Twenty-five individuals with aSAH underwent TTM between March 2008 and December 2012. Six patients had hypothermia of less than 48 h duration and were excluded. Among the remaining 19 patients who comprised the prolonged TTM group, five did not require DHC. A total of 16 patients who underwent DHC alone without hypothermia were identified for the comparison group.
There were no baseline between-group differences in sex, body mass index (BMI), or WFNS scores on admission (Table 1). However, the patients in TTM group were younger and had higher APACHE II scores. All patients were modified Fisher SAH grade 3 or 4. There were no group differences in documented history of hypertension, renal disease, headaches/migraines, or daily alcohol use. Regarding other medical comorbidities, one patient in the TTM group had a diagnosis of asthma. In the DHC-only group, two patients had diabetes, one had history of congestive heart failure, one had a diagnosis of chronic obstructive pulmonary disease, two patients had documented history of coronary artery disease, and one patient had a history of stroke.
There were no significant TTM versus DHC-only group differences in survival to discharge (59 vs. 69 %) or in the mean modified Rankin score on follow-up (3.6 vs. 3.7); follow-up ranged between 1 and 6 months. TTM group had longer ICU length of stay (22 vs. 16 days, p = 0.03) as well as hospital length of stay (24 vs. 19 days, p = 0.03). Please see Table 2 for details on clinical outcomes of the TTM patients per category.
Decompressive Hemicraniectomy, Intracranial Pressure, and Cerebral Perfusion Pressure
On the day of hypothermia initiation, median maximal ICP was 23.5 mmHg (IQR 18.5-27.5), decreasing to 21 mmHg (IQR 16-24.5) within 24 h of hypothermia initiation. Median lowest CPP on the day of hypothermia was 61 mmHg (IQR 54-64), increasing to 63 mmHg (IQR 60-71.25) within 24 h of hypothermia. Please see Fig. 1 for the course of ICP and CPP variation over duration of hypothermia treatment. All patients in the TTM group and 13 in the DHC-only group had EVDs placed.
DHC in the group without TTM was performed on a median hospital stay day 2 (IQR 1-3). Fourteen of the 19 TTM patients underwent DHC on a median day 5 (IQR 3-10). Median day of hypothermia initiation was day 2 (IQR 2-4), and median duration of TTM, including cooling and rewarming, was 7 days (IQR 4-12). Five of the TTM patients had DHC prior to initiation of hypothermia and one had it on the same day as hypothermia initiation. The remaining eight patients who underwent DHC did so after the initiation of hypothermia.
With regard to medications administered for ICP management (Table 3), the TTM group received significantly more hypertonic saline and mannitol and half of these patients required barbiturates, while no patients in the DHC-only group received barbiturates. The TTM group received significantly more paralytics (100 vs. 69 %).
Organ Systems Parameters
Patients in the TTM group were on MV support significantly longer than the DHC-only group (16 vs. 9 days, p = 0.04). They had significantly higher cumulative fluid balance (12.8 vs. 5.1 L, p = 0.009) and more days with severe hypoxemia (PaO2/FiO2 <300), 10 vs. 6 (Table 3). Since duration of MV support was significantly different between the two groups and since MV is a risk for lung injury, we examined whether the proportion of days with severe hypoxemia (PaO2/FiO2 <300) differed. We found that the proportion of days on MV with severe hypoxemia was comparable between groups (57 % of MV days for the TTM group vs. 47 % of MV days for the DHC-only group). Notably, radiographic evidence of aspiration (either via chest X-ray (CXR) or CT) was present on admission in three patients in TTM, and in one patient in the DHC-only group. Two more patients in the TTM group had evidence of aspiration during their hospital course; one during hypothermia and another following rewarming. In the subgroup of TTM patients with severe hypoxemia (n = 6, 32 %) prior to hypothermia, there was a median improvement in oxygenation (increase in PaO2/FiO2 by 17) by day 10 or the last day of hypothermia compared to a median decline in PaO2/FiO2 by 150 in those without initial hypoxemia (p = 0.03).
Overall, within the TTM group, there were little fluctuations in the surrogate measures of oxygenation (PEEP, PaO2), ventilation (PaCO2, pH), and lung protective ventilation (ideal VT, dynamic compliance) as illustrated in Figs. 2, 3, and 4.
Among patients who received hypothermia, there was an increase in the aPTT values during hypothermia (Fig. 5). Notably, almost half of these patients received subcutaneous heparin after the aneurysm was secured. Despite this, there was no increase in the development of intracerebral or other hemorrhage; nor were there any statistical differences in the amount of red blood cells or other blood products transfused (Table 3) between groups. In addition, the lowest documented hemoglobin and platelet counts did not differ.
Renal and Liver Function
There were no group differences for the highest documented creatinine during the hospital course, and no patients required dialysis. With regard to indices of liver function, no differences in the highest INR values were observed between groups, nor in the worst values of albumin, bilirubin, alkaline phosphatase, alanine transaminase, or aspartate transaminase, during the hospital course (Table 3).
There were no baseline group differences in systolic or diastolic function (Table 1). Of the 19 TTM patients, one patient developed bradycardia (defined as heart rate <40) on 2 occasions in 1 day but remained hemodynamically unaffected by these episodes. Of note, the patient received two doses of labetalol prior to episodes of bradycardia. One other patient developed Torsades de Pointes on day 13 of hypothermia while receiving 0.45 mcg/kg/min of norepinephrine and 15 mcg/kg/min of dopamine for CPP augmentation for symptomatic vasospasm that responded to magnesium and decrease in pressor doses by half. This same patient had Takotsubo cardiomyopathy and documented episodes of bradycardia prior to hypothermia on admission. The mean QTc prior to hypothermia was 477 (SD 29); it increased to 501 (SD 40) within the first 24 h of hypothermia, then decreased to 476 (SD 33) by day two and remained essentially unchanged throughout the remaining 8 days (Fig. 6).
Eighteen patients who had TTM protocol-driven (i.e., scheduled) blood cultures performed (from pre-hypothermia and up to the 10 days of hypothermia) remained with negative cultures, while 2 of the 14 control patients who had blood cultures drawn (up to hospital day 14) on a clinical basis proved to be positive. There were no differences in frequency of positive sputum cultures between groups, 85 % (n = 13) versus 78 % (n = 9) (Table 3).
There were no group differences with regard to the following documented adverse events throughout hospital stay: critical illness myopathy, gastro-intestinal bleed, rebleeding, shock, supraventricular tachycardia, Torsades de Pointes, cardiomyopathy, vasospasm, Terson’s syndrome, dysautonomia, and seizures.