Several months ago, I sat down and talked about the management of neurologic emergencies in the prehospital environment with Dr. Erin McDonough, an Emergency Physician and Neurointensivist who attends both in the ED and the Neurosciences ICU, and is a member of the Cincinnati Stroke Team. In the brief podcast found below and on iTunes, we covered a wide range of topics including blood pressure management in spontaneous ICH, aneurysmal SAH, and ischemic stroke and some of the more rare complications associated with tPA administration.
While discussing acute ischemic stroke in the podcast, Dr. McDonough frequently refers to the “penumbra”. This is an area of brain tissue with compromised blood flow that surrounds an area of infarcted brain. Pathophysiologically, in an acute ischemic stroke, a thrombus or embolus suddenly occludes an arterial vessel, resulting in an interruption in blood flow to the downstream brain tissue. The reduction in blood flow falls below the threshold required to sustain its most basic metabolic functions, resulting in cell death. This is called the “core infarct”. There is often an area of brain tissue surrounding this core infarct with reduced blood flow, but not enough to cause the tissue to infarct. This is the “penumbra”. It can be absent, small, or VERY large. Blood flow in some areas of the penumbra maybe so low that the affected brain tissue is unable to function, resulting in clinical deficits, but not infarction. If cerebral blood flow is reduced further via a decrease in blood pressure (not necessarily hypotension), hypocarbia, hyperoxia, or hypovolemia, the penumbra can go from being viable brain tissue to infarcted, unrecoverable brain tissue.
What does that mean in lay terms and why was any of that important?
So there's this bit of brain that is near areas of ischemic stroke which is vulnerable to injury. If you compromise its blood flow in any way (read: hypotension or even relative hypotension), those cells may just up and die. The more dead brain, the worse your patient may do.
Intracerebral Hemorrhage (non-traumatic)
For many years, it was believed that the tissue surrounding an intracerebral hemorrhage, whether spontaneous or via trauma, was “penumbral”. More recently, this has been demonstrated to be a false assumptionthus, aggressive BP management should not lead to worse outcomes.
Why even consider aggressive blood pressure management? The thought is that an aggressive reduction in blood pressure would lead to a decrease in hemorrhage volume and potentially improve patient important outcomes like mortality and disability.
Does the evidence support aggressive blood pressure management?
Depends who you ask.
The current AHA guidelines, published in 2012, recommend a reduction of blood pressure to less than 180 mmHg systolic. (2)
Since then, a large, international, randomized trial of aggressive blood pressure management in intracerebral hemorrhage was published in the NEJM in June 2013. (3) The INTERACT2 trial randomized patients who had an ICH within the previous 6 hours to receive either aggressive blood pressure management (<140 mmHg) or guideline-recommended (<180 mmHg). The trial was open label (one of its potential weaknesses) so any combination of medications could be used to lower the patient's blood pressure. The primary outcome of the trial was "poor outcome" which was defined as mortality or disability (modified Rankin scale of 3-5) 90 days from the time of randomization. The randomized groups were well matched in terms of known prognostic factors and follow up was excellent in both the standard therapy and aggressive therapy cohorts. The intensive group were enrolled a little earlier from time of symptom onset and (as one would expect) received more anti-hypertensive medications.
What did INTERACT2 show?
There was no statistical difference in terms of the primary outcome. The "poor outcome" was occurred in 52% of the intensive group and in 55.6% of the standard group. OR 0.87 with a confidence interval that ranged from 0.75 to 1.01. There was also no difference between the groups in terms of adverse events (neurologic deterioration, recurrent hemorrhage, acute coronary event, etc).
There are 2 possible interpretations of these findings.
Interpretation 1: There's no statistical difference in terms of primary outcome between these 2 groups. It is just as likely that there is no benefit as there is a benefit. The fact that the majority of patients were from China raises concerns about external validity. Add to this some concerns about the ordinal analysis used by the authors to state the a benefit in their secondary outcomes (see these posts from EMNerd and Skeptics Guide to EM), and you can see that some have concerns about the implementation of aggressive blood pressure management.
Interpretation 2: There is potential benefit from aggressive therapy it just didn't happen to reach statistical significance in this trial (OR for improved outcome potentially as good as 0.75). And, from this trial, there are no real adverse outcomes from a more intensive approach. Thus, an intensive approach to blood pressure control is reasonable and, in the very least, safe.
So what do we do in practice?
The AHA guidelines and suggest lowering BP to a SBP <180 mmHg. Locally both our neurosurgery and neurology colleagues, however, tend to target a SBP <160 mmHg (some will go for <140 mmHg).
Subarachnoid Hemorrhage (non-traumatic)
There are, unfortunately, few studies that look at blood pressure management in subarachnoid hemorrhage. These patient's would also not be expected to have an ischemic penumbra and thus should tolerate a more aggressive approach to blood pressure management. And, blood pressure management may attenuate further bleeding from the aneurysm.
(See the comments section below for additional comments from Dr. Chris Zammit)
So what do we do in practice?
We tend to target a SBP <140 mmHg but you could also consider targeting a SBP <160 mmHg which is what the most recent AHA/ASA guidelines recommend - Category IIa, Level C evidence (4)
Patients with ischemic stroke that we are usually transporting on Air Care are either being transported for intra-arterial intervention at UCMC or are s/p tPA administration.
After administration of tPA, the patient's blood pressure should be kept less than 180/105 for 24 hours. Elevation of blood pressure above this level will lead to increased risk of intracranial hemorrhage. However, as described above, overly aggressive blood pressure management leading to hypotension can expand the size of the core infarct and worsen patient outcomes. If the patient has baseline uncontrolled hypertension, even normal blood pressures could lead to relative hypotension and worsened outcomes. This is worth particular consideration in the intubated AIS patient. Take note of their BP prior to intubation and attempt to maintain this BP throughout your intubation and during transport. Your sedatives, particularly propofol, can cause sharp drops in the blood pressure, which should be avoided. So, be aggressive, just not too aggressive. (5)
Other weird things tPA can do
tPA related hypotension - It is possible that this some form of reperfusion effect. If you are transporting a patient and they become markedly hypotension, stop the tPA, give IV fluids wide open, and consider pressors (but do so with extreme caution as hypertension may predispose the patient to intracranial hemorrhage).
tPA related angioedema - This can occur during or after the infusion in ~1% of patients. If the infusion is still running, stop the infusion. Otherwise, you can treat this as standard angioedema with IM epinephrine (but BE CAREFUL if the BP is already high!!), H1 and H2 blockers, as well as steroids. Weirdly this is often unilateral angioedema and is ipsilateral to the side of the acute ischemic stroke (i.e. right MCA = right sided angioedema)
Just hope that you won't have to do a cric...
- Ramos-Cabrer, P., Campos, F., Sobrino, T., & Castillo, J. (2011) Targeting the Ischemic Penumbra. Stroke. 42; S7-S11. doi: 10.1161/STROKEAHA.110.596684
- Morgenstern, L., et al. (2010) AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage. Stroke. 41. 2108-2129. DOI: 10.1161/STR.0b013e3181ec611b http://stroke.ahajournals.org/content/41/9/2108.full.pdf
- Anderson, C. et al. The INTERACT Investigators. (2013) Rapid Blood Pressure Lowering in Patients with Acute Intracerebral Hemorrhage. New England Journal of Medicine. 368 (25). 2355-2365. DOI: 10.1056/NEJMoa1214609. http://www.nejm.org/doi/full/10.1056/NEJMoa1214609
- Connolly, E. et al. (2012) AHA/ASA Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage. Stroke; 43: 1711-1737. doi: 10.1161/STR.0b013e3182587839. http://stroke.ahajournals.org/content/43/6/1711.full.pdf+html
- Jauch, E. et al (2013) Guidelines for the Early Management of Patients with Acute Ischemic Stroke. Stroke. 44: 870-947. doi: 10.1161/STR.0b013e318284056a http://stroke.ahajournals.org/content/44/3/870.full.pdf+html