Augmentation Of Cerebral Perfusion Pressure Research Articles

Brain Regional Energy Metabolism in Patients with Traumatic Brain Injury: A Cerebral Microdialysis Guided Study.

In traumatic brain injuries (TBI), cerebral microdialysis (CMD)-derived parameters, especially the lactate to pyruvate ratio (LP ratio), have been utilized for cerebral perfusion optimization. The objectives were to identify cerebral ischemia as measured by CMD in TBI patients requiring decompressive craniectomy and to observe the correlation between cerebral perfusion pressure (CPP), intracranial pressure (ICP), and CMD variables in these patients. Our secondary aim was to observe the effect of CPP augmentation on ischemia biomarkers. After the Institute Ethics Committee approvals, seven adult patients requiring decompressive craniectomy following TBI were enrolled and CMD data were obtained prospectively for 72 h. CPP was augmented by 20% with noradrenaline infusion if LP ratio >40. Correlations were done with bootstrapping (n = 500) to obtain the confidence intervals (CI) due to the small sample size. One patient had cerebral ischemia (median LP ratio of 265.5 and median pyruvate of 38 μmol/L), while another patient had non-ischemic mitochondrial dysfunction (median LP ratio 40.7 and median pyruvate 278.5). The coefficients of correlation between the LP ratio with CPP and ICP were r = -0.05 (CI = -0.14-0.03) and r = 0.09 (CI = -0.03-0.24), respectively. The coefficient of correlation between cerebral and blood glucose was r = 0.38, (CI - 0.35-0.14). Only two patients needed CPP augmentation, however, postaugmentation cerebral biochemistry did not change appreciably. CMD can identify cerebral ischemia, however, no correlations were observed between the LP ratio and CPP or ICP. CPP augmentation did not improve cerebral biochemistry. More studies are required to understand and treat cerebral metabolism in TBI.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. Individualized limits of autoregulation were computed in 55 patients (mean age 38years, mean monitoring time 92h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14mm Hg to 79 ± 17mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6mm Hg to 21.9 ± 5.6mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60min after compared with before an intervention (11% vs. 23%, p = 0.05). Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Safety and Efficacy of 23.4% Sodium Chloride Administered via Peripheral Venous Access for the Treatment of Cerebral Herniation and Intracranial Pressure Elevation.

Sodium chloride (NaCl) 23.4% solution has been shown to reduce intracranial pressure (ICP) and reverse transtentorial herniation. A limitation of 23.4% NaCl is its high osmolarity (8008mOsm/l) and the concern for tissue injury or necrosis following extravasation when administered via peripheral venous access. The use of this agent is therefore often limited to central venous or intraosseous routes of administration. Our objective was to evaluate the safety and efficacy of administration of 23.4% NaCl via peripheral venous access compared with administration via central venous access. We reviewed pharmacy records to identify all administrations of 23.4% NaCl at our institution between December 2017 and February 2020. Medical records were then reviewed to identify complications, such as extravasation, soft tissue injury or necrosis, hypotension (mean arterial pressure less than 65mm Hg), pulmonary edema, hemolysis, and osmotic demyelination. We also compared the change in physiological variables, such as ICP, mean arterial pressure, cerebral perfusion pressure, and heart rate, as well as laboratory values, such as sodium, chloride, bicarbonate, creatinine, and hemoglobin, following administration of 23.4% NaCl via the peripheral and central venous routes. We identified 299 administrations of 23.4% NaCl (242 central and 57 peripheral) in 141 patients during the study period. There was no documented occurrence of soft tissue injury or necrosis in any patient. One patient developed hypotension following central administration. Among the 38 patients with ICP monitoring at the time of drug administration, there was no significant difference in median ICP reduction (- 13mm Hg [central] vs. - 24mm Hg [peripheral], p = 0.21) or cerebral perfusion pressure augmentation (16mm Hg [central] vs. 15mm Hg [peripheral], p = 0.87) based on route of administration. Peripheral venous administration of 23.4% NaCl is safe and achieves a reduction in ICP equivalent to that achieved by administration via central venous access.

Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain.

Low cerebral blood flow (CBF) states have been demonstrated in children early after traumatic brain injury (TBI), and have been correlated with poorer outcomes. Cerebral perfusion pressure (CPP) support following severe TBI is commonly implemented to correct cerebral hypoperfusion, but the efficacy of various vasopressors has not been determined. Sixteen 4-week-old female swine underwent nonimpact inertial brain injury in the sagittal plane. Intraparenchymal monitors were placed to measure intracranial pressure (ICP), CBF, brain tissue oxygen tension (PbtO2), and cerebral microdialysis 30 min to 6 h post-injury. One hour after injury, animals were randomized to receive either phenylephrine (PE) or norepinephrine (NE) infusions titrated to a CPP>70 mm Hg for 5 h. Animals were euthanized 6 h post-TBI, and brains were fixed and stained to assess regions of cell and axonal injury. After initiation of CPP augmentation with NE or PE infusions, there were no differences in ICP between the groups or over time. Animals receiving NE had higher PbtO2 than those receiving PE (29.6±10.2 vs. 19.6±6.4 torr at 6 h post-injury, p<0.05). CBF increased similarly in both the NE and PE groups. CPP support with PE resulted in a greater reduction in metabolic crisis than with NE (lactate/pyruvate ratio 16.7±2.4 vs. 42.7±10.2 at 6 h post-injury, p<0.05). Augmentation of CPP to 70 mm Hg with PE resulted in significantly smaller cell injury volumes at 6 h post-injury than CPP support with NE (0.4% vs. 1.4%, p<0.05). Despite similar increases in CBF, CPP support with NE resulted in greater brain tissue oxygenation and hypoxic-ischemic injury than CPP support with PE. Future clinical studies comparing the effectiveness of various vasopressors for CPP support are warranted.

Brain tissue oxygenation–guided management of diabetic ketoacidosis induced cerebral edema*

Type 1 diabetes mellitus is the most common chronic disease of childhood. Diabetic ketoacidosis is a well-known complication of diabetes mellitus and can be associated with devastating cerebral edema resulting in severe long-term neurologic disability. Despite the significant morbidity and mortality associated with this condition, relatively few treatments are recommended for these patients. The authors present two patients in which they used both intracranial pressure and brain tissue oxygenation monitoring to manage diabetic ketoacidosis-associated cerebral edema with favorable neurologic outcomes. Pediatric intensive care unit in a tertiary care teaching hospital. Two children presented to the emergency room with vague complaints and were found to have diabetic ketoacidosis. During treatment, both patients became comatose with head computed tomography scans revealing diffuse cerebral edema and herniation syndrome. Intracranial pressure and brain tissue oxygenation monitors were placed to guide therapy. Multiple episodes of brain tissue hypoxia were noted in both patients. Intracranial pressure control with intubation, sedation, and hyperosmolar therapy improved episodes of decreased brain tissue oxygenation associated with intracranial hypertension. Brain tissue oxygenation was also noted to be significantly less than the target value on several occasions even when intracranial pressure was controlled and an age-appropriate cerebral perfusion pressure goal was met. Augmentation of cerebral perfusion pressure above age-appropriate goal with fluid boluses and inotropic agents increased brain tissue oxygenation in these instances. Both children had very low Glasgow Coma Scale scores at admission, but ultimately had favorable neurologic outcomes. Multimodal neuromonitoring of both intracranial pressure and brain tissue oxygenation during episodes of clinically apparent diabetic ketoacidosis-associated cerebral edema allows for the detection and treatment of episodes of elevated intracranial pressure and/or brain tissue hypoxia that may be of clinical significance.

Early cerebral perfusion pressure augmentation with phenylephrine after traumatic brain injury may be neuroprotective in a pediatric swine model*

Cerebral perfusion pressure<40 mm Hg following pediatric traumatic brain injury has been associated with increased mortality independent of age, and current guidelines recommend maintaining cerebral perfusion pressure between 40 mm Hg-60 mm Hg. Although adult traumatic brain injury studies have observed an increased risk of complications associated with targeting a cerebral perfusion pressure>70, we hypothesize that targeting a cerebral perfusion pressure of 70 mm Hg with the use of phenylephrine early after injury in the immature brain will be neuroprotective. Animals were randomly assigned to injury with a cerebral perfusion pressure of 70 mm Hg or 40 mm Hg. Diffuse traumatic brain injury was produced by a single rapid rotation of the head in the axial plane. Cerebral microdialysis, brain tissue oxygen, intracranial pressure, and cerebral blood flow were measured 30 min-6 hrs postinjury. One hour after injury, cerebral perfusion pressure was manipulated with the vasoconstrictor phenylephrine. Animals were euthanized 6 hrs posttraumatic brain injury, brains fixed, and stained to assess regions of cell injury and axonal dysfunction. University center. Twenty-one 4-wk-old female swine. Augmentation of cerebral perfusion pressure to 70 mm Hg resulted in no change in axonal dysfunction, but significantly smaller cell injury volumes at 6 hrs postinjury compared to cerebral perfusion pressure 40 (1.1% vs. 7.4%, p<.05). Microdialysis lactate/pyruvate ratios were improved at cerebral perfusion pressure 70 compared to cerebral perfusion pressure 40. Cerebral blood flow was higher in the cerebral perfusion pressure 70 group but did not reach statistical significance. Phenylephrine was well tolerated and there were no observed increases in serum lactate or intracranial pressure in either group. Targeting a cerebral perfusion pressure of 70 mm Hg resulted in a greater reduction in metabolic crisis and cell injury volumes compared to a cerebral perfusion pressure of 40 mm Hg in an immature swine model. Early aggressive cerebral perfusion pressure augmentation to a cerebral perfusion pressure of 70 mm Hg in pediatric traumatic brain injury before severe intracranial hypertension has the potential to be neuroprotective, and further investigations are needed.

Lund Concept for the Management of Traumatic Brain Injury

The "Lund concept" involving a "volume-targeted" strategy for intracranial pressure control originated in the University of Lund, Sweden, more than 20 years ago and has remained controversial ever since. It is based on the premise that the blood-brain barrier is disrupted after traumatic brain injury and cerebral autoregulation is impaired; hence, the transcapillary water exchange is determined by the differences in hydrostatic and colloid osmotic pressure between the intracapillary and extracapillary compartments. The Lund concept argues that the only way of inducing transcapillary reabsorption of interstitial fluid is to control the transcapillary osmotic and hydrostatic differences and utilizes a complex combination pharmacotherapy involving β1-antagonist metoprolol, α2-agonist clonidine, low-dose thiopental, dihydroergotamine, and maintenance of colloid osmotic pressure by red blood cell transfusion and albumin administration. Although improved outcomes compared with historical controls and other institutions have been reported with treatment strategies based on the Lund concept by a few nonrandomized studies from various Swedish neurological centers, the protocol has never been subjected to a randomized trial and has not been evaluated outside Sweden. It deemphasizes the effect of secondary cerebral ischemia and contradicts the common treatment goal of cerebral blood flow optimization by augmentation of cerebral perfusion pressure. In fact, good evidence exists against the use of many individual components of the Lund therapy in traumatic brain injury. In the absence of strong evidence to support it, the Lund concept is unlikely to gain acceptance elsewhere.

Medical Management of Compromised Brain Oxygen in Patients with Severe Traumatic Brain Injury

Brain tissue oxygen (PbtO(2)) monitoring is used in severe traumatic brain injury (TBI) patients. How brain reduced PbtO(2) should be treated and its response to treatment is not clearly defined. We examined which medical therapies restore normal PbtO(2) in TBI patients. Forty-nine (mean age 40 ± 19 years) patients with severe TBI (Glasgow Coma Scale [GCS] ≤ 8) admitted to a University-affiliated, Level I trauma center who had at least one episode of compromised brain oxygen (PbtO(2) <25 mmHg for >10 min), were retrospectively identified from a prospective observational cohort study. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), and PbtO(2) were monitored continuously. Episodes of compromised PbtO(2) and brain hypoxia (PbtO(2) <15 mmHg for >10 min) and the medical interventions that improved PbtO(2) were identified. Five hundred and sixty-four episodes of compromised PbtO2 were identified from 260 days of PbtO2 monitoring. Medical management used in a "cause-directed" manner successfully reversed 72% of the episodes of compromised PbtO(2), defined as restoration of a "normal" PbtO(2) (i.e. ≥ 25 mmHg). Ventilator manipulation, CPP augmentation, and sedation were the most frequent interventions. Increasing FiO(2) restored PbtO(2) 80% of the time. CPP augmentation and sedation were effective in 73 and 66% of episodes of compromised brain oxygen, respectively. ICP reduction using mannitol was effective in 73% of treated episodes, though was used only when PbtO(2) was compromised in the setting of elevated ICP. Successful medical treatment of brain hypoxia was associated with decreased mortality. Survivors (n = 38) had a 71% rate of response to treatment and non-survivors (n = 11) had a 44% rate of response (P = 0.01). Reduced PbtO(2) may occur in TBI patients despite efforts to maintain CPP. Medical interventions other than those to treat ICP and CPP can improve PbtO(2). This may increase the number of therapies for severe TBI in the ICU.

Response to Letter by Stocchetti and Colombo

I am very grateful for the comments of Drs Stocchetti and Colombo and their valuable remarks on several points of our study. I comment further on these remarks, because this might clarify some of the concerns. The partial pressure of brain tissue oxygen (PtiO2) might become unreactive to augmentation of cerebral perfusion pressure (CPP) in cases of extreme vessel …

Continuous monitoring of the microcirculation in neurocritical care: an update on brain tissue oxygenation

This article summarizes recent clinical and experimental studies of parenchymal brain tissue oxygen monitoring and considers future directions for its use in neurocritical care. Recent reports have focused on the relationship between brain tissue oxygen tension (PbrO2) and other physiologic parameters such as mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and fraction of inspired oxygen. PbrO2 appears to reflect both regional and systemic oxygen concentrations as well as microvascular perfusion through natural tissue gradients. Defining an absolute critically low PbrO2 threshold has been challenging, but levels below 14 mmHg may have a pathophysiologic basis. Newer studies have examined dynamic changes in PbrO2 during oxygen reactivity testing and during augmentation of cerebral perfusion pressure. PbrO2 monitoring has now been described in a wide range of neurocritical care conditions including head trauma, subarachnoid hemorrhage, nontraumatic intracerebral hemorrhage, brain death, and brain tumor resection. The use of brain tissue oxygen monitoring is maturing as a tool to detect and treat secondary brain injury. PbrO2 measurements can provide continuous quantitative data about injury pathophysiology and severity that may help optimize neurointensive care management. Prospective trials of PbrO2 guided treatment protocols are now needed to demonstrate impact on clinical outcomes.

Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury*

In this study we have used O positron emission tomography, brain tissue oxygen monitoring, and cerebral microdialysis to assess the effects of cerebral perfusion pressure augmentation on regional physiology and metabolism in the setting of traumatic brain injury. Prospective interventional study. Neurosciences critical care unit of a university hospital. Eleven acutely head-injured patients requiring norepinephrine to maintain cerebral perfusion pressure. Using positron emission tomography, we have quantified the response to an increase in cerebral perfusion pressure in a region of interest around a brain tissue oxygen sensor (Neurotrend) and microdialysis catheter. Oxygen extraction fraction and cerebral blood flow were measured with positron emission tomography at a cerebral perfusion pressure of approximately 70 mm Hg and approximately 90 mm Hg using norepinephrine to control cerebral perfusion pressure. All other aspects of physiology were kept stable. Cerebral perfusion pressure augmentation resulted in a significant increase in brain tissue oxygen (17 +/- 8 vs. 22 +/- 8 mm Hg; 2.2 +/- 1.0 vs. 2.9 +/- 1.0 kPa, p < .001) and cerebral blood flow (27.5 +/- 5.1 vs. 29.7 +/- 6.0 mL/100 mL/min, p < .05) and a significant decrease in oxygen extraction fraction (33.4 +/- 5.9 vs. 30.3 +/- 4.6 %, p < .05). There were no significant changes in any of the microdialysis variables (glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol). There was a significant linear relationship between brain tissue oxygen and oxygen extraction fraction (r = .21, p < .05); the brain tissue oxygen value associated with an oxygen extraction fraction of 40% (the mean value for oxygen extraction fraction in normal controls) was 14 mm Hg (1.8 kPa). The cerebral perfusion pressure intervention resulted in a greater percentage increase in brain tissue oxygen than the percentage decrease in oxygen extraction fraction; this suggests that the oxygen gradients between the vascular and tissue compartments were reduced by the cerebral perfusion pressure intervention. Cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry. Our results suggest that the ischemic level of brain tissue oxygen may lie at a level below 14 mm Hg (1.8 kPa); however, the data do not allow us to be more specific.

Treatment of Traumatic Brain Injury: One Size Does Not Fit All

Treatment of Traumatic Brain Injury: One Size Does Not Fit All

Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) using 15O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 +/- 4 to 90 +/- 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO2 were associated with the greatest reduction in OEF (r2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 +/- 16 to 5 +/- 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 +/- 1.5 versus 4.3 +/- 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO2 and neuronal electrical function will require further study.

Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury

To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury. Prospective, controlled, trial. Neurosciences critical care unit. Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.