Systematic Review of Hyperbaric Oxygen for Late Radiation Tissue Injury (Bowel, Bladder)
Systematic Review of Hyperbaric Oxygen for Late Radiation Tissue Injury (Bowel, Bladder)
RUNNING HEAD: SYSTEMATIC REVIEW OF HBO2 FOR BOWEL/BLADDER LRTI
ABSTRACT
Background: This systematic review evaluated comparative studies to determine if hyperbaric oxygen therapy (HBO2) is beneficial to late radiation tissue injury (LRTI) of the bowel and/or bladder.
Methods: Inclusion criteria were a comparative study that evaluated the effect of HBO2 on patients with LRTI (≥3 months duration and/or ≥6 months after radiation therapy) to the bowel/bladder compared to patients who did not receive HBO2 or received placebo/sham procedure; complete outcomes data must have corresponded to the tools used to measure change in LRTI symptoms. Studies that were statistically underpowered and/or evaluated animals were excluded. Medline was searched through May 4, 2023, Embase through May 29, 2023, and Google Scholar through May 5, 2023. The Cochrane risk-of-bias tool and GRADE approach were used with a certainty of outcomes assessment.
Results: Three RCTs were included with 273 subjects. Two double-blinded studies evaluated rectal symptoms, and one open study evaluated cystitis. One study had a low risk of bias, and two had some concerns. All had moderate certainty of outcomes. There is moderate certainty with a weak recommendation for using HBO2 for rectal complications or cystitis.
Discussion: The highly heterogeneous design of the trials made meta-analysis impossible, but moderate certainty of the beneficial effect of HBO2 on LRTI to the rectum and bladder was confirmed. With the weak recommendation, a discussion should take place between the patient and their physician as to whether or not the patient is likely to benefit from HBO2.
Funding: Undersea and Hyperbaric Medical Society
Registration: PROSPERO (CRD42023433886) on June 20, 2023
Keywords: cancer; chronic wounds; comparative studies; cystitis; hyperbaric oxygen therapy; LRTI; proctitis
Key Points
- An updated systematic review of all comparative studies that evaluated the effect of HBO2 on LRTI to the bowel and bladder was performed.
- Three RCTs, including 2 double-blinded trials and 1 open trial, were included that evaluated rectal and bladder symptoms of LRTI and had low to moderate risk of bias and moderate certainty of outcomes.
- Using the GRADE approach, there is moderate certainty with a weak recommendation for using HBO2 for rectal complications or cystitis, meaning the decision to use HBO2 is contextual, requiring a decision made between the physician and the patient to determine the potential benefit of HBO2 based on clinical judgment of severity and symptom duration.
INTRODUCTION
Many patients with pelvic cancers receive radiation as a component of their treatment. These cancers include tumors of the genital system, the anus, the colorectal system, and the bladder. The American Cancer Society predicts that in 2023, there will be about 660,000 patients diagnosed with cancers at these sites [1]. Most cancers are treated with radiation at some time during their therapy [2]. Cancers involving these pelvic organs are responsible for nearly 25% of all cancer deaths [1]. In the United States, 29% of cancer survivors are reported to have undergone radiation therapy for their cancer [3]. The number of cancer survivors who undergo radiation is expected to increase from 3 million in 2016 to 4.2 million in 2030 [3]. As more patients survive cancer, the complications and consequences of their treatments are becoming more noticeable. From 2005 to 2016, there were 482,525 hospitalizations due to radiation-induced complications, with the most common reason being radiation-induced cystitis, accounting for 4.8% of radiation-related hospitalizations [4]. These hospitalization costs totaled a staggering $4.9 billion.
Radiation injuries are divided broadly into acute and late or chronic injuries. For the most part, acute injuries are due to direct radiation cell kill in sensitive tissues and usually resolve within a few weeks after completion of radiation with supportive care, including hydration, nutritional support, and analgesics [5,6]. However, late radiation tissue injuries (LRTI) do not occur until months or even years after the completion of radiation therapy. They are not self-limited, often progressive, and require the evolution of the effects of cytokines and growth factors for their expression [5,6]. These injuries are delayed because they typically develop after a latent period marked by the resolution of acute radiation injury; they are chronic because they are present for prolonged periods and often progress over time. Among cancer survivors who have undergone radiotherapy, between 5% and 15% will develop LRTI symptoms [7]. LRTI rates are similar for those who have specifically undergone pelvic radiotherapy and developed symptoms to the bowel and bladder, although international case series have reported incidence rates of LRTI as high as 47% [7-11]. Previously, definitive care has been limited to surgical removal of the affected part, which often further harms patients’ quality of life and may not be possible because the consequences of such surgeries may be life-threatening or at least diminish the quality of life to an intolerable extent [7,12]. Surgical repair risks disfigurement, infection, chronic nonhealing wounds, and additional extension of radiation damage in surgically stressed tissues.
Hyperbaric oxygen therapy (HBO2) has emerged as a nonsurgical alternative to treating LRTI of the bowel and bladder. However, the majority of the evidence supporting its use is from low-quality case series and noncomparative studies [7]. Most systematic reviews recommending the use of HBO2 on LRTI of the bowel and bladder were likewise of poor quality, included noncomparative studies, and/or were merely narrative, comprehensive reviews of the literature [13-22]. Only 1 systematic review, a Cochrane review, has been performed that evaluated comparative studies [specifically, randomized controlled trials (RCTs) and quasi-RCTs, in which randomization methodology was flawed] comparing the effect of HBO2 vs no HBO2 on general LRTI [7]. The broad inclusion criteria allowed for the inclusion of trials that had flawed designs, including being underpowered and/or having inappropriate statistical analysis that could not properly determine the benefit of the intervention, and allowed for incomplete outcomes data reporting. Among the 18 trials included in this review, there was some evidence that HBO2 improved outcomes in LRTI of the bowel and bladder. No trials were included in this systematic review that evaluated the effect of HBO2 on chronic radiation cystitis. As this Cochrane review had a questionable method for study inclusion and focused on all LRTI and not injury specific to the bowel and bladder [7], a more comprehensive systematic review of comparative study design and bladder and bowel outcomes and their certainty is needed to support the use of HBO2 more definitively on LRTI of the bowel and bladder. The objective of this current study was to perform a systematic review of the evidence from comparative studies to determine if HBO2 incurs any benefits or harms when used for LRTI of the bowel and/or bladder.
METHODS
In lieu of a study protocol, this systematic review was registered on PROSPERO (CRD42023433886) on June 20, 2023. The inclusion criteria for this review were any comparative study (retrospective and prospective, RCTs, and nonrandomized) that evaluated the effect of HBO2 administered in a clinical setting as 100% of breathable oxygen with a pressure of at least 2.0 ATA in a hyperbaric chamber on patients who had LRTI to the bowel and/or bladder [15], compared to patients who did not receive HBO2 (controls) or received placebo/sham procedures. LRTI to the bowel and/or bladder was defined as a radiation-induced injury with a duration of at least 3 months and/or occurring at least six months after the completion of the radiation treatment, including radiation-induced proctitis, cystitis, and related symptoms, such as chronic rectal bleeding, diarrhea, and hematuria. Additionally, all studies had to include endpoints that evaluated the change in LRTI symptoms to the bowel and bladder after HBO2 was completed, which could be measured by a variety of instruments and patient-reported outcomes. Outcomes data must have been clear, complete, and corresponded to the tools used to measure change in LRTI symptoms of bowel and bladder. The study had to have an adequate power calculation (≥80%) [23,24], but if none was reported, then it had to have had a reasonable expectation based on sample size and trial design that the trial would likely succeed in regard to the primary endpoint. Exclusion criteria were studies that compared HBO2 to a different advanced therapy, evaluated the effect of HBO2 on acute radiation injury (presenting less than three months after radiation therapy), evaluated the effect of HBO2 on animals, were underpowered with small sample sizes that could not detect statistical significance, and/or reported p values only without providing the outcomes data from which these values were determined.
Relevant literature was searched using three online databases. No language restrictions were applied to this literature search. One reviewer searched Medline for all comparative studies through May 4, 2023, and Embase for all comparative studies through May 29, 2023. Google Scholar was also searched, but given that this database retrieves an unspecific myriad of publications that become increasingly less relevant and less related to the topic while descending the retrieval list, the reviewer only searched for RCTs through May 5, 2023.
The Mesh term for hyperbaric oxygen is “hyperbaric oxygenation.” The following search strategy was utilized to retrieve all comparative studies in Medline:
"hyperbaric oxygenation"[Mesh] OR "hyperbaric oxygen" OR "hyperbaric oxygen therapy" OR "hyperbaric oxygen treatment" AND ("proctitis" OR "cystitis" OR "bowel" OR "bladder").
The following search strategy was used to retrieve all comparative studies in Embase: (‘proctitis’/exp OR ‘procitis’ OR ‘proctitis’ OR ‘rectal inflammation’ OR ‘rectitis’ OR ‘rectum inflammation’ OR ‘intestine’/exp OR ‘bowel’ OR ‘gut’ OR ‘intestinal tract’ OR ‘intestine’ OR ‘intestine lumen’ OR ‘intestines’ OR ‘intestinum’ OR ‘cystitis’/exp OR ‘acute cystitis’ OR ‘bladder inflammation’ OR ‘cystitis’ OR ‘cystitis emphysematosus’ OR ‘cystitis follicularis’ OR ‘emphysematous cystitis’ OR ‘follicular cystitis’ OR ‘inflammation, bladder’ OR ‘megacystitis’ OR ‘papillary cystitis’ OR ‘pericystitis’ OR ‘polypoid cystitis’ OR ‘bladder’/exp OR ‘bladder’ OR ‘urinary bladder’ OR ‘urine bladder’ OR ‘vesica urinaria’) AND (‘hyperbaric oxygen therapy’/exp OR ‘hbo-therapy’ OR ‘high pressure oxygen’ OR ‘high tension o2’ OR ‘high tension oxygen’ OR ‘hyperbaric medicine’ OR ‘hyperbaric o2’ OR ‘hyperbaric oxygen’ OR ‘hyperbaric oxygen therapy’ OR ‘hyperbaric oxygen treatment’ OR ‘hyperbaric oxygenation’ OR ‘hyperbaric oxygenisation’ OR ‘hyperbaric oxygenization’ OR ‘hyperbaric therapy’ OR ‘oxygen, hyperbaric’) AND (‘placebo’/exp OR ‘placebo’ OR ‘placebo gel’ OR ‘placebos’ OR ‘control’/exp OR ‘control’ OR ‘internal-external control’ OR ‘sham procedure’/exp OR sham).
The following strategy was used to retrieve RCTs from Google Scholar: “allintitle: randomized OR controlled OR radiation OR radiotherapy proctitis OR cystitis OR bowel OR bladder "hyperbaric oxygen."
One reviewer screened titles and abstracts to identify potential comparative studies. Full-text articles of potentially eligible studies and those with insufficient information in their titles/abstracts were retrieved to determine their potential eligibility. Internal citations were also considered for eligibility, and authors consulted with experts from the Undersea and Hyperbaric Medical Society (UHMS) on other potential references that could have been missing from the literature search results. Two reviewers screened potentially eligible articles and selected them. When they had any doubts over study eligibility, all 3 authors discussed the study’s eligibility and made a consensus decision.
One reviewer extracted the following data from all studies, with agreement from a second reviewer: study year, country (-ies), trial design, indications, power calculations, allocation concealment methodology, group treatment allocations, treatment duration, follow-up duration, primary endpoint(s), number of patients [including in intention-to-treat (ITT) analyses, as applicable], patient age, comorbidities, attrition, primary outcomes, adverse events related to HBO2, and statistical analysis. All study data were collected into an Excel spreadsheet and tabulated for synthesis. No assumptions were made for other missing data, although no attempt was made to contact the original study authors for additional information, as there was sufficient information provided for analysis. The corresponding author can be contacted for data availability.
Two reviewers assessed the risk of bias of RCTs using the Cochrane risk-of-bias tool for randomized trials (RoB 2), which assesses bias over 5 domains: (1) the quality of randomization, (2) the effect of assignment to intervention, (3) missing outcome data, (4) outcome measurement, and (5) selection of reported results [25]. For nonrandomized studies, the Risk of Bias in Non-randomized Studies – of Interventions (ROBINS-I) tool was used, which assesses confounding, classification of interventions, deviations from intended interventions, missing data, outcome measurement, and selection of reported results [26]. If the 2 reviewers did not reach consensus on their assessments, then the third author was consulted to make the final assessment.
Given that previous systematic reviews have reported the high heterogeneity of LRTI symptoms and tools used to measure outcomes in clinical studies [7,13-22], no meta-analysis was planned for this systematic review. Meta-analysis is not without its limitations, as it does not consider factors that increase the risk of bias, especially with regards to the certainty of outcomes, [24] which are not necessarily comprehensively evaluated by all domains of traditional risk of bias assessments. One reviewer performed an independent assessment of certainty of outcomes based on select study data extracted from each trial. The methodology used to assess certainty of outcomes has been previously described in detail [24]. Briefly, one reviewer applied a binary score (yes/no) to determine if patients and study assessors were blinded; detailed allocation concealment information was provided, the trial was powered at ≥80%, and an ITT analysis was conducted on all subjects randomized to study groups for the primary endpoint. A modified ITT analysis was acceptable, provided that the population was clearly defined. The attrition rate was calculated as a percentage of total subjects in each group at the end of the study, and the reviewer calculated whether there was a difference of at least 20% between the groups. The second reviewer verified the assessment of the first reviewer, and if there were any disagreements, the third reviewer was consulted so that consensus could be reached. The second reviewer calculated the 95% confidence intervals (CIs), if they were not reported with outcome data. If the selected studies involved secondary endpoints that assessed change in LRTI symptoms, then those endpoints were tabulated and multiplicity adjustment was performed, if not already done by the study authors. A binary score was applied to determine if at least one secondary endpoint became statistically nonsignificant, and the reviewer calculated the percentage of affected endpoints that became nonsignificant after multiplicity adjustment. All factors were assessed at a study level; frequency/percentages were used to assess the factors across the body of evidence (i.e., all trials). If each study characteristic was scored with a “yes”, then high certainty of outcomes were determined. If at least half of the characteristics were scored “yes”, then there was moderate certainty. If less than half were “yes”, then there was low certainty [24].
Two reviewers used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach to rank the body of evidence obtained for the research question as very low, low, moderate, and high [27]. An overall recommendation (strong vs weak) was made regarding the evidence; a weak recommendation indicated that engaging in a shared decision-making process is essential, while a strong recommendation suggested that it is not usually necessary to present the alternative treatment option. If there was disagreement on the GRADE assessment, the third reviewer was consulted to reach consensus.
RESULTS
The literature search retrieved 756 records from all three databases. The PRISMA 2020 flow diagram is presented in Figure 1 with complete details of the study selection process. After removing duplicates and screening abstracts, 23 reports were retrieved and assessed for eligibility. Four reports from 3 RCTs were included in this systematic review [28-31]. The Oscarsson study had 2 reports included, the second report being an erratum of the first [30,31]. Among the 19 reports determined to be ineligible for this review, 13 (68%) were excluded because they did not evaluate the therapeutic effect of HBO2 on LRTI on the bowel and/or bladder [32-44]. Among these excluded studies, one study evaluated the physiological effect of HBO2 on radiation-induced cystitis but did not analyze the therapeutic effect [40], and 11 studies evaluated the adjuvant use of HBO2 with radiation, but they did not report data on radiation-induced complications [32-35,37-43]. Five (26%) reports were excluded due to having incomplete population and outcome data. Among these reports, an abstract of a conference presentation of the Oscarsson study was excluded [45]. In one study, it was unclear how many in the patient population had LRTI (vs acute radiation injury); a nonstandard statistical analysis was employed; and the head-to-head design was not useful for determining the beneficial effect [46]. One study was a very unclear and incomplete report that implied the population had acute radiation injury instead of LRTI [47]. Another was a poster presentation reporting incomplete interim data of a study that was terminated early due to recruitment issues before the HBO2 effect on LRTI could be determined [48]. The fifth report excluded due to incomplete data evaluated the adjuvant use of HBO2 with radiation therapy, and while long-term radiation complications were mentioned as additional outcomes, the outcome data were incomplete to be able to fully assess the beneficial effect [49]. The last report was excluded because the study was a very small, nonrandomized dosing trial that was not powered to detect statistical significance [50].
There were 273 subjects enrolled in the 3 RCTs included in this review, 153 (56%) of whom were allocated to receive HBO2. Table 1 provides a summary of the trial design and outcomes for each study. The trials occurred in nine different countries. They were highly heterogeneous in design. Both the Clarke and Glover studies evaluated bowel-related LRTI; however, Clarke et al. specifically focused on proctitis (damage to rectal tissue) [28], whereas Glover et al. had a primary endpoint based on a modified Inflammatory Bowel Disease Questionnaire (IBDQ) that analyzed rectal bleeding amongst a subgroup of patients [29]. Oscarsson et al. studied the effect of HBO2 on cystitis (bladder inflammation) [30,31]. The trials defined LRTI as occurring from at least 3 months and with a duration of at least 3 months to lasting at least 12 months after radiation. Limited patient demographic and comorbidity data were provided, but all trials reported detailed safety data (adverse events), which were not unexpected for HBO2 (Table 1). Patients allocated to receive HBO2 received standard regimens of at least 30 to more than 40 treatments, administered over four to 11.5 weeks. Follow-up duration lasted from 15.5 weeks to five years.
Each trial used a different scoring instrument to assess change in LRTI symptoms (Table 1). Clarke et al. reported a relatively large effect size, with the SOMA-LENT score nearly doubling for the HBO2 group compared to the sham (p = .0019, Table 1) [28]. Glover et al. reported differences for rectal bleeding approaching significance (Mann-Whitney test U score = 1.60, p = .092; mITT: U Score = 2.06, p = .040, Table 1) [29]. This subgroup analysis (n = 40), however, was substantially statistically underpowered. Oscarsson et al. reported that the Expanded Prostate Index Composite urinary score increased 17.8 points in the HBO2 group vs 7.7 points in the control group, which was a 2.3-fold difference in increase (p = .013, Table 1). Quality-of-life improvements in SF-36 scores were also consistently higher for the HBO2 group and statistically significant for the general health domain (p = .006) [22,28].
Table 2 summarizes the risk of bias assessment for all three trials. The Clarke trial was low-risk, while the other two trials had some concerns (Table 2). Table 3 expands on the risk of bias assessment with a summary of the certainty of outcomes. In Table 3, all three trials scored “yes” for at least half of the characteristics, and their body of evidence demonstrates moderate certainty of outcomes. The Clarke and Glover studies utilized innovative double-blind, sham designs; Clarke et al. proved their sham procedure, which briefly simulated HBO2, successfully blinded patients by surveying subjects to confirm they were unaware of treatment allocation [28]. Oscarsson et al. conducted an open trial, which demonstrated the selection bias incurred from lack of blinding with an unusually high rate of patient consent refusal after randomization to the control group [30,31].
All trials used a modified-ITT (mITT) analysis, which involved randomized and treated patients instead of all patients randomized with reasonable explanations provided (Table 1). Given that the two treated populations were probably not that different, the use of mITT likely did not incur much bias for the outcomes. All outcome data related to the change in LRTI symptoms were for primary endpoints; thus, secondary endpoints were not evaluated for this review. As such, no multiplicity adjustment was analyzed or performed. The authors reported 95% CIs for outcome data (Table 1). The Oscarsson et al. trial was the only one with adequate power calculation [30,31]. The Clarke trial lacked a power calculation, had insufficient data for a post hoc calculation, and had incomplete attrition data. However, their outcomes were still considered reasonable due to the following factors which increased certainty: their p values were not marginal (which would be expected for a power <80%, Table 1); they implemented a crossover design which provided reasonable results; they reported low attrition for the most important period of the trial through one-year follow-up; and they performed a sensitivity analysis for right-censored outcomes to address attritions [28]. Although the Glover study was powered at 80%, subgroup analysis for rectal bleeding was underpowered, as previously mentioned, and there was no sensitivity analysis for patients with missing outcomes, who were excluded from the mITT analysis. Neither the Glover nor the Oscarsson study had issues with attrition (Tables 1 and 3).
Considering the evidence from the three trials, the GRADE assessment determined moderate certainty with a weak recommendation for using HBO2 for rectal complications or cystitis.
DISCUSSION
In this updated systematic review of the beneficial effect of HBO2 on LRTI to the bowel and bladder, more critical inclusion criteria were employed compared to the recently published Cochrane review [7]. The Cochrane review included all RCTs and quasi-RCTs without considering the appropriateness of their design and statistical analysis. Consequently, the authors included two trials excluded in the current systematic review [46,47]. In both trials, English language usage was a reporting barrier; it appeared that acute radiation injury was included in the study population, and it was impossible to determine how many patients truly had LRTI. In one trial, the authors used nonstandard statistical analysis and a head-to-head design that could not adequately determine a beneficial effect [46], while the other trial’s publication was a very unclear and incomplete report that rendered impossible proper evaluation of the trial data [47]. Current evidence from three comparative trials supports the use of HBO2 in treating the complications of cystitis due to LRTI. Regarding the gastrointestinal system and LRTI, the data supporting treatment are strongest for radiation-induced rectal bleeding, and future research questions should focus specifically on LRTI to the rectum. Safety data from these studies demonstrate that the HBO2 was tolerable (Table 1). The three trials were published within the past 15 years and represented diverse patient populations from nine countries on four continents. Using the GRADE approach, the findings of this systematic review show that for LRTI on normal tissue, the evidence of the therapy in terms of positive outcomes is moderate with a weak recommendation. Clinicians unfamiliar with GRADE terminology may incorrectly assume that a “weak” recommendation suggests unconvincing evidence of benefit from HBO2, but such is not the case. In the context of GRADE, a weak recommendation means only that an intervention is not universally appropriate and that the decision to use HBO2 must be made on a case-by-case basis by evaluating the risks and benefits of each patient. In fact, moderate certainty means that the true effect is probably close to the estimated effect [27]. In other words, for LRTI of the rectum and/or bladder, the outcomes found in the selected studies (taken together) would not be substantially different, even if another three to five well-conducted RCTs were published. To put this finding in perspective, a recent secondary analysis of a systematic review of 142 RCTs that evaluated treatment effectiveness on venous leg ulcers reported high bias and poor uncertainty of outcomes among 86.3% of those trials [24]. Rather than have dozens of poorly designed comparative RCTs with high bias and low certainty, the evidence for using HBO2 on LRTI to the rectum and/or bladder is limited to a handful of well-conducted RCTs.
The harms of HBO2 are minimal, and the only absolute contraindication of HBO2 is untreated pneumothorax, which is very rare [51]. Therefore, the weak, contextual recommendation supporting the use of HBO2 on LRTI to the rectum and/or bladder means that, in rare circumstances, few patients with LRTI might have potential contraindications to HBO2. In real-world practice, most patients with LRTI to the rectum and bladder are candidates for HBO2. However, a conversation with their physician to first discuss the potential benefits and risks is recommended before consent to treatment.
Limitations
The heterogeneous nature of the trials included in this review made meta-analysis impossible. While statistical syntheses could not be performed, the use of the Cochrane RoB 2 tool, the uncertainty of outcomes assessment, and the application of the GRADE approach allowed for objective conclusions to be reached on the level of certainty and strength of evidence. The authors of this review made every attempt possible to capture all eligible comparative studies. Although publication bias is always a possibility, a June 23, 2023, search for planned, ongoing, and terminated trials on clinicaltrials.gov suggests that there are no pending publications nor any future studies evaluating the effect of HBO2 on LRTI on the rectum and/or bladder planned. While more innovative, comparative trials are certainly welcome for this subject, recruitment challenges hinder their design and implementation, so a more pragmatic design may be necessary for future trials [7,30,31,48]. A final limitation to be noted is that this review did not evaluate LRTI recurrence. A meta-analysis of 499 patients with radiation-induced hemorrhagic cystitis reported LRTI recurrence in 14% of patients occurring three to 120 months after the initial HBO2 regimen was completed [52]. Oscarsson et al. were the only authors to evaluate radiation cystitis in this review, and their follow-up period of no longer than 20.5 weeks would have been too short to adequately evaluate recurrence (Table 1). Clarke et al. had an adequately long follow-up period of five years, but few patients returned for the last follow-up visit. High attrition rates are likely to be a challenge of evaluating LRTI recurrence over the long-term in comparative trials.
Although not evaluated by this systematic review, multiple case series support successful treatment of LRTI by HBO2 at other sites, including skin, bone, head, and neck [7]. Since LRTI of all soft tissues have a similar pathophysiology, success consistently at 1 anatomic site is likely to support the application of HBO2 to other tissues and organs. Recently, a real-world cost analysis among 3,309 Medicare beneficiaries determined that HBO2 applied to patients with delayed radiation cystitis reduced urinary bleeding by 36%, blood transfusions for hematuria by 78%, endoscopic procedures by 31%, mortality by 53%, and unadjusted Medicare costs by $5,059 per patient, which increased to a savings of $11,548 per patient when at least 40 HBO2 treatments were provided [53].
In conclusion, there is moderate certainty from the three trials evaluated in this systematic review that HBO2 demonstrates a clinically meaningful improvement in LRTI rectal and bladder symptoms. Using the GRADE approach, the analysis resulted in a weak recommendation, meaning that a discussion should occur between the patient and their physician regarding whether the patient is likely to benefit from HBO2. More innovative, comparative studies are needed to capture the effect of HBO2 on larger patient populations affected by LRTI, particularly on other bowel symptoms beyond rectal bleeding.
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Figure Legends
Figure 1. PRISMA 2020 flow diagram.