Key Points:
- Study examined outcomes of new therapeutic cooling protocol for acute ischemic stroke
- Risk of pneumonia may be increased
Findings from the latest iteration of the ICTuS study suggest that therapeutic cooling for acute ischemic stroke may place patients at increased risk for pneumonia. Even so, the investigators are not daunted and hope to find the correct recipe that will make therapeutic cooling a valid clinical option in the near future.
Results of ICTuS 2 were published online November 10, 2016, ahead of print in Stroke. The original ICTuS trial showed in 2005 that “endovascular cooling with a proactive antishivering regimen can be accomplished in awake stroke patients,” researchers wrote at the time, it but did not establish the efficacy of the approach.
For the newer study, Patrick Lyden, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), and colleagues treated patients with acute ischemic stroke to 24 hours of cooling followed by a 12-hour rewarm as per the original ICTuS protocol, but with the addition of safety procedures and 4°C saline infusions for faster cooling. Cooling was provided via a femoral venous intravascular cooling catheter after intravenous r-tPA. All patients received intravenous r-tPA within 3 hours of symptom onset, had an NIHSS of 7 to 20 (left brain stroke) or ≤ 24 (right brain stroke), and were aged 22 to 82 years.
Patients received antishivering measures, consisting of meperidine, buspirone, and skin warming, for all 36 hours of cooling and rewarming. Breakthrough shivering was treated with escalating intravenous meperidine. If shivering could not be controlled without respiratory compromise, the target temperature was increased in 0.5°C increments until shivering stopped. All patients were monitored for evidence of pneumonia and treated promptly with antibiotics if it arose.
Of the intended 1,600 subjects, only 120 were enrolled (63 of whom were randomized to receive therapeutic hypothermia) before the study was stopped following the approval of intra-arterial neurothrombectomy and the expiration of the initial funding period. The investigators did see an improvement in cooling rates from previous protocols with a cold saline bolus, without seeing any fluid overload (table 1).
Table 1. Effect of Cold Saline Bolus on Core Body Temperature
|
|
Normothermia |
Hypothermia |
P Value |
|
Start of Saline Bolus, °C |
36.5 ± 0.5 |
36.4 ± 0.9 |
NS |
|
End of Saline Bolus, °C |
36.4 ± 0.5 |
35.5 ± 1.2 |
.0001 |
What with the small sample size, investigators were unsurprised to find few statistically significant differences in outcomes between patients who underwent therapeutic hypothermia and those who did not. Baseline levels of high-sensitivity C-reactive protein (hs-CRP) were similar for both groups and increased significantly in both groups at 24 hours. Similar numbers of patients in both groups achieved the primary outcome of a 90-day mRS score of 0-1 (table 2).
Table 2. Outcomes and Adverse Events – Intent to Treat Analysis
|
|
Hypothermia |
Normothermia |
OR (95% CI) |
|
90-Day mRS 0-1 |
33% |
38% |
0.81 (0.36–1.85) |
|
Mortality |
15.9% |
8.8% |
1.95 (0.56–7.79) |
|
Pneumonia |
19% |
10.5% |
1.99 (0.63–6.98). |
Pneumonia Remains a Challenge
To Neurovascular Exchange, Dr. Lyden said he is particularly concerned about the increased rate of pneumonia seen among patients treated with hypothermia. While the rate was not significantly higher than that seen among patients who did not experience hypothermia, he still fears it is a real effect, given that it also occurred in the previous feasibility study. He suspects the sedation required to control shivering places patients at increased risk for aspiration pneumonia.
But Dr. Lyden still expressed high hopes for therapeutic cooling in the stroke setting. “Therapeutic hypothermia is the most potent neuroprotectant ever studied in the lab,” he pointed out. “There has been more rigor assigned to proving its benefits than any neuroprotection ever studied. The problem is translating that to humans with stroke and head trauma. We don’t know everything we need to know yet about how to cool. How cold is the right temperature? How long should we cool patients for? How quickly?”
Therapeutic cooling can work hand-in-hand with thrombectomy, he pointed out, because the cooling can be provided right after intravenous tPA.
Dr. Lyden and his team are currently working on new experimental protocols aimed at producing cooling more quickly and briefly, because results to date in animal models suggest this strategy provides better outcomes. “My feeling is that if we can work out the details of how fast and how long and how deep to cool patients, we should be able to move this into clinical applicability very quickly,” he predicted.
Source:
Lyden P, Hemmen T, Grotta J, et al. Results of the ICTuS 2 Trial (Intravascular Cooling in the Treatment of Stroke 2). Stroke. 2016;Epub ahead of print.
Disclosures:
Dr. Lyden reports receiving reimbursement for travel expenses related to his role on the Data Safety Monitoring Board for Zol1 and being a PI for the original ICTuS trial.
