Treating necrotizing fasciitis with or without hyperbaric oxygen therapy

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1 Treating necrotizing fasciitis with or without hyperbaric oxygen therapy Zaheed Hassan 1,2,3, Robert F. Mullins 1,2,3, Bruce C. Friedman 2,3,4, Joseph R. Shaver 2,3,4, Claus Brandigi 1,2,3, Badrul Alam 3, Mohammad A.H. Mian 3 1 Joseph M Still Burn Centers, Inc., Augusta, Georgia, USA; 2 Joseph M Still Burn Center at Doctors Hospital, Augusta, Georgia, USA; 3 Joseph M Still Research Foundation, Inc., Augusta, GA, USA; 4 Acute Care Consultants, Inc., Augusta, Georgia, USA Corrresponding author: Dr. Mohammad A.H. Mian mah.mian@jmsburncenters.com Abstract There is not enough clinical data to support the benefit of adjuvant HBO 2 therapy for necrotizing fasciitis (NF). We retrospectively reviewed our 67 NF cases to compare the outcomes of adjuvant HBO 2 therapy versus non-hbo 2 therapy. The overall outcome and morbidity criteria were compared between a group of 29 NF patients who received the adjuvant HBO 2 and a group of the remaining 38 NF patients treated by only surgery and other standards of care. This study did not find any difference between the groups in average length of hospital stay, and their mortality. However, six (25%) of the non-hbo 2 group patients required amputation of extremities compared to one of the HBO 2 group (Fisher exact p = 0.09). Although the benefit of adjuvant HBO 2 therapy remains controversial for NF, and the outcomes of this study are not statistically significant, there is a trend in clinical outcomes which shows that the therapy has the potential to reduce the number of amputation and salvage extremities. These findings necessitate multicenter, prospective, case control study to assess the possible benefit of adjuvant HBO 2 therapy for NF. Introduction Necrotizing fasciitis (NF) is a rapidly progressive infection of fascia and deep soft tissue with subsequent necrosis of fascia and overlying skin (1). There is minimal or no involvement of muscle (1). Most of the time NF is life-threatening due to systemic bacterial infection and toxicity (2). NF is a poly-microbial infection, including hemolytic streptococcus, staphylococcus aureus, enteric bacilli and anaerobic organisms (3). The conventional management protocol of NF follows resuscitation, aggressive debridements and fasciotomy, broad-spectrum antibiotic therapy and supportive care (4). Early diagnosis and adequate nutritional support can improve the survival rate (5). In spite of the controversy in using hyperbaric oxygen therapy (HBO 2 ) in different critical clinical conditions (1,6,7), there is a wide body of acceptance in adjuvant therapy of HBO 2 for NF (2,8-12). It is generally believed and a number of studies have shown that HBO 2 therapy directly inhibits the production of toxins that can lead to toxemia (13,14). HBO 2 reinstates the defense against infection by increasing free radicals, which helps neutrophil-mediated killing of some common bacteria (15,16). In addition, HBO 2 therapy acts as a bactericide for certain anaerobes (17) and a bacteriostat for certain species of Escherichia and pseudomonas (18,19). In an animal model it was observed that HBO 2 apart from its direct bactericidal or oxygen delivery effect, potentially functions as an immune modulator, causing protection in sepsis (20). HBO 2 therapy for NF is generally safe if the chamber pressures do not exceed 3 atmosphere absolute (ATA) and the length of treatment remains <120 minutes (21-23). A few reported side effects Copyright 2010 Undersea and Hyperbaric Medical Society, Inc. 115

2 are aural pain and sinus discomfort (21). One study suggested considering routine prophylactic myringotomy prior to initiating HBO 2 therapy (10). The purpose of our study was to share our six and half years of experience in managing NF cases through a comparative analysis of the outcomes between the NF patients who received adjuvant HBO 2 and those who did not receive HBO 2 therapy at our regional burn center. Methods A retrospective chart review was carried out in 67 patients treated for NF between January 2002 and June The overall outcome and morbidity criteria were compared between a group of 29 NF patients who received the adjuvant HBO 2 and a group of the remaining 38 NF patients treated by only surgery and other standards of care. The HBO 2 therapy for the NF patient is a routine practice in this center, and the critical care physician makes the final decision for the therapy. In certain situations the therapy cannot be given to some of the patients. For example, some patients are claustrophobic; some may experience earache upon compression but refuse a myringotomy; at times patient size may be too large to fit in the chamber; and the patient may be too sick e.g., requiring increased ventilator support and yet being hemodynamically unstable. In this study, these kinds of patients were selected as the non-hbo 2 control group. Their ages, sex, race, etiology of NF, current smoking habits as reported in each patient s chart, alcohol use as reported in the chart, complicated admission, and pre-existing medical condition variables were all compared with the HBO 2 group. The diagnosis of NF was made on the basis of patient signs and symptoms and was confirmed intraoperatively. Complicated admission in NF was defined as previously treated in other facilities without improvement, systemic involvement with signs of septicemia, cyanotic skin discoloration, fluid overload, cellulitis, acute respiratory distress syndrome, seizure, anemia, sepsis and multisystem organ failure. Diabetes mellitus, hypotension on admission and peripheral vascular disease (PVD) were consideredpre-existing medical risk factors for NF (24). This study considered the average number of surgical debridements required per patient, length of hospital stay of survived patients, days on ventilator, and amputations required for the patients with extremity-associated NF as parameters of morbidity. Number of debridements, length of hospital stay and duration of ventilation days were calculated only among the survived population to avoid the likeness of opportunity in the survival group. Ventilator days were calculated as the total cumulative number of days on and off the patient received ventilator support. The number of debridements was calculated by total number of operation room (OR) visits for surgical debridement per patient. Statistical analysis of the data was performed using chi square, ANOVA and multiple variable linear regression. Data analysis was done to compare between groups using Epi- Info 3.4 statistical software. A p-value of less than 0.05 was considered as statistically significant. Results The two groups were statistically comparable in terms of age (p=0.75), sex (p =0.44), race (p =0.31), and most of the risk factors including complications at the time of admission (p = 1.00), smoking habits (p =0.56), alcohol use (p =0.80), comorbidity with NF-predisposed risk diseases (p =0.47 Tables 1 and 2). This study did not find any difference between mortality of HBO 2 and non-hbo 2 groups [5 (17%) for HBO 2 vs. 10 (26%) for non- HBO 2, p=0.37]; among the subset of survived patients in the mean length of hospital stay (28.45 days for HBO 2 vs days for non-hbo 2, p=0.30); in the mean number of ventilator-free days (22.8 days for HBO 2 vs. 21 days for non-hbo 2, p=0.89); and number of amputations (one amputation for HBO 2 vs. six amputations for non-hbo 2, p=0.09 Tables 1 and 2) of the patients who had associated NF at the extremities. Among the patients who survived at discharge or survived more than 15 days in the hospital stay and did not require 116

3 Characteristics Sex TABLE 1 Total Study n (%) FREQUENCY HBO 2 group (29) n (%) Non-HBO 2 group (38) n (%) p-value Male 38 (57%) 18 (62%) 20 (53%) 0.44* Race White African American 45 (68%) 21 (31%) 21 (75%) 7 (25%) 24 (64%) 14 (36%) 0.31* Etiology Spontaneous 25 (37%) 14 (48%) 11 (29%) 0.11* Trauma 13 (19%) 5 (17%) 8 (21%) 0.70* Surgical procedure 15 (22%) 6 (21%) 9 (23%) 0.77* Brown Recluse spider bite 5 (8%) 1 (3%) 4 (11%) 0.38 ƒ Others 9 (13%) 3 (10%) 6 (15%) Smoker 30 (46%) 12 (41%) 18 (49%) 0.56* Alcohol user 18 (29%) 8 (31%) 10 (28%) 0.80 * Complicated admission 58 (87%) 25 (86%) 33 (87%) 1.00* Comorbidity 47 (70%) 19 (66%) 28 (74%) 0.47* Diabetes mellitus 35 (52%) 14 (48%) 21 (55%) 0.57* MRSA or group A streptococcus 20 (30%) 11 (38%) 9 (24%) 0.21* Amputation (n=43) 7 (16%) 1 (5%) 6 (25%) 0.09 ƒ Patient died 15 (22%) 5 (17%) 10 (26%) 0.37* * Chi-square test; ** No growth in seven patients tissue samples ƒ Fisher exact test; Associated limb affected necrotizing fasciitis Table 1: Comparative univariate statistics of the characteristics between HBO 2 and Non-HBO 2 group categorical variables. 117

4 TABLE 2 Characteristics Total mean +/-SD (range) Mean age in years /-14.2 (20 86) (n = 67) FREQUENCY HBO 2 group Non-HBO 2 group mean +/-SD mean +/-SD (range) (range) / (20 76) (n = 29) / (27 86) (n = 38) p-value 0.75 Mean LOS in days / / / (Only survived patients) (2 226) (n=52) (4 112) (n=24) (2 226) (n=28) Mean number of ventilatorfree days (only survived patients) / (1-70) (n=13) / (7-49) (n=5) / (1-70) (n=8) 0.89 Mean number of debridements (survived > 15 days and no amputation) 3.4 +/- 2.4 (0 10) (n=56) 4.2 +/- 2.7 (0 10) (n=27) 2.7 +/- 1.8 (0 7) (n=29) 0.03 Student t-test; Kruskal-Wallis test; SD = standard deviation Table 2: Comparative univariate statistics of the characteristics and outcome between HBO 2 and Non-HBO 2 group of continuous variables. amputation, the difference in the mean number of surgical debridement procedures between the HBO 2 and non-hbo 2 group (4.15 +/ vs / respectively, p=0.03) was statistically significant. All patients required admission to the intensive care unit, and there were 15 (22%) deaths during their hospital stay. The first death in the HBO 2 group occurred at the tenth day; and death in the non- HBO 2 group occurred at Day 13 from admission. In the expired patients, seven died due to multiorgan failure, five died of respiratory failure, two due to cardiac cause, and one due to renal failure. Possible etiological factors for NF that could be identified were 25 (37%) of a presumably idiopathic process; 15 (22%) following surgery; 13 (19%) due to trauma; five (8%) following a brown recluse spider bite; and 1 due to calciphylaxis (Table 1). The average number of HBO 2 treatment among the patients who survived more than 30 days in hospital was / (range 2 49). All but one patient had 90 minutes treatment, and the number of treatment per day was mostly two treatments (average /- 0.32), with the average of atmosphere per treatment / ATA ranged from 2.2 to 2.5. For comparing the outcomes between the groups, only the mean number of surgical debridement were statistically significant (p=0.03). A multiple variable linear regression model was drawn to show the association between the HBO 2 therapy and number of surgical debridement controlling for alcohol use, days on ventilator support, diabetes status, MRSA or group A streptococcus infection, and if NF 118

5 TABLE 3 Variable Coefficient Std error F-test p-value Alcohol users (Yes/No) Days in ventilator Diabetes (Yes/No) HBO 2 used (Yes/No) MRSA or group A streptococcus (Yes/No) Trunk (Yes/No) deficiency, one developed spontaneously, and the other following a brown recluse spider bite. The median time taken to admit patients to the burn center once, diagnosed as NF at the referring facilities, was 24 hours; there was no difference in time to referral between survived patients and those who died (p=0.71). The median time taken for the HBO 2 group was 23.5 hours; for the non-hbo 2 group 60.0 hours. The difference was not significant (p=0.56). At the initial wound culture and grams stain, 60 (90%) showed growth of at least one organism. Table 4 (Page 120) summarizes the pathogens isolated from infected tissues of the patients. Forty (61%) cultures grew with mixed flora and gram-positive bacteria; gram-negative rods were most common. The most prevalent pathogens found were Staphylococcus sp. 42 (61%) including MRSA. The distribution of pathogens between groups was not equal. The non-hbo 2 group had a significant number of pseudomonas infections compared to the HBO 2 group (p< 0.01), and the overall number of infections caused by gram-negative orr 2 = 0.46 Survived or length of hospital stay more than 15 days Table 3: Multiple variable linear regression model showing association between variables and number of surgical debridements. affected the trunks. These variables were shown to be closely or significantly associated with a number of surgical debridements in crude analysis. The regression model shows that the subset of patients who needed ventilator support, their days in ventilator (coefficient 0.05, p<0.05), HBO 2 group (coefficient 1.49, p<0.05), infected with MRSA or group A streptococcal organism (coefficient 1.47, p<0.05), and had associated trunk involvement (coefficient 1.52, p<0.05) were associated with an increasing number of surgical debridements controlling for other risk factors, e.g., alcohol use and diabetes (Table 3, above). A total of 43 patients had affected extremities and one of 19 patients in the HBO 2 group and six of 24 (25%) in the non-hbo 2 group required amputation (p=0.09). In crude analysis, none of the variables were shown to be significantly different between the patients who had amputation and who did not, and further statistical analysis was not done. Among the seven patients who had amputations, four (57%) presumably developed NF following trauma, one due to circulatory 119

6 Bacteria species Staphylococcus sp. MRSA Staph. aureus Staph. epidermitis Staph. hominis Staph. lugdunensis Staph. simulans Others Streptococcus sp. Group B Strep. Group A Strep. Strep. viridans Strep. bivis Microaerophilic strep. Peptostreptococcus sp. Other Strep. sp. Study population n (%) 42 (63) 12 (18) 22 (33) 8 (12) FREQUENCY HBO 2 group Non- HBO 2 group p-value 0.93* 0.60* 0.07* 0.46** Entercocci sp. 13 (19) ** Yeast Candida albican Others 18 (27) * Gram-negative 29 (45) ** E. coli 13 (19) ** Pseudomonas sp. 12 (18) ** Acinetobacter sp. 12 (18) ** Other G-negative rods 17 (25) ** Stenotrophomonas maltophilia 9 (13) ** Other Enterobacteriaceae 7 (10) 1 6 * Chi-square 2-tailed p-value ** Yates Chi-square p -value TABLE 4 Table 4: Distribution of isolated organisms between HBO 2 and non-hbo 2 therapy groups. ganisms were significantly higher in the non-hbo 2 group compared to the HBO 2 group (p<0.01). Infection caused by more than one pathogen or MRSA or group A streptococcal organisms did not increase the chance of death nor did it increase the chance of having an amputation or the mean number of surgical debridements. Discussion This study did not find any significant improvements in the outcomes in NF patients by using adjuvant HBO 2 therapy compared to non-hbo 2 therapy, but for extremity-affected patients, the HBO 2 group required one amputation compared to six in the non-hbo 2 group. However, the study was under- 120

7 powered to demonstrate statistical significance at the 0.05 level. There were no significant differences between the mortality in the HBO 2 and non- HBO 2 groups (17% and 26%, respectively, p=0.37), and this finding is consistent with previously reported studies (1, 25, 26). Brown and his colleagues found 2.4 debridements in an HBO 2 and 1.3 in a non-hbo 2 group (25), and a similar finding was observed by Shupak and his colleagues (2.3 in HBO 2 vs. 1.5 in non- HBO 2 )(1). None of the differences were statistically significant. We compared the average number of surgical debridements between the HBO 2 and non- HBO 2 groups among all survived patients or who survived more than 15 days in hospital stay and did not have amputation. The study showed that the average number of debridements was significantly higher in the HBO 2 group compared to the non-hbo 2 group, controlling for other variables. The possible explanations for higher number of surgeries in the HBO 2 group could be that due to higher number of amputations in the non-hbo2 group, the patients in this group had a fewer number of surgical debridements compared to the HBO 2 group. However, there was no significant different in outcomes in terms of mortality, amputation and length of hospital stay. Our study observed an increased number of debridements among the patients with MRSA or group-a streptococcal infection associated trunk-affected NF, and those who required longer days on ventilator support. Previous studies have reported that better results can be achieved with fewer HBO 2 sessions (9), and others suggested that fulminant NF warrants more aggressive use of HBO 2 therapy (27). There is a negligible incidence of oxygen toxicity, and it can be further reduced if treatments have a five-minute interval of air break after every 30 minutes of therapy (2). Some suggested an aggressive HBO 2 therapy after surgical debridements with three sessions in a monoplace chamber at ATA, 100% oxygen for 90 minutes during the first 24 hours, with appropriate air breaks as necessary; and from the second day, twice-daily therapies can follow until granulation is obtained to a total of therapies (12); but the optimal HBO 2 dosing for NF is unknown. In our burn center 86% of our patients received two treatments per day with a median of 2.26 ATA atmospheric pressure for an average of 90 minutes, with a total average number of treatments of / (range 2-49). This observation suggests that the HBO 2 therapy of the center was neither aggressive nor fewer than normal and thus, the study could not determine the differences between the normal and aggressive use of HBO 2 therapy. Due to the fact that pulmonary dysfunction at the time of HBO 2 can reduce the expected arterial oxygen tension considerably, a fixed-dose HBO 2 therapy may not be appropriate for all patients (28). One study showed that HBO 2 therapy in burn injury permits shorter hospital stays and a reduced number of surgeries (29). In our cohort of NF patients, there was no statistically significant difference in the length of hospital stay. On the contrary, we found an increased number of surgeries in the HBO 2 group. Wilkinson and Doolette from Australia reported an increased number of amputations in the non-hbo 2 group, with 0% (n=12) versus 50% (n=4) amputation in HBO 2 and non-hbo 2 groups respectively (p=0.05) (10). In our study, a univariate analysis showed a lower number of amputations for the HBO 2 group than non-hbo 2, and the severity of the disease between the groups was not significant. However, the non-hbo 2 group had higher number of gram-negative, especially pseudomonas, infections than the HBO 2 group, but there was no statistical difference found between the patients who had amputation and the patients who did not have amputation when crude analysis was observed for gram-negative pathogens and pseudomonas infection. NF caused by trauma is 5.52 times more likely to require amputation compared to other causes of NF (p=0.06). Unlike previous studies, the infection with Staphylococcus sp. was the highest in our studied population, whereas a number of other studies observed E. coli as the most prevalent pathogen (1,30). In most instances, HBO 2 therapy is advised for patients who are deteriorating under standard treatment for NF. Therefore, the outcome results between HBO 2 and non-hbo 2 groups in most of the retrospective studies would not be comparable 121

8 (9,22,25). This study does not show any statistically significant clinical benefit of the therapy in reducing the mortality or morbidity. However, increased sample size might have obtained statistically significant results. A prospective, randomized clinical trial would be appropriate to assess the benefit of HBO 2 therapy, but due to the seriousness of the illness in most of the NF patients, the ethical quandary of a randomized controlled trial would be difficult to carry out. This study warrants further in-depth study to explore the benefit of adjuvant HBO 2 therapy for treating necrotizing fasciitis. n References 1. Shupak A, Shoshani O, Goldenberg I, et al.: Necrotizing Fasciitis: An indication for hyperbaric oxygenation therapy? Surgery, 1995; 118(5): Jillali N, Withey S, Butler PE. Hyperbaric oxygen as adjuvant therapy in the management of necrotizing fasciitis. The American Journal of Surgery, 2005; 189( Kihiczak GG, Schwartz RA, Kapila R. Necrotizing fasciitis: a deadly infection. J Eur Acad Dermatol Venereol, 2006; 20(4): Jillali N. Necrotizing fasciitis: its aetiology, diagnosis and management. J Wound Care, 2003; 12(8): Majeski JA, Alexander JW. Early diagnosis, nutritional support, and immediate extensive debridement improve survival in necrotizing fasciitis. AM J Surg, 1983; 145(6): Ledingham IM, Tehrani MA. Diagnosis, clinical course and treatment of acute dermal gangrene. Br J Surg, 1975; 62(5): Ioriani P, Oliver GC. Synergistic soft tissue infections of the perineum. Dis Colon Rectum, 1992; 35(7): Riseman JA, Zamboni WA, Curtis A, et al.: Hyperbaric oxygen therapy for necrotizing fasciitis reduces mortality and the need for debridements. Surgery, 1990; 108(5): Maisel RH, Karlen R. Cervical Necrotizing Fasciitis. Laryngoscope, 1994; 104(7): Wilkinson D, Doolette D. Hyperbaric Oxygen treatment and survival from Necrotizing Soft Tissue Infection. Arch Surg, 2004; 139(12): Green RJ, Dafoe DC, Raffin TA. Necrotizing Fasciitis. Chest, 1996; 110(1): Maynor M - Necrotizing Fasciitis, Accessed on April 4, 2007, topic332.htm 13. Tibbles PM, Edelsberg JS. Hyperbaric-Oxygen Therapy. N Engl J Med, 1996; 334(25): Lampl L, Frey G, Fischer D, et al.: Hyperbaric oxygenation: utility in intensive therapy - part 2. Anasthesiol Intensivmed Notfallmed Schmerzther: AINS, 2009; 44(10): Hunt TK. The physiology of wound healing. Ann Emerg Med 1988; 17(12): Knighton DR, Halliday B, Hunt TK. Oxygen as an antibiotic: a comparison of the effects of inspired oxygen concentration and antibiotic administration on in vivo bacterial clearance. Arch Surg, 1986; 121(2): Hill GB, Osterhout S. Experimental Effects of Hyperbaric Oxygen on Selected Clostridial Species. II. In-vivo Studies in Mice. J Infect Dis, 1972; 125(1): Boehme DE, Vincent K, Brown O. Oxygen and toxicity inhibition of amino acid biosynthesis. Nature, 1976; 262( Park MK, Muhvich KH, Myers RA, et al.: Hyperoxia prolongs the aminoglycoside-induced postantibiotic effect in Pseudomonas aeruginosa. Antimicrob Agents Chemother, 1991; 35(4): Buras JA, Holt D, Orlow D, et al.: Hyperbaric oxygen protects from sepsis mortality via an interleukin-10 dependent mechanism. Crit Care Med, 2006; 32(10): Plafki C, Peters P, Almeling M, et al.: Complications and side effects of hyperbaric oxygen therapy. Aviat Space Environ Med, 2000; 71(2):

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