KYUSHU UNIVERSITY HOSPITAL (Fukuoka, Japan)

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1 Acute Medicine & Surgery 2016; 3: doi: /ams2.195 Original Article Sarcopenia is a predictive factor for prolonged intensive care unit stays in high-energy blunt trauma patients Tomohiko Akahoshi, 1,2 Mitsuhiro Yasuda, 1 Kenta Momii, 1 Kensuke Kubota, 1 Yuji Shono, 1 Noriyuki Kaku, 1 Kentaro Tokuda, 1 Takashi Nagata, 1,2 Tomoharu Yoshizumi, 3 Ken Shirabe, 3 Makoto Hashizume 2 and Yoshihiko Maehara 1,3 1 Emergency and Critical Care Center, 2 Disaster and Emergency Medicine, and 3 Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan Aim: Sarcopenia has been increasingly reported as a prognostic factor for outcome in settings such as cirrhosis, liver transplantation, and emergent surgery. We aimed to elucidate the significance of sarcopenia in severe blunt trauma patients. Methods: We retrospectively analyzed 84 patients emergently admitted to the intensive care unit at Kyushu University Hospital (Fukuoka, Japan) from May 2012 to April We assessed the amount of skeletal muscle present according to computed tomography and its relevance to ventilation-free days, patients length of stay in the intensive care unit, and 28-day mortality. Results: Twenty-five (29.7%) patients were defined as sarcopenic. Sixteen (19.7%) patients required 15 days or more in the intensive care unit. The major reason was a prolonged ventilation requirement due to flail chest (n = 7) or pneumonia (n = 3). Sarcopenic patients stays in intensive care were significantly longer than those of non-sarcopenic patients (18.7 versus 6.4 days, respectively; P < 0.001). Univariate and multivariate analyses showed sarcopenia to be a significant risk factor for prolonged intensive care unit stay. Conclusion: Sarcopenia is a risk factor that predicts prolonged intensive care unit stay in high-energy blunt trauma patients. Key words: High-energy blunt trauma, intensive care unit, muscle atrophy, sarcopenia INTRODUCTION SARCOPENIA, THE LOSS of skeletal muscle, has been advocated as a way of estimating the nutritional status of elderly patients over 65 years of age. 1 Sarcopenia has been increasingly reported to be relevant to mortality in patients with colorectal cancer, 2 those undergoing liver resection 3 and liver transplantation, 4 and even in middleaged patients younger than 65 years old. It has recently been reported that sarcopenia relates to mortality and critical care requirements in elderly patients. 5 However, no studies have assessed the influence of sarcopenia in adult high-energy trauma patients hospitalized in an intensive care unit (ICU). Recently, Yoshizumi et al. 7 examined skeletal muscle volume in healthy Japanese donors for liver transplantation. Corresponding: Tomohiko Akahoshi, MD, PhD, Department of Surgery and Science, Kyushu University, Maidashi, Higashiku, Fukuoka , Japan. tomohiko@surg2.med. kyushu-u.ac.jp. Received 6 Sep, 2015; accepted 8 Jan, 2016; online publication 2 May, 2016 These authors measured skeletal muscle volume at the L3 vertebral level and found that skeletal muscle volume significantly correlated with body surface area (BSA). Their formula for calculating skeletal muscle area using BSA should more accurately estimate the ideal skeletal muscle volume of individual patients. Therefore, our study aimed to elucidate the significance of sarcopenia in severe blunt trauma patients using that formula to predict the outcomes of high-energy blunt trauma patients in the ICU. METHODS KYUSHU UNIVERSITY HOSPITAL (Fukuoka, Japan) is an urban trauma center and treats patients with highenergy injuries. Approximately 250 trauma patients are transferred to our emergency department annually. Roughly 40% of these patients have an injury severity score (ISS) 9, and 96% represent blunt injury mechanisms. With the approval of our institutional review board, we retrospectively reviewed 85 trauma patients who were admitted to Kyushu University s ICU between April 2012 and December Patients were included if they were: (i) injured by 326

2 Acute Medicine & Surgery 2016; 3: Sarcopenia prolonged intensive care unit stays 327 a high-energy blunt mechanism; (ii) not dead on arrival; (iii) older than 20 years. The definition of a high-energy blunt mechanism was as follows: a high speed crash and/or highly damaged vehicle was involved, a fellow passenger died, the patient was ejected from a vehicle, the patient was run over or propelled >5 m by a motor vehicle, the patient was thrown a long distance from a motorcycle, the patient fell from >6 m, or the patient was caught in a machine. Among the 89 patients who fulfilled the above criteria, five patients were excluded. Three were excluded because of severe brain damage and two because of uncontrolled bleeding; these patients did not all receive aggressive care before ICU admission and were primarily observed until death in the ICU. The data for the remaining 84 patients were analyzed. This study was retrospectively carried out in accordance with the ethical guidelines of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. This study was carried out after approval from the ethical committee at Kyushu University. Criteria for admission to and discharge from ICU The criteria for admission to the ICU in cases of highenergy blunt trauma are: (i) disturbance of consciousness or coma; (ii) acute respiratory failure requiring mechanical ventilation support; (iii) shock or a hemodynamically unstable state requiring invasive monitoring and/or vasoactive drugs; (iv) severe metabolic disorder due to organ injury (including liver injury and renal injury). Criteria for leaving the ICU are that the patient no longer requires ventilation, continuous renal replacement therapy, invasive monitoring, and/or vasoactive drugs. The status of each patient was evaluated and judged by a lead doctor in the ICU. Physical characteristics and variables Demographic data obtained included age, sex, mechanism of injury, head, chest, and abdomen abbreviated Acute Injury Scale (AIS) score, ISS score, prognostic score, systolic blood pressure on admission (mmhg), height (m), weight (kg), length of hospital stay and ICU stay (days), number of days that mechanical ventilation was required, and 28-day mortality. Height (m) and weight (kg) were used to calculate body mass index (calculated as weight in kilograms divided by height in meters squared) and BSA (calculated according to the following formula: BSA ðm 2 Þ¼square root ðbw ðkgþ height ðcmþ=3; 600ÞÞ: Computed tomography analysis Computed tomography images were used to determine the quantity of skeletal muscle. The skeletal muscle cross-sectional area (cm 2 ) was manually measured at the caudal end of the third lumbar vertebra (Fig. 1). The following formulas were used for estimating skeletal muscle area: Male skeletal muscle area ðcm 2 Þ ¼ 126:9 BSA 66:2 Female skeletal muscle area ðcm 2 Þ ¼ 125:6 BSA 81:1 If the actual measured skeletal muscle area (SMA) was less than 80% of the estimated SMA, the patient was defined as sarcopenic. All computed tomography scanning was carried out in the emergency room within 1 h of patient arrival by ambulance. The muscle volume was measured using imaging software, the Synapse Vincent volume analyzer (Fujifilm, Tokyo, Japan), by an observer who was blinded to the outcome and disease severity. Statistics The patients were first divided into two groups according to whether they were sarcopenic. The groups were compared using Student s t-test or the v 2 -test depending on the nature of the parameter. As the study was retrospective, P-values <0.01 were considered statistically significant. The patients were then divided into two groups according to whether their ICU stay was or <15 days. These groups were compared by Student s t-test or v 2 -test, with P-values <0.01 considered to be statistically significant. Variables identified as significant were used in the subsequent univariate and multivariate logistic regression analyses. Data are expressed as mean SD. All statistical analyses were carried out with Stat-View version 5.0 software (Abacus Concepts; SAS Institute, Tokyo, Japan). RESULTS Stay in ICU was longer in sarcopenic patients TWENTY-FIVE (29.7%) OF the 84 patients were defined as sarcopenic. Table 1 shows the characteristics

3 328 T. Akahoshi et al. Acute Medicine & Surgery 2016; 3: (A) (B) Fig. 1. Representative computed tomography image used for measuring skeletal muscle area. The cross-sectional skeletal muscle area (in cm 2 ) was manually measured at the caudal end of the third lumbar vertebra. A, Images from a 50-year-old male non-sarcopenic patient with flail chest who stayed in the intensive care unit for 5 days. B, Images from a 45-year-old male sarcopenic patient with flail chest who stayed in the intensive care unit for 70 days. of the sarcopenic and non-sarcopenic groups. There were no significant differences between the groups in terms of sex, body mass index, age, injury mechanism, vital signs, radiographic assessment (AIS), Revised Trauma Score, or prognostic score. Notably, the ICU stays of the sarcopenic patients were significantly longer than those of the non-sarcopenic patients (18.7 versus 6.4 days, respectively; P < 0.001). The mean ICU stay and ventilationfree days of the sarcopenic patients were approximately three times longer than that of the non-sarcopenic patients. Except actual SMA, ICU stay, and ventilationfree days, no other parameters significantly differed between sarcopenic and non-sarcopenic patients (Table 2). Table 3 shows clinical parameters at admission in the sarcopenic and non-sarcopenic patients, none of which significantly differed between the groups. Comparison between patients with ICU stays and <15 days Sixteen (19.7%) patients required 15 days in the ICU. Skeletal muscle area was significantly less and the rates of sarcopenia and chest AIS > 3 were significantly higher in these patients relative to those with ICU stays <15 days (Table 4). Major reason for prolonged ICU stay was a requirement for ventilation The reason for prolonged ICU stay ( 15 days) was determined by clinical record review. Thirteen of the 16 patients with ICU stays 15 days were sarcopenic. Prolonged ventilation was required because of flail chest in seven patients and pneumonia in five patients. Two patients required continuous hemodiafiltration. Two non-sarcopenic patients had prolonged ICU stays because of repeated damage control surgeries. Sarcopenia is a significant risk factor predicting prolonged ICU stays of 15 days in high-energy blunt trauma patients Univariate analysis showed only sarcopenia to be a significant risk factor for ICU stays 15 days (odd rate, 14.46; 95% confidence interval, ; P < ). Supposed risk factors, such as ISS, age, and chest AIS > 3 were not found to be significant in this analysis (Table 5). After controlling for age and sex, a multiple logistic regression model showed sarcopenia to be the only significant risk factor for predicting an ICU stay 15 days (odd risk, 19.89; 95% confidence interval, ; P < 0.001) (Table 6).

4 Acute Medicine & Surgery 2016; 3: Sarcopenia prolonged intensive care unit stays 329 Table 1. Comparison of clinical characteristics between sarcopenic and non-sarcopenic high-energy blunt trauma patients at Kyushu University Hospital (n = 84) Sarcopenic Non-sarcopenic P-value No. of patients Age, years 56.7 (18.4) 43.2 (14.2) n.s. Sex Male, n n.s. Female, n Height, m 1.59 (0.09) 1.62 (0.23) n.s. Weight, kg 57.3 (11.6) 56.2 (11.2) n.s. Body mass index 22.2 (3.6) 21.6 (3.2) n.s. BSA, m (0.20) 1.58 (0.19) n.s. Actual skeletal muscle area, cm (31.8) (30.1) < Estimated skeletal muscle area, cm (32.4) (27.4) n.s. Injury mechanism Traffic accident n.s. Fall from a height 5 4 Vital signs on arrival SBP, mmhg 121 (33) 138 (41) n.s. HR, mmhg 91 (22) 84 (25) n.s. GCS 11.5 (2.6) 12.3 (2.0) n.s. Radiographic assessment Head AIS 5 6 n.s. Chest AIS n.s. Abdomen AIS 8 18 n.s. Pelvic AIS 9 30 n.s. ISS 30.4 (22.4) 22.9 (15.4) n.s. RTS 6.8 (1.3) 7.0 (1.2) n.s. Ps 0.69 (0.33) 0.76 (0.29) n.s. ECOG PS 0/1 25/1 58/1 n.s AIS, abbreviated injury score; BSA, body surface area; ECOG, Eastern Cooperative Oncology Group; GCS, Glasgow Coma Scale; HR, heart rate; ICU, intensive care unit; ISS, injury severity score; n.s., not significant; Ps, probability of survival; PS, performance status; RTS, revised trauma score; SBP, systolic blood pressure. Bold values were significant difference. DISCUSSION HIGH ENERGY BLUNT TRAUMA is inevitable in urbanized areas. Because ICU care is very expensive in most countries, the length of patients ICU stay is very important for economic reasons in addition to its impact on prognosis. Three patients died in our ICU during the study period: one had diffuse axonal injury and two had traumatic subarachnoid hemorrhage. Except for these patients with unrecoverable brain injuries, no eligible patients died during their ICU stays throughout the study period. Because mortality comprised such a small number, it was not statistically analyzed. Rather, we assessed the ICU stay length. Japanese health insurance supports most of the cost for ICU stays up to 14 days, so we selected 15 days in the ICU as the cutoff for our analysis. Most research looking at prognosis following highenergy blunt trauma has identified severity score, gastrointestinal bleeding, high APACHE score, and low Glasgow Coma Scale score as risk factors. 8,9 Recently, a number of scoring systems have been developed to evaluate patients prognosis following blunt thoracic trauma; these include the Thoracic Trauma Score, Pulmonary Contusion Score, and Wagner Score, which are considered to be independent indicators of prognosis that consider mortality and morbidity following blunt thoracic trauma. 10,11 Age 65 years has been described as a major predictor of mortality and the need for ventilation. 10,12 However, no published reports have investigated the influence of sarcopenic status on blunt thoracic trauma patients. Sarcopenia may serve as a predictive factor in addition to the previously mentioned scores.

5 330 T. Akahoshi et al. Acute Medicine & Surgery 2016; 3: Table 2. Clinical results of traumatic patients with sarcopenic or non-sarcopenic state Sarcopenic Non-sarcopenic P-value Length of ICU <0.01 stay, days Ventilationfree <0.01 days Hospital stay, days day mortality ICU, intensive care unit. Table 3. Laboratory data of sarcopenic and non-sarcopenic patients at admission to intensive care unit (n = 84) Sarcopenic (n = 25) Non-sarcopenic (n = 59) P-value ph (0.126) (0.063) n.s. Lactate, mg/dl 20.5 (11.0) 17.5 (8.0) n.s. Hemoglobin, 11.7 (2.5) 12.5 (1.7) n.s. g/dl WBC, /ll (6.840) (4.011) n.s. Platelets, (69.1) (62.1) n.s /ll Total protein, 7.0 (0.73) 7.1 (0.70) n.s. mg/dl Albumin, g/dl 3.43 (0.78) 3.78 (0.60) n.s. Creatine, mg/dl 1.24 (1.36) 0.84 (0.19) n.s. PT-INR 1.24 (1.19) 1.08 (0.11) n.s. CRP, mg/dl 0.24 (0.37) 0.11 (0.17) n.s. CRP, C-reactive protein; n.s., not significant; PT-INR, prothrombin time international normalized ratio; WBC, white blood cell count. Recently, the skeletal muscle index (cm 2 /m 2 ) at the L3 vertebral level has been the primary measure used for assessing patients and predicting various clinical outcomes. Moisey et al. 5 defined values of 38.9 cm 2 /m 2 for women and 55.4 cm 2 /m 2 for men as indicative of sarcopenia, whereas Du et al. 6 used values of 38.5 cm 2 /m 2 for women and 52.4 cm 2 /m 2 for men. However, 73% (73/100) 5 and 71% (106/149) 6 of patients, respectively, were defined as sarcopenic in these studies. According to these criteria, 55 of 78 (71%) patients in our study would have been diagnosed as sarcopenic, even younger patients aged years. It is possible that the cut-offs used for defining sarcopenia in studies from North American and European countries are not suitable in other countries. Alternatively, measurement Table 4. Comparison of clinical characteristics between patients with intensive care unit (ICU) stays and <15 days (n = 81) ICU stay 15 days <15 days P-value No. of patients Age, years 45.8 (20.9) 45.7 (16.4) n.s. Sex, n Male 8 37 n.s. Female 8 28 Body mass index 20.6 (3.1) 21.9 (4.0) n.s. SMA, cm 2 /m (28.3) (37.6) < Sarcopenia, n (%) 13 (81.3) 11 (16.9) < Radiographic assessment Head AIS 2 10 n.s. Chest AIS < Abdomen AIS 5 18 n.s. Pelvic AIS 8 27 n.s. ISS 29.1 (23.2) 22.3 (16.2) n.s. RTS 6.3 (1.6) 7.2 (0.9) n.s. Ps 0.68 (0.33) 0.78 (0.28) n.s. AIS, abbreviated injury score; BSA, body surface area; ISS, injury severity score; n.s., not significant; Ps, probability of survival; RTS, revised trauma score; SMA, skeletal muscle area. Table 5. Univariate analysis of risk factors for intensive care unit stays 15 days in high-energy blunt trauma patients (n = 81) OR 95% CI P-value Sex Age BMI Sarcopenia < ISS Chest AIS > AIS, abbreviated injury score; BMI, body mass index; CI, confidence interval; OR, odd rate; ISS, injury severity score. of the psoas muscle has been used for assessing sarcopenia in cirrhotic Japanese patients. However, Yoshizumi et al. 7 showed that the psoas muscle did not reflect the total amount of skeletal muscle in some patients. Therefore, we chose a BSA-based formula for estimating total skeletal muscle area

6 Acute Medicine & Surgery 2016; 3: Sarcopenia prolonged intensive care unit stays 331 Table 6. Multiple logistic regression model of factors predicting an intensive care unit stay 15 days after controlling for age and sex at the L3 vertebra by computed tomography. 7 According to this methodology, close to 30% of the study patients were sarcopenic. Our methodology may be superior to the other available methods in identifying sarcopenic patients at risk for prolonged ICU stays. In our study, the most frequent disease that prolonged ICU stays was flail chest. For patients to recover from flail chest, bone and muscle healing is necessary. It is logical that sarcopenic patients with muscle atrophy are less able to recover from such injuries. Other studies have reported that early operative rib fracture fixation reduces comorbidities, hospital stays, and medical costs in flail chest patients. 13,14 In particular, sarcopenic patients with flail chest may require early surgical intervention, and early surgical fixation may reduce the need for mechanical ventilation in these patients. Therefore, we now intend to carry out early surgical fixation in sarcopenic patients when possible. In conclusion, sarcopenia is a risk factor that predicts prolonged ICU stays in high-energy blunt trauma patients. Because sarcopenic patients with severe chest injuries tend to remain in the ICU for long periods, more attention should be paid to providing intensive care for these patients. CONFLICT OF INTEREST N ONE. REFERENCES OR 95% CI P-value Sarcopenia < Chest AIS > AIS, abbreviated injury score; CI, confidence interval; OR, odd rate. 1 Fearon KC. Cancer cachexia and fat-muscle physiology. N. Engl. J. Med. 2011; 365: Miyamoto Y, Baba Y, Sakamoto Y et al. Sarcopenia is a negative prognostic factor after curative resection of colorectal cancer. Ann. Surg. Oncol. 2015; 22: Harimoto N, Shirabe K, Yamashita YI et al. Sarcopenia as a predictor of prognosis in patients following hepatectomy for hepatocellular carcinoma. Br. J. Surg. 2013; 100: Masuda T, Shirabe K, Ikegami T et al. Sarcopenia is a prognostic factor in living donor liver transplantation. Liver Transpl. 2014; 20: Moisey LL, Mourtzakis M, Cotton BA et al. Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU patients. Nutrition and Rehabilitation Investigators Consortium (NUTRIC). Crit. Care 2013; 17: R Du Y, Karvellas CJ, Baracos V, Williams DC, Khadaroo RG. Sarcopenia is a predictor of outcomes in very elderly patients undergoing emergency surgery. Surgery 2014; 156: Yoshizumi T, Shirabe K, Nakagawara H et al. Skeletal muscle area correlates with body surface area in healthy adults. Hepatol. Res. 2014; 44: Chiarchiaro J, Buddadhumaruk P, Arnold RM, White DB. Quality of communication in the ICU and surrogate s understanding of prognosis. Crit. Care Med. 2015; 43: Almahmoud K, Namas RA, Abdul-Malak O et al. Impact of injury severity on dynamic inflammation networks following blunt trauma. Shock 2015; 22: Pape HC, Remmers D, Rice J, Ebisch M, Krettek C, Tscherne H. Appraisal of early evaluation of blunt chest trauma: development of a standardized scoring system for initial clinical decision making. J. Trauma 2000; 49: Mommsen P, Zeckey C, Andruszkow H et al. Comparison of different thoracic trauma scoring systems in regards to prediction of post-traumatic complications and outcome in blunt chest trauma. J. Surg. Res. 2012; 176: Huber S, Biberthaler P, Delhey P et al. Predictors of poor outcomes after significant chest trauma in multiply injured patients: a retrospective analysis from the German Trauma Registry (Trauma Register DGU â ). Trauma Register DGU. Scand. J. Trauma Resusc. Emerg. Med. 2014; 22: Slobogean GP, MacPherson CA, Sun T, Pelletier ME, Hameed SM. Surgical fixation vs nonoperative management of flail chest: a meta-analysis. J. Am. Coll. Surg. 2013; 216: Bhatnagar A, Mayberry J, Nirula R. Rib fracture fixation for flail chest: what is the benefit? J. Am. Coll. Surg. 2012; 215: