UPPER LIMB
Necrotising soft-tissue infections of the upper limb RISK FACTORS FOR AMPUTATION AND DEATH K. Uehara, H. Yasunaga, Y. Morizaki, H. Horiguchi, K. Fushimi, S. Tanaka From Department of Orthopaedic Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan K. Uehara, MD, Orthopaedic Surgeon Y. Morizaki, MD, Assistant Professor S. Tanaka, MD, PhD, Professor Department of Orthopaedic Surgery, The University of Tokyo, Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan. H. Yasunaga, MD, PhD, Professor Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan. H. Horiguchi, PhD, Principal Researcher Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, 2-5-21 Higashigaoka, Meguro-ku, Tokyo, Japan. K. Fushimi, MD, PhD, Professor Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan Correspondence should be sent to Dr Y. Morizaki; e-mail: [email protected] ©2014 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.96B11. 34888 $2.00 Bone Joint J 2014;96-B:1530–4. Received 4 August 2014; Accepted after revision 21 August 2014
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Necrotising soft-tissue infections (NSTIs) of the upper limb are uncommon, but potentially life-threatening. We used a national database to investigate the risk factors for amputation of the limb and death. We extracted data from the Japanese Diagnosis Procedure Combination database on 116 patients (79 men and 37 women) who had a NSTI of the upper extremity between 2007 and 2010. The overall in-hospital mortality was 15.5%. Univariate analysis of in-hospital mortality showed that the significant variables were age (p = 0.015), liver dysfunction (p = 0.005), renal dysfunction (P < 0.001), altered consciousness (p = 0.049), and sepsis (p = 0.021). Logistic regression analysis showed that the factors associated with death in hospital were age over 70 years (Odds Ratio (OR) 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR 15.4; 95% CI 3.8 to 62.8; p < 0.001). Univariate analysis of limb amputation showed that the significant variables were diabetes (p = 0.017) mellitus and sepsis (p = 0.001). Multivariable logistic regression analysis showed that the factors related to limb amputation were sepsis (OR 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR 1.6; 95% CI 1.1 to 21.1; p = 0.038). For NSTIs of the upper extremity, advanced age and renal dysfunction are both associated with a higher rate of in-hospital mortality. Sepsis and diabetes mellitus are both associated with a higher rate of amputation. Cite this article: Bone Joint J 2014;96-B:1530–4.
Necrotising soft-tissue infection (NSTI), classically called necrotising fasciitis, is a rapidly progressive, potentially fatal infectious disease which primarily involves fascia, muscle, skin, or subcutaneous fat.1 Between 500 and 1500 cases are reported in the United States each year:2 6% to 27% of these involve the upper limbs.3-5 Although rare, clinicians need to be aware of NSTIs, as they can easily result in amputation or death. Although many patients with a NSTI of the upper limb also have comorbidities such as diabetes mellitus, old age and renal dysfunction, little is known about the risk factors associated with amputation and death. Some studies have reported the incidence of death in hospital and amputation but they were mostly single institution case series.1,4-10 The purpose of this study was to identify the risk factors for amputation and death in patients with a NSTI of the upper limb.
Materials and Methods The Diagnosis Procedure Combination (DPC) database is a nationwide database in Japan
which consists of the discharge summary and administrative financial data.11-13 The DPC hospitals are surveyed between 1st July and 31st December each year by the DPC study group, in collaboration with the Japanese government. All 82 academic hospitals in Japan are obliged to participate in the DPC survey, whereas participation by community hospitals is voluntary. For this study, we used data obtained in this manner between 1st July and 31st December for the years 2007 to 2010, inclusive. During this period, data from about 11.6 million inpatients from approximately 900 hospitals were added to the database: this represents approximately 45% of all patients admitted to hospital in Japan. Researchers use the DPC database to identify, track, and analyse national trends in healthcare use, access, quality, outcomes, and costs. The database includes the following data: patients’ age and gender; diagnoses; comorbidities at admission, and complications after admission recorded according to the International Classification of Diseases, Tenth Revision (ICD-10)14 codes and text data in the THE BONE & JOINT JOURNAL
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Table I. Characteristics of the study population Total (n = 116) Gender (males) (%) Mean age (SD) (yrs) Number of deaths (%) Median timing of surgery after admission (IQR) (days) Days of surgery < 1 (%) Limb amputation (%) Amputation at first surgery (%) Site of amputation (%) Shoulder Upper arm Digit Not described Pre-operative comorbidities (%) Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis
79 (68.1) 66.7 (16.4) 18 (15.5) 2 (1 to 11) 51(44.0) 13(11.2) 7(6.0) 3(2.5) 3(2.5) 3(2.5) 4(3.4) 13(11.2) 5(4.3) 22(19.0) 38(32.8) 20(17.2) 32(27.6)
SD, standard deviation; IQR, interquartile range
Table II. Univariate analysis of risk factors of mortality with necrotising fasciitis of the upper extremities
Gender (male) Mean age (yrs) (SD) Performing surgery within 24 hours from admission Amputation Amputation at first surgical intervention Pre-operative comorbidities Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis SD,
Died
Survived
(n = 18)
(n = 98)
p-value
10 66.9 (16.6) 8 3 1
69 64.6 (14.7) 43 10 6
0.214 0.002 0.964 0.424 0.926
5 3 11 3 6 9
8 2 11 35 14 23
0.439 0.005 < 0.001 0.114 0.049 0.021
standard deviation; p values calculated using t-test (age) and chi squared test for other variables
Japanese language; procedures coded with the original Japanese codes; administered drugs; length of hospital stay and in-hospital deaths. The anonymous nature of the data meant that the requirement for informed consent could be waived. Study approval was obtained from our institutional review board. All patients with a NSTI, defined as an ICD-10 code of M72.6 (necrotising fasciitis of the upper extremities), were included. The following information was extracted from the DPC database: gender; age; primary diagnosis; preoperative comorbidities; surgical procedure (amputation or debridement); surgical site (shoulder, upper arm, elbow, forearm, wrist, or digit); the dates of admission and surgery; death in hospital; level of consciousness and coexisting sepsis. VOL. 96-B, No. 11, NOVEMBER 2014
Statistical analysis. We used chi-squared tests and t-tests as appropriate for univariate analyses to compare patient characteristics and outcomes between subgroups. Multivariable logistic regression analyses for patient characteristics were performed to adjust for concurrent effects of various factors on the occurrence of death in hospital or limb amputation. In the regressions, the occurrence of death in hospital was modelled as a function of old age and renal dysfunction. The occurrence of limb amputation was modelled as a function of sepsis and diabetes mellitus. The threshold for significance was a p-value < 0.05.
Results From the DPC database, a total of 2362 patients with a NSTI (ICD-10 code M72.6: necrotising fasciitis) were
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Table III. Adjusted risks of mortality with necrotising fasciitis of the upper extremities
Age ≤ 70 years Over 70 years Sepsis Renal dysfunction Liver dysfunction Altered consciousness
OR
95% CI
p-value
10 1.0 6.6 1.4 15.4 7.7 2.3
1.5 to 28.2 0.4 to 5.2 3.8 to 62.8 0.3 to 204.3 0.6 to 9.2
0.011 0.605 < 0.001 0.224 0.229
OR,odds ratio; CI, confidence interval Multivariate analysis
Table IV. Univariate analysis of risk factors of limb amputation with necrotising fasciitis of the upper extremities
Gender (males) Mean age (yrs) (SD) Performing surgery within 24 hrs after admission Pre-operative comorbidities Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis
Amputated
Salvaged
(n = 10)
(n = 88)
p-value
8 64.9 (16.7) 5
61 66.4 (16.4) 38
0.483 0.793 0.681
1 0 1 7 3 6
7 2 10 28 11 17
0.708 0.630 0.897 0.017 0.134 0.004
SD, standard deviation; p values calculated using t-test (age) and chi squared test for other variables
identified. From these, we isolated 116 patients who had undergone surgery for a NSTI of the upper limb. There were 79 men and 37 women with a mean age of 66.7 years (standard deviation (SD) 16.4) (Table I). Overall, 18 patients died in hospital, giving an overall in-hospital mortality of 15.5%, and 13 (11.2%) underwent amputation of the upper limb. The median timing of surgery was two days (interquartile range (IQR) 1 to11) after admission. The site of amputation was the shoulder, upper arm or digit in three patients (2.5%) each: data were not available for the other four patients (3.4%). In all, seven patients (6.0%) underwent amputation as a first surgical intervention. Univariate analysis for in-hospital mortality showed that these significant variables were age (p = 0.015, t-test); liver dysfunction (p = 0.005, chi-squared test); renal dysfunction (p < 0.001, chi-squared test); altered consciousness (p = 0.049, chi-squared test) and sepsis (p = 0.021, chisquared test) (Table II). Amputation as the first operation was not associated with any deaths (p = 0.983, chi-squared test), and this was not affected by whether the surgery was performed within one day of admission or later (p = 0.926, chi-squared test). The number of days after admission until surgery was not associated with mortality (p = 0.388, t-test). Logistic regression analysis showed that the factors that correlated with in-hospital mortality were those patients over
seventy years of age (Odds Ratio (OR), 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR, 15.4; 95% CI 3.8 to 62.8; p < 0.001) (Table III). Univariate analysis for limb amputation showed that the significant variables were diabetes mellitus (p = 0.017, chisquared test) and sepsis (p = 0.001, chi-squared test) (Table IV). Logistic regression analysis showed that the factors correlated with limb amputation were sepsis (OR, 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR, 1.6; 95% CI 1.1 to 21.1; p = 0.038) (Table V).
Discussion The main strength of our study is the use of a large administrative database. Nationwide inpatient databases such as the National Inpatient Sample and the DPC database have been increasingly used to assess trends and outcomes of various surgical procedures.11-18 By using these, researchers can easily survey rare diseases, such as NSTIs of the upper extremities. To our knowledge, our study population of 116 patients is the largest used to analyse the risk factors for death and amputation. Use of the large nationwide database allowed us to establish the rates of death in hospital and amputation while controlling for confounding variables. Numerous studies have examined the factors associated with increased mortality in NSTIs.1,4-9 Unfortunately, all of THE BONE & JOINT JOURNAL
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Table V. Adjusted risks of limb amputation with necrotising fasciitis of the upper extremities
Sepsis Diabetes mellitus
OR
95% CI
p-value
1.8 1.6
1.5 to 25.0 1.1 to 21.1
0.013 0.038
OR,odds ratio; CI, confidence interval Multivariate analysis
these were retrospective and many had small sample sizes and different patient populations. Furthermore, as the risk factors analysed in each study were so different, it is hard to compare them. There was, however, one predictor of mortality which was mentioned in several reports, the time from hospital admission to first surgical debridement.6-8 In a study of 65 patients with a NSTI (40% with lower and upper extremity infections), McHenry et al7 found that the mean time from admission to surgery was 90 hours (SD 95) for those who died in hospital from the condition and 25 hours (SD 39) for survivors. Wong et al8 showed that a delay of more than 24 hours from admission to surgery was the only independent predictor of mortality after adjusting for age, gender, diabetes mellitus, and hypotension. However, only nine of 89 cases were upper extremity infections. In a series reported by Elliott et al6 the mean time to first debridement was 1.2 days (standard error (SEM) 0.2) for survivors and 3.1 days (SEM 1.0) for non-survivors; in this series, only 11 of the 198 patients had a NSTI of the upper limb. Having reviewed these studies, Sunderland and Friedrich1 concluded that the first 24 hours may be the optimal window of opportunity for the successful surgical treatment of NSTIs. However, in findings similar to our own, Ogilivie and Miclau9 found no correlation between the number of days after admission until surgery and mortality. We assume that this difference arose from the distribution of the site of infection. Our study included only patients with a NSTI of the upper limb: 43% of the cohort reported by Ogilivie and Miclau9 had disease of the upper limb, which is a much higher figure than that of Elliott et al (5.6%)6 and Wong et al (10.1%),8 which may suggest that a NSTI of the upper limb is less aggressive than one that affects other anatomical regions. No patient who underwent amputation as their first surgical intervention died. However, we were unable to determine if any patients might have been spared immediate amputation and managed, at least initially, by debridement. Other previously reported risk factors for death from a NSTI of the upper extremity include: altered consciousness; respiratory disease; white blood cell count > 13 000 /mm3; creatinine > 2.0 mg/dl; heart disease; and clostridial infection.1 We found that altered consciousness, sepsis, liver dysfunction, renal dysfunction, and age were all risk factors for death. Altered consciousness or sepsis may reflect a more serious general condition. Liver dysfunction or renal dysfunction may be a reflection of an immune-compromised state. Anaya et al10 are the only group to have previously evaluated risk factors for upper limb amputation in NSTIs. A VOL. 96-B, No. 11, NOVEMBER 2014
retrospective review of 166 patients (58% of whom had an infection in the upper or lower limbs) was performed using data gathered on hospital admission. The patients were relatively young and healthy (mean age 45.6 years; SD 15.0; 69% without comorbidities), and the most common aetiology was intravenous drug abuse (29.5%). Independent risk factors for limb amputation were found to be clostridial infection, heart disease, and shock (systolic blood pressure < 90 mm Hg). Clostridial infection was more common in this series, and the infection associated with intravenous drug abuse. In our study, the risk factors for limb amputation were sepsis and diabetes mellitus. The limitations of the present study are those inherent to all administrative database studies. First, the DPC database does not provide important clinical data such as the results of laboratory tests, microbiological cultures, and imaging tests. The coding has not been directly validated against clinical data, and access to the patient’s medical records is not possible. Recorded diagnoses, including diagnosis of comorbidities, in the retrospective database were less well validated than those in prospective studies. Second, the sample collection in the DPC survey is not based on a random sampling method, and the patient distribution is somewhat biased to those in larger hospitals. Third, we did not include patients with NSTI of the upper extremities who were treated without surgery as we do not have detailed information about each of their situations. Despite these limitations, we believe that the use of this nationwide database enabled us to perform a quantitative study of this rare condition, and that our study contains information of clinical importance, which provides a basis for future research. In conclusion, with NSTIs of the upper extremities, advanced age and renal dysfunction were associated with higher rate of death in hospital. Sepsis and diabetes mellitus were associated with higher rate of limb amputation. This study was funded by a Grant-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan (Grant number: H25-Policy-010), and by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Council for Science and Technology Policy, Japan (Grant number: 0301002001001). No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by G. Scott and first proof edited by A. Ross.
References 1. Sunderland IR, Friedrich JB. Predictors of mortality and limb loss in necrotizing soft tissue infections of the upper extremity. J Hand Surg Am 2009;34:1900–1901. 2. Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J 1997;90:1065– 1068.
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3. Angoules AG, Kontakis G, Drakoulakis E, et al. Necrotising fasciitis of upper and lower limb: a systematic review. Injury 2007;38(Suppl5):S19–S26. 4. Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg 2007;119:1803–1807. 5. Liu YM, Chi CY, Ho MW, et al. Microbiology and factors affecting mortality in necrotizing fasciitis. J Microbiol Immunol Infect 2005;38:430–435. 6. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg 1996;224:672–683. 7. McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality for necrotizing soft-tissue infections. Ann Surg 1995;221:558–563. 8. Wong CH, Chang HC, Pasupathy S, et al. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg [Am] 2003;85A:1454–1460. 9. Ogilvie CM, Miclau T. Necrotizing soft tissue infections of the extremities and back. Clin Orthop Relat Res 2006;447:179–186. 10. Anaya DA, McMahon K, Nathens AB, et al. Predictors of mortality and limb loss in necrotizing soft tissue infections. Arch Surg 2005;140:151–157. 11. Kadono Y, Yasunaga H, Horiguchi H, et al. Statistics for orthopedic surgery 20062007: data from the Japanese Diagnosis Procedure Combination database. J Orthop Sci 2010;15:162–170.
12. Kuwabara K, Matsuda S, Imanaka Y, et al. Injury severity score, resource use, and outcome for trauma patients within a Japanese administrative database. J Trauma 2010;68:463–470. 13. Yasunaga H, Yanaihara H, Fuji K, et al. Impact of hospital volume on postoperative complications and in-hospital mortality after renal surgery: data from the Japanese Diagnosis Procedure Combination Database. Urology 2010;76:548–552. 14. No authors listed. World Health Organization: International Classification of Diseases (ICD) 2014 www.who.int/whosis/icd10/ (date last accessed 1 October 2014). 15. Boakye M, Patil CG, Santarelli J, et al. Cervical spondylotic myelopathy: complications and outcomes after spinal fusion. Neurosurgery 2008;62:455–461. 16. Deyo RA, Mirza SK, Martin BI, et al. Trends, major medical complications, and charges associated with surgery for lumbar spinal stenosis in older adults. JAMA 2010;303:1259–1265. 17. Shen Y, Silverstein JC, Roth S. In-hospital complications and mortality after elective spinal fusion surgery in the united states: a study of the nationwide inpatient sample from 2001 to 2005. J Neurosurg Anesthesiol 2009;21:21–30. 18. Patil CG, Lad SP, Santarelli J, Boakye M. National inpatient complications and outcomes after surgery for spinal metastasis from 1993-2002. Cancer 2007;110:625– 630.
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Necrotising soft-tissue infections of the upper limb RISK FACTORS FOR AMPUTATION AND DEATH K. Uehara, H. Yasunaga, Y. Morizaki, H. Horiguchi, K. Fushimi, S. Tanaka From Department of Orthopaedic Surgery, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan K. Uehara, MD, Orthopaedic Surgeon Y. Morizaki, MD, Assistant Professor S. Tanaka, MD, PhD, Professor Department of Orthopaedic Surgery, The University of Tokyo, Graduate School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan. H. Yasunaga, MD, PhD, Professor Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan. H. Horiguchi, PhD, Principal Researcher Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, 2-5-21 Higashigaoka, Meguro-ku, Tokyo, Japan. K. Fushimi, MD, PhD, Professor Department of Health Policy and Informatics, Tokyo Medical and Dental University Graduate School of Medicine 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan Correspondence should be sent to Dr Y. Morizaki; e-mail: [email protected] ©2014 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.96B11. 34888 $2.00 Bone Joint J 2014;96-B:1530–4. Received 4 August 2014; Accepted after revision 21 August 2014
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Necrotising soft-tissue infections (NSTIs) of the upper limb are uncommon, but potentially life-threatening. We used a national database to investigate the risk factors for amputation of the limb and death. We extracted data from the Japanese Diagnosis Procedure Combination database on 116 patients (79 men and 37 women) who had a NSTI of the upper extremity between 2007 and 2010. The overall in-hospital mortality was 15.5%. Univariate analysis of in-hospital mortality showed that the significant variables were age (p = 0.015), liver dysfunction (p = 0.005), renal dysfunction (P < 0.001), altered consciousness (p = 0.049), and sepsis (p = 0.021). Logistic regression analysis showed that the factors associated with death in hospital were age over 70 years (Odds Ratio (OR) 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR 15.4; 95% CI 3.8 to 62.8; p < 0.001). Univariate analysis of limb amputation showed that the significant variables were diabetes (p = 0.017) mellitus and sepsis (p = 0.001). Multivariable logistic regression analysis showed that the factors related to limb amputation were sepsis (OR 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR 1.6; 95% CI 1.1 to 21.1; p = 0.038). For NSTIs of the upper extremity, advanced age and renal dysfunction are both associated with a higher rate of in-hospital mortality. Sepsis and diabetes mellitus are both associated with a higher rate of amputation. Cite this article: Bone Joint J 2014;96-B:1530–4.
Necrotising soft-tissue infection (NSTI), classically called necrotising fasciitis, is a rapidly progressive, potentially fatal infectious disease which primarily involves fascia, muscle, skin, or subcutaneous fat.1 Between 500 and 1500 cases are reported in the United States each year:2 6% to 27% of these involve the upper limbs.3-5 Although rare, clinicians need to be aware of NSTIs, as they can easily result in amputation or death. Although many patients with a NSTI of the upper limb also have comorbidities such as diabetes mellitus, old age and renal dysfunction, little is known about the risk factors associated with amputation and death. Some studies have reported the incidence of death in hospital and amputation but they were mostly single institution case series.1,4-10 The purpose of this study was to identify the risk factors for amputation and death in patients with a NSTI of the upper limb.
Materials and Methods The Diagnosis Procedure Combination (DPC) database is a nationwide database in Japan
which consists of the discharge summary and administrative financial data.11-13 The DPC hospitals are surveyed between 1st July and 31st December each year by the DPC study group, in collaboration with the Japanese government. All 82 academic hospitals in Japan are obliged to participate in the DPC survey, whereas participation by community hospitals is voluntary. For this study, we used data obtained in this manner between 1st July and 31st December for the years 2007 to 2010, inclusive. During this period, data from about 11.6 million inpatients from approximately 900 hospitals were added to the database: this represents approximately 45% of all patients admitted to hospital in Japan. Researchers use the DPC database to identify, track, and analyse national trends in healthcare use, access, quality, outcomes, and costs. The database includes the following data: patients’ age and gender; diagnoses; comorbidities at admission, and complications after admission recorded according to the International Classification of Diseases, Tenth Revision (ICD-10)14 codes and text data in the THE BONE & JOINT JOURNAL
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Table I. Characteristics of the study population Total (n = 116) Gender (males) (%) Mean age (SD) (yrs) Number of deaths (%) Median timing of surgery after admission (IQR) (days) Days of surgery < 1 (%) Limb amputation (%) Amputation at first surgery (%) Site of amputation (%) Shoulder Upper arm Digit Not described Pre-operative comorbidities (%) Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis
79 (68.1) 66.7 (16.4) 18 (15.5) 2 (1 to 11) 51(44.0) 13(11.2) 7(6.0) 3(2.5) 3(2.5) 3(2.5) 4(3.4) 13(11.2) 5(4.3) 22(19.0) 38(32.8) 20(17.2) 32(27.6)
SD, standard deviation; IQR, interquartile range
Table II. Univariate analysis of risk factors of mortality with necrotising fasciitis of the upper extremities
Gender (male) Mean age (yrs) (SD) Performing surgery within 24 hours from admission Amputation Amputation at first surgical intervention Pre-operative comorbidities Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis SD,
Died
Survived
(n = 18)
(n = 98)
p-value
10 66.9 (16.6) 8 3 1
69 64.6 (14.7) 43 10 6
0.214 0.002 0.964 0.424 0.926
5 3 11 3 6 9
8 2 11 35 14 23
0.439 0.005 < 0.001 0.114 0.049 0.021
standard deviation; p values calculated using t-test (age) and chi squared test for other variables
Japanese language; procedures coded with the original Japanese codes; administered drugs; length of hospital stay and in-hospital deaths. The anonymous nature of the data meant that the requirement for informed consent could be waived. Study approval was obtained from our institutional review board. All patients with a NSTI, defined as an ICD-10 code of M72.6 (necrotising fasciitis of the upper extremities), were included. The following information was extracted from the DPC database: gender; age; primary diagnosis; preoperative comorbidities; surgical procedure (amputation or debridement); surgical site (shoulder, upper arm, elbow, forearm, wrist, or digit); the dates of admission and surgery; death in hospital; level of consciousness and coexisting sepsis. VOL. 96-B, No. 11, NOVEMBER 2014
Statistical analysis. We used chi-squared tests and t-tests as appropriate for univariate analyses to compare patient characteristics and outcomes between subgroups. Multivariable logistic regression analyses for patient characteristics were performed to adjust for concurrent effects of various factors on the occurrence of death in hospital or limb amputation. In the regressions, the occurrence of death in hospital was modelled as a function of old age and renal dysfunction. The occurrence of limb amputation was modelled as a function of sepsis and diabetes mellitus. The threshold for significance was a p-value < 0.05.
Results From the DPC database, a total of 2362 patients with a NSTI (ICD-10 code M72.6: necrotising fasciitis) were
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Table III. Adjusted risks of mortality with necrotising fasciitis of the upper extremities
Age ≤ 70 years Over 70 years Sepsis Renal dysfunction Liver dysfunction Altered consciousness
OR
95% CI
p-value
10 1.0 6.6 1.4 15.4 7.7 2.3
1.5 to 28.2 0.4 to 5.2 3.8 to 62.8 0.3 to 204.3 0.6 to 9.2
0.011 0.605 < 0.001 0.224 0.229
OR,odds ratio; CI, confidence interval Multivariate analysis
Table IV. Univariate analysis of risk factors of limb amputation with necrotising fasciitis of the upper extremities
Gender (males) Mean age (yrs) (SD) Performing surgery within 24 hrs after admission Pre-operative comorbidities Lung dysfunction Liver dysfunction Renal dysfunction Diabetes mellitus Altered consciousness Sepsis
Amputated
Salvaged
(n = 10)
(n = 88)
p-value
8 64.9 (16.7) 5
61 66.4 (16.4) 38
0.483 0.793 0.681
1 0 1 7 3 6
7 2 10 28 11 17
0.708 0.630 0.897 0.017 0.134 0.004
SD, standard deviation; p values calculated using t-test (age) and chi squared test for other variables
identified. From these, we isolated 116 patients who had undergone surgery for a NSTI of the upper limb. There were 79 men and 37 women with a mean age of 66.7 years (standard deviation (SD) 16.4) (Table I). Overall, 18 patients died in hospital, giving an overall in-hospital mortality of 15.5%, and 13 (11.2%) underwent amputation of the upper limb. The median timing of surgery was two days (interquartile range (IQR) 1 to11) after admission. The site of amputation was the shoulder, upper arm or digit in three patients (2.5%) each: data were not available for the other four patients (3.4%). In all, seven patients (6.0%) underwent amputation as a first surgical intervention. Univariate analysis for in-hospital mortality showed that these significant variables were age (p = 0.015, t-test); liver dysfunction (p = 0.005, chi-squared test); renal dysfunction (p < 0.001, chi-squared test); altered consciousness (p = 0.049, chi-squared test) and sepsis (p = 0.021, chisquared test) (Table II). Amputation as the first operation was not associated with any deaths (p = 0.983, chi-squared test), and this was not affected by whether the surgery was performed within one day of admission or later (p = 0.926, chi-squared test). The number of days after admission until surgery was not associated with mortality (p = 0.388, t-test). Logistic regression analysis showed that the factors that correlated with in-hospital mortality were those patients over
seventy years of age (Odds Ratio (OR), 6.6; 95% confidence interval (CI) 1.5 to 28.2; p = 0.011) and renal dysfunction (OR, 15.4; 95% CI 3.8 to 62.8; p < 0.001) (Table III). Univariate analysis for limb amputation showed that the significant variables were diabetes mellitus (p = 0.017, chisquared test) and sepsis (p = 0.001, chi-squared test) (Table IV). Logistic regression analysis showed that the factors correlated with limb amputation were sepsis (OR, 1.8; 95% CI 1.5 to 24.0; p = 0.013) and diabetes mellitus (OR, 1.6; 95% CI 1.1 to 21.1; p = 0.038) (Table V).
Discussion The main strength of our study is the use of a large administrative database. Nationwide inpatient databases such as the National Inpatient Sample and the DPC database have been increasingly used to assess trends and outcomes of various surgical procedures.11-18 By using these, researchers can easily survey rare diseases, such as NSTIs of the upper extremities. To our knowledge, our study population of 116 patients is the largest used to analyse the risk factors for death and amputation. Use of the large nationwide database allowed us to establish the rates of death in hospital and amputation while controlling for confounding variables. Numerous studies have examined the factors associated with increased mortality in NSTIs.1,4-9 Unfortunately, all of THE BONE & JOINT JOURNAL
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Table V. Adjusted risks of limb amputation with necrotising fasciitis of the upper extremities
Sepsis Diabetes mellitus
OR
95% CI
p-value
1.8 1.6
1.5 to 25.0 1.1 to 21.1
0.013 0.038
OR,odds ratio; CI, confidence interval Multivariate analysis
these were retrospective and many had small sample sizes and different patient populations. Furthermore, as the risk factors analysed in each study were so different, it is hard to compare them. There was, however, one predictor of mortality which was mentioned in several reports, the time from hospital admission to first surgical debridement.6-8 In a study of 65 patients with a NSTI (40% with lower and upper extremity infections), McHenry et al7 found that the mean time from admission to surgery was 90 hours (SD 95) for those who died in hospital from the condition and 25 hours (SD 39) for survivors. Wong et al8 showed that a delay of more than 24 hours from admission to surgery was the only independent predictor of mortality after adjusting for age, gender, diabetes mellitus, and hypotension. However, only nine of 89 cases were upper extremity infections. In a series reported by Elliott et al6 the mean time to first debridement was 1.2 days (standard error (SEM) 0.2) for survivors and 3.1 days (SEM 1.0) for non-survivors; in this series, only 11 of the 198 patients had a NSTI of the upper limb. Having reviewed these studies, Sunderland and Friedrich1 concluded that the first 24 hours may be the optimal window of opportunity for the successful surgical treatment of NSTIs. However, in findings similar to our own, Ogilivie and Miclau9 found no correlation between the number of days after admission until surgery and mortality. We assume that this difference arose from the distribution of the site of infection. Our study included only patients with a NSTI of the upper limb: 43% of the cohort reported by Ogilivie and Miclau9 had disease of the upper limb, which is a much higher figure than that of Elliott et al (5.6%)6 and Wong et al (10.1%),8 which may suggest that a NSTI of the upper limb is less aggressive than one that affects other anatomical regions. No patient who underwent amputation as their first surgical intervention died. However, we were unable to determine if any patients might have been spared immediate amputation and managed, at least initially, by debridement. Other previously reported risk factors for death from a NSTI of the upper extremity include: altered consciousness; respiratory disease; white blood cell count > 13 000 /mm3; creatinine > 2.0 mg/dl; heart disease; and clostridial infection.1 We found that altered consciousness, sepsis, liver dysfunction, renal dysfunction, and age were all risk factors for death. Altered consciousness or sepsis may reflect a more serious general condition. Liver dysfunction or renal dysfunction may be a reflection of an immune-compromised state. Anaya et al10 are the only group to have previously evaluated risk factors for upper limb amputation in NSTIs. A VOL. 96-B, No. 11, NOVEMBER 2014
retrospective review of 166 patients (58% of whom had an infection in the upper or lower limbs) was performed using data gathered on hospital admission. The patients were relatively young and healthy (mean age 45.6 years; SD 15.0; 69% without comorbidities), and the most common aetiology was intravenous drug abuse (29.5%). Independent risk factors for limb amputation were found to be clostridial infection, heart disease, and shock (systolic blood pressure < 90 mm Hg). Clostridial infection was more common in this series, and the infection associated with intravenous drug abuse. In our study, the risk factors for limb amputation were sepsis and diabetes mellitus. The limitations of the present study are those inherent to all administrative database studies. First, the DPC database does not provide important clinical data such as the results of laboratory tests, microbiological cultures, and imaging tests. The coding has not been directly validated against clinical data, and access to the patient’s medical records is not possible. Recorded diagnoses, including diagnosis of comorbidities, in the retrospective database were less well validated than those in prospective studies. Second, the sample collection in the DPC survey is not based on a random sampling method, and the patient distribution is somewhat biased to those in larger hospitals. Third, we did not include patients with NSTI of the upper extremities who were treated without surgery as we do not have detailed information about each of their situations. Despite these limitations, we believe that the use of this nationwide database enabled us to perform a quantitative study of this rare condition, and that our study contains information of clinical importance, which provides a basis for future research. In conclusion, with NSTIs of the upper extremities, advanced age and renal dysfunction were associated with higher rate of death in hospital. Sepsis and diabetes mellitus were associated with higher rate of limb amputation. This study was funded by a Grant-in-Aid for Research on Policy Planning and Evaluation from the Ministry of Health, Labour and Welfare, Japan (Grant number: H25-Policy-010), and by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST program) from the Council for Science and Technology Policy, Japan (Grant number: 0301002001001). No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by G. Scott and first proof edited by A. Ross.
References 1. Sunderland IR, Friedrich JB. Predictors of mortality and limb loss in necrotizing soft tissue infections of the upper extremity. J Hand Surg Am 2009;34:1900–1901. 2. Majeski J, Majeski E. Necrotizing fasciitis: improved survival with early recognition by tissue biopsy and aggressive surgical treatment. South Med J 1997;90:1065– 1068.
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K. UEHARA, H. YASUNAGA, Y. MORIZAKI, H. HORIGUCHI, K. FUSHIMI, S. TANAKA
3. Angoules AG, Kontakis G, Drakoulakis E, et al. Necrotising fasciitis of upper and lower limb: a systematic review. Injury 2007;38(Suppl5):S19–S26. 4. Golger A, Ching S, Goldsmith CH, Pennie RA, Bain JR. Mortality in patients with necrotizing fasciitis. Plast Reconstr Surg 2007;119:1803–1807. 5. Liu YM, Chi CY, Ho MW, et al. Microbiology and factors affecting mortality in necrotizing fasciitis. J Microbiol Immunol Infect 2005;38:430–435. 6. Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg 1996;224:672–683. 7. McHenry CR, Piotrowski JJ, Petrinic D, Malangoni MA. Determinants of mortality for necrotizing soft-tissue infections. Ann Surg 1995;221:558–563. 8. Wong CH, Chang HC, Pasupathy S, et al. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg [Am] 2003;85A:1454–1460. 9. Ogilvie CM, Miclau T. Necrotizing soft tissue infections of the extremities and back. Clin Orthop Relat Res 2006;447:179–186. 10. Anaya DA, McMahon K, Nathens AB, et al. Predictors of mortality and limb loss in necrotizing soft tissue infections. Arch Surg 2005;140:151–157. 11. Kadono Y, Yasunaga H, Horiguchi H, et al. Statistics for orthopedic surgery 20062007: data from the Japanese Diagnosis Procedure Combination database. J Orthop Sci 2010;15:162–170.
12. Kuwabara K, Matsuda S, Imanaka Y, et al. Injury severity score, resource use, and outcome for trauma patients within a Japanese administrative database. J Trauma 2010;68:463–470. 13. Yasunaga H, Yanaihara H, Fuji K, et al. Impact of hospital volume on postoperative complications and in-hospital mortality after renal surgery: data from the Japanese Diagnosis Procedure Combination Database. Urology 2010;76:548–552. 14. No authors listed. World Health Organization: International Classification of Diseases (ICD) 2014 www.who.int/whosis/icd10/ (date last accessed 1 October 2014). 15. Boakye M, Patil CG, Santarelli J, et al. Cervical spondylotic myelopathy: complications and outcomes after spinal fusion. Neurosurgery 2008;62:455–461. 16. Deyo RA, Mirza SK, Martin BI, et al. Trends, major medical complications, and charges associated with surgery for lumbar spinal stenosis in older adults. JAMA 2010;303:1259–1265. 17. Shen Y, Silverstein JC, Roth S. In-hospital complications and mortality after elective spinal fusion surgery in the united states: a study of the nationwide inpatient sample from 2001 to 2005. J Neurosurg Anesthesiol 2009;21:21–30. 18. Patil CG, Lad SP, Santarelli J, Boakye M. National inpatient complications and outcomes after surgery for spinal metastasis from 1993-2002. Cancer 2007;110:625– 630.
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