Jeon S, Lim DG, Kim H, You SB, Kim HJ, Yoon JP, Yang K, Park SJ, Ri HS. Relevant clinical factors for early extubation in living-donor liver transplantation: A single-center retrospective cohort study. World J Clin Cases 2025; 13(14): 102693 [DOI: 10.12998/wjcc.v13.i14.102693]
Corresponding Author of This Article
Hyun-Su Ri, Assistant Professor, MD, PhD, Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, No. 807 Hoguk-ro, Daegu 41944, South Korea. johnri@naver.com
Research Domain of This Article
Anesthesiology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Soeun Jeon, Department of Anesthesia and Pain Medicine, Kyungpook National University Chilgok Hospital, Daegu 41404, South Korea
Dong Gun Lim, Hyunjee Kim, Hyun-Su Ri, Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, Daegu 41944, South Korea
Seung-Bin You, Hyun-Su Ri, Department of Anesthesiology and Pain Medicine, Kyungpook National University Hospital, Daegu 41944, South Korea
Hye-Jin Kim, Jung-Pil Yoon, Department of Anesthesia and Pain Medicine, Pusan National University Yangsan Hospital, Yangsan 50612, South Korea
Jung-Pil Yoon, Department of Anesthesia and Pain Medicine, Pusan National University, School of Medicine, Yangsan 50612, South Korea
Kwangho Yang, Department of Surgery, Pusan National University Yangsan Hospital, Yangsan 50612, South Korea
Kwangho Yang, Department of Surgery, Pusan National University, College of Medicine, Yangsan 50612, South Korea
Soon-Ji Park, Department of Anesthesia and Pain Medicine, Daedong Hospital, Busan 47737, South Korea
Author contributions: Jeon S and Ri HS contributed to the conceptualization of the manuscript, data collection, statistical analysis, original draft writing, and revising the manuscript; Lim DG, Kim HJ, You SB, and Yang K contributed to the analysis of the data, critical review of the manuscript for important intellectual content, and manuscript editing; Kim HJ, Yoon JP, Park SJ, and Ri HS were responsible for data collection and figure creation; Jeon S, Lim DG, Kim H, You SB, Kim HJ, Yoon JP, Yang K, Park SJ, and Ri HS critically reviewed and provided final approval of the manuscript; and all authors were responsible for the decision to submit the manuscript for publication.
Institutional review board statement: This study was approved by the Pusan National University Yangsan Hospital, approval No. 05-2021-196.
Informed consent statement: The informed consent was waived by the Institutional Review Board.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The data that support the findings of this study are available from the corresponding author, upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hyun-Su Ri, Assistant Professor, MD, PhD, Department of Anesthesiology and Pain Medicine, School of Medicine, Kyungpook National University, No. 807 Hoguk-ro, Daegu 41944, South Korea. johnri@naver.com
Received: October 27, 2024 Revised: December 20, 2024 Accepted: January 3, 2025 Published online: May 16, 2025 Processing time: 81 Days and 14.3 Hours
Abstract
BACKGROUND
Clinical guidelines for early extubation after liver transplantation remain lacking, with significant variations in the rates of early extubation across transplantation centers.
AIM
To identify clinical factors, including the use of epidural analgesia, associated with early extubation in living-donor liver transplantation (LDLT).
METHODS
The medical records of LDLT recipients were analyzed in this study, categorizing them based on extubation timing as delayed (leaving the operating room without extubation) or early (tracheal tube removed immediately after surgery). A multivariate binary logistic regression analysis was performed. Subgroup analysis was conducted, excluding patients contraindicated for epidural analgesia owing to significant coagulopathy.
RESULTS
Total of 159 patients, 93 (58.5%) underwent early extubation. Relevant clinical factors of early extubation were shorter anhepatic time [adjusted odds ratio (OR) = 0.439, 95% confidence interval (CI): 0.232-0.831; P = 0.011], absence of high-dose vasoactive drug use at the end of surgery (OR = 0.235, 95%CI: 0.106-0.519; P < 0.001), and the use of epidural analgesia (OR = 15.730, 95%CI: 1.919-128.919; P = 0.010). In a subgroup analysis of 67 patients, epidural analgesia remained a relevant clinical factor for early extubation (adjusted OR = 19.381, 95%CI: 2.15-174.433; P = 0.008).
CONCLUSION
Shorter anhepatic time, absence of high-dose vasoactive drug use at the end of surgery, and the use of epidural analgesia are relevant clinical factors of early extubation following LDLT.
Core Tip: This study identifies three relevant clinical factors of early extubation after living-donor liver transplantation (LDLT): Shorter anhepatic time, absence of high-dose vasoactive drugs at the end of surgery, and the use of epidural analgesia. These findings suggest that epidural analgesia may hold promise as a component of enhanced recovery protocols for patients undergoing LDLT. However, further research is needed to confirm safety across various coagulation profiles and to evaluate its broader impact on postoperative outcomes comprehensively.
Citation: Jeon S, Lim DG, Kim H, You SB, Kim HJ, Yoon JP, Yang K, Park SJ, Ri HS. Relevant clinical factors for early extubation in living-donor liver transplantation: A single-center retrospective cohort study. World J Clin Cases 2025; 13(14): 102693
Although enhanced recovery after surgery (ERAS) protocols became essential in the 2000s, their application in liver transplantation remains limited due to the complexity and high-risk nature of the procedure and associated anesthetic management[1]. Recent advancements in surgical and anesthetic techniques, however, have sparked increased interest in incorporating ERAS protocols into liver transplantation to improve perioperative outcomes[1]. A critical component of these protocols, early extubation, is defined as either the immediate removal of the endotracheal tube after surgery or, more broadly, extubation within the first few postoperative hours[2]. This approach, implemented in liver transplantation since the 1990s, aims to enhance postoperative recovery[2]. Early extubation has been shown to decrease postoperative pulmonary complications, reduce sedative and opioid use, and improve liver graft function by enhancing hepatosplanchnic circulation. Furthermore, it is associated with shorter hospital and intensive care unit (ICU) stays, as well as reduced healthcare costs[2,3].
Despite these benefits, early extubation carries potential risks, including increased respiratory effort, aspiration pneumonia, and the possibility of reintubation[4,5]. These risks underscore the importance of meticulous patient selection to ensure both safety and efficacy[4,5]. However, the absence of consensus clinical guidelines for early extubation following liver transplantation, combined with significant variability in extubation practices across transplant centers, highlights the need for further research and standardization[2]. Therefore, this retrospective cohort study aims to identify clinical factors associated with early extubation following living-donor liver transplantation (LDLT). Furthermore, as secondary outcomes, the study investigates the potential relationship between epidural analgesia and early extubation after LDLT.
MATERIALS AND METHODS
Study design and participants
The institutional review board of Pusan National University Yangsan Hospital approved this retrospective cohort study as exempt, approval No. 05-2021-196. The study included recipients of LDLT performed between January 2013 and December 2019 at the same institution. Patients were excluded if they had duplicated data, were < 18 years old, required preoperative ventilator support, underwent liver retransplantation, had planned postoperative ventilator care due to impaired oxygenation [baseline partial pressure of arterial oxygen (PaO2) to fractional inspired oxygen fraction (FiO2) ratio (PaO2/FiO2 ratio) ≤ 200 mmHg)], or had > 10% missing data.
Anesthetic management
Experienced transplant anesthesiologists and surgeons consistently performed anesthesia and surgery. In the operating room, monitoring followed American Society of Anesthesiologists (ASA) standards[6], with additional measures including bispectral index, train-of-four, inferior vena cava and femoral arterial pressure, and advanced hemodynamic monitoring using a PreSep central venous catheter and the EV1000 platform (Edwards Lifesciences, Irvine, CA, United States).
The selection of anesthetic agents and techniques was left to the discretion of the attending anesthesiologists but followed the hospital’s established guidelines. The hospital’s guidelines for contraindications to epidural analgesia aligned with general recommendations, including patients who declined the procedure, had thoracolumbar vertebral abnormalities, elevated intracranial pressure, infection at the epidural puncture site, hemodynamic instability, or significant coagulopathy, defined as a prothrombin time-international normalized ratio (PT-INR) > 1.5 or platelets < 70 × 103/μL[7,8]. Additionally, if needle placement in the epidural space was unsuccessful after three attempts, the procedure was discontinued. None of the patients included in this study had elevated intracranial pressure or active infections. However, given the high prevalence of coagulopathy among candidates for liver transplantation, a subgroup analysis was conducted to address potential bias related to the use of epidural analgesia. This subgroup analysis excluded patients with significant coagulopathy, as defined above, who were ineligible for epidural analgesia.
For patients who underwent epidural analgesia, the epidural catheter was placed in the lower thoracic epidural space (T6-8) based on the surgical incision site before the induction of general anesthesia. As a component of preemptive analgesia, local anesthetics (4-6 mL of 0.2% ropivacaine or 0.25% levobupivacaine) and a supplemental opioid (50 µg of fentanyl) were epidurally administered. The loading dose was completed within 30 minutes of anesthesia induction, with no further epidural medication being administered during the main surgical procedure. Approximately 30 minutes before surgery completion, epidural analgesia was resumed using patient-controlled analgesia (drug concentration: 0.2% ropivacaine or 0.25% levobupivacaine and fentanyl 0.5 µg/mL; program: Background infusion 1 mL/hour, bolus 3 mL, and 30-minute lockout interval).
Anesthesia was induced intravenously with propofol (1-2 mg/kg) and muscle relaxants (cisatracurium: 0.1-0.2 mg/kg or rocuronium: 0.6-1 mg/kg). The maintenance involved continuous inhalation of desflurane and intermittent boluses of nondepolarizing muscle relaxants (cisatracurium or rocuronium). Remifentanil was intravenously administered for analgesia during anesthesia induction and maintenance. Hemodynamic parameters were managed intraoperatively to maintain a mean blood pressure of ≥ 60 mmHg and oxygen saturation ≥ 94%. Intraoperative red blood cell (RBC) transfusions were performed with hemoglobin ≥ 7 g/dL as the target. Additionally, fresh frozen plasmas (FFPs) and fibrinogen were administered based on thromboelastography results.
Extubation criteria in the operating room
Early extubation was defined as the removal of the tracheal tube in the operating room immediately after surgery. In contrast, delayed extubation referred to the patient leaving the operating room with the tracheal tube still in place. The timing of extubation was determined by the attending anesthesiologist in consultation with the transplant surgical team, based on the following established extubation criteria post-surgery[9,10]: (1) Alertness and cooperation; (2) Absence of apnea; (3) Adequate oxygenation: PaO2/FiO2 ≥ 150 mmHg; (4) Adequate ventilation: Tidal volume 5 mL/kg, respiratory rate ≤ 30 breaths/minute, and end-tidal carbon dioxide < 45 mmHg; (5) Full neuromuscular recovery: Sustained head lift and train-of-four > 0.9 at the adductor pollicis muscle; (6) Stable hemodynamics with minimal or no vasopressor support; (7) Body temperature ≥ 35°C; and (8) No signs of early surgical complications. All patients were transferred to the ICU for postoperative care.
Data collection
The following data were extracted from electronic medical records: (1) Baseline patient characteristics - age, sex, ASA classification, height, weight, causes of liver disease, model for end-stage liver disease (MELD) score, functional capacity, left ventricular ejection fraction, pulmonary artery pressure, comorbidities, and West-Haven criteria for hepatic encephalopathy[11,12]; (2) Baseline laboratory findings, such as PaO2/FiO2 ratio, hemoglobin, platelets, PT-INR, activated partial thromboplastin time (aPTT), ammonia, bilirubin, albumin, glucose, and creatinine (PaO2/FiO2 ratio was measured immediately after intubation. Conversely, other baseline laboratory data were obtained from the most recent measurements before operating room entry); (3) Baseline systolic pressure (SBP) and mean blood pressure and heart rate (HR); (4) Intraoperative data - surgery type (emergency or elective), operation time, anhepatic time, hourly estimated blood loss (EBL), hourly urine output, hourly fluid or blood product administration, and presence of epidural analgesia; (5) Occurrence of postreperfusion syndrome: Defined as a > 30% reduction in mean arterial pressure from baseline lasting at least 1 minute, during the first 5 min minutes after the liver graft reperfusion[13]; (6) Laboratory findings at the end of surgery (ES) - PaO2/FiO2 ratio, lactate, and glucose; (7) Vital signs at the ES - SBP, HR, central venous pressure (CVP), and body temperature; and (8) High-dose vasoactive drug at the ES: Defined as ≥ 0.1 µg/kg/minute of norepinephrine-equivalent dose to maintain the target blood pressure.
Statistical analysis
All analyses were conducted using IBM SPSS Statistics (version 25; IBM Corporation, Armonk, NY, United States) and MedCalc® (version 18.11.6; MedCalc Software Ltd., Ostend, Belgium). Continuous variables are expressed as mean ± SD or as median and interquartile range (Q1, Q3). Categorical variables are expressed as absolute counts and percentages. The results of binary logistic regression analyses were expressed as adjusted odds ratio (OR) with a 95% confidence interval (CI). Patients were categorized based on the timing of extubation (delayed vs early). Normally distributed and nonparametric data were analyzed using independent t-test and Mann-Whitney U test, respectively. Categorical data were evaluated using the χ2 test (applying Yates’ continuity correction for the 2 × 2 contingency tables) or Fisher’s exact test.
For the multivariate binary logistic regression analysis, preoperative and intraoperative variables (Tables 1 and 2) were included as candidate predictors. To address multicollinearity among candidate predictors, a single predictor was selected for inclusion in the multivariate analysis when correlations existed. The selections were as follows: Body mass index was chosen over height, weight, malnutrition, and obesity; MELD score over ASA physical status and preoperative PT-INR, aPTT, platelets, bilirubin, and albumin; preoperative delirium over West-Haven criteria for encephalopathy; baseline SBP over baseline HR; anhepatic phase duration over operation time; hourly total blood product administration over CVP at the ES, hourly EBL, packed RBCs, platelets, and FFPs; and high-dose vasoactive drugs at the ES over SBP and HR at the ES.
Table 1 Comparison of preoperative characteristics between the delayed and early extubation group, n (%).
Variables
Whole group (n = 159)
Subgroup (n = 67)
Delayed extubation (n = 66)
Early extubation (n = 93)
P value
Delayed extubation (n = 20)
Early extubation (n = 47)
P value
Age (year)
53.4 (8.2)
54.9 (7.5)
0.246
55.1 (7.1)
55.0 (8.2)
0.965
Sex (male)
49 (74.2)
70 (75.3)
> 0.999
16 (80.0)
39 (83.0)
0.741
ASA
-
-
0.163
-
-
0.527
II
18 (27.3)
14 (15.1)
-
7 (35.0)
12 (25.5)
-
III
39 (59.1)
65 (69.9)
-
12 (60.0)
29 (61.7)
-
IV
9 (13.6)
14 (15.1)
-
1 (5.0)
6 (12.8)
-
Height (cm)
165.9 (8.2)
165.5 (7.9)
0.755
166.4 (8.9)
165.7 (7.3)
0.752
Weight (kg)
64.7 (12.5)
63.3 (10.5)
0.439
66.1 (11.0)
64.4 (9.1)
0.499
BMI (kg/m2)
23.4 (3.4)
23.0 (2.7)
0.430
23.8 (3.0)
23.4 (2.4)
0.528
Malnutrition (BMI < 18.5)
5 (7.6)
8 (8.6)
> 0.999
0 (0.0)
2 (4.3)
> 0.999
Obesity (BMI > 30)
3 (4.5)
1 (1.1)
0.308
1 (5.0)
1 (2.1)
0.511
Etiology
Viral
43 (65.2)
71 (76.3)
0.172
13 (65.0)
39 (83.0)
0.121
Alcoholic
20 (30.3)
19 (20.4)
0.215
4 (20.0)
6 (12.8)
0.470
Malignancy
40 (60.6)
59 (63.4)
0.844
16 (80.0)
35 (74.5)
0.760
Autoimmune
1 (1.5)
1 (1.1)
> 0.999
1 (5.0)
0 (0.0)
0.299
Others
4 (6.1)
5 (5.4)
> 0.999
1 (5.0)
2 (4.3)
> 0.999
MELD score
15.0 (7.0-23.0)
10.0 (8.0-16.0)
0.113
7.5 (7.0-11.8)
8.0 (7.0-10.0)
0.418
Functional capacity ≥ 4 METs
24 (36.4)
38 (40.9)
0.683
12 (60.0)
23 (48.9)
0.574
Preoperative cardiac echo findings
LVEF (%)
67.0 (63.0-70.3)
66.0 (63.3-69.0)
0.515
64.5 (62.3-68.5)
67.0 (64.0-69.3)
0.149
Pulmonary hypertension
4 (6.1)
4 (4.4)
0.721
0 (0.0)
1 (2.1)
> 0.999
Comorbidity
Preoperative RRT
4 (6.1)
2 (2.2)
0.234
1 (5.0)
0 (0.0)
0.299
Hypertension
11 (16.7)
19 (20.4)
0.695
5 (25.0)
12 (25.5)
> 0.999
Diabetes mellitus
18 (27.3)
35 (37.6)
0.232
5 (25.0)
13 (27.7)
> 0.999
Cerebro-cardiovascular disease
0 (0.0)
2 (2.2)
0.511
0 (0.0)
1 (2.1)
> 0.999
Preoperative delirium
8 (12.1)
2 (2.2)
0.017
0 (0.0)
0 (0.0)
N/A
Hepatopulmonary syndrome
11 (16.7)
13 (14.0)
0.854
2 (10.0)
4 (8.7)
> 0.999
West-Haven criteria on encephalopathy
-
-
0.234
-
-
> 0.999
Grade 0-1
62 (93.9)
91 (97.8)
-
20 (100.0)
46 (97.9)
-
Grade 2
4 (6.1)
2 (2.2)
-
0 (0.0)
1 (2.1)
-
Grade 3-4
0 (0.0)
0 (0.0)
-
0 (0.0)
0 (0.0)
-
Baseline laboratory findings
PaO2/FiO2 ratio
306.0 (254.3-409.8)
333.0 (275.5-411.8)
0.253
322.5 (271.3-406.8)
365.0 (287.0-434.0)
0.276
Hemoglobin (g/dL)
11.3 (2.3)
11.4 (2.4)
0.732
12.9 (2.2)
12.3 (2.4)
0.347
Platelets (103/μL)
64.0 (41.0-99.5)
77.0 (52.0-119.2)
0.191
110.5 (98.0-157.3)
113.0 (85.0-148.0)
0.337
PT-INR
1.4 (1.2-1.7)
1.3 (1.2-1.5)
0.003
1.2 (1.1-1.2)
1.2 (1.1-1.3)
0.962
aPTT (second)
48.4 (39.4-56.4)
41.0 (37.5-47.3)
0.002
38.6 (34.7-43.9)
38.3 (35.3-42.4)
0.784
Ammonia (μmol/L)
36.0 (25.8-49.5)
34.0 (23.0-49.0)
0.355
31.5 (23.3-36.8)
26.0 (20.0-41.0)
0.661
Bilirubin (mg/dL)
2.4 (1.4-4.3)
1.4 (1.1-2.6)
< 0.001
1.5 (1.0-2.2)
1.2 (0.9-1.5)
0.081
Albumin (g/dL)
3.1 (0.5)
3.2 (0.5)
0.518
3.5 (0.5)
3.3 (0.5)
0.314
Glucose (g/dL)
117.0 (104.0-134.3)
120.0 (105.8-140.8)
0.446
123.5 (105.5-159.3)
120.0 (106.0-141.0)
0.627
Creatinine (mg/dL)
0.8 (0.6-0.9)
0.7 (0.6-0.9)
0.306
0.8 (0.6-0.9)
0.7 (0.6-0.8)
0.497
SBP, baseline (mmHg)
128.0 (115.3-139.0)
128.0 (116.8-147.0)
0.437
131.5 (120.0-144.5)
137.0 (120.0-148.0)
0.330
HR, baseline (beats/minute)
78.0 (68.0-89.3)
80.5 (66.8-91.8)
0.719
72.0 (67.0-85.8)
80.0 (65.0-95.0)
0.388
Table 2 Comparison of intraoperative characteristics between the delayed and early extubation group, n (%).
Variables
Whole group (n = 159)
Subgroup (n = 67)
Delayed extubation (n = 66)
Early extubation (n = 93)
P value
Delayed extubation (n = 20)
Early extubation (n = 47)
P value
Emergency surgery
4 (6.1)
0 (0.0)
0.028
0 (0.0)
0 (0.0)
N/A
Operation time (hour)
10.8 (9.8-12.7)
9.9 (8.6-12.2)
0.009
11.1 (9.9-13.5)
9.5 (8.1-12.3)
0.025
Anhepatic time (hour)
1.7 (1.3-2.4)
1.4 (1.2-1.8)
0.006
1.7 (1.1-2.5)
1.4 (1.2-1.8)
0.176
Hourly EBL (mL/hour)
212.8 (130.0-415.6)
156.5 (107.1-234.0)
0.004
136.3 (87.7-214.9)
134.5 (102.4-202.3)
0.934
Hourly urine output (mL/hour)
72.9 (51.5-118.9)
92.4 (58.3-134.7)
0.193
97.6 (62.7-162.6)
104.1 (64.5-141.3)
0.924
Hourly administered fluids or blood products
Crystalloid (mL/hour)
170.9 (127.6-240.9)
174.2 (116.8-253.7)
0.776
180.8 (134.5-239.1)
176.8 (133.7-271.0)
0.696
Colloid (mL/hour)
48.0 (34.1-72.9)
40.5 (32.1-58.6)
0.167
34.3 (24.0-55.2)
42.9 (33.1-60.8)
0.198
PRBCs (units/hour)
0.4 (0.0-1.0)
0.2 (0.0-0.5)
0.005
0.0 (0.0-0.4)
0.0 (0.0-0.3)
0.492
FFPs (units/hour)
0.3 (0.0-1.0)
0.2 (0.0-0.4)
0.039
0.0 (0.0-0.2)
0.0 (0.0-0.3)
0.951
Platelets (units/hour)
0.0 (0.0-0.8)
0.0 (0.6)
0.128
0.0 (0.0-0.6)
0.0 (0.0-0.0)
0.399
Total blood products (units/hour)
1.1 (0.0-2.9)
0.8 (0.0-1.5)
0.032
0.0 (0.0-1.1)
0.0 (0.0-0.9)
0.646
Epidural analgesia
1 (1.5)
22 (23.7)
< 0.001
1 (5.0)
22 (46.8)
0.001
Postreperfusion syndrome
58 (87.9)
72 (77.4)
0.140
17 (85.0)
32 (68.1)
0.259
Laboratory findings, ES
PaO2/FiO2 ratio
345.5 (303.3-421.3)
374.0 (312.5-436.0)
0.235
343.0 (263.8-435.5)
377.0 (315.0-442.0)
0.351
Lactate (mmol/L)
5.3 (4.1-8.2)
5.6 (3.9-7.0)
0.577
5.2 (4.4-8.2)
5.8 (4.3-7.4)
0.973
Glucose (g/dL)
198.5 (174.8-223.0)
201.0 (170.0-226.5)
0.575
193.0 (171.5-206.0)
194.0 (170.0-216.0)
0.574
SBP, ES (mmHg)
105.0 (95.0-116.3)
130.0 (120.0-145.0)
< 0.001
112.5 (100.0-130.0)
130.0 (120.0-145.0)
0.002
HR, ES (beats/minute)
85.0 (75.0-96.3)
95.0 (85.0-107.5)
< 0.001
87.5 (76.3-105.0)
95.0 (85.0-105.0)
0.153
CVP, ES (mmHg)
6.0 (4.0-7.3)
5.0 (2.5-7.0)
0.030
5.5 (3.0-7.0)
5.0 (3.0-7.0)
0.709
High-dose vasoactive drug, ES
51 (77.3)
36 (38.7)
< 0.001
12 (60.0)
15 (31.9)
0.061
The selection of predictor variables in the multivariate model was performed using the forward selection method based on the Wald statistic; variables were entered into the model if P < 0.05. Patients with missing data for any predictors were excluded from the logistic regression analysis. Additionally, parameters consistently reported in the literature as predictors of early extubation after liver transplantation were included in the final model regardless of P value, including MELD scores, postreperfusion syndrome, high-dose vasoactive drugs at the ES, anhepatic time, and hourly total blood product administration[14-18]. The sample size evaluation was conducted post hoc. Conventionally, the one-in-ten rule (a minimum of 10 events per predictor variable) was used to evaluate the sample size of logistic regression[19]. However, studies report that this rule is overly conservative as a general recommendation[19]. Vittinghoff and McCulloch[19] show that 5 events per predictor to 9 events per predictor variable could be sufficient for logistic analysis, a view that has been widely accepted in recent years. In this study, both perspectives were considered in evaluating the sample size.
RESULTS
Patient’s characteristics at baseline
Total of the 197 patient records retrieved, 38 were excluded (Figure 1). Among these, one patient was excluded due to missing more than 10% of the required data, including the PaO2/FiO2 ratio at baseline and ES, vital signs at baseline and ES, EBL, urine output, fluid or blood product administration, and the occurrence of postreperfusion syndrome. Of the 159 samples included in this study, 66 (41.5%) and 93 (58.5%) were cases of delayed and early extubation, respectively. Preoperative characteristics showed that the delayed extubation group had a higher incidence of preoperative delirium and higher levels of PT-INR, aPTT, and bilirubin than those of the early extubation group (Table 1). Table 2 summarizes the intraoperative characteristics of the patients. The delayed extubation group had a higher incidence of emergency surgery, longer operative times, and longer anhepatic periods than those of the early extubation group. The early extubation group exhibited lower EBL per hour and fewer transfusions of packed RBCs, FFPs, and total blood products per hour than those of the delayed extubation group. At the ES, the early extubation group showed higher SBP and HR, lower CVP, and lesser requirement for high-dose vasoactive drugs than those of the delayed extubation group. Epidural analgesia was more frequently applied in the early extubation than in the delayed extubation group [n (%): 22 (23.7) vs 1 (1.5), P < 0.001].
Figure 1 Study flow chart.
EMR: Electronic medical record; PaO2: Partial pressure of arterial oxygen; FiO2: Fractional inspired oxygen fraction; PT-INR: Prothrombin time-international normalized ratio.
Clinical factors associated with early extubation
The results of variable selection using the forward selection method showed that the following variables were relevant clinical factors of early extubation following LDLT: Anhepatic time (adjusted OR = 0.439, 95%CI: 0.232-0.831; P = 0.011), epidural analgesia (OR = 15.730, 95%CI: 1.919-128.919; P = 0.010), and high-dose vasoactive drugs at the ES (OR = 0.235, 95%CI: 0.106-0.519; P < 0.001; Table 3). Although MELD score (adjusted OR = 1.000, 95%CI: 0.938-1.066; P = 0.994), the presence of postreperfusion syndrome (OR = 1.172, 95%CI: 0.402-3.420; P = 0.771), and hourly total blood product administration (OR = 0.874, 95%CI: 0.592-1.291; P = 0.499) were included in the final model, none showed statistical significance (Table 3). The evaluation of logistic regression model performance is provided in Supplementary Appendix 1.
Table 3 Multivariate analysis of variables associated with early extubation.
Variable
Whole group (n = 159)
Subgroup (n = 67)
Adjusted OR (95%CI)
P value
Adjusted OR (95%CI)
P value
Anhepatic time (hour)
0.439 (0.232-0.831)
0.011
0.344 (0.116-1.018)
0.054
Epidural analgesia (Reference. No)
15.730 (1.919-128.919)
0.010
19.381 (2.153-174.433)
0.008
High-dose vasoactive drug, ES (Reference. No)
0.235 (0.106-0.519)
< 0.001
0.355 (0.091-1.391)
0.137
MELD score
1.000 (0.938-1.066)
0.994
1.080 (0.926-1.259)
0.325
Postreperfusion syndrome (Reference. No)
1.172 (0.402-3.420)
0.771
0.978 (0.171-5.593)
0.980
Total blood products (units/hour)
0.874 (0.592-1.291)
0.499
0.858 (0.410-1.797)
0.685
Subgroup analysis
A subgroup analysis was conducted, excluding patients with contraindications for epidural analgesia owing to significant coagulopathy (PT-INR > 1.5 or platelets < 70 × 103/μL). Of the 67 samples included in the subgroup analysis, 20 (29.9%) and 47 (70.1%) were cases of delayed and early extubation, respectively (Figure 1). The two groups were comparable regarding preoperative characteristics (Table 1). Intraoperatively, the delayed extubation group exhibited a longer operation time and lower SBP at the ES than the early extubation group (Table 2). Furthermore, epidural analgesia was more frequently utilized in the early extubation group than in the delayed extubation group [n (%): 22 (46.8) vs 1 (5.0), P = 0.001].
Using the forward selection method, epidural analgesia was identified as a relevant clinical factor for early extubation after LDLT (adjusted OR = 19.381, 95%CI: 2.153-174.433; P = 0.008) (Table 3). Although anhepatic time (adjusted OR = 0.344, 95%CI: 0.116-1.018; P = 0.054), high-dose vasoactive drugs at the ES (adjusted OR = 0.355, 95%CI: 0.091-1.391; P = 0.137), MELD score (adjusted OR = 1.080, 95%CI: 0.926-1.259; P = 0.325), presence of postreperfusion syndrome (adjusted OR = 0.978, 95%CI: 0.171-5.593; P = 0.980), and hourly total blood product administration (adjusted OR = 0.858, 95%CI: 0.410-1.797; P = 0.685) were included in the final model, none of these variables demonstrated statistical significance (Table 3). The assessment of logistic regression model performance in the subgroup analysis is detailed in Supplementary Appendix 1.
DISCUSSION
In this retrospective study, shorter anhepatic time, absence of high-dose vasoactive drugs at the ES, and epidural analgesia were identified as relevant clinical predictors of early extubation after LDLT. Subgroup analysis excluding patients with significant coagulopathy further suggested that epidural analgesia could be a potential predictor. Previous studies show that prolonged mechanical ventilation and intubation after liver transplantation are connected to several risk factors[14-18]. Preoperatively, these include a high MELD score, elevated aspartate aminotransferase levels, hypocalcemia, and hepatic encephalopathy. Intraoperative factors encompass hemodynamic fluctuations, postreperfusion syndrome, longer surgery duration, oliguria, and RBC transfusions[14-18]. These risk factors are challenging to optimize owing to the inherent challenge of adjusting the preoperative condition of a patient or altering surgical techniques in liver transplantation. Therefore, clinicians should focus on controllable factors, particularly those related to anesthesia - such as epidural analgesia - and select the most appropriate anesthetic approach to enhance early extubation and improve outcomes.
Our study revealed epidural analgesia as a relevant clinical factor of early extubation following LDLT. To address potential bias from coagulopathy, a subgroup analysis of patients without significant coagulopathy revealed that epidural analgesia remained a relevant clinical factor associated with early extubation. Epidural analgesia is widely adopted in thoracic and abdominal surgery owing to its benefits in improving postoperative pulmonary outcomes, enhancing pain control, reducing systemic opioid use, improving diaphragmatic function, and facilitating early extubation[5]. A large systematic review of 141 RCTs by Rodgers et al[20] report that epidural analgesia reduces postoperative pulmonary embolism, pneumonia, respiratory depression, and overall mortality by 55%, 39%, 59%, and approximately one-third, respectively[5,20]. In cardiac surgery, cautious efforts to apply epidural analgesia exist despite concerns regarding anticoagulation[4]. Epidural analgesia shows its potential for facilitating early extubation and reducing the risk of myocardial ischemia through its sympatholytic effects following cardiac surgery[4]. Numerous studies also report that epidural analgesia does not significantly increase the risk of neuraxial bleeding or damage in cardiac surgery[4].
Despite its benefits for improving pulmonary outcomes, epidural analgesia is rarely used in patients with liver transplants, primarily owing to concerns regarding epidural hematoma, similar to its use in cardiac surgery. Nevertheless, Aniskevich and Pai[21], Aniskevich and Scott[22] show the potential advantages of epidural analgesia in liver transplantation, including improvements in respiratory function and overall patient comfort, which enhance postoperative recovery. In a 10-year experience report, Tenling et al[8] successfully employed epidural analgesia in selected patients with liver transplants with stable coagulation profiles (international normalized ratio < 1.5, aPTT < 45 second, platelets > 70 × 109/L) without complications. Similarly, Hausken et al[23] report effective pain control and no serious bleeding or neurological complications in patients with stable coagulation (international normalized ratio < 1.5, platelets > 100 × 109/L). Our study findings align with these findings, showing no bleeding-related complications associated with epidural anesthesia. Overall, while epidural analgesia may be a viable option for liver transplantation after carefully assessing the risks and benefits, further research is needed to more precisely establish safety margins concerning coagulation profiles in this patient population.
In the present study, a shorter anhepatic time was a significant factor for early extubation after LDLT in the overall and subgroup analyses. Acho et al[15] also report that anhepatic time predicts early extubation, with patients having an anhepatic time > 75 minutes less likely to be extubated immediately post-surgery. Similarly, in a retrospective study by Saeyup et al[24] on pediatric patients with LDLT, anhepatic time was the sole predictor of early extubation, emphasizing its vital role in graft function. In this study, the administration of high-dose vasoactive drugs at the ES was associated with early extubation failure in the overall analysis. Although this factor was included in the final model of the subgroup analysis, it was not statistically significant. Unstable hemodynamics or high-dose vasoactive drug use are generally regarded as relative contraindications for ventilator weaning and tracheal extubation[25]. Therefore, the inclusion of high-dose vasoactive drugs at the ES in our final model acts as an adjustment for hemodynamic instability during this critical phase. Suphathamwit et al[26] report a higher rate of early extubation among patients who did not require inotropes or vasopressors at the ES. Similarly, Lee et al[27] observed that patients in the early extubation group exhibit more stable intraoperative circulatory conditions, evidenced by reduced reliance on potent vasopressors.
Conventionally, early extubation following liver transplantation is avoided, with patients remaining sedated and on mechanical ventilation in the ICU for approximately 48 hours before extubation[21,28-30]. This approach is based on the belief that delayed extubation would reduce surgical stress, improve hepatic and splanchnic blood flow to support graft function, and maintain hemodynamic stability[30]. However, recent studies suggest that delayed extubation may hinder recovery after liver transplantation[2,31-35]. Xu et al[31] investigated the effects of early extubation on adverse outcomes related to mechanical ventilation in patients undergoing orthotopic liver transplantation. Their findings reveal that patients in the early extubation group experience superior outcomes, including lower 30-day mortality, reduced acute kidney injury incidence, and fewer pulmonary complications[31]. Acho et al[15] reported that early extubation significantly reduced ICU stays and pulmonary complications, with no observed differences in reintubation rates between the early and delayed extubation groups after liver transplantation. Similarly, Caballero et al[18] demonstrated that early extubation was associated with shorter median ICU and hospital stays following liver transplantation. In line with these findings, we observed a trend toward shorter ICU and hospital stays in the early extubation group, with comparable reintubation and reoperation rates between the groups after LDLT (Supplementary Table 1). However, as our findings are based on unadjusted comparisons, their broader applicability is limited and requires further investigation.
A sufficient sample size is essential in logistic regression analysis to minimize the risk of overfitting and ensure adequate statistical power. This study included a total of 159 cases, with 93 involving early extubation. The final model included six variables: Anhepatic time, epidural analgesia, the administration of high-dose vasoactive drugs, MELD score, postreperfusion syndrome, and hourly administered total blood products. The adequacy of the sample size was evaluated using both conventional methods and the approach proposed by Vittinghoff and McCulloch[19] Based on these assessments, the sample size in this study could be regarded as sufficient.
This study has some limitations. First, as a retrospective chart review, establishing a definitive cause-and-effect relationship between potential predictors and early extubation following LDLT remains challenging. Second, the relatively small sample size and extended recruitment period of over 7 years may introduce bias owing to advancements in surgical and anesthetic techniques during that time. Third, as the study was conducted at a single center, its findings may have limited generalizability to other institutions. Fourth, to reduce selection bias associated with the general condition of patients receiving epidural anesthesia, a subgroup analysis was performed, excluding patients with coagulopathy. Nevertheless, the potential for selection bias remains, as patients with conditions such as hemodynamic instability or spinal abnormalities were likely excluded from receiving epidural anesthesia. This limitation may have influenced the outcomes and should be taken into account when interpreting the findings. Consequently, a gradual and cautious approach is recommended before broadly applying these results.
CONCLUSION
In conclusion, this study identified shorter anhepatic time, the absence of high-dose vasoactive drug use at the ES, and the application of epidural analgesia as relevant clinical factors of early extubation following LDLT. These findings suggest that epidural analgesia may serve as a promising component of ERAS protocols for patients undergoing LDLT, when its application is appropriate. However, further research is needed to establish the safety margins regarding coagulation profiles and to evaluate their overall effect on postoperative outcomes.
ACKNOWLEDGEMENTS
We express our sincere appreciation to Professor Won Kee Lee, PhD in Statistics, Department of Medical Informatics, School of Medicine, Kyungpook National University, for his invaluable contributions and meticulous statistical guidance in this research.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author’s Membership in Professional Societies: Korean Society of Anesthesiologists; Korean Society of Transplantation Anesthesiologists.
Specialty type: Medicine, research and experimental
Country of origin: South Korea
Peer-review report’s classification
Scientific Quality: Grade C, Grade D
Novelty: Grade C, Grade C
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade B, Grade B
P-Reviewer: Liu HQ S-Editor: Bai Y L-Editor: A P-Editor: Wang WB
Olawin AM, Das JM.
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