- Email: [email protected]
End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions
Accepted Manuscript Title: End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions Author: Jan A. Graw, Claudia D. Spies, Klaus-D. Wernecke, Jan-P. Braun PII: DOI: Reference:
S1473-0502(16)00051-3 http://dx.doi.org/doi: 10.1016/j.transci.2016.03.005 TRASCI 1978
To appear in:
Transfusion and Apheresis Science
Received date: Revised date: Accepted date:
11-1-2016 21-3-2016 22-3-2016
Please cite this article as: Jan A. Graw, Claudia D. Spies, Klaus-D. Wernecke, Jan-P. Braun, End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions, Transfusion and Apheresis Science (2016), http://dx.doi.org/doi: 10.1016/j.transci.2016.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions
Jan A. Graw1, Claudia D. Spies1, Klaus-D. Wernecke2, Jan-P. Braun3 1
Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and
Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Germany 2
Charité - Universitätsmedizin Berlin and SOSTANA GmbH, Berlin, Germany
3
Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum
Hildesheim, Germany
Short title: Withholding blood transfusions in the SICU Address of correspondence: Jan A. Graw, MD Department of Anesthesiology and Intensive Care Medicine Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum Charitéplatz 1, 10117 Berlin Tel. +49 (30) 450 531051 ; Fax: +49 (30) 450 531911 E-mail: [email protected]
Total words in manuscript: 3006 1 Page 1 of 19
Abstract
Background: End-of-life decisions (EOLD) are common on the intensive care unit (ICU). EOLDs underlie a dynamic process and limitation of ICU-therapies is often done sequentially. Questionnaire-based and observational studies on medical ICUs and in palliative care reveal blood transfusions as the first therapy physicians withhold as an EOLD.
Methods: To test whether this practice also applies to surgical ICU-patients, in an observational study, all deceased patients (n=303) admitted to an academic surgical ICU in a three-year period were analyzed for the process of limiting ICU-therapies.
Results: Restriction of further surgery (85.4%) and limiting doses of vasopressors (75.8%) were the most frequent forms of limitations in surgical ICU therapies. Surgical patients, who had blood transfusions withheld (44.6%), had more ICU-therapies withheld or withdrawn simultaneously than patients who had transfusions maintained (5±2 vs. 2±1, p<0.001). Secondary EOLDs and subsequent limitations occurred less frequently in patients that had transfusions withheld with their first EOLD (17.1% vs. 35.6%, p<0.05).
Conclusion: Limitation orders for blood transfusions are not a prioritized decision in EOLDs of surgical ICU patients. Withholding blood transfusions correlates with discontinuation of further significant life-support therapies. This suggests that EOLDs to withhold blood transfusions are part of the most advanced limitations of therapy on the surgical ICU.
2 Page 2 of 19
Keywords: end-of-life decision, blood transfusion, intensive care medicine, surgical intensive care unit, withholding therapy, limitation order
3 Page 3 of 19
Introduction
Decisions to limit life-sustaining treatment precede most deaths on European intensive care units (ICUs) [1-3]. End-of-life decisions (EOLDs) underlie a dynamic process where intensive care therapy shifts from full life-support to a palliative approach. ICU-therapies that are commonly limited include endotracheal intubation, mechanical ventilation, renal replacement therapy, catecholamine infusions, surgery, antimicrobial therapy, blood product transfusions, nutrition and hydration. Most patients on the ICU require several of those interventions and physicians generally withhold or withdraw therapeutic approaches sequentially in an EOLD [3,4].
Questionnaire-based studies revealed that in palliative care blood transfusions are the most likely therapy that physicians from different medical backgrounds would like to withdraw first [5,6]. Blood transfusions are a life saving therapy and one of the most common procedures in intensive care medicine [7]. Besides culture, religion, and legislation, a physician’s base specialty influences his decision making in end-of-life therapy [8-10]. Surgery often is part of vigorous efforts to reverse acute life-threatening illnesses [9]. Furthermore, patients admitted to the ICU postoperatively receive on average more blood transfusions than those admitted for medical reasons [11].
To our knowledge no observational data exist about physician preferences to withhold or withdraw blood transfusions on surgical ICU-patients. Therefore, in a retrospective analysis 4 Page 4 of 19
on our surgical ICU we analyzed the sequence of ICU-therapies that were limited and compared characteristics and the decision making process in surgical ICU-patients who had blood transfusions withheld with surgical ICU-patients who continued to receive blood products after an EOLD.
5 Page 5 of 19
Methods
The study was approved from the Medical Ethics Committee of Charité University Hospital (number of ethical approval EA1/292/10). All patients (n=4510) admitted between August 2008 and September 2011 to a 22-bed academic ICU with twenty-four/seven coverage by board certified intensive care medicine consultants, were included in the study. Two hundred twenty-six (74.6%) of all deceased patients (n=303) were surgical ICU patients and 157 (69.5%) of them received a decision to “withhold or withdraw life support” (WH/WDLS) [10].
Decisions to limit life-sustaining ICU-treatment such as “Do-not-resuscitate” (DNR) orders and WH/WDLS orders were taken in EOLD conferences as prescribed previously [3]. Every participant of the EOLD-conference had to give consent to the decision when associated life support was withheld or withdrawn. WH/WDLS orders differentially included withholding or withdrawing endotracheal intubation, mechanical ventilation, renal replacement therapy, catecholamine infusions, surgery, antimicrobial therapy, blood product transfusions, nutrition, and fluid therapy. Non-documented treatment options were considered continued. As the withdrawal of a blood transfusion literally relates to a discontinuation of an ongoing transfusion we used the term “withholding” for both the “withholding” and “withdrawing” of blood products. Collected data always refer to a patient’s first WH/WDLS decision. Time, participants and the results of end-of-life conferences were documented in the daily progress
6 Page 6 of 19
notes in an electronic patient data management system (PDMS) (Copra System, Sabachswalden, Germany). Furthermore, all documentation of ward rounds, orders and progress notes, as well as data from vital signs monitors, daily ICU scores like the simplified acute physiology score II (SAPS II) and sequential organ failure assessment (SOFA), and all medical or nursing events to the patient were prospectively recorded in the PDMS.
Results are expressed as arithmetic mean ± standard deviation (SD) or median with interquartile range [IQR] for continuous variables, as appropriate and frequencies (%) for categorical variables. Differences between groups were tested by the non-parametric (exact) Wilcoxon-Mann-Whitney test for independent groups. Frequencies were tested by the (exact) Chi-square-test. A two-tailed p-value <0.05 was considered statistically significant. All tests were conducted in the area of exploratory data analysis. Therefore, no adjustments for multiple testing have been made. All numerical calculations were performed with IBM SPSS Statistics, Version 22.
7 Page 7 of 19
Results:
After restriction of further surgery (85.4%), defining a maximum dose of vasopressor hemodynamic support (75.8%), and withholding anti-infective drugs (47.1%), blood transfusions were withheld in 70 (44.6%) deceased surgical ICU-patients (Tab.1, relative frequencies for ICU therapies withheld: supplemental figure 1). Each patient with a WH/WDLS decision had an average of three different ICU therapies withheld at the same time. Patients who had blood transfusions withheld (n=70) usually had more ICU therapies withheld or withdrawn than patients who had blood transfusions maintained (n=87) [number (medianIQR) of ICU-therapies withheld or withdrawn: 21 for transfusions continued vs. 53 for transfusions withheld (p<0.001)]. Figure 1 shows the number of ICU therapies that were withheld or withdrawn together with or without blood transfusions.
There were 31 (35.6%) patients that initially had transfusions continued and received additional WH/WDLS orders during their ICU course. In contrast, only 12 (17.1%) patients had additional WH/WDLS orders when transfusions were withheld with the first WH/WDLS order (p=0.012). In patients that had blood transfusions withheld, time from the WH/WDLS decision to death was shorter than in patients that had transfusions continued (Tab.2).
There were no differences in patients’ characteristics, urgency of ICU-admission, comorbidities, ICU severity scores, organ replacement technology, advanced care planning,
8 Page 8 of 19
and participation frequencies of decision makers for WH/WDLS decisions between patients that had transfusions continued and those that had transfusions withheld (Tab.2).
9 Page 9 of 19
Discussion
WH/WDLS orders in surgical patients were predominantly aimed at preventing an escalation of potentially stressful ICU therapies like further surgical procedures or a potentially harmful increase in the use of vasopressors. Less than half of the surgical patients with a WH/WDLS order received a decision to withhold blood transfusions indicating that withholding blood transfusions is not a prioritized decision in EOLDs of surgical ICU patients. Furthermore, when blood transfusions were withheld, further life-support therapies were discontinued simultaneously. This suggests that WH/WDLS orders for blood transfusions were part of the most advanced limitations of therapy on the surgical ICU.
A patient’s death generally can be expected soon after an EOLD and this period is even shorter when treatment is withdrawn instead of withheld [1,3]. It is not surprising that with a higher number of simultaneously withheld or withdrawn ICU therapies, the period from EOLD to death is further shortened. The decision to withhold blood products is frequently taken together with a decision to withhold or withdraw on average four other ICUtherapies, mostly further surgery, vasopressors, and antibiotics.
Postoperative bleeding is a major complication of surgery. Patients admitted to the ICU after elective high-risk surgery frequently receive blood products during their postoperative course [11]. Transfusions are predominantly based on the blood loss that is associated with the extent of the intervention or with operative and postoperative 10 Page 10 of 19
complications. Postoperative bleeding is often considered to be iatrogenic and there is evidence that physicians rather prefer to withdraw life support for a primary illness than for an iatrogenic complication [12]. In medical patients blood transfusions are more often directly associated with treatment or complications of the underlying disease [13]. These factors might explain why withholding blood transfusions in surgical ICU-patients is less common than in medical ICU-patients. Recently, it was demonstrated that the process of EOLD making on surgical ICUs differs in certain aspects from the decision-making process on medical ICUs [10,14]. Here we show that also the culture of withholding blood transfusions after a WH/WDLS decision differs between specialties.
While studies in palliative care and on medical ICUs reported that blood transfusions were the primary therapy that was withheld in EOLDs, data obtained on mixed medicalsurgical ICUs reveal contrary results [5,15]. Smedira and coworkers demonstrated that out of 12 ICU-therapies, only mechanical ventilation, vasopressors, and supplemental oxygen were withheld more frequently than blood transfusions after a WH/WDLS decision [4]. In contrast, two independent studies on Canadian medical-surgical ICUs showed that withholding blood transfusions was rare in comparison to withholding or withdrawing any other ICU-therapy [16,17]. There are also quite a few studies, which provide data on therapies that are withheld or withdrawn on ICUs and do not report WH/WDLS decisions on withholding blood transfusions [1,18,19]. To the best of our knowledge here we report for the first time the
11 Page 11 of 19
frequency and associated factors of a decision to withhold blood transfusions in surgical ICUpatients only.
Lately, there are increasing national and international efforts to formulate recommendations for the allocation of blood products in palliative care situations [20,21]. However, so far these recommendations are mainly based on theoretically discussed case scenarios. As pointed out here, current clinical practice can differ from data obtained from questionnaire-based hypothetical studies.
This study is limited by its’ retrospective character and the single center design. Our results are mainly hypothesis generating and further prospective analysis is needed to determine whether terminal ill patients of different medical specialties also require different approaches and management guidelines in rationing blood transfusions.
Taken together, the findings in this patient cohort suggest that limitation orders for blood transfusions are not a prioritized decision in EOLDs of surgical ICU patients. Moreover, EOLDs to withhold blood transfusions might be part of the most advanced limitations of therapy on the surgical ICU.
.
12 Page 12 of 19
Financial Support/Funding: No external funding was received for this study.
Declaration of conflicting interests: The authors declare that there is no conflict of interest
Ethical approval: Charité University Medicine EA1/292/10
13 Page 13 of 19
References
1. Esteban A, Gordo F, Solsona JF, Alia I, Caballero J, et al. (2001) Withdrawing and withholding life support in the intensive care unit: a Spanish prospective multi-centre observational study. Intensive Care Med 27: 1744-1749. 2. Sprung CL, Cohen SL, Sjokvist P, Baras M, Bulow HH, et al. (2003) End-of-life practices in European intensive care units: the Ethicus Study. JAMA 290: 790-797. 3. Graw JA, Spies CD, Wernecke KD, Braun JP (2012) Managing end-of-life decision making in intensive care medicine--a perspective from Charite Hospital, Germany. PLoS One 7: e46446. 4. Smedira NG, Evans BH, Grais LS, Cohen NH, Lo B, et al. (1990) Withholding and withdrawal of life support from the critically ill. N Engl J Med 322: 309-315. 5. Hinkka H, Kosunen E, Metsanoja R, Lammi UK, Kellokumpu-Lehtinen P (2002) Factors affecting physicians' decisions to forgo life-sustaining treatments in terminal care. J Med Ethics 28: 109-114. 6. Metaxa V, Lavrentieva A (2015) End-of-life decisions in Burn Intensive Care Units - An International Survey. Burns 41: 53-57. 7. Lelubre C, Vincent JL (2011) Red blood cell transfusion in the critically ill patient. Ann Intensive Care 1: 43. 8. Sprung CL, Carmel S, Sjokvist P, Baras M, Cohen SL, et al. (2007) Attitudes of European physicians, nurses, patients, and families regarding end-of-life decisions: the ETHICATT study. Intensive Care Med 33: 104-110. 9. Bacchetta MD, Eachempati SR, Fins JJ, Hydo L, Barie PS (2006) Factors influencing DNR decision-making in a surgical ICU. J Am Coll Surg 202: 995-1000. 10. Graw JA, Spies CD, Kork F, Wernecke KD, Braun JP (2014) End-of-life Decisions in Intensive Care Medicine-Shared Decision-Making and Intensive Care Unit Length of Stay. World J Surg. 11. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, et al. (2002) Anemia and blood transfusion in critically ill patients. JAMA 288: 1499-1507. 12. Christakis NA, Asch DA (1993) Biases in how physicians choose to withdraw life support. Lancet 342: 642-646. 13. Pereira J, Phan T (2004) Management of bleeding in patients with advanced cancer. Oncologist 9: 561-570. 14. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, et al. (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34: 344-353. 15. Asch DA, Faber-Langendoen K, Shea JA, Christakis NA (1999) The sequence of withdrawing life-sustaining treatment from patients. Am J Med 107: 153-156. 16. Keenan SP, Busche KD, Chen LM, McCarthy L, Inman KJ, et al. (1997) A retrospective review of a large cohort of patients undergoing the process of withholding or withdrawal of life support. Crit Care Med 25: 1324-1331. 17. Wood GG, Martin E (1995) Withholding and withdrawing life-sustaining therapy in a Canadian intensive care unit. Can J Anaesth 42: 186-191. 18. Hoel H, Skjaker SA, Haagensen R, Stavem K (2014) Decisions to withhold or withdraw life-sustaining treatment in a Norwegian intensive care unit. Acta Anaesthesiol Scand 58: 329-336.
14 Page 14 of 19
19. Phua J, Joynt GM, Nishimura M, Deng Y, Myatra SN, et al. (2015) Withholding and Withdrawal of Life-Sustaining Treatments in Intensive Care Units in Asia. JAMA Intern Med. 20. Smith LB, Cooling L, Davenport R (2013) How do I allocate blood products at the end of life? An ethical analysis with suggested guidelines. Transfusion 53: 696-700. 21. Alt-Epping B, Simon A, Nauck F (2010) [Blood product substitution in palliative care]. Dtsch Med Wochenschr 135: 2083-2087.
15 Page 15 of 19
Figure captions
Figure 1
Percentage of patients who had various numbers of ICU-therapies withheld or withdrawn after a WH/WDLS order (ICU=Intensive care unit; WH/WDLS=withhold/withdraw life support)
Supplemental Figure 1 Relative frequencies of ICU-therapies withheld simultaneously. Relative frequencies of ICU-therapies withheld in relation to the number of ICU-therapies that were withheld simultaneously after a WH/WDLS order (ICU=Intensive care unit; WH/WDLS=withhold/withdraw life support; I.V.=Intravenous)
16 Page 16 of 19
Table 1
ICU life support withheld/withdrawn
All (n=157)
(%)
Surgery
134
(85.4)
Vasopressor dose limit defined
119
(75.8)
Antibiotics
74
(47.1)
Blood products
70
(44.6)
Vasopressors
68
(43.3)
Dialysis
42
(26.8)
Nutrition
24
(15.3)
Ventilation
23
(14.6)
Intravenous Fluids
16
(10.2)
Intubation
12
(7.6)
Table 1 Frequency of ICU-therapies withheld or withdrawn after a WH/WDLS decision. Ranking by frequency (ICU=Intensive care unit)
17 Page 17 of 19
Table 2 All
Age, years, mean (±SD) Gender, male, n (%) Urgency of surgery, n (%) Elective Non planned Emergency Comorbidities, n (%) Liver cirrhosis Portal hypertension Status post oesophageal bleeding Hepatic encelopathy Cardiac insufficiency NYHA IV Chronic pulmonary disease Chronic obstructive pulmonary disease (COPD) Lung fibrosis Terminal renal insufficiency Steroid medication Chemotherapy Immunosuppression therapy AIDS Leukemia Lymphoma Metastasing cancer Severity Scores, mean (± SD) APACHE II SAPS II SOFA (day before EOLD/death) ICU-LOS, days, median (IQR) Organ replacement, n (%) Ventilation Tracheostomy Dialysis IABP VAD ECMO/ECLS Vasopressors Blood products, n, mean (Min-Max) Decision makers’ participation in EOLD conferences, n, (%) Attending intensivist Surgeon Nurse Family/surrogate decision maker Advanced care planning, n, (%) Advance directive with living and therapeutic will Advance directive with patient´s surrogate decision maker Patients with an attorney during ICU stay Time until WH/WDLS, days, median (IQR) Time WH/WDLS until death, days, median (IQR)
n = 157 72.3 (±11.4) 96 (61.1)
Transfusion continued n = 87 72.6 (±12.8) 55 (63.2)
Transfusion withheld n = 70 72.0 (±9.5) 41 (58.6)
p*1
0.400 0.553
39 35 83
(24.8) (22.3) (52.9)
23 17 47
(26.4) (19.5) (54.0)
16 18 36
(22.9) (25.7) (51.4)
0.634
17 7 4 1 39 42 33
(10.8) (4.5) (2.5) (0.6) (24.8) (26.8) (21.0)
10 3 1 1 26 27 21
(11.5) (3.4) (1.1) (1.1) (29.9) (31.0) (24.1)
7 4 3 0 13 15 12
(10.0) (5.7) (4.3) (0.0) (18.6) (21.4) (17.1)
0.765 0.701 0.325 1.000 0.103 0.177 0.285
2 25 8 4 3 0 1 1 12
(1.3) (15.9) (5.1) (2.5) (1.9) (0.0) (0.6) (1.3) (7.6)
1 17 6 3 3 0 1 1 7
(1.1) (19.5) (6.9) (3.4) (3.4) (0.0) (1.1) (1.1) (8.0)
1 8 2 1 0 0 0 1 5
(1.4) (11.4) (2.9) (1.4) (0.0) (0.0) (0.0) (1.4) (7.1)
1.000 0.167 0.300 0.629 0.254 1.000 1.000 1.000
30.0 59.7 10.0 9
±7.9 ±17.1 ±3.7 (3-33)
30.4 59.6 10.9 10
±7.4 ±16.8 ±3.7 (4-36)
29.4 59.7 10.1 9
±8.5 ±17.7 ±3.8 (3-26)
0.303 0.983 0.146 0.295
148 55 116 31 16 21 139 30.5
(94.3) (35.0) (73.9) (19.7) (10.2) (13.4) (88.5) (0-225)
81 28 70 17 9 13 80 34.5
(93.1) (32.2) (80.5) (19.5) (10.3) (14.9) (92.0) (0-225)
67 27 47 14 7 8 59 25.5
(95.7) (38.6) (67.1) (20.0) (10.0) (11.4) (84.3) (0-154)
0.732 0.404 0.057 0.943 0.943 0.327 0.207 0.117
171 67 75 96
(100.0) (42.7) (47.8) (61.2)
87 39 42 53
(100.0) (44.8) (48.3) (60.9)
84 28 33 43
(96.6) (40.0) (47.1) (61.4)
0.254 0.543 0.888 0.948
17
(10.8)
10
(11.5)
7
(10.0)
0.765
16
(10.2)
7
(8.0)
9
(12.9)
0.322
85 9 0
(54.1) (3-26) (0-2)
45 9 1
(51.7) (4-27) (0-3)
40 8.5 0
(57.1) (2-26) (0-1)
0.498 0.615 0.003
18 Page 18 of 19
Table 2 Characteristics of surgical patients that received a WH/WDLS decision (ICULOS=Intensive care unit length of stay; *1=between patients that had transfusions continued and those that had transfusions withheld; SD=Standard Deviation; IQR=Interquartile Range; Min=Minimum; Max=Maximum; IABP=intra-aortic balloon pump; VAD=ventricular assist device; ECMO/ECLS=extracorporal membrane oxygenation/life system; WH/WDLS=withhold/withdraw life support; night shifts were from 10 p.m. to 7 a.m.)
19 Page 19 of 19
S1473-0502(16)00051-3 http://dx.doi.org/doi: 10.1016/j.transci.2016.03.005 TRASCI 1978
To appear in:
Transfusion and Apheresis Science
Received date: Revised date: Accepted date:
11-1-2016 21-3-2016 22-3-2016
Please cite this article as: Jan A. Graw, Claudia D. Spies, Klaus-D. Wernecke, Jan-P. Braun, End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions, Transfusion and Apheresis Science (2016), http://dx.doi.org/doi: 10.1016/j.transci.2016.03.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
End-of-life decisions in surgical intensive care medicine – the relevance of blood transfusions
Jan A. Graw1, Claudia D. Spies1, Klaus-D. Wernecke2, Jan-P. Braun3 1
Department of Anesthesiology and Intensive Care Medicine, Campus Charité Mitte and
Campus Virchow Klinikum, Charité - Universitätsmedizin Berlin, Germany 2
Charité - Universitätsmedizin Berlin and SOSTANA GmbH, Berlin, Germany
3
Department of Anesthesiology and Intensive Care Medicine, HELIOS Klinikum
Hildesheim, Germany
Short title: Withholding blood transfusions in the SICU Address of correspondence: Jan A. Graw, MD Department of Anesthesiology and Intensive Care Medicine Charité - Universitätsmedizin Berlin, Campus Charité Mitte and Campus Virchow Klinikum Charitéplatz 1, 10117 Berlin Tel. +49 (30) 450 531051 ; Fax: +49 (30) 450 531911 E-mail: [email protected]
Total words in manuscript: 3006 1 Page 1 of 19
Abstract
Background: End-of-life decisions (EOLD) are common on the intensive care unit (ICU). EOLDs underlie a dynamic process and limitation of ICU-therapies is often done sequentially. Questionnaire-based and observational studies on medical ICUs and in palliative care reveal blood transfusions as the first therapy physicians withhold as an EOLD.
Methods: To test whether this practice also applies to surgical ICU-patients, in an observational study, all deceased patients (n=303) admitted to an academic surgical ICU in a three-year period were analyzed for the process of limiting ICU-therapies.
Results: Restriction of further surgery (85.4%) and limiting doses of vasopressors (75.8%) were the most frequent forms of limitations in surgical ICU therapies. Surgical patients, who had blood transfusions withheld (44.6%), had more ICU-therapies withheld or withdrawn simultaneously than patients who had transfusions maintained (5±2 vs. 2±1, p<0.001). Secondary EOLDs and subsequent limitations occurred less frequently in patients that had transfusions withheld with their first EOLD (17.1% vs. 35.6%, p<0.05).
Conclusion: Limitation orders for blood transfusions are not a prioritized decision in EOLDs of surgical ICU patients. Withholding blood transfusions correlates with discontinuation of further significant life-support therapies. This suggests that EOLDs to withhold blood transfusions are part of the most advanced limitations of therapy on the surgical ICU.
2 Page 2 of 19
Keywords: end-of-life decision, blood transfusion, intensive care medicine, surgical intensive care unit, withholding therapy, limitation order
3 Page 3 of 19
Introduction
Decisions to limit life-sustaining treatment precede most deaths on European intensive care units (ICUs) [1-3]. End-of-life decisions (EOLDs) underlie a dynamic process where intensive care therapy shifts from full life-support to a palliative approach. ICU-therapies that are commonly limited include endotracheal intubation, mechanical ventilation, renal replacement therapy, catecholamine infusions, surgery, antimicrobial therapy, blood product transfusions, nutrition and hydration. Most patients on the ICU require several of those interventions and physicians generally withhold or withdraw therapeutic approaches sequentially in an EOLD [3,4].
Questionnaire-based studies revealed that in palliative care blood transfusions are the most likely therapy that physicians from different medical backgrounds would like to withdraw first [5,6]. Blood transfusions are a life saving therapy and one of the most common procedures in intensive care medicine [7]. Besides culture, religion, and legislation, a physician’s base specialty influences his decision making in end-of-life therapy [8-10]. Surgery often is part of vigorous efforts to reverse acute life-threatening illnesses [9]. Furthermore, patients admitted to the ICU postoperatively receive on average more blood transfusions than those admitted for medical reasons [11].
To our knowledge no observational data exist about physician preferences to withhold or withdraw blood transfusions on surgical ICU-patients. Therefore, in a retrospective analysis 4 Page 4 of 19
on our surgical ICU we analyzed the sequence of ICU-therapies that were limited and compared characteristics and the decision making process in surgical ICU-patients who had blood transfusions withheld with surgical ICU-patients who continued to receive blood products after an EOLD.
5 Page 5 of 19
Methods
The study was approved from the Medical Ethics Committee of Charité University Hospital (number of ethical approval EA1/292/10). All patients (n=4510) admitted between August 2008 and September 2011 to a 22-bed academic ICU with twenty-four/seven coverage by board certified intensive care medicine consultants, were included in the study. Two hundred twenty-six (74.6%) of all deceased patients (n=303) were surgical ICU patients and 157 (69.5%) of them received a decision to “withhold or withdraw life support” (WH/WDLS) [10].
Decisions to limit life-sustaining ICU-treatment such as “Do-not-resuscitate” (DNR) orders and WH/WDLS orders were taken in EOLD conferences as prescribed previously [3]. Every participant of the EOLD-conference had to give consent to the decision when associated life support was withheld or withdrawn. WH/WDLS orders differentially included withholding or withdrawing endotracheal intubation, mechanical ventilation, renal replacement therapy, catecholamine infusions, surgery, antimicrobial therapy, blood product transfusions, nutrition, and fluid therapy. Non-documented treatment options were considered continued. As the withdrawal of a blood transfusion literally relates to a discontinuation of an ongoing transfusion we used the term “withholding” for both the “withholding” and “withdrawing” of blood products. Collected data always refer to a patient’s first WH/WDLS decision. Time, participants and the results of end-of-life conferences were documented in the daily progress
6 Page 6 of 19
notes in an electronic patient data management system (PDMS) (Copra System, Sabachswalden, Germany). Furthermore, all documentation of ward rounds, orders and progress notes, as well as data from vital signs monitors, daily ICU scores like the simplified acute physiology score II (SAPS II) and sequential organ failure assessment (SOFA), and all medical or nursing events to the patient were prospectively recorded in the PDMS.
Results are expressed as arithmetic mean ± standard deviation (SD) or median with interquartile range [IQR] for continuous variables, as appropriate and frequencies (%) for categorical variables. Differences between groups were tested by the non-parametric (exact) Wilcoxon-Mann-Whitney test for independent groups. Frequencies were tested by the (exact) Chi-square-test. A two-tailed p-value <0.05 was considered statistically significant. All tests were conducted in the area of exploratory data analysis. Therefore, no adjustments for multiple testing have been made. All numerical calculations were performed with IBM SPSS Statistics, Version 22.
7 Page 7 of 19
Results:
After restriction of further surgery (85.4%), defining a maximum dose of vasopressor hemodynamic support (75.8%), and withholding anti-infective drugs (47.1%), blood transfusions were withheld in 70 (44.6%) deceased surgical ICU-patients (Tab.1, relative frequencies for ICU therapies withheld: supplemental figure 1). Each patient with a WH/WDLS decision had an average of three different ICU therapies withheld at the same time. Patients who had blood transfusions withheld (n=70) usually had more ICU therapies withheld or withdrawn than patients who had blood transfusions maintained (n=87) [number (medianIQR) of ICU-therapies withheld or withdrawn: 21 for transfusions continued vs. 53 for transfusions withheld (p<0.001)]. Figure 1 shows the number of ICU therapies that were withheld or withdrawn together with or without blood transfusions.
There were 31 (35.6%) patients that initially had transfusions continued and received additional WH/WDLS orders during their ICU course. In contrast, only 12 (17.1%) patients had additional WH/WDLS orders when transfusions were withheld with the first WH/WDLS order (p=0.012). In patients that had blood transfusions withheld, time from the WH/WDLS decision to death was shorter than in patients that had transfusions continued (Tab.2).
There were no differences in patients’ characteristics, urgency of ICU-admission, comorbidities, ICU severity scores, organ replacement technology, advanced care planning,
8 Page 8 of 19
and participation frequencies of decision makers for WH/WDLS decisions between patients that had transfusions continued and those that had transfusions withheld (Tab.2).
9 Page 9 of 19
Discussion
WH/WDLS orders in surgical patients were predominantly aimed at preventing an escalation of potentially stressful ICU therapies like further surgical procedures or a potentially harmful increase in the use of vasopressors. Less than half of the surgical patients with a WH/WDLS order received a decision to withhold blood transfusions indicating that withholding blood transfusions is not a prioritized decision in EOLDs of surgical ICU patients. Furthermore, when blood transfusions were withheld, further life-support therapies were discontinued simultaneously. This suggests that WH/WDLS orders for blood transfusions were part of the most advanced limitations of therapy on the surgical ICU.
A patient’s death generally can be expected soon after an EOLD and this period is even shorter when treatment is withdrawn instead of withheld [1,3]. It is not surprising that with a higher number of simultaneously withheld or withdrawn ICU therapies, the period from EOLD to death is further shortened. The decision to withhold blood products is frequently taken together with a decision to withhold or withdraw on average four other ICUtherapies, mostly further surgery, vasopressors, and antibiotics.
Postoperative bleeding is a major complication of surgery. Patients admitted to the ICU after elective high-risk surgery frequently receive blood products during their postoperative course [11]. Transfusions are predominantly based on the blood loss that is associated with the extent of the intervention or with operative and postoperative 10 Page 10 of 19
complications. Postoperative bleeding is often considered to be iatrogenic and there is evidence that physicians rather prefer to withdraw life support for a primary illness than for an iatrogenic complication [12]. In medical patients blood transfusions are more often directly associated with treatment or complications of the underlying disease [13]. These factors might explain why withholding blood transfusions in surgical ICU-patients is less common than in medical ICU-patients. Recently, it was demonstrated that the process of EOLD making on surgical ICUs differs in certain aspects from the decision-making process on medical ICUs [10,14]. Here we show that also the culture of withholding blood transfusions after a WH/WDLS decision differs between specialties.
While studies in palliative care and on medical ICUs reported that blood transfusions were the primary therapy that was withheld in EOLDs, data obtained on mixed medicalsurgical ICUs reveal contrary results [5,15]. Smedira and coworkers demonstrated that out of 12 ICU-therapies, only mechanical ventilation, vasopressors, and supplemental oxygen were withheld more frequently than blood transfusions after a WH/WDLS decision [4]. In contrast, two independent studies on Canadian medical-surgical ICUs showed that withholding blood transfusions was rare in comparison to withholding or withdrawing any other ICU-therapy [16,17]. There are also quite a few studies, which provide data on therapies that are withheld or withdrawn on ICUs and do not report WH/WDLS decisions on withholding blood transfusions [1,18,19]. To the best of our knowledge here we report for the first time the
11 Page 11 of 19
frequency and associated factors of a decision to withhold blood transfusions in surgical ICUpatients only.
Lately, there are increasing national and international efforts to formulate recommendations for the allocation of blood products in palliative care situations [20,21]. However, so far these recommendations are mainly based on theoretically discussed case scenarios. As pointed out here, current clinical practice can differ from data obtained from questionnaire-based hypothetical studies.
This study is limited by its’ retrospective character and the single center design. Our results are mainly hypothesis generating and further prospective analysis is needed to determine whether terminal ill patients of different medical specialties also require different approaches and management guidelines in rationing blood transfusions.
Taken together, the findings in this patient cohort suggest that limitation orders for blood transfusions are not a prioritized decision in EOLDs of surgical ICU patients. Moreover, EOLDs to withhold blood transfusions might be part of the most advanced limitations of therapy on the surgical ICU.
.
12 Page 12 of 19
Financial Support/Funding: No external funding was received for this study.
Declaration of conflicting interests: The authors declare that there is no conflict of interest
Ethical approval: Charité University Medicine EA1/292/10
13 Page 13 of 19
References
1. Esteban A, Gordo F, Solsona JF, Alia I, Caballero J, et al. (2001) Withdrawing and withholding life support in the intensive care unit: a Spanish prospective multi-centre observational study. Intensive Care Med 27: 1744-1749. 2. Sprung CL, Cohen SL, Sjokvist P, Baras M, Bulow HH, et al. (2003) End-of-life practices in European intensive care units: the Ethicus Study. JAMA 290: 790-797. 3. Graw JA, Spies CD, Wernecke KD, Braun JP (2012) Managing end-of-life decision making in intensive care medicine--a perspective from Charite Hospital, Germany. PLoS One 7: e46446. 4. Smedira NG, Evans BH, Grais LS, Cohen NH, Lo B, et al. (1990) Withholding and withdrawal of life support from the critically ill. N Engl J Med 322: 309-315. 5. Hinkka H, Kosunen E, Metsanoja R, Lammi UK, Kellokumpu-Lehtinen P (2002) Factors affecting physicians' decisions to forgo life-sustaining treatments in terminal care. J Med Ethics 28: 109-114. 6. Metaxa V, Lavrentieva A (2015) End-of-life decisions in Burn Intensive Care Units - An International Survey. Burns 41: 53-57. 7. Lelubre C, Vincent JL (2011) Red blood cell transfusion in the critically ill patient. Ann Intensive Care 1: 43. 8. Sprung CL, Carmel S, Sjokvist P, Baras M, Cohen SL, et al. (2007) Attitudes of European physicians, nurses, patients, and families regarding end-of-life decisions: the ETHICATT study. Intensive Care Med 33: 104-110. 9. Bacchetta MD, Eachempati SR, Fins JJ, Hydo L, Barie PS (2006) Factors influencing DNR decision-making in a surgical ICU. J Am Coll Surg 202: 995-1000. 10. Graw JA, Spies CD, Kork F, Wernecke KD, Braun JP (2014) End-of-life Decisions in Intensive Care Medicine-Shared Decision-Making and Intensive Care Unit Length of Stay. World J Surg. 11. Vincent JL, Baron JF, Reinhart K, Gattinoni L, Thijs L, et al. (2002) Anemia and blood transfusion in critically ill patients. JAMA 288: 1499-1507. 12. Christakis NA, Asch DA (1993) Biases in how physicians choose to withdraw life support. Lancet 342: 642-646. 13. Pereira J, Phan T (2004) Management of bleeding in patients with advanced cancer. Oncologist 9: 561-570. 14. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, et al. (2006) Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 34: 344-353. 15. Asch DA, Faber-Langendoen K, Shea JA, Christakis NA (1999) The sequence of withdrawing life-sustaining treatment from patients. Am J Med 107: 153-156. 16. Keenan SP, Busche KD, Chen LM, McCarthy L, Inman KJ, et al. (1997) A retrospective review of a large cohort of patients undergoing the process of withholding or withdrawal of life support. Crit Care Med 25: 1324-1331. 17. Wood GG, Martin E (1995) Withholding and withdrawing life-sustaining therapy in a Canadian intensive care unit. Can J Anaesth 42: 186-191. 18. Hoel H, Skjaker SA, Haagensen R, Stavem K (2014) Decisions to withhold or withdraw life-sustaining treatment in a Norwegian intensive care unit. Acta Anaesthesiol Scand 58: 329-336.
14 Page 14 of 19
19. Phua J, Joynt GM, Nishimura M, Deng Y, Myatra SN, et al. (2015) Withholding and Withdrawal of Life-Sustaining Treatments in Intensive Care Units in Asia. JAMA Intern Med. 20. Smith LB, Cooling L, Davenport R (2013) How do I allocate blood products at the end of life? An ethical analysis with suggested guidelines. Transfusion 53: 696-700. 21. Alt-Epping B, Simon A, Nauck F (2010) [Blood product substitution in palliative care]. Dtsch Med Wochenschr 135: 2083-2087.
15 Page 15 of 19
Figure captions
Figure 1
Percentage of patients who had various numbers of ICU-therapies withheld or withdrawn after a WH/WDLS order (ICU=Intensive care unit; WH/WDLS=withhold/withdraw life support)
Supplemental Figure 1 Relative frequencies of ICU-therapies withheld simultaneously. Relative frequencies of ICU-therapies withheld in relation to the number of ICU-therapies that were withheld simultaneously after a WH/WDLS order (ICU=Intensive care unit; WH/WDLS=withhold/withdraw life support; I.V.=Intravenous)
16 Page 16 of 19
Table 1
ICU life support withheld/withdrawn
All (n=157)
(%)
Surgery
134
(85.4)
Vasopressor dose limit defined
119
(75.8)
Antibiotics
74
(47.1)
Blood products
70
(44.6)
Vasopressors
68
(43.3)
Dialysis
42
(26.8)
Nutrition
24
(15.3)
Ventilation
23
(14.6)
Intravenous Fluids
16
(10.2)
Intubation
12
(7.6)
Table 1 Frequency of ICU-therapies withheld or withdrawn after a WH/WDLS decision. Ranking by frequency (ICU=Intensive care unit)
17 Page 17 of 19
Table 2 All
Age, years, mean (±SD) Gender, male, n (%) Urgency of surgery, n (%) Elective Non planned Emergency Comorbidities, n (%) Liver cirrhosis Portal hypertension Status post oesophageal bleeding Hepatic encelopathy Cardiac insufficiency NYHA IV Chronic pulmonary disease Chronic obstructive pulmonary disease (COPD) Lung fibrosis Terminal renal insufficiency Steroid medication Chemotherapy Immunosuppression therapy AIDS Leukemia Lymphoma Metastasing cancer Severity Scores, mean (± SD) APACHE II SAPS II SOFA (day before EOLD/death) ICU-LOS, days, median (IQR) Organ replacement, n (%) Ventilation Tracheostomy Dialysis IABP VAD ECMO/ECLS Vasopressors Blood products, n, mean (Min-Max) Decision makers’ participation in EOLD conferences, n, (%) Attending intensivist Surgeon Nurse Family/surrogate decision maker Advanced care planning, n, (%) Advance directive with living and therapeutic will Advance directive with patient´s surrogate decision maker Patients with an attorney during ICU stay Time until WH/WDLS, days, median (IQR) Time WH/WDLS until death, days, median (IQR)
n = 157 72.3 (±11.4) 96 (61.1)
Transfusion continued n = 87 72.6 (±12.8) 55 (63.2)
Transfusion withheld n = 70 72.0 (±9.5) 41 (58.6)
p*1
0.400 0.553
39 35 83
(24.8) (22.3) (52.9)
23 17 47
(26.4) (19.5) (54.0)
16 18 36
(22.9) (25.7) (51.4)
0.634
17 7 4 1 39 42 33
(10.8) (4.5) (2.5) (0.6) (24.8) (26.8) (21.0)
10 3 1 1 26 27 21
(11.5) (3.4) (1.1) (1.1) (29.9) (31.0) (24.1)
7 4 3 0 13 15 12
(10.0) (5.7) (4.3) (0.0) (18.6) (21.4) (17.1)
0.765 0.701 0.325 1.000 0.103 0.177 0.285
2 25 8 4 3 0 1 1 12
(1.3) (15.9) (5.1) (2.5) (1.9) (0.0) (0.6) (1.3) (7.6)
1 17 6 3 3 0 1 1 7
(1.1) (19.5) (6.9) (3.4) (3.4) (0.0) (1.1) (1.1) (8.0)
1 8 2 1 0 0 0 1 5
(1.4) (11.4) (2.9) (1.4) (0.0) (0.0) (0.0) (1.4) (7.1)
1.000 0.167 0.300 0.629 0.254 1.000 1.000 1.000
30.0 59.7 10.0 9
±7.9 ±17.1 ±3.7 (3-33)
30.4 59.6 10.9 10
±7.4 ±16.8 ±3.7 (4-36)
29.4 59.7 10.1 9
±8.5 ±17.7 ±3.8 (3-26)
0.303 0.983 0.146 0.295
148 55 116 31 16 21 139 30.5
(94.3) (35.0) (73.9) (19.7) (10.2) (13.4) (88.5) (0-225)
81 28 70 17 9 13 80 34.5
(93.1) (32.2) (80.5) (19.5) (10.3) (14.9) (92.0) (0-225)
67 27 47 14 7 8 59 25.5
(95.7) (38.6) (67.1) (20.0) (10.0) (11.4) (84.3) (0-154)
0.732 0.404 0.057 0.943 0.943 0.327 0.207 0.117
171 67 75 96
(100.0) (42.7) (47.8) (61.2)
87 39 42 53
(100.0) (44.8) (48.3) (60.9)
84 28 33 43
(96.6) (40.0) (47.1) (61.4)
0.254 0.543 0.888 0.948
17
(10.8)
10
(11.5)
7
(10.0)
0.765
16
(10.2)
7
(8.0)
9
(12.9)
0.322
85 9 0
(54.1) (3-26) (0-2)
45 9 1
(51.7) (4-27) (0-3)
40 8.5 0
(57.1) (2-26) (0-1)
0.498 0.615 0.003
18 Page 18 of 19
Table 2 Characteristics of surgical patients that received a WH/WDLS decision (ICULOS=Intensive care unit length of stay; *1=between patients that had transfusions continued and those that had transfusions withheld; SD=Standard Deviation; IQR=Interquartile Range; Min=Minimum; Max=Maximum; IABP=intra-aortic balloon pump; VAD=ventricular assist device; ECMO/ECLS=extracorporal membrane oxygenation/life system; WH/WDLS=withhold/withdraw life support; night shifts were from 10 p.m. to 7 a.m.)
19 Page 19 of 19