Blood transfusions in sepsis, the elderly and patients with TBI

Blood transfusions in sepsis, the elderly and patients with TBI Shabbir Alekar MICU, CH Baragwanath Academic Hospital & The University of the Witwatersrand CCSSA Congress 11 June 2015

Packed RBC - complications Early Haemolytic reactions Non haemolytic febrile reactions Allergic reactions to proteins TRALI Bacterial contamination TACO Hypothermia Hyperkalaemia Coagulopathy Late Infection transmission Viral Bacterial Parasites GVHD Iron overload Immune sensitisation

Talk outline The aetiology of anaemia in ICU Physiological adaptation to anaemia The physiological rationale for PRBCT The (un)physiological effect of PRBCT The evidence Sepsis The elderly TBI Conclusion

Delivery of oxygen Delivery of O₂ = Cardiac output x oxygen content of arterial blood DO₂ = CO X CaO₂

Delivery of oxygen Delivery of O₂ = Cardiac output x oxygen content of arterial blood DO₂ = CO X CaO₂ CaO₂ = (1.34 x Hb x %saturation) + (PaO₂ x 0.003)

Aetiology of anaemia in critical illness Shortened RBC life span Haemolysis Phlebotomy losses Oozing from injury sites Invasive procedures GIT losses

Aetiology of anaemia in critical illness Shortened RBC life span Haemolysis Phlebotomy losses Oozing from injury sites Invasive procedures GIT losses Diminished RBC production Nutritional deficiencies Anaemia of inflammation

Anaemia of inflammation Inflammation increased IL-1, IL-6 and TNF-α Impaired RBC production Altered iron metabolism Altered erythropoetin production and signalling

Many studies have shown a worse outcome in patients with anaemia Carson et al. Lancet 1996; 348: 1055-60 Khamies et al. Chest 2001; 120:1262-1270 Chambellan et al. Chest 2005; 128:1201-1208 Ezekowitz et al. Circulation 2003; 107:223-225

Physiological adaptation to anaemia

Respiratory adaptation Increased minute ventilation Improved V/Q matching leads to improvement in oxygenation

Cardiovascular adaptation Aortic chemoreceptors activation of sympathetic nervous system increased cardiac output due to increased stroke volume and heart rate

Cardiovascular adaptation Aortic chemoreceptors activation of sympathetic nervous system increased cardiac output due to increased stroke volume and heart rate Vasoconstriction of the splanchnic circulation increased venous return and preload Preferential vasodilatation of vital organs increase in coronary circulation (up to 6X) and cerebral circulation

Microcirculatory adaptation Increased capillary recruitment and density increased tissue blood flow improved oxygen delivery

Microcirculatory adaptation Increased capillary recruitment and density increased tissue blood flow improved oxygen delivery Increased 2,3DPG, NO mediated signalling, acidosis right shift of the oxyhaemoglobin curve less oxygen affinity of haemoglobin

Cellular adaptation Hypoxia cellular elements stabilise HIF-α Increases expression of VEGF increased angiogenesis Increases anaerobic metabolism

The anaemia of inflammation could be an adaptive phenomenon

Undesirable effects of PRBC transfusion Increased viscosity

Undesirable effects of PRBC transfusion Increased viscosity Right shift of the Hb dissociation curve

Undesirable effects of PRBC transfusion Increased viscosity Right shift of the Hb dissociation curve Transfusion related immunomodulation (TRIM)

The evidence: PRBCT in ICU

The TRICC trial 838 patients enrolled (critically ill with normovolemia) Assigned to one of two treatment groups Restrictive strategy Hb between 7 and 9 Liberal strategy Hb between 10 and 12

The TRICC trial Maintaining patients in the restrictive range (7.0 9.0) Decreased the average number of RBC units transfused by 54% Decreased exposure to any RBC unit by 33%

Overall 30 day survival

Patients with Apache II score 20

Patients younger than 55 years

TRICC trial- secondary outcomes Higher rates of two cardiac events in the liberal group Myocardial infarction 2.9% vs 0.7% (p=0.02) Pulmonary oedema 10.7% vs 5.3% (p<0,01)

The TRISS trial Multicentre Scandinavian trial Randomised 1005 patients with septic shock into two groups Lower threshold ( 7g/dl) Higher threshold ( 9g/dl)

TRISS - outcomes Median cumulative number of blood transfusions 1 unit in the lower threshold group 4 in the higher threshold group

TRISS - outcomes Median cumulative number of blood transfusions 1 unit in the lower threshold group 4 in the higher threshold group No transfusion required 36.1% in the lower threshold group 1.2% in the higher threshold group

TRISS primary outcome 90 day mortality 216 patients in the lower threshold group (43.0%) 223 in the higher threshold group (45%) Relative risk 0.94; p=0.44

TRISS Primary outcome subgroup analysis No significant difference in pre-specified subgroups Age > 70 or 70 Presence or absence of chronic cardiovascular disease Baseline SAPS II score > 53 or 53

Traumatic Brain Injury Primary injury Secondary injury Cerebral hypoxia: hypotension, hypoxemia, (anaemia?) Fever Hypo- and hypercapnoea Hypo- and hyperglycaemia

Cerebral DO₂ DO₂ = CO x CaO₂ Cerebral DO₂ = Cerebral Blood Flow x CaO₂ Cerebral DO₂ = CBF x (1.34 x Hb x %saturation) + (PaO₂ x 0.003)

Cerebral DO₂ in anaemia Cerebral DO₂ normally exceeds cerebral basal metabolic requirements for oxygen by a wide margin significant physiological reserve anaemia leads to increased cerebral oxygen extraction

Cerebral DO₂ in anaemia Anaemia leads to an increase in CBF Increase in cardiac output leads to increase in cerebral perfusion pressure Anaemia leads to increased production of nitric oxide and upregulation of cerebral β₂ receptors cerebral vasodilation Reduced haemoglobin concentration decreases viscosity increased microcirculatory flow

Anaemia and TBI Autoregulatory mechanisms may be unreliable in TBI Vasodilation due to anaemia may increase cerebral oedema and ICP, especially if intracranial compliance is limited Brain tissue surrounding the infarct may be more vulnerable to small drops in Hb

Anaemia and TBI Many studies have reported an association with reduced haemoglobin levels and worse outcomes Sekhon MS et al. Crit Care 2012, 16:R128 Retrospective cohort study of 169 patients with TBI showed a mean 7 day Hb concentration < 9g/dl was associated with increased hospital mortality

Anaemia and TBI Many studies have reported an association with reduced haemoglobin levels and worse outcomes Sekhon MS et al. Crit Care 2012, 16:R128 Oddo M, et al. Intensive Care Medicine 2012,38(9):1497-504 Retrospective analysis of 80 patients showed that an Hb of <9 was associated with a worse neurological outcome only if associated with PbtO₂<20

RBC transfusion and TBI Cerebral oxygenation seems to improve slightly and inconsistently with transfusion Smith MJ et al. Crit Care Med. 2005;33(5):1104-8 Prospective observational study of 35 patients with TBI/SAH before and after PRBCT An increase in PbtO₂ after was observed in 26 patients; however a decrease in PbtO₂ was observed in 9 patients

RBC transfusion and TBI No recent RCT has shown benefit from a liberal transfusion strategy in TBI Some have shown significant harm from a liberal transfusion strategy Warner MA, et al. J Neurosurg 2010, 113(3):539-546 Retrospective analysis of 139 patients with moderate anaemia (Hct 0,21 to 0,30) Transfusion and admission GCS were the two variables that predicted a worse neurological outcome at 6 months

RBC transfusion and TBI No recent RCT has shown benefit from a liberal transfusion strategy in TBI Some have shown significant harm from a liberal transfusion strategy Warner MA, et al. J Neurosurg 2010, 113(3):539-546 Salim A, et al. J Am Coll Surg 2008, 207(3):398-406 retrospective review of 1150 TBI patients showed that blood transfusion was significantly associated with higher mortality (OR 2.19) and complications (ARDS, infection, AKI)

RBC transfusion and TBI Issues with interpretation of the literature Inconsistent definition of severe TBI Inconsistent definition of severe anaemia Admission Hb vs mean ICU stay Hb Variable outcomes recorded - mortality, short term neurological outcomes, long term neurological outcomes

The evidence for PRBCT in ICU No consideration of the effect of anaemia on the patient No consideration of the physiological effect of the PRBCT on the patient Restrictive vs liberal strategies are compared, not with usual practice Heterogeneous patient populations with varying pathophysiology

Conclusion Anaemia is associated with increased mortality and morbidity Anaemia may be a reflection of disease severity Anaemia may be an adaptive process

Conclusion Anaemia is associated with increased mortality and morbidity Anaemia may be a reflection of disease severity Anaemia may be an adaptive process Blood transfusion has unwanted effects including inefficient oxygen delivery and TRIM There is a trend towards a lower transfusion trigger Studies in different populations have shown conflicting results