Post on 08-Mar-2021
June 14, 2018 N Engl J Med 2018; 378:2263-2274DOI:10.1056/NEJMoa1801601
2018/7/3 �� ICU Journal Club�� ��
Introduction
Introduction•-�B&65C71*ADE+!��8�+8+!�� B.�C8#'2"�$8�4��H��A8-�B 4/�:,GF?;>
Ann Surg 1961; 154: 803-10Surgery 2003; 133: 49-55
Intensive Care Med 1994; 20: 203-9Br J Anaesth 2004; 93: 121-8
•)0�-A9<E�%�@/�!��-��A-�I-�G=?7L��B/�
→�(83-6kgB�3��
World J Surg 2004; 28: 1046-51Ann Surg 2003; 238: 641-8
World J Surg 2004; 28: 1046-51Lancet 2002; 359: 1812-8
World J Surg 2013; 37: 1193-202
Clin Nutr 2012; 31: 783-800
Introduction
• 46� �0��8)7/"���8�5("�!��8�&)7 Ann Surg 2003; 238: 641-8
Lancet 2002; 359: 1812-8Anesthesiology 2005; 103: 25-32
•��.3"� ���%;D>D<=8-$7
•?CABD=8�,� ���3"enhanced recovery after surgeryEERAS�F2����.#7
�ERASG�� �8�'7��2�$�8��(*:9@B9D
Clin Nutr 2012; 31: 783-800Acta Anaesthesiol Scand 2016; 60: 289-334Lon don: National Institute for Health and Care Excellence, 2017
Clin Nutr 2012; 31: 783-800Acta Anaesthesiol Scand 2016; 60: 289-334JAMA Surg 2017; 152: 292-8
21��1�+-
Introduction
• 505."+�&8/2@&�/?;&��9�,�(�9BFEHD:���Clin Nutr 2012; 31: 783-800Lon don: National Institute for Health and Care Excellence, 2017
JAMA Surg 2017; 152: 292-8Anesth Analg 2012; 114: 640-51
•�,�(�:.�%�9GDCA-=.!#A�<#�$%.#���A�1'36
• 505*(�>. ��1).��!��2) .�%�3) .���)�4)A��47@
1)Chest 1999; 115: 1371-72)Nat Rev Nephrol 2010; 6: 107-15
3)Proc Natl Acad Sci U S A 2005; 102: 3429-344)Anesth Analg 2001; 93: 405-9
Introduction•�'$�=��1;��4+�6��8��0<2,;
•�8%�5$�7�-
• RELIEF")��@?>.*,��6�!�&�
�'$� VS ���5$�ALiberal)
�'$��37+Liberal�9:8���.�/(�65,� �.*,
�#
Methods
Trial design
RELIEF�'REstrictive versus LIbEral Fluid Therapy in Major
Abdominal Surgery •������&�./,-��#��� �'•���" �+�(*��•!��%�)Liberal�+� •���3000�•�$2013�5�-2016�9�
Patient selection
•���)#!�����,�-•���� �• ���2����•����3���• �*' +(&"*$*%�����
Inclusion Criteria
• 70���• ��#��1��>32<�BA8.@• ���1��>32<�BA8.@• !�% +�$?EOGLO9 ���C38.@• &%�FNDHIO>200 μmol/L (>2.8 mg/dL)• BMI ≥35 kg/m2
• &DMJKO<30 g/L• ���(*�Panaerobic threshold ; ATQ
<12 mL/kg/min����35�
�',�;/6-:A0R7��C=54�"1�)
Inclusion Criteria
•��'2&��'7/-4+-0;"!*�– ASA-PS 3 or 4– �� ���– BMI 30–35 kg/m2
– ��)$#(������– �56.93: <100 g/L– ���-8,12:150–199 μmol/L (>1.7 mg/dL)– ���� �<anaerobic threshold ; AT= 12–14 mL/kg/min�
���$%��
Exclusion Criteria
•���+• ASA-PS 5•/�N�,D@L��&)�•#K?>I�)�+•"5+•TPQV�+W�*�G.��,0= F>8��K F:�+X('2�$���+8TUR-P87�SURO��+8%)��+8��!341+FE
�-6�H;A8EM<YB��G9CIJL� I5�
Randomization•��+�"�'WHODAS,12&�0�
•���'�����>ICU/HDU/��?* ��• 2<69=3=*'!��#�ALiberal�B@A@+:<48�/�)
��(.-$�,�� WHO$���%��7591;WHODAS2.0
Trial Treatments
• ERAS:<96;5 -.•$��(��!"5��-.• �2��0��"��2��+��,4.•./-*ARB1ACE-I3��5 -.•$�2*����*�)�'*ERAS8=7*�"*#�����5%&-.
$�
Trial Treatments
•-�82+H0�F%&(#I82'�G��?C•�!36��"M1<L• Goal-directed(GD)RUNOH�$M.4ZCVP9��3WTPY97/SQVXY
• 5���sBP≦90mmHgM�,�F�)Z�*G�@D� >BC
• HDU9ICUEK-�24�5JEI�@(#
-�
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•-�G6�+M�?D:DK9,�;��ALJE� AL=FM��
Trial Treatments
•���balanced salt solution�����• Hb70 g/L������� �����������������������
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Trial Treatments
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375ml��
375ml/h4���1500ml
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Trial Treatments
•�!9#���8�06,(���,��)�9 �-�&7�:,�38FKCAJ*"�
• ITT'�,PP'�,sensitivity'�;$42•(���9�69%�@?:,�#��, +8�5.$=<2
•��8:,IGDLC/2EKLBHLC>��/2
19�
Blinding and Data quality
•+(��,ECA2?�' ,��FGIL:<7B8/DQSM�>�6A�56.4
• Primary OutcomeA&�2?��FGIL;,DQSM�>�6A�=3T�)��U
• Secondary Outcome;��•��ORKS;,PRHN9���%A$1,JSG:���7��A�"14
• 1632�:� /PRHN�0@4-7,��9�*#�A!54
Measurments and Patient follow-up•��&*"3��1�1+96;<•�/�5QoR-155�!*��• 1 � ��� Hb Hct 12���� CRP��• 3 � QoR-155��• 30 �.7:85�'��& ��,��5,4
Primary Outcome2&$0Secondary Outcome#�%)*!-!"��&(
• 30 �.QoR-15,WHODAS5���• 3,6,12"��.WHODAS5��
WHODAS
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QoR-15
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Trial Outcomes
hPrimary Outcomei8�1�NB�QJ/�LMFVKO• WHODAS 24-��(=25%��RB�EU)H6G%���3NB�EUO�4
hSecondary Outcomei• ��6��D30!�R(�.D�9 70�0f 70D�8=��'D��=`eYD5,gD7*�>�(6d24"@�gDCRP$C�D<7DICU+�&@D A&@D���ICU �D��R;D90!�R6�#1)R2/.DYbW\^c�(8�1!D3!g
��6��S6��Y_X]`WN:f[Zea1-3N�IJQVTP?0g
Statistical Analysis
• Modified ITT��*�"#��• 13-0��(������#��*�)(!�"%�*��
•�*�'��$��'��*/+24•�*�'��!��&� % �%.4,*��
Statistical Analysis
•��1(�*"��$'�1�265%)��• Type 1 error 0.05)��•���90%�96?8�0.8�log-rank test��• 2650�, �@��/$"-� �1 �850�A ��
• :4=?(!*� � (1#)2��$2800�,5>;<537+�0.%&
Statistical Analysis
•+�� �?2016�6�30�=��40'�<#"46.�>#"!=91:*)
• 2578�GSVMR�Y��=PIUW2&F86�(1443�Z46�,;0Primary Outcome2300�<0��CDA/1 .�"�!85X786•5>6@0JVQTJHLG3000�=�B46
• 380���>��A43?.�2�E�(2;E<��• �80%• OKWN�0.75
•�->$%;?533�>events2#"Y .�"�!82%Z[�80%0OKWN�0.78
Statistical Analysis
• Primary Outcome1��AKaplan-Meier method8��• 2�"1$5��1� '!)73.1=:@<�ACox proportional hazards model. • 9>?;'!)6/&,+��2%���0�#*%
Schoenfeld residuals testing0�-(�����8�,+
•��5$��3.1�"1��4��0�,+
Statistical Analysis
• V%�8��2?6ACMDO<-/5?0;FQSN;�";�110��8.?=- ��,�@��37 ��:PHE�@��3-ExactRGHKBJE���8&:$�36
• 30��9�+�:��36�T�'���(U:�*2?6LSI@�/7-2!;�+�(9'2:)4>ACMDO@Wilcoxon-Breslow-Gehan��8�#36
Statistical Analysis• A40P]_fakSE*,@�����5���O)JL
• �H�$WQPMNFY� S'Qob�"JE�H�$WR� S����)[JL
• ;#R?C[cqfornKYLWE�NRsecondary outcomeQ��<)HB/IZL• Holm-Bonferroni+[/FE&�0)RLWg\jmrp^e`lr.0.049[/FN>�JL
• ��E�D��E�%%=R��s�tE3727 9R(-EGXT1*!�:6R�/ULS��/[�Vdhbnri<)[8ML
Results
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FigS1
FigS1
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Trial Treatment
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PACU
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Day1 PACU�
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���� ��$Liberal� �����!�
�$���% Liberal� ��"����
��������� ��
Liberal�� ��
SSI�����
Liberal 81.9%
Restrictive 82.3%
Primary Outcome
�1��������������" �������!�!��� �������
�������Liberal��� ��������
Prespecified Subgroups��� ���� ��
�� � ������Liberal��� ��������
Fig2
Table S8 : �������
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Table S9 :�����������
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Secondary Outcomes
SSI�� ������
������������
AKI��� ������
Table3
Cr � �) �
Stage 1 1.5���8��90.3 mg/dl��8��
0.5 ml/kg/hr16�*��$%
Stage 2 2���8Cr8�� 0.5 ml/kg/hr112�*��$%
Stage 3 3���8Cr8��9 �8Cr14.0 mg/dl��
0.3 ml/kg/hr124�*��$%.9��112�*��$%
9&���#�8�'2017/6/6 ICU���A-��!B ;<�"
Stage159���/<.Stage2@3�59���701�>3=6���/<AKICKDIGO�,5�(
�) �?+�24:.Stage2@3?�>34���/<
Adverse events
�39*�4���70���:Liberal 4+"��:�' 4�,&
MildE�!-%�4.=B@A+����8;5?6�)>.2/7,
ModerateE����8�)>.21SevereE����>� 0+����C#���<�(��D>�$51=
TableS13
Sensitivity Analyses
Discussion
Discussion��D"#
•)���NJID46�%D�*'.�)C76?5-��0$A Liberal$H�,;=�1"#H(652�DB6���H+�;=
•�)1��D2�DB6���C�EB8>=-��0$ 81.9% vs Liberal$ 82.3% Hazard� 1.05 ; 95%�3/0.88-1.24 ; PQ0.61
• ��&��D �E5-��0$@��C�8>=
-��0$ 8.6% vs Liberal$ 5.0% Hazard� 1.71 ; 95%�3/1.29-2.27 ; P<0.001
•KOLMPJH!�A;=-��0H<FA5��&��9 �<F:A9G8>=
Discussion•�����'"#-��)��(+ '��$.-
Ann Surg 2003; 238: 641-8
Acta Anaesthesiol Scand 2009; 53: 843-51
Restrictive /1.75L/day Balanced 1.75-2.75L/dayliberal 02.75L/day
�� � 24��*%
Restrictive 1.7L 1.9LBalanced 3.0L 3.0L
•��(��%)
Restrictive 1.0-2.7LBalanced 2.8-5.4L
•��(��%)
��(��(�����(��)��&�!,.-
Discussion/=:4
• ERASAD@CBE#"�?%.</5?�
•��8�$�6"�9�(4,<•�7+�����9�����;�& ���7!�2<5->=3-<
)Ann Surg 2003; 238: 641-8 Lancet 2002; 359: 1812-8
*Anesthesiology 2005; 103: 25-32•��8�06��E�'"�8��?�13-<
Clin Nutr 2012; 31: 783-800Acta Anaesthesiol Scand 2016; 60: 289334
Proc Nutr Soc 2010; 69: 488-98Acta Anaesthesiol Scand 2009; 53: 843-51London: National Institute for Health and Care Excellence, 2017
Nat Rev Nephrol 2010; 6: 107-15
Ann Surg 2003; 238: 641-8
:#";53�B�*"C3�H�2>9&)P%)�6�E�� H�.?G
:LJIO;NOKM9-�'$�9��/07
:�4;1999�11�Q2001�8�:�1;&)P%)�,H�=@ASA-PS 1-3E���'172�:Primary Outcome;�,30��FAD�� <!�>@�'�:Secondary Outcome;��9(��9�+
8
0�3$
Restricted Regimen Standard Regimen
(.�;4� ��G? 6%HAES500ml��
3rd space loss ��G? &9
1!7KE7ml/kg/hr<3!7KE5ml/kg/hr<3!7�83ml/kg/hr
,:9I1� 5%XVO*500ml 0�:#H�@D&9500ml��
/ HAESM /6F�6��<BC? /6
+500mlKE���
/500mlKE&91000-15000ml��< /500ml��EJHAESM��
3/J /1500mlM2=D>L-�<YZUP\TU�M�"H?B
0�3$
Restricted Regimen Standard Regimen
0� `5%XVO*1000ml��`V]a_�$F�6MHAESE1�`�5��
%�b+� �?B
1kg����bW^R[V'
1000-2000mlIP\QS^NV��AI�J�)���
Methods
Ann Surg 2003; 238: 641-8
HAESb Hydroxyethyl starch 6% in normal saline
����
Ann Surg 2003; 238: 641-8
��� Day1
���R�median 2740 mL [range, 1100–8050] S�median 5388 mL [range, 2700–11083]
P<0.0005
Day 1R�median 500 mL [range, 0–5000] S�median 1500 mL [range, 0–6000]
P�0.003
�
Ann Surg 2003; 238: 641-8���
��
����
Day1
����
Day2 R��1kg��S��3.5kg�
Per-protocol��
��
Ann Surg 2003; 238: 641-8
ITT��
28(33%) 44(51%) 0.013 27(31%) 47(55%) 0.002
���� �����������
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Ann Surg 2003; 238: 641-8
R
R
R S
S
R
R S
S
R SR S
R S
R S
R S
R SR S
SS
S
SS
R S
SS
SS
Major Complications
Minor Complications
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Ann Surg 2003; 238: 641-8
�� ����
�
Anesthesiology 2005; 103:25–32
;$#<61�&\RPG)CLiberalD1�&\LPG)I�0@:)(4�+�E��[��!I�,AH
;PMKZ<WZNV�:��>:-�'%�.8
;�/<2�#)(4�+I ?BASA-PS 1-3E���'152�;Primary Outcome<��GBF��!=" @B�'�;Secondary Outcome<����:�7�5:�+3��E�3��[STQLXOQ���[�+3��EJYRUZ���[SpO2��:1*I ?B�'�
9
Primary Outcome ��0i�:•�K�&w�K[mB\'^poVl_]j�Ki9D�Td9D\'^po
•�KQMwC�%�@A,V( 7EV��KuvsV?L�j!Fq�Ge_gXNn��0ekg^gX
•@>�B2wrtvl_]jCTdI%•;,w<K�8�6i Hh�ZV38���i3-V4E/��V�1�TO�i2c��q+a`•�J�&0w"�P�VS�V3-V4E/��gfi0.\WnV��Td9D$\10���•#E0w9D�&VU/��*VS=VS��V4E/)�/��iYb2R5��q+a`
Primary Outcome ��7d�@•�;,�yCK-MBf`epurqvTd�'YST��f`eQ1�5•!���bA0GyH�74w kYsWYXVD#�Y*-2GY3Wxb6"Kw�#�YTP�2GYAB2Gx
•�%Dy12N�aL�•EJ<U�y&`c6"KlMgY24(T��$>•����:R7�?y��87d��:RYCS�=�9a"KZiYPF/200)3YPAWP18mmHg)3h_^e��OI"K]c[
•A�+7yCTaA�+lMgj•F��yntmoqv�].��d50%lQ\j
�� �������3L� *#%�!'(�&�)&+5% dextrose–0.45% NaCl 1L����������1������������ "$10mg����
��
RPG,4ml/kg/hr
LPG,���10ml/kg��2ml/kg/hr
� 5% dextrose–0.45% NaCl 1-1.5ml/kg/hr Anesthesiology 2005; 103:25–32
Methods
����
Anesthesiology 2005; 103:25–32
��
Anesthesiology 2005; 103:25–32
Primary Outcome
P �0.046
������������ �
Anesthesiology 2005; 103:25–32
���$)*��&�'� ��!"���$���� ��#"
Secondary OutcomeLPG RPG P�
���� Day1 1.93 � 0.52 kgDay3 1.85 � 0.62 kg
Day1 0.51 � 0.67 kgDay3 0.24 � 0.61 kg
P < 0.01
��,.� 4 [3–7] days 3 [2–7] days P < 0.001
���� 6 [4–9] days 4 [3–9] days P < 0.001
���� 9 days (7–24) 8 days (6–21) P < 0.01
451-701�+836:(���$��#";� �(%!<
-9+/2:�SpO2(� %�#"
451-701 +836:
-9+/2: SpO2
Anesthesiology 2005; 103:25–32
�)'$��!%�� ���$�
•�����"� �• &(�#�$�������•������� �
Anesthesiology 2005; 103:25–32
�Ann Surg 2003; 238: 641-8
�
Discussion��D"#
•)���NJID46�%D�*'.�)C76?5-��0$A Liberal$H�,;=�1"#H(652�DB6���H+�;=
•�)1��D2�DB6���C�EB8>=-��0$ 81.9% vs Liberal$ 82.3% Hazard� 1.05 ; 95%�3/0.88-1.24 ; PQ0.61
• ��&��D �E5-��0$@��C�8>=
-��0$ 8.6% vs Liberal$ 5.0% Hazard� 1.71 ; 95%�3/1.29-2.27 ; P<0.001
•KOLMPJH!�A;=-��0H<FA5��&��9 �<F:A9G8>=
Discussion
•�=��>+&�(�F��4C@=9>;-• Liberal;&�=�/+�*�&�AB@��9,C1:F�36
• 1D?9+&�<AC�"/����F' 25C:-ED806•�+�*!9�$)����/.76
GGG� =#��%/��2DC
Limitations
•(��D#��91A5H4WTQZ]MC�2K�7>�'�95I
•)�24�/FADU\RN[A5H4=D�D,�E��<JB8?>
•)�1-3�E�.� A:B8?>�&96>•TX^O^Y]S4��AE4Liberal%D�91��D�0�!� 938?>
• Secondary OutcomeE"�9�B;4V^PYL]�*A+�A:B6>G4$�9/-?@6I�'�95I
Editorial
Editorial• 1990��[G<�Y�BZ'&E�!��a;I4-6kgZ�A��a>\UIR
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Ann Surg 2003; 238: 641-8
C928.8�<�Z��)�LG?$acfdegbY�TNWV YXSR
• QZ�G?$@Z %YTIU�HZ/0��LVUMRBr J Anaesth 2004; 93: 121-8JAMA 1993; 270: 2699-707BMJ 1999; 318: 1099-103World J Surg 2004; 28: 1046-51
Ann Surg 1961; 154: 803-10Surgery 2003; 133: 49-55Intensive Care Med 1994; 20: 203-9
Editorial��5��
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