Hyperbaric oxygen therapy in patients with hypoxic ischemic encephalopathy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263236
Source of Support: None, Conflict of Interest: None
Keywords: Disorders of consciousness, hyperbaric oxygen therapy, hypoxic ischemic encephalopathy
The diagnostic term 'hypoxic ischemic encephalopathy (HIE)' encompasses a complex constellation of pathophysiological and molecular injuries to the brain resulting in coma. Patients in a persistent vegetative state (PVS) are those who are wakeful without awareness. Those patients regaining awareness are in a minimally conscious state (MCS), or locked-in state, based on their ability to respond to speech or obey commands.
Hyperbaric oxygen therapy (HBOT) reduces brain edema, enhances angiogenesis, and decreases inflammation. A recent randomized control trial on stroke patients treated with HBOT showed an increased perfusion in regions of low activity living cells, of which the diencephalon was a major area. The default maintenance network, responsible for internal awareness, is maintained by the cortico-thalamic projections., It has been hypothesized that improved diencephalon perfusion with HBOT may contribute to the recovery of consciousness.
There is dearth of knowledge with regard to the clinical efficacy of HBOT in patients with HIE, and its optimal timing. This prompted us to study our HIE patients treated by HBOT and compare their outcomes with HIE patients who did not receive HBOT.
Initial care and patient selection
Our standard of care for patients with HIE consisted of addressing the immediate reason for admission, which may have been the event itself, metabolic derangements, infections, or the need of care facilitating procedures such as a tracheostomy change or a percutaneous endoscopic gastrostomy. Once the immediate issues were sorted out, the next step was to identify noxious stimuli that could impair neurological recovery such as bedsores, naso-gastric tube/tracheostomy-related micro-aspiration, urinary tract infection, aspiration pneumonia, constipation, and spasticity. Physical therapy in the form of tilt-tabling and passive range of movement was started once the patient was stable. A standard coma stimulation program utilizing tactile, visual, and auditory components was performed by family members. From that point, the patient's baseline disorder of consciousness (DOC) and coma recovery scale-revised (CRS-R) were assessed and a neurostimulant (amantadine up to a dose of 100 mg twice a day) was started if the degree of DOC warranted it. If there was no improvement with the prior treatment and no cardiac risk existed, methylphenidate was also used, up to 10 mg twice daily. If extrapyramidal symptoms or decorticate/decerebrate posturing were noted, levodopa/carbidopa 110/25 mg was given twice daily. After 2 weeks of observation, if there was no change observed in CRS-R, patients (based on their affordability, willingness to undergo the therapy and fulfilling the inclusion criteria) were offered HBOT if they had: HIE more than 1 month from injury but earlier than 12 months, and the total CRS-R score was less than 7 at 1 month from injury. Patients were excluded from further analysis if they had received non-allopathic care, were lost to follow-up or had expired at any time during the first year.
Hyperbaric oxygen therapy
The treatment plan was made by the corresponding author who has primary certification in Hyperbaric and Underwater Medicine. Most cases received 20 sessions of HBOT with 100% oxygen at two absolute atmosphere pressure (ATA) for 1 h in a multiplace chamber with an attendant present (Baromedic Healthcare M6 model). Two patients received three sets of 20 sessions, once in each treatment interval, for a total of 60 sessions. Prophylactic myringotomies were not done for any of the patients, as they did not show signs of distress or pain during the treatment, nor was bleeding from the external acoustic meatus or upper tract congestion noted. Through the treatment course, many patients did have increased respiratory secretions as a result of the cold from the decompression phase of treatment, which was managed with mucolytics, bronchodilators and chest therapy. We did not encounter any other adverse effects.
Patients were recruited between January 2015 and June 2017. Due to the strict adherence to the exclusion criteria, we ended up with a small sample size in the end. The following data were collected at baseline: MRI brain and albumin to assess for severity of the disease. The MRI findings were categorized as those with and without a prior brain lesion (i.e., concomitant traumatic brain injury, prior stroke, or central nervous system infection). Albumin was used as a marker of nutritional well-being.
We collected follow-up data at three intervals from the time of injury: 1–3 months, 4–8 months, and 9–12 months. At each time interval, the following parameters were measured for cases and controls: CRS-R, DOC scale, and Karnofsky performance scale (KPS). While those in the HBOT group stayed in the hospital for 3–4 more weeks, the length of stay for the control group was influenced primarily by admission goals and management of related infections/complications. We identified no confounding factors.
We used mean and standard deviation to define the dispersion. Baseline data were assessed using Pearson's chi-square test. Levene's test for equality of variance and two-tailed t-test were used for ordinal outcome measures, as the numbers at each interval was not the same between the case and control groups and because of the presence of a limited sample size. Changes in categorical outcome measures were measured using Wilcoxon rank-sum test.
In [Table 1], we have compared the baseline characteristics of cases and controls at recruitment. All patients had baseline MRI brain and serum albumin level assessment. The two groups were similar for the mean age, MRI findings, and serum albumin level, except in the interval 3, where albumin was lower in the control group, and MRI was worse in the control group. We have compared the follow-up data between cases and controls at three time intervals in [Table 2]. There were 15 male and 20 female patients. The age range was from 20 to 57 years. The number of patients and controls who were compared at 1–3 month, 4–8 month, and 9–12 month intervals are presented in [Table 2]. At interval 3, as the numbers of available patients were low, ordinal and categorical outcome variable statistics were deferred.
At 1–3 months, the two groups were comparable at baseline. The CRS-R total had a P value of 0.007 favoring the cases. There was greater mean change in the motor, followed by the visual and auditory subsets, on CRS-R in cases versus controls. KPS was better in the cases, but the mean change between the groups was similar. With regard to the level of consciousness, more patients reached the locked-in-syndrome state in the case group than the control group.
At 4–8 months, the two groups were comparable at baseline. Of the original nine cases, seven were excluded as they had started non-allopathic treatment (2), were lost to follow-up (4), or had expired (1), and seven prior patients from the control group became cases. The CRS-R total had a P value of 0.005 favoring the cases. There was a greater mean change in the visual and auditory subsets in cases versus controls. The post-KPS was better in the cases but the mean change between the groups was similar. With regard to the level of consciousness, more patients reached MCS+/− in the case group than the control group.
At 9–12 months, the groups were not comparable at baseline. While there were no exclusions from the original case group, seven controls-cum-cases were excluded as they had started non-allopathic treatment (n = 3), had expired (n = 3), or at the time of analysis, had not reached the third interval (n = 1). Six controls became cases. CRS-R total had a P value of 0.005; there was a greater mean change in the oromotor followed by the visual and auditory subsets in cases versus controls. Post-procedural KPS was better in the controls and the mean change was slightly more for cases. With regard to the level of consciousness, more patients reached MCS − in the case than the control group.
The initial presentation of HIE is coma, that is, pathologic unconsciousness due dysfunction of the reticular activating system or both cerebral hemispheres. Clinically, consciousness is composed of both arousability and awareness. Patients in a persistent vegetative state (PVS) are those who improve to a state of wakefulness without awareness. Those who regain awareness emerge into a minimally conscious state (MCS). This is divided into MCS+ (able to follow commands or respond to speech) and MCS− (preserved visual pursuit, localization of pain or appropriate smiling to emotional stimuli). Awareness, being internal or external, has corresponding brain networks. The default mode network (DMN) regulates the internal awareness  while the extrinsic control network (ECN) regulates the external awareness. Both balance each other and self-awareness manifests. The DMN activity disappears in brain death and decreases in persistent vegitative state (PVS). In MCS patients, this is preserved due to the active central thalamic nuclei and their projections. As both networks regain their function, clinical recovery of consciousness is appreciated. As gray matter uses 2.5 times more adenosine-tri-phosphate (ATP) than white matter, HIE damages primarily the cerebral cortex and deep nuclei. These areas that are critical to the DMN function, when damaged, result in widespread mesocircuit-level depression of background synaptic activity. This manifests as disordered consciousness.
There are significant blood vessels/cm 2 of brain tissue. When the cerebral blood flow is decreased, oxygen consumption is increased in the acute phase after severe brain injury. Hyperbaric oxygen induces angiogenesis and reduces inflammatory mediators like hypoxia inducible factor-1alpha, matrix metallopeptidase 9 (MMP-9), cyclooxygenase-2, nogo-A, and myeloperoxidase. The net effect is restoration of cellular energetics, reduction of oxidative stress/inflammation, and repair of cellular damage and recovery. HBOT has been retrospectively studied in adults with HIE with inclusion of patients >2 years following their injury, who are otherwise functional, and able to do computerized neurocognitive testing. A systematic review of the Chinese literature reveals 20 reports of HBOT in HIE for neonates. Regardless, there is ample level 1 evidence for its use in adult traumatic brain injury, and acute ischemic stroke  with respect to improving consciousness in acute care. This is the first prospective study to carry out the same procedure in HIE. Though clinically, tracking the recovery from coma is challenging, the CRS-R has multiple studies proving its sensitivity and reliability in diagnosing and monitoring progress in patients with deteriorated consciousness.
The results of our study imply that HIE patients who had received HBOT show an improvement, especially when the therapy is given in the first three months, and to a lesser extent, when given in the first 9 months following the insult. Recovery mainly lies in the domains of motor, visual and auditory functions. Moreover, the treated patients improved to a state where communication became possible. There are no similarly designed studies to compare our outcome with, but our CRS-R subdomain outcomes correlated with known recovery patterns.
In our patients, with regard to KPS, there was no significant difference in the mean outcomes. This was expected due to the severity of the disease where the patient was maximally dependant. Considering the changes in CRS-R, while the patients did not gain their functions, they were able to express themselves better than the controls. While the natural history of the disease is not altered with this therapy, there is a degree of improvement in the quality of life evidenced by improvement in the DOC for the case group. Our caregivers often express concern if they have no reliable way to communicate with the patient. As the cases improved, many were able to blink once or twice reliably to communicate “yes” and “no”. Four regained facial emotional expressions alongside this. Two patients were able to sit with support, but due to spasticity, could not use their arms. In general, the families of these patients expressed a degree of satisfaction with the treatment outcomes. The patients receiving this treatment need at least 20 sessions, with changes being noted after the fifth session.
The limitations of this study were the small number of cases and controls, and lack of randomization and blinding, as well as introducing an observer and a selection bias. We did not use any investigative markers to document the progress. Our study indicated the need for further research on the same topic using larger number of patients in a randomized design. In addition to clinical measures, incorporating objective parameters such as SPECT cerebral blood flow, functional MRI and biochemical markers may add more validity to outcomes. We gathered EEG data in the same patients to detail the severity of the disease, but as there were no standard scales to measure the degree of abnormality for this population, we could not utilize this data.
HBOT given in the first nine months post-HIE can result in a better recovery and functional outcome. Improving the level of consciousness in this population can facilitate care, communication, and quality of life. This is the first publication of this nature.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2]