1

[ Critical Care Guideline and Consensus Statement ] 56

2 57
3 58
4 59
5 60
6
7
Red Blood Cell Transfusion in Critically Ill 61
62
8
9
Q1 Q37
Adults 63
64
10 An American College of Chest Physicians Clinical Practice Guideline 65
11 66
12 Q38 Angel O. Coz Yataco, MD; Israa Soghier, MD; Paul C. Hébert, MD; Emilie Belley-Cote, MD; Margaret Disselkamp, MD; 67
13 68
David Flynn, MS; Karin Halvorson, MD; Jonathan M. Iaccarino, MD; Wendy Lim, MD; Christina C. Lindenmeyer, MD;
14 69
Q2 Peter J. Miller, MD; Kevin O’Neil, MD; Kathryn M. Pendleton, MD; Lisa Vande Vusse, MD; and Daniel R. Ouellette, MD
15 70
16 71
17 72
18 BACKGROUND: Blood products frequently are administered to critically ill patients. Consid- 73
19 ering recent trials and practice variability, a comprehensive review of current evidence was 74
20 75
deemed essential to offer pertinent guidance to critical care practitioners. This American
21 76
College of Chest Physicians (CHEST) guidelines panel examined the literature on RBC
22 77
transfusions among critically ill patients overall and specific subgroups, including patients
23 78
24
with gastrointestinal bleeding, acute coronary syndrome (ACS), cardiac surgery, isolated
79
25 troponin elevation, and septic shock, to provide evidence-based recommendations. 80
26 STUDY DESIGN AND METHODS: A panel of experts developed 6 Population, Intervention, 81
27 Comparator, and Outcome questions addressing RBC transfusions in critically ill patients 82
28 and performed a comprehensive evidence review. The panel applied the Grading of Rec- 83
29 ommendations, Assessment, Development, and Evaluations approach to assess the certainty 84
30 85
of evidence and to formulate and grade recommendations. A modified Delphi technique was
31 86
used to reach consensus on the recommendations.
32 87
33 RESULTS: The initial search identified a total of 3,082 studies, and after the initial screening, 88
34 38 articles were reviewed. Among them, 23 studies met inclusion criteria, comprising 22 89
35 randomized controlled trials and 1 cohort study. Based on the analysis of these studies, the 90
36 panel formulated 2 strong and 4 conditional recommendations. The overall quality of evi- 91
37 dence for recommendations ranged from very low to moderate. 92
38 93
CONCLUSIONS: In most critically ill patients, a restrictive strategy was preferable to a
39 94
permissive approach because it does not increase the risk of death or complications, but does
40 95
41
decrease RBC use significantly. Data from critically ill subpopulations also supported a
96
42 restrictive approach, except in patients with ACS, for whom favoring a restrictive approach 97
43 could increase adverse outcomes. CHEST 2024; -(-):--- 98
44 99
KEY WORDS: acute coronary syndrome; cardiac surgery; critically ill; GI bleed; red blood cell;
45 100
46
Q5 sepsis; septic shock; transfusion
101
47 102
48 103
49 ABBREVIATIONS: ACS = acute coronary syndrome; CHEST = Amer- College of Medicine of Case Western Reserve University (A. O. C. Y.), 104
50 ican College of Chest Physicians; ESICM = European Society of Cleveland, OH; the Division of Pulmonary and Critical Care Medicine 105
51 Intensive Care Medicine; GIB = gastrointestinal bleeding; LOS = length (I. S.), Department of Medicine, Salem Hospital/Massachusetts General 106
of stay; MD = mean difference; MI = myocardial infarction; RBC = red Brigham, Salem; the Boston University Chobanian & Avedisian School
52 blood cell; RCT = randomized controlled trial; RR = risk ratio of Medicine (D. F.), Boston, MA; the American College of Chest 107
53 Q3 AFFILIATIONS: From the Critical Care Medicine Division and Pul- Physicians (I. S. and J. M. I.), Glenview, IL; the Department of Critical 108
54 monary Medicine Division (A. O. C. Y.), Integrated Hospital-Care Care and Pulmonary Medicine (M. D.), Lexington Veterans Affairs 109
Institute, the Department of Gastroenterology, Hepatology and Healthcare System, Lexington, KY; the Department of Medicine
55 (K. H.), John A. Burns School of Medicine, University of Hawaii, 110
Nutrition (C. C. L.), Cleveland Clinic; the Cleveland Clinic Lerner

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111 Summary of Recommendations and ischemia, we suggest a restrictive RBC transfusion 166
112 Suggestions strategy over a permissive RBC transfusion strategy 167
113 168
These recommendations do not apply to critically ill (Conditional Recommendation, Very Low Certainty of
114 169
Q6 adults with hemodynamic instability due to acute Evidence).
115 170
Q7
116 hemorrhage, or those with neurological injuries or 6. In patients with septic shock and end-organ 171
117 trauma. hypoperfusion, we suggest against adding permissive 172
118 RBC transfusion thresholds to usual care (Conditional 173
1. In critically ill patients, we recommend a restrictive
119 Recommendation, Low Certainty of Evidence). 174
RBC transfusion strategy over a permissive RBC
120 175
121
transfusion strategy (Strong Recommendation, Remarks: Studies evaluating protocol driven approaches Q9 176
122 Moderate Certainty of Evidence). to goal-directed therapy in septic shock were not 177
123 considered in the evidence review. 178
2. In critically ill patients with acute gastrointestinal
124 179
bleeding, we recommend a restrictive RBC transfusion
125 180
126
strategy over a permissive RBC transfusion strategy Background 181
127
(Strong Recommendation, Moderate Certainty of In the United States, approximately 25% of critically ill 182
128 Evidence). patients receive RBC transfusions, totaling approximately 183
129
3. In critically ill patients with acute coronary 1.8 million units annually.1-3 The primary indication is 184
130 low hemoglobin (80%), whereas less frequently 185
syndrome, we suggest against a restrictive RBC
131 encountered indications include active bleeding (27%) 186
transfusion strategy (Conditional Recommendation,
132 and hemodynamic instability (23%).3,4 Since the 187
133
Low Certainty of Evidence). 188
publication of the TRICC trial,5 > 30 trials have examined Q10
134 4. In critically ill patients undergoing cardiac surgery, 189
RBC transfusion strategies in a variety of clinical settings.
135 190
we suggest a restrictive RBC transfusion strategy over Recently, new studies and updated meta-analyses and
136
Q8 191
a permissive RBC transfusion strategy in the guidelines have been published. Despite this evidence,
137 192
perioperative period (Conditional Recommendation, significant variability exists in clinical practice regarding
138 193
139
Moderate Certainty of Evidence). the indications for RBC transfusions, with most occurring 194
140 5. In critically ill patients with isolated elevation of in patients with hemoglobin levels of > 7 g/dL.3 195
141 196
serum troponin without other evidence of cardiac Although RBC transfusions can be life-saving, they carry
142 197
143
significant risks of adverse effects, including transfusion- 198
144 related acute lung injury, transfusion-associated 199
Honolulu, HI; the Section of Pulmonary, Critical Care, Allergy and
145 Immunologic Disease (P. J. M.), Section on Hematology and Oncology,
circulatory overload, and immunomodulating effects 200
146 Department of Medicine, Section on Critical Care Medicine, Depart- that may increase the risk of nosocomial infections.1,6 201
ment of Anesthesiology, Wake Forest School of Medicine, Winston- These side-effects may be severe and even life-
147 202
Salem; the Wilmington Health and MICU (K. O.), Novant New
148 Hanover Regional Medical Center, Wilmington, NC; the Division of threatening. The entire process, from distribution to 203
149 Pulmonary, Allergy, Critical Care and Sleep Medicine (K. M. P.), administration of RBCs, incurs substantial costs, which 204
Department of Medicine, University of Minnesota, Minneapolis, MN;
150 vary globally.7,8 Optimal health care delivery minimizes 205
the Division of Pulmonary, Critical Care and Sleep Medicine (L. V. V.),
151 Department of Medicine, University of Washington, Seattle, WA; the unnecessary RBC transfusions, preserving them for 206
152 Division of Pulmonary and Critical Care Medicine (D. R. O.), Henry 207
Ford Hospital, Detroit, MI; the Bruyere Research Institute (P. C. H.), patient groups with proven benefit. By optimizing the
153 208
University of Ottawa, Ottawa; the Population Health Research Insti- management of limited resources like RBCs, both
154 tute, (E. B.-C.), and the Department of Medicine (W. L.), McMaster 209
individual patients and the broader at-risk critically ill
155 University, Hamilton, ON, Canada. 210
156 DISCLAIMER: American College of Chest Physician guidelines are population stand to benefit.9 Given new evidence and 211
157
intended for general information only, are not medical advice, and do ongoing variability in practice, an expert panel 212
not replace professional medical care and physician advice, which al-
158 ways should be sought for any medical condition. The complete identified, synthesized, and weighted the evidence to 213
159 disclaimer for this guideline can be accessed at https://www.chestnet. provide clinical recommendations for RBC transfusion 214
org/Guidelines-and-Resources.
160 in critically ill patients. 215
Q4 CORRESPONDENCE TO: Angel O. Coz Yataco, MD; email: cozyata@
161 ccf.org 216
162 Copyright Ó 2024 The Author(s). Published by Elsevier Inc under li- 217
163 cense from the American College of Chest Physicians. This is an open Methods 218
access article under the CC BY-NC-ND license (http://
164 Standardized methodology for clinical practice guidelines 219
creativecommons.org/licenses/by-nc-nd/4.0/).
165 as per American College of Chest Physicians (CHEST) 220
DOI: https://doi.org/10.1016/j.chest.2024.09.016

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221 policy was followed. At this juncture, with several studies Study Selection and Data Extraction 276
222 underway in critically ill patients with neurologic injuries 277
Relevant citations identified during the literature
223 278
and the trauma population, we decided to forego recom- search were reviewed in duplicate using predefined
224 279
mendations in these critical care subgroups. criteria over 2 rounds of study selection: reviewing ti-
225 280
226
tles and abstracts in the first round and reviewing full 281
Expert Panel Composition
227 texts in the second round (e-Figs 1-6). Data were 282
The cochairs nominated a diverse and multidisciplinary
228 extracted, analyzed, and summarized for each individ- 283
panel based on their expertise encompassing critical
229 ual Population, Intervention, Comparator, and 284
care medicine, cardiology, hematology, and gastroenter-
230 Outcome question. 285
ology and hepatology. The final panel consisted of the 2
231 286
232
guideline cochairs, 9 panelists, 2 methodologists, 1 medi- Assessing the Quality of Evidence 287
233 cal librarian, and 1 liaison to CHEST Guidelines Oversight Risk of bias was assessed using the Cochrane Risk of Bias 288
234 Committee. Tool for RCTs and the Risk of Bias in Nonrandomized 289
235 Studies of Intervention based on study design.11,12 A 290
Conflicts of Interest
236 meta-analysis was performed when possible using a 291
237 Financial relationships for each chair and the panelists 292
random effects model. Results are reported as risk ratios
238 were reviewed by the CHEST Professional Standards 293
(RRs) for dichotomous outcomes and mean differences
239 Committee for potential conflicts of interest according 294
(MDs) for continuous outcomes with accompanying
240 to the CHEST Conflict of Interest Policy.10 295
241
95% CIs. The overall certainty of the evidence was 296
242
Question Development assessed for each outcome of interest using the Grading 297
243 The panel developed 6 clinical questions using the Pop- of Recommendations, Assessment, Development, and 298
244 ulation, Intervention, Comparator, and Outcome format Evaluations approach (e-Table 3).13 299
245 regarding the transfusion of RBC in different clinical 300
246
Development of Recommendations 301
scenarios. The panel ranked outcomes for each question
247 to determine critical and important outcomes a priori The panel reviewed and discussed the evidence. Recom- 302
248 mendations were drafted using the Grading of Recom- 303
(e-Table 1).
249 mendations, Assessment, Development, and 304
250 Literature Search Evaluations approach, with strong recommendations us- 305
251 A comprehensive search of MEDLINE, Embase, and the ing the wording “we recommend” and conditional rec- 306
252 307
Cochrane Central Register of Controlled Trials using ommendations using the wording “we suggest.”14
253 308
relevant key words was performed in May 2021 Panel members voted individually via SurveyMonkey
254 309
(e-Table 2), with an updated search performed in MED- on the direction and strength of the recommendation.15
255 310
LINE in January 2024. Searches were limited to English Per CHEST policy, consensus was achieved with
256 311
257
language randomized controlled trials (RCT), cohort 80% agreement in directionality with at least 75% of 312
258 studies, and case-control studies with at least 30 partic- the panel participating. The guidelines were reviewed 313
259 ipants. Systematic reviews and prior guidelines were and approved by the Guidelines Oversight Committee 314
260 reviewed for context and completeness. and CHEST presidential leadership. 315
261 316
262 317
263 Results 1. In critically ill patients, we recommend a restrictive 318
264 The hemoglobin thresholds prompting RBC transfusion RBC transfusion strategy over a permissive RBC 319
265 varied across studies, with a restrictive threshold transfusion strategy (Strong Recommendation, 320
266 generally defined as a hemoglobin level of 7 to 8 g/dL Moderate Certainty of Evidence). 321
267 and a permissive threshold typically ranging from a 322
268 hemoglobin level of 8.5 to 10 g/dL (Table 1). 323
Justification
269 324
Hemodynamic instability typically has been defined as
270 This recommendation, applicable to most critically 325
hypotension (mean arterial pressure, < 65 mm Hg, or
271 ill patients, is supported by evidence from several high- 326
systolic BP, < 100 mm Hg), tissue hypoperfusion caused
272 quality RCTs involving approximately 16,000 patients. 327
273
by acute bleeding, or both. 328
Comparisons between a restrictive and a permissive RBC
274 Question 1: Should critically ill patients be treated with transfusion strategy yielded no significant differences in 329
275 330
a restrictive or permissive RBC transfusion strategy? ICU mortality (RR, 1.00; 95% CI, 0.8-1.25),5,16-19 30-day

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331 TABLE 1 ] Hemoglobin Thresholds in Studies Included the publication of the TRICC trial,5 all studies have 386
Q32
332 per Recommendation favored a more restrictive approach with the possible 387
333 388
Hemoglobin Threshold, g/dL exception of the recently published MINT trial.20 In the Q11
334 389
Population Restrictive Permissive trials evaluating ICU mortality, the clinical teams were
335 390
Overall critically ill 7.0-8.0 9.0-10.0 encouraged strongly to transfuse 1 RBC unit at a time
336 391
Gastrointestinal bleeding 7.0-8.0 8.0-10.0 and repeat hemoglobin measurements after each unit.
337 392
338 Acute coronary syndrome 7.0-8.0 10.0
Using this approach, the number of RBC units 393
339 Underwent cardiac surgery 7.5-8.0 8.5-10.0
transfused was decreased by 50%.5,16-19 394
340 395
Isolated troponin elevation N/A N/A Given the complexity of ICU care, specific
341 396
Septic shock 7.0 9.0 subpopulations were addressed in subsequent
342 397
recommendations.
343 Data are presented as ranges. N/A ¼ no studies available. 398
344 What Others Are Saying 399
345 5,17-30 400
mortality (RR, 0.99; 95% CI, 0.87-1.13), or 1-year This recommendation aligned with those of other
346 31,32 401
mortality (RR, 0.99; 95% CI, 0.87-1.13). Although the professional societies, including the Critical Care
347 402
348
restrictive group exhibited a slightly longer ICU length of Societies Collaborative, the European Society of 403
349 stay (LOS) than the permissive group (MD, þ0.12 days; Intensive Care Medicine (ESICM), and the Association 404
350 95% CI, þ0.01 to þ0.23 days), this finding is not for the Advancement of Blood & Biotherapies.37-39 405
351 clinically significant. Additionally, no difference in 406
352 hospital LOS was found (MD, –0.2 days; 95% CI, –0.51 Research Priorities 407
353 to þ0.12 days).5,17-21,23-29,33-36 Although the use of restrictive RBC transfusion 408
354 strategies alone may not need much further inquiry, 409
355
The restrictive approach proved superior to the 410
using individual patient data meta-analysis may help to
356 permissive strategy in reducing adverse event rates (RR, 411
identify more specific subgroup effects, particularly in
357 0.45; 95% CI, 0.22-0.94), but not in reducing secondary 412
patients with various forms of cardiovascular diseases,
358 infections (RR, 1.03; 95% CI, 0.94-1.12). Similarly, no 413
ranging from acute ischemia to chronic heart diseases.
359 differences were found in organ-specific or system- 414
360
Research on measures of oxygen use or biomarkers of 415
specific adverse events, including cardiac, renal,
361
oxygen delivery in tissue beds and overall may allow 416
pulmonary, and thromboembolic complications
362 more targeted approaches to RBC transfusions. 417
(Table 2).5,18-30,33-36
363 418
Question 2: Should critically ill patients who have
364 Given the absence of a discernible impact on mortality 419
acute gastrointestinal bleeding be treated with a
365 and the potential reduction in overall adverse events, a 420
restrictive or permissive RBC transfusion strategy?
366 restrictive approach was determined to be the preferred 421
367 strategy. This approach minimized RBC use without any 2. In critically ill patients with acute gastrointestinal 422
368 clinical consequences in most critically ill patients. Since bleeding, we recommend a restrictive RBC transfusion 423
369 424
370 425
371
TABLE 2 ] Pooled Analysis Comparing Restrictive vs Permissive Strategies in Overall Critically Ill Patients 426
372 Outcome Relative Risk (95% CI) Absolute Risk (95% CI) 427
373 ICU mortality 1.00 (0.80-1.25) 0 fewer per 1,000 (46 fewer-57 more) 428
374 429
1-y mortality 0.99 (0.87-1.13) 4 fewer per 1,000 (54 fewer-54 more)
375 430
30-d mortality 0.99 (0.87-1.13) 1 fewer per 1,000 (14 fewer-14 more)
376 431
ICU length of stay 0.12 d higher (0.01 higher-0.23 higher) Q33
377 432
378 Hospital length of stay 0.2 d lower (0.51 lower-0.12 higher) 433
379 Adverse events 0.45 (0.22-0.94) 8 fewer per 1,000 (11 fewer-1 fewer) 434
380 Secondary infections 1.03 (0.94-1.12) 3 more per 1,000 (6 fewer-13 more) 435
381 Cardiac adverse events 0.94 (0.77-1.16) 4 fewer per 1,000 (16 fewer-11 more) 436
382 Renal adverse events 0.99 (0.89-1.10) 1 fewer per 1,000 (9 fewer-8 more) 437
383 438
Pulmonary adverse events 0.98 (0.88-1.08) 2 fewer per 1,000 (15 fewer-10 more)
384 439
Thromboembolism 0.83 (0.60-1.15) 4 fewer per 1,000 (9 fewer-3 more)
385 440

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441 strategy over a permissive RBC transfusion strategy Given the lower risk of mortality and adverse reactions, 496
442 (Strong Recommendation, Moderate Certainty of the adoption of a restrictive transfusion strategy 497
443 498
Evidence). emerged as the preferred recommendation. The
444 499
restrictive strategy was superior in patients with and
445 500
Justification without portal hypertension-related GIB. Notably,
446 501
Acute gastrointestinal bleeding (GIB) is a life- portal pressure gradients increased in patients treated
447 502
448 threatening condition that often necessitates ICU care, with a permissive strategy within the first 5 days of 503
449 including the critical decision of when to transfuse bleeding onset.24 504
450 RBCs. We identified 3 relevant RCTs that included 505
451 What Others Are Saying 506
patients with acute upper GIB and an observational
452 507
study of patients with acute lower GIB.24-26,40 This recommendation aligned with those of the
453 American Association for the Study of Liver Diseases, 508
454 Villanueva et al24 randomized 921 patients with acute the American College of Gastroenterology, and the 509
455 upper GIB and early access to endoscopy to either a 510
American Gastroenterological Association.41-44
456 restrictive or permissive RBC transfusion strategy. The 511
457 restrictive approach led to lower rates of rebleeding, 512
Research Priorities
458 513
fewer adverse events, and lower 6-week all-cause
459 Studying the feasibility, implementation, and adherence 514
mortality. An open-label, cluster RCT with 936 patients
460 to a restrictive transfusion strategy in acute GIB is a 515
reported no significant mortality difference between
461 priority. Additionally, examining interprofessional 516
both RBC transfusion strategies, but noted lower
462 knowledge transmission through a systems-based 517
463
transfusion rates and decreased health care costs with 518
approach that adheres to the principles of quality
464 the restrictive approach.26 A smaller single-center open- 519
improvement is essential.
465 label RCT showed that a restrictive approach was 520
466 noninferior to a permissive strategy.25 In aggregate, the Question 3: Should critically ill patients with acute 521
467 restrictive transfusion strategy reduced short-term coronary syndrome be treated with a restrictive or 522
468 mortality (RR, 0.68; 95% CI, 0.48-0.97) without affecting permissive RBC transfusion strategy? 523
469 hospital LOS (MD, –0.69 days; 95% CI, –1.98 524
470 to þ0.60 days). 3. In critically ill patients with acute coronary 525
471 syndrome, we suggest against a restrictive RBC 526
472 The restrictive approach proved superior to the transfusion strategy (Conditional Recommendation, 527
473 permissive strategy with lower risk of acute transfusion Low Certainty of Evidence). 528
474 reactions and serious adverse transfusion effects. 529
475 However, no significant differences were found in the Justification 530
476 risk of infections, need for surgery in upper GIB 531
The optimal transfusion strategy for patients with acute
477 532
(Table 3), or organ-specific or system-specific adverse coronary syndrome (ACS) has been controversial,
478 533
events, including cardiac, renal, pulmonary, and balancing improved oxygen delivery to the myocardium
479Q12 534
thromboembolic (EP-2). The data on lower GI bleeding against the potential expansion of vascular volume and
480 535
was limited to a retrospective study, which did not show increase in blood viscosity from overtransfusion.45 This
481 536
482
differences in mortality or need for surgery between a recommendation is supported by 4 RCTs involving a 537
483 restrictive and a permissive approach.40 total of 4,324 patients.20-23 538
484 539
485 540
TABLE 3 ] Pooled Analysis Comparing Restrictive vs Permissive Strategies in Gastrointestinal Bleeding
486 541
487 Outcome Relative Risk (95% CI) Absolute Risk (95% CI) 542
488 30-d mortality 0.68 (0.48-0.97) 27 fewer per 1,000 (43 fewer-2 fewer) 543
489 Hospital length of stay 0.69 d lower (1.98 lower-0.6 higher) 544
Q34

490 545
Need for surgery in upper gastrointestinal bleeding 0.67 (0.16-2.91) 13 fewer per 1,000 (33 fewer-74 more)
491 546
Acute transfusion reactions 0.35 (0.20-0.61) 37 fewer per 1,000 (45 fewer-22 fewer)
492 547
Adverse transfusion effectsa 0.73 (0.58-0.91) 54 fewer per 1,000 (83 fewer-18 fewer)
493 548
494 Infections in upper gastrointestinal bleeding 0.96 (0.79-1.17) 11 fewer per 1,000 (58 fewer-47 more) 549
495 a 550
Serious adverse events defined as an event that endangers the health or safety of the patient.

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551 The pooled analysis showed a trend toward higher restrictive transfusion strategy outweighed the potential 606
552 mortality with the restrictive approach (RR, 1.13; benefits on lower rates of infection and 607
553 608
95% CI, 0.67-1.91), but this difference was not thromboembolism.
554 609
statistically significant. The MINT trial substantially
555 What Others Are Saying 610
influenced this analysis because of its large sample size
556 611
because it recruited 3 times more patients than the other The ESICM guidelines, released before the publication of
557 612
558
studies combined. The 30-day mortality in the restrictive the MINT trial, suggested an RBC transfusion threshold 613
559 group was 9.9%, compared with 8.3% in the permissive of 9 to 10 g/dL in patients with ACS.20,37 However, given 614
560 group, a difference not reaching statistical significance that it is unclear if a difference in outcomes occurs at 615
561 (RR, 1.19; 95% CI, 0.96-1.47). However, cardiac death higher hemoglobin levels, even in the range of a 616
562 rates were 5.5% in the restrictive group and 3.2% in the permissive approach, the panel opted to suggest against 617
563 permissive group (RR, 1.74; 95% CI, 1.26-2.40). a restrictive approach. 618
564 Moreover, the point estimates for myocardial infarction 619
565 Research Priorities 620
(MI) or death and for recurrent MI consistently favored
566 621
the permissive strategy.20 Although a statistically Studies exploring the impact on patient outcomes of a
567 restrictive hemoglobin threshold of 8 g/dL or 9 g/dL are 622
significant increase in adverse outcomes such as death
568 623
and recurrent MI might not have been found, concern necessary. Further exploration of effect modifiers within
569 624
exists that a restrictive approach allowing hemoglobin the MINT trial may help to guide clinicians. Subgroup
570 625
levels of 7 or 8 g/dL might increase the risk of adverse analysis, especially focused on type 1 MI vs 2 MI, as well
571 626
572 outcomes in patients with acute MI. From these data, it as patients with heart failure and chronic kidney disease, 627
573 was unclear whether a gradient effect was present in are welcomed. 628
574 which risk progressively increased to < 10 g/dL or a Question 4: Should critically ill patients undergoing 629
575 threshold effect at 10 g/dL. That is, these data do not 630
cardiac surgery be treated with a restrictive or
576 indicate whether 9 g/dL is as safe as 10 g/dL. Patient 631
permissive RBC transfusion strategy?
577 symptoms and physiologic variables should be 632
578 considered when choosing a transfusion threshold for 4. In critically ill patients undergoing cardiac surgery, 633
579 we suggest a restrictive RBC transfusion strategy over 634
patients with ACS.
580 a permissive transfusion strategy in the perioperative Q13 635
581 Long-term follow-up of patients described a 1-year period (Conditional Recommendation, Moderate 636
582 mortality of 23.1% in the restrictive and 20.4% in the 637
Certainty of Evidence).
583 permissive group (RR, 1.87; 95% CI, 0.74-4.69).31 638
584 Moreover, no significant differences were identified in Justification 639
585 640
hospital LOS, ICU LOS, or the risk of adverse events This recommendation is substantiated by 7 high-quality
586 641
(Table 4). Overall, the increased point estimates in the clinical trials mostly of patients undergoing coronary
587 642
risk of 30-day mortality, need for revascularization, and artery bypass graft, valvular surgery, or both.27-29,33-36
588 643
cardiac and renal adverse effects associated with a Despite the moderate certainty of evidence, a
589 644
590 645
591 TABLE 4 ] Pooled Analysis Comparing Restrictive vs Permissive Strategies in Patients With Acute Coronary 646
592 Syndrome 647
593 648
Outcome Relative Risk (95% CI) Absolute Risk (95% CI)
594 649
30-d mortality 1.13 (0.67-1.91) 10 more per 1,000 (26 fewer-73 more)
595 650
596 Need for revascularization 1.09 (0.73-1.63) 2 more per 1,000 (6 fewer-13 more) 651
597 Hospital length of stay MD 0.02 d more (0.37 fewer-0.41 more) Q35 652
598 Adverse transfusion effects 1.87 (0.31-11.06) 1 more per 1,000 (1 fewer-10 more) 653
599 Infections 0.87 (0.17-4.40) 10 fewer per 1,000 (61 fewer-252 more) 654
600 655
Cardiac adverse events 1.16 (0.94-1.45) 10 more per 1,000 (4 fewer-29 more)
601 656
Renal adverse events 1.06 (0.84-1.32) 7 more per 1,000 (20 fewer-39 more)
602 657
Thromboembolism 0.75 (0.46-1.24) 5 fewer per 1,000 (10 fewer-5 more)
603 658
604 Pulmonary adverse events 0.96 (0.77-1.19) 3 fewer per 1,000 (17 fewer-14 more) 659
605 660
MD ¼ mean difference.

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661 conditional recommendation was issued because the Society of Thoracic Surgeons, which recommend a 716
662 studies showed serious imprecision in the point restrictive approach in this patient population.37,46 717
663 718
estimates for several outcomes.
664 Research Priorities 719
665 Three studies examined 30-day mortality comparing 720
Further research may clarify the optimal RBC
666 both transfusion strategies in patients undergoing 721
transfusion strategy for patients undergoing cardiac
667 cardiac surgery.27-29 Mazer et al27 enrolled 5,243 722
668
surgery. The TRICS-IV trial, currently underway, Q14
723
patients, showing that a restrictive strategy was
669
compares the two transfusion strategies in moderate to 724
noninferior to a permissive approach and led to 20% less
670 high-risk patients 65 years of age and younger to ensure 725
patients receiving RBC transfusions. Two smaller
671 that the benefits of a restrictive strategy also apply to this 726
studies, although using slightly different transfusion
672 younger high-risk patient population.47 727
thresholds, yielded similar outcomes.28,29 In aggregate,
673 728
no significant difference was found between the Question 5: Should critically ill patients with an
674 729
675 restrictive and permissive RBC transfusion threshold for isolated elevation of serum troponin levels without 730
676 30-day mortality (RR, 1.12; 95% CI, 0.95-1.32). The other evidence of cardiac ischemia be treated with a 731
677 hospital LOS did not differ between strategies (MD, restrictive or a permissive RBC transfusion strategy? 732
678 –0.02 days; 95% CI, –0.19 to þ0.15 days), whereas the 5. In critically ill patients with isolated elevation of 733
679 ICU LOS favored the permissive strategy (MD, 734
serum troponin without other evidence of cardiac
680 0.12 days; 95% CI, 0.03-0.21 days), a finding without ischemia, we suggest a restrictive RBC transfusion
735
681 clinical significance.27-29,33-36 736
682
strategy over a permissive RBC transfusion strategy 737
683 One small study evaluated adverse transfusion reactions, (Conditional Recommendation, Very Low Certainty of 738
684 but reported no events in either group.36 No differences Evidence). 739
685 were found between the restrictive and permissive 740
Justification
686 strategies in terms of infections, thromboembolism, or 741
687 cardiac, renal, or pulmonary complications No data are available regarding RBC transfusion 742
688 (Table 5).27-29,33-36 thresholds for critically ill patients with isolated elevated 743
689 troponin levels without evidence of cardiac ischemia, 744
690 Overall, no important differences in outcomes or defined as clinical symptoms, ECG changes, or both 745
691 adverse events were noted between strategies among the consistent with ischemia.48 Despite the absence of 746
692 8,208 patients enrolled in the 7 trials. However, 747
evidence, the panel identified this as an important
693 considering the 40% lower number of RBC units 748
clinical question and formulated a recommendation
694 transfused to patients in the restrictive group, a 749
using the collective experience approach recommended
695 750
restrictive strategy is the preferred approach.28 by the Grading of Recommendations, Assessment,
696 751
697 Development, and Evaluations criteria, considering 752
What Others Are Saying several factors. First, no universally agreed-on definition
698 753
699 This recommendation aligned with those of other for elevated troponin exists. This is attributable to the 754
700 professional societies, including the ESICM and the availability of various troponin assays for clinical use, 755
701 756
702 757
TABLE 5 ] Pooled Analysis Comparing Restrictive vs Permissive Strategies in Patients Who Have Undergone
703 Cardiac Surgery 758
704 759
Outcome Relative Risk (95% CI) Absolute Risk (95% CI)
705 760
706 30-d mortality 1.12 (0.95-1.32) 8 more per 1,000 (3 fewer-21 more) 761
707 ICU length of stay MD 0.12 d more (0.03 more-0.21 more) 762
Q36

708 Hospital length of stay MD 0.02 d lower (0.19 lower-0.15 higher) 763
709 Infections 1.07 (0.94-1.22) 6 more per 1,000 (5 fewer-19 more) 764
710 765
Cardiac adverse events 1.00 (0.75-1.32) 0 fewer per 1,000 (14 fewer-18 more)
711 766
Renal adverse events 1.03 (0.86-1.23) 2 more per 1,000 (7 fewer-12 more)
712 767
Thromboembolism 0.82 (0.36-1.88) 2 fewer per 1,000 (8 fewer-10 more)
713 768
714 Pulmonary adverse events 1.05 (0.89-1.24) 6 more per 1,000 (14 fewer-30 more) 769
715 770
MD ¼ mean difference.

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771 resulting in variability in both reported units and administration and hemodynamic stabilization. 826
772 accepted normal troponin values.49 Moreover, troponin Moreover, RBC transfusion practices in septic shock 827
773 828
levels represent a test value, rather than a specific clinical have shifted54,55 toward a restrictive approach.39,56,57
774 829
diagnosis, particularly in critically ill patients, in whom Consequently, the addition of RBC transfusions to usual
775 830
elevated troponin levels may indicate diverse conditions care, aiming for higher hemoglobin levels, implies a
776 831
unrelated to ACS.50-53 Considering the heterogeneity of permissive transfusion strategy, whereas usual care
777 832
778
conditions leading to elevated troponin levels in the adheres to a restrictive approach. Studies evaluating 833
779 absence of acute cardiac ischemia, the risk-benefit RBC transfusions as part of a resuscitation bundle were 834
780 assessment regarding RBC transfusion strategy will not included, because the effect of transfusions could not 835
781 depend on individual clinical circumstances. In general, be isolated from the effect of other bundle elements. 836
782 we suggest adopting a restrictive RBC transfusion 837
This recommendation is informed by 3 RCTs and long-
783 strategy as the first-line approach. However, the decision 838
784
term follow-up of an RCT cohort.16,19,30,32 Two of the 839
to transfuse should consider various clinical factors,
785
RCTs focused on general critically ill patients, whereas 1 840
including vasculopathy, intravascular volume status,
786 RCT included patients with cancer, all of whom had 841
troponin level and rate of rise, biventricular cardiac
787 septic shock, with higher RBC transfusion rates in the 842
function, myocardial strain or trauma, renal
788 permissive groups compared with the restrictive groups. 843
dysfunction, sepsis, and surrogates of end-organ
789 844
perfusion. In certain circumstances, clinicians may TRISS, the largest study including > 1,000 patients, Q16
790 845
791
choose to transfuse RBCs to increase oxygen-carrying reported similar 30-day mortality rates in the permissive 846
792 capacity. (35%) and restrictive (33%) approaches.30 In patients 847
793 with cancer, lower, albeit not statistically significant, 30- 848
What Others Are Saying day mortality (hazard ratio, 0.74; 95% CI, 0.53-1.04;
794 849
795 No recommendations from other professional societies P ¼ .08) and ICU mortality rates (33.6% vs 43.7%; 850
796 have been published. P ¼ .071) were reported in the permissive compared 851
797 with the restrictive group,19 findings consistent with a 852
798
Question 6: Should critically ill patients with septic 853
smaller study in general critically ill patients.16 The
799 shock with end-organ hypoperfusion be treated with 854
pooled analysis showed no significant difference
800 RBC transfusion in addition to usual care or usual 855
between permissive and restrictive RBC transfusion
801 care alone? 856
strategies in terms of ICU mortality (RR, 0.84; 95% CI,
802 857
6. In patients with septic shock and end-organ 0.62-1.13) or 30-day mortality (RR, 0.93; 95% CI,
803 858
804
hypoperfusion, we suggest against adding permissive 0.72-1.21). Longer-term follow-up at 1 year reported 859
805 RBC transfusion thresholds to usual care (Conditional mortality rates of 55.8% in the permissive group and 860
806 Recommendation, Low Certainty of Evidence). 53.5% in the restrictive cohort (RR, 0.97; 95% CI, 861
807 0.85-1.09; P ¼ .62).32 No difference was found in terms 862
Q15 Remarks: Studies evaluating protocol driven approaches
808 of ICU and hospital LOS between both strategies. 863
to goal-directed therapy in septic shock were not
809 864
considered in the evidence review. Given that the studies evaluating adverse transfusion
810 865
811
reactions were not powered a priori to detect such 866
Justification events, the number of events was very low. No strategy
812 867
813 Sepsis care has evolved over the last 2 decades, with was superior regarding the need for renal replacement, 868
814 usual care including prompt antibiotic and fluid cardiac, or pulmonary complications (Table 6).19,30 869
815 870
816 TABLE 6 ] Pooled Analysis Comparing Permissive vs Restrictive Strategies in Patients With Septic Shock 871
817 872
Outcome Relative Risk (95% CI) Absolute Risk (95% CI)
818 873
819 ICU mortality 0.84 (0.62-1.12) 71 fewer per 1,000 (169 fewer-58 more) 874
820 30-d mortality 0.93 (0.72-1.21) 27 fewer per 1,000 (108 fewer-81 more) 875
821 Adverse transfusion reactions 0.33 (0.01-8.15) 1 fewer per 1,000 (2 fewer-11 more) 876
822 Need for renal replacement therapy 0.98 (0.61-1.57) 2 fewer per 1,000 (34 fewer-50 more) 877
823 878
Cardiac complications 0.60 (0.27-1.31) 11 fewer per 1,000 (19 fewer-8 more)
824 879
Pulmonary complications 1.05 (0.60-1.82) 10 more per 1,000 (77 fewer-159 more)
825 880

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881 Overall, although the data show that the permissive critically ill population, a restrictive approach is 936
882 strategy might result in benefit, it does not exclude deemed cost-effective overall and among most 937
883 938
possible harm because the RR crosses the null threshold. subpopulations because no significant impact on
884 939
In the absence of clear benefit and with similar rates of overall mortality in any major subgroups was
885 940
adverse effects, neither strategy is deemed clinically observed, except for ACS. Therefore, in the general
886 941
favorable. However, a restrictive approach results in critically ill population, in the absence of benefit
887 942
888
fewer RBC units transfused, optimizing resource use and resulting from a permissive strategy, a restrictive 943
889 decreasing costs.30 strategy would be considered a preferred option 944
890 under most circumstances. 945
What Others Are Saying
891 946
892 The recommendation to not add a permissive RBC Equity 947
893 transfusion strategy to usual care aligns with the most Access to RBC transfusions is influenced by geographic 948
894 recent ESICM and the Surviving Sepsis Campaign location and resource allocation. A restrictive RBC 949
895 guidelines.37,58 transfusion strategy can reduce inequity by ensuring that 950
896 951
individuals most in need of RBCs receive them. This
897 Research Priorities 952
may be even more relevant during major blood
898 Future studies including populations typically 953
shortages or in rural areas with limited resources.
899 954
underrepresented in sepsis trials, such as patients with Moreover, in countries with higher rates of blood-borne
900 955
malignancies (solid and hematologic), liver disease, and infections, a restrictive approach will reduce exposure.
901 956
chronic coronary disease, are welcome. Additionally, However, the impact of provider biases on transfusion
902 957
903
further evidence is needed regarding the benefits of RBC practices in settings of limited RBC availability remains 958
904 transfusions in severe hypoxemia or tissue unclear. 959
905 hypoperfusion. 960
906 Acceptability and Feasibility 961
907 Additional Considerations The evidence suggested that most practitioners and 962
908 centers have adopted a restrictive RBC transfusion 963
The statements on cost, equity, acceptability, feasibility,
909 964
and implementation were consolidated, given the strategy, indicating stakeholder acceptability.63
910 965
significant overlap across various Population, However, some patients may reject transfusions
911 966
Intervention, Comparator, and Outcome questions. based on personal values or religious beliefs.64 The
912 967
panel believed that implementing restrictive
913 968
Cost transfusion strategies is feasible through behavior
914 969
915 Economic considerations are important when deciding modification interventions, including education, 970
916 on RBC transfusion strategies for critically ill patients. In institutional guidelines, and audit and feedback. 971
917 the United States, the hospital cost of an RBC unit is Furthermore, additional blood conservation 972
918 approximately $207,59 with administrative, logistic, and strategies, such as reduced laboratory testing, 973
919 labor costs totaling up to $1,183.60,61 A restrictive optimization of perioperative antiplatelet and 974
920 strategy spares 36% of patients from RBC transfusions, anticoagulation regimens, intraoperative blood 975
921 reduces the number of RBC units transfused by 50%, conservation, and small-volume blood sampling, are 976
922 977
and reduces costs by 33% compared with a permissive crucial. These interventions have demonstrated
923 978
approach.28,30 effectiveness in reducing the odds of transfusion,
924 979
inappropriate transfusion rates, and the number of
925 Cost-effectiveness analysis of RBC transfusions in 980
RBC units transfused per patient.65-67
926 patients undergoing cardiac surgery revealed that 981
927 expenses from surgery to the third postoperative month 982
Implementation
928 were slightly higher in the permissive group than in the 983
929 For patients reluctant to accept transfusions based 984
restrictive group, driven by RBC costs. However, the
930 on personal values or religious beliefs, a thorough 985
differences in quality-adjusted life-years were negligible.
931 discussion with the patient or surrogate should 986
Therefore, the restrictive strategy in these patients was
932 occur before deciding to transfuse. As soon as an 987
933
considered cost-effective.62 988
RBC transfusion is decided on, the optimal
934 Although a definitive evaluation of cost-effectiveness implementation strategy encompasses a restrictive 989
935 990
is challenging because of limited studies in the approach and transfusing 1 RBC unit at a time. This

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991 1046
CRITICALLY ILL PATIENT - RBC
992 1047
TRANSFUSION BEING CONSIDERED
993 1048
994 1049
995 1050
996 Acute 1051
997 bleeding with 1052
Resuscitate Yes hemodynamic
998 1053
instability?
999 1054
1000 No 1055
1001 No 1056
1002 Bleeding 1057
Controlled? Yes
1003 1058
1004 New New 1059
1005 bleeding bleeding 1060
1006 1061
1007 OTHER 1062
POST- ISOLATED ACUTE
SEPTIC GI MEDICAL
1008 CARDIAC TROPONIN CORONARY 1063
SHOCK BLEED CRITICAL
1009 SURGERY ELEVATION SYNDROME 1064
ILLNESS
1010 1065
1011 1066
1012 1067
1013 1068
Transfuse 1 unit of Hgb Transfuse 1 unit of Hgb
1014 PRBC and Yes < 7-8 g/dL? PRBC and Yes < 9-10 g/dL? 1069
1015 recheck Hgb recheck Hgb 1070
1016 1071
1017 No No 1072
1018 1073
1019 1074
print & web 4C=FPO

Hemoglobing target Hemoglobing target

1020 1075
6 7 8 9 10
1021 1076
1022 HEMOGLOBIN (g / dL) 1077
1023 1078
Figure 1 – ---. Q31Q39
1024 1079
1025 1080
1026 threshold and single-unit recommendation does not Summary 1081
1027 apply to patients actively bleeding at a rate In the United States, approximately 5 million 1082
1028 exceeding the ability to transfuse single units or 1083
patients are admitted to the ICU annually, and
1029 await hemoglobin test results safely. The 1084
one-quarter of them receive RBC transfusions
1030 1085
recommendation can be applied to patients whose during their stay.1-3,73 Most clinical trials support a
1031 1086
acute bleeding has subsided. If acute bleeding occurs restrictive transfusion strategy, showing no
1032 1087
during a patient’s stay, this approach should be significant differences in mortality or adverse
1033 1088
1034
suspended and then reapplied after bleeding is outcomes overall and in all patient subgroups, 1089
1035 controlled (Fig 1). except for critically ill patients with ACS.20,22,23 1090
1036 Adopting a restrictive strategy could decrease the 1091
The panel suggested conducting audits or
1037 number of patients receiving RBC transfusions by 1092
observational studies using hospital databases to
1038 approximately 40%.38 On a large scale, this could 1093
understand current practices. Proven
1039 represent sparing 0.5 million patients from RBC 1094
1040
implementation strategies to overcome barriers to 1095
transfusions.
1041 changing transfusion include academic detailing, 1096
1042 audit-feedback approaches, standard order sets, A limitation of this guideline is the quality of the 1097
1043 computerized order entry decision support, evidence, which ranged from moderate to very low. 1098
1044 reminders, and alerts. These approaches require For conditions like ACS and septic shock, the 1099
1045 resources, leadership, and clinical oversight.68-72 number of studies was small, and the inferences 1100

10 Guideline and Consensus Statement [ -#- CHEST - 2024 ]

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1101 were not strong. No studies specifically addressed w:text¼When%20supplies%20are%20low%20it,meet%20hospital% 1156
1102 20and%20patient%20needs 1157
critically ill patients with elevated troponin levels.
1103 9. Lotterman S, Sharma S. Blood transfusion. StatPearls. StatPearls 1158
Moreover, the studies did not assess additional Publishing; 2023. Updated June 20, 2023. National Library of
1104 Medicine website. https://www.ncbi.nlm.nih.gov/books/NBK4 1159
aspects of the transfusion process (storage age,
1105 99824/ 1160
Q23
donor characteristics, processing, storage solutions).
1106 10. American College of Chest Physicians (CHEST). Chest guideline 1161
These guidelines provide an opportunity for development and submissions. American College of Chest
1107 1162
institutions to develop local policies, monitor their Physicians website. https://www.chestnet.org/guidelines-and-topic-
1108 collections/guidelines/topic-submissions 1163
Q24

1109 impact on transfusion practices, and to create a 11. Boutron, et al. Considering bias and conflicts of interest among the 1164
1110 framework to longitudinally optimize RBC use. included studies. In: Cochrane Handbook for Systematic Reviews of 1165
Interventions. Version 6.3. 2022. The Cochrane Collaboration
1111 website. Accessed November, 2022, https://training.cochrane.org/ 1166
1112Q17 handbook/current/chapter-07 1167
Q25
Funding/Support
1113 12. Higgins, et al. Assessing risk of bias in a randomized trial. In: 1168
1114 The authors have reported to CHEST that no funding Cochrane Handbook for Systematic Reviews of Interventions. Version 1169
6.3. 2022. The Cochrane Collaboration website. Accessed November,
1115 was received for this study. 2022, https://training.cochrane.org/handbook/current/chapter-08 1170
Q26

1116 13. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 1171
1117Q18 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4): 1172
Financial/Nonfinancial Disclosures 401-406.
1118 1173
1119 None declared. 14. Andrews JC, Schunemann HJ, Oxman AD, et al. GRADE guidelines:
1174
15. Going from evidence to recommendation-determinants of a
1120 recommendation’s direction and strength. J Clin Epidemiol. 1175
1121 Acknowledgments 2013;66(7):726-735. 1176
1122 Author contributions: A. C. Y., I. S., and D. R. O had full access to all 15. Jaeschke R, Guyatt GH, Dellinger P, et al. Use of GRADE grid to 1177
the data in the study and take full responsibility for the integrity of the reach decisions on clinical practice guidelines when consensus is
1123 data and the accuracy of the data analysis. P. C. H., E. B.-C., M. D., elusive. BMJ. 2008;337:a744. 1178
1124Q19 P.F., K. H., J. M. I., W. L., C. C. L., P. J. M., K. O., K. M. P., and L. V. V. 16. Mazza BF, Freitas FG, Barros MM, Azevedo LC, Machado FR. 1179
1125 contributed substantially to the study design, data interpretation, and Blood transfusions in septic shock: is 7.0 g/dL really the 1180
writing of the manuscript. appropriate threshold? Rev Bras Ter Intensiva. 2015;27(1):36-43. 1181
1126
Q20 Additional information: The e-Appendix, e-Figures, and e-Tables are 17. Hebert PC, Wells G, Marshall J, et al. Transfusion requirements in 1182
1127
available online under “Supplementary Data.” critical care. A pilot study. Canadian Critical Care Trials Group.
1128 JAMA. 1995;273(18):1439-1444. 1183
1129 1184
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