The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased with Elevations in Intracranial Pressure.

BACKGROUND: The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. We sought to delineate the ULA in a neonatal swine model. METHODS: Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF; n = 10), controlled cortical impact (CCI; n = 10), or impact + infusion (CCI + INF; n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flux recordings during arterial hypertension until lethality. An increase in red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression and static rates of autoregulation (SRoRs) were determined above and below this inflection. RESULTS: When identified, the ULA (median [interquartile range]) was as follows: sham group: 102 mmHg (97-109), INF group: 75 mmHg (52-84), CCI group: 81 mmHg (69-101), and CCI + INF group: 61 mmHg (52-57; p = 0.01). Both groups with interventricular infusion had significantly lower ULA compared with the sham group. CONCLUSION: Neonatal piglets without intracranial pathological conditions tolerated acute hypertension, with minimal perturbation of cerebral blood flow. Piglets with acutely elevated intracranial pressure, with or without trauma, demonstrated loss of autoregulation when subjected to arterial hypertension.

The upper limit of cerebral blood flow autoregulation is decreased with elevations in intracranial pressure.

BACKGROUND: The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. OBJECTIVE: To delineate the ULA in an infant swine model. METHODS: Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF) (n = 10), controlled cortical impact (CCI) (n = 10), or CCI + INF (n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flowmetry recordings during arterial hypertension to lethality using an aortic balloon catheter. An increase of red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression, and static rates of autoregulation were determined above and below this inflection. The ULA was rendered as the first instance of an upward deflection of Doppler flux causing a static rate of autoregulation decrease greater than 0.5. RESULTS: ULA was identified in 55% of piglets after sham surgery, 70% after INF, 70% after CCI, and 91% after CCI with INF (P = .36). When identified, the median (interquartile range) ULA was as follows: sham group, 102 mm Hg (97-109 mm Hg); INF group, 75 mm Hg (52-84 mm Hg); CCI group, 81 mm Hg (69-101 mm Hg); and CCI + INF group, 61 mm Hg (52-57 mm Hg) (P = .01). In post hoc analysis, both groups with interventricular INF had significantly lower ULA than that observed in the sham group. CONCLUSION: Neonatal piglets without intracranial pathology tolerated acute hypertension with minimal perturbation of cerebral blood flow. Piglets with acutely increased intracranial pressure with or without trauma demonstrated loss of autoregulation when subjected to arterial hypertension.

The role of inflammatory processes in Alzheimer's disease.

It has become increasingly clear that inflammatory processes play a significant role in the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by the activation of astrocytes and microglia and the release of proinflammatory cytokines and chemokines. Vascular inflammation, mediated largely by the products of endothelial activation, is accompanied by the production and the release of a host of inflammatory factors which contribute to vascular, immune, and neuronal dysfunction. The complex interaction of these processes is still only imperfectly understood, yet as the mechanisms continue to be elucidated, targets for intervention are revealed. Although many of the studies to date on therapeutic or preventative strategies for AD have been narrowly focused on single target therapies, there is accumulating evidence to suggest that the most successful treatment strategy will likely incorporate a sequential, multifactorial approach, addressing direct neuronal support, general cardiovascular health, and interruption of deleterious inflammatory pathways.

Static autoregulation is intact early after severe unilateral brain injury in a neonatal Swine model.

BACKGROUND: Autoregulation is impaired by traumatic brain injury. Cerebral blood flow disturbances are spatially heterogeneous, but autoregulation is often reported as a global metric. OBJECTIVE: We tested lateralization of autoregulatory responses in the neonatal piglet brain during hypotension early after unilateral injury. METHODS: Neonatal piglets (5-7 days old) had controlled cortical impact (severe, n = 12; moderate, n = 13; sham, n = 13) and recovery for 6 hours. The lower limit of autoregulation (LLA) and static rate of autoregulation (SRoR) were determined for each subject and compared among groups and between the ipsilateral and contralateral hemispheres. RESULTS: The LLA was not increased by injury (sham, 34 mm Hg [29-39 mm Hg]; moderate injury, 37 mm Hg [33-41 mm Hg]; severe injury, 35 mm Hg [32-38 mm Hg]; P = .93, mean [95% confidence interval]). SRoR, when measured ipsilateral to injury and above the LLA, showed intact autoregulation and was not lower than SRoR in uninjured subjects (sham, 0.82 [0.53-1.1]; moderate injury, 1.0 [0.60-1.5]; severe, 0.91 [0.33-1.5]; P = .44). The average hemispheric LLA difference was 2.7 mm Hg, (95% limits of agreement, -7.5 to 7.0; bias, -0.25; Spearman r = 0.73; P < .0001). Ipsilateral and contralateral SRoR measurements also showed correlation in the injured groups (Spearman r = 0.85, P < .0001). CONCLUSION: LLA was not increased by controlled cortical impact, nor did SRoR measurements demonstrate ineffective autoregulation when cerebral perfusion pressure was greater than and within 10 mm Hg of the LLA. Cerebral perfusion pressure optimization, indicated by autoregulation measurements, was significantly similar in the 2 hemispheres despite severe unilateral injury.

Noninvasive autoregulation monitoring in a swine model of pediatric cardiac arrest.

BACKGROUND: Cerebrovascular autoregulation after resuscitation has not been well studied in an experimental model of pediatric cardiac arrest. Furthermore, developing noninvasive methods of monitoring autoregulation using near-infrared spectroscopy (NIRS) would be clinically useful in guiding neuroprotective hemodynamic management after pediatric cardiac arrest. We tested the hypotheses that the lower limit of autoregulation (LLA) would shift to a higher arterial blood pressure between 1 and 2 days of recovery after cardiac arrest and that the LLA would be detected by NIRS-derived indices of autoregulation in a swine model of pediatric cardiac arrest. We also tested the hypothesis that autoregulation with hypertension would be impaired after cardiac arrest. METHODS: Data on LLA were obtained from neonatal piglets that had undergone hypoxic-asphyxic cardiac arrest and recovery for 1 day (n = 8) or 2 days (n = 8), or that had undergone sham surgery with 2 days of recovery (n = 8). Autoregulation with hypertension was examined in a separate cohort of piglets that underwent hypoxic-asphyxic cardiac arrest (n = 5) or sham surgery (n = 5) with 2 days of recovery. After the recovery period, piglets were reanesthetized, and autoregulation was monitored by standard laser-Doppler flowmetry and autoregulation indices derived from NIRS (the cerebral oximetry [COx] and hemoglobin volume [HVx] indices). The LLA was determined by decreasing blood pressure through inflation of a balloon catheter in the inferior vena cava. Autoregulation during hypertension was evaluated by inflation of an aortic balloon catheter. RESULTS: The LLAs were similar between sham-operated piglets and piglets that recovered for 1 or 2 days after arrest. The NIRS-derived indices accurately detected the LLA determined by laser-Doppler flowmetry. The area under the curve of the receiver operator characteristic curve for cerebral oximetry index was 0.91 at 1 day and 0.92 at 2 days after arrest. The area under the curve for hemoglobin volume index was 0.92 and 0.89 at the respective time points. During induced hypertension, the static rate of autoregulation, defined as the percentage change in cerebrovascular resistance divided by the percentage change in cerebral perfusion pressure, was not different between postarrest and sham-operated piglets. At 2 days recovery from arrest, piglets exhibited neurobehavioral deficits and histologic neuronal injury. CONCLUSIONS: In a swine model of pediatric hypoxic-asphyxic cardiac arrest with confirmed brain damage, the LLA did not differ 1 and 2 days after resuscitation. The NIRS-derived indices accurately detected the LLA in comparison with laser-Doppler flow measurements at those time points. Autoregulation remained functional during hypertension.

Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia.

OBJECTIVE: Knowledge remains limited regarding cerebral blood flow autoregulation after cardiac arrest and during postresuscitation hypothermia. We determined the relationship of cerebral blood flow to cerebral perfusion pressure in a swine model of pediatric hypoxic-asphyxic cardiac arrest during normothermia and hypothermia and tested novel measures of autoregulation derived from near-infrared spectroscopy. DESIGN: Prospective, balanced animal study. SETTING: Basic physiology laboratory at an academic institution. SUBJECTS: Eighty-four neonatal swine. INTERVENTIONS: Piglets underwent hypoxic-asphyxic cardiac arrest or sham surgery and recovered for 2 hrs with normothermia followed by 4 hrs of either moderate hypothermia or normothermia. In half of the groups, blood pressure was slowly decreased through inflation of a balloon catheter in the inferior vena cava to identify the lower limit of cerebral autoregulation at 6 hrs postresuscitation. In the remaining groups, blood pressure was gradually increased by inflation of a balloon catheter in the aorta to determine the autoregulatory response to hypertension. Measures of autoregulation obtained from standard laser-Doppler flowmetry and indices derived from near-infrared spectroscopy were compared. MEASUREMENTS AND MAIN RESULTS: Laser-Doppler flux was lower in postarrest animals compared to sham-operated controls during the 2-hr normothermic period after resuscitation. During the subsequent 4-hr recovery, hypothermia decreased laser-Doppler flux in both the sham surgery and postarrest groups. Autoregulation was intact during hypertension in all groups. With arterial hypotension, postarrest, hypothermic piglets had a significant decrease in the perfusion pressure lower limit of autoregulation compared to postarrest, normothermic piglets. The near-infrared spectroscopy-derived measures of autoregulation accurately detected loss of autoregulation during hypotension. CONCLUSIONS: In a pediatric model of cardiac arrest and resuscitation, delayed induction of hypothermia decreased cerebral perfusion and decreased the lower limit of autoregulation. Metrics derived from noninvasive near-infrared spectroscopy accurately identified the lower limit of autoregulation during normothermia and hypothermia in piglets resuscitated from arrest.

Monitoring cerebral blood flow pressure autoregulation in pediatric patients during cardiac surgery.

BACKGROUND AND PURPOSE: The limits of cerebral blood flow-pressure autoregulation have not been adequately defined for pediatric patients. Mean arterial blood pressure below these limits might contribute to brain injury during cardiac surgery. The purpose of this pilot study was to assess a novel method of determining the lower limits of pressure autoregulation in pediatric patients supported with cardiopulmonary bypass. METHODS: A prospective, observational pilot study was conducted in children (n=54) undergoing cardiac surgery with cardiopulmonary bypass for correction of congenital heart defects. Cerebral oximetry index (COx) was calculated as a moving, linear correlation coefficient between slow waves of arterial blood pressure and cerebral oximetry measured with near-infrared spectroscopy. An autoregulation curve was constructed for each patient with averaged COx values sorted by arterial blood pressure. RESULTS: Hypotension was associated with increased values of COx (P<0.0001). For 77% of patients, an individual estimate of lower limits of pressure autoregulation could be determined using a threshold COx value of 0.4. The mean lower limits of pressure autoregulation for the cohort using this method was 42+/-7 mm Hg. CONCLUSIONS: This pilot study of COx monitoring in pediatric patients demonstrates an association between hypotension during cardiopulmonary bypass and impairment of autoregulation. The COx may be useful to identify arterial blood pressure-dependent limits of cerebral autoregulation during cardiopulmonary bypass. Larger trials with neurological outcomes are indicated.

Noninvasive autoregulation monitoring with and without intracranial pressure in the naive piglet brain.

BACKGROUND: Cerebrovascular autoregulation monitoring is often desirable for critically ill patients in whom intracranial pressure (ICP) is not measured directly. Without ICP, arterial blood pressure (ABP) is a substitute for cerebral perfusion pressure (CPP) to gauge the constraint of cerebral blood flow across pressure changes. We compared the use of ABP versus CPP to measure autoregulation in a piglet model of arterial hypotension. METHODS: Our database of neonatal piglet (5-7 days old) experiments was queried for animals with naïve ICP that were made lethally hypotensive to determine the lower limit of autoregulation (LLA). Twenty-five piglets were identified, each with continuous recordings of ICP, regional cerebral oximetry (rSo2), and cortical red cell flux (laser Doppler). Autoregulation was assessed with the cerebral oximetry index (COx) in 2 ways: linear correlation between ABP and rSo2 (COx(ABP)) and between CPP and rSo2 (COx(CPP)). The lower limits of autoregulation were determined from plots of red cell flux versus ABP. Averaged values of COx(ABP) and COx(CPP) from 5 mm Hg ABP bins were used to show receiver operating characteristics for the 2 methods. RESULTS: COx(ABP) and COx(CPP) yielded identical receiver operating characteristic curve areas of 0.91 (95% confidence interval [CI], 0.88-0.95) for determining the LLA. However, the thresholds for the 2 methods differed: a threshold COx(ABP) of 0.5 was 89% sensitive (95% CI, 81%-94%) and 81% specific (95% CI, 73%-88%) for detecting ABP below the LLA. A threshold COx(CPP) of 0.42 gave the same 89% sensitivity (95% CI, 81%-94%) with 77% specificity (95% CI, 69%-84%). CONCLUSIONS: The use of ABP instead of CPP for autoregulation monitoring in the naïve brain with COx results in a higher threshold value to discriminate ABP above from ABP below the LLA. However, accuracy was similar with the 2 methods. These findings support and refine the use of near-infrared spectroscopy to monitor autoregulation in patients without ICP monitors.