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ORIGINAL ARTICLE
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Does hyperbaric oxygen therapy have a role in acute fracture healing?


1 Department of Aviation Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India
2 Department of Orthopaedics, Command Hospital Air Force, Bengaluru, Karnataka, India
3 Department of Orthopaedics, Command Hospital, Chandi Mandir, Haryana, India
4 Department of Radiodiagnosis, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission23-May-2020
Date of Decision20-Jul-2020
Date of Acceptance04-Aug-2020
Date of Web Publication30-Sep-2020

Correspondence Address:
Munish Sood,
Department of Orthopaedics, Command Hospital, Chandi Mandir - 134 107, Haryana
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmms.jmms_63_20

  Abstract 


Background: Fracture healing is a complex biological phenomenon which is influenced by various environmental factors. From time immemorial, there has been a constant endeavor to look for means to enhance fracture healing which would limit disability and restore preinjury level of function at the earliest. Hyperbaric oxygen therapy is one such therapy which has shown some role in enhancing fracture healing in established fracture nonunion but its role in acute fracture healing has not been studied. Materials and Methods: The study was conducted in a military hyperbaric oxygen therapy (HBOT) facility co-located with a tertiary care military hospital. Sixty patients between 20 and 50 years of age with acute closed fractures of the metacarpal, planned to be managed conservatively, were equally randomized to the HBOT (n = 30) and sham HBOT (n = 30) group. Patients in the sham HBOT group, apart from receiving standard of care for the fracture, received a sham exposure of HBOT for 4 weeks, whereas those in the HBOT group, received HBOT therapy for the same duration. The patients were actively followed up for 6 months. Primary outcome measure was rate of fracture healing as assessed by radiology and ultrasound evaluation and functional recovery as assessed by the disabilities of the arm, shoulder, and hand score (DASH). Secondary outcomes included the assessment quality of life and complication rate. Results: The 6-month follow-up rate was 100%. All fractures in both the groups united, there was no significant difference in rate of fracture healing at 12 weeks (P = 0.731) or functional outcome at 24 weeks, as assessed by DASH score (P = 0.127), between the groups. There were 6 (20%) malunions in sham HBOT group and 2 (07%) in HBOT group. There were four cases of reflex sympathetic dystrophy in sham HBOT group and three cases in HBOT group. Conclusions: HBOT in acute diaphyseal fractures does not alter the rate of healing when assessed clinicoradiologically and has no effect on functional outcome at 6 months of follow-up.
Level of Evidence: Level I

Keywords: Acute fracture, fracture healing, functional outcome, hyperbaric oxygen



How to cite this URL:
Gambhir S, Kulshrestha V, Sood M, Sahu S. Does hyperbaric oxygen therapy have a role in acute fracture healing?. J Mar Med Soc [Epub ahead of print] [cited 2020 Nov 28]. Available from: https://www.marinemedicalsociety.in/preprintarticle.asp?id=296798




  Introduction Top


Fracture-healing is a complex biological process that involves the spatial and temporal orchestration of numerous cell types, hundreds of genes, and intricate organization of an extracellular matrix, all working toward restoring the bone's mechanical strength, and rapid return to full function. It has often been argued that nature has optimized this process and thus it would be difficult to accelerate fracture-healing using some intervention. How can science conceivably improve on 600 million years of vertebrate evolution? Nevertheless, it is just this goal that has inspired an intense effort among basic-science and clinical investigators from a vast array of biotechnology and bioengineering disciplines at academic as well as industrial laboratories, to seek a means of accelerating the healing of fractured bones.[1] The rapidly growing global burden of road-traffic accidents and fragility fractures makes research on fracture repair a vital component of the efforts needed to face this rising public health challenge. The focus on developing new and innovative strategies to treat fractures is easily justifiable given the potential human benefit from such discoveries.[2] Although a large number of these fractures heal with operative and nonoperative immobilization techniques, the convalescence and rehabilitation period is usually long involving months to years depending on site, nature, and severity of fracture. Apart from this, 5%–10% of all fractures go into delayed and nonunion requiring further therapeutic intervention leading to increased medical expense, prolonged disability, and loss of productive man hours.[3]

Efforts to develop advanced methods for the stimulation of fracture-healing are proceeding along several pathways. While substantial progress has been made in the fracture fixation techniques and development of osteoconductive materials, newer technologies, such as the use of recombinant growth factors and more advanced systems for the biophysical and mechanical stimulation of fractures such as use of hyperbaric oxygen therapy, require more investigations. Lack of oxygen has been considered a limiting factor in fracture healing; multi-potent fibroblasts seen in fracture callus require increased oxygen tension and compressive forces to lay down bone. There are a number of experimental studies which have shown positive effect of hyperbaric oxygen therapy on fracture healing.[4],[5] However, there are surprisingly few clinical trials which have studied the role of hyperbaric oxygen on human fracture healing. Few trials which exist have focused on healing of delayed union and nonunion of fractures and even these as shown by Cochrane database analyses are of poor design. The role of hyperbaric oxygen in acute fracture healing has not been evaluated in human clinical trial. This study was designed as a prospective randomized double-blind parallel assigned efficacy trial, which would evaluate the effect of hyperbaric oxygen therapy in the rate of fracture healing and functional outcome.


  Materials and Methods Top


This study is a double-blind (Subject, Assessor) prospective study (Hyperbaric Oxygen Therapy [HBOT] vs. Sham HBOT), with parallel assignment of patients. The study was conducted at a military HBOT facility with patients being referred from tertiary care military hospital.

Inclusion criterion

The patients were included in the study if they (1) had closed simple acute fractures of the metacarpal bones (AO type A), being managed conservatively, who reported within 7 days of injury (2) were male, age between 20 and 50 years (3) were willing to follow-up for 6 months (4) agreed to provide an informed consent.

Exclusion criterion

They would be excluded if they had (1) any contraindication to hyperbaric oxygen therapy, (2) a moderate to severe head injury (a Glasgow Coma Scale score of <12), or are poly-traumatized with an Injury Severity Score of >17, (3) a pathological fracture, (4) an open fracture, and (5) inability to comply with follow-up (inability to read or complete questionnaire).

The enrolled patients were randomly assigned to HBOT and sham-HBOT group using a computer generated block randomization sequence (using Stata software), the assignment was parallel. The first group (Group 'C' Control; Sham-HBOT group) received standard of care treatment for the fracture and in addition received sham-hyperbaric oxygen therapy for 4 weeks starting within 1 week of injury. The second (Group 'T' Treatment; HBOT group) received hyperbaric oxygen therapy apart from standard of care treatment for the fracture for 4 weeks starting within 7 days of injury. The patients were subjected to HBOT at a pressure of 2.5 ATA for 90 min. The ascent and descent rate of the chambers was 3 ft/min. The primary outcome measures were improved the rate of fracture healing as assessed by digital radiographs and ultrasonography (3, 6, and 12 weeks) and functional outcome as assessed by the disabilities of the arm, shoulder, and hand score (DASH) score;[6] a patient reported functional outcome score assessed at 6, 12, and 24 weeks after fracture. Secondary outcome measures included incidence of complications related to fracture healing like delayed union or nonunion and overall health assessment using a validated general health assessment tool (Euro-Quol 5 D) at 6, 12 and 24 weeks after fracture.[7] The EQ-5D (mobility, self-care, usual activity, pain, and anxiety) was used as weighted average calculated at each time point of follow-up. Adverse effect of the protocol (HBOT) was defined as any unexpected event that necessitated another medication or intervention such as seizure and barotraumas. We also recorded occurrence of any complications related to fracture healing such as delayed union, nonunion, or malunion which would affect our outcome measures. A note would be made at 6 weeks and 6 months follow-up if required about occurrence of complex regional pain syndrome (CRPS) which would be diagnosed by the presence of dysesthetic pain and hyperesthesia over the involved limb, vasomotor changes, skin atrophy, and diffuse osteopenia.

The sample size calculation was done based on primary outcome measures. To detect at least 20% difference in fracture healing rate as calculated on a 10-point score system given a standard deviation (SD) of 2 points, we would need 22 cases. Literature shows that the minimum clinically significant difference in DASH score should be 10 between the control group and intervention group.[8] Assuming final DASH average score of 20 and 10 in the two groups with SD of 10 and 7, respectively, a beta error of 0.05 and a power of 0.90, it was anticipated that 16 patients would be required in each group. Keeping loss to follow-up into consideration we recruited 60 patients.

The statistical analysis was performed with Stata Version 10 (StataCorp LP, Texas, USA). The distributions of patient demographics and baseline injury data including fracture type, mode of injury, side of injury (dominant or nondominant), body mass index (BMI), and bone mineral density (BMD) would be compared between study groups to identify any difference that might confound outcome comparisons. These factors were then added to multivariable regression model as described below. The DASH score as assessed at baseline, 6, 12, and 24 weeks and fracture healing score assessed at 3, 6 and 12 weeks was regressed on two indicator variables: (1) treatment modality (HBOT vs. Sham-HBOT) and (2) follow-up time. The repeated measurements of each patient was pooled and analyzed together in one overall linear regression model. This approach allowed for the assessment of an overall effect of treatment and time on the outcome while considering all available data, and avoiding multiple analyses at each follow-up. In addition, it allowed us for quantification of the effect of treatment at each follow-up time point within the same model. The factors fracture classification, dominant/non-dominant side of injury and BMD were added to the regression model for statistical adjustment of baseline group differences. The Wald test was used to investigate the overall effect of treatment and follow-up time on the DASH score and fracture healing, as well as any interaction between treatment and time (i.e., does any treatment group difference vary according to the follow-up time?). If the overall treatment effect was statistically significant, then the full regression model (including the interaction parameter) were used to test the effect size (i.e., group differences) at each follow-up time point using the Wald test and these differences were quantified. The occurrences of complications including delayed union or reflex sympathetic dystrophy (RSD) were compared between groups using the univariable Fisher's exact test and treatment effect were quantified by the relative risk (RR) and its 95% confidence interval. Multivariable binomial regression analysis will be used to adjust the RR estimations for group differences regarding fracture type. All estimates of treatment effect were provided with their 95% confidence intervals. Any result was considered to be significant at P < 0.025 as per the Bonferroni correction used to cater for two primary outcomes (fracture healing and functional outcome; 95% confidence limits and effect size was always calculated).


  Results Top


Patient demographics and baseline characteristics

Sixty patients with metacarpal fractures were recruited. Thirty patients were randomized each to sham HBOT and HBOT group. The follow-up rate was 100% at each time point of follow-up up to 6 months [Figure 1]. The mean age for sham HBOT-treated patients (control group), 26.7 years was similar to that for the HBOT group (treatment group; 27.7 years). The mechanism of injury was uniformly distributed in both groups with half of the injuries resulting from sports (50% in both groups). Nine patients (45%) had dominant side injury in the Sham HBOT group as compared to 12 (60%) in HBOT group. According to the AO fracture classification, >90% (n = 19) patients had type A.1 and A.2 fracture in each group. Average BMI in the both groups was below 25. None of the patients had osteopenia (BMD; T-Score <-1.0) or osteoporosis (BMD; T-Score <-2.5) in any group the average BMD (T-score) was >-1.0 [Table 1].
Figure 1: Flow chart of patient enrollment

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Table 1: Demographic data of patients including the fracture type

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Hyperbaric oxygen therapy details

The mean delay between the time of injury and HBOT/Sham HBOT was 4.5 days (range: 3–7 days). All the patients received 20 sittings over 4 weeks.

Disabilities of the arm, shoulder, and hand scores

There was no significant difference in baseline DASH scores of both the groups (P < 0.685). There was less than three-point difference in DASH scores of the two groups at each time-point of follow-up (P < 0.127 [Table 2]. In both the groups, there was progressive improvement in average DASH scores at each time point of follow-up [Table 2] and [Figure 2].
Table 2: Difference in disabilities of the arm, shoulder, and hand score from baseline to each follow.up time between the two groups

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Figure 2: DASH Score in Sham HBOT (C) and HBOT (T) groups at each follow-up

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Fracture healing

All fractures in both the groups united by 6 months of follow-up. There was no significant difference in fracture healing score at each follow-up (3, 6, 12 weeks) as assessed by digital radiographs and ultrasound on a 9-point fracture healing scale [P < 0.731; [Table 3]. At each time point of follow-up, there was a difference of <2 points in fracture healing score between the two groups. In both the groups, there was a progressive improvement in fracture healing score from 03 to 12 weeks of follow-up [Table 3].
Table 3: Difference in fracture healing score at each follow-up time between the groups

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General health Index (EuroQol-5D)

There was no significant difference in baseline EQ-5D weighted scores of both the groups (P < 0.902). There was <0.03 points difference in EQ-5D scores of the two groups at each time-point of follow-up [P < 0.741; [Table 4]. In both the groups, there was progressive improvement in average EQ-5D scores at each time point of follow-up [Table 4] and [Figure 3]. Patients with RSD in both groups had lower EQ-5D scores at each follow-up; however, at 6 months their EQ-5D scores approached closer to that of other patients [Figure 3].
Table 4: Difference in EuroQol-5D scores at each follow-up time between sham hyper baric oxygen therapy and hyper baric oxygen therapy group

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Figure 3: EuroQol 5D score in Sham HBOT (C) and HBOT (T) groups at each follow-up

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Complications and reoperation

Malunion and CRPS were two complications of fracture healing noticed in both the groups. However, there was no significant difference in the occurrence of these complications in the two groups [P < 0.167; [Table 5]. The adverse effect of HBOT was observed in four patients who developed otalgia due to congestion of ear drum, in two cases, the symptoms subsided with decongestant drugs in 72 h and they were continued in HBOT group whereas the other two were shifted to sham HBOT group. All of them were followed up in HBOT group as per intention to treat analysis.
Table 5: Complications seen in sham hyper baric oxygen therapy and hyper baric oxygen therapy group

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  Discussion Top


Hyperbaric oxygen therapy is an adjunctive therapy which has been shown to modulate fracture healing in experimental studies. Various studies have suggested that HBOT might improve outcome following fractures where delayed or nonunion is likely.[9],[10] In animal studies, HBOT has been shown to improve both bone regeneration and removal of dead bone.[9],[10],[11],[12] The only randomized trial available in the literature was done by Lindstrom in 1998 where he looked at effect of HBOT given for 5 days to 20 cases of closed fracture tibia which were nailed.[13] They looked at the blood flow and transcutaneous oxygen of the effected limb and reported increase in vascularity; they neither looked at the fracture healing or functional outcome. There have been few reports of clinical improvement in fracture healing in cases of delayed and nonunions after HBOT (Atesalp 2002) since then, however, despite nearly 40 years of interest in the delivery of HBOT to patients with these problems, little comparative clinical evidence of effectiveness exists.[14],[15] These published review concluded that “There is insufficient evidence to support or refute the use of hyperbaric oxygen therapy for treatment of fractures, whether to aid healing of acute injuries or as a therapy for established nonunion.[16]

This study was designed keeping in mind the deficiencies in existing literature and the suggestions given by Cochrane review in designing and planning further studies evaluating effect of hyperbaric oxygen therapy (HBOT) on fracture healing. We looked at effect of HBOT on fracture healing and functional outcome in simple closed metacarpal shaft fractures. Metacarpal fractures were chosen for the study as it is easier to follow-up and assess these patients in an outpatient setting without compromising their treatment and being a small long bone it mimics fracture healing of all long bones and its results can further be extrapolated for other shaft fractures. The duration (20 sittings over 04 weeks) and schedule of HBOT (2.5 ATA for 90 min) chosen was based on earlier studies and established protocols in our department. To remove subject and assessor bias, we gave sham HBO to comparison group.

The study showed that there was no significant difference in either the rate of fracture healing (P < 0.731) or functional outcome (P < 0.127) till 6 months of follow-up in young healthy adults with simple acute metacarpal fractures given HBO therapy when compared to those who were given sham HBO therapy. The DASH score had a difference of less than three points at each time point of follow-up which was much lower than clinically significant difference of 10 points. The quality of life index calculated as weighted average of EQ 5D scores was comparable in two groups throughout the follow-up period. The rate of fracture healing as assessed by plain radiography and ultrasound was similar in two groups. The incidence of complications was again comparable in the two groups (malunion and CRPS). HBO therapy had few minor adverse effects such as otalgia which were easily controlled using drugs. HBO therapy did not produce any serious adverse event.

The study had a few limitations, since it was conducted in military setting all the patients were young active males with good bone quality hence our results may not extrapolate to general population where the bone density may vary much more. However, the results hold true for healthy bones with normal BMD which evoke normal fracture healing response. The study only looked at effect of HBO on early fracture healing response seen in acute fractures and did not look at delayed or nonunions.

The major strengths of our study are, its prospective randomized design with 100% follow-up, a-priori calculation of sample size to give it enough power to look at clinically significant difference in outcomes in terms of function and rate of fracture healing, appropriate comparator group using sham HBO therapy with blinding of subject and assessor, use of well-defined validated outcome measures, meticulous reporting of complications and adverse events, and use of adequate duration and schedule of HBO therapy.


  Conclusion Top


We need to reorient our future approach in conducting further trials in the use of HBO therapy in fracture healing. The study conclusively proves that HBO does not have any role in either enhancing the rate of fracture healing or improving functional outcome when used in acute fractures in healthy bones. Hence, it is unlikely to be of any benefit in healthy young patients with simple acute fractures. However, in view of the existing literature, evidence of its effect on fracture healing in experimental and animal studies and few human trials showing clinical improvement in delayed and nonunion, further effort should be made to design high quality clinical trials to assess its effect on complex fractures, nonunions, and fractures in bones with altered metabolism.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Xu ZH, Jiang Q, Chen DY, Xiong J, Shi DQ, Yuan T, et al. Extracorporeal shock wave treatment in nonunions of long bone fractures. Int Orthop 2009;33:789-93.  Back to cited text no. 1
    
2.
Morshed S, Bhandari M. Clinical trial design in fracture-healing research: Meeting the challenge. J Bone Joint Surg Am 2008;90 Suppl 1:55-61.  Back to cited text no. 2
    
3.
Kürklü M, Yurttaş Y, Köse O, Demiralp B, Yüksel HY, Kömürcü M. Adjunctive hyperbaric oxygen therapy in the treatment of atrophic tibial nonunion with Ilizarov external fixator: A radiographic and scintigraphic study in rabbits. Acta Orthop Traumatol Turc 2012;46:126-31.  Back to cited text no. 3
    
4.
Neves PC, Abib SC, Neves RF, Pircchio O, Saad KR, Saad PF, et al. Effect of hyperbaric oxygen therapy combined with autologous platelet concentrate applied in rabbit fibula fraction healing, CLINICS 2013;68:1239-46.  Back to cited text no. 4
    
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Demirtaş A, Azboy I, Bulut M, Uçar BY, Alemdar C, Alabalık U, et al. The effect of hyperbaric oxygen therapy on fracture healing in nicotinized rats Ulus Travma Acil Cerrahi Derg 2014;20:161-6.  Back to cited text no. 5
    
6.
Hudak PL, Amadio PC, Bombardier C. Development of an upper extremity outcome measure: The DASH (disabilities of the arm, shoulder and hand) [corrected]. The Upper Extremity Collaborative Group (UECG) Am J Ind Med 1996;29:602-8.  Back to cited text no. 6
    
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Brauer CA, Rosen AB, Greenberg D, Neumann PJ. Trends in the measurement of health utilities in published cost-utility analyses. Value Health 2006;9:213-8.  Back to cited text no. 7
    
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Gummesson C, Atroshi I, Ekdahl C. The disabilities of the arm, shoulder and hand (DASH) outcome questionnaire: Longitudinal construct validity and measuring self-rated health change after surgery. BMC Musculoskelet Disord 2003;4:11.  Back to cited text no. 8
    
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Kucukdeveci O, Sarisozen B, Atici T, Ozcan R. The effect of nicotine on distraction osteogenesis: An experimental study on rabbits. J Trauma 2009;67:1376-83.  Back to cited text no. 9
    
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Pedersen TO, Xing Z, Finne-Wistrand A, Hellem S, Mustafa K. Hyperbaric oxygen stimulates vascularization and bone formation in rat calvarial defects. Int J Oral Maxillofac Surg 2013;42:907-14.  Back to cited text no. 10
    
11.
Milovanova TN, Bhopale VM, Sorokina EM, Moore JS, Hunt TK, Hauer-Jensen M, et al. Hyperbaric oxygen stimulates vasculogenic stem cell growth and differentiation in vivo. J Appl Physiol (1985) 2009;106:711-28.  Back to cited text no. 11
    
12.
Park KM, Kim C, Park W, Park YB, Chung MK, KimBone S. Regeneration effect of hyperbaric oxygen therapy duration on calvarial defects in irradiated rats. Bio Med Res Int 2019;1-9.  Back to cited text no. 12
    
13.
Lindström T, Gullichsen E, Lertola K, Niinikoski J. Effects of hyperbaric oxygen therapy on perfusion parameters and transcutaneous oxygen measurements in patients with intramedullary nailed tibial shaft fractures. Undersea Hyperb Med 1998;25:87-91.  Back to cited text no. 13
    
14.
Atesalp AS, Komurcu M, Basbozkurt M, Kurklu M. The treatment of infected tibial nonunion with aggressive debridement and internal bone transport. Mil Med 2002;167:978-81.  Back to cited text no. 14
    
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Millar IL, McGinnes RA, Williamson O, Lind F, Jansson KA, Hajek M, et al. Hyperbaric oxygen in lower limb trauma (HOLLT); protocol for a randomised controlled trial. BMJ Open 2015;5:1-74, e008381.  Back to cited text no. 15
    
16.
Butler J, Foex B. Best evidence topic report. Hyperbaric oxygen therapy in acute fracture management. Emerg Med J 2006;23:571-2.  Back to cited text no. 16
    


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