Stuart McKechnie

Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients

Forward This document aims to summarize the current literature guiding the use of red cell transfusion in critically ill patients and provides recommendations to support clinicians in their day-to-day practice. Critically ill patients differ in their age, diagnosis, co-morbidities, and severity of illness. These factors influence their tolerance of anaemia and alter the risk to benefit ratio of transfusion. The optimal management for an individual may not fall clearly within our recommendations and each decision requires a synthesis of the available evidence and the clinical judgment of the treating physician. This guideline relates to the use of red cells to manage anaemia during critical illness when major haemorrhage is not present. A previous British Committee for Standards in Haematology (BCSH) guideline has been published on massive haemorrhage (Stainsby et al, 2006), but this is a rapidly changing field. We recommend readers consult recent guidelines specifically addressing the management of major haemorrhage for evidence-based guidance. A subsequent BCSH guideline will specifically cover the use of plasma components in critically ill patients.

Evidence and triggers for the transfusion of blood and blood products.

Allogeneic red cell transfusion is a commonly used treatment to improve the oxygen carrying capacity of blood during the peri‐operative period. Increasing arterial oxygen content by increasing haemoglobin does not necessarily increase tissue oxygen delivery or uptake. Although the evidence‐base for red cell transfusion practice is incomplete, randomised studies across a range of clinical settings, including surgery, consistently support the restrictive use of red cells, with no evidence of benefit for maintaining patients at higher haemoglobin thresholds (liberal strategy). A recent meta‐analysis of 7593 patients concluded that a restrictive transfusion strategy was associated with a reduced risk of healthcare‐associated infections (pneumonia, mediastinitis, wound infection, sepsis) when compared with a liberal transfusion strategy. The degree to which the optimal haemoglobin concentration or transfusion trigger should be modified for patients with additional specific risk factors (e.g. ischaemic heart disease), remains less clear and requires further research. Although most clinical practice guidelines recommend restrictive use of red cells, and many blood transfusion services have seen marked falls in overall usage of red cells, the use of other blood components such as fresh frozen plasma, platelets, and cryoprecipitate has risen. In clinical practice, administration of fresh frozen plasma is usually guided by laboratory tests of coagulation, mainly prothrombin time, international normalised ratio and activated partial thromboplastin time, but the predictive value of these tests to predict bleeding is poor.

Psychological intervention to prevent ICU-related PTSD: who, when and for how long?

Experiencing treatment on a modern intensive care unit (ICU) is a potentially traumatic event. People who experience traumatic events have an increased risk of depression, anxiety disorders and post-traumatic stress disorder (PTSD). Extended follow-up has confirmed that many patients suffer physical and psychological consequences of the ICU treatment up to 12 months after hospital discharge. PTSD in particular has become increasingly relevant in both the immediate and longer-term follow-up care of these patients. The extent to which the consequences of critical illness and the treatments received in the ICU contribute to the development of PTSD is poorly understood and more rigorous studies are needed. Understanding the factors associated with a poor psychological recovery after critical illness is essential to generate models of causality and prognosis, and to guide the delivery of effective, timely interventions.

Fresh versus old red cell transfusions: what have the recent clinical trials found?

Purpose of reviewRed blood cell transfusion is a common treatment for anaemia worldwide, but concerns continue to be raised about adverse effects of cellular blood components, which are biological products. One hypothesis for the adverse effects associated with blood transfusion is the harmful effects of storage on red cells that have been demonstrated in laboratory and animal studies. Over the past few years, a number of more significant randomized controlled trials comparing ‘fresh’ versus ‘older’ blood have been published in an attempt to address the clinical consequences of storage age, with two further large trials ongoing. Recent findingsThese recent trials enrolled approximately 4000 participants across a variety of populations – cardiac surgical, critically ill, paediatric and acute hospitalized in-patients. All trials achieved statistically significant separation of red cell storage duration between both groups. The results of all these trials have found no clinical benefit to using fresher red cells when compared with older or standard-issue red cells. However, certain subgroups of patients either receiving red cells stored at more extreme ages of storage or those with additional risks for impaired microcirculations (critically ill elderly, severe sepsis and major haemorrhage) were either underrepresented or not included in these trials. SummaryAt present, on the basis of recent trials, there is no indication for blood transfusion services to implement preferential utilization of fresher red cell units.

Use of Plasma for Acquired Coagulation Factor Deficiencies in Critical Care.

Coagulopathy in critically ill patients is common and often multifactorial. Fresh frozen plasma (FFP) is commonly used to correct this either prophylactically or therapeutically. FFP usage is mainly guided by laboratory tests of coagulation, which have been shown to have poor predictive values for bleeding. Viscoelastic tests are an attractive option to guide hemostatic therapy, but require rigorous evaluation. The past few years have seen a gradual reduction in national use of FFP potentially due to an increased awareness of risks such as transfusion-related acute lung injury, patient blood management strategies to reduce transfusion in general, and increased awareness of the lack of high-quality evidence available to support FFP use. Within critical care, FFP is administered before invasive procedures/surgery, to treat major traumatic and nontraumatic hemorrhage, disseminated intravascular coagulation, and for urgent warfarin reversal if first-line agents, such as prothrombin complex concentrate (PCC) are not available. Alternative agents such as fibrinogen concentrate and PCC need further evaluation through large-scale clinical trials.

Serum hepcidin potentially identifies iron deficiency in survivors of critical illness at the time of hospital discharge

Anaemia is common in patients admitted to and discharged from intensive care (ICU) and is associated with poor quality of life in ICU survivors (Walsh et al, 2010; Lasocki et al, 2014). The majority of ICU patients will have an anaemia of inflammation (AI) as a collective result of functional iron deficiency, leading to iron restricted erythropoiesis, increased cytokine production, suppressed bone marrow activity and reduced red blood cell life span (Lasocki et al, 2010). Identifying iron deficiency in this context is challenging because commonly used tests, such as ferritin and transferrin saturation, are significantly confounded by inflammation. Hepcidin is a circulating polypeptide, which, via its inhibitory action on the key iron exporter ferroportin, acts as a key regulator in iron homeostasis (Girelli et al, 2016). Inhibition of ferroportin results in retention of iron within enterocytes, macrophages and hepatocytes with a consequent decrease in serum iron levels, thereby restricting its availability for erythropoiesis. Hepcidin expression is increased by inflammation and iron overload but reduced in iron deficiency, hypoxia and enhanced erythropoietic drive. Elevated hepcidin levels restricting the use of iron, along with suppressed bone marrow function, may partly explain why trials of iron supplementation in the acute phase of critical illness have not shown any benefit (Litton et al, 2016; Shah et al, 2016). Hepcidin may be a better marker of iron deficiency (or requirement for iron) than the routine biochemical assays in current use, allowing more precise identification of anaemic patients likely to respond to iron therapy (Girelli et al, 2016). In order to identify a potential cohort of patients who would probably respond [i.e. increase haemoglobin (Hb) concentration] to iron supplementation, we investigated the utility of serum hepcidin concentrations of ICU survivors at hospital discharge. Patients recruited to the RECOVER (Evaluation of a Rehabilitation Complex Intervention for Patients Following Intensive Care Discharge) trial and who consented to a biomarker sub-study were eligible (Walsh et al, 2015). RECOVER was a randomized controlled trial examining the effect of a complex rehabilitation package on physical outcome in ICU survivors. Laboratory tests recorded included Hb concentration, serum creatinine, albumin and C-reactive protein (CRP). Serum hepcidin was measured by enzyme-linked immunosorbent assay (ELISA) (hepcidin-25 high sensitivity ELISA, DRG Instruments, Marburg, Germany). Other markers of iron status and erythropoiesis, such as ferritin, serum iron, transferrin saturation (Tsat), soluble transferrin receptor (sTfR), erythropoietin, vitamin B12 and folate, were also analysed. Anaemia was defined according to World Health Organization (WHO) guidelines: males Hb <130 g/l and females Hb <120 g/l. A ferritin cut-off of <15 lg/l was used to diagnose iron deficiency anaemia (WHO, 2001). In the presence of inflammation (defined as CRP >8 mg/l), a ferritin cut-off of 150 lg/l was used to differentiate between combined anaemia of iron deficiency and inflammation (IDI) (ferritin <150 lg/l) and AI (ferritin >150 lg/l) as previous reported (Lee et al, 2002). Baseline characteristics are shown in Table 1. Median (interquartile range, IQR) CRP for the entire cohort was 36 (15–72) mg/l, reflecting ongoing inflammation even at hospital discharge. 110/117 (94%) patients were anaemic with a CRP of >8 mg/l prior to hospital discharge. Of these, 89/110 (81%) had AI and 11/110 (10%) had IDI (Table 2). 10 patients developed anaemia that appeared unrelated to iron, B12, and/or folate deficiency or inflammation. Laboratory results are shown in Table 2. Median (IQR) serum hepcidin concentration was significantly lower in the IDI group and there was no statistical difference in CRP concentrations between both groups, indicating the difference in hepcidin values may not reflect a higher level of inflammation in the AI group. Levels of the sTfR-ferritin index, another potential marker of iron deficiency in inflammation, were higher in the IDI group and linear regression of (log) sTfR-ferritin index with (log) hepcidin showed a strong association (co-efficient 0 8, P < 0 001). There were no significant differences in age, illness severity, Hb and renal function between both groups. The maximal Youden index was achieved at a hepcidin cut-off of <19 ng/ml, with a sensitivity of 73% and specificity of 74%. Using current definitions of iron deficiency, 11/110 patients would be considered eligible for oral iron replacement. Applying a hepcidin cut-off <19 ng/ml, a further 24 patients would be included, raising this to 32% of the anaemic cohort. This study has confirmed a high prevalence of anaemia at time of hospital discharge in ICU survivors (Walsh et al, 2010). While inflammatory processes are still active in this patient group, as evidenced by the raised median CRP in the correspondence

Peri-procedural management of bleeding risks in critical care patients: A local audit and national survey

Estimation of bleeding risk in critical care patients undergoing interventional radiological procedures is frequently made on the basis of blood tests. If these tests are abnormal, fresh frozen plasma and/or platelet transfusions may be given to reduce the risk of bleeding. We performed an audit and national survey of the use of fresh frozen plasma and platelet transfusions prior to interventional radiological procedures. We identified 68 consecutive chest, abdominal or pelvic drain insertions in 54 critical care patients between 2008 and 2011 at a single intensive care unit. Eight (12.3%) patients were transfused fresh frozen plasma prior to drain insertion despite having a prothrombin time below 22 s. One patient with a prothrombin time above this threshold received fresh frozen plasma. One patient received a platelet transfusion, at double dose, despite a platelet count above 50 × 109/l. A national survey of interventional radiologists demonstrated extensive variability in safe thresholds for invasive procedures and usage of fresh frozen plasma. There is a need for further clarification around coagulopathy and interventional radiology in the critical care setting.

Clinical bleeding and thrombin generation in admissions to critical care with prolonged prothrombin time: an exploratory study: THROMBIN GENERATION IN CRITICAL ILLNESS

Prolongation of prothrombin time (PT) is often recorded in critical illness, but has limited ability to predict risk of bleeding. This exploratory study was aimed at assessing a role for thrombin generation (TG) to predict bleeding.

Does the implementation of a novel intensive care discharge risk score and nurse-led inpatient review tool improve outcome? A prospective cohort study in two intensive care units in the UK

Objective To develop a clinical prediction model for poor outcome after intensive care unit (ICU) discharge in a large observational data set and couple this to an acute post-ICU ward-based review tool (PIRT) to identify high-risk patients at the time of ICU discharge and improve their acute ward-based review and outcome. Design Retrospective patient cohort of index ICU admissions between June 2006 and October 2011 receiving routine inpatient review. Prospective cohort between March 2012 and March 2013 underwent risk scoring (PIRT) which subsequently guided inpatient ward-based review. Setting Two UK adult ICUs. Participants 4212 eligible discharges from ICU in the retrospective development cohort and 1028 patients included in the prospective intervention cohort. Interventions Multivariate analysis was performed to determine factors associated with poor outcome in the retrospective cohort and used to generate a discharge risk score. A discharge and daily ward-based review tool incorporating an adjusted risk score was introduced. The prospective cohort underwent risk scoring at ICU discharge and inpatient review using the PIRT. Outcomes The primary outcome was the composite of death or readmission to ICU within 14 days of ICU discharge following the index ICU admission. Results PIRT review was achieved for 67.3% of all eligible discharges and improved the targeting of acute post-ICU review to high-risk patients. The presence of ward-based PIRT review in the prospective cohort did not correlate with a reduction in poor outcome overall (P=0.876) or overall readmission but did reduce early readmission (within the first 48 hours) from 4.5% to 3.6% (P=0.039), while increasing the rate of late readmission (48 hours to 14 days) from 2.7% to 5.8% (P=0.046). Conclusion PIRT facilitates the appropriate targeting of nurse-led inpatient review acutely after ICU discharge but does not reduce hospital mortality or overall readmission rates to ICU.

604: PREVALENCE AND MANAGEMENT OF ANAEMIA IN ICU SURVIVORS: A RETROSPECTIVE STUDY.

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) Learning Objectives: Red blood cell transfusions are commonly used in critically ill children. The benefit of transfusions remains the subject of much controversy. According to current literature, lower transfusion thresholds are well tolerated in critically ill stabilized patients. With this study, we aim to study the impact of a publication (TRIPICU 2007) on transfusion practice in our Institution. Methods: Single center retrospective chart review of patients admitted to a tertiary pediatric intensive care unit (PICU) receiving a blood transfusion over 2 time periods: before TRIPICU (2005-2006, period 1) and after TRIPICU (2008-2009, period 2). Inclusion criteria were those of TRIPICU study (no volume resuscitation nor change in inotropic support in the last 2 hours prior to transfusion).Variables of interest included: body weight, age,diagnosis and evaluation of hemodynamic status at the time of transfusion: systolic blood pressure, inotrope use and/or their escalation and volume resuscitation. We identified the overall mean hemoglobin (Hb) before transfusion, the proportion of patients transfused with Hb>9.5g/dL and the transfusion dose (ml/kg) in those 2 time periods.We also measured PICU mortality during these two periods (28-day mortality in the TRIPICU study was 4.3%). Results: From 545 transfused patients, 243 met inclusion criteria: 146 patients in period 1 and 97 in period 2. Median age was 5.2 years and weight 16.85kg. There was no significant difference between mean Hb before transfusion in period 1 (8.1 ± 2.0 g/dL) and in period 2 (8.0 ± 1.5 g/dL, p= 0.58).In period 1, 22% of patients were transfused with Hb>9.5g/dL and 15.4 % in period 2 (p=0.20). Mean transfusion dose in period 1 was 12 ± 9 ml/kg and 11 ± 8 ml/kg in period 2 (p =0.32). Mortality in period 1 was 11.5% and 15.4% in period 2 (p=0.38). Conclusions: In our institution, the publication of the TRIPICU study did not farther contribute to decrease the transfusion thresholds, as they were already very restrictive. The relationship between these thresholds and the higher mortality in our population compared to the TRIPICU population must be further explored.