Cerebrovascular autoregulation after rewarming from hypothermia in a neonatal swine model of asphyxic brain injury

Abstract

After hypoxic brain injury, maintaining blood pressure within the limits of cerebral blood flow autoregulation is critical to preventing secondary brain injury. Little is known about the effects of prolonged hypothermia or rewarming on autoregulation after cardiac arrest. We hypothesized that rewarming would shift the lower limit of autoregulation (LLA), that this shift would be detected by indices derived from near-infrared spectroscopy (NIRS), and that rewarming would impair autoregulation during hypertension. Anesthetized neonatal swine underwent sham surgery or hypoxic-asphyxic cardiac arrest, followed by 2 h of normothermia and 20 h of hypothermia, with or without rewarming. Piglets were further divided into cohorts for cortical laser-Doppler flow (LDF) measurements during induced hypotension or hypertension. We also tested whether indices derived from NIRS could identify the LDF-derived LLA. The LLA did not differ significantly among groups with sham surgery and hypothermia (29 ± 8 mmHg), sham surgery and rewarming (34 ± 7 mmHg), arrest and hypothermia (29 ± 10 mmHg), and arrest and rewarming (38 ± 11 mmHg). The LLA was not affected by arrest (P = 0.60), temperature (P = 0.08), or interaction between arrest and temperature (P = 0.73). The NIRS-derived indices detected the LLA accurately, with the area under the receiver-operator characteristic curves of 0.81-0.96 among groups. In groups subjected to arrest and hypothermia, with or without rewarming, the slope of LDF relative to cerebral perfusion pressure during hypertension was not significantly different from zero (P > 0.10). In conclusion, rewarming did not shift the LLA during hypotension or affect autoregulation during hypertension after asphyxic cardiac arrest. The NIRS-derived autoregulation indices identified the LLA accurately.

Keywords: cardiac arrest; cerebral blood flow; near-infrared spectroscopy; neonatal hypoxic-ischemic encephalopathy; pig.

Fig. 1.

Study design flowchart. The 2nd surgery (cranial surgery and placement of a balloon catheter in the inferior vena cava for hypotension cohorts or descending aorta for hypertension cohorts) was performed 18 h after resuscitation. ↓ BP, induced hypotension blood pressure; ↑ BP, induced hypertension blood pressure.

Fig. 2.

Two representative piglets from each experimental group were selected to illustrate variation among individual animals in the laser-Doppler flow (LDF) responses to hypotension. From each experimental group, 1 piglet was selected with a relatively horizontal, autoregulatory plateau. As a contrast, another piglet from the same group was selected with a LDF curve that was not horizontal when cerebral perfusion pressure (CPP) exceeded the lower limit of autoregulation (LLA). LDF measurements were averaged into 5 mmHg bins of CPP. The calculated LLA is demarcated with a dotted line. When CPP exceeded the LLA, some piglets had autoregulatory plateaus that were relatively horizontal (left column), whereas others had LDF curves that were not horizontal (right column). A and B: sham, hypothermic piglets; C and D: postarrest, hypothermic piglets; E and F: sham, rewarmed piglets; G and H: postarrest, rewarmed piglets.

Fig. 3.

A: during hypotension, LDF was similar among treatment groups at each level of CPP (treatment effect, P = 0.96; n = 6). B: the hemoglobin volume index (HVx) became more positive with hypotension, indicating impaired vasoreactivity. HVx was similar across groups at each CPP (P > 0.05; n = 6). C: the cerebral oximetry index (COx) became more positive with hypotension, indicating impaired cerebral autoregulation. COx was similar among groups at each CPP (P > 0.10; n = 6). To compare CPP relative to each animal's LLA, CPP was centered at 0 on the x-axis. D: with hypotension, LDF was similar among groups at each CPP (P = 0.51; n = 6). E: HVx became more positive during hypotension as the LLA was crossed, indicating impaired vasoreactivity. HVx was similar among groups at each CPP (P > 0.05; n = 6). F: COx became more positive during hypotension as the LLA was crossed, indicating impaired cerebral autoregulation. COx was similar among groups at each CPP (P > 0.05; n = 6). Hypothermic sham (open triangles), hypothermic arrest (solid triangles), rewarmed sham (open circles), rewarmed arrest (solid circles). Data are shown as means ± SD.

Fig. 4.

Regional cerebral oxyhemoglobin saturation (rSO₂) measurements were averaged into 5 mmHg bins of CPP. Absolute rSO₂ decreased with progressive hypotension in (A) sham piglets that remained hypothermic (n = 6) or were rewarmed (n = 5) and (B) postarrest piglets that remained hypothermic (n = 6) or were rewarmed (n = 6). Hypothermic piglets (open squares); rewarmed piglets (solid circles). Data are shown as means ± SD. C: each piglet's lower LLA, which was calculated from the LDF vs. CPP curve, was compared with the inflection point calculated from the rSO₂ vs. CPP curve during hypotension. There was good correlation between the LDF-derived LLA and the rSO₂ inflection point. Postarrest rewarmed piglets (circles; n = 6); sham rewarmed piglets (squares; n = 5); postarrest hypothermia piglets (triangles; n = 6); sham hypothermia piglets (inverted triangles; n = 5). For the 22 piglets combined: r = 0.727; 95% confidence intervals (CI) 0.429–0.881; P = 0.0001. The dotted line demarcates a perfect correlation of r = 1.0.

Fig. 5.

Spline regression model fit lines (±95% CI) of the HVx index. Each piglet's lower LLA is centered at 0 on the x-axis to compare each animal's CPP relative to its LLA. HVx became more positive as CPP decreased below the LLA in the (A) hypothermic arrest, (B) hypothermic sham, (C) rewarmed arrest, and (D) rewarmed sham groups. The slope of the relationship with CPP was significantly negative in the hypothermic arrest (*P < 0.001) and rewarmed arrest (**P = 0.045) groups. In the hypothermic arrest group, the relationship for HVx was biphasic, with the slope below the LLA significantly more negative than the slope above the LLA (P < 0.001).

Fig. 6.

Spline regression model fit lines (±95% CI) of the COx index. Each piglet's lower LLA is centered at 0 on the x-axis to compare each animal's CPP relative to its LLA. COx became more positive as CPP decreased below the LLA in the (A) hypothermic arrest, (B) hypothermic sham, (C) rewarmed arrest, and (D) rewarmed sham groups. The slope of the relationship with CPP was significantly negative in the rewarmed arrest group (*P = 0.016). In the rewarmed arrest group, the relationship for COx was biphasic, with the slope below the LLA significantly more negative than the slope above the LLA (P = 0.047).

Fig. 7.

A: during hypertension, LDF remained relatively constant in postarrest and sham-operated piglets after hypothermia or hypothermia with rewarming (n = 6). Hypothermic sham (open triangles); hypothermic arrest (solid triangles); rewarmed sham (open circles); rewarmed arrest (solid circles). A dashed line demarcates LDF at 100% of baseline. Data are shown as means ± SD. B: the autoregulatory index was calculated as the change in LDF (as a percentage of baseline) compared with the change in CPP (as a percentage of baseline; ΔLDF%/ΔCPP%). The ΔLDF%/ΔCPP% was >0 in the hypothermic shams (slope 0.24; 95% CI 0.07, 0.42; *P = 0.015). The slopes did not differ from 0 in the rewarmed sham, hypothermic arrest, and rewarmed arrest groups. There were no differences in ΔLDF%/ΔCPP% among groups (P = 0.162). Data are displayed as means ± SE.