Roman Hlatky

Nitric oxide in traumatic brain injury.

Nitric oxide (NO) is a gaseous chemical messenger which has functions in the brain in a variety of broad physiological processes, including control of cerebral blood flow, interneuronal communications, synaptic plasticity, memory formation, receptor functions, intracellular signal transmission, and release of neurotransmitters. As might be expected from the numerous and complex roles that NO normally has, it can have both beneficial and detrimental effects in disease states, including traumatic brain injury. There are two periods of time after injury when NO accumulates in the brain, immediately after injury and then again several hours‐days later. The initial immediate peak in NO after injury is probably due to the activity of endothelial NOS and neuronal NOS. Pre‐injury treatment with 7‐nitroindazole, which probably inhibits this immediate increase in NO by neuronal NOS, is effective in improving neurological outcome in some models of traumatic brain injury (TBI). After the initial peak in NO, there can be a period of relative deficiency in NO. This period of low NO levels is associated with a low cerebral blood flow (CBF). Administration of L‐arginine at this early time improves CBF, and outcome in many models. The late peak in NO after traumatic injury is probably due primarily to the activity of inducible NOS. Inhibition of inducible NOS has neuroprotective effects in most models.

Patterns of Energy Substrates during Ischemia Measured in the Brain by Microdialysis

The purpose of this study was to examine the patterns of change in microdialysate concentrations of glucose, lactate, pyruvate, and glutamate in the brain during periods of hypoxia/ischemia identified by monitoring brain tissue pO2 (PbtO2). Of particular interest was a better understanding of what additional information could be obtained by the microdialysis parameters that was not available from the PbtO2. Fifty-seven patients admitted with severe traumatic brain injury who had placement of both a brain tissue pO2 (PbtO2) and microdialysis probe were studied. The microdialysis probe was perfused with Ringers solution at 0.3 microL/min and dialysate was collected at 1-h intervals. The concentration of glucose, pyruvate, lactate, and glutamate were measured in each dialysate sample. Changes in the microdialysis parameters were examined during episodes where the PbtO2 decreased to below 10 mm Hg. Ten episodes of tissue hypoxia/ischemia identified by a decrease in PbtO2 below 10 mm Hg were observed during the period of monitoring. The concentration of the dialysate glucose closely followed the PbtO2. The dialysate pyruvate concentration was more variable and in some patients transiently increased as the PbtO2 dropped below 10 mm Hg. The dialysate concentration of lactate was significantly increased as the PbtO2 decreased to less than 10 mm Hg. Dialysate glutamate was significantly elevated only when PbtO2 decreased to very low levels. Although changes in the PbtO2 provided the earliest sign of hypoxia/ischemia, the microdialysis assays provided additional information about the consequences that the reduced tissue pO2 has on brain metabolism, which may be helpful in managing these critically ill patients.

Brain tissue oxygen tension response to induced hyperoxia reduced in hypoperfused brain

OBJECTIVES Increasing PaO2 can increase brain tissue PO2 (PbtO2). Nevertheless, the small increase in arterial O2 content induced by hyperoxia does not increase O2 delivery much, especially when cerebral blood flow (CBF) is low, and the effectiveness of hyperoxia as a therapeutic intervention remains controversial. The purpose of this study was to examine the role of regional (r)CBF at the site of the PO2 probe in determining the response of PbtO2 to induced hyperoxia. METHODS The authors measured PaO2 and PbtO2 at baseline normoxic conditions and after increasing inspired O2 concentration to 100% on 111 occasions in 83 patients with severe traumatic brain injury in whom a stable xenon-enhanced computed tomography measurement of CBF was available. The O2 reactivity was calculated as the change in PbtO2 x 100/change in PaO2. RESULTS The O2 reactivity was significantly different (p < 0.001) at the 5 levels of rCBF (<10, 11-15, 16-20, 21-40, and > 40 ml/100 g/min). When rCBF was < 20 ml/100 g/min, the increase in PbtO2 induced by hyperoxia was very small compared with the increase that occurred when rCBF was > 20 ml/100 g/min. CONCLUSIONS Although the level of CBF is probably only one of the factors that determines the PbtO2 response to hyperoxia, it is apparent from these results that the areas of the brain that would most likely benefit from improved oxygenation are the areas that are the least likely to have increased PbtO2.

Evolution of Brain Tissue Injury after Evacuation of Acute Traumatic Subdural Hematomas

OBJECTIVE Acute traumatic subdural hematoma complicated by brain parenchymal injury is associated with a 60 to 90% mortality rate. Early surgical evacuation of the mass lesion is essential for a favorable outcome, but the severity of the underlying brain injury determines the outcome, even when surgery has been prompt. The purpose of this study was to analyze tissue biochemical patterns in the brain underlying an evacuated acute subdural hematoma to identify a characteristic pattern of changes that might indicate evolving brain injury. METHODS Prospectively collected data from 33 patients after surgical evacuation of acute subdural hematoma were analyzed. Both a brain tissue oxygen tension probe and an intracerebral microdialysis probe were placed in brain tissue exposed at surgery. On the basis of the postoperative clinical course, the patients were divided into three groups: patients with early intractable intracranial hypertension, patients with evolution of delayed traumatic injury (DTI), and patients with an uncomplicated course (the no-DTI group). RESULTS The overall mortality rate was 46%, with 100% mortality in the intracranial hypertension group (five patients). Mortality in the DTI group was 53% compared with only 9% in the no-DTI group (P = 0.002). There were no significant differences in the initial computed tomographic scan characteristics, such as thickness of the subdural hematoma or amount of midline shift, among the three groups. Physiological variables, as well as the microdialysate measures of brain biochemistry, were markedly different in the intracranial hypertension group compared with the other groups. Differences between the other two groups were more subtle but were significant. Significantly lower values of brain tissue oxygen tension (14 +/- 8 mm Hg versus 27 +/- 14 mm Hg) and higher dialysate values of lactate and pyruvate were documented in patients who developed a delayed injury compared with patients with uncomplicated courses (4.1 +/- 2.3 mmol/L versus 1.7 +/- 0.7 mmol/L for lactate, and 104 +/- 47 micromol/L versus 73 +/- 54 micromol/L for pyruvate at 24 h after injury). CONCLUSION Evolution of DTI in the area of brain underlying an evacuated subdural hematoma is associated with a significant increase in mortality. Postoperatively decreasing brain tissue oxygen tension and increasing dialysate concentrations of lactate and pyruvate in this area may warn of evolving brain injury and evoke further diagnostic and therapeutic activity.

The Role of Endothelial Nitric Oxide Synthase in the Cerebral Hemodynamics after Controlled Cortical Impact Injury in Mice

Traumatic brain injury causes a reduction in cerebral blood flow, which may cause additional damage to the brain. The purpose of this study was to examine the role of nitric oxide produced by endothelial nitric oxide synthase (eNOS) in these vascular effects of trauma. To accomplish this, cerebral hemodynamics were monitored in mice deficient in eNOS and wild-type control mice that underwent lateral controlled cortical impact injury followed by administration of either L-arginine, 300 mg/kg, or saline at 5 min after the impact injury. The eNOS deficient mice had a greater reduction in laser Doppler flow (LDF) in the contused brain tissue at the impact site after injury, despite maintaining a higher blood pressure. L-Arginine administration increased LDF post-injury only in the wild-type mice. L-Arginine administration also resulted in a reduction in contusion volume, from 2.4 +/- 1.5 to 1.1 +/- 1.2 mm(3) in wild-type mice. Contusion volume in the eNOS deficient mice was not significantly altered by L-arginine administration. These differences in cerebral hemodynamics between the eNOS-deficient and the wild-type mice suggest an important role for nitric oxide produced by eNOS in the preservation of cerebral blood flow in contused brain following traumatic injury, and in the improvement in cerebral blood flow with L-arginine administration.

Role of Nitric Oxide in Cerebral Blood Flow Abnormalities after Traumatic Brain Injury

Nitric oxide (NO) has important regulatory functions within the central nervous system. NO is oxidized in vivo to nitrate and nitrite (NOx). Measurement of these products gives an index of NO production. The purpose of this study was to examine the relation between the brain extracellular concentration of NO metabolites and cerebral blood flow (CBF) after severe traumatic brain injury. Using a chemiluminescence method, NOx concentrations were measured in 6,701 microdialysate samples obtained from 60 patients during the first 5 d after severe head injury. Regional and global values of CBF obtained by xenon-enhanced computed tomography were used for analyses. Dialysate NOx values were the highest within the first 24 h after brain trauma and gradually decreased over the 5 postinjury d (time effect, P < 0.001). Mean dialysate concentration of NOx was 15.5 ± 17.6 μmol/L (minimum 0.3, maximum 461 μmol/L) and 65% of samples were between 5 and 20 μmol/L. There was a significant relation between regional CBF and dialysate NOx levels (r2 = 0.316, P < 0.001). Dialysate NOx levels (9.5 ± 2.2 μmol/L) in patients with critical reduction of regional CBF (<18 mL · 100 g−1 · min−1) were significantly lower than in patients with normal CBF (18.6 ± 8.1 μmol/L; P < 0.001). This relation between the dialysate concentration of NOx and regional CBF suggests some role for NO in the abnormalities of CBF that occur after traumatic brain injury.

Brain tissue PO2: correlation with cerebral blood flow.

This investigation analyzed 22 xenon CT cerebral blood flow (CBF) studies from 18 severely head-injured patients (Glasgow motor score < 6) who underwent xenon CT scanning while brain tissue oxygen tension (PbtO2) was being monitored. CBF was determined both in a localized region of interest around the actual or estimated location of the tip of the PbtO2 probe and in the entire corresponding CT slice. Linear regression analysis was used to examine the relationship between these CBF measurements and PbtO2 values recorded immediately prior to the xenon CT CBF study. PbtO2 varied linearly with both regional CBF (rCBF) and global CBF measurements, but the average global CBF value was significantly higher than the average rCBF value. Very low values were significantly less common for global CBF than for rCBF. Further investigation is necessary to determine how probe placement near contused areas vs. in normal tissue affects our understanding of the relationship between rCBF, global CBF, PbtO2, and cerebral oxygen consumption.

Significance of a reduced cerebral blood flow during the first 12 hours after traumatic brain injury.

AbstractBackground: It is controversial whether a low cerebral blood flow (CBF) simply reflects the severity of injury or whether ischemia contributes to the brain’s injury. It is also not clear whether posttraumatic cerebral hypoperfusion results from intracranial hypertension or from pathologic changes of the cerebral vasculature. The answers to these questions have important implications for whether and how to treat a low CBF. Methods: We performed a retrospective analysis of 77 patients with severe traumatic brain injury who had measurement of CBF within 12 hours of injury. CBF was measured using xenon-enhanced computed tomography (XeCT). Global CBF, physiological parameters at the time of XeCT, and outcome measures were analyzed. Results: Average global CBF for the 77 patients was 36±16 mL/100g/minutes. Nine patients had an average global CBF <18 (average 12±5). The remaining 68 patients had a global CBF of 39±15. The initial ICP was >20 mmHg in 90% and >30 mmHg in 80% of patients in the group with CBF<18, compared to 33% and 16%, respectively, in the patients with CBF≥18. Mortality was 90% at 6 months postinjury in patients with CBF<18. Mortality in the patients with CBF>18 was 19% at 6 months after injury. Conclusion: In patients with CBF<18 mL/100 g/minutes, intracranial hypertension plays a major causative role in the reduction in CBF. Treatment would most likely be directed at controlling intracranial pressure, but the early, severe intracranial hypertension also probably indicates a severe brain injury. For levels of CBF between 18 and 40 mL/100 g/minutes, the presence of regional hypoperfusion was a more important factor in reducing the average CBF.

Intracranial Pressure Response to Induced Hypertension: Role of Dynamic Pressure Autoregulation

OBJECTIVE:Induced hypertension is commonly used to improve cerebral perfusion, but this treatment may have the deleterious side effect of raising intracranial pressure (ICP). We tested the hypothesis that dynamic pressure autoregulation testing could identify patients who might develop increased ICP during induced hypertension. METHODS:Twenty-two studies were performed in 21 patients. Baseline dynamic testing of autoregulation by cuff deflation and carotid compression techniques was performed. After phenylephrine was infused to increase mean arterial pressure by 20 to 30 mm Hg, cuff deflation tests were repeated. RESULTS:The average increase in mean arterial pressure was 32.2 ± 16.1 mm Hg. This increase was accompanied by increased flow velocity (P < 0.001), brain tissue PO2 (P = 0.011), and regional cerebral blood flow (P = 0.008). Also, dynamic pressure autoregulation consistently improved (P = 0.015). Induced hypertension caused increased ICP (iICP) in 12 patients and a decrease in ICP (dICP) in 9. Baseline jugular venous oxygen saturation in the iICP group was 82 ± 10% compared with 70 ± 10% in dICP patients (P = 0.02). Baseline dynamic autoregulatory index for the cuff deflation tests (1.8 ± 1.4) and baseline transient hyperemic response ratio for the carotid compression tests (1.11 ± 0.07) were significantly lower in iICP patients (dICP group: autoregulatory index 3.2 ± 1.7, P = 0.06; transient hyperemic response ratio 1.26 ± 0.11, P = 0.009). Flow velocity increased more with the increase in blood pressure in the iICP group than in the dICP group: 19.0 ± 6.8 cm/s versus 10.2 ± 6.3 cm/s (P = 0.007). CONCLUSION:The patients who had an increase in ICP with induced hypertension had a greater degree of impairment of autoregulation and induced hypertension resulted in a greater increase in flow velocity.

Analysis of dynamic autoregulation assessed by the cuff deflation method

IntroductionDynamic testing of cerebral pressure autoregulation is more practical than static testing for critically ill patients. The process of cuff deflation is innocuous in the normal subject, but the systemic and cerebral effects of cuff deflation in severely head-injured patients have not been studied: The purposes of this study were to examine the physiological effects of cuff deflation and to study their impact on the calculation of autoregulatory index (ARI).MethodIn 24 severely head-injured patients, 388 thigh cuff deflations were analyzed. The physiological parameters were recorded before, during, and after a transient decrease in blood pressure. Autoregulation was graded by generating an ARI value from 0 to 9.ResultsMean arterial blood pressure (MAP) dropped rapidly during the first 2–3 seconds, but the nadir MAP was not reached until 8±7 seconds after the cuff deflation. MAP decreased by an average value of 19±5 mm Hg. Initially the tracings for MAP and cerebral perfusion pressure (CPP) were nearly identical, but after 30 seconds, variable increases in intracranial pressure caused some differences between the MAP and CPP curves. The difference between the ARI values calculated twice using MAP as well as CPP was zero for 70% of left-sided studies and 73% for right-sided studies and less than or equal to 1 for 93% of left- and 95% of right-sided cuff deflations.ConclusionTransient and relatively minor perturbations were detected in systemic physiology induced by dynamic testing of cerebral pressure autoregulation. Furthermore, this study confirms that the early changes in MAP and CPP after cuff deflation are nearly identical. MAP can substitute for CPP in the calculation of ARI even in the severely brain-injured patient.