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JC: ATACH-II SECONDARY ANALYSIS ON CEREBRAL MICROBLEEDS

Cerebral Microbleeds and the Effect of Intensive Blood Pressure Reduction on Hematoma Expansion and Functional Outcomes. A Secondary Analysis of the ATACH-2 Randomized Clinical Trial. 

Presented by Dr Jonathon Slater


STUDY QUESTION:

In patients with intracerebral haemorrhage (ICH) is there an interaction between underlying small vessel disease (number of microbleeds and location) and intensive systolic blood pressure (SBP) control which may lead to a worse functional outcome or significant haematoma expansion?

HOW DOES THIS RELATE TO OUR PRACTICE ON NCCU?

Systolic blood pressure control in spontaneous ICH is frequently managed on or about 140mmHg (range 120mmHg – 160mmHg) and differs depending on the aetiology, location, and other medical comorbidities. The 120mmHg – 160mmHg range is within current research guidelines and recommendations. 

WHAT DO WE CURRENTLY KNOW ABOUT THIS AREA?

Specifically, there is little known about cerebral microbleeds. It is known that these microbleeds are remnants of prior micro-haemorrhages at the level of arterioles and capillaries and that such events can be visualised on T2 weighted (blood-sensitive) GRE MRI scans. In addition, these microbleeds are markers of underlying cerebral small vessel disease usually representing hypertensive arteriopathy.

There are two competing theories as to the impact of these microbleeds in ICH: 

  1. The fragility of cerebral microbleeds may increase the risk of haematoma expansion (and therefore increase the burden of injury).
  2. The vessels become more resilient over time and are therefore somewhat protective against further expansion. 

Haematoma expansion occurs early – usually within the first few hours and as much as a 10% increase can have a devastating effect. The jury is still out on the level of blood pressure reduction that provides the greatest benefit for reducing hematoma expansion. There is however, greater research, evidence, and understanding of the ‘general principals and management of ICH’:

  1. ICH is graded (Lisk) into 4 categories:
    1. 0 = No Intraventricular haemorrhage (IVH).
    1. 1 = Blood in the 3rdventricle or <1/3 of 1 lateral ventricle
    1. 2 = Blood in <1/2 of both lateral ventricles or 2/3 of 1 ventricle
    1. 3 = 1 ventricle completely filled or 2 more than 50% filled
  • Poorer outcomes for ICH are frequently seen with
    • Haematoma expansion 
    • ICH volume >60mls
    • IVH extension
    • ICH in certain areas (eg: cerebellum – requiring a high neurosurgical intervention; pons – 100% mortality) 
    • Low GCS <5 (and less researched)
  • Studies tend to remove those at highest risk – ICH has an on or about 20% mortality at 24 hours. The major RCTs exclude on or about 9 in 10 patients and as such generalisation/applicability of the results may be difficult. 
  • Early treatment of ICH has a positive impact – for instance, patients <70 years of age, with small ICH (<5mls), without IVH, and treated within 2.5 hours were shown to have reduced haematoma expansion and a ‘favourable’ OR for poor outcome of 0.28 at 90 days (FAST trial). The journal club today will look at the interplay of rapid initial treatment, prevention of haematoma expansion, and the effect of cerebral microbleeds. 
  • There are often difficult and competing risks – intracerebral pressure (ICP) in traumatic ICH may limit blood pressure targets and where there is suspicion of elevated ICP, CPP of 60-80mmHg is recommended and relaxing the lowering of BP targets may be needed.
  • Blood pressure is frequently elevated in acute non-traumatic ICH. Most research suggests 140mmHg is a reasonable systolic target although the INTERACT2 trial provides a cautionary tail that lower blood pressure (SBP <140mmHg) may improve functional outcomes. Ordinal analysis of Rankin scores (rather than ‘favourable’ vs ‘unfavourable’ scores) and quality of life scores were improved in the more intensive therapy group. However, many patients received mannitol (ICP monitoring data was not provided) and the use of specific antihypertensives not available in all countries may reduce the external validity. Further, whilst the use of multiple different antihypertensive agents was pragmatic in the trial, there may be some benefit from specific antihypertensives via non blood pressure pleiotropic effects that may have affected the results. 
  • The ATACH-2 trial showed no difference between Intensive and ‘Standard’ blood pressure treatment strategies for the first 24 hours on functional outcome at 3 months or haematoma expansion. The study ended early due to futility. Greater renal adverse events at 7 days were noted in the intensive therapy group.
  • Commonly used medications include, but are not limited to labetalol, hydralazine, nicardipine, clevidipine, and phentolamine.

WHY WAS THIS STUDY NEEDED?

Understanding whether cerebral microbleeds require greater blood pressure control will improve our appreciation of both the pathology and management of ICH with concurrent small vessel disease. More broadly speaking it will also help smaller centres to align their practices with tertiary and quaternary referral centres. 

AT JOURNAL CLUB WE SHOULD DISCUSS THE FOLLOWING:

  1. Is there an interaction between underlying small vessel disease and intensive systolic blood pressure (SBP) control for functional outcome and haematoma expansion?
  2. Blood pressure targets in ICH and exceptions to general rule
  3. The high level of practice variation
  4. Differences between the ATACH-2 and INTERACT2 trials

SHOULD WE CHANGE PRACTICE ON NCCU

No! As we will discuss at the journal club, cerebral microbleeds did not appear to have an impact on functional outcomes or mortality. Additionally, their presence was not associated with haematoma expansion or response to blood pressure management. 


Presented by Capt (MD) Dimitrios Sidiras HAF

STUDY QUESTION:

In patients undergoing cardiac surgery, who have a moderate-to-high risk of death, is a restrictive transfusion strategy (trigger = 75 g/L) non-inferior to a liberal strategy (Trigger = 95 g/L intraoperatively/ICU or 85 g/L on the ward) with respect to a composite outcome of death, myocardial infarction, stroke and acute kidney injury requiring dialysis at 6 months after surgery?

HOW DOES THIS RELATE TO OUR PRACTICE ON NCCU?

The most common situation leading to massive transfusion is cardiac surgery, but trauma, where physical injury and blood loss combine, remains the best-studied example and trauma patients are the other large group of patients consuming large amounts of red cells.

We currently follow the NICE guidelines for red blood cells transfusion which sets a threshold of 70 g/L and a hemoglobin concentration target of 70–90 g/L after transfusion (for patients with acute coronary syndrome, the trigger is 80 g/L and the hemoglobin concentration target is 80–100 g/L after transfusion). Our local TBI protocol sets a threshold of 90 g/L. This does not apply to major haemorrhage, history of acute coronary syndrome or chronic anaemia.

Trauma patients in need of the major haemorrhage protocol are transfused in the Emergency Department, aiming for a haemoglobin concentration target above 80 g/L. However the suspicion of major haemorrhage is not based on haemoglobin concentration, but instead on the mechanism of injury and the vital signs.

WHAT DO WE CURRENTLY KNOW ABOUT THIS AREA?

At present most centres are using the 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery (or something very close to that). In addition, we need to find a balance between optimal patient care and the appropriate use of a limited resource.

The two approaches to blood transfusion currently are:

  • The restrictive approach, which is based on limiting the infectious and non infectious (TRALI, pulmonary oedema, multiorgan system dysfunction etc.) risks of transfusion
  • The liberal approach, which is based on the fact that patients who are at high perioperative risk may be more susceptible to anaemia-induced tissue hypoxia

When it comes to the brain…..the evidence is conflicting!

There is clear clinical and guideline agreement that Hb less than 70 g/L in critically ill patients with TBI requires red blood cell transfusion (RBCT). However, the exact threshold between 70 and 100 g/L remains a contentious issue. Recent data from a randomized controlled trial (RCT) and meta-analysis found no difference in neurological outcome between the restrictive and liberal transfusion strategies, but the overall quality of the evidence was low. Several observational studies have shown an association between anemia and poor outcomes in patients with TBI. However, other studies evaluating anemia and TBI outcomes have not demonstrated a consistent risk of harm (see further reading section).

Additionally, several studies have shown that RBCT administration in TBI is associated with increased mortality, decreased functional outcomes, increased ICU length of stay, and impaired cerebral autoregulation. A liberal transfusion strategy applying a threshold trigger of 100 g/l was associated with an increased risk of progressive cerebral hemorrhagic injury and thromboembolic events. However, evidence from other observational studies in patients with TBI is conflicting, with data to support a lack of association between RBCT administration and worse outcome in TBI.

WHY WAS THIS STUDY NEEDED?

Patients undergoing cardiac surgery often have significant transfusion requirements and there is wide variation in transfusion practices among clinicians and institutions. Robust evidence has emerged in other patient populations (general critical illness, septic shock, etc) that a restrictive transfusion strategy is at least as good as (and possibly better than) a liberal one. If a restrictive strategy is shown to be noninferior to a liberal one, and this can influence practice, there is the potential for significant cost savings and decreased use of a scarce and limited resource.

AT JOURNAL CLUB WE SHOULD DISCUSS THE FOLLOWING:

  • Should we compare transfusion practices in cardiac surgery with those in trauma and TBI?
  • Transfusion thresholds for trauma and TBI. We aim for higher than other critically ill groups. Why? Do latest studies agree with that?
  • This study is unusual in that it is about patients at a higher risk of death and other complications than some of the other studies.
  • It also shows that a RCT overturned TITRe2
  • It focuses on transfusion of red blood cells only
  • No data exists for transfusion and TBI. How would data like CENTER-TBI answer this question in TBI?
  • How often do we ignore guidelines and stick to personal experience or instincts?

SHOULD WE CHANGE PRACTICE ON NCCU

We are already following a rather restrictive strategy when it comes to transfusing red blood cells, so we are probably going to the right direction according to this study. Furthermore, we base our practice on a multivariable approach that includes fluid resuscitation and coagulopathy.

Maybe we should wait for the next big “transfusion in trauma” or “transfusion in TBI”  study focusing on non-inferiority of restrictive transfusion strategy and then check how cost/effective is our practice. In any case, excessive concern about cost-effectiveness shouldn’t change our approach to cases where we highly suspect major haemorrhage: We should have a low threshold for transfusion.

FURTHER READING

The Bottom Line

Hematology Times

EuroSCORE I

Transfusion practices in traumatic brain injury

Variation in blood transfusion and coagulation management in TBI at the ICU

RBCT in Patients With TBI: A Systematic Review and Meta-Analysis