Jennifer K. Lee

Continuous Time-Domain Analysis of Cerebrovascular Autoregulation Using Near-Infrared Spectroscopy

Background and Purpose— Assessment of autoregulation in the time domain is a promising monitoring method for actively optimizating cerebral perfusion pressure (CPP) in critically ill patients. The ability to detect loss of autoregulatory vasoreactivity to spontaneous fluctuations in CPP was tested with a new time-domain method that used near-infrared spectroscopic measurements of tissue oxyhemoglobin saturation in an infant animal model. Methods— Piglets were made progressively hypotensive over 4 to 5 hours by inflation of a balloon catheter in the inferior vena cava, and the breakpoint of autoregulation was determined using laser-Doppler flowmetry. The cerebral oximetry index (COx) was determined as a moving linear correlation coefficient between CPP and INVOS cerebral oximeter waveforms during 300-second periods. A laser-Doppler derived time-domain analysis of spontaneous autoregulation with the same parameters (LDx) was also determined. Results— An increase in the correlation coefficient between cerebral oximetry values and dynamic CPP fluctuations, indicative of a pressure-passive relationship, occurred when CPP was below the steady state autoregulatory breakpoint. This COx had 92% sensitivity (73% to 99%) and 63% specificity (48% to 76%) for detecting loss of autoregulation attributable to hypotension when COx was above a threshold of 0.36. The area under the receiver-operator characteristics curve for the COx was 0.89. COx correlated with LDx when values were sorted and averaged according to the CPP at which they were obtained (r=0.67). Conclusions— The COx is sensitive for loss of autoregulation attributable to hypotension and is a promising monitoring tool for determining optimal CPP for patients with acute brain injury.

Cerebrovascular Reactivity Measured by Near-Infrared Spectroscopy

BACKGROUND AND PURPOSE The pressure reactivity index (PRx) describes cerebral vessel reactivity by correlation of slow waves of intracranial pressure (ICP) and arterial blood pressure. In theory, slow changes in the relative total hemoglobin (rTHb) measured by near-infrared spectroscopy are caused by the same blood volume changes that cause slow waves of ICP. Our objective was to develop a new index of vascular reactivity, the hemoglobin volume index (HVx), which is a low-frequency correlation of arterial blood pressure and rTHb measured with near-infrared spectroscopy. METHODS Gradual hypotension was induced in piglets while cortical laser-Doppler flux was monitored. ICP was monitored, and rTHb was measured continuously using reflectance near-infrared spectroscopy. The HVx was recorded as a moving linear correlation between slow waves (20 to 300 seconds) of arterial blood pressure and rTHb. Autoregulation curves were constructed by averaging values of the PRx or HVx in 5-mm Hg bins of cerebral perfusion pressure. RESULTS The laser-Doppler flux-determined lower limit of autoregulation was 29.4+/-6.7 mm Hg (+/-SD). Coherence between rTHb and ICP was high at low frequencies. HVx was linearly correlated with PRx. The PRx and HVx both showed higher values below the lower limit of autoregulation and lower values above the lower limit of autoregulation. Areas under the receiver operator characteristic curves were 0.88 and 0.85 for the PRx and HVx, respectively. CONCLUSIONS Coherence between the rTHb and ICP waveforms at the frequency of slow waves suggests that slow waves of ICP are related to blood volume changes. The HVx has potential for further development as a noninvasive alternative to the PRx.

Continuous Measurement of Autoregulation by Spontaneous Fluctuations in Cerebral Perfusion Pressure: Comparison of 3 Methods

Background and Purpose— Clinical application of continuous autoregulation monitoring would benefit from a comparison of curves generated by online monitoring with standard autoregulation curves in animal models. We characterized the accuracy of 3 continuous monitors of autoregulation in a piglet model of hypotension. Methods— Piglets 5 to10 days old with intracranial pressure (ICP) at naïve or elevated (20 mm Hg) levels had gradual arterial hypotension induced by a balloon catheter in the inferior vena cava. Elevated ICP was maintained by a continuous infusion of artificial cerebrospinal fluid. Three indices of autoregulation were simultaneously and continuously calculated. A moving, linear Pearsons coefficient between spontaneous slow waves of cerebral perfusion pressure and slow waves of laser-Doppler flux or cortical oxygenation rendered the laser-Doppler index and cerebral-oximetry index, respectively. Similar correlation between slow waves of arterial blood pressure and ICP rendered the pressure-reactivity index. The lower limit of autoregulation was determined directly for each animal by plotting laser-Doppler cortical red blood cell flux as a function of cerebral perfusion pressure. Receiver-operator characteristics were determined for the 3 indices. Results— The areas under the receiver-operator characteristics curves for discriminating the individual lower limit of autoregulation at low and high ICP were 0.89 and 0.85 for the laser-Doppler index, 0.89 and 0.84 for the cerebral-oximetry index, and 0.79 and 0.79 for the pressure-reactivity index. The pressure-reactivity index performed equally well at low and high ICPs. Conclusions— Continuous monitoring of autoregulation by spontaneous slow waves of cerebral perfusion pressure can accurately detect loss of autoregulation due to hypotension in piglets by all 3 modalities.

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.

Continuous Monitoring of Cerebrovascular Pressure Reactivity After Traumatic Brain Injury in Children

OBJECTIVE: We hypothesized that pressure reactivity index (PRx) values indicating preserved cerebrovascular pressure autoregulation would be associated with survival in children with traumatic brain injury (TBI). This hypothesis was tested in a prospective, blinded, observational, pilot study. METHODS: Twenty-one children admitted between May 2006 and September 2008 with severe TBI necessitating invasive intracranial pressure monitoring were enrolled in this study. The PRx was continuously monitored as a moving, linear correlation coefficient between low-frequency waves of intracranial and arterial blood pressures. Positive values of PRx approaching 1 indicate impaired cerebrovascular pressure reactivity, whereas negative PRx values or values close to 0 indicate preserved cerebrovascular pressure reactivity. Survival was the primary outcome and was compared with the average PRx value obtained during the intracranial pressure-monitoring period. RESULTS: PRx was associated with survival in this cohort; survivors (N = 15) had a mean PRx ± SD of 0.08 ± 0.19, and nonsurvivors (N = 6) had a mean PRx of 0.69 ± 0.21 (P = .0009). In this sample, continuous PRx monitoring suggested impaired cerebrovascular pressure reactivity at low levels of cerebral perfusion pressure (CPP) and intact cerebrovascular pressure reactivity at higher levels of CPP. CONCLUSIONS: Intact cerebrovascular pressure reactivity quantified with the PRx is associated with survival after severe head trauma in children. The PRx is CPP dependent in children. The PRx may be useful for defining age-specific and possibly patient-specific optimal targets for CPP after TBI.

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.

The lower limit of cerebral blood flow autoregulation is increased with elevated intracranial pressure.

BACKGROUND: The cerebral perfusion pressure that denotes the lower limit of cerebral blood flow autoregulation (LLA) is generally considered to be equivalent for reductions in arterial blood pressure (ABP) or increases in intracranial pressure (ICP). However, the effect of decreasing ABP at different levels of ICP has not been well studied. Our objective in the present study was to determine if the LLA during arterial hypotension was invariant with ICP. METHODS: Using continuous ventricular fluid infusion, anesthetized piglets were assigned to 1 of 3 groups: naïve ICP (n = 10), moderately elevated ICP (20 mm Hg; n = 11), or severely elevated ICP (40 mm Hg; n = 9). Gradual hypotension was induced by inflation of a balloon catheter in the inferior vena cava. The LLA was determined by monitoring cortical laser-Doppler flux. RESULTS: The naïve ICP group had an average CPP at the LLA (LLACPP) of 29.8 mm Hg (95% CI: 26.5–33.0 mm Hg). However, the moderately elevated ICP group had a mean LLACPP of 37.6 mm Hg (95% CI: 32.0–43.2 mm Hg), and the severely elevated ICP group had a mean LLACPP of 51.4 mm Hg (95% CI: 41.2–61.7 mm Hg). The LLA significantly differed among groups, and the increase in LLA correlated with the increase in ICP. CONCLUSIONS: In this atraumatic, elevated ICP model in piglets, the LLA had a positive correlation with ICP, which suggests that compensating for an acute increase in ICP with an equal increase in ABP may not be sufficient to prevent cerebral ischemia.

Cerebrovascular autoregulation and neurologic injury in neonatal hypoxic-ischemic encephalopathy.

Background:Neonates with hypoxic–ischemic encephalopathy (HIE) are at risk of cerebral blood flow dysregulation. Our objective was to describe the relationship between autoregulation and neurologic injury in HIE.Methods:Neonates with HIE had autoregulation monitoring with the hemoglobin volume index (HVx) during therapeutic hypothermia, rewarming, and the first 6 h of normothermia. The 5-mm Hg range of mean arterial blood pressure (MAP) with best vasoreactivity (MAPOPT) was identified. The percentage of time spent with MAP below MAPOPT and deviation in MAP from MAPOPT were measured. Neonates received brain magnetic resonance imaging (MRI) 3–7 d after treatment. MRIs were coded as no, mild, or moderate/severe injury in five regions.Results:HVx identified MAPOPT in 79% (19/24), 77% (17/22), and 86% (18/21) of the neonates during hypothermia, rewarming, and normothermia, respectively. Neonates with moderate/severe injury in paracentral gyri, white matter, basal ganglia, and thalamus spent a greater proportion of time with MAP below MAPOPT during rewarming than neonates with no or mild injury. Neonates with moderate/severe injury in paracentral gyri, basal ganglia, and thalamus had greater MAP deviation below MAPOPT during rewarming than neonates without injury.Conclusion:Maintaining MAP within or above MAPOPT may reduce the risk of neurologic injuries in neonatal HIE.

Efficacy of Chest Compressions Directed by End‐Tidal CO2 Feedback in a Pediatric Resuscitation Model of Basic Life Support

Background End‐tidal carbon dioxide (ETCO2) correlates with systemic blood flow and resuscitation rate during cardiopulmonary resuscitation (CPR) and may potentially direct chest compression performance. We compared ETCO2‐directed chest compressions with chest compressions optimized to pediatric basic life support guidelines in an infant swine model to determine the effect on rate of return of spontaneous circulation (ROSC). Methods and Results Forty 2‐kg piglets underwent general anesthesia, tracheostomy, placement of vascular catheters, ventricular fibrillation, and 90 seconds of no‐flow before receiving 10 or 12 minutes of pediatric basic life support. In the optimized group, chest compressions were optimized by marker, video, and verbal feedback to obtain American Heart Association‐recommended depth and rate. In the ETCO2‐directed group, compression depth, rate, and hand position were modified to obtain a maximal ETCO2 without video or verbal feedback. After the interval of pediatric basic life support, external defibrillation and intravenous epinephrine were administered for another 10 minutes of CPR or until ROSC. Mean ETCO2 at 10 minutes of CPR was 22.7±7.8 mm Hg in the optimized group (n=20) and 28.5±7.0 mm Hg in the ETCO2‐directed group (n=20; P=0.02). Despite higher ETCO2 and mean arterial pressure in the latter group, ROSC rates were similar: 13 of 20 (65%; optimized) and 14 of 20 (70%; ETCO2 directed). The best predictor of ROSC was systemic perfusion pressure. Defibrillation attempts, epinephrine doses required, and CPR‐related injuries were similar between groups. Conclusions The use of ETCO2‐directed chest compressions is a novel guided approach to resuscitation that can be as effective as standard CPR optimized with marker, video, and verbal feedback.

Rewarming from therapeutic hypothermia induces cortical neuron apoptosis in a swine model of neonatal hypoxic-ischemic encephalopathy.

The consequences of therapeutic hypothermia for neonatal hypoxic–ischemic encephalopathy are poorly understood. Adverse effects from suboptimal rewarming could diminish neuroprotection from hypothermia. Therefore, we tested whether rewarming is associated with apoptosis. Piglets underwent hypoxia–asphyxia followed by normothermic or hypothermic recovery at 2 hours. Hypothermic groups were divided into those with no rewarming, rewarming at 0.5 °C/hour, or rewarming at 4 °C/hour. Neurodegeneration at 29 hours was assessed by hematoxylin and eosin staining, TUNEL assay, and immunoblotting for cleaved caspase-3. Rewarmed piglets had more apoptosis in motor cortex than did those that remained hypothermic after hypoxia–asphyxia. Apoptosis in piriform cortex was greater in hypoxic–asphyxic, rewarmed piglets than in naive/sham piglets. Caspase-3 inhibitor suppressed apoptosis with rewarming. Rapidly rewarmed piglets had more caspase-3 cleavage in cerebral cortex than did piglets that remained hypothermic or piglets that were rewarmed slowly. We conclude that rewarming from therapeutic hypothermia can adversely affect the newborn brain by inducing apoptosis through caspase mechanisms.