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Gait Speed and Grip Strength Are Associated With Dropping Out of the Liver Transplant Waiting List
Gait Speed and Grip Strength Are Associated With Dropping Out of the Liver Transplant Waiting List S.S. Kulkarnia,*, H. Chenb, D.A. Josbenoc, A. Schmotzera, C. Hughesd, A. Humard, P. Soode, V. Rachakondab, M.A. Dunnb, and A.D. Tevard a Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; bDepartment of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; cDepartment of Physical Therapy, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; dStarzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania; and eDepartment of Medicine and Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
ABSTRACT Introduction. Frailty measures can predict perioperative surgical risk in liver transplant patients. The 5-meter walk test (5MWT) and hand grip strength (HGS) are easy and reproducible frailty measures. We hypothesized that they could capture frailty in liver transplant listed patients and would be associated with dropping out of the waiting list. Methods. We conducted a retrospective analysis of patients undergoing outpatient liver transplant listing at the University of Pittsburgh Medical Center from 2013 to 2016. We compared demographics, baseline laboratory markers, 5MWT, and HGS between patients who were dropped from the waiting list for medical reasons and those who remained or were successfully transplanted. Bivariate statistical analysis was performed using Fisher exact or c2 tests. Results. We reviewed 197 patients listed for liver transplant. Average age was 57.1 years (range 20e74), and patients were predominantly white (90.4%). Patients’ most common etiology of liver disease was hepatitis C (32.5%), 14 (7.1%) had a previous liver transplant, and average Model for End-Stage Liver Disease score upon listing was 16.0. Of the cohort, 38 (19.3%) were ultimately dropped from the waitlist due to nonehepatocellular carcinomaerelated reasons. Patients dropped from the waiting list had weaker HGS (46.14 lb vs 59.6 lb; P < .005) and slower 5MWT speed (5MWT: 0.92 m/s vs 1.03 m/s; P < .005). Conclusion. The 5MWT and HGS can easily measure frailty in patients being evaluated for liver transplant. These tests are associated with waiting list dropout, indicating that they can be valuable tools in the evaluation of these patients.
F
RAILTY is becoming increasingly recognized as an important predictor of perioperative risk and mortality in a variety of surgical fields. Although difficult to define, frailty is characterized by a lack of physiologic reserve to compensate for a significant systemic insult. Frail patients, usually the elderly and/or those with multiple comorbidities, are at an increased risk of postoperative morbidity, mortality, and the need for long-term or permanent nursing home care [1]. In liver transplant, frailty has been associated with increased post-transplant outcomes as well as worse patient-reported quality of life [2e4]. Furthermore, frailty has been associated with poor liver transplant waiting list performance. ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e4 (2019)
Multiple studies have demonstrated that hepatocellular carcinoma (HCC) progression is an important and common cause of dropping out of the liver transplant waitlist. However, up to 20% of patients on the waiting list are delisted for other medical reasons, many of which are associated with higher frailty [5]. The majority of these patients (over 80%) have at least 1 liver offered for transplantation before
*Address correspondence to Shreyus S. Kulkarni, University of Pittsburgh, Presbyterian Hospital, 200 Lothrop St. F677, Pittsburgh, PA 15222. Tel: (443) 474-8783. E-mail: kulkarniss@upmc. edu 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.030
1
2
delisting, but do not undergo transplantation for a number of reasons [6]. Identification of these frail and vulnerable patients would create opportunities to design waiting list interventions to enhance functional status, physiologic reserve, and the likelihood of undergoing a liver transplant. However, identifying these patients can be challenging. Liver transplant patient frailty has been measured in a variety of ways, including radiographic sarcopenia and frailty surveys such as the Fried Frailty criteria [3e5]. More recently, performance-based measures have been shown to identify frailty in liver transplant patients; these offer the advantage of being accurate and reproducible in the outpatient setting. The 5-meter walk test (5MWT), which is a test of patients’ self-selected gait speed, and hand grip strength (HGS) are 2 outpatient tests that have been shown to measure performance status as well as predict perioperative mortality and long-term survival [7,8]. These tests are becoming increasingly utilized in many surgical fields, most notably in cardiac surgery, where the 5MWT is recommended as part of routine preoperative risk assessment [9,10]. The 5MWT and HGS offer the advantages of being quick, reproducible, and easily conducted by any healthcare team member. We routinely conduct the 5MWT and HGS on all of the patients who present to our center for outpatient liver transplant evaluation. In this study, we hypothesized that these tests would be associated with frailty and the likelihood of dropping out of the liver transplant waiting list.
METHODS AND MATERIALS Sample Selection We conducted a retrospective review at the University of Pittsburgh Medical Center’s Starzl Transplant Institute of patients who were evaluated on an outpatient basis and successfully listed for liver transplant between July 2013 and July 2016. We excluded those patients who were ultimately dropped from the waiting list due to progression of their HCC outside of the Milan criteria.
Variables Data were collected from the Center’s transplant registry exclusively by clinical members of the transplant team. Data collection variables consisted of patient demographics, etiology of liver disease, liver function tests, Model for End-Stage Liver Disease (MELD) score, presence of HCC, 5MWT speed, HGS in pounds, and reason for delisting if removed from the waiting list. A medical assistant in the transplant clinic conducted the 5MWT and HGS for all patients. A length of 5 meters was marked in a hallway, and patients were timed walking from one end to the other. Times were measured 3 times and averaged to calculate a gait speed in meters per second (m/s). They were given a sufficient rest between passes. Patients who used a walker, cane, and so on were allowed to use these during the test. HGS was measured using a commerciallyavailable dynamometer. HGS was measured in the patients’ dominant hand three times and averaged. It should be noted that none of the patients in the study underwent any interventions such as exercise programs while on the waitlist.
KULKARNI, CHEN, JOSBENO ET AL
Delisting Process At our center, the evaluation and identification of patients with worsening debility to the point that liver transplant would be contraindicated is an important and difficult aspect of their care. Patients with a significant degree of disability or high MELD are seen routinely in a waitlist clinic. Those patients who experience significant deterioration in their condition have their cases reviewed by a multi-disciplinary team of transplant hepatologists and surgeons. If both the medical and surgical teams feel that the patient’s condition has deteriorated to the point that liver transplant would be contraindicated, they are moved to an inactive status on the waiting list. If the patient is unable to improve their condition, they are removed from the waitlist. This formal process involves written notification and discussion with patient. In the event that the patient’s condition improves, they can be relisted. This is done after repeat evaluation and presentation at a multidisciplinary liver transplant selection committee meeting.
Statistical Analysis We calculated means from the raw data and made comparisons between patients that were delisted versus patients that remained on the waitlist or were transplanted using Fisher exact or c2 tests as appropriate. We considered P values of less than .05 to be statistically significant. All data were analyzed using Stata 14 (StataCorp, College Station, TX, United States).
RESULTS
From July 2013 to July of 2016, we identified 197 patients who were evaluated as outpatients and successfully listed for liver transplant. The patients had an average age of 57.1 years (range 20 to 74) and were predominantly white (90.4%). Hepatitis C was the most common etiology of liver disease. Sixty-four (32.5%) patients had a diagnosis of HCC, 14 (7.1%) patients had a previous liver transplant, and the average MELD score upon listing was 16.0. Of the 197 patients, 38 (19.3%) were ultimately dropped from the waitlist due to non-HCC related reasons. Their reasons for delisting are depicted below in Figure 1, with the most common reasons being complications of sepsis (53%) and hemorrhage (18%). The others either underwent a liver transplant or remained listed at the time of the conclusion of data review. The 2 groups were largely similar in terms of comorbidities, 1 1 1 2 3% 3% 3% 5% Sepsis
2 5%
Bleeding Failure to Thrive
2 5%
Pancreatitis
2 5%
20 53%
Drug Relapse Renal Failure New Malignancy Respiratory Failure
7 18%
Stroke
Fig 1. Etiology of complications leading to waiting list dropout.
LIVER TRANSPLANT WAITING LIST DROPOUTS
3
but those patients who were dropped from the waiting list had a lower prevalence of HCC (11% vs 38%, P < .005) and a higher average baseline MELD score (19.1 vs 15.3, P < .005). HGS upon initial listing was associated with dropping out of the waitlist (46.14 lbs vs 59.6 lbs; P < .005), as was 5MWT speed upon initial listing (0.92 m/s vs 1.03 m/s; P < .005). These and further data are enumerated in Table 1.
DISCUSSION
In this study, we have shown that the 5MWT and HGS can indicate frailty in liver transplant patients. In our study, 19% of the patients were ultimately delisted due to medical reasons, which is in line with previously published reports. Those patients had significantly slower gait speed and weaker HGS compared to those who were not delisted, indicating a higher degree of frailty. Frailty has been associated with poor waiting list performance in prior studies. As stated earlier, roughly 20% of patients are delisted due to non-HCC related reasons [5]. Furthermore, frailty predicts poor overall waiting list quality of life and medical status. Our group previously showed that frailty, specifically a slower 5MWT, is associated with a longer hospital stays while on the waiting list [11]. This corroborates our finding of increased waitlist dropout amongst those patients with slower gait speed and weaker HGS. Our data showed that the 2 groups of patients were largely similar except for frailty scores. In this study, patients who were delisted due to progression of their HCC were excluded. We believe that this is appropriate in the study of frailty and waiting list performance, as these patients’ delisting is a function of their aggressive tumor biology as opposed to frailty. In fact, we found that that in our study, the delisted patients were even less likely to have HCC. They had a higher average MELD score upon listing, and one could argue that delisting was a function of worse underlying liver disease and associated medical complications. Table 1. Comparison of Patients Transplanted or Remaining on Waiting List vs Waiting List Dropouts
Age (years) Dialysis (yes) Prior liver transplant (yes) BMI (kg/m2) GFR (mL/min) Ascites (yes) Albumin (g/dL) Serum Na (mEq/L) HCC (yes) MELD 5MWT (m/s) HGS (lb)
On Waiting List (159)
Waiting List Dropouts (38)
P Values
56.7 7 (4.4%) 11 (6.9%)
58.8 0 (0%) 3 (7.9%)
.23 .19 .83
29.3 65.7 13 (8.2%) 3.2 134.2 60 (37.7%) 15.3 1.03 59.60
29.5 65.0 3 (7.9%) 2.9 132.3 4 (10.5%) 19.1 0.92 46.14
.79 .92 .95 <.005 .01 <.005 <.005 <.005 <.005
Abbreviations: 5MWT, 5-meter walk test; BMI, body mass index; GFR, glomerular filtration rate; HCC, hepatocellular carcinoma; HGS, hand grip strength; MELD, Model for End-Stage Liver Disease.
Yet, it has previously been shown that frailty predicts waiting list mortality, post-transplant mortality, and quality of life independent of liver dysfunction [2,5,12]. Liver dysfunction, as measured by MELD score, can modulate other estimates of frailty, but this modulation is often inconsistent and unreliable. For example, several studies have shown that patients with a higher body mass index (BMI) have worse outcomes after liver transplant. However, a 2015 study by Bambha et al showed that, in fact, patients with a BMI and lower MELD had higher post-transplant mortality and graft loss [13]. It should be additionally noted that in our study, even BMI was not significantly associated with waiting list dropout. Thus, liver dysfunction may modulate some measures of frailty, but a MELD score in and of itself is not always the best indicator of liver transplant patient outcomes or waiting list performance. These are better predicted by true frailty measures. In essence, frailty is best measured by tests that are designed to specifically measure frailty. As we have seen, there are number of ways to measure frailty, such as Fried Frailty criteria or surveys of activities of daily living. However, these can be unpredictable. Provider assessments and patient assessments of physical performance do not reliably indicate patients’ actual performance status [14]. The same is true of radiographic measures of sarcopenia. Many studies have found an association between sarcopenia and frailty. However, measurements of sarcopenia are limited by differing measurement methodology and a lack of consensus definitions for frailty thresholds [15]. Furthermore, in liver transplants sarcopenia has been shown to be inferior to gait speed in measuring functional capacity, quality of life, and waiting list mortality [16]. Performance-based measures such as gait speed are the most reliable means of assessing frailty, and priority should be given to tests that can be easily conducted and performed in the clinic [17]. Both the 5MWT and HGS can be easily conducted in the outpatient setting and are highly reproducible. They can be realistically completed in just a few minutes per patient with minimal interruption to a clinic schedule. The 5MWT and HGS are less time-consuming and less burdensome to the patient than other performance-based frailty measures such as the 6-minute walk test or chair stands. They are therefore easily implemented and incorporated into the standard liver transplant outpatient evaluation. Our data is limited due to its retrospective nature. We were able to identify increased frailty by retrospectively studying patients who were or were not delisted. However, we did not prospectively follow patients based on their gait speed and HGS to assess these tests’ predictive capabilities. Furthermore, we did not measure the ability of these tests to prognosticate morbidity and mortality after liver transplantation. Our focus in this study was solely to determine the association of the 5MWT and HGS with waiting list dropout. As of yet, we have not developed formal cutoff values for these tests, per se, to guide listing. An average 13 lbs. HGS difference between delisted and listed patients is
4
significant; however, more testing needs to be done to assess the 0.11 m/s difference in 5MWT speed. While this was statistically significant, its clinical significance has yet to be determined. This small difference may make frailty stratification by gait speed challenging. A great deal of further work needs to be done to characterize the true predictive and prognosticative capabilities of these tests. However, we anticipate that eventually it will be possible to incorporate them explicitly into a comprehensive transplant evaluation to identify patients who may benefit from successful completion of a pre-habilitation program prior to listing. CONCLUSIONS
The 5MWT and HGS are easily conducted outpatient tests that can indicate a higher likelihood of liver transplant waitlist dropout. Not only do these tests offer liver transplant programs the opportunity to identify a subset of vulnerable end-stage liver patients, they also allow for the identification of patients who might benefit from focused intervention programs. By using these quick and reliable performance-based frailty measures, we can better identify which patients who might benefit from pre-habilitation to improve their performance status and ultimately improve their chances of undergoing a successful liver transplant. REFERENCES [1] Patridge JS, Harari D, Dhesi JK. Frailly in the older surgical patient: a review. Age Ageing 2012;41:142e7. [2] Derck JE, Thelen AE, Cron DC, Friedman JF, Gerebics AD, Englesbe MJ, et al. Quality of life in liver transplant candidates: frailty is a better indicator than severity of liver disease. Transplantation 2015;99:340e4. [3] Underwood PW, Cron DC, Terjimanian MN, Wang SC, Englesbe MJ, Waits SA. Sarcopenia and failure to rescue following liver transplantation. Clin Transplant 2015;29:1076e80. [4] Englesbe MJ, Patel SP, He K, Lynch RJ, Schaubel DE, Harbaugh C, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg 2010;211:271e8.
KULKARNI, CHEN, JOSBENO ET AL [5] Lai JC, Feng S, Terrault NA, Lizaola B, Hayssen H, Covinsky K. Frailty predicts waitlist mortality in liver transplant candidates. Am J Transplant 2014;14:1870e9. [6] Lai JC, Feng S, Roberts JP. An examination of liver offers to candidates on the liver transplant wait-list. Gastroenterology 2012;143:1261e5. [7] Schaubert KL, Bohannon TW. Reliability and validity of three strength measures obtained from community-dwelling elderly persons. J Strength Cond Res 2005;19:717e20. [8] Kim HJ, Park I, Lee HJ, Lee O. The reliability and validity of gait speed with different walking pace and distances against general health, physical function, and chronic disease in aged adults. J Exerc Nutrition Biochem 2016;20:46e50. [9] Shih T, Paone G, Theurer PF, McDonald D, Shahian DM, Prager RL. The Society of Thoracic Surgeons adult cardiac surgery database version 2.73: more is better. Ann Thorac Surg 2015;100: 516e21. [10] Afilalo J, Kim S, O’Brien S, Brennan JM, Edwards FH, Mack MJ, et al. Gait speed and operative mortality in older adults following cardiac surgery. JAMA Cardiol 2016;1:314e21. [11] Dunn MA, Josbeno DA, Tevar AD, Rachakonda V, Ganesh SR, Schmotzer AR, et al. Frailty as tested by gait speed is an independent risk factor for cirrhosis complications that require hospitalization. Am J Gastroenterol 2016;111:1768e75. [12] Dolgin NH, Martins PN, Movahedi B, Lapane KL, Anderson FA, Bozorgzadeh A. Functional status predicts postoperative mortality after liver transplantation. Clin Transplant 2016;30:1403e10. [13] Bambha KM, Dodge JL, Gralia J, Sprague D, Biggins SW. Low, rather than high, body mass index confers increased risk for post-liver transplant death and graft loss: risk modulated by model for end-stage liver disease. Liver Transpl 2015;21:1286e94. [14] Dunn MA, Josbeno DA, Schmotzer AR, Tevar AD, DiMartini AF, Landsittel DP, et al. The gap between clinically assessed physical performance and objective physical activity in liver transplant candidates. Liver Transpl 2016;22:1324e32. [15] Kallwitz ER. Sarcopenia and liver transplant: the relevance of too little muscle mass. World J Gastroenterol 2015;21:10982e93. [16] Yadav A, Chang YH, Carpenter S, Silva AC, Rakela J, Agel BA, et al. Relationship between sarcopenia, six-minute walk distance and health-related quality of life in liver transplant candidates. Clin Transplant 2015;29:134e41. [17] Lai JC, Volk ML, Strasburg D, Alexander N. Performancebased measures associate with frailty in patients with end-stage liver disease. Transplantation 2016;100:2656e60.
ABSTRACT Introduction. Frailty measures can predict perioperative surgical risk in liver transplant patients. The 5-meter walk test (5MWT) and hand grip strength (HGS) are easy and reproducible frailty measures. We hypothesized that they could capture frailty in liver transplant listed patients and would be associated with dropping out of the waiting list. Methods. We conducted a retrospective analysis of patients undergoing outpatient liver transplant listing at the University of Pittsburgh Medical Center from 2013 to 2016. We compared demographics, baseline laboratory markers, 5MWT, and HGS between patients who were dropped from the waiting list for medical reasons and those who remained or were successfully transplanted. Bivariate statistical analysis was performed using Fisher exact or c2 tests. Results. We reviewed 197 patients listed for liver transplant. Average age was 57.1 years (range 20e74), and patients were predominantly white (90.4%). Patients’ most common etiology of liver disease was hepatitis C (32.5%), 14 (7.1%) had a previous liver transplant, and average Model for End-Stage Liver Disease score upon listing was 16.0. Of the cohort, 38 (19.3%) were ultimately dropped from the waitlist due to nonehepatocellular carcinomaerelated reasons. Patients dropped from the waiting list had weaker HGS (46.14 lb vs 59.6 lb; P < .005) and slower 5MWT speed (5MWT: 0.92 m/s vs 1.03 m/s; P < .005). Conclusion. The 5MWT and HGS can easily measure frailty in patients being evaluated for liver transplant. These tests are associated with waiting list dropout, indicating that they can be valuable tools in the evaluation of these patients.
F
RAILTY is becoming increasingly recognized as an important predictor of perioperative risk and mortality in a variety of surgical fields. Although difficult to define, frailty is characterized by a lack of physiologic reserve to compensate for a significant systemic insult. Frail patients, usually the elderly and/or those with multiple comorbidities, are at an increased risk of postoperative morbidity, mortality, and the need for long-term or permanent nursing home care [1]. In liver transplant, frailty has been associated with increased post-transplant outcomes as well as worse patient-reported quality of life [2e4]. Furthermore, frailty has been associated with poor liver transplant waiting list performance. ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e4 (2019)
Multiple studies have demonstrated that hepatocellular carcinoma (HCC) progression is an important and common cause of dropping out of the liver transplant waitlist. However, up to 20% of patients on the waiting list are delisted for other medical reasons, many of which are associated with higher frailty [5]. The majority of these patients (over 80%) have at least 1 liver offered for transplantation before
*Address correspondence to Shreyus S. Kulkarni, University of Pittsburgh, Presbyterian Hospital, 200 Lothrop St. F677, Pittsburgh, PA 15222. Tel: (443) 474-8783. E-mail: kulkarniss@upmc. edu 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.030
1
2
delisting, but do not undergo transplantation for a number of reasons [6]. Identification of these frail and vulnerable patients would create opportunities to design waiting list interventions to enhance functional status, physiologic reserve, and the likelihood of undergoing a liver transplant. However, identifying these patients can be challenging. Liver transplant patient frailty has been measured in a variety of ways, including radiographic sarcopenia and frailty surveys such as the Fried Frailty criteria [3e5]. More recently, performance-based measures have been shown to identify frailty in liver transplant patients; these offer the advantage of being accurate and reproducible in the outpatient setting. The 5-meter walk test (5MWT), which is a test of patients’ self-selected gait speed, and hand grip strength (HGS) are 2 outpatient tests that have been shown to measure performance status as well as predict perioperative mortality and long-term survival [7,8]. These tests are becoming increasingly utilized in many surgical fields, most notably in cardiac surgery, where the 5MWT is recommended as part of routine preoperative risk assessment [9,10]. The 5MWT and HGS offer the advantages of being quick, reproducible, and easily conducted by any healthcare team member. We routinely conduct the 5MWT and HGS on all of the patients who present to our center for outpatient liver transplant evaluation. In this study, we hypothesized that these tests would be associated with frailty and the likelihood of dropping out of the liver transplant waiting list.
METHODS AND MATERIALS Sample Selection We conducted a retrospective review at the University of Pittsburgh Medical Center’s Starzl Transplant Institute of patients who were evaluated on an outpatient basis and successfully listed for liver transplant between July 2013 and July 2016. We excluded those patients who were ultimately dropped from the waiting list due to progression of their HCC outside of the Milan criteria.
Variables Data were collected from the Center’s transplant registry exclusively by clinical members of the transplant team. Data collection variables consisted of patient demographics, etiology of liver disease, liver function tests, Model for End-Stage Liver Disease (MELD) score, presence of HCC, 5MWT speed, HGS in pounds, and reason for delisting if removed from the waiting list. A medical assistant in the transplant clinic conducted the 5MWT and HGS for all patients. A length of 5 meters was marked in a hallway, and patients were timed walking from one end to the other. Times were measured 3 times and averaged to calculate a gait speed in meters per second (m/s). They were given a sufficient rest between passes. Patients who used a walker, cane, and so on were allowed to use these during the test. HGS was measured using a commerciallyavailable dynamometer. HGS was measured in the patients’ dominant hand three times and averaged. It should be noted that none of the patients in the study underwent any interventions such as exercise programs while on the waitlist.
KULKARNI, CHEN, JOSBENO ET AL
Delisting Process At our center, the evaluation and identification of patients with worsening debility to the point that liver transplant would be contraindicated is an important and difficult aspect of their care. Patients with a significant degree of disability or high MELD are seen routinely in a waitlist clinic. Those patients who experience significant deterioration in their condition have their cases reviewed by a multi-disciplinary team of transplant hepatologists and surgeons. If both the medical and surgical teams feel that the patient’s condition has deteriorated to the point that liver transplant would be contraindicated, they are moved to an inactive status on the waiting list. If the patient is unable to improve their condition, they are removed from the waitlist. This formal process involves written notification and discussion with patient. In the event that the patient’s condition improves, they can be relisted. This is done after repeat evaluation and presentation at a multidisciplinary liver transplant selection committee meeting.
Statistical Analysis We calculated means from the raw data and made comparisons between patients that were delisted versus patients that remained on the waitlist or were transplanted using Fisher exact or c2 tests as appropriate. We considered P values of less than .05 to be statistically significant. All data were analyzed using Stata 14 (StataCorp, College Station, TX, United States).
RESULTS
From July 2013 to July of 2016, we identified 197 patients who were evaluated as outpatients and successfully listed for liver transplant. The patients had an average age of 57.1 years (range 20 to 74) and were predominantly white (90.4%). Hepatitis C was the most common etiology of liver disease. Sixty-four (32.5%) patients had a diagnosis of HCC, 14 (7.1%) patients had a previous liver transplant, and the average MELD score upon listing was 16.0. Of the 197 patients, 38 (19.3%) were ultimately dropped from the waitlist due to non-HCC related reasons. Their reasons for delisting are depicted below in Figure 1, with the most common reasons being complications of sepsis (53%) and hemorrhage (18%). The others either underwent a liver transplant or remained listed at the time of the conclusion of data review. The 2 groups were largely similar in terms of comorbidities, 1 1 1 2 3% 3% 3% 5% Sepsis
2 5%
Bleeding Failure to Thrive
2 5%
Pancreatitis
2 5%
20 53%
Drug Relapse Renal Failure New Malignancy Respiratory Failure
7 18%
Stroke
Fig 1. Etiology of complications leading to waiting list dropout.
LIVER TRANSPLANT WAITING LIST DROPOUTS
3
but those patients who were dropped from the waiting list had a lower prevalence of HCC (11% vs 38%, P < .005) and a higher average baseline MELD score (19.1 vs 15.3, P < .005). HGS upon initial listing was associated with dropping out of the waitlist (46.14 lbs vs 59.6 lbs; P < .005), as was 5MWT speed upon initial listing (0.92 m/s vs 1.03 m/s; P < .005). These and further data are enumerated in Table 1.
DISCUSSION
In this study, we have shown that the 5MWT and HGS can indicate frailty in liver transplant patients. In our study, 19% of the patients were ultimately delisted due to medical reasons, which is in line with previously published reports. Those patients had significantly slower gait speed and weaker HGS compared to those who were not delisted, indicating a higher degree of frailty. Frailty has been associated with poor waiting list performance in prior studies. As stated earlier, roughly 20% of patients are delisted due to non-HCC related reasons [5]. Furthermore, frailty predicts poor overall waiting list quality of life and medical status. Our group previously showed that frailty, specifically a slower 5MWT, is associated with a longer hospital stays while on the waiting list [11]. This corroborates our finding of increased waitlist dropout amongst those patients with slower gait speed and weaker HGS. Our data showed that the 2 groups of patients were largely similar except for frailty scores. In this study, patients who were delisted due to progression of their HCC were excluded. We believe that this is appropriate in the study of frailty and waiting list performance, as these patients’ delisting is a function of their aggressive tumor biology as opposed to frailty. In fact, we found that that in our study, the delisted patients were even less likely to have HCC. They had a higher average MELD score upon listing, and one could argue that delisting was a function of worse underlying liver disease and associated medical complications. Table 1. Comparison of Patients Transplanted or Remaining on Waiting List vs Waiting List Dropouts
Age (years) Dialysis (yes) Prior liver transplant (yes) BMI (kg/m2) GFR (mL/min) Ascites (yes) Albumin (g/dL) Serum Na (mEq/L) HCC (yes) MELD 5MWT (m/s) HGS (lb)
On Waiting List (159)
Waiting List Dropouts (38)
P Values
56.7 7 (4.4%) 11 (6.9%)
58.8 0 (0%) 3 (7.9%)
.23 .19 .83
29.3 65.7 13 (8.2%) 3.2 134.2 60 (37.7%) 15.3 1.03 59.60
29.5 65.0 3 (7.9%) 2.9 132.3 4 (10.5%) 19.1 0.92 46.14
.79 .92 .95 <.005 .01 <.005 <.005 <.005 <.005
Abbreviations: 5MWT, 5-meter walk test; BMI, body mass index; GFR, glomerular filtration rate; HCC, hepatocellular carcinoma; HGS, hand grip strength; MELD, Model for End-Stage Liver Disease.
Yet, it has previously been shown that frailty predicts waiting list mortality, post-transplant mortality, and quality of life independent of liver dysfunction [2,5,12]. Liver dysfunction, as measured by MELD score, can modulate other estimates of frailty, but this modulation is often inconsistent and unreliable. For example, several studies have shown that patients with a higher body mass index (BMI) have worse outcomes after liver transplant. However, a 2015 study by Bambha et al showed that, in fact, patients with a BMI and lower MELD had higher post-transplant mortality and graft loss [13]. It should be additionally noted that in our study, even BMI was not significantly associated with waiting list dropout. Thus, liver dysfunction may modulate some measures of frailty, but a MELD score in and of itself is not always the best indicator of liver transplant patient outcomes or waiting list performance. These are better predicted by true frailty measures. In essence, frailty is best measured by tests that are designed to specifically measure frailty. As we have seen, there are number of ways to measure frailty, such as Fried Frailty criteria or surveys of activities of daily living. However, these can be unpredictable. Provider assessments and patient assessments of physical performance do not reliably indicate patients’ actual performance status [14]. The same is true of radiographic measures of sarcopenia. Many studies have found an association between sarcopenia and frailty. However, measurements of sarcopenia are limited by differing measurement methodology and a lack of consensus definitions for frailty thresholds [15]. Furthermore, in liver transplants sarcopenia has been shown to be inferior to gait speed in measuring functional capacity, quality of life, and waiting list mortality [16]. Performance-based measures such as gait speed are the most reliable means of assessing frailty, and priority should be given to tests that can be easily conducted and performed in the clinic [17]. Both the 5MWT and HGS can be easily conducted in the outpatient setting and are highly reproducible. They can be realistically completed in just a few minutes per patient with minimal interruption to a clinic schedule. The 5MWT and HGS are less time-consuming and less burdensome to the patient than other performance-based frailty measures such as the 6-minute walk test or chair stands. They are therefore easily implemented and incorporated into the standard liver transplant outpatient evaluation. Our data is limited due to its retrospective nature. We were able to identify increased frailty by retrospectively studying patients who were or were not delisted. However, we did not prospectively follow patients based on their gait speed and HGS to assess these tests’ predictive capabilities. Furthermore, we did not measure the ability of these tests to prognosticate morbidity and mortality after liver transplantation. Our focus in this study was solely to determine the association of the 5MWT and HGS with waiting list dropout. As of yet, we have not developed formal cutoff values for these tests, per se, to guide listing. An average 13 lbs. HGS difference between delisted and listed patients is
4
significant; however, more testing needs to be done to assess the 0.11 m/s difference in 5MWT speed. While this was statistically significant, its clinical significance has yet to be determined. This small difference may make frailty stratification by gait speed challenging. A great deal of further work needs to be done to characterize the true predictive and prognosticative capabilities of these tests. However, we anticipate that eventually it will be possible to incorporate them explicitly into a comprehensive transplant evaluation to identify patients who may benefit from successful completion of a pre-habilitation program prior to listing. CONCLUSIONS
The 5MWT and HGS are easily conducted outpatient tests that can indicate a higher likelihood of liver transplant waitlist dropout. Not only do these tests offer liver transplant programs the opportunity to identify a subset of vulnerable end-stage liver patients, they also allow for the identification of patients who might benefit from focused intervention programs. By using these quick and reliable performance-based frailty measures, we can better identify which patients who might benefit from pre-habilitation to improve their performance status and ultimately improve their chances of undergoing a successful liver transplant. REFERENCES [1] Patridge JS, Harari D, Dhesi JK. Frailly in the older surgical patient: a review. Age Ageing 2012;41:142e7. [2] Derck JE, Thelen AE, Cron DC, Friedman JF, Gerebics AD, Englesbe MJ, et al. Quality of life in liver transplant candidates: frailty is a better indicator than severity of liver disease. Transplantation 2015;99:340e4. [3] Underwood PW, Cron DC, Terjimanian MN, Wang SC, Englesbe MJ, Waits SA. Sarcopenia and failure to rescue following liver transplantation. Clin Transplant 2015;29:1076e80. [4] Englesbe MJ, Patel SP, He K, Lynch RJ, Schaubel DE, Harbaugh C, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg 2010;211:271e8.
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