Model-derived assessment of cerebrovascular resistance and cerebral blood flow following traumatic brain injury.

The published guidelines point out the need for the development of methods that individualize patient cerebral perfusion management and minimize secondary ischemic complications associated with traumatic brain injury. A laboratory method has been developed to determine model-derived assessments of cerebrovascular resistance (mCVR) and cerebral blood flow (mCBF) from cerebrovascular pressure transmission, and the dynamic relationship between arterial blood pressure (ABP) and intracranial pressure (ICP). The aim of this two-fold study is to (1) evaluate relative changes in the model-derived parameters of mCVR and mCBF with the corresponding changes in the pial arteriolar vascular parameters of pial arteriolar resistance (PAR) and relative pial arteriolar blood flow (rPABF); and (2) examine the efficacy of the proposed modeling methodology for continuous assessment of the state of cerebrovascular regulation by evaluating relative changes in the model-derived parameters of CBF and cerebrovascular resistance in relation to changes of cerebral perfusion pressure prior to and following fluid percussion brain injury. Changes of ABP, ICP, PAR, relative arteriolar blood flow (rPABF) and the corresponding model-derived parameters of mCBF and mCVR induced by acute hypertensive challenge were evaluated before and following fluid percussion injury in piglets equipped with cranial windows. Before fluid percussion, hypertensive challenge resulted in a significant increase of PAR and mCVR, whereas both rPABF and mCBF remained constant. Following fluid percussion, hypertensive challenge resulted in a significant decrease of PAR and mCVR and consistent with impaired cerebrovascular regulation. Hypertensive challenge significantly increased both rPABF and mCBF, which approximately doubled with increased CPP with correlation values of r = 0.96 (P < 0.01) and r = 0.97 (P

Assessment of cerebrovascular resistance with a model of cerebrovascular pressure transmission.

A method to assess continuous changes of cerebrovascular resistance based on a biomechanical model of cerebrovascular pressure transmission is developed. Such a method provides an end-point measure to assess new and/or existing management strategies during intensive-care management of patients with brain injury. Changes of both pial arteriolar resistance and cerebrovascular resistance derived by a physiologically based biomechanical model of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure (ABP) and intracranial pressure (ICP), were compared to test the validity of the modeling procedure. Pressor challenge was administered to normoxic (N=5) and hypoxic (N=5) piglets equipped with closed cranial windows. Pial arteriolar diameters were used to compute arteriolar resistance. Percent change of pial arteriolar resistance (%DeltaPAR) and percent change of model-derived cerebrovascular resistance (%DeltasCVR) in response to pressor challenge were computed. During intact cerebrovascular regulation and during hypoxia-induced impairment of cerebrovascular regulation, changes in pial arteriolar resistance were accurately predicted by the proposed modeling method designed to assess changes of cerebrovascular resistance.

Influence of hypercapnic vasodilation on cerebrovascular autoregulation and pial arteriolar bed resistance in piglets.

Changes in both pial arteriolar resistance (PAR) and simulated arterial-arteriolar bed resistance (SimR) of a physiologically based biomechanical model of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure and intracranial pressure, are used to test the hypothesis that hypercapnia disrupts autoregulatory reactivity. To evaluate pressure reactivity, vasopressin-induced acute hypertension was administered to normocapnic and hypercapnic (N = 12) piglets equipped with closed cranial windows. Pial arteriolar diameters were used to compute arteriolar resistance. Percent change of PAR (%DeltaPAR) and percent change of SimR (%DeltaSimR) in response to vasopressin-induced acute hypertension were computed and compared. Hypercapnia decreased cerebrovascular resistance. Indicative of active autoregulatory reactivity, vasopressin-induced hypertensive challenge resulted in an increase of both %DeltaPAR and %DeltaSimR for all normocapnic piglets. The hypercapnic piglets formed two statistically distinct populations. One-half of the hypercapnic piglets demonstrated a measured decrease of both %DeltaPAR and %DeltaSimR to pressure challenge, indicative of being pressure passive, whereas the other one-half demonstrated an increase in these percentages, indicative of active autoregulation. No other differences in measured variables were detectable between regulating and pressure-passive piglets. Changes in resistance calculated from using the model mirrored those calculated from arteriolar diameter measurements. In conclusion, vasodilation induced by hypercapnia has the potential to disrupt autoregulatory reactivity. Our physiologically based biomechanical model of cerebrovascular pressure transmission accurately estimates the changes in arteriolar resistance during conditions of active and passive cerebrovascular reactivity.

Assessment of cerebrovascular resistance with model of cerebrovascular pressure transmission.

BACKGROUND: A two step modeling method of cerebrovascular pressure transmission, the dynamic relationship between arterial blood pressure (ABP) and intracranial pressure (ICP) has been developed as a means to continuously assess cerebrovascular regulation and resistance. Initially, system identification modeling was used to construct a numerical model of cerebrovascular pressure transmission. Next, the modal frequencies of the numerical model and the actual ABP recording were used to manipulate the parameters of a physiologically-based biomechanical model such that: (1) the actual and simulated ICP; and (2) the numerical and biomechanical model modal frequencies match. MATERIALS AND METHODS: This study was designed to compare changes of cerebrovascular resistance of the biomechanical model with the expected changes of cerebrovascular resistance associated with the occurrence of either a plateau wave or refractory intracranial hypertension. Pressure recordings from five patients with plateau waves and five patients with intracranial hypertension were used. FINDINGS: Vascular resistance decreased significantly during the plateau wave and was inversely related to CPP, indicating active vasoreactivity. In contrast, vascular resistance increased significantly during intractable intracranial hypertension and was directly related to CPP, indicating impaired cerebrovascular regulation. CONCLUSIONS: Such results support the use of the modeling method as a means to continuously assess changes of cerebrovascular regulation and resistance.

Stroke with subarachnoid hemorrhage: assessment of cerebrovascular pressure regulation and simulated cerebrovascular resistance.

BACKGROUND: Monitoring methods designed to assess cerebrovascular regulation and increased cerebrovascular resistance (CVR) of patients with subarachnoid hemorrhage (SAH) would facilitate therapeutic intervention and potentially reduce secondary complications. The aim of this study was to assess changes of cerebrovascular regulation and CVR by evaluating changes of cerebrovascular pressure transmission in patients with SAH. METHODS: Admission Hunt-Hess grades, Fisher scores, Glasgow Outcome Scores (GOS) at 6 months, and pressure recordings were obtained from 20 patients. Biomechanical models of cerebrovascular pressure transmission were constructed over one-minute intervals for the initial and final two hours of post-hemorrhage monitoring. FINDINGS: Classified according to the GOS score at 6 months, eight patients died (GOS 1), five were severely disabled (GOS 3), and seven patients were moderately disabled (GOS 4). During the initial monitoring period 100%, 80%, and 28.6% of groups with GOS 1, 3, and 4 demonstrated impairment of cerebrovascular regulation; whereas, in the final monitoring period 100%, 100%, and 14.3% respectively demonstrated impairment. Between monitoring periods, simulated CVR (sCVR) significantly increased (p < 0.001) for patients with GOS 1 and 3 and decreased for those with GOS 4 with mean resistance for the latter group significantly lower (p < 0.001) than other means. CONCLUSIONS: Loss of cerebrovascular regulation and increased sCVR were observed in SAH patients with poor outcome.

Mode changes of cerebrovascular pressure transmission induced by cerebral vasodilation.

Changes in the modes of cerebrovascular pressure transmission during cerebral vasodilation induced by hypercapnic challenge were examined as a means for developing the basis for a bedside method to evaluate regulation of cerebral blood flow. Recordings of arterial blood pressure (ABP) and intracranial pressure (ICP) obtained from a piglet preparation equipped with a cranial window were used to determine serial changes of the highest modal frequency (HMF) and dampening factor (DF) of a numerical system identification model of cerebrovascular pressure transmission. Resistance and compliance elements of a Windkessel model of ICP dynamics selected to provide the mathematical structure for the system identification modeling approach were also manipulated to obtain a match with HMF, DF, and the experimental and simulated recordings of ICP. During hypercapnic challenge, significant increases of ICP, pial arterial diameter (PAD) and partial pressure of arterial blood carbon dioxide increases, and a decrease of arterial pH were observed. Vasodilation changed the modes of the system identification model of cerebrovascular pressure transmission from a dominantly over-damped process to an under-damped one with a significant increase in HMF and decrease in DF. Simulations of the Windkessel circuit model required a decrease in the relative resistance and an increase in relative compliance of the arterial-arteriolar vascular bed consistent with the observed increases in PAD induced by vasodilation. Evaluation of changes in the modes of cerebrovascular pressure transmission may provide means of assessing the state of cerebrovascular vasodilation and autoregulation of cerebral blood flow in the clinical setting.

Assessment of cerebrovascular autoregulation: changes of highest modal frequency of cerebrovascular pressure transmission with cerebral perfusion pressure.

BACKGROUND AND PURPOSE: Development of a method to continuously assess cerebrovascular autoregulation of patients with traumatic brain injury would facilitate therapeutic intervention and thus reduce secondary complications. METHODS: Changes in arterial blood pressure (ABP), intracranial pressure (ICP), cerebral blood flow velocity (CBFV), and pial arteriolar diameter (PAD) induced by acute pressor challenge (norepinephrine; 1 microg/[kg. min]) were evaluated in both uninjured and fluid percussion injured piglets equipped with cranial windows. The linear correlation coefficient and corresponding slope of the regression line of the relationship between highest modal frequency (HMF) of cerebrovascular pressure transmission of ABP to ICP and cerebral perfusion pressure (CPP) were determined for each challenge. RESULTS: For all uninjured piglets, pressor challenge resulted in an inverse relationship between HMF and CPP characterized by significant negative correlation values and negative corresponding regression line slopes with respective group mean values (+/-SD) of -0.50 (+/-0.14) and -0.6 (+/-0.44) Hz/mm Hg, respectively. Consistent with functional autoregulation of the uninjured preparations, pressor challenge resulted in a decrease of PAD, and CBFV remained relatively constant. For all injured piglets, pressor challenge resulted in direct relationship between HMF and CPP, characterized by positive correlation values and corresponding regression line slopes with group mean values of 0.48 (+/-0.21) and 1.13 (+/-2.08) Hz/mm Hg, respectively. Consistent with impaired autoregulation, PAD and CBFV increased during pressor challenge after brain injury. CONCLUSIONS: Evaluation of changes of the HMF of cerebrovascular pressure transmission with respect to CPP changes permits continuous monitoring of cerebral autoregulation.

Heme oxygenase inhibition reduces neuronal activation evoked by bicuculline in newborn pigs.

Carbon monoxide (CO) is a product of heme degradation by heme oxygenase (HO) that is highly expressed in the brain. The present study addresses the hypothesis that CO can be involved in brain neuronal function. The effects of the HO inhibitor, tin protoporphyrin (SnPP), on brain electrical activity and pial arteriolar diameter were examined using quantitative electroencephalography (EEG) and cranial window techniques in the bicuculline model of sustained generalized seizures in newborn pigs. SnPP (3 mg/kg i.v.) inhibits brain HO as indicated by blocking cerebral vasodilation to heme and decreasing CO concentration in cortical periarachnoid cerebrospinal fluid. The quantitative spectral analysis of digitalized scalp EEG recordings was performed to determine the EEG amplitude and spectral power within a 1-15-Hz frequency range. SnPP did not affect basal brain EEG parameters. Bicuculline (3 mg/kg i.v.) immediately (in <1 min) evoked bursts of brain electrical activity characterized by four- to seven-fold increases in EEG amplitude and power in all analyzed frequency bands that occurred simultaneously with cerebral vasodilation. Increased EEG activity and cerebral vasodilation were sustained for a 2h period. SnPP inhibited cerebral vasodilation but did not affect the EEG amplitude evoked by bicuculline. However, 20-40% reductions of the power in 7.5 Hz (theta), 10 and 12.5 Hz (alpha), and a 15-Hz (beta) bands, the major evoked EEG spectral components, were observed for the duration of seizures in SnPP-treated animals. These findings suggest that endogenous CO can have proconvulsant action and affect neuronal activation during seizures.

Modeling modulation of intracranial pressure by variation of cerebral venous resistance induced by ventilation.

To test, theoretically, the hypothesis that: (1) cyclic extravascular compressional modulation of the terminal venous bed occurs with positive pressure inhalation; and (2) the degree of modulation is diminished with increasing vascular dilation induced by increasing the level of the partial pressure of arterial blood carbon dioxide (PCO2), two modifications of Ursino's model of cerebrospinal fluid dynamics were made: (1) terminal venous bed resistance was synchronously modulated with the ventilation cycle; and (2) both the depth of modulation and cerebrovascular resistance were progressively reduced with increasing levels of PCO2. Recordings of intracranial pressure (ICP) and arterial blood pressure of piglets were obtained and correlated at different levels of hypercapnia. Simulated and experimental correlation values progressively increased monotonically as the level of PCO2 increased. Group (n = 4) mean values of correlation (+/- standard deviation) were 0.54 (+/- 0.17), 0.61 (+/- 0.08), 0.79 (+/- 0.06), 0.86 (+/- 0.04), 0.87 (+/- 0.05) for respective mean PCO2 levels (+/- standard deviation) of 32.9 (+/- 1.75), 41.4 (+/- 2.5), 55.9 (+/- 4.0), 72.5 (+/- 6.45), and 87.4 (+/- 7.25) mmHg. These results support the stated premise that dilation of the cerebrovasculature reduces the influence of positive pressure ventilation on the ICP recording by increasing the venous pressure and thus diminishing the likelihood of vascular compression.

Intracranial pressure dynamics: changes of bandwidth as an indicator of cerebrovascular tension.

The transmission bandwidth (BW) of arterial blood pressure (ABP) to intracranial pressure (ICP) was examined as a means of bedside monitoring of the state of cerebrovascular tension. Changes of BW of a black box identification model, relative arteriolar resistance and intracranial compliance were obtained from a piglet model equipped with a cranial window during induction of asphyxia, hypercapnia, and hypoxia. Changes of black box BW values and simulated changes of BW produced by a physiologically based lump parameter model of ICP dynamics are used to evaluate the hypothesis that during active cerebrovascular tension, changes of BW are inversely related to cerebral perfusion pressure (CPP), and during passive cerebrovascular tension, changes of BW are not inversely related to changes of CPP. Induction of asphyxia (n = 3) produced BW changes of the black box model that were simulated as an active cerebrovascular tension phase during decreasing CPP followed by a passive tension phase. Reventilation after prolonged asphyxia produced significant increases of BW that were simulated by a passive tension. Hypercapnic (n = 6) and hypoxic (n = 6) challenges produced: (1) significant changes of BW that were matched with simulations of the lumped parameter model for active tension; and (2) relationships between values of BW and relative average cerebral arteriolar resistance and intracranial compliance were inverse and correlated to a regression function of approximately x(-1). Changes of BW of the black box model and the simulations of the lumped parameter model support the feasibility of the stated hypothesis. As such, the evaluation of changes of BW of the black box model with respect to changes of CPP may be a useful method for monitoring the state of cerebrovascular tension.

Cerebrovasodilatory contribution of endogenous carbon monoxide during seizures in newborn pigs.

Carbon monoxide (CO) and the excitatory amino acid glutamate both dilate cerebral arterioles in newborn pigs. The key enzyme in CO synthesis is heme oxygenase, which is highly expressed in neurons with glutamatergic receptor activity as well as cerebral microvessels. During seizures the extracellular level of glutamate is increased, which results in excessive depolarization of neurons. We hypothesized that CO is a mediator of excitatory amino acid-induced dilation of the cerebral microvasculature during seizures. Three groups of piglets were examined: 1) i.v. normal saline (sham control), 2) topical chromium mesoporphyrin (Cr-MP, 15 x 10(-6) M), and 3) i.v. tin-protoporphyrin (Sn-PP, 4 mg/kg). Synthetic metalloporphyrins (Cr-MP and Sn-PP) are heme oxygenase inhibitors, thereby reducing CO synthesis. Implanted closed cranial windows were used to monitor changes in pial arteriolar diameters. Seizures were induced by administration of i.v. bicuculline. Changes in pial arteriolar diameters were monitored during 30 min of status epilepticus. The percent increase in pial arteriolar dilation in the saline group during seizures was 68 +/- 3%. In the metalloporphyrin groups, the pial arteriolar dilation was markedly reduced (35 +/- 3% and 13 +/- 1%, for Cr-MP and Sn-PP, respectively; p < 0.05, compared with the saline group). We conclude that metalloporphyrins by inhibition of heme oxygenase and prevention of CO synthesis attenuate pial arteriolar dilation during seizures. Therefore, CO appears to be involved in cerebral vasodilation caused by glutamatergic seizures.