Efeitos da oxigenioterapia hiperbárica no tratamento da lesão medular traumática: revisão sistemática

OBJETIVO: realizar uma revisao sistematica dos estudos experimentais e clinicos relacionados com a utilizacao da oxigenioterapia hiperbarica no traumatismo raquimedular. METODOS: noventa e tres estudos foram identificados no Pubmed, sendo selecionados 11 artigos para analise, 9 experimentais e 2 clinicos, publicados entre 1963 e 2009. Os estudos experimentais apresentaram diferentes formas de tratamento, sendo o desfecho final mensurado pelas diferentes avaliacoes: funcional, histologica, bioquimica e eletrofisiologica. RESULTADOS: na maioria dos estudos foi observada uma recuperacao da funcao locomotora, histologica e/ou bioquimica. Entretanto, os resultados dos estudos clinicos se mostraram controversos, pelo fato de as amostras serem heterogeneas e a administracao da oxigenioterapia hiperbarica ser diferente quanto a dose e o tempo de aplicacao. CONCLUSAO: considerando os resultados desta revisao, sera necessaria a realizacao de mais estudos para se ter uma definicao sobre a eficacia da oxigenioterapia hiperbarica na lesao medular aguda.


RESUMEN
Objetivo: realizar una revisión sistemática de estudios experimentales y clínicos que evaluaban los efectos de la terapia hiperbárica en el traumatismo raquimedular.Métodos: se identificaron noventa y tres estudios en el Pubmed.De estos, por un conjunto de criterios de inclusión y exclusión, se seleccionaron 11  There are few data on SCI in Brazil.According to Masini 3 , an incidence of 10,000 new cases of SCI per year in Brazil is estimated, mainly due to trauma.
In relation to the SCI pathophysiology, after the primary mechanical injury, a cascade of events is triggered, which leads to degeneration and death of the potentially viable neuronal tissue 4 .Among the secondary injury components, hypoxia/ischemia is considered one of the most important factors implicated in the neuronal tissue injury 5 .Anatomical 6 , biochemical 7,8 , and physiological 9 studies have demonstrated that spinal cord microvascular potency and blood flow decrease just after severe contusion or compression injury.Available evidence suggests that oxygen radical formation and cell membrane lipid peroxidation have an important role in the progression of the secondary injury 4,10,11 .
The use of HBOT is well established for the treatment of decompression sickness, including the spinal cord decompression 36,37 .To date, however, there are few studies exploring the utilization of HBOT in the treatment of SCI in humans, and few experimental studies with animal models.Also, the treatment mechanisms or the extent of hyperbaric oxygenation remains unclear.The aim of this paper is to review the literature on this subject and define the role of HBOT in SCI.

Literature review
A search in the MEDLINE database was conducted in May 2009, covering the period from May 1963 to May 2009.The selected studies were clinical trials and experimental studies on the efficacy of HBOT in SCI.For the electronic search strategy, the following terms were used as keywords in these combinations: "hyperbaric oxygen and SCI" or "HBOT and SCI", without filters.

Inclusion and exclusion criteria
The selected articles were identified from titles and abstracts, by two independent reviewers, considering inclusion and exclusion criteria.The inclusion criteria included original studies in humans or animals, presenting abstracts in the PubMed database, in English, Portuguese or Spanish language, which tested the efficacy of HBOT after SCI and presented a Control Group in the study design.The exclusion criteria were: no abstracts in PubMed database, published in other languages, review articles, studies evaluating preconditioning with HBOT and which evaluated the role of the HBOT in decompression sickness or studies without a Control Group (case report or case series).
Full text reprints were obtained for relevant and potentially relevant studies, which seemed to meet the inclusion criteria and for those that had insufficient data in the abstract to make a clear decision.

RESULTS
The search retrieved 93 articles.After the abstract review, only 15 met the inclusion criteria, 6 were clinical trials and 9 experimental studies.The remaining 78 articles were excluded due to: reviews, case reports, or case series (n=26), without abstracts and/or were published in other languages (n=28), not concerning (or not involving spinal) SCI and/ or other treatment modalities (n=13), regarding decompression sickness (n=7), and used as preconditioning therapy (n=4).Four of the 15 articles selected could not be found in full text and were excluded.Nine of the 11 articles were experimental studies, and the remaining articles were clinical trials.
The results of the clinical trials 20,39 are summarized in Table 2. Asamoto et al. 20 evaluated the efficacy of HBOT in 34 patients with hyperextension SCI.These patients were allocated either to the HBOT Group (n=13) or to the Control Group (n=21).The clinical evaluation consisted of the Neurological Cervical Spine Scale (NCSS) and American Spinal Injury Association (ASIA) scale at admission and after treatment (the article did not specify when the functional evaluation occurred after treatment).There was a significant improvement in spinal function in the HBO Group.Yeo 39 conducted a non-randomized comparative study, with 35 SCI patients treated using HBOT and 63 in the Control Group.All patients who underwent only one session were excluded from the final analysis.The primary outcome used was the observation of clinical improvement at least of two levels in the Frankel Grade, between the pre and posttreatment There was no significant improvement between the two groups, and none of the patients in the HBOT Group with complete lesion before treatment has improved.

DISCUSSION
The main objective of this systematic review was to define what has already been established about the role of HBOT in SCI.Few studies about this therapy for SCI were identified in the literature.Most of the studies reviewed were experimental.In general, they have demonstrated good functional, histological and biochemical outcomes in the animals with SCI exposed to HBOT.
The first studies that evaluated the effect of HBOT were conducted in 1976 and 1977 by Yeo et al. 27,28 in a sample composed by sheep, comparing HBOT with no treatment.The results suggested that HBOT applied two hours after SCI produces significant recovery of motor function in paraplegic sheep, compared with the untreated Control Group.The 1976 study 27 did not provide histopathological analyses, this outcome was described in the following year.The 1977 study 28 demonstrated better histological outcome in the HBOT Group, with less central cystic degeneration, compared with the Control Group.
Murakami et al. 26 showed the influence of HBOT on delayed neuronal cell death in the spinal motor neurons.They demonstrated that if one session of HBOT is given 30 minutes after the SCI, this treatment has protective effects against ischemic spinal cord damage.The animals had less neurologic deficits and less degeneration of spinal motor neurons in ventral gray matter.These results were not found in the group that received HBOT six hours after SCI.
According to the Higgins et al. study 22 , in a period of six hours after surgery, the spinal cord evoked potentials were monitored for evidence of neuronal's recovery conduction through the site of injury and following histological evaluation.This study shows better results in cats with early therapy and less severe injuries.The histological evaluation showed no differences between Treatment and Control Groups.A noteworthy feature of this study is the recording of the spinal cord evoked potentials, an objective physiologic measure of the neuronal conduction during and after the SCI.These observations suggest that HBOT treatments can mediate preservation of marginally injured neuronal elements of long tracts of the spinal cord, during the early phases of traumatic SCI.Increasing magnitudes of impact force and delay in the onset of HBOT treatment markedly diminished the protective effects of HBOT on long-tract neuronal conduction following traumatic SCI.
Yu et al. 29 investigated the effects of HBOT on the progress of secondary damage following SCI induced by a weight-drop device in rats.They compared three groups: a single HBOT administration, repeated applications of HBOT once daily in the following four days, and Control Group.The spinal cords were evaluated 6 hours, 12 hours, 1 day, 2 days, 3 days, and 4 days after the operation.Their results showed that the early onset of HBOT significantly diminished the number of apoptotic cells one day after the injury.The gene expression of glial cell line-derived neurotrophic factor (GDNF) and inducible nitric oxide synthase (iNOS) was significantly attenuated one day after the injury in the HBOT groups, compared with the Control Group.Also, in this study, it was observed that repeated hyperbaric oxygen treatment did not have greater effects than the single treatment on apoptosis and iNOS.According to some authors, overexposure to oxygen may induce neurotoxicity by increasing free oxygen radicals 40,41 .
The experiment of Huang et al. 24 evinced a benefit of multiple sessions of HBOT.The authors evaluated whether serial HBOT, compared with a single session of it, extends the therapeutic windows after acute SCI with a rat model.The rats that received single HBOT intervention beginning at 30 minutes and 3 hours and those that received multiple HBOT treatment, starting at six hours following injury, had significantly greater neurological recoveries than those in the Untreated SCI Group.These rats also retained more sparing tissue than controls.The authors state that more frequent exposure to HBOT could help sustain its positive effects on the metabolism of the spinal cord and regeneration of the neuronal structure.
Gelderd et al. 21evaluated the combination of HBOT and dimethyl sulfoxide, a substance with various effects, such as reduction of tissue edema and inflammation, dispersion of microthrombi (due to the anticoagulant and hemodiluting properties), enhancing the penetration of several compounds across the blood brain barrier and the free radical scavenging property.The clinical outcome was 2) Tempol -treated 3) HBOT treated 4) X-irradiated + tempol-treated 5) X-irradiated + HBOT-treated 6) Untreated control    25 conducted a study to compare the effects of HBOT with methylprednisolone after experimental SCI in rats.In this study, HBOT was administered immediately after the SCI.Five days after the SCI, the spinal cord was evaluated in relation to oxidative status with thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px).The authors observed that only the HBOT reduced the level of oxidative damage after SCI.The results of oxidative damage did not differ between the Untreated and the Methylprednisolone Group.
Only one study, designed to test the efficacy of HBOT, antioxidant nitroxide tempol and x-irradiation, associated or alone, in reducing histological damage and functional disability, demonstrated that a single hour session, 20 minutes after the SCI, does not promote histological or functional recovery 23 .It was observed that only x-irradiation and tempol administered alone significantly improved function and reduced histological damage.There were no differences compared with the Untreated Group in the groups that received HBOT alone or associated with tempol or x-irradiation, or in the group that received xirradiation associated with tempol.
Regarding the clinical studies, the samples were heterogeneous, the application of HBO was not equal for all patients in every study, and the results were controversial.In the study of Yeo 39 , the randomization procedure is unclear as well as the criterion used to define the number of pressurizations.The primary outcome utilized was the observation of a clinical improvement of two levels on the Frankel scale, at least between the pre and posttreatment evaluation.The statistical analysis showed no significant improvement between the two groups and none of patients in the HBO-therapy group with a complete lesion before treatment has improved.
In the study of Asamoto et al. 20 , the randomization process was unclear, the delay between admission and HBOT was within 24 hours and the duration of therapy ranged from 3 to 33 days (mean 12.1 days), because the protocol changed across the study observational time.The clinical evaluation consisted of the NCSS and ASIA impairment scale in the admission and after treatment.The mean improvement was 75.2 and 65.1% in the HBOT and Control Group, respectively (p<0.05).

CONCLUSION
The majority of experimental studies with HBOT in the treatment of SCI had good results of this therapy.The quality of the two clinical trials reviewed was poor and cannot provide clear information about this treatment in humans with acute SCI.Further studies are needed to define the role of HBOT in SCI.

TABLE 2 -
Characteristics of clinical studiesassessed by reflexes, sensory and motor functions.The best results were provided by the combined therapy.The only difference between the Treatment and Control Group was a decrease in cavitation size and increased number of nerve fibers within the scar in animals showing coordinated hind limb movements.Kahraman et al.