Cerebral blood flow is decoupled from blood pressure and linked to EEG bursting after resuscitation from cardiac arrest

Abstract

In the present study, we have developed a multi-modal instrument that combines laser speckle imaging, arterial blood pressure, and electroencephalography (EEG) to quantitatively assess cerebral blood flow (CBF), mean arterial pressure (MAP), and brain electrophysiology before, during, and after asphyxial cardiac arrest (CA) and resuscitation. Using the acquired data, we quantified the time and magnitude of the CBF hyperemic peak and stabilized hypoperfusion after resuscitation. Furthermore, we assessed the correlation between CBF and MAP before and after stabilized hypoperfusion. Finally, we examined when brain electrical activity resumes after resuscitation from CA with relation to CBF and MAP, and developed an empirical predictive model to predict when brain electrical activity resumes after resuscitation from CA. Our results show that: 1) more severe CA results in longer time to stabilized cerebral hypoperfusion; 2) CBF and MAP are coupled before stabilized hypoperfusion and uncoupled after stabilized hypoperfusion; 3) EEG activity (bursting) resumes after the CBF hyperemic phase and before stabilized hypoperfusion; 4) CBF predicts when EEG activity resumes for 5-min asphyxial CA, but is a poor predictor for 7-min asphyxial CA. Together, these novel findings highlight the importance of using multi-modal approaches to investigate CA recovery to better understand physiological processes and ultimately improve neurological outcome.

Keywords: (110.6150) Speckle imaging; (120.5475) Pressure measurement; (170.1610) Clinical applications; (170.2655) Functional monitoring and imaging; (170.3880) Medical and biological imaging; (170.5380) Physiology.

Fig. 1

Cardiac arrest (CA) experimental design and setup. (A) Diagram of CA timeline. Experiment began (t = 0) with an isoflurane/oxygen mix. At t = 2min, isoflurane was turned off, Vecuronium administered, and animal exposed to room air. The ventilator was then turned off to initiate the asphyxial CA period that lasted 5- or 7-min. Approximately 1min prior to initiation of cardiopulmonary resuscitation (CPR), epinephrine, sodium bicarbonate and saline were administered and the ventilator restarted. CPR was then performed for ~1min until ROSC, after which data acquisition continued for ~90min post-ROSC. (B) Schematic of multi-instrument design to perform laser speckle imaging (LSI), arterial blood pressure measurements, and electroencephalography (EEG). (1) LSI camera with laser line filter and adjustable camera lens; (2) 809nm light source for LSI to display speckle pattern on rat cortex; (3) EEG wire that connected EEG screw electrodes to EEG preamplifier; (4) EEG preamplifier with 0.35Hz high pass filter; (5) intubation tubing connected to ventilator; (6) ventilator with adjustable settings; (7) femoral artery catheter; (8) syringe to administer fluids for dehydration and remove blood for arterial blood gas (ABG) measurements; (9) blood pressure transducer; (10) femoral vein catheter; (11) syringe to administer epinephrine, sodium bicarbonate and saline prior to CPR and ROSC; (12) stereotaxic frame with rat mounted; (13) brain illuminated by laser light with EEG screw electrodes. (C) Magnified view of animal head that shows location of EEG electrodes and craniectomy.

Fig. 2

CBF characteristics. Median-filtered relative SFI maps from a representative 5-min asphyxia experiment acquired during (A) baseline, where black rectangle represents ROI selected to avoid specular reflection, and a 1mm scale bar, (B) cardiac arrest, (C) hyperemic peak, and (D) stabilized hypoperfusion. The vertical color bar indicates relative SFI units. (E) A representative 5-min asphyxia experiment that shows relative SFI time course plot with schematic of CBF characteristics. Black vertical line represents start of asphyxia, green vertical line represents ROSC, and purple vertical line represents stabilized hypoperfusion. Double-arrowed red line with letter F represents percent SFI above baseline at hyperemic peak, double-arrowed dark magenta line with letter G represents time from ROSC to hyperemic peak, double-arrowed orange line with letter H represents percent SFI below baseline at stabilized hypoperfusion, double-arrowed navy blue line with letter I represents time from ROSC to stabilized hypoperfusion. Comparison between 5- and 7-min asphyxial durations for (F) percent SFI above baseline at hyperemic peak (44.13$\pm$11.06% vs 37.11$\pm$28.80%, p = 0.28), (G) time from ROSC to hyperemic peak (5.19$\pm$1.10min vs 5.99$\pm$1.26min, p = 0.12), (H) percent SFI below baseline at stabilized hypoperfusion (44.95$\pm$9.50% vs 42.26$\pm$11.40%, p = 0.33), (I) time from ROSC to stabilized hypoperfusion (15.60$\pm$3.67min vs 23.76$\pm$5.12min, p = 0.003). Asterisk represents significant differences (p < 0.05).

Fig. 3

CBF and MAP comparison. (A) A representative 5-min asphyxia experiment that shows relative SFI (top) and MAP (bottom) time-course plots. Black vertical line represents start of asphyxia, green vertical line represents ROSC, and purple vertical line represents stabilized hypoperfusion. The relative SFI time-course shows that CBF is much lower than baseline at stabilized hypoperfusion, while the MAP is nearly 100mmHg at stabilized hypoperfusion. The gap from ~21- to 23-min on the MAP time-course is due to ABG being taken. (B) The same 5-min asphyxia experiment from (A) that compares MAP and relative SFI before stabilized hypoperfusion (blue) and after stabilized hypoperfusion (red). Before stabilized hypoperfusion MAP and relative SFI are significantly correlated for the representative rat (R = 0.77, p = 1$\times$10⁻⁹³). After stabilized hypoperfusion, CBF is at a major deficit compared to baseline, while MAP is maintained near baseline, circled in red.

Fig. 4

Initial EEG burst. (A) A representative 5-min asphyxia experiment that shows EEG time-course to illustrate detection of initial EEG burst post-ROSC. EEG data shown was recorded from the upper-left electrode in Fig. 1(C). Black vertical line represents start of asphyxia, green vertical line represents ROSC, and red circle of inset is the first EEG burst detected by automated algorithm post-ROSC. (B) Comparison between 5-min and 7-min asphyxial durations for the time from ROSC to initial EEG burst (12.17$\pm$2.17min vs 16.97$\pm$3.67min, p = 0.007). Asterisk represents significant difference (p < 0.05).

Fig. 5

Initial EEG burst begins after CBF hyperemic phase and before stabilized hypoperfusion. (A) Representative relative SFI and EEG time-courses to illustrate initial EEG burst occurs after CBF hyperemic phase and before stabilized hypoperfusion. EEG data shown was recorded from the upper-left electrode in Fig. 1(C). Black vertical line represents start of asphyxia, green vertical line represents ROSC, and red vertical line represents initial EEG burst. (B and C) AUC from ROSC to burst vs time to burst after ROSC shows a significant positive correlation for relative SFI (left) (R = 0.84, p = 0. 0003) and MAP (right) (R = 0.80, p = 0. 001). (D and E) AUC from ROSC to burst is significantly less for 5-min asphyxia than 7-min asphyxia for relative SFI (left) (1290$\pm$140 vs 1781$\pm$286, p = 0.002) and non-significantly time-integrated MAP (right) (1331$\pm$257 vs 1645$\pm$378, p = 0.1). (F and G) The predictive burst ratio was non-significant comparing 5- and 7-min asphyxial durations for relative SFI (left) (258.0$\pm$28.1 vs 254.5$\pm$40.8, p = 0.86) and MAP (right) (269.7$\pm$47.5 vs 249.7$\pm$43.3, p = 0.45). Asterisks represent significant differences (p <0.05).

Fig. 6

Representative predictive burst times for initial EEG burst using predictive burst model. (A) A representative 5-min asphyxial experiment that used relative SFI data to predict the initial EEG burst time, percent error of 3.42% obtained. (B) Same 5-min asphyxial experiment used as (A), but used MAP to predict initial EEG burst time, percent error of 12.10% obtained. (C) A representative 7-min asphyxial experiment that used relative SFI to predict initial EEG burst time, a percent error of 39.37% obtained. (D) Same 7-min asphyxial experiment used as (C), but used MAP to predict initial EEG burst time, percent error of 52.96% obtained. Gap from ~140 to ~170 of predictive burst ratio is due to ABG being taken.