Beyond Antibiotics – Oxygen for Necrotizing Fasciitis

Hyperbaric oxygen therapy involves breathing 100% oxygen at a higher atmospheric pressure (usually 2.5-3 atm) and it has recently been widely used for multiple diseases. Recall Boyle’s law: 

Increasing pressure decreases the volume, so pressurizing the human body causes a decrease in volume of gas-filled spaces (1). As such, it has clinical uses in arterial gas emboli as well as decompression sickness (2). Another interesting utility, at least as it relates to infectious disease, is its use in necrotizing fasciitis. Recall this is an infection that involves rapid progression of fascia and subcutaneous tissue due to bacterial proliferation in the fascia with thrombosis, and occlusion of skin vessels and secondary ischemia and gangrene.This is typically caused by anaerobic infections.

The mechanism of action includes hyperoxia, creation of free radical species, increased oxidative burst ability in leukocytes, and vasoconstriction leading to decreased edema (1). It also decreases reperfusion influx of leukocytes (3), and in experimental models, it has been shown to actually be bactericidal to several Clostridia species (4, 5) as well as staphylococcus (6) by increasing the phagocytic function of neutrophils. Furthermore, it allows fibroblast growth and collagen construction increase, and suppresses alpha toxin production in gas gangrene (7). Hyperbaric oxygen also enhances the activity of some antibiotics such as imipenem and tobramycin, and may have direct bactericidal activity in vitro against most gram positive and gram negative organisms (8). So it seems like a fairly good adjuvant therapy for necrotizing fasciitis, however there is little high quality data, mostly due to the critical nature of the disease as well as its rarity.

In general, typical hyperbaric oxygen therapy (HBOT) involves three therapies with 100% oxygen at 2-3 atm in the first 24hrs, followed by twice in the next 24hrs, and then daily as long as necrosis is present (9). The data, overall, seems to suggest some benefit for the use of HBOT, though this is usually more consistent with larger cohorts of patients. For instance, a case series of 26 patients with Fournier’s gangrene (the bad necrotizing fasciitis, if it could get any worse) found that HBOT was associated with improved in-hospital mortality (93% vs 58%, p=0.05), with logistic regression showing that relative risk of survival was times greater in the HBOT group (10). Another case series (11) of 42 patients found that mortality was actually higher in the HBOT group, 26.9%, compared to the non-HBOT group, 12.5%. In yet another study of 29 patients (12), HBOT was associated with lower mortality despite that group being associated with a higher severity of illness on admission (23% vs 66%, p <0.02). Further the HBOT group required 1.2 debridements compared to 3.3 (p <0.03). And just to make things more confusing, a multicenter, retrospective study (13) of 54 patients with truncal necrotizing fasciitis (30 treated with HBOT and 24 without) found no difference in mortality rates (30% in the HBOT group vs 42%). Furthermore, there was no difference in length of hospital stay, ICU stay, or duration of antibiotics, with the HBOT group having more surgeries. Notably, there was a trend favoring HBOT, but this did not reach statistical significance. These studies tend to be inconsistent given the multiple confounders, including that most of the time, patients in the HBOT group have to be stable prior to reaching the stage they can get such therapy.

Larger retrospective studies tend to give more consistent results. For instance, a single-center retrospective study (14) of 341 patients found that patients treated with HBOT had lower mortality (33/275, 12%) compared to those without HBOT (16/66, 24.3%, p= 0.01), though it should be noted that patients in the HBOT group had lower APACHE III scores (reflecting lower severity of illness), be younger, and more likely to have perineal disease. Despite this, multivariate analysis demonstrated that HBOT was associated with decreased mortality:

There are limitations with the study, with 82% of these patients being transferred from another facility, reflecting their overall stability prior to the transfer and essentially “eliminating” much sicker patients that would have otherwise been evaluated. Another large retrospective study (15)  of 117 patients with necrotizing fasciitis receiving HBOT found they had lower in-hospital mortality rate compared to the control cohort (5% vs 12%, p <0.028). When stratified by severity of illness (using the University Health Consortium severity illness score), the effect was only seen in those with extreme illness:

Multivariate analysis also found that patients who did not get HBOT were more likely to die compared to those who did (OR 10.6, 95% CI 5.23-25.1). Similar findings were reported in a single center retrospective study that evaluated 44 patients with 33 receiving HBOT (16). Mortality in the HBOT group was 6% (95% CI 1-20%) compared to the non-HBOT group, 36% (95% CI 11-69%). This was a relative risk reduction of 83%, NNT of 3. Two logistic regression models incorporating age, creatinine, and HBOT were generated, with both models showing benefit of HBOT:

Furthermore, HBOT was associated with long-term survival:

The authors also evaluated 5 retrospective studies, finding a significant mortality benefit of HBOT over none (235 mortality vs 48%, NNT=4). 

A systematic review of 21 studies, which included 19 case control studies, evaluated a total of 1155 patients (17). Given the large heterogeneity of these studies, there was no pooled estimates attempted. Despite this, the review found that all but 3 studies demonstrated mortality benefit for hyperbaric oxygen therapy:

Despite these data, the IDSA guidelines do not recommend the use of HBOT (18). As you can see, all of these studies are retrospective cohort studies and are usually single center. Their rationale for this comes down to prioritizing surgery over HBOT. 

References:

1. Thom SR. Hyperbaric oxygen: its mechanisms and efficacy. Plast Reconstr Surg. 2011 Jan;127 Suppl 1(Suppl 1):131S-141S. doi: 10.1097/PRS.0b013e3181fbe2bf. PMID: 21200283; PMCID: PMC3058327.
2. Leach RM, Rees PJ, Wilmshurst P. Hyperbaric oxygen therapy. BMJ. 1998 Oct 24;317(7166):1140-3. doi: 10.1136/bmj.317.7166.1140. PMID: 9784458; PMCID: PMC1114115.
3. Zamboni WA, Wong HP, Stephenson LL. Effect of hyperbaric oxygen on neutrophil concentration and pulmonary sequestration in reperfusion injury. Arch Surg. 1996 Jul;131(7):756-60. doi: 10.1001/archsurg.1996.01430190078020. PMID: 8678778.
4. Kaye D. Effect of hyperbaric oxygen on Clostridia in vitro and in vivo. Proc Soc Exp Biol Med. 1967 Feb;124(2):360-6. doi: 10.3181/00379727-124-31743. PMID: 4289714.
5. Hill GB, Osterhout S. Experimental effects of hyperbaric oxgen on selected clostridial species. I. In-vitro studies. J Infect Dis. 1972 Jan;125(1):17-25. doi: 10.1093/infdis/125.1.17. PMID: 4332847.
6. Mader JT, Brown GL, Guckian JC, Wells CH, Reinarz JA. A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis. 1980 Dec;142(6):915-22. doi: 10.1093/infdis/142.6.915. PMID: 7462700.
7. Ürütük, Füsun. (2020). Current Approach to Hyperbaric Oxygen Therapy. Istanbul Medical Journal. 21. 234-241. 10.4274/imj.galenos.2020.89725. 
8. Memar MY, Ghotaslou R, Samiei M, Adibkia K. Antimicrobial use of reactive oxygen therapy: current insights. Infect Drug Resist. 2018 Apr 24;11:567-576. doi: 10.2147/IDR.S142397. PMID: 29731645; PMCID: PMC5926076.
9. Shah J. Hyperbaric oxygen therapy. J Am Col Certif Wound Spec. 2010 Apr 24;2(1):9-13. doi: 10.1016/j.jcws.2010.04.001. PMID: 24527137; PMCID: PMC3601859.
10. Hollabaugh RS Jr, Dmochowski RR, Hickerson WL, Cox CE. Fournier’s gangrene: therapeutic impact of hyperbaric oxygen. Plast Reconstr Surg. 1998 Jan;101(1):94-100. doi: 10.1097/00006534-199801000-00016. PMID: 9427921.
11. Mindrup SR, Kealey GP, Fallon B. Hyperbaric oxygen for the treatment of fournier’s gangrene. J Urol. 2005 Jun;173(6):1975-7. doi: 10.1097/01.ju.0000158129.56571.05. PMID: 15879795.
12. Riseman JA, Zamboni WA, Curtis A, Graham DR, Konrad HR, Ross DS. Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery. 1990 Nov;108(5):847-50. PMID: 2237764.
13. Brown DR, Davis NL, Lepawsky M, Cunningham J, Kortbeek J. A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy. Am J Surg. 1994 May;167(5):485-9. doi: 10.1016/0002-9610(94)90240-2. PMID: 8185032.
14. Devaney B, Frawley G, Frawley L, Pilcher DV. Necrotising soft tissue infections: the effect of hyperbaric oxygen on mortality. Anaesth Intensive Care. 2015 Nov;43(6):685-92. doi: 10.1177/0310057X1504300604. PMID: 26603791.
15. Shaw JJ, Psoinos C, Emhoff TA, Shah SA, Santry HP. Not just full of hot air: hyperbaric oxygen therapy increases survival in cases of necrotizing soft tissue infections. Surg Infect (Larchmt). 2014 Jun;15(3):328-35. doi: 10.1089/sur.2012.135. Epub 2014 May 1. PMID: 24786980; PMCID: PMC4696431.
16. Wilkinson D, Doolette D. Hyperbaric oxygen treatment and survival from necrotizing soft tissue infection. Arch Surg. 2004 Dec;139(12):1339-45. doi: 10.1001/archsurg.139.12.1339. PMID: 15611459.
17. Faunø Thrane J, Ovesen T. Scarce evidence of efficacy of hyperbaric oxygen therapy in necrotizing soft tissue infection: a systematic review. Infect Dis (Lond). 2019 Jul;51(7):485-492. doi: 10.1080/23744235.2019.1597983. Epub 2019 Apr 15. PMID: 30985236.
18. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. doi: 10.1093/cid/ciu444. Erratum in: Clin Infect Dis. 2015 May 1;60(9):1448. Dosage error in article text. PMID: 24973422.