July 14, 2016

Journal Club Synopsis:  ICH and TBI:  Challenging Standard Management

A big thank you to Harwood for another peaceful summer escape to the marshlands and forest.  Also big thanks to presenters Patrick Holland, Dan DeWeert, Jenny Denk, Dan Nejak, Nate West (barbarian), and Mike Stanek (wizard).

1.      Qureshi AI, et al: Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage. N Engl J Med  2016 June 8.

Although evidence has suggested that hematoma expansion and morbidity/mortality in hypertensive patients with ICH might be reduced with early reduction in SBP, there has been no consensus for blood pressure targets in these patients.  In this RCT of 1000 adult patients with ICH and elevated BP presenting to 110 international sites (including ACMC; go E. Kulstad and Stanek!), 500 patients were randomized to a SBP target of 110-139 mm Hg (intensive treatment) and 500 to a SBP target of 140-179 mm Hg (standard treatment).  Inclusion criteria were at least one initial SBP of ≥ 180, supratentorial ICH with hemorrhage volume < 60 cm3, GCS ≥ 5, and initiation of antihypertensive treatment within 4.5 hours after symptom onset.  Primary outcome was death or disability defined as modified Rankin scale score of 4-6 at 3 months.  Secondary outcomes included scores on a health state index and ICH expansion at 24 hours.  Serious adverse events and safety outcomes including neurologic deterioration and renal adverse events were also recorded.  Nicardipine was used as the first-line antihypertensive, and if needed, labetolol was the preferred second-line agent.

Results:  The primary outcome of death or disability was observed in 39% of the intensive-therapy group, and in 38% of the standard-treatment group (no significant difference).  There were no significant differences in health state index scores.  Interestingly, although there was a trend towards more expansion of ICH in the standard treatment group, this did not translate to higher morbidity/mortality for these patients.  The rate of serious adverse events and early neurologic deterioration was higher in the intensive treatment group.  There was a significantly higher rate of renal adverse events within 7 days in the intensive treatment group (9% intensive, 4% standard). 

Systolic blood pressure was relatively tightly controlled for both groups, resulting in a study that really compared SBP of 140s to SBP of 120s.  It is therefore unclear if a maintaining a higher SBP, e.g. SBP 160-170, would result in the same outcomes.  Points were also made that the majority of patients presented with a GCS of 15, limiting the external validity in a sicker patient population, and that the best goal may be a smooth maintenance of blood pressure, rather than a forced low target that results in significant SBP variability.  Not surprisingly, there were many more treatment failures (inability to achieve/maintain target SBP) in the intensive treatment group.  There was a trend favoring intensive treatment in patients presenting with low GCS scores (3-11).

Bottom line:  a target SBP of 140s resulted in similar death/disability compared to a target SBP of 120s in patients with relatively small volume ICH and overall high initial GCS scores.  Tight SBP control was associated with a trend toward more serious adverse events as well as a significantly higher rate of adverse renal events.  Aggressive reduction of SBP in patients with ICP does not demonstrate a death/disability benefit and is associated with increased incidence of serious adverse events. 

2.      Baharoglu MI, et al:  Platelet transfusion versus standard care after acute stroke due to spontaneous cerebral haemorrhage associated with antiplatelet therapy (PATCH): a randomised, open-label, phase 3 trial.  Lancet  2016 25;387:2605-2613.

Ok, so aggressive BP control doesn’t work in ICH.  How about platelet transfusion for patients taking anti-platelet agents?  People taking anti-platelet agents have increased mortality after ICH, and it’s intuitively attractive to transfuse platelets in this population.  In this small study (41 sites, 6 years...190 patients-ouch!), adults presenting within 6 hours of symptom onset after supratentorial non-traumatic ICH symptom with a GCS score of ≥ 8, who had received anti-platelet therapy for at least 7 days prior, were randomized open label to either receiving standard care or standard care + platelet transfusion within 90 minutes of brain imaging. Most patients were taking aspirin and if randomized to platelets received one platelet concentrate (5 donor units).  Those taking ADP receptor inhibitors such as clopidogrel (Plavix) and randomized to platelets received two platelet concentrates.  Primary outcome was a shift towards death or dependence rated on the modified Rankin Scale at 3 months.

Results:  The odds of death or dependence were significantly higher in the 97 patients in the platelet group as compared with the 93 patients in the standard care group (odds ratio 2.05, 95% CI 1.18-3.56). Serious adverse events were more frequent in the platelet group (42% vs. 29%) including significantly increased rates of serious adverse events due to ICH, and hospital mortality was higher in the platelet group as well (24% vs. 17%). 

Limitations:  an unknown number of patients were eligible for the trial, and the small trial size with limited enrollment over 6 years are threats to the external validity of the study.  There were also a number of patients enrolled who met an exclusion criteria, or protocol violation.  This trial specifically evaluated patients not heading to the OR; future study would be necessary to evaluate outcomes in surgical patients with ICH.  This study did not assess platelet function.

Bottom line: mortality and morbidity were higher in patients receiving platelet transfusions after non-traumatic ICH than in patients receiving standard care.   This may be due to potential inflammatory and pro-thrombotic effects of platelet transfusion.

3.      Patanwala AE, et al:  Succinylcholine Is Associated with Increased Mortality When Used for Rapid Sequence Intubation of Severely Brain Injured Patients in the Emergency Department.  Pharmacotherapy  2016;36(1):57-63.

A youtube video should be imminent, as of course this article interpretation was performed using LARP (Live Action Role Playing).  For a less dramatic synopsis, this was a chart review from a single academic center.  A total of adult 233 patients with TBI requiring intubation were either intubated with succinylcholine (149 patients) or rocuronium (84 patients).  Agent choice was by provider preference.  Mortality was 23% in both groups, with the same first-pass success rate.  Groups were similar except for a higher rate of hypotension in the succinylcholine group.

 When stratified by “Head Abbreviated Injury Score,” rocuronium mortality was 22% in the low score group and 23% in the high score group, while succinylcholine mortality was 14% and 44%.  Authors therefore attempt to draw the conclusion that in more severely brain injured patients, rocuronium is the preferred neuromuscular blocker.  The only problem with this conclusion is that overall mortality rates for the 2 agents were identical, implying that for the lesser brain injured patients, succinylcholine should therefore be the safer agent.  This indeed was the trend, although it didn’t reach statistical significance.  Especially in this retrospective trial, sub-group analysis by Head AIS should be hypothesis generating. 

Rocuronium needs to be given at 1.5 mg/kg IV to provide similar intubating conditions to succinylcholine, and if dosed correctly, provides several potential advantages (avoid theoretical increase in ICP and hyperK with succinylcholine, longer paralysis facilitates multiple imaging studies, etc).  What’s the downside to rocuronium?  Medical staff forget to initiate a long active sedative immediately after intubating, leading the horrible potential of awake but paralyzed patients.  In addition, for certain clinical conditions such as seizures, a shorter acting paralytic allows for earlier repeat neurologic exams. 

Bottom line, for the stated primary outcome of in-hospital mortality, the 2 agents performed equally well.  The “head AIS” is not meant as an initial injury scoring scale, and GCS, which can be determined at presentation quickly, did not discriminate between rocuronium and succinylcholine.  If only for simplicity and to decrease cognitive load, rocuronium should usually be your neuromuscular blocking agent of choice.

Journal Club bottom lines:

1.      In patients with ICH and hypertension, lower SBP to 140s.  Maintaining smooth BP control is more beneficial than an aggressively low target SBP in the 120s.

2.      Platelet transfusions in patients with non-traumatic ICH who are taking anti-platelet agents is associated with increased rates of death or dependence. 

3.      Use rocuronium at 1.5 mg/kg IV instead of succinylcholine.  Except maybe in seizure patients who need early neuro-rechecks.  Just remember to start a long acting sedative right away!!