Necrotizing fasciitis following venomous snakebites in a tertiary hospital of southwest Taiwan

Accepted Manuscript Title: Necrotizing Fasciitis Following Venomous Snakebites in a Tertiary Hospital of Southwest Taiwan Authors: Yao-Hung Tsai, Wei-Hsiu Hsu, Kuo-Chin Huang, Pei-An Yu, Chi-Lung Chen, Liang Tseng Kuo PII: DOI: Reference:

S1201-9712(17)30210-2 http://dx.doi.org/doi:10.1016/j.ijid.2017.08.005 IJID 3010

To appear in:

International Journal of Infectious Diseases

Received date: Revised date: Accepted date:

3-6-2017 4-8-2017 8-8-2017

Please cite this article as: Tsai Yao-Hung, Hsu Wei-Hsiu, Huang Kuo-Chin, Yu PeiAn, Chen Chi-Lung, Kuo Liang Tseng.Necrotizing Fasciitis Following Venomous Snakebites in a Tertiary Hospital of Southwest Taiwan.International Journal of Infectious Diseases http://dx.doi.org/10.1016/j.ijid.2017.08.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Necrotizing Fasciitis Following Venomous Snakebites in a Tertiary Hospital of Southwest Taiwan Running Title: Snakebite Necrotizing Fasciitis

Yao-Hung Tsai, M.D. 1,2 Wei-Hsiu Hsu, M.D.1,2 Kuo-Chin Huang, M.D. 1,2 Pei-An Yu, M.D. 1 Chi-Lung Chen, M.D.1,2 Liang Tseng Kuo, M.D.1,2

Institution: 1

Department of Orthopaedic Surgery, Chia-Yi Chang Gung Memorial Hospita, Taiwan,

Republic of China 2 College

of Medicine, Chang Gung University at Taoyuan, Taiwan

Correspondence and reprint requests to: Yao-Hung Tsai, M.D. Department of Orthopaedic Surgery, Chia-Yi Chang Gung Memorial Hospital, No. 6, West Sec, Chia-Pu Road. Putz City, Cha-I, 613, TAIWAN, Republic of China Tel.: 886-5-3621000, ext. 2855 Fax: 886-5-3623005 E-mail:[email protected]

1

Hightlights  Necrotizing fasciitis after snakebites is a true surgical emergency, and need an emergent surgical fasciotomy.  We identified the risk factors associated the development of necrotizing fasciitis from cellulitis.  Physicians should monitor closely the victims suffered from venomous snakebites and the possibility of necrotic soft tissue infections.

Abstract Background: Necrotizing fasciitis following venomous snakebites is uncommon. The purpose of this study was to describe the initial clinical features of necrotizing fasciitis after snakebites, and to identify the risk factors for patients with cellulitis who later developed necrotizing fasciitis. Methods: Sixteen patients with surgically-confirmed necrotizing fasciitis and 25 patients diagnosed with cellulitis following snakebites were retrospectively reviewed over a 6-year period. Differences in patient characteristics, clinical presentations, snake species and laboratory data were compared between the necrotizing fasciitis and the cellulitis groups. Results: None of 41 patients died after being bitten by a snake. Twenty-nine patients (70.7%) were bitten by a cobra. Enterococcus species and Morganella morganii were the most common pathogens identified in wound cultures. Relative to the cellulitis group, the necrotizing fasciitis group had significantly higher rates of hemorrhagic bullae (p=0.000), patients with underlying chronic disease (p=0.019), white blood cell counts (p=0.035), segmented white cell counts (p=0.02), and days of hospitalization (p=0.001). Conclusions: Victims of venomous snakebites should be admitted for close monitoring of

2

secondary wound infections. The risk factors of developing necrotizing fasciitis from cellulitis following a snakebites were associated with chronic underlying diseases and leukocytosis (total white blood- cell counts ≥ 10000 cells/mm3 and ≥ 80% of segmented leukocyte forms). Physicians should be alert to a worsening wound condition after a snakebite, and surgical interventions should be performed for established necrotizing fasciitis with the empirical use of third-generation cephalosporins plus other regimens.

Key words: Necrotizing fasciitis, snakebites, venomous 1. Introduction Taiwan is situated on the boundary of tropic and subtropic regions with a warm and humid climate. Various kinds of snakes are found in Taiwan, and therefore; venomous and nonvenomous snakebites are often seen in the emergency room.1,2,3 The six most common venomous snakes with recorded bites on humans include the Taiwan cobra (Naja atra), Taiwan habu (Trimeresurus mucrosquamatus, Protobothrops mucrosquamatus), Trimeresurus stejnegeri, Bungarus multicinctus, Deinagkistrodon acutus, and Daboia russelii siamensis.1-3 The standard therapy of antivenom administration can decrease the toxic hemorrhagic or neurotoxic effects of venom.1-5 However, the development of compartment syndrome and soft tissue bacterial infections can not be prevented by antivenom treatment.1,6 Wound infections following venomous snakebites, such as cellulitis and necrotizing fasciitis, are not common; however, they have been reported in up to 30.8% of patients after a snakebite and they require aggressive treatment.7-10 Necrotizing fasciitis secondary to snakebites can cause extensive local tissue destruction and progressive sepsis complicated with acute renal failure, thrombocytopenia, and coagulopathy, which is a true surgical emergency requiring fasciotomy or amputation, broad-spectrum antibiotics, and intensive unit care.2,7,11,12 The purpose of this study was to describe the initial clinical features of necrotizing fasciitis after snakebites, and to identify the risk factors for patients with cellulitis who later develope necrotizing fasciitis. 3

2. Methods 2.1 Study design and setting We reviewed the medical records of 83 patients with snakebites who were admitted to the emergency department of Chia-Yi Chang Gung Memorial Hospital in Taiwan from June 2010 to July 2016. Of these patients, 42 (50.6%) were discharged from the emergency room after antivenom therapy, and 41 patients were admitted for intravenous antibiotics or surgery and were enrolled in this study. Sixteen patients (19.3%) with surgically-confirmed necrotizing fasciitis were categorized into the necrotizing fasciitis group, and 25 patients (30.1%) who did not receive surgey were categorized into the cellulitis group. The snake species involved was confirmed primarily by witnesses or identification through a venomous snake chart by the patient or family. If the snake species could not be identified, it was categorized as an unknown species. Intravenous antivenom was initially administered to all patients, and broad-spectrum antibiotics were given at the emergency room or after admission to a ward. The emergent operations of fasciotomy and excisional debridement were immediately performed in cases where necrotizing fasciitis was suspected and diagnosed at the time of admission to the emergency room or at the time of consultation in the ward. Cultures of purulent fluid and tissue specimens were obtained during the operations. Histopathological tissue specimens were confirmed the diagnoses by pathologist. The definite diagnoses of necrotizing fasciitis were based on clinical, surgical or histopathologic findings. 2.2 Microbiology laboratory procedures The cultured specimens, obtained from the wounds or the blood, were confirmed by microbiologic evaluation. Identification of these microorganisms was based on standard phenotypic tests used in clinical microbiology laboratories. Antimicrobial susceptibility was determined by the hospital microbiology laboratory via the standard disk diffusion technique.

The susceptibility interpretative critieria for these microorganisms in our microbiological lab was

4

performed as recommended by the Clinical and Laboratory Standards Institute. 2.3 Clinical assessment Data collected from the medical records of the 41 patients including age, gender, comorbidities, the involved limbs, clinical presentation of hemorrhagic bullae, doses of antivenom used, the snake species, laboratory data, the duration of hospitalization, and the clinical outcomes, were compared between the necrotizing fasciitis group and cellulitis group. We also analyzed the 16 patients with necrotizing fasciitis for the time from the snakebite to the presentation at the emergency room, the time interval between the diagnosis and first surgery, and the microbiological results. 2.4 Statistical analysis Statistical analyses were performed using SPSS version 12.0 (SPSS, Chicago, Illinois). We used the two-tailed t-test for continuous variables (age, hospital stay, leukocyte count, band forms, segmented forms, platelet count, creatinine, activated partial thromboplastin time (aPTT), prothrombin time and international normalized ratio (INR); and Fisher’s exact test for categorical variables (gender, wound location, presentation of hemorrhagic bullae, underlying chronic disease, total white blood cell counts ≥ 10000 cells/mm3, segmented forms ≥ 80%) to identify significant relationships between the risk factors and outcomes in the two groups. To identify risk actual factors of progression from cellulitis to necrotizing fasciitis following a snakebite, we used binary logistic regression analysis to examine parameters that showed a difference (p < 0.05) in a univariate analysis. A p value of less than 0.05 was considered to be statistically significant. 3. Results We enrolled that 41 patients were admitted for intravenous antibiotics or surgery.(Fig.1) The most common complaints of the enrolled patients were pain and swelling of the involved limbs with edematous, ecchymosis, and erythematous skin lesions at the time of admission to the emergency room. None of the 41 patients died after being bitten by a snakebite, and no bacterial growth was noted in the blood culture of any of the patients. Culture findings of the specimens obtained from the wounds of the necrotizing fasciitis group confirmed the bacterial species a few 5

days after surgery. No significant changes in platelets counts or thrombocytopenia below 50 000 cells/mm3 was noted in any of the patients, and no abnormalities in creatinine level or abnormal values of prothrombin time INR and aPTT were found. 3.1 Patient characteristics in the necrotizing fasciitis group The necrotizing fasciitis group included ten men and six women with a mean age of 64.7 years (range, 48 to 80 years). Twelve patients were bitten by a cobra, one by Protobothrops mucrosquamatus, and three by unknown species. The mean dose of antivenom administered before surgical intervention was 5.28 vials (range, 1 to 14 vials). The treatments administered and patient outcomes are summarized in Table 1. Four patients had a history of hepatitis B or C alone, one patient had hepatitis B and gout, four had gout, and one had diabetes mellitus alone. Three patients with heart diseases or hypertension were receiving regular medical treatmentm and three patients reported no underlying chronic disease. Nine patients had upper limb skin lesions and seven had lower limb skin lesions. All of the patients had the presentation of hemorrhagic bullous lesions and initially underwent fasciotomy and debridement, but none of these patients underwent a limb amputation. Seven patients received skin grafts, one patient received flap reconstruction, four patients underwent debridement, and four received only wound care after initial fasciotomy.(Fig.2 &3) Ten patients had polymicrobial infections and two patients had monomicrobial infections. Enterococcus faecalis was the most common gram-positive pathogen, and Morganella morganii was the most common gram-negative bacteria. Additional pathogens identified in the polymicrobial cultures invluded Shewanella putrefaciens, Serratia marcescens, and Bacteroides fragilis. Four patients had no bacterial growth in wound or blood cultures. Enterococcus faecalis was susceptible to ampicillin, gentamicin, penicillin, and vancomycin. Morganella morganii, Shewanella putrefaciens and Serratia marcescens were susceptible to amikacin, ceftazidime, ciprofloxacin, and piperacillin/tazobactam. Bacteroides fragilis was susceptible to metronidazole, clindamycin and chloramphenicol. No cases of acute renal failure or coagulation abnormalities were noted.(Table 2) One patient had a body temperature of >38.5oC. None of the patients were 6

hypotensive, and none were admitted to the intensive care unit. The mean hospital stay for patients with necrotizing fasciitis was 29.5 days (range, 12 - 50 days). Broad-spectrum antibiotics were administered to the patients with suspected necrotizing fasciitis at the emergency room, and were continued after surgery. We then changed the antibiotics to specifically target the cultured bacteria a few days later. Ceftriaxone alone was given to three patients, third-generation cephalosporins (ceftriaxone or ceftazidime) plus metronidazole to five, ceftriaxone plus other antibiotics (amikacin, augmentin, teicoplanin, vancomycin or gentamicin) in five, ciprofloxacin in one, piperacillin/tazobactam in one, and oxacillin plus gentamicin in one. 3.2 Patient characteristics in the cellulitis group The cellulitis group included 19 men and six women with a mean age of 55.3 years (range, 11 -80 years). Seventeen patients were bitten by a cobra, three by Protobothrops mucrosquamatus, two by Trimeresurus stejnegeri and three by an unknown species. A mean of 4.44 vials (range, 1 to 14 vials) of antivenom were given dueing hospitalization. Three patients had a history of hepatitis B and one patient had hepatitis C. Three patients had diabetes mellitus alone, one had both hepatitis B and diabetes mellitus, one had gout, one had coronary heart disease, and one had end-stage renal disease. Fourteen patients had no underlying chronic disease. Thirteen patients had upper limb skin lesions and 12 had lower limb skin lesions. All of the involved limbs presented with local tenderness, erythema, swelling, and heat, and one patient had a small hemorrhagic blister on the right hand. One patient was febrile, and none of the patienta had a systolic blood pressure of ≤90 mm Hg. The mean duration of hospital stay was 4.8 days (range, 2 to 11 days). The wound culture of the second finger bitten by a cobra in the patient with coronary heart disease revealed Enterococcus faecalis and Morganella morganii. The specimens obtained from the wounds or blood of the other 24 patients showed no bacterial growth. Intravenous or oral antibiotics were administered initially in the emergency room, including cefazolin to ten patients, cefazolin plus gentamicin to five, oxacillin to two, oxacillin plus gentamicin to one, oral 7

amoxicillin to two, oral dicloxacillin to one, ceftriaxone to one, and augmentin to two patients. One patient did not receive antibiotics as he was allergic to drugs. 3.3 Comparison of necrotizing fasciitis and cellulitis groups There were no significant differences in age, sex, doses of antivenom or wound location between the two groups. The necrotizing fasciitis group had significantly higher rates of the presentation of hemorrhagic bullae (p=0.000), patient with underlying chronic disease (p=0.019), total white blood cell counts (p=0.035), segmented white cell counts (p=0.02), and days of hospitalization (p=0.001) compared to the cellulitis group. The patients with a white blood cell count ≥ 10000 cells/mm3 and segmented forms ≥ 80% were significantly associated with necrotizing fasciitis (Table 3). The binary logistic regression analysis identified four variables predicting risk factors of progression from cellulitis to necrotizing fasciitis: increased segmented forms, patient with underlying chronic disease, white blood cell counts ≥ 10000 cells/mm3 and segmented forms ≥ 80% (Table 4).

4. Discussion Snake venom consist of systemically and locally acting toxins; including neurotoxins, myotoxins, cardiotoxins, hemostasis toxins, and renal toxins, that can cause respiratory distress, paralysis of the extremities, rhabdomyolysis, acute kidney injury, compartment syndrome, wound necrosis, coagulopathy, persistent mydriasis and cardiac dysrhythmia.1,2,5,7,13 Antivenom therapy can decrease the envenomation effects on coagulation, the central nerve system, the cardiovascular system and the gastrointestinal system; however, antivenom can not reverse the effects of local tissue damage or necrosis.13,14 The venom of the Taiwan cobra consists of cardiotoxin, cobratoxin and myotoxic phospholipase A2, which can cause neurotoxicity with muscle weakness and local purulent inflammation with tissue destruction.1,2,8 Many studies have reported that cobra bites rarely result in systemic neurotoxic effects, but often cause more severe

8

wound complications than other kinds of snakebites in Taiwan.1-3,5,8 In this study, 29 patients were bitten by a cobra, aof whom 12(41.3%) developed necrotizing fasciitis despite the prompt and repeated administration of antivenom. We found no significant difference in the number of antivenom vials given between the cellulitis group and necrotizing fasciitis group, which may indicate the inability of antivenom therapy to reverse the local extensive tissue necrosis from cellulitis. Envenomation often affects the hematologic system and results in coagulopathy.13,15 Renal failure following lethal envenomation may result from intravascular hemolysis, hypotension, or nephrotoxic effects on renal tubular glomerular epithelial cells and the vasculature.3,13,14 Laboratory data of blood counts, creatinine and coagulation profiles, such as activated partial thromboplastin time (aPTT), prothrombin time, and international normalized ratio (INR) should be obtained on admission and closely observed thereafter.13,15,16 In our study, none of the 41 patients who received immediate antivenom therapy at the emergency room had an abnormally prolonged aPTT or prothrombin time after admission, and none developed coagulopathy or acute renal failure after snakebites. Wound infections after snakebites, such as cellulitis and necrotizing fasciitis, had been reported in many literatures, and emergency surgical fasciotomy is required for necrotizing fasciitis.1-9,12-14 The common signs and symptoms of cellulitis, such as erythema, swelling, heat and local pain may develop in the early hours to days of evolution. However, the risk factors progressing from cellulitis to necrotizing fasciitis secondary to a snakebite provided have seldom been investigated. By univariate analysis, we found the patients with the necrotizing fasciitis were highly associated with the presentation of hemorrhagic bullae, total white blood cell counts and the segmented leukocyte forms, and chronic underlying diseases, such as hepatitis, diabetes mellitus, heart disease, hypertension, gout and end-stage renal disease. However, by binary logistic regression analysis, the following factors predicted the risk factors of progression from cellulitis to necrotizing fasciitis: chronic underlying diseases, the segmented leukocyte forms, total white blood cell counts ≥ 10000 cells/mm3 and the segmented forms ≥ 80%. Although the 9

total white blood cell counts did not reveal a significant difference in binary logistic regression analysis (p=0.052), we consider that leukocystosis with higher total white blood cell counts should be noticed for the progression to necrotizing fasciits. Shek et al. and Liu et al. recommended that prophylactic broad-spectrum antibiotics may be beneficial for the victims of local envenomation owing to the multiple pathogenic bacteria found in the months of snakes, especially the corba bite.8,17 Enterococcus faecalis and Morganella morganii were the most common bacteria identified in our study, which is similar to other studies.1,2,5,12,17 Chen et al. recommended empirical antibiotic therapy; such as oral amoxicillin/clavulanate plus ciprofloxacin or parenteral piperacillin/tazobactam alone, for minor wound

infections

secondary

to

snakebites,

and

Huang

et

al.

suggested

using

piperacillin/tazobactam, quinolone, second- or third-generation cephalosporins for severe wound infections following snakebites. 2,5 We previously suggested using ceftriaxone to cover all types of necrotizing fasciitis because the clinical signs and symptoms of necrotizing fasciitis are characteristically indistinguishable between gram-positive and gram-negative bacteria initially, and it takes 3 to 4 days to obtain the results of microbiological analyses and antimicrobial sensitivity of the specimens.18 Thus, we used third-generation cephalosporins plus other antibiotics to cover both gram-positive and gram-negative organisms, and none of the patients died. There are two limitations to this study. First, the validity and reliability of this study may be diminished by the relatively small number of patients with necrotizing fasciitis. Second, we did not follow up the conditions of the 42 patients who only received antivenom therapy and were discharged from emergency room. In the United States, admission for 24 hours is strongly recommended after a snakebite for continuous monitoring for the development of clinical symptoms.13 This may have helped to elucidate why these patients did not develop cellulitis or necrotizing fasciitis. In conclusion, the risk factors of progression from cellulitis to necrotizing fasciitis following a snakebite included chronic underlying diseases and leukocytosis (total white blood- cell counts 10

≥ 10000 cells/mm3 and ≥ 80% of segmented leukocyte forms). Physicians should be alert to a worsening wound condition after a snakebite, and surgical intervention should be performed for established necrotizing fasciitis with the empirical use of third-generation cephalosporin plus other regimens. Declarations Funding This work was supported in part by grants from Chang Gung Memorial Hospital in Taiwan (Grant No. CORPG6E0031 to Yao-Hung Tsai). Disclosure statement All contributing authors declare no conflicts of interest. Ethical approval and consent to participate The study protocol was approved by the Institutional Review Board of Chang Gung Medical Foundation. (103-2081B)

No Conflict of interest

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References 1. Shih YC, Ma H, Yeh FL, Lin JT, Hwang CH, Wang MS, Perng CK, Shen BH, Vhen CH. Risk factors of surgical intervention in the management of venomous snakebite in northern Taiwan. J Plast Surg Asso ROC 2006; 15:367-376. 2. Chen CM, Wu KG, Chen CJ, Wang CM, Bacterial infection in association with snakebite: a ten-year experience in a norther Taiwan. J Microbiol Immunol Infect 2011;44:456-460. 3. Chang KP, Lai CS, Lin SD. Management of poisonous snake bites in southern Taiwan. Kaohsing J Med Sci 2007; 23:511-518. 4. Warrell DA. Venomous animals. Medicine 2007; 35:659-662. 5. Huang LW, Wang JD, Huang JA, Hu SY, Wang LM, Tsan YT. Wound infections secondary to snakebite in central Taiwan. J Venom Anim Toxins incl Trop Dis 2012; 18:272-276. 6. Hsu CP, Chung JF, Hsu YP, Wang SY, Fu CY, Yuan KC, Chen CH, Kang SC, Liao CH. Predictors of the development of post-snakebite compartment syndrome. Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine 2005;23:97. 7. Nadiyah A, Azira NMS, Nazli Z, Zeehaida M. Post viper bite Pasteurella multocida necrotizing fasciitis complicates with septicaemia and renal failure. Tropocal Biomedicine 2015;32:608-612. 8. Liu PY, Shi ZY, Lin CF, Huang JA, Liu JW, Chan KW, Tung KC. Shewanella infection of snake bites: a twelve-year retrospective study. Clinics 2012;67:431-435. 9. Otero R, Gutierrez J, Beatriz Mesa M, Duque E, Rodriguez O, Luis Arango J, et al. Complications of Bothrops, Porthidium, and Bothriechis snakebites in Colombia. A clinical and epidemiological study of 39 cases attended in a university hospital. Toxicon 2002;40:1107-114.. 10. Otero-Patino R. Epidemiological, clinical and therapeutic aspects of Bothrops asper bites. Toxicon 2009;54:998-1011, 11. Cumpston KL. Is there a role for fasciotomy in Crotalinae envenomations in North America?

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Clin Toxicol 2011; 49:351-365. 12. Wang OF, Lam TSK, Fung HT, Choy CH. Five-year experience with Chines cobra (Naja atra)- related injuries in two acute hospitals in Hong Kong. Hong Kon Med J 2010; 16:36-43. 13. Anz AW, Schweppe M, Halvorson J, Bushnell B, Sternberg M, Koman LA. Management of venomous snakebite injury to the extremities. J Am Acad Orthop Surg 2010;18:749-759. 14. Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med 2002;347:347-356. 15. Lincz LF, Scorgie FE, Johnston CI, O’Leary M, Prasad R, Seldon M, Favaloro E, Isbister GK. Comparative sensitivity of commercially available aPTT reagents to mulga snake (Pseudechis australis) venom. Pathology 2014;40:444-449. 16. Ireland G, Brown SG, Buckley NA, etal. Changes in serial laboratory test results in snakebite patients: when can we safely exclude envenoming? Med J Aust 2010;193:285-290. 17. Shek KC, Tsui KL, Lam KK, et al. Oral bacterial flora of the Chinese cobra (Naja atra) and bamboopit viper (Trimeresurus albolabris) in Hong Kong SAR, China. Hong Kong Med J 2009;15:183-190. 18. Tsai YH, Huang KC, Shen SH, et al: Microbiology and surgical indicators of necrotizing fasciitis in a tertiary hospital of southwest Taiwan. Int J Infect Dis 2012; 16:e159-165.

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Legends Figure 1. Flow Chart of Patient Inclusion Figure 1. Flow Chart of Patient Inclusion

83 patients with snakebites admitted to the emergency department Jun 2010 - Jul 2016

41 patients (49.4%) included admitted for intravenous antibiotics or surgery

16 patients (19.3%) necrotizing fasciitis group Surgically and pathologically

42 patients (50.6%) excluded discharged from the emergency room after antivenom therapy

25 patients (30.1%) cellulitis group admitted for intravenous antibiotics without surgery

-confirmed

All patients survived

14

Figure 2. A 53-year-old female (case 11) with no chronic underlying diseases suffered from an unknown snake bite on her right lateral foot. (A) Two puncture wounds on the right lateral foot were found at ER. (B) Four days later, preoperative photographs of her right foot revealed erythema, hemorrhagic bullae and subcutaneous bleeding. (C) The wound showed turbid fluid accumulated in the subcutaneous area and fascia with skin erosion. (D) After emergency fasciotomy and repeated debridement, she received skin graft on the 33th day after fasciotomy. The wound culture confirmed the presence of Enterococcus faecalis and Shewanella putrefaciens.

15

Figure 3. A 58- year-old male (case 9) with a history of hepatitis C was bitten by a cobra on the left hand while working on a farm. (A) His left hand revealed patchy purpura and edema with hemorrhagic bullaes on the forearm in the emergency room 3 hours after the bite. (B) After fasciotomy, his left hand showed bloody clots and turbid fluid accumulated in the fascia layer. (C) The skin lesion extended to the forearm, and the fascial layer revealed edematous and purulent necrotic tissues. A cultured specimen confirmed Enterococcus faecalis, Morganella morganii and Bacteroides fragilis a few days later. (D) He had received debridement and a skin graft, and he was discharged on the 26th day after admission.

16

Table 1 Characteristics of Snakebite Necrotizing Fasciitis Patients Chronic Patient Age(yr) Gender Underlying

Duration of Site

Disease

Interval A Snake

Interval B Operations

Interval C Result

(days)

Species

(hours)

(First, Final) (days)

Intensive Body

Hospitalization Care Unit Temperature (days)

Stay

>38.5℃

1

54

M

Heart disease

right forearm

5

Cobra

2

Fas, Debride 14

Survival

18

N

N

2

80

F

Heart disease

right hand

2

Cobra

2

Fas,STSG

22

Survival

38

N

N

3

64

M

HC

left leg

2

Cobra

2

Fas,STSG

32

Survival

45

N

Y

4

57

M

Nil

left leg

3

Cobra

2

Fas,STSG

21

Survival

27

N

N

5

74

M

Gout

left hand

4

Cobra

3

Fas

0

Survival

20

Y

N

6

76

M

Gout

right foot

6

Cobra

16

Fas

0

Survival

27

N

N

7

51

F

Nil

left leg

3

Unknown

2

Fas, STSG

20

Survival

50

N

N

8

76

M

HC

right hand

3

Cobra

6

Fas, Debride 19

Survival

25

N

N

9

58

M

HC

left forearm

1

Cobra

10

Fas, STSG

20

Survival

26

N

N

10

80

F

Hypertension

Right hand

3

Cobra

4

Fas, STSG

15

Survival

30

N

N

11

53

F

Nil

right leg

4

Unknown

2

Fas, STSG

33

Survival

50

N

N

12

68

F

HB

right hand

1

P.mucrosquamatus 4

Fas

0

Survival

14

N

N

13

84

F

Gout

right leg

7

Unknown

10

Fas, Flap

13

Survival

47

N

N

14

59

M

Gout

left foot

2

Cobra

8

Fas

0

Survival

15

N

N

15

48

M

DM

left hand

1

Cobra

5

Fas, Debride 9

Survival

12

N

N

16

53

M

HB, Gout

left Hand

1

Cobra

7

Fas, Debride 15

Survival

28

N

N

64.7

3

5.31

14.56

29.5

Note. 1. HC, hepatitis C; HB, hepatitis B; DM, diabetes mellitus. 2. Interval A, time from snakebite to diagnosis of necrotizing fasciitis; Interval B, time from first consultation at ER or ward to first operation; 17

Interval C, time from first operation to final operation. 3. Fas, fasciotomy; STSG, split-thickness skin graft.

18

Table 2 Laboratory Data of Snakebite Necrotiing Fasciitis Patients Patient Bacteria

White Blood Band Segmented Platelet

Creatinine Albumin

Cell Count

(umol/L) Level

Forms Forms

(cells/mm3)

(%)

(%)

Count (per mm3)

C-Reactive ESR

Protein

(g/dL)

(umol/L) (mg/L)

INR aPTT (second)

1

No growth

12000

0

71.5

254000

0.9

3

20.7

16

0.94 32.7

2

15000

2.5

82

220000

1.3

3

14

8.05

1

3

No growth E. faecalis, S. marcescens, B. fragilis

8500

0

86

144000

0.46

3

8

72

0.97 26.1

4

E. faecalis, S. putrefaciens

6700

0

55

154000

1.4

3.6

49

19.95

1

5

E. faecalis, M. morganii

10100

0

82.4

176000

1.92

3

27

115

1.09 34.2

6

M. morganii S. putrefaciens

17000

2.5

85

233000

1.55

4

32

8.94

1.07 27.1

7

E. faecalis. M. morganii,B. fragilis

11400

0

89.3

134000

0.54

3.3

81

168

1.07 34.5

8

E. faecalis, M. morganii

22000

0

85

280000

1.47

3.3

67

7.15

0.99 28.3

9

E. faecalis, M. morganii, B. fragilis

3900

0

62.4

150000

1.19

4

70

30

1

10

No growth

8000

2

74

180000

0.89

3

51

54.7

0.97 25.2

11

0

85

166000

0.72

2.7

49

174

0.93 22.6

12

E. faecalis, M. morganii,S. putrefaciens 10500 No growth 10800

0

69.7

195000

0.67

3

62

10

1.06 27.2

13

E. faecalis, M. morganii

7000

0

84

184000

1.01

2

54

94.2

1.01 26.5

14

E. faecalis, M. morganii

6800

0

55.3

178000

1.31

3

65

25

1.18 26.9

15

E. faecalis

13100

0

59

199000

1

3

50

30.8

1.13 25.4

16

E. faecalis

10100

1

84

75000

0.74

3.3

32

15

0.97 24.7

10806.2

0.5

75.6

182625

1.07

3.14

45.7

53.1

1.02 28.58

19

25 31.6

39.3

Note: E., Enterococcus; M., Morganella; S. putrefaciens, Shewanella putrefaciens; S. marcescens, Serratia marcescens; B, Bacteroides.

20

Table 3 Comparison Between Snakebite Necrotizing Fasciitis Group and Cellulitis Group for Charcteristics and Laboratory data at First Consultation and Treatment Necrotizing Fasciitis

Cellulitis

Variable

Group

Group

Number

16

25

Age (years)

Mean 64.7

55.3

Sex Male Mortality rate

Lower extremity Presentation of hemorragic bullae

10

19

6

6

0

0 0.522

9

13

7

12

16

1

Underlying chronic disease

0.000* 0.019*

Yes

13

11

No

3

14

Doses of antivenom use

0.07 0.18

Wound location Upper extremity

P value

Mean 5.38 ± 3.34

4.44 ± 2.93

0.35

Snake species 21

Taiwan cobra Protobothrops mucrosquamatus

12

17

1

3

Trimeresurus stejnegeri

0

2

Unknown

3

3

10806 ± 4455

8368 ± 2730

0.035*

≥ 10000

10

7

0.031*

< 10000

6

18

Band forms (%)

0.50 ± 0.95

0.04 ± 0.2

0.73

Segmented forms (%)

75.6 ± 11.9

63.8 ± 17.3

0.022*

≥ 80

9

6

0.04*

< 80

7

19

Laboratory data White blood (cells/mm3)

Mean cell

count

Platelet count (per mm3)

182265 ± 49400 203000 ± 17500

0.27

Creatinine (umol/L)

1.07 ± 0.41

1.21 ± 1.78

0.75

Prothrombin time - INR

1.02 ± 0.09

0.99 ± 0.06

0.165

aPTT (second)

28.58 ± 4.55

27.99 ± 1.84

0.56

4.8 ± 2.5

0.001*

Hospital days

Mean 29.5 ± 12.9

* mean p < 0.05 and the difference was significant

22

Table 4. Binary Logistic Analysis of Independent Risk Factors for Snakebite Necrotizing Fasciitis Group and Cellulitis Group Variable

Odds ratio

p Value

Total white blood cell count Segmented forms Presentation of hemorragic bullae White blood cell count ≥ 10000 Segmented forms ≥ 80

1 1.052 2.585E10 4.286 4.071

0.052 0.029* 0.998 0.033* 0.041*

Underlying chronic disease

5.515

0.024*

* mean p < 0.05 and the difference was significant

23