recently, trials have examined intensive and frequent multisensory stimulation delivered over a period of one to two  weeks. These studies reported significant improvements on the GCS (Abbasi et al. 2009; Megha et al. 2013; Moattari et al. 2016; Urbenjaphol et al. 2009), RLAS (Urbenjaphol et al. 2009), WNSSP (Megha et al. 2013; Moattari et al. 2016), and Sensory Modality Assessment & Rehabilitation Technique (Moattari et al. 2016; Urbenjaphol et al. 2009) when compared to standard care.

The type of stimulation and form of delivery may have an impact on its effectiveness. In two early trials, it was demonstrated that specific, directed, and regulated stimulation yielded greater improvements on the GCS and RLAS (Wood et al. 1992), as well as the Sensory Stimulation Assessment Measure (Hall et al. 1992) when compared to indiscriminate stimulation. A later retrospective study found that patients had greater improvements on the Wessex Head Injury Matrix following enriched stimulation than basic cognitive stimulation (Di Stefano et al. 2012). In a recent trial, Megha et al. (2013) found that stimulation delivered five times a day generated greater improvements on GCS and WNSSP than when delivered twice a day. Further, Moattari et al. (2016) showed that stimulation was most effective at improving GCS, RLAS, and WNSSP when delivered by a family member.

Studies evaluating auditory stimulation over standard care have also shown favourable results. In a trial evaluating a stimulation program involving multiple sounds (e.g. voices, music, radio, television, instruments), Davis & Giminez (2003) reported significant improvements in patient scores on the GCS, RLAS, and Sensory Stimulation Assessment Measure. Patients who listened to recordings of familiar voices or music had shorter coma duration (Gorji et al. 2014) and showed improvements on GCS (Tavangar et al. 2015) and Coma/Near Coma Scale (Pape et al. 2015) than those receiving standard care. Similarly, patients were found to have a greater response to the sound of their name than a musical sound (Cheng et al., 2013). Patient responsiveness to both sounds was associated with higher Coma Recovery Scale scores.

We identified two systematic reviews evaluating the effectiveness of sensory stimulation in improving consciousness of individuals in a coma or vegetative state following ABI. In a Cochrane review, Lombardi et al. (2002) identified three clinical trials with a total of 68 patients. The studies were found to be of poor quality, and there was considerable diversity between them in terms of experimental design and conduct. As well, a quantitative meta-analysis was not possible due to the lack of consistent outcome measures. The authors concluded that there was no reliable evidence supporting the efficacy of intensive multisensory stimulation programs. They recommended that larger multicenter RCTs be conducted with rigorous methodology and specific outcomes for impairment and disability. However, in a more recent review, Padilla and Domina (2016) found strong evidence for multisensory stimulation improving arousal and enhancing clinical outcomes. The authors recommended early, frequent, and sustained stimulation that is tailored to patient tolerance and preferences.

Conclusions

There is Level 1a evidence that multisensory stimulation and familiar auditory stimulation are more effective at improving consciousness and cognitive function post ABI than standard care.

There is Level 1b evidence that multisensory stimulation delivered five times per day is more effective at improving consciousness and cognitive function post ABI than stimulation delivered twice a day.

There is Level 1b evidence that multisensory stimulation delivered by a family member is more effective at improving consciousness and cognitive function post ABI when compared to stimulation delivered by a nurse.

There is Level 2 evidence that specific, directed, and regulated sensory stimulation is more effective at improving consciousness and cognitive function post ABI than indiscriminate stimulation.

There is Level 2 evidence that sensory stimulation may improve clinical outcomes, physiological parameters, and behaviours indicative of consciousness post ABI.

 

Sensory stimulation, both unimodal and multimodal, may increase recovery of consciousness and improve level of cognitive function post ABI.

Sensory stimulation may be most effective when it is early, frequent, and sustained as well as specific, directed, and regulated.

Sensory stimulation may be most effective when stimuli are familiar or delivered by a familiar individual.

 

 

Music Therapy

Musical sounds stimulate the auditory pathway and activate an emotional response in the brain.  If the music is familiar to the patient, then the stimuli can become meaningful for them.  Anecdotally, it has been noted that music encourages arousal from coma post ABI. We identified two studies which used music therapy as a specific treatment for this purpose.

The RCP made no specific recommendations regarding the use of music therapy for the recovery of consciousness post ABI.

Table: Music Therapy for Recovery of Consciousness Post ABI

Discussion

A case series of patients who received a combination of unimodal stimulation, multimodal stimulation, and music therapy (Wilson et al. 1992) found that half had increased frequency of behaviours suggestive of emergence from coma. Using an innovative approach termed “musicokinetic therapy”, Noda et al. (2004) treated patients with vertical motions on a trampoline while listening to live music in synchrony with the vertical motion. The rationale for this approach was that the therapy should result in the activation of multiple pathways within the brain simultaneously to more effectively promote awareness of environmental stimuli. The authors reported significantly better Persistent Vegetative State (PVERSUS) scores post treatment, and that treatment was most effective when initiated within six months of injury. Despite these positive findings, the practicality of providing this therapy to patients with brain injury is questionable, given the inherent limitations of applying this intervention in clinical practice. In a prospective trial conducted by Sun and Chen (2015), participants were subjected to either musical stimuli or silence. They reported no significant difference between groups in GCS improvement, but noted significantly greater brain activity in the musical stimuli group. Although the results showed no measurable improvement in consciousness, the increased brain activity suggests that music therapy may improve outcomes with the right protocol, and thus warrants future research.

Conclusions

There is Level 4 evidence that music therapy as an adjunct to other modes of sensory stimulation may be used to promote emergence from coma post ABI.

 

Music therapy may be useful in promoting emergence from coma post ABI.

 

 

Electrical Stimulation

Electrical stimulation is a common therapeutic approach used in the rehabilitation of a variety of neurological diseases. Some reports have proposed that electrical stimulation may be beneficial in patients with severe ABI. It is believed that electrical stimulation applied peripherally may stimulate the reticular activating centre and cortical areas responsible for consciousness and arousal (Peri et al. 2001). Stimulation of the median nerve has been shown to cause significant increments in blood flow and improved electroencephalogram activity (Cooper et al. 1999).

The RCP reported that the research regarding neurostimulation, including electrical stimulation, only showed modest results in recovery of consciousness ("Prolonged disorders of consciousness: National clinical guidelines"  2013). The authors cautioned against the use of invasive techniques, such as those that involve electrode implantation, due to significant ethical concerns. As such, it was recommended that neurostimulation only be used as part of an approved and registered clinical trial.

Individual Studies

Table: Electrical Stimulation for Recovery of Consciousness Post ABI

Discussion

Four studies investigating the efficacy of median nerve electrical stimulation in promoting emergence from coma were identified. In the first of these studies, the authors reported that patients treated with stimulation showed better improvements on the GCS and GOS as well as shorter lengths of stay in the intensive care unit when compared to sham-stimulated controls (Cooper et al. 1999). However, the lack of statistical group comparisons weakens any conclusions that could be drawn from these findings. In a high quality RCT, Peri et al. (2001) found that median nerve electrical stimulation did not significantly improve the duration of coma, GOS scores, or functional independence/assessment measure scores over sham stimulation.

Liu et al. (2003) employed a single group design and reported that median nerve electrical stimulation caused considerable increments in CPP. They also found elevations in dopamine levels, which may been involved in the regulation of consciousness (Krimchansky et al. 2004). However, the authors failed to demonstrate a direct correlation between dopamine levels and increased levels of consciousness. More recently, Lei et al. (2015) determined that patients who received median nerve electrical stimulation showed no more improvement after two weeks than patients who received standard care. However, six-month follow-up data showed that a significantly higher proportion of patients who the stimulation regained consciousness. Although these results suggest median nerve electrical stimulation improves consciousness, there are higher levels of evidence to the contrary. Future studies are encouraged to utilize an RCT design.

Conclusions

There is Level 1b evidence that median nerve electrical stimulation does not improve emergence from coma post ABI when compared to sham stimulation.

 

Median nerve electrical stimulation does not improve emergence from coma post ABI.

 

Pharmacological Interventions

Amantadine

Amantadine is a dopamine agonist that acts both pre- and post-synaptically to upregulate dopamine activity (Meythaler et al. 2002). Dopamine is thought to be involved in frontal lobe stimulation and plays a role in behavior, mood, language, motor control, hypothalamic function and arousal (Sawyer et al. 2008). Amantadine was initially developed for prophylactic use as an antiviral agent in the prevention of influenza A, but is now commonly used in the treatment of Parkinson’s disease.  Its properties as a potential neuroactive agent were quickly recognized (Zafonte et al. 2001), and there is interest in its use as a potential treatment in the management of ABI (Schneider et al. 1999). Researchers believe that amantadine could significantly improve arousal in patients who are comatose. Potential side effects include over-stimulation, peripheral edema, livido reticularis, and lowering of the seizure threshold; however these are easily reversible (Schneider et al. 1999). The favorable risk-benefit profile of amantadine suggests that it may be an attractive treatment option for inducing arousal from coma (Hughes et al. 2005).

The RCP reported that the preliminary research on amantadine was positive, but suggested that its longer-term effects required further exploration ("Prolonged disorders of consciousness: National clinical guidelines"  2013). The authors concluded that there was insufficient evidence to make formal recommendations regarding its use in enhancing recovery of consciousness. However, if medication is prescribed for patients with DOC, it was recommended that it be done in the setting of a clinical trial with formal monitoring and blinded assessors.

Individual Studies

Table: Amantadine for Recovery of Consciousness Post ABI

Discussion

Three retrospective studies that assessed amantadine were identified. In a case-control study, Hughes et al. (2005) found that patients receiving amantadine were no more likely to emerge from coma compared to those not receiving it. However, the authors mentioned that potential confounders may have affected the results, and that the point at which patients were considered to have emerged from the coma was arbitrarily assessed. In a chart review, Whyte et al. (2005) only selected patients who received amantadine 4-16 weeks post injury, in order to assess its potential in improving consciousness after medical stability was reached. The authors noted that patients who received amantadine showed significant improvements in disability one week after administration when compared to patients treated by other methods. They also reported no significant difference between groups in the time to first response to directions. In another chart review, patients who were treated with amantadine showed significant improvements in consciousness at discharge and decreased mortality rates when compared to those who did not receive it (Saniova et al. 2004). While the retrospective nature of these studies makes it difficult to draw conclusions, all authors recommended amantadine as a safe intervention with promising potential but suggested that further research was warranted.

Two RCTs have evaluated the effectiveness of amantadine in improving consciousness in adults. Using a crossover design, Meythaler et al. (2002) assessed patients for orientation, cognitive function, functional independence, and disability. The authors found that patients who received amantadine made significant gains on all outcome measures over six weeks, but made no further gains when switched to placebo for another six weeks. Patients initially receiving placebo made small gains, but went on to make further improvements after amantadine induction. While patients made some natural recovery on placebo, the authors noted that patients made more pronounced improvements on amantadine. They also suggested that amantadine aids in recovery regardless of the time of administration. Similarly, a trial by Giacino et al. (2012) found a significant improvement in disability in participants who received amantadine over four weeks when compared to placebo. However, following a two-week follow-up without amantadine treatment, their recovery slowed such that overall improvements were similar between the two groups (Giacino et al. 2012). The authors recommended that amantadine treatment may continue until recovery goals are reached, although it should be approached with caution.

Conclusions

There is Level 1a evidence that amantadine effectively improves consciousness, cognitive function, and disability when compared to placebo.

 

Amantadine may improve consciousness, cognitive function, and disability post ABI.

 

Other Medications

Individual Studies

Table: Other Medications for Recovery of Consciousness Post ABI

Discussion

Two clinical trials have evaluated other pharmacological interventions for restoring consciousness post ABI: citicoline (Shokouhi et al. 2014) and antiepileptics (Bagnato et al. 2013). In both trials, consciousness improved similarly in both the treated and untreated control groups over time, and thus the medications provided no discernable benefit. Given the limited research on each of these medications, additional clinical trials are required prior to making firm conclusions.

Conclusions

There is Level 1b evidence that citicoline is not effective at restoring consciousness post ABI.

There is Level 2 evidence that antiepileptics are not effective at restoring consciousness post ABI.

 

Citicoline and antiepileptics may not be effective interventions for restoring consciousness post ABI. However, further research is required.