Therapeutic mechanisms, efficacy and safety of hyperbaric oxygen therapy for vascular dementia: a literature review
Cece Kooper (10745564)
University of Amsterdam
MSc in Brain and Cognitive Sciences
domain: Cognitive Neuroscience Date: 1 November 2019
Supervisor: Prof. dr. R.A. van Hulst MD,
Amsterdam UMC, AMC, Department Anaesthesiology, Hyperbaric Medicine
Co-assessor: Prof. dr. W.A. van Gool MD,
Abstract
Objective: Vascular dementia (VD) is described as a clinical pathological condition in which
cerebral lesions of vascular origin lead to diverse cognitive impairments. VD highly affects patients’ daily life yet currently no treatment for VD is obtaining consistent significant results. Recently, hyperbaric oxygen therapy (HBOT) is suggested to be an efficient adjunctive treatment for VD. HBOT involves breathing 100% oxygen in a high-pressure chamber. To date, HBOT is a well-known treatment for 14 indications such as decompression sickness, and radiation injury. This review aimed at evaluating the therapeutic mechanisms, efficacy, and safety of HBOT specifically for people suffering from vascular dementia.
Methods: A literature search was conducted to evaluate English papers (clinical trials and
animal studies) that were published before October 2019. We searched the UvA CataloguePlus, PubMed, and Web of Science databases. Also, the reference lists of all relevant papers were searched for additional eligible studies.
Results: This review included 3 human studies involving 380 VD patients and 1 animal
study. The three included randomized clinical trials compared HBOT as an adjunctive therapy to either donepezil, memantine + Aricept, or oxiracetam. Cognitive efficacy was assessed using the Mini Mental State Examination (MMSE) and showed significant improvements after HBOT. The adverse effects of HBOT were only mentioned in one human study in which no obvious side effects occurred.
Conclusions: HBOT as adjunctive treatment significantly improved cognitive impairments in
VD patients compared to the patients receiving only conventional therapy and only HBOT. We found underlying mechanisms possibly accounting for the cognitive improvements including increased neurogenesis, and elevated Humanin levels. Thus, we suggest HBOT to be a promising adjunctive treatment for vascular dementia patients. However, this review lacks sufficient evidence on providing HBOT as a routine adjunctive therapy for VD. Therefore, more research in HBOT is of need to unravel the safety and most favourable dosage of treatment for vascular dementia.
Keywords: Vascular Dementia, Hyperbaric Oxygen Therapy, Cognitive Efficacy, Clinical
Table of Contents
List of abbreviations3 1. Introduction 4
Vascular dementia 4
Neuroprotective role of Humanin 9
Current treatment for vascular dementia patients 9
Hyperbaric oxygen therapy 10
Mechanisms of HBOT on the brain 12
Hyperbaric oxygen therapy and vascular dementia 14
Aim 14
2. Methods 15
2.1. Data source and search strategy 15
2.2. Study selection, inclusion criteria, and data extraction 15
3. Results 16
3.1. Study inclusion and characteristics 16
3.2. Cognitive efficacy 18
Clinical studies 18
Animal study 19
3.3. Safety 19
3.4. Biochemical and physiological changes 19
Clinical studies 19
Animal study 20
4. Discussion 21 References 27
List of Abbreviations
The following table describes numerous abbreviations (and acronyms) used throughout the literature review. Abbreviation Meaning AAR AD ATA BCCAO CCH DCX DSM HBOT MMSE N NINDS-AIREN rCBF rCBV RCT SD UHMS VCD
Active avoidance response Alzheimer’s disease Atmosphere absolute
Bilateral common carotid artery occlusion Chronic cerebral hypoperfusion
Doublecortin
Diagnostic and statistical manual of mental disorders Hyperbaric oxygenation therapy
Mini mental state examination Sample size
National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences
Regional cerebral blood flow Regional cerebral blood volume Randomized controlled trial Standard deviation
Undersea and hyperbaric medical society Vascular cognitive disorder
1. Introduction Vascular dementia
According to the World Health Organization (2015) dementia affected 47 million people worldwide, of whom mostly elderly. Contemplating the aging global population, reviews estimate that by 2030 the number of people affected will have increased to 75 million and this will reach 131 million people by 2050 (Prince, Comas-Herrera, Knapp, Guerchet, & Karagiannidou, 2016). Vascular dementia (VD) is with 15-30% of all dementia cases the second-largest type in the world, after Alzheimer’s disease (AD) (Goodman et al., 2017; O 'Brien & Thomas, 2015). The exact number of people affected by VD, now defined as major vascular cognitive disorder (VCD) by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), has been difficult to establish due to inconsistencies in definitions and variation in diagnosis criteria since the 1960s (APA, 2013; Goodman et al., 2017; Sachdev et al., 2014; Smith, 2017).
Main risk factors of vascular dementia include stroke, age, genetic disposition and vascular risk factors such as cardiac diseases, obesity, diabetes, and hypertension (O'Brien & Thomas, 2015; Sahathevan, Brodtmann, & Donnan, 2012). Vascular dementia is described as a clinical pathological condition in which cerebral lesions of vascular origin lead to diverse cognitive deficits, the possible affected cognitive domains are described in Table 1 (Sachdev et al., 2014).
Table 1
Description of possible affected cognitive domains in VD
statement.”, by Sachdev et al., 2014, Alzheimer Disease and Associated Disorders, 28(3), p. 209.
Overall, VD patients’ daily life is highly affected, and they experience a lower quality of life due to psychological and physical problems. In addition, life expectancy is decreased, varying from 3 to 5 years after VD is diagnosed (Kua et al., 2014). Cognitive changes in VD patients are much more variable than in other neurological disorders, such as AD (O’Brien & Thomas, 2015). In particular, depression and apathy are more common among VD patients compared to AD, and unlike commonly thought, impairments in learning and memory are not necessary for the diagnosis of VD (Petersen & O’Brien, 2006; Sachdev et al., 2014).
To diagnose VD a cognitive deficit needs to be present, as well as determination (through neuroimaging techniques) that vascular disease is the dominant pathology accounting for the cognitive deficit (Jellinger, 2008; Sachdev et al., 2014). Surprisingly, no globally validated neuropathologic criteria of vascular dementia exist, resulting in high variability between laboratories worldwide in morphologic examination procedures and techniques (Jellinger, 2008). Therefore, previous research of Gold et al. (2002) compared the clinical with the neuropathological diagnosis of 89 autopsied patients with dementia, examining the sensitivity and specificity of commonly used diagnostic criteria. Disturbingly, the report for VD showed very low sensitivity. For example, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV from APA, 1994) criteria was 0.50, and National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN from Román et al., 1993) criteria was 0.55. The specificity for vascular dementia of DSM-IV as well as NINDS-AIREN was 0.84. Thus, Gold et al. showed that these diagnostic criteria are more effective in excluding other types of dementia instead of correctly detecting vascular dementia patients.
Moreover, finding the exact contribution of cerebrovascular pathology to cognitive decline in VD is extremely difficult (Jellinger, 2007; O’Brien & Thomas, 2015). Nevertheless, studies have shown that clinical features and cognitive changes are highly dependent on the particular neural substrates affected by the vascular pathology, resulting in several subtypes of VD. An overview of VD subtypes according to O’Brien and Thomas (2015) is presented in Table 2 accompanied by their imaging and pathological changes. The
most common subtype is subcortical vascular dementia (O’Brien & Thomas, 2015).
Table 2
Subtypes of VD with imaging and pathological changes
Note. Reprinted from “Non-Alzheimer’s dementia 3 Vascular dementia.”, by O'Brien and
Thomas, 2015, The Lancet, 386(10004), p. 1699.
The main pathological changes leading to the subtypes of vascular dementia are dependent upon different anatomic and pathophysiological factors: multifocal (diffuse lesions) or focal disease; large or small cerebral vessel infarcts; the number of lesions as well as the volume of brain destruction; and importantly the affected location (whether it is strategically/functionally important) (Enciu, Constantinescu, Popescu, Mureşanu, & Popescu, 2011; Jellinger, 2008). Besides, reduction in the cerebral blood flow, at a higher rate compared to the healthy elderly, plays a role in causing all subtypes of VD (Enciu et al., 2011).
The pathophysiology of VD shows that for example lesions in white matter, thalamus, and subfrontal areas cause interruption of thalamo-, striato-, corticocortical as well as ascending
pathways. Furthermore, multiple findings on the pathophysiology of VD have been evaluated by Jellinger (2007) and suggest that strategically small lesions (e.g. thalamus) with a mixture of small and large vessel infarcts may interrupt pathways, involving cognition, memory, and behaviour. Jellinger also indicates that damage in the subcortical grey matter may directly influence cognitive performance. A brief overview of the complex relationship of pathogenic factors causing VD is schematically presented in Figure 1 (Jellinger, 2007).
Figure 1. Schematic overview of pathogenic factors causing VD.
Note. Reprinted from “The enigma of vascular cognitive disorder and vascular dementia.” by
Jellinger., 2007, Acta neuropathologica, 113(4), p. 368.
Numerous animal studies have also investigated the pathophysiology of VD by deprivation of oxygen and glucose which causes chronic cerebral hypoperfusion (CCH) through bilateral common carotid artery occlusion (BCCAO). This commonly used model, to reflect VD, shows learning and memory impairments in rats after permanent BCCAO (Farkas, Luiten, & Bari, 2007). Moreover, pathophysiological characteristics of CCH in rats result in neuronal damage to the hippocampus, the cerebral cortex, and the white matter regions, which is associated with the initiation and progression of VD (Farkas et al., 2007).
Vascular dementia at the cellular level is correlated with neuronal death and interruption of neuronal networks, which might be the result of cell signalling defects and molecular dyshomeostasis (Enciu et al., 2011). Accordingly, Kwon et al. (2014) showed in a rat study that vascular dementia might be related to the inhibition of neurogenesis (also using CCH). Furthermore, research showed that stronger endothelial dysfunction, compared to normal aging mechanisms, has been related to the presence or progression of cerebral small and large vessel disease and is associated with VD (Enciu et al., 2011; Zuliani et al., 2008).
At the molecular level, Du et al. (2017) investigated the therapeutic mechanisms of VD using CCH, also through BCCAO in rats. Specifically, Du et al. suggest molecular mechanisms of VD include oxidative stress, inflammation, neurotransmitter system dysfunction, mitochondrial dysfunction, alterations of growth factors, and abnormal lipid metabolism. Consequently, suggesting that these are all contributing factors at the molecular level in the progression of cognitive deficits in VD. In sum, the schematic causative role of CCH in VD is shown in Figure 2 with the involvement of biochemical changes, all reflecting the complexity of VD (Du et al., 2017).
Figure 2. Schematic mechanisms on a molecular level of VD in animal models.
Note. Reprinted from “Molecular Mechanisms of Vascular Dementia: What Can Be Learned
from Animal Models of Chronic Cerebral Hypoperfusion?”, by Du et al., 2017, Molecular
Neurobiology, 54(5), p. 3677. Neuroprotective role of Humanin
Humanin (a 24-amino acid secreted bioactive peptide) was first identified in the brains of patients with AD in 2001. Later, research showed that a synthetic derivative of Humanin (Gly14-Humanin) improved cognitive decline in mice (Zhang et al., 2012). Subsequently, more studies showed that Gly14-Humanin played a neuroprotective role against cell death associated with AD and other insults (Murakami, Nagahama, Maruyama, & Niikura, 2017; Yuan et al., 2016). Interestingly, an animal study (also using CCH) with a novel homologous of Humanin (Rattin) showed neuroprotective effects in VD rats (Zhang, Zhang, & Yifengh, 2013). Even though the relation between VD patients’ cognitive decline and Humanin is still unclear, previous studies suggest an important role of Humanin in cognitive decline.
Current treatment for vascular dementia patients
Problematically, to date, an efficient treatment for patients clinically diagnosed with VD is still lacking. Currently, treatment is focused on the management of symptoms, slowing the progress of VD and early treatment of risk factors for cerebrovascular disease (Sorrentino, Migliaccio, & Bonavita, 2008). Previous pharmacotherapeutic approaches for VD are mostly cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) and memantine, yet show inconsistent results for VD patients (Auchus et al., 2007; Ballard et al., 2008; Black et al., 2003; Erkinjuntti et al., 2002; Jellinger, 2008; Kwon et al., 2014; Narasimhalu et al., 2010; Wilkinson et al., 2003). Moreover, a recent review found that donepezil and galantamine have modest benefits on cognition in VD patients, while their reported efficacy on activities of daily living and global benefits remain insignificant (Farooq, Min, Goshgarian, & Gorelick,
2017). In addition, the cost of treatment and care for dementia is enormous, resulting in medical and financial burdens on families as well as the society. In sum, VD has become a public health problem while presently no treatment is capable of obtaining consistent beneficial results once VD is clinically diagnosed.
Difficulties regarding finding an effective treatment for VD are partly due to the existence of many subtypes. Research into the prevention of risk factors is useful. However, more research regarding effective treatment is necessary once VD is clinically diagnosed and is of high medical, economical as well as of social need. Remarkably, recent studies have shown therapeutic effects in VD patients with hyperbaric oxygenation therapy (HBOT) as an adjunctive treatment.
Hyperbaric oxygenation therapy
Hyperbaric oxygenation therapy involves inhaling 100 percent oxygen in a chamber or tube that contains above standard atmospheric pressure (1.0 ATA, 101.325 kPa) (Camporesi & Bosco, 2014). For clinical purposes, the pressure of the chamber or tube during HBOT must equal or exceed 1.4 bar (UHMS, 2019). HBOT is mostly known as treatment for decompression sickness, as first published by Behnke and Saw in 1937 (Camporesi & Bosco, 2014; Carney, 2013). Consequently, there has been a rise in interest and use of HBOT for indications characterized by compromised tissue oxygenation and perfusion. Accepted clinical indications of HBOT with a high level of evidence include carbon monoxide poisoning, open fractures and/or with crush injury, refractory diabetic wound healing and radiation injuries (Mathieu, Marroni, & Kot, 2017). HBOT can be administered in two ways, using a mono- (single patient) or multi-place chamber (several patients treated simultaneously) (AHRQ, 2003). One session usually lasts between 90 and 120 minutes at a pressure between 2.0-2.5 bar. However, oxygen dosage, duration, and number of sessions have not been standardized (AHQR, 2003; Camporesi & Bosco, 2014).
The therapeutic mechanisms of HBOT are based on elevation of both 1) the partial pressure of inspired oxygen and 2) the hydrostatic pressure (Carney, 2013). Elevation of the hydrostatic pressure increases the partial pressure of gases (oxygen and nitrogen) and reduces the volume of gas-filled spaces according to Boyle's law. Based on the intracellular generation of reactive species, breathing oxygen under pressure will increase the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS is part of normal metabolism, and together with RNS, they play a central role in coordinating cell signalling and protective pathways. Finally, this increase of ROS and RNS due to HBOT can lead to improved neovascularization and improved post-ischemic tissue survival (Thom, 2011). Moreover, the effect of hyperbaric oxygenation is not simply compensation of the oxygen deficit but can alter protein expression, modulate signalling pathways and affect vascular structure and function (Drenjancevic & Kibel, 2014).
HBOT has been used over more than a century, for numerous clinical as well as animal studies to unravel its efficiency and underlying mechanisms. To date, 14 indications are recognized in the United States by the Undersea and Hyperbaric Medical Society (UHMS), an international scientific organization that plays a key role in providing scientific data for HBOT (UHMS, 2019). However, HBOT is also used in many off-label indications (that are not yet accepted by UHMS). Three examples of such off-label conditions from 2011 are aseptic bone necrosis, global brain ischemia, and autism (Kot & Mathieu, 2011). The use of HBOT in off-label indications highly contributes to the controversial attitude towards possible new indications for HBOT. This controversial attitude has also ensured that many practitioners remain unaware of HBOT findings or are concerned about the execution of the treatment.
In addition, the controversiality surrounding HBOT research is partly due to often little substantial clinical evidence and lack of correctly designed control groups to filter out a
possible placebo effect. Lansdorp and Van Hulst (2018) recently described the difficulties regarding randomized controlled trials (RCTs) and HBOT in clinical studies. For example, sham therapy must use pressure so that patients equalize their ears, similar to HBOT, and remain blind to their given treatment. However, pressure also affects the partial pressure of gases which could activate the sham treatment. To illustrate, air at atmospheric pressure consists of 21% oxygen and is equal to a partial pressure of oxygen of 0.21 ATA. If atmospheric pressure is increased to 2.5 ATA, the partial pressure of oxygen (multiplied by 2.5) would increase to 0.52 ATA, which is the equivalent of 52% oxygen under atmospheric pressure.
Also, uncertainty about the frequency and severity of adverse events associated with HBOT contributes to the controversial attitude. Hadanny et al. (2016) conducted a retrospective analysis of 2,334 patients’ side effects while being treated with HBOT for several different indications. The most commonly observed side effect of patients in HBOT were ear problems (13.3% of all patients; 0.06% of all sessions), due to the increased pressure, and mostly occurred during patients’ first session. Other short-term side effects include dizziness/weakness (1.5%), claustrophobia (more in mono-place chambers; 0.3%), and visual disturbances (0.3%) (Hadanny et al., 2016). In addition, more rare but serious side effects include central nervous system oxygen toxicity (more common with used pressures greater than 2.0 bar), and pulmonary oxygen toxicity which happens very rarely (Hadanny et al., 2016).
Furthermore, no long-term side effects of HBOT are shown in Camporesi (2014) his evaluation of previous clinical studies including a follow-up period to 8 years. Overall, mono-and multi-place chambers are considered safe mono-and effective between 1.5 mono-and 3.0 bar for less than 120 minutes per session (Hadanny et al., 2016; Thom, 2011; Tibbles & Edelsberg, 1996). Interestingly, even though ear problems are the most common side effect, Hadanny et al.
revealed that neurologic indications had significantly fewer ear problems (and adverse effects) compared to other indications. Also, considering that VD mostly affects people of age, it is important that HBOT is generally a safe treatment for elderly (Jain, 2017).
Mechanisms of HBOT on the brain
The basic mechanisms of HBOT are thought to achieve physiologic effects in brain tissue by 1) increasing the oxygen supply and 2) raising the oxygen partial pressure. Through animal studies focussed on brain injury, the associated effective mechanisms of HBOT include: improvement of cerebral oxygenation to relief hypoxia; improvement of microcirculation; enhancing damaged mitochondrial recovery to improve cerebral aerobic metabolism; and vasoconstrictive effects to relief cerebral edema (Calvert, Cahill, & Zhang, 2007; Rockswold, Rockswold, & Defillo, 2007). Some suggested effective mechanisms of HBOT in facilitating cell survival in brain tissue by Calvert et al. (2007) are visualized in Figure 3.
HBOT can facilitate cell survival through (1) improve oxygenation to relief the hypoxia; (2) improve energy metabolism; (3) reduce intracranial pressure.
Note. Reprinted from “Hyperbaric oxygen and cerebral physiology”, by Calvert et al., 2007, Neurological Research, 29, p. 7.
Furthermore, a meta-analysis for acute stroke, including 51 animal studies, showed a neuroprotective effect and reduced infarct size after HBOT at 2.0 bar (Xu et al., 2016). In addition, effective neuroprotective mechanisms associated with HBOT focussed on cerebral ischemia also included: relieving cerebral edema and increasing neural regeneration; but even reducing damage to the blood-brain barrier; reducing apoptosis; and reducing oxidative stress (Matchett, Martin, & Zhang, 2009; Veltkamp et al., 2005). Interestingly, a recent study investigating HBOT at 2.0 bar in AD mice, show a reduction of neuroinflammation and reduced hypoxia (Shapira, Solomon, Efrati, Frenkel, & Ashery, 2018).
In addition to the animal studies, Rockswold et al. (2001) his study included patients suffering from severe brain injury and showed that HBOT reduced the (previously increased) intracranial pressure and improved cerebral aerobic metabolism. Thus, even though most known and described mechanisms are obtained by animal studies focussing on numerous different neurological indications, they suggest neuroprotective effects. Therefore, previously described mechanisms of HBOT on the brain, suggest beneficial for the treatment of VD.
Hyperbaric oxygen therapy and vascular dementia
Interestingly, Xiao, Wang, Jiang, and Luo (2012) conducted a systematic review of clinical studies to support HBOT as a treatment for VD. However, they concluded insufficient evidence since they included one RCT involving 64 VD patients. Importantly, a recent meta-analysis on HBOT for VD recommended HBOT as a safe, and effective adjunctive treatment for VD (You et al., 2019). Nevertheless, underlying mechanisms remain unclear. In sum, due
to high variability in VD subtypes and inconsistent clinical recommendations regarding HBOT as an adjunctive treatment for VD, previous studies need to be critically evaluated.
Aim
This literature review will focus on the therapeutic mechanisms, efficacy, and safety of HBOT specifically as adjunctive treatment for VD. Therefore, clinical as well as animal studies using HBOT in VD will be critically evaluated. Previous study designs, clinical outcomes, and adverse effects will be reviewed. We speculate, based on increased oxygenation of brain tissue, and improved energy metabolism, both facilitating cerebral cell regeneration and improvement of neurogenesis, to find improved clinical outcomes for VD patients after HBOT. Finally, this will provide a better view of whether HBOT is a beneficial (adjunctive) therapy to people suffering from vascular dementia. If HBOT is considered effective and safe as adjunctive treatment for VD, thus hypotheses are confirmed, finding the most favourable dosage of hyperbaric oxygenation treatment is of need.
2. Methods
2.1. Data Source and Search Strategy
The UvA CataloguePlus, Web of Science, and PubMed databases were used till September 27, 2019, to search for articles containing a reference to vascular dementia as well as hyperbaric oxygen therapy. Specifically, the following terms were used for the search: “vascular dementia” OR “vascular cognitive disorder” or relevant abbreviations (VD, VaD, VCD) in conjunction with the search term: AND “hyperbaric oxygenation” OR “hyperbaric oxygen therapy” (HBO, HBOT). Publications from the last 10 years had preference. The reference lists of articles found by this search strategy, especially review articles, have also been inspected and used when relevant to add eligible studies.
2.2. Study selection, inclusion criteria, and data extraction
After the search, articles were then screened to exclude duplicates and publications which did not meet the inclusion criteria. The inclusion criteria of this review were: 1) HBOT was used as (adjunctive) treatment for vascular dementia; 2) the study design included a control group plus participants were allocated randomly; and 3) vascular dementia was clinically diagnosed. Literature in any other language than English was excluded. A flowchart presenting the study selection is presented in Figure 5.
Figure 5. Flowchart summarising the study identification and exclusion procedure.
3. Results
3.1. Study inclusion and characteristics
455 articles were identified with the search in three databases, seven duplicates were removed, which left 448 articles for further screening. After reading the titles (and abstract when relevant) 440 articles were removed, most were irrelevant studies, reviews, written in a
different language than English, or used patients that did not meet VD diagnostic criteria. After screening the full text, four articles were removed since they had only accessible abstracts in English. Finally, this review included three clinical studies shown with their characteristics in Table 3, with a total of 380 VD patients (207 patients in experimental groups and 173 patients in control groups). One study used HBOT + donepezil, one HBOT + memantine + Aricept and one used only HBOT as well as HBOT + oxiracetam. In addition, this review included one animal study specifically for VD and HBOT, see characteristics in Table 4, to further unravel underlying mechanisms. All the included studies have taken place in the People’s Republic of China.
ab le 3 ha ra ct er is tic s of th e cl in ic al s tu di es in cl ud ed in th e re vi ew ud y St ud y pe ri od / D ia gn os ti c cr it er ia Sa m pl e si ze E (M /F ) C ( M /F ) M ea n ag e E (S D ) C (S D ) In te rv en ti on E C T re at m en t du ra ti on M ai n ou tc om e A dv er se ef fe ct s u et a l., 19 20 16 2 01 8 / D S M -5 & N IN D S -A IR E N 79 ( 44 /3 5) 79 ( 42 /3 7) 69 .2 ( 8. 4) 67 .8 (7 .1 ) 10 0% O2 2. 0 A T A (6 0 m in , 5 d /w ) + d on ep ez il hy dr oc hl or id e (5 m g/ d) do ne pe zi l hy dr oc hl or id e (5 m g/ d) 12 w ee ks M M SE , se ru m H um an in le ve ls (p g. /m L ) N ot r ep or te d in , 2 01 6 20 12 2 01 4 / M R I & N at io na l In st it ut e of Ps yc ho a nd St ro ke o f U S 64 ( 33 /3 1) 62 ( 32 /3 0) 68 .8 ( 4. 9) 69 .8 (4 .3 ) 10 0% O2 (1 20 m in , e ve ry d ay ) + m em an ti ne ( 10 m g/ tim e, 2 ti m es /d ) + A ri ce pt ( 5-10 m g/ d) m em an ti ne (1 0 m g/ tim e, 2 ti m es /d ) + A ri ce pt (5 -1 0 m g/ d) 60 d ay s se ru m in di ca to rs , en do th el ia l fu nc tio n N ot r ep or te d u, 2 01 5 20 13 2 01 4 / D S M -I V (A ) 32 -(B ) 32 32 (A ) > 4 0 (B ) > 4 0 > 4 0 (A ) 10 0% O2 (6 0 m in , e ve ry d ay ) (B ) 10 0% O2 (6 0 m in , e ve ry d ay ) + o xi ra ce ta m (4 0 m g w it h 25 0 m L of p hy si ol og ic al sa li ne , 1 /d ) ox ir ac et am (4 0 m g w it h 25 0 m L o f ph ys io lo gi ca l sa li ne , 1 /d ) 3 w ee ks M M SE N o ob vi ou s si de e ff ec ts se d ab br ev ia ti on s an d m ea ni ng : E , e xp er im en ta l gr ou p; C , c on tr ol g ro up ; S D , s ta nd ar d de vi at io n; M , m al e; F , f em al e; M M SE , m in i-m en ta l st at e ex am in at io n; d , d ay ; w , w ee k; O2 , yg en ; A T A , a tm os ph er e ab so lu te . ab le 4 ha ra ct er is tic s of th e an im al s tu dy in cl ud ed in th e re vi ew ud y A ni m al : m od el Sa m pl e si ze C V D H B O T A ge In te rv en ti on C V D H B O T T re at m en t du ra ti on M ai n ou tc om e A dv er se ef fe ct s ha ng e t ., 20 10 Sp ra gu e-D aw le y ra ts : C hr on ic ce re br al hy po pe rf us io n 10 10 10 2 mon th s N on e N on e > 9 5% O2 2. 0 A T A (1 20 m in , e ve ry da y) 10 d ay s A A R , P ir b lo od fl ow , i m m un oh is to -ch em is tr y of n es ti n an d do ub le co rt in N ot r ep or te d se d ab br ev ia ti on s an d m ea ni ng : C , c on tr ol g ro up ( he al th y ra ts ); V D , v as cu la r de m en tia g ro up ( ra ts w it h bi la te ra l c om m on c ar ot id a rt er y oc cl us io n) ; H B O T , v as cu la r de m en ti a gr ou p d H B O T ( ra ts w ith b il at er al c om m on c ar ot id a rt er y oc cl us io n) ; A T A , a tm os ph er e ab so lu te ; A A R , a ct iv e av oi da nc e re sp on se ; P ir , p ir if or m c or te x.
3.2. Cognitive efficacy Clinical studies
Cognitive efficacy was assessed using Katzman et al. (1988) commonly used Chinese version of the Mini Mental State Examination (MMSE) in two included studies. MMSE scores have a range of 0-30 and scores below 24 in patients reflect cognitive decline. The MMSE score, as the mean and standard deviation (SD) per group, before and after treatment of both studies are presented in Table 5 as well as sample size, days of treatment and p-value. Furthermore, the MMSE scores of Xu et al. (2019) were not correlated with variables such as: age, sex, body-mass-index, education, p > .05, with the exception for Humanin, r = .409, p = .012.
In Bu’s (2015) study all groups showed significantly increased MMSE scores after 3 weeks of treatment. Moreover, the group that received only HBOT had an efficiency (meaning an increased MMSE score of more than 1) of 56.25%; only oxiracetam had 81.25%; and the combination of HBOT + oxiracetam had 93.75%.
Table 5
MMSE scores, before and after treatment [mean (SD)]. Significant results are presented in bold. Results are adapted from Xu et al. (2019) and Bu (2015).
Treatment Sample size Days of treatment
Before treatment After treatment p-value
donepezil 79 60 18.28 (2.32) * 20.06 (2.75) ** .627* HBOT + donepezil 79 60 18.09 (2.58)* 21.68 (2.36) ** .001** HBOT 32 21 16.86 (3.12) 18.13 (3.13) < .05 oxiracetam 32 21 16.91 (3.21) 18.64 (2.92) < .05 HBOT + oxiracetam 32 21 16.83 (3.13) 20.82 (2.81) < .01
Note. * p-value represents comparison between donepezil and HBOT + donepezil before
treatment; ** p-value represents comparison between donepezil and HBOT + donepezil after treatment.
The Sprague-Dawley rats in Zhang et al. (2010) his study that reflected vascular dementia underwent surgery (by BCCAO) causing chronic cerebral hypoperfusion which is associated with the initiation and progression of VD (Du et al., 2017; Kwan et al., 2014). The rats their cognitive function was assessed using the one-way active avoidance test based on the experiment of Solomon, Kamin, and Wynne (1953). The one-way active avoidance test is commonly used for learning and memory assessments in rats (Miyamoto et al., 1986). It consists of one light and one dark chamber (also known as shuttle box) in which the rat can move freely and contains a training period in which rats are conditioned, via a foot shock, to a five seconds light stimulus in the dark chamber. During the test phase the active avoidance response (AAR) is counted (whether the rat moved to the other compartment after the light switched off). The score was defined as the ratio of the number of AAR and total sessions. The VD rats without HBOT had an AAR ratio of 27.5% (30 days after surgery), significantly lower than the healthy rats in the control group with an AAR ratio of 87.5%, p < .01. Importantly, VD rats after ten days of HBOT showed significantly higher AAR rates (49.5%) compared to the VD rats without treatment, p < .01.
3.3. Safety
Only one included study in this review mentioned adverse effects: Bu (2015) (N = 64 receiving HBOT) did not find obvious side effects of HBOT for patients with vascular dementia.
3.4. Biochemical and physiological changes Clinical studies
Xu et al. (2019) examined patients’ blood samples, to detect Serum Humanin levels, before treatment showing no significant differences in Serum Humanin levels (picogram per
millilitre) between the control (donepezil) group (M = 126.3, SD = 7.0) and HBOT (+ donepezil) group (M = 124.8, SD = 6.2), p = .156. After 12 weeks of treatment the control group showed (M = 143.1, SD = 8.6) significantly lower Serum Humanin levels than the HBOT group (M = 146.5, SD = 9.4), p = .019. Also, results indicated a positive correlation between MMSE scores and Serum Humanin levels (r = .409, p = .012), even after adjusting
for confounding factors in VD patients ( β = .312, p = .002).
Yin (2016) also examined patients’ blood samples, and showed that the Serum
transforming growth factor- β (TGF- β ) and Insulin-like growth factor-1 (IGF-1) levels
of HBOT (+ memantine and Aricept) group were significantly higher and intercellular adhesion molecule-1 (ICAM-1) levels were lower after 60 days of treatment compared to the control (memantine and Aricept) group, p < .05. Next, endothelin values after treatment were significantly lower in the HBOT group than the control group, whereas endothelial progenitor cell contents in blood were significantly higher, p < .05.
Animal study
Zhang et al. (2010) showed that VD rats had reduced regional cerebral blood flow (rCBF), and increased relative cerebral blood volume (rCBV) in the piriform cortex compared to control rats, all p < .01. However, after ten days of HBOT, the VD rats showed increased rCBF, and decreased rCBV in the piriform cortex compared to the untreated VD group and were not significantly different from the control rats, p > .05. Furthermore, the number of doublecortin-positive (DCX+) and Nestin-positive cells in rats of the control group, VD group, and VD + HBOT group were assessed through immunohistochemical detection. The results showed an increased number of cells after HBOT, representing increased neurogenesis. The mean number of cells and standard deviations per group, separate for the hippocampus and piriform cortex, are presented in Table 6.
Table 6
Results reflecting the promoted neurogenesis after HBOT in rats. Expression of DCX and Nestin positive cells in the hippocampus and piriform cortex, assessed 30 days after surgery and/or the start of HBOT [mean (SD)].
Group Hippocampus
DCX(+) cells Nestin(+) cells
Piriform cortex DCX(+) cells
(total number/Pir zone)
Nestin(+) cells
(total number/10*40 visual field)
Control 123.74 (16.90) 131.98 (13.24) 36.56 (2.83) 39.77 (4.06)
VD 66.27 (9.22)* 160.46 (17.38)* 9.94 (2.10)* 50.98 (3.59)*
VD + HBOT 115.13 (18.28)* # 187.82 (15.49)* # 31.26 (2.17)* # 65.55 (6.12)* #
Used abbreviations: DCX, doublecortin; HBOT; hyperbaric oxygenation therapy; VD, vascular dementia meaning rats with bilateral common carotid artery occlusion; Pir, piriform cortex.
Note. * p < .01, compared to Control group; # p < .01, compared to VD group; Results are
adapted from Zhang et al. (2010).
4. Discussion
In this review, we only found three clinical studies and one animal study. Nevertheless, the main results of this review regarding the efficacy and safety indicate that: HBOT adjunctive to conventional therapy improved cognitive functioning in VD patients the most, as measured by MMSE, compared to only conventional therapy and only HBOT. Global efficacy or daily life benefits were not assessed in the included human studies. Furthermore, also in rats, HBOT improved cognitive functioning, as measured by the AAR ratio. Lastly, the safety of HBOT was mentioned in only one of the included studies, in which no obvious side effects occurred. Thus, these results suggest promising therapeutic effects of HBOT for vascular dementia patients yet lack sufficient evidence on providing HBOT as a routine adjunctive therapy for VD.
Also addressed in this review are the possible effective biochemical and physiological mechanisms as a result of HBOT in VD, accounting for the cognitive improvements. Results of Xu et al. (2019) indicate that the cognitive improvements of VD patients are correlated with the Serum Humanin levels. Furthermore, the results of Yin (2016) showed optimized endothelial function as well as significant changes in Serum indicators after HBOT. The observed biochemical changes indicate that HBOT involves improving the nerve cell protection, inhibiting the apoptosis of neurons, reducing the degree of oxidative stress, and decreasing the occurrence of neuron damage in VD patients. In addition, physiological changes of HBOT measured in the animal study of Zhang et al. (2010) involve increased cerebral blood flow in the piriform cortex, accounting for restoration in cerebral blood supply. Also, results showed increased DCX-positive and Nestin-positive cells after HBOT, both associated with increased neurogenesis in the piriform cortex and hippocampus of VD rats. Thus, diverse possible underlying mechanisms of HBOT suggest neuroprotective effects for vascular dementia.
The novelty of this review remains that only randomized controlled studies, published in English accessible journals are included in addition with one animal study focused on the underlying mechanisms to unravel HBOT specifically in VD. Especially the included clinical studies, using different diagnostic criteria for VD, are highly important for unravelling whether HBOT is beneficial for patients suffering from vascular dementia.
This review showed two clinical studies in which HBOT, supplementary to the conventional therapy, improved cognitive functioning (assessed by MMSE scores) in VD patients. That is in line with the previous studies included in the meta-analysis of You et al. (2019) as well as the hypothesis of Efrati and Ben-Jacob’s (2014) review reflecting on neurotherapeutic effects of HBOT.
On the other hand, in contrast with You et al. (2019), this review could not include enough studies to already recommend the best dosage for HBOT as an adjunctive treatment for VD. You et al. concluded, based on 25 clinical studies, that 60 minutes of daily HBOT for seven to eight weeks is the most effective treatment for VD. We could not include any study of that review because all studies were in Chinese or did simply not appear in multiple online databases. Whereas Xiao et al. (2012) included only one study in their systematic review of which they stated the study protocol was missing. Therefore, both previously published reviews should be questioned seriously. In contrast, this review only contains English accessible, randomized controlled trials allowing for better reliability on the interpretation of results.
Nevertheless, included studies did also have limitations that will be discussed. First, the results of this review represent the lack of agreement on the dosage and the duration of HBOT. To specify, hyperbaric oxygen therapy dosage varied highly between the included clinical studies from 3 weeks (60 minutes every day, total = 21 hours), 12 weeks (60 minutes 5 days per week, total = 60 hours) to 60 days (120 minutes every day, total = 120 hours). Besides, only one study explicitly mentioned the used pressure profile which makes comparing and interpreting the results as well as the mechanisms less precise. Also, it disables evaluating the most efficient profile for VD patients.
Next, the clinical studies were lacking good sham therapy, making the interpretations of cognitive improvements as a result of hyperbaric oxygen therapy less valid. Especially, in multi-place chambers, HBOT also contains a social aspect next to the regular placebo-effect. Since patients are placed together in one chamber for 60-120 minutes per day this might have positive effects of its own. This is partly illustrated by a systematic review on HBOT in multi-place chambers that showed patients' quality of life improved after adjunctive HBOT compared to conventional therapy in numerous diseases, including post stroke
(Nourmohammadi, Doaee, Mazloum Fazel, & Mousavi, 2017). Quality of life included domains related to physical, mental, emotional, and social well-being. Thereby, including a good sham therapy is of need to correctly interpret the results due to the effects of HBOT mechanisms.
In general, all included studies are recently conducted and both clinical studies that assessed cognitive functioning used MMSE scores, resulting in highly comparable data. Nonetheless, the MMSE of Folstein, Folstein, and McHugh (1975) was initially devised to detect Alzheimer’s disease and might be less sensitive to impairments in VD patients (Ylikoski et al., 2007). Other cognitive functions such as memory and language are much more variably affected in vascular dementia compared to AD. Consequently, the Montreal cognitive assessment scale or the vascular dementia assessment scale (highlighting mental speed, attention and executive function) are more likely to pick up impairments in VD patients and could thus provide better insights whether HBOT is an efficient adjunctive treatment (Lees et al., 2014; Ylikoski et al., 2007).
Lastly, a common and general problem affecting vascular dementia research is the lack of globally accepted consensus on pathological criteria as described in our introduction (Gold et al., 2002). Used diagnostic criteria in this review include DSM-IV and NINDS-AIREN that both contain very low sensitivity (respectively 0.50 and 0.55). In addition, Yin (2016) used next to a neuroimaging technique, criteria for senile VD that are not commonly used, and sensitivity and specificity are unknown. Moreover, we included studies that did not make a difference in the previous described subtypes of VD (presented in Table 2). Hereby, correctly interpreting the results is more difficult and should be taken into account.
Interpretation of the measured underlying mechanisms indicates an important role of Serum Humanin levels in the cognitive decline of VD patients. Xu et al. (2019) assessed both MMSE scores and blood samples ensuring for correlational analyses. Consequently, the found
relation between elevated Humanin levels and cognitive improvement seems essential. In contrast, Yin’s (2016) clinical study investigating Serum indicators was lacking the used profile pressure as well as any efficacy score regarding cognitive outcomes or daily life benefits. Therefore, Yin’s results suggesting the optimized endothelial function after HBOT should be interpreted with extra care.
Even though the human studies outweigh the animal study, it should be noticed that Zhang et al. (2010) showed small sample sizes in his animal study (N = 10). Positively, his study did assess cognitive efficacy, and VD rats showed cognitive deficits which is in favour of generalizing the results to the VD population. Also, the rats in his study underwent permanent BCCAO, which is similar to most previously described studies that investigated the pathophysiological changes of VD, ensuring for applicable results. Therefore, his results that indicate HBOT can increase neurogenesis seem useful for the interpretation of therapeutic mechanisms.
In sum, many significant biochemical and physiological changes after HBOT as adjunctive treatment for VD patients are shown, that could account for the improved cognitive functioning. But taken together the lack of sham therapy, absence of frequency and severity of side effects, absence of used profiles in combination with high variation in the number of sessions disables answering the preferable dosage and whether HBOT is safe for VD patients. Nevertheless, all of the above must be standardised in future research to provide a more specific recommendation on HBOT as a routine adjunctive treatment for VD patients.
HBOT as treatment for VD has different challenges in research practices. However, difficulties can be challenged in future research. To elaborate, due to the narrative review of Lansdorp and Van Hulst (2018) the best sham therapy for HBOT studies contain: 1) a lower pressure than the HBOT experimental group and 2) breathing air (21% oxygen). Although
taken into account patients’ unwillingness to be signed to sham therapy, plus the ethical considerations regarding sham therapy, makes it difficult to accomplish future RCTs.
The previously described knowledge gap regarding vascular dementia can also be challenged. Moreover, future research into defining more distinct diagnostic criteria for VD and creating consensus on pathologic criteria is of high need. Consequently, this will allow for better interpretation of all future vascular dementia research. Finally, the aim is that if enough clinical evidence for HBOT in VD is established, this should be implemented and could help improve many patients’ (and thus caretakers’) daily life.
In conclusion, hyperbaric oxygen therapy showed cognitive improvements as an adjunctive treatment for vascular dementia. To date, considering the strengths and weaknesses of previous studies, the most favourable dosage of HBOT that should be recommended and implemented as an adjunctive treatment for VD remains unclear. First, more reliable studies that include sham therapy and state the used pressure profile, should be conducted preferably in an international multicentre trial. Nevertheless, promising results regarding cognitive improvements are present, yet in this review global efficacy, daily life benefits and safety of HBOT for VD remain unanswered. Importantly, the affected population by VD is still increasing and more research into vascular dementia in general and in combination with HBOT is of high need to improve the daily life of millions of people worldwide.
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