Perioperative blood transfusion decreases long-term survival in pediatric living donor liver transplantation

Table 1 Modified Clavien-Dindo classification for pediatric liver transplantation

Grade	Definition
I	Complication that requires the use of simple analgesics, antipyretics, anti-emetics, diuretics, electrolytes and physiotherapy
II	Complication requiring other drugs, different from grade I, blood transfusion or parenteral nutrition
III	Complication requiring surgical, endoscopic or radiologic intervention under any kind of anesthesia
IIIa	Low complexity procedures: Small and medium surgery, endoscopy and colonoscopy, US, CT, ERCP or PTCD, arteriography and angioplasty of portal vein or suprahepatic veins and hepatic artery, biopsies, simple teeth extractions, drainages, ostomies and central catheter passage for medication, dialysis or chemotherapy
IIIb	High complexity procedures: Large surgery, multiple teeth extractions, vascular and biliodigestive re-anastomosis, laparotomy and thoracotomy
IV	Life-threatening complication (including CNS1 complications) requiring ICU admission
IVa	Dysfunction of one organ (including dialysis)
IVb	Dysfunction of two or more organs
V	Death of patient

¹Cerebral hemorrhage, ischemic stroke, subarachnoid bleeding, excluding transient ischemic attack. Suffix “d” (for "disability") indicates that the patient still has complication, at time of discharge, requiring follow-up and must be entered to the degree of complication (e.g., IVa-d degree). US: Ultrasound; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography; PTCD: Percutaneous transhepatic cholangiography or drainage; CNS: Central nervous system; ICU: Intensive care unit.

Table 2 Univariate and multiple logistic regression analyses of perioperative data stratified by the severity of complications

Variables	mean ± SD or No (%)		P value	OR	95%CI	P value
	MiC, n = 109	MaC, n = 131
Male gender	54 (49.5)	52 (39.7)	0.081
Age (d)	632 ± 440	512 ± 490	< 0.001
Weight (kg)	9.67 ± 2.91	8.61 ± 3.09	< 0.001
Height (cm)	76.6 ± 11.2	71.9 ± 11.6	< 0.001
WAZ	-1.28 ± 1.24	-1.49 ± 1.31	0.105
HAZ	-0.28 ± 1.15	-0.54 ± 1.24	0.012
WHZ	-1.60 ± 1.34	-2.43 ± 1.48	< 0.001
BMIZ	-0.20 ± 1.11	-0.36 ± 1.39	0.001
Ascites	78 (71.6)	108 (82.4)	0.057
PELD score	16.2 ± 7.0	17.8 ± 8.2	0.14
Kasai surgery	50 (45.9)	61 (46.6)	0.698
Portal hypertension	97 (88.9)	131 (100.0)	0.132
Hepatopulmonary syndrome	16 (14.7)	15 (11.5)	0.414
Infections 30 d pre-LT	0.4 ± 0.6	0.6 ± 0.7	0.081
eGFR (mL/min/1.73 m2)1	228 ± 121	187 ± 104	0.006
Hemoglobin (g/dL)2	10.2 ± 1.5	9.3 ± 1.5	< 0.001
Platelets (× 103/mm3)2	196 ± 112	193 ± 118	0.789
INR2	1.24 ± 0.25	1.49 ± 0.56	< 0.001
Sodium (mEq/L)2	137 ± 2.7	135 ± 4.3	< 0.001
Potassium (mEq/L)2	4.4 ± 0.5	4.3 ± 0.7	0.613
Glucose (mEq/L)2	104 ± 59	92 ± 60	0.313
Albumin (g/dL)2	2.9 ± 0.9	2.5 ± 0.8	0.002
Total Bilirubin (g/dL)2	11.9 ± 7.3	13.4 ± 8.8	0.304
GBWR (%)	3.3 ± 1.1	3.7 ± 1.2	0.035
RBC (mL/kg)3	31.1 ± 25.4	46.7 ± 39.7	< 0.001	1.018	1.007-1.028	0.001
FFP (mL/kg)3	0.3 ± 2.6	3.0 ± 11.5	0.015
Platelets (mL/kg)3	0.1 ± 0.8	1.2 ± 6.0	0.021
Cryoprecipitate (mL/kg)3	0.0 ± 0.0	0.1 ± 1.2	0.196

¹Estimated glomerular filtration rate by simplified Schwartz's formula.

²Blood samples collected up to 72 h before liver transplantation (LT) anesthetic induction.

³Blood samples collected up to 2 h after the onset of LT anesthetic induction.

SD: Standard deviation; MiC: Minor complications group (I-IIIa); MaC: Major complications group (IIIb-V); WAZ: Weight-for-age z-score; HAZ: Height-for-age z-score; WHZ: Weight-for-height z-score; BMIZ: Body-mass-index-for-age z-score; PELD: Pediatric end-stage liver disease; LT: Liver transplantation; INR: International normalization ratio; GBWR: Graft-to-body-weight ratio; RBC: Red blood cells; FFP: Fresh frozen plasma; eGFR: Estimated glomerular filtration rate.

Table 3 Univariate analysis of preoperative, intraoperative and early postoperative data according to perioperative red blood cell volume transfused

Variables	mean ± SD or No. (%)		P value
	LTr, n = 103	HTr, n = 137
Male gender	48 (46.6)	58 (42.3)	0.565
Age (d)	764 ± 544	419 ± 350	< 0.001
Weight (kg)	10.67 ± 3.20	7.88 ± 2.29	< 0.001
Height (cm)	80.0 ± 12.1	69.4 ± 8.7	< 0.001
WAZ	-0.90 ± 1.20	-1.75 ± 1.21	< 0.001
HAZ	-0.11 ± 1.41	-0.54 ± 1.24	0.012
WHZ	-1.60 ± 1.34	-2.43 ± 1.48	< 0.001
BMIZ	0.20 ± 1.20	-0.36 ± 1.39	0.001
Ascites	72 (69.9)	115 (83.9)	0.036
PELD score	14.1 ± 6.2	19.1 ± 7.9	< 0.001
Extra-hepatic cholestasis	67 (65.0)	105 (76.6)	0.029
Intrahepatic cholestasis	13 (12,6)	5 (3.6)	0.002
Cirrhosis	6 (5.8)	12 (8.8)	0.373
Metabolic diseases	7 (6.8)	10 (7.3)	0.852
Malignant diseases	7 (6.8)	3 (2.2)	0.159
Miscellany	3 (2.9)	2 (1.5)	0.751
Kasai surgery	40 (38.8)	74 (54.0)	0.016
Portal hypertension	96 (93.2)	132 (96.3)	0.132
Hepatopulmonary syndrome	19 (18.4)	12 (8.7)	0.043
Infections ≤ 30 d pre-LT	0 ± 1	1 ± 1	0.01
eGFR (mL/min/1.73 m2)1	229 ± 121	188 ± 105	0.006
Hemoglobin (g/dL)2	10.2 ± 1.5	9.3 ± 1.5	< 0.001
Platelets (× 103/mm3)2	196 ± 112	193 ± 118	0.789
INR2	1.24 ± 0.25	1.49 ± 0.56	< 0.001
Sodium (mEq/L)2	137 ± 2.6	135 ± 4.4	< 0.001
Potassium (mEq/L)2	4.3 ± 0.5	4.4 ± 0.6	0.613
Glucose (mEq/L)2	104 ± 59	92 ± 60	0.313
Albumin (g/dL)2	2.9 ± 0.9	2.5 ± 0.8	0.002
Total bilirubin (g/dL)2	11.9 ± 7.3	13.4 ± 8.8	0.304
Hemoglobin (g/dL)3	8.6 ± 1.5	7.6 ± 1.2	< 0.001
INR3	1.23 ± 0.42	1.67 ± 0.75	< 0.001
Sodium (mEq/L)3	135 ± 8	134 ± 5	0.002
Warm ischemia time (min)	42.2 ± 12.9	42.9 ± 11.4	0.515
Cold ischemia time (min)	53.3 ± 34.8	67.1 ± 56.3	0.118
Anesthetic time (h)	9.7 ± 1.6	10.8 ± 1.9	< 0.001
Surgical time (h)	7.8 ± 1.5	9.0 ± 1.9	0.001
Crystalloid (mL/kg)4	179 ± 67	251 ± 105	0.015
Colloid (mL/kg)4	33.6 ± 20.8	43.1 ± 19.7	< 0.001
Diuresis (mL/kg)4	47.5 ± 22.9	61.3 ± 36.6	0.013
GBWR (%)	2.9 ± 1.0	3.9 ± 1.1	< 0.001
Extubation in OR	24 (23.1)	16 (11.8)	0.014
Intubation period ≥ 48 h	7 (6.7)	35 (25.7)	< 0.001
ICU length of stay (d)	4 ± 5	8 ± 13	0.001
Hospital length of stay (d)	17 ± 13	23 ± 21	0.010

¹Estimated glomerular filtration rate, preoperative calculated by Schwartz's formula.

²Blood samples collected up to 72 h before liver transplantation (LT) anesthetic induction.

³Blood samples collected up to 2 h after the onset of LT anesthetic induction.

⁴Intraoperative volume indexed by body's weight. Extra-hepatic cholestasis, extra-hepatic biliary atresia, coledocus cyst; intrahepatic cholestasis, Alagille's syndrome, non-syndromic biliary hypoplasia, primary sclerosing cholangitis, progressive intrahepatic familial cholestasis; cirrhosis, idiopathic, autoimune and cryptogenic; metabolic diseases, glycogenesis, Cligger-Najar's disease, tyrosinemia, cystic fibrosis, alpha-1 anti trypsin deficiency, urea cycle defects, type 1 oxaluria; malignant diseases, hepatoblastoma and hepatocarcinoma and hepatic miscellany diseases, Budd-Chiari syndrome, Caroli's disease and unclarified fibrosis. SD: Standard deviation; LTr: Low-volume transfusion group; HTr: High-volume transfusion group; WAZ: Weight-for-age z-score; HAZ: Height-for-age z-score; WHZ: Weight-for-height z-score; BMIZ: Body-mass-index-for-age z-score; PELD: Pediatric end-stage liver disease; LT: Liver transplantation; INR: International normalized ratio; GBWR: Graft-to-body-weight ratio; OR: Operating room; ICU: Intensive care unit; eGFR: Estimated glomerular filtration rate.

Table 4 Comparative analysis of postoperative complications during the hospitalization period using the modified Clavien–Dindo classification

Variables	All patients, n = 240
	All complications during hospitalization, n = 783
	mean ± SD or No. (%)	P value
	LTr, n = 103	HTr, n = 137
Patients with any complication	95 (92.2)	132 (96.4)	0.264
Patients with major complications (IIIb-V)	41 (39.8)	90 (65.7)	< 0.001
Complications per patient	2.5 ± 1.7	3.8 ± 3.6	0.007
Number of major complications (IIIb-V)	54/262 (20.6)	207/521 (39.7)	< 0.001
Median of the highest degrees of complication	IIIa (I-IVb)	IVa (I-V)	< 0.001
Median grade of complications per patient	II (I-IIIb)	II (I-V)	< 0.001

SD: Standard deviation; LTr: Low transfusion group; HTr: High transfusion group.

Table 5 Comparative analysis of type and grade of postoperative complications along the four periods of follow-up

Complication		Hospitalization			1 yr			5 yr			10 yr
Type	Grade	LTr	HTr	P value	LTr	HTr	P value	LTr	HTr	P value	LTr	HTr	P value
Bleeding (%)	Minor	1(0.4)	6(1.1)	0.252	5(0.9)	11(1.3)	0.61	5(0.5)	13(0.9)	0.237	5(0.5)	13(0.9)	0.236
	Major	0(0)	9(1.8)	0.211	1(0.2)	9(1.0)	0.465	1(0.1)	9(0.7)	0.467	1(0.1)	9(0.6)	0.297
	Subtotal	1(0.4)	15(2.9)	0.016	6(1.1)	20(2.3)	0.178	6(0.6)	22(1.6)	0.052	6(0.6)	22(1.4)	0.068
Cardiovascular (%)	Minor	17(6.5)	29(5.6)	0.754	19(3.6)	32(3.6)	0.662	24(2.6)	39(2.8)	0.518	25(2.5)	42(2.7)	0.381
	Major	0(0)	17(3.3)	0.028	0(0)	18(2.0)	0.017	0(0)	18(1.3)	0.005	0(0)	18(1.2)	0.005
	Subtotal	17(6.5)	46(8.9)	0.319	19(3.6)	50(5.8)	0.098	24(2.6)	57(4.1)	0.075	25(2.5)	60(3.9)	0.282
Dermatologic (%)	Minor	9(3.4)	5(1.0)	0.093	25(4.7)	16(1.8)	0.009	52(5.6)	58(4.1)	0.322	59(5.8)	71(4.6)	0.583
	Major	0(0)	1(0.2)	1	1(0.2)	1(0.1)	0.406	7(0.8)	10(0.7)	0.168	8(0.8)	10(0.7)	0.114
	Subtotal	9(3.4)	6(1.2)	0.049	26(4.9)	17(1.9)	0.003	59(6.4)	68(4.8)	0.134	67(6.6)	81(5.3)	0.209
Gastrointestinal (%)	Minor	5(1.9)	13(2.5)	0.336	15(2.8)	30(3.4)	0.353	30(3.3)	44(3.1)	0.721	33(3.2)	49(3.2)	0.65
	Major	0(0)	1(0.2)	1	1(0.2)	4(0.5)	1	3(0.3)	6(0.5)	0.704	3(0.3)	6(0.4)	0.713
	Subtotal	5(1.9)	14(2.7)	0.627	16(3.0)	34(3.9)	0.488	33(3.6)	50(3.6)	1	36(3.5)	55(3.6)	1
Infectious (%)	Minor	21(8)	32(6.1)	1	86(16.2)	116(13.2)	0.577	188(20.3)	235(16.7)	0.434	207(20.3)	257(16.8)	0.394
	Major	32(12.2)	82(15.8)	0.013	43(8.1)	106(12.1)	0.028	56(6.0)	132(9.4)	0.02	60(5.9)	133(8.7)	0.022
	Subtotal	53(20.2)	114(21.9)	0.66	129(24.3)	222(25.3)	0.729	244(26.3)	367(26.1)	0.948	267(26.2)	390(25.5)	0.743
Malignancy (%)	Minor	0(0)	0(0)	1	4(0.8)	9(1.0)	0.576	13(1.4)	32(2.3)	0.067	13(1.3)	35(2.3)	0.027
	Major	0(0)	0(0)	1	4(0.8)	3(0.3)	0.058	9(1.0)	13(0.9)	0.137	11(1.1)	14(0.9)	0.07
	Subtotal	0(0)	0(0)	1	8(1.6)	12(1.4)	1	22(2.4)	45(3.2)	0.296	24(2.4)	49(3.2)	0.253
Metabolic (%)	Minor	86(32.8)	134(25.7)	0.786	89(16.8)	140(16.0)	0.494	96(10.4)	146(10.4)	0.329	102(10.0)	151(9.9)	0.416
	Major	1(0.4)	0(0)	0.207	2(0.4)	0(0)	0.052	2(0.2)	0(0)	0.069	2(0.2)	0(0)	0.077
	Subtotal	87(33.2)	134(25.7)	0.085	91(17.2)	140(16.0)	0.605	98(10.6)	146(10.4)	0.942	104(10.2)	151(9.9)	0.846
Miscellany (%)	Minor	8(3.1)	25(4.8)	0.067	30(5.7)	48(5.5)	0.093	66(7.2)	71(5.1)	0.179	73(7.2)	74(4.8)	0.1
	Major	1(0.4)	5(1.0)	1	3(0.6)	7(0.8)	0.702	4(0.4)	14(1.0)	0.792	5(0.5)	14(0.9)	1
	Subtotal	9(3.5)	30(5.8)	0.217	33(6.3)	55(6.3)	1	70(7.6)	85(6.1)	0.18	78(7.7)	88(5.8)	0.07
Neuropsyquiatric (%)	Minor	3(1.1)	2(0.4)	0.391	7(1.3)	4(0.5)	0.135	17(1.8)	14(1.0)	0.2	24(2.4)	23(1.5)	0.297
	Major	1(0.4)	1(0.2)	0.371	1(0.2)	1(0.1)	0.406	1(0.1)	1(0.1)	0.459	2(0.2)	1(0.1)	0.188
	Subtotal	4(1.5)	3(0.6)	0.169	8(1.5)	5(0.6)	0.134	18(1.9)	15(1.1)	0.116	26(2.6)	24(1.6)	0.109
PNF (%)	Minor	0(0)	0(0)	1	0(0)	0(0)	1	0(0)	0(0)	1	0(0)	0(0)	1
	Major	0(0)	5(1.0)	0.587	0(0)	5(0.6)	0.593	0(0)	5(0.4)	0.332	0(0)	5(0.3)	0.329
	Subtotal	0(0)	5(1.0)	0.175	0(0)	5(0.6)	0.164	0(0)	5(0.4)	0.164	0(0)	5(0.3)	0.164
Rejection (%)	Minor	40(15.3)	32(6.1)	0.004	73(13.8)	66(7.5)	0.003	111(12.0)	102(7.3)	0.106	117(11.5)	125(8.2)	0.03
	Major	0(0)	1(0.2)	1	1(0.2)	4(0.5)	1	4(0.4)	8(0.6)	0.526	5(0.5)	8(0.5)	0.363
	Subtotal	40(15.3)	33(6.3)	<0.001	74(14.0)	70(8.0)	<0.001	115(12.4)	110(7.9)	<0.001	122(12.0)	133(8.7)	<0.001
Renal (%)	Minor	2(0.8)	3(0.6)	1	3(0.6)	3(0.3)	0.693	4(0.4)	3(0.2)	0.469	4(0.4)	4(0.3)	0.731
	Major	2(0.8)	5(1.0)	0.637	2(0.4)	7(0.8)	1	5(0.5)	9(0.7)	0.535	5(0.5)	9(0.6)	0.547
	Subtotal	4(1.6)	8(1.6)	1	5(1.0)	10(1.1)	0.796	9(0.9)	12(0.9)	0.945	9(0.9)	13(0.9)	1
Respiratory (%)	Minor	8(3.1)	24(4.6)	0.093	75(14.2)	110(12.6)	0.934	161(17.4)	247(17.6)	0.141	177(17.4)	261(17.1)	0.106
	Major	7(2.7)	36(6.9)	0.539	9(1.7)	53(6.0)	0.096	14(1.5)	70(5.0)	0.029	15(1.5)	71(4.7)	0.017
	Subtotal	15(5.8)	60(11.5)	0.014	84(15.9)	163(18.6)	0.217	175(18.9)	317(22.6)	0.038	192(18.9)	332(21.8)	0.041
Surgical (%)	Minor	8(3.1)	9(1.8)	0.617	19(3.6)	23(2.6)	0.631	33(3.6)	49(3.5)	0.732	43(4.2)	66(4.3)	0.487
	Major	10(3.8)	44(8.4)	0.711	12(2.3)	51(5.8)	0.509	20(2.2)	56(4.0)	1	20(2.0)	58(3.8)	0.682
	Subtotal	18(6.9)	53(10.2)	0.166	31(5.9)	74(8.4)	0.092	53(5.8)	105(7.5)	0.118	63(6.2)	124(8.1)	0.079
Total minor complications (%)		208(79.4)	314(60.3)	<0.001	450(84.9)	608(69.3)	<0.001	800(86.4)	1053(75.0)	<0.001	882(86.6)	1171(76.7)	<0.001
Total major complications (%)		54(20.6)	207(39.7)		80(15.1)	269(30.7)		126(13.6)	351(25.0)		137(13.4)	356(23.3)
Total complications per group (%)		262(33,5)	521(66,5)		530(37,7)	877(62,3)		926(39,7)	1404(60,3)		1019(40,0)	1527(60,0)
Total complications per period (%)		783(30,8)			1407(55,3)			2330(91,5)			2546(100)

HTr: High-volume transfusion group; LTr: Low-volume transfusion group; PNF: Primary non-function.

Table 6 Patients with early and late liver transplantation specific complications and 30 d and 10 years mortality rate

Variables	Early complications			Late complications
	No. (%)	No. (%)	P value	No. (%)	No. (%)	P value
	LTr, n = 103	HTr, n = 137		LTr, n = 103	HTr, n = 137
PNF	0 (0.0)	5 (3.6)	0.072	0 (0.0)	0	NA
Biliary fistula	4 (3.9)	10 (7.3)	0.267	0 (0.0)	1 (0.7)	NA
Biliary stenosis	0	0	NA	15 (14.6)	14 (10.2)	0.307
Hepatic arthery thrombosis	2 (1.9)	6 (4.4)	0.478	0 (0.0)	3 (2.2)	0.261
Portal vein thrombosis	6 (5.1)	16 (11.7)	0.113	3 (2.9)	6 (4.4)	0.554
Reoperation	9 (8.7)	36 (26.3)	< 0.001	4 (3.9)	13 (9.5)	0.298
Retransplantation	0 (0.0)	3 (2.2)	0.262	2 (1.9)	4 (2.9)	0.306
30 d mortality	0 (0.0)	9 (3.6)	0.008	NA	NA	NA
10 yr mortality	NA	NA	NA	8 (7.8)	26 (19.0)	0.137

LTr: Low-volume transfusion group; HTr: High-volume transfusion group; PNF: Primary non-function.

Table 7 Independent risk factors for death identified by simple and multiple Cox regression

			All patients n = 240
Variables	Estimative	HR	95%CI	P value	HR	P value
		Univariate			Multivariate
Male gender	-0.062	0.94	0.514-1.718	0.841
Age (d)	-0.024	0.977	0.950-1.004	0.095
Weight (kg)	-0.17	0.844	0.738-0.964	0.012
Height (cm)	-0.044	0.957	0.924-0.990	0.013
WAZ	-0.243	0.784	0.623-0.986	0.037
HAZ	-0.085	0.918	0.734-1.148	0.455
WHZ	-0.235	0.791	0.649-0.963	0.019
BMIZ	-0.084	0.919	0.723-1.168	0.49
PELD score	0.022	1.022	0.982-1.064	0.282
Biliary Atresia	-0.426	0.653	0.357-1.195	0.167
Kasai surgery	-0.214	0.808	0.440-1.483	0.491
Infections ≤ 30 d pre-LT	0.348	1.416	1.023-1.960	0.036
eGFR (mL/min/1.73 m2)1	-0.005	0.995	0.991-0.999	0.010	0.995	0.023
Surgical time (hours)	0.012	1.013	0.856-1.197	0.884
Hemoglobin (g/dL)2	-0.206	0.814	0.657-1.008	0.059
INR2	0.259	1.295	0.722-2.322	0.386
Sodium (mEq/L)2	-0.014	0.986	0.916-1.061	0.704
Albumin (g/dL)2	-0.116	0.89	0.615-1.290	0.539
Lactate (mmoL/L)3	-0.021	0.979	0.914-1.048	0.541
GBWR (%)	0.149	1.16	0.909-1.481	0.232
RBC > 27.5 mL/kg	1.316	3.73	1.730-8.042	0.001	3.031	0.009
Presence of major complication	0.384	1.469	0.799-2.701	0.261

¹Estimated glomerular filtration rate, preoperative calculated by Schwartz's formula.

²Blood samples collected up to 72 h before liver transplantation (LT).

³Blood samples collected up to 2 h after the onset of LT anesthetic induction. WAZ: Weight-for-age z-score; HAZ: Height-for-age z-score; WHZ: Weight-for-height z-score; BMIZ: Body-mass-index-for-age z-score; PELD: Pediatric end-stage liver disease; LT: Liver transplantation; INR: International normalized ratio; GBWR: Graft-to-body-weight ratio; RBC: Red blood cells; eGFR: Estimated glomerular filtration rate; HR: Hazard ratio.