Prevalence, Management, and Outcomes of Critically Ill Patients with Prothrombin Time Prolongation in United Kingdom Intensive Care Units*

Continuing Medical Education Article

Prevalence, management, and outcomes of critically ill patients with prothrombin time prolongation in United Kingdom intensive care units*

Timothy S. Walsh, MD; Simon J. Stanworth, MD; Robin J. Prescott, PhD; Robert J. Lee, MSc; Douglas M. Watson, MSc; Duncan Wyncoll, FRCA; Writing Committee of the Intensive Care Study of Coagulopathy (ISOC) Investigators

LEARNING OBJECTIVES After participating in this educational activity, the participant should be better able to: 1. Assess risk factors for the development of international normalized ratio abnormalities in patients with coagulopathy. 2. Examine implications of abnormal international normalized ratio values in the administration of fresh frozen plasma. 3. Evaluate incidence of abnormal international normalized ratio values in critically ill patients. Unless otherwise noted, the faculty’s, staff’s, and authors’ spouse(s)/life partner(s) (if any) have nothing to disclose. The authors have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity. All faculty and staff in a position to control the content of this CME activity have disclosed that they have no financial relationship with, or financial interests in, any commercial companies pertaining to this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Objective: Coagulopathy occurs frequently in critically ill patients, cell transfusions were all independent risk factors for international but its epidemiology, current treatment, and relation to patient out- normalized ratio abnormalities (all p < .001). In all regression models, come are poorly understood. We described the prevalence, risk there was a strong independent association between abnormal interna- factors, and treatment of prolongation of the prothrombin time in tional normalized ratio values and greater intensive care unit mortality critically ill patients using the international normalized ratio to standard- (p < .0001), particularly when international normalized ratio increased ize data and explored its association with intensive care unit survival. after intensive care unit admission. Among patients with abnormal Design: Prospective multiple center observational cohort study. international normalized ratios, 33% received fresh-frozen plasma trans- Setting: Twenty-nine adult intensive care units in the United fusions during their intensive care unit stay, but the pretransfusion Kingdom. international normalized ratio value varied widely. Fifty-one percent of Patients: All sequentially admitted patients over an 8-wk period. fresh-frozen plasma treatments were to nonbleeding patients and 40% Interventions: None. to nonbleeding patients whose international normalized ratio was nor- Measurements and Main Results: Prospective daily data were mal or only modestly deranged (<2.5). The dose of fresh-frozen plasma collected concerning prevalence, predefined risk factors, and treat- administered was highly variable (median dose 10.8 mL/kg؊1 (first, third .(ment of coagulopathy throughout intensive care unit admission. Of quartile 7.2, 14.4; range, 2.4–41.1 mL/kg؊1 1923 intensive care unit admissions, 30% developed abnormal inter- Conclusions: Prothrombin time prolongation is prevalent in critically national normalized ratio values (defined as an international normal- ill patients and is independently associated with greater intensive care ized ratio >1.5). Most international normalized ratio abnormalities unit mortality. Wide variation in fresh-frozen plasma treatment exists were minor and short-lived (73% of worst international normalized suggesting clinical uncertainty regarding best practice, particularly as a ratio values 1.6–2.5). Male sex, chronic liver disease, sepsis, warfa- prophylactic treatment. (Crit Care Med 2010; 38:1939–1946) rin therapy, increments in Acute Physiology and Chronic Health KEY WORDS: transfusion; critical illness; coagulation; prothrom- Evaluation II score, severity of renal and hepatic dysfunction, and red bin time; coagulopathy; fresh-frozen plasma

*See also p. 2065. ical Statistician (RJL), Centre for Population Health Supplemental digital content is available for this ar- Professor (TSW), Edinburgh University, Edinburgh. Sciences, University of Edinburgh, Edinburgh, UK; Clin- ticle. Direct URL citations appear in the printed text and UK; Consultant in Critical Care (TSW), Anaesthetics, ical Effectiveness Coordinator (DMW), Better Blood are provided in the HTML and PDF versions of this article Critical Care, and Pain Medicine, Edinburgh Royal In- Transfusion, Scottish National Blood Transfusion Ser- on the journal’s Web site (www.ccmjournal.com). ﬁrmary, Little France Crescent, Edinburgh. UK; Consul- vice, Gartnavel, Glasgow, UK; and Consultant Intensiv- For information regarding this article, E-mail: tant Haemotologist (SJS), John Radcliffe Hospital, NHS ist (DW), Guy’s & St. Thomas’ NHS Foundation Trust, [email protected] Blood & Transplant/Oxford Radcliffe Hospitals, Oxford, London, UK. Copyright © 2010 by the Society of Critical Care UK; Senior Clinical Lecturer (SJS), University of Oxford, This study was funded by research grants from the Medicine and Lippincott Williams & Wilkins Oxford, UK; Emeritus Professor of Health Technology National Health Service Blood & Transplant and Scot- Assessment (RJP), Public Health Sciences, Old Medical tish National Blood Transfusion Service and the Trans- DOI: 10.1097/CCM.0b013e3181eb9d2b School, University of Edinburgh, Edinburgh, UK; Med- fusion Medicine Education and Research Foundation.

Crit Care Med 2010 Vol. 38, No. 10 1939 he disease processes that The Multicentered Research Ethics Commit- verification and validation before analysis of cause critical illness can im- tee waived the need for patient consent. the final data set. pair blood coagulation, in- Study Subjects. All patients admitted to Analysis. Preagreed definitions were used creasing the risk of bleeding general adult ICUs were screened. The only (see supplementary data, Supplemental Digital T predefined exclusions were ICU readmissions Content 1, http://links.lww.com/CCM/A162). (1). In addition, excessive activation of during the same hospital stay, transfers from The severity of PT prolongation used the worst coagulation pathways may result in mi- other ICUs, and admissions where life expect- recorded INR during the ICU stay. Duration of crovascular thrombosis resulting in or- ancy was considered Ͻ4 hrs. Specialist medi- PT prolongation episodes was described using gan dysfunction as a result of inflamma- cal and surgical cardiac ICUs were excluded. Kaplan-Meier methods to allow for censored tion and impaired tissue oxygen supply. Screening logs captured all admissions to en- patients who did not complete an episode as a Studying the epidemiology and clinical sure accurate denominator data. result of death or discharge before resolution importance of coagulopathy is challeng- Data Collection. Data collection included of PT abnormality. ing as a result of the complex interaction age, sex, source of admission, primary reason A range of predefined factors at ICU admis- between these physiological systems and for ICU admission, Acute Physiology and sion were agreed by consensus a priori as the assays used to assess them. The most Chronic Health Evaluation II score, estimated potential risk factors for PT prolongation and dry weight, medical history, and details of he- widely used laboratory assay of coagula- were compared between patients with and matology blood results and blood components tion factor activity, particularly in rela- without PT prolongation during their ICU used in the 24 hrs before admission. Daily data stay. We developed a regression model explor- tion to acquired disease-related defects, is collection included routine laboratory tests, ing the relation between patient characteris- the prothrombin time (PT), and this may all procedures, and the occurrence of clini- tics at ICU admission and the presence of PT be standardized against control tests ei- cally significant hemorrhage (defined a priori prolongation during admission. We also cal- Ͼ ther to calculate a prothrombin ratio or, as estimated total cumulative blood loss 300 culated the prevalence of systemic inflamma- mLor1Uofredcells and/or bleeding from a in many hospitals, using the interna- tory response syndrome, infection, circulatory critical site such as intracranial). The timing tional normalized ratio (INR). Fresh- shock, acute lung injury, acute renal failure, of all blood component transfusions was re- frozen plasma (FFP) is a common treat- hepatic dysfunction, moderate hemorrhage, corded. For all FFP transfusions, clinicians ment for coagulopathy, but current and major hemorrhage during the 24 hrs be- recorded the clinical indication as “coagulopa- clinical guidelines concerning its use are thy with bleeding,” “coagulopathy with no fore onset of PT prolongation. based largely on expert opinion or data bleeding,” or “coagulopathy with no bleeding Management of PT Prolongation With from relatively poor-quality studies (2–5). before an invasive procedure.” FFP. We calculated the proportion of patients Several studies have examined the use of Existing local practices for reporting of with PT prolongation who received FFP dur- FFP in various patient populations (6– coagulation tests were used, which comprised ing ICU admission, the indications for FFP transfusion, and the volume of FFP received 13), but the prevalence, severity, and risk either INR or PT. For comparative analysis per transfusion episode. For these calcula- between hospital laboratories, PT values were factors for coagulopathy during an epi- tions, the estimated patient dry weight at ICU converted to INR (INR ϭ [PT/MNPT]ISI,in sode of critical illness are poorly de- admission was used to estimate dose in mL/ scribed. In addition, the association be- which MNPT and ISI were the laboratory- kgϪ1. The INR values preceding FFP transfu- tween coagulation disturbances and specific mean normal PT and international sion episodes were used as measures of trans- patient outcome is unknown. This infor- specificity index (the mean ISI for these hos- fusion triggers. mation is needed to design high-quality pitals was 1.06, close to 1), respectively. We Relationship Between PT Prolongation trials of FFP treatment and make clinical chose this approach a priori as the best and ICU Outcome. We developed logistic re- practice more evidence-based. We carried method of adjusting for interinstitutional dif- gression models to explore the association be- ferences in thromboplastin sensitivities, be- out a multicentered study to describe the tween PT prolongation during ICU stay and cause standardization of PT assays was not mortality during admission. First, we included epidemiology of a key marker of coagu- feasible, and 10 of 29 hospitals reported only all measured baseline characteristics at ICU lopathy, prolongation of the PT, in criti- INR data. For our primary analysis, we defined admission and then entered the first INR value cally ill patients and its association with PT prolongation as an INR Ͼ1.5. We chose into the model to explore the importance of patient survival. Participants in this CME this cutoff because many clinicians base trans- PT prolongation at ICU admission. In further activity should be better able to assess the fusion decisions on this value, and we aimed to models, we explored differences between pa- risk factors for coagulopathy in critically generate pragmatic clinically relevant esti- tients whose severity of PT prolongation wors- ill patients, and evaluate the incidence mates for the epidemiology of coagulation dis- ened from those in whom it resolved or remained unaltered. In these models, we used and appropriate management and admin- turbances. We recognized that this cutoff was both absolute INR values and changes in INR istration of FFP to these patients. semiarbitrary and also calculated prevalence from the first recorded INR (delta INR). data for patients in whom a worst INR Ͼ1.2 and Ͼ2 was reported as a sensitivity analysis. METHODS If a patient developed PT prolongation RESULTS equivalent to an INR Ͼ1.5, an additional data Participating Centers. Twenty-nine inten- collection form was completed, including the There were 2386 admissions during the sive care units (ICUs) in the United Kingdom study period to the 29 adult ICUs (14 in participated comprising a total of 301 critical presence of systemic inflammatory response syndrome, infection, hemorrhage, red cell England, 12 in Scotland, two in Northern care beds. The ICUs were in 19 tertiary hospi- Ireland, one in Wales). Of these, 1990 ad- tals and 10 regional hospitals and included transfusions, and organ dysfunction during two ICUs with specialist liver units and five the 24 hrs before onset of the PT abnormality. missions were eligible for data collection. ICUs admitting patients requiring neurointen- Data collection was continued from the The 396 exclusions comprised 138 read- sive care. All ICUs recruited admissions over a period of admission to ICU death, discharge, missions, 96 locally agreed exclusions, 83 4- to 8-wk period during which clinical care of or 30 continuous days in the ICU. All data transfers from other ICUs, 70 patients all patients remained the responsibility of at- forms underwent quality control and query where admission was expected to be Ͻ4 tending clinicians to reflect “usual practice.” resolution followed by computer-based data hrs, and nine others. Of 1990 eligible ad-

1940 Crit Care Med 2010 Vol. 38, No. 10 Table 1. Characteristics of the study cohort at admission to the ICU and of the subgroups with or without PT prolongation during the ICU stay

Admissions With INR Admissions With Normal All Admissions (n ϭ 1923) Ͼ1.5 (n ϭ 576) INR Test (n ϭ 1347) p

Age, mean years (SD; minimum–maximum) 58.3 (18.8; 9–100) 60.8 (18.0; 9–100) 57.8 (19.1; 10–97) .0002 Male, no. (%) 1087 (57) 295 (51.2) 792 (58.9) .002 Mean APACHE II score (SD) 18.4 (8.3) 21.4 (17.1) 17.1 (7.9) Ͻ.0001 Source of admission, no. (%) Emergency department 479 (25) 110 (19.3) 369 (27.5) Ͻ.0001 Operating room 801 (42) 222 (38.9) 579 (43.2) Transfer from ward 522 (27) 203 (35.6) 319 (23.8) Transfer from other hospital 110 (6) 36 (6.3) 74 (5.5) Type of admission, no. (%) Medical 875 (46) 273 (47.5) 602 (44.7) .007 Surgical 908 (47) 277 (48.2) 631 (46.9) Trauma 138 (7) 25 (4.4) 113 (8.4) Risk factors for coagulopathy Chronic coagulation disorder, no. (%) 7 (Ͻ0.1) 1 (0.2) 6 (0.5) .66 Chronic liver disease, no. (%) 119 (6) 83 (14.4) 36 (2.7) Ͻ.0001 Chronic renal failure with dialysis, no. (%) 54 (3) 26 (4.5) 28 (2.1) .005 Warfarin therapy before ICU admission, no. (%) 47 (2) 41 (7.1) 6 (0.5) Ͻ.0001 Sepsis at admission 499 (26) 206 (35.8) 293 (21.8) Ͻ.0001 Highest recorded creatinine concentration during 24 hrs before ICU admission Ͻ150 1047 292 (63.1) 755 (78.2) Ͻ.0001 151–300 242 111 (24.0) 131 (13.6) Ͼ300 ␮mol/L 140 60 (13.0) 80 (8.3) Highest bilirubin recorded during 24 hrs before ICU admission Ͻ20 847 215 (59.6) 632 (83.4) Ͻ.0001 20–100 230 114 (31.6) 116 (15.3) Ͼ100 ␮mol/L 42 32 (8.9) 10 (1.3) Blood transfusion during initial treatment period 0 units 1378 351 (60.9) 1027 (76.2) Ͻ.0001 1–4 units 332 128 (22.2) 204 (15.1) 5–8 units 113 50 (8.7) 63 (4.7) Ͼ8 units 100 47 (8.2) 53 (3.9) Median length of ICU stay (Q1, Q3) 2.0 (0.8, 5.5) 3.0 (1.1, 8.1) 1.8 (0.8, 4.3) Outcome, no. (%) Discharged from ICU 1521 (79) 355 (62) 1166 (87) a Still in ICU after 30 days 38 (2) 18 (3) 20 (1) Died in ICU within 30 days 364 (19) 203 (35) 161 (12)

ICU, intensive care unit; PT, prothrombin time; INR, international normalized ratio; APACHE, Acute Physiology and Chronic Health Evaluation. aSee regression analysis for ICU outcome. missions, 67 did not have adequately com- sion subsequently developed it during tial PT value was available for 549 (95%) plete data for analysis. The final total of ICU stay, and the overall prevalence of PT of the episodes of PT prolongation (mean 1923 admissions (96.6% of all eligible ad- prolongation at some time during ICU value 53.2 secs; SD 29.8 secs). missions) used 11,075 ICU days, of which stay was 30.0% (32.4% if the pre-ICU The median (first, third quartile) du- data were complete for 11,014 days period was also included). For the sensi- ration of PT prolongation was 2.9 days (99.4%). Demographic and diagnostic tivity analysis, 59.9% of patients had a (1.9, 5.5 days) and the episode had re- characteristics of the cohort are shown in worst INR of Ͼ1.2 and 13.6% of patients solved at the time of ICU discharge in 215 Table 1. A total of 11,153 INR and/or PT had a worst INR of Ͼ2. (37%) cases. For unresolved episodes, coagulation tests were undertaken, which Most (n ϭ 526 [91%]) of the patients 198 (34%) patients were discharged alive equated to 5.8 tests per admission and 1.01 with INR Ͼ1.5 had a single episode of PT from the ICU with ongoing PT prolonga- tests per ICU day. For 1882 (17%) of these prolongation, but 40 (7%) had two epi- tion, and 160 (28%) died in the ICU be- tests, INR was Ͼ1.5. sodes, five (1%) had three episodes, four fore the episode resolved. Three patients Prevalence, Severity, and Duration of (1%) had four episodes, and one patient had ongoing PT prolongation after 30 PT Prolongation. A flow diagram showing had five episodes. Many patients had days in the ICU when data collection the pattern of PT prolongation in relation short-lived minor derangements of the stopped. to ICU admission is shown in Figure 1. PT and in 158 (27%) of patients, a single Characteristics of Patients With PT PT prolongation was documented in INR result in the range of 1.6–2.0 was Prolongation. Admission characteristics 12.9% of patients during the 24 hrs be- recorded. The worst recorded INR value for patients with and without PT prolon- fore admission and was present at ICU was Յ2.5 for 421 patients (73% of cases); gation are compared in Table 1. Patients admission in 22.8% of patients. Combin- for more severe derangements, the worst with PT prolongation were more likely to ing these periods gave a prevalence of value was 2.6–3.5 for 79 (14%) of cases, be older, female, have higher Acute Physi- 25.2%. Only 9.6% of the 1438 patients 3.6–5.0 for 46 (8%) of cases, and Ͼ5.0 in ology and Chronic Health Evaluation II without PT prolongation at ICU admis- 30 (5%) of cases. A paired activated par- scores, have chronic liver disease and dial-

Crit Care Med 2010 Vol. 38, No. 10 1941 Figure 1. Flow chart illustrating the prevalence of prothrombin time (PT) prolongation in the study population in relation to intensive care unit (ICU) admission. INR, international normalized ratio.

ysis-dependent renal failure, have sepsis, and be receiving warfarin therapy. More patients with PT prolongation were admit- Table 2. Multivariate regression analysis showing admission factors independently associated with PT ted from the general hospital wards rather prolongation during ICU admission than the operating room or emergency de- Worst INR Ͼ1.5 Worst INR Ͼ2 partment. They were more likely to have elevated plasma bilirubin and creatinine Variable Odds Ratio (95% CI) p Odds Ratio (95% CI) p concentrations and to have received blood transfusions before ICU admission. Ͻ Male 1.45 1.16–1.81 .001 1.85 1.36–2.50 .0001 During the 24 hrs before onset of PT APACHE II score 0–9 1 1 prolongation, there was a high preva- 10–19 1.79 1.15–2.81 .01 1.21 0.60–2.47 .60 lence of documented systemic inflamma- 20–29 2.65 1.67–4.21 Ͻ.0001 2.49 1.23–5.05 .01 tory response syndrome (61.4%) and Ͻ Ͻ 30–39 3.77 2.14–6.63 .0001 4.99 2.28–10.91 .0001 proven or clinically suspected infection Ն40 7.61 3.09–18.72 Ͻ.001 9.74 3.40–27.90 Ͻ.0001 Admitted from (46.8%). Considering specific organ dys- Operating room 1 1 function, the prevalence of circulatory Emergency department 0.89 0.65–1.22 .47 1.59 1.01–2.48 .04 shock was 69.4%, acute lung injury Ward 1.14 0.85–1.52 .39 1.75 1.17–2.62 .006 51.9%, acute renal failure 13.9%, and Other 1.24 0.77–1.99 .38 2.07 1.11–3.89 .02 Chronic liver disease 4.64 2.93–7.35 Ͻ.0001 2.86 1.72–4.75 Ͻ.0001 liver dysfunction 7.4%. The prevalence of Warfarin 20.24 8.23–49.75 Ͻ.0001 21.08 10.25–43.35 Ͻ.0001 moderate and major hemorrhage was Creatinine, ␮mol/L 6.9% and 2.3%, respectively. Ͻ150 1 1 In a multivariate logistic regression 150–300 1.66 1.20–2.30 .002 2.12 1.43–3.16 .0002 model, the factors found to have indepen- Ͼ300 1.46 0.97–2.21 .07 1.30 0.77–2.18 .33 Bilirubin, ␮mol/L dent associations with PT prolongation are Ͻ20 1 1 shown in Table 2. In the final model, the 20–100 2.15 1.53–3.03 Ͻ.0001 2.48 1.63–3.77 Ͻ.0001 probability of PT prolongation in ICU was Ͼ Ͻ 100 4.37 1.92–9.93 .0004 6.54 2.97–14.43 .0001 markedly increased by male sex, warfarin RBC units 01 1 therapy at ICU admission, greater Acute 1–4 1.71 1.28–2.30 .0003 1.54 1.03–2.31 .04 Physiology and Chronic Health Evaluation 5–8 2.62 1.68–4.08 Ͻ.0001 2.33 1.24–4.18 .005 II score, the presence of chronic liver dis- Ͼ8 3.01 1.86–4.86 Ͻ.0001 3.31 1.77–6.20 .0002 ease, and elevated plasma bilirubin, sepsis, Sepsis 2.08 1.63–2.67 Ͻ.0001 1.84 1.32–2.56 .0003 and blood transfusions during the 24 hrs PT, prothrombin time; ICU, intensive care unit; INR, international normalized ratio; CI, confidence before onset. Associations were similar interval; APACHE, Acute Physiology and Chronic Health Evaluation; RBC, red blood cells. when the model included a worst INR of Data using worst INR Ͼ2 is included as a sensitivity analysis for more severe PT prolongation. Ͼ1.5 or Ͼ2.0, with the exception of an

1942 Crit Care Med 2010 Vol. 38, No. 10 Figure 2. International normalized ratio (INR) values preceding fresh-frozen plasma (FFP) transfusion for all the FFP transfusion episodes documented in the study population. The numbers and proportions of all episodes are broken down for FFP transfusions that were and were not associated with hemorrhage. association with nonoperating room ad- though this difference was clinically small the operating room were all independently missions in the model using INR Ͼ2.0. (median 2.1 [first, third quartile 1.9, 2.6] vs. associated with greater ICU mortality. No Use of FFP. In total, 215 patients 1.9 [1.7, 2.4]; p Ͻ .0001). Confirmed infec- statistically significant associations were (11.2%) received FFP during the study, tion was less prevalent for episodes treated found with sepsis (p ϭ .06), sex, admitting which was administered during 159 of 642 with FFP (40.7% vs. 51.4%, p ϭ .04), but specialty, chronic ischemic heart disease, episodes of PT prolongation (24.8%). For there was no difference in the prevalence of chronic liver disease, chronic renal failure, the majority (94) of PT prolongation epi- preexisting chronic liver disease, warfarin warfarin therapy at ICU admission, or sodes, one FFP transfusion treatment oc- therapy, systemic inflammatory response plasma creatinine (all p Ͼ .3). When the curred; two treatments occurred in 38, syndrome, shock, acute lung injury, or re- admission INR was introduced into the three treatments in 16, and Ͼ3 treatments nal or liver dysfunction. model, admission INR was strongly associ- in 11 PT prolongation episodes. A number The reasons given for FFP administra- ated with ICU mortality after adjusting for of FFP treatments occurred to patients tion were bleeding (n ϭ 124 [45.9%]), the other factors (Table 3; the 47 patients without PT prolongation; 63 of these were prophylaxis for a procedure (n ϭ 45 receiving warfarin therapy were excluded to patients who developed PT prolongation [16.7%]), and in 100 cases (37.0%), no from this model). In all of the models ex- during their ICU stay but had normal INR procedure was planned and no bleeding ploring the importance of the highest INR values at the time they received FFP. Fifty- was present. There was wide variation in after ICU admission, there was a strong six patients received 64 FFP treatments in the dose of FFP used; the median (first, association between a higher or increasing the ICU but never had documented PT pro- third quartile; range) volume of FFP INR value and greater ICU mortality, even longation (3% of the entire cohort). For 24 transfused per treatment was 803 mL after allowing for the initial INR (all p Ͻ of these treatments, no activated partial PT (541, 1093; 220–2775 mL), which .0001). The differences in absolute risk for value was measured during the 24 hrs be- equated to a median (first, third quartile; ICU death are illustrated in Table 4. An fore FFP administration; for the other 40 range) dose of 10.8 mL/kgϪ1 (7.2, 14.4; increase in the INR of Ͼ1 during the ICU treatments, activated partial PT was mea- 2.4–41.1 mL/kgϪ1). Considering all 404 stay was associated with an approximately sured but was only mildly prolonged in 23 FFP transfusion treatments, 51.3% were 40% absolute increase in ICU death rate in cases (median activated partial PT value for to patients in whom no hemorrhage was patients with and without PT prolongation the 40 cases 42 secs (interquartile range, present. The INR values preceding FFP at ICU admission. 33.5–51.5 secs). None of these patients transfusion varied widely and were often were recorded as having disorders for only mildly increased (Fig. 2). Notably, DISCUSSION which FFP treatment is indicated for rea- for 40.4% of all FFP treatments, there sons other than coagulation disturbances was no hemorrhage and the preceding We have shown that 30% of admissions (for example, plasmapheresis-responsive INR was Յ2.5 and for 13.5% of all treat- to general ICUs in the United Kingdom diseases). The total number of FFP treatments there was no hemorrhage and the develop prolongation of the PT during the ments in the entire cohort was 404. preceding INR was Յ1.5. ICU period of their critical illness (using Episodes of PT prolongation were more Mortality. In unadjusted analysis, the an INR cutoff value of Ͼ1.5 to define PT likely to be treated with FFP if they were ICU mortality was higher for patients with prolongation). In most cases, derange- associated with moderate hemorrhage (risk PT prolongation than those without (35% ment of PT was mild (75% INR Յ2.5) and difference 20.1% vs. 2.3%), severe hemor- vs. 12%). In the regression model incorpo- short-lived (27% had a single INR value rhage (risk difference 8.1% vs. 0.2%), and rating all factors listed in Table 1, greater of 1.6–2.0). Despite this, patients with PT red blood cell transfusions (risk difference age, Acute Physiology and Chronic Health prolongation were at significantly in- 48.4% vs. 7.9%; all comparisons p Ͻ .001). Evaluation II score, bilirubin concentra- creased risk of death compared with pa- The maximum INR was higher for episodes tion, transfusion of Ͼ8 units of red blood tients without PT prolongation, even af- of PT prolongation treated with FFP, al- cells, and admissions that were not from ter adjusting for illness severity at

Crit Care Med 2010 Vol. 38, No. 10 1943 Table 3. Risk factors for death in ICU product for managing PT prolongation at the time of the study and administration of Variable Odds Ratio 95% CI p other products such as prothrombin complex and factor concentrates are very un- Age (decade) 1.23 1.13–1.33 Ͻ.0001 APACHE II likely to have confounded our data because 0–9 Reference they were not provided by the blood ser- 10–19 1.79 0.83–3.86 .14 vices and no clinicians reported using 20–29 4.85 2.25–10.45 Ͻ.0001 them. Our data confirm the high levels of 30–39 10.32 4.51–23.62 Ͻ.0001 Ն40 27.52 8.54–88.69 Ͻ.0001 clinical uncertainty in current clinical Admitted from practice (14–16). Mildly deranged INR val- Operating room Reference ues may be associated with near normal Emergency department 3.29 2.23–4.87 Ͻ.0001 coagulation factor levels (17), and the doses Ͻ Transfer from ward 3.40 2.38–4.86 .0001 of FFP required to achieve clinically mean- Other 2.65 1.46–4.81 .001 Bilirubin, ␮mol/L ingful changes in coagulation factor con- Ͻ20 Reference tent are difficult to predict (18–21). Abnor- 20–100 1.51 1.02–2.24 .04 malities of PT/INR are also poor predictors Ͼ100 1.72 0.80–3.68 .16 of procedure-related bleeding risk (22–26), RBC units Ͼ8 2.26 1.29–3.95 .004 First INR in ICU and the quality of evidence supporting pro- Յ1.5 Reference phylactic FFP transfusion is poor (27, 28). 1.6–2.5 2.62 1.92–3.59 Ͻ.0001 Our data support the need for high-quality Ն2.6 4.06 2.20–7.51 Ͻ.0001 clinical evidence to guide management decisions and create greater consistency in ICU, intensive care unit; CI, confidence interval; APACHE, Acute Physiology and Chronic Health clinical practice. Evaluation; RBC, red blood cells; INR, international normalized ratio. Data are for the final model incorporating admission characteristics and the INR value at ICU PT prolongation, especially worsening admission. The small number of patients on warfarin therapy at ICU admission were excluded from PT, had a strong independent association this model (n ϭ 47). with a greater chance of dying in ICU. This relationship has several possible explana- tions and despite our inclusion of a range of Table 4. Survival in ICU by initial INR in ICU and study provides a detailed prospective de- predefined factors is potentially subject to increment to maximum INR in ICU in patients scription of coagulation disturbances in an residual confounding by factors that we did with more than one PT test unselected population of critically ill pa- not adequately adjust for in our regression tients. The definition of abnormal PT was First INR in First INR in models, but our data support the hypothe- ICU Յ1.5 ICU Ͼ1.5 based on a laboratory threshold INR value sis that coagulopathy, or treatments such Ͼ Delta INRa Dead/Total (%) Dead/Total (%) 1.5, which is commonly used by clini- as FFP that are associated with it, contrib- cians. A more inclusive (INR Ͼ1.2) and ute directly to adverse outcomes during 0 58/632 (9.2) 50/186 (26.9) exclusive (INR Ͼ2.0) cutoff revealed a prev- critical illness. For example, many patients 0.1–0.2 57/343 (16.6) 14/41 (34.2) alence range of 14–60%, although the in- with PT prolongation who received FFP 0.3–0.5 29/130 (22.3) 18/51 (35.3) clusive extreme almost certainly included had infection, systemic inflammatory re- 0.6–1.0 9/32 (28.1) 14/25 (56.0) Ͼ1.0 13/24 (54.2) 21/32 (65.6) many patients without clinically important sponse syndrome, or circulatory shock. The coagulation factor abnormalities. We be- risk–benefit balance of correcting coagu- ICU, intensive care unit; INR, international lieve a prevalence of 30% is an accurate lopathy in these patients is uncertain and it normalized ratio; PT, prothrombin time. pragmatic estimate of prevalence for this is noteworthy that sepsis therapies showing aDifference between maximum INR in ICU population given that detailed quantitative most promise in recent years have had and initial INR in ICU. correlations with individual coagulation anticoagulant rather than procoagulant factor levels is not feasible for such a large properties (29–31). FFP transfusions have cohort. Although the INR was developed to well-recognized risks, including transfu- admission and a range of potentially im- standardize assessment of the response to sion-related acute lung injury and transfu- portant patient comorbidities and acute vitamin K antagonists, it does provide a sion-associated circulatory overload (6, 8, illness characteristics. Worsening PT pro- means of comparing data between labora- 10, 32, 33), and it is relevant that 52% of longation was strongly associated with a tories by adjusting for the use of different patients with PT prolongation fulfilled di- greater chance of dying in the ICU. thromboplastins between laboratories, agnostic criteria for acute lung injury. Our large overall sample size (represent- which we considered important in the These observations provide further justifi- ing approximately 12% of all admissions to study. cation for the need for adequately powered ICUs in the United Kingdom during the There was wide variation in the manage- studies addressing the risk–benefit profile period of the study) and the number, char- ment of PT prolongation with FFP in terms of FFP transfusions. acteristics, and geographic dispersion of of dose, the indication for correcting PT participating ICUs suggest our population prolongation, and the pretransfusion INR. CONCLUSION was representative of adult general ICUs in Of note, 40% of all FFP treatments were the United Kingdom. We included a rela- administered to patients without hemor- Our large epidemiologic study has tively high number of teaching hospital rhage in whom preceding coagulation tests shown that PT prolongation is prevalent ICUs, which may have a more complex case were normal or only modestly deranged in critically ill patients and is strongly mix than smaller ICUs, but despite this, our (INR Յ2.5). FFP was the standard blood associated with a greater risk of death. PT

1944 Crit Care Med 2010 Vol. 38, No. 10 abnormalities are often relatively minor trie.* Western General Hospital, Edin- ponent Therapy. Anesthesiology 1996; 84: and short-lived, but clinicians frequently burgh, Claire Battison, Louise Sinclair, and 732–747 treat PT prolongation with FFP even in Charles Wallis.* Western Infirmary, Glas- 6. Holness L, Knippen MA, Simmons L, et al: the absence of hemorrhage. Clinical prac- gow, Alexander Binning,* Stephen Hender- Fatalities caused by TRALI. Transfus Med tice varies widely both in terms of INR son, and Marie Pollock. England: Birming- Rev 2004; 18:184–188 7. Dara SI, Rana R, Afessa B, et al: Fresh frozen transfusion triggers and the dose of FFP ham, Selly Oak, Ben Trumper, Tony plasma transfusion in critically ill medical administered. Clinical trials are urgently Whitehouse,* and Mav Manji. Bristol– patients with coagulopathy. Crit Care Med needed to improve the evidence base for Southmead, Tracey Fleming, Sally Grier, 2005; 33:2667–2671 coagulopathy treatment, particularly be- and Jasmeet Soar.* Chelmsford–Broom- 8. Gajic O, Dzik WH, Toy P: Fresh frozen cause the risk–benefit profile of blood field, Christine Mitchell-Inwang, and Alis- plasma and platelet transfusion for nonbleed- products is increasingly questioned and dair Short.* Leeds–General Infirmary, Stu- ing patients in the intensive care unit: Ben- costs of production continue to increase. art Elliot and Andrew Bodenham.* efit or harm? Crit Care Med 2006; 34: At the conclusion of this CME activity, Leeds–St James’s, Judith Thornton and S170–S173 participants should be better able to as- Stuart Murdoch.* London–Chelsea and 9. Rana R, Fernandez-Perez E, Khan SA: Trans- sess the risk factors for coagulopathy in Westminster, Adrian Wagstaff and Neil fusion-related acute lung injury and pulmo- nary edema in critically ill patients: A retro- critically ill patients, and evaluate the in- Soni.* London–Royal London, Gail Mar- spective study. Transfusion 2006; 46: cidence and appropriate management shall, Andrew Ely, and Maria Heeley.* Lon- 1478–1483 and administration of fresh FFP to these don–St Thomas’s, Tony Sherry, Katie Lei, 10. Popovsky MA: Transfusion-associated circu- patients. John Smith, Laura Campbell-Stephen, and latory overload: the plot thickens. Transfu- Duncan Wyncoll.* Manchester–Royal Infir- sion 2009; 49:2–4 ACKNOWLEDGMENTS mary, Emma McClure, John Butler,* Tony 11. Khan H, Belsher J, Yilmaz M, et al: Fresh- Dunne, Jane Eddleston, and Dougal Atkin- frozen plasma and platelet transfusions are The following individuals contributed to son. Newcastle–Freeman, Sue Whitehead, associated with development of acute lung the ISOC study: ISOC Organizing Commit- Andrew Kilner,* and Jonathon Wallis.* injury in critically ill medical patients. Chest tee—Simon Stanworth (cochairman); Tim Newcastle–Royal Victoria, Simon Bau- 2007; 131:1308–1314 Walsh (cochairman); Douglas Watson douin,* Sue Whitehead, and Jonathon Wal- 12. Spence RK: Clinical use of plasma and plasma fractions. Best Pract Res Clin (study coordinator); Heather Smethurst lis.* Oxford–John Radcliffe, John Corcoran, Haematol 2006; 19:83–96 (study coordinator); Brian McClelland; Caroline Allen, Duncan Young,* and Julian 13. Watson GA, Sperry JL, Rosengart MR, et al: Robert Lee (statistician); Robin Prescott Millo.* Portsmouth–Queen Alexandra, Fresh frozen plasma is independently associ- (statistician); and Caroline Maciver. ISOC Caroline Cawkill, Allison Hyson, Martin ated with a higher risk of multiple organ Study Group Participating Hospitals and Tweeddale, and Philip Young.* Reading– failure and acute respiratory distress syn- Individuals—Wales: Cardiff, University Royal Berkshire, Carys Jones, Linda Hosie, drome. J Trauma 2009; 67:221–227 Hospital of Wales, Elizabeth Hutcheon and and Carl Waldmann.* Other: Medical Sta- 14. Wallis JP, Dzik S: Is fresh frozen plasma George Findlay. Northern Ireland: Belfast, tistics Unit, University of Edinburgh, Rob- overtransfused in the United States? Trans- Royal Victoria, Gavin Lavery,* and Gillian ert Lee and Robin Prescott. National Blood fusion 2004; 44:1674–1675 Thompson. Belfast, Ulster Hospital, John Service, Simon Stanworth, Mike Patel, 15. Palo R, Capraro L, Hovilehto S, et al: Popu- lation-based audit of fresh frozen plasma Mcateer* and John Trinder. Scotland: Ab- Caroline Hughes, and Heather Smethurst. transfusion practices. Transfusion 2006; 46: erdeen Royal Infirmary, Jane Taylor, Steve Scottish National Blood Transfusion Ser- 1921–1925 Stott,* Sian Roughton, Sally Hall, and vice, Douglas Watson, Hamish Davidson, 16. Stanworth SJ, Tinmouth AT: Plasma trans- Heather Tennant. Dumfries & Galloway and Brian McClelland. In addition, he ISOC fusion & use of albumin. In: Rossi’s Principles Royal Infirmary, Wayne Wrathall.* Glas- Organizing Committee would like to ac- of Transfusion Medicine. Fourth Edition. Si- gow Royal Infirmary, Lindsey Donaldson* knowledge support from Beverley Hunt, mon TL (Ed). Chichester, Wiley-Blackwell, and Myles Cassidy. Monkland’s Hospital, Heidi Doughty, Janet Birchall, Derek Nor- 2009, pp 287–297 Sanjiv Chohan,* Isabel Paterson, Sandra folk, Shubha Allard, and Liz Love. *ISOC 17. 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