Online correlation of spontaneous arterial and intracranial pressure fluctuations in patients with diffuse severe head injury

Determination of relevant clinical monitoring parameters for helping guide the intensive care therapy in patients with severe head injury, is one of the most demanding issues in neurotrauma research. New insights into cerebral autoregulation and metabolism have revealed that a rigid cerebral perfusion pressure (CPP) regimen might not be suitable for all severe head injured patients. We thus developed an online analysis technique to monitor the correlation (AI rho) between the spontaneous fluctuations of the mean arterial blood pressure (MABP) and the intracranial pressure (ICP). In addition, brain tissue oxygen (PtiO2) and metabolic microdialysate measures including glucose and lactate were registered. We found that in patients with good outcome, the AI rho values were significantly lower as compared with patients with poor outcome. Accordingly, microdialysate glucose and lactate were significantly higher in the good outcome group. We conclude that online determination of AI rho offers a valuable additional and technically easily performable tool for guidance of therapy in patients with severe head injury.

Brain edema and increased intracranial pressure in the pathophysiology of bacterial meningitis

A number of advances in our understanding of the pathophysiology of bacterial meningitis have been made in recent years. In vivo studies have shown that bacterial cell wall fragments and endotoxins are highly active components, independent of the presence of viable bacteria in the subarachnoid space. Their presence in the cerebrospinal fluid is associated with the induction of inflammation and with the development of brain edema and increased intracranial pressure. Antimicrobial therapy may cause an additional increase of harmful bacterial products in the cerebrospinal fluid and thereby potentiate these pathophysiological alterations. These changes may contribute to the development of brain damage during meningitis. Some promising experimental work has been directed toward counteracting the above phenomena with non-steroidal or steroidal anti-inflammatory agents as well as with monoclonal antibodies. Although considerable advances have been made, further research needs to be done in these areas to improve the prognosis of bacterial meningitis.

Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal fluid concentrations of lactate and protein in experimental meningitis

Brain water content (brain edema), intracranial pressure, and cerebrospinal fluid (CSF) concentrations of lactate and protein increased significantly during 24 h of experimental meningitis due to Streptococcus pneumoniae, but changes were similar in normal and neutropenic rabbits. In sterile meningitis induced by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP), low and high doses of fMLP were equally effective in inducing CSF pleocytosis, whereas only high doses of fMLP caused brain edema. High doses of fMLP injected intracisternally during pneumococcal meningitis also increased brain water content. The fMLP did not significantly increase intracranial pressure or CSF concentrations of lactate or protein in sterile or pneumococcal meningitis, nor did it cause brain edema in neutropenic animals. Thus, granulocytes may contribute to brain edema during meningitis if adequately stimulated, but intracranial pressure and CSF protein and lactate concentrations appear independent of granulocytes. Stimulation does not appear to occur early in meningitis, when granulocytes were without effect on brain edema.

Normobaric hyperoxia--induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study

OBJECT: The effect of normobaric hyperoxia (fraction of inspired O2 [FIO2] concentration 100%) in the treatment of patients with traumatic brain injury (TBI) remains controversial. The aim of this study was to investigate the effects of normobaric hyperoxia on five cerebral metabolic indices, which have putative prognostic significance following TBI in humans. METHODS: At two independent neurointensive care units, the authors performed a prospective study of 52 patients with severe TBI who were treated for 24 hours with 100% FIO2, starting within 6 hours of admission. Data for these patients were compared with data for a cohort of 112 patients who were treated in the past; patients in the historical control group matched the patients in our study according to their Glasgow Coma Scale scores after resuscitation and their intracranial pressure within the first 8 hours after admission. Patients were monitored with the aid of intracerebral microdialysis and tissue O2 probes. Normobaric hyperoxia treatment resulted in a significant improvement in biochemical markers in the brain compared with the baseline measures for patients treated in our study (patients acting as their own controls) and also compared with findings from the historical control group. In the dialysate the glucose levels increased (369.02 +/- 20.1 micromol/L in the control group and 466.9 +/- 20.39 micromol/L in the 100% O2 group, p = 0.001), whereas the glutamate and lactate levels significantly decreased (p < 0.005). There were also reductions in the lactate/glucose and lactate/pyruvate ratios. Intracranial pressure in the treatment group was reduced significantly both during and after hyperoxia treatment compared with the control groups (15.03 +/- 0.8 mm Hg in the control group and 12.13 +/- 0.75 mm Hg in the 100% O2 group, p < 0.005) with no changes in cerebral perfusion pressure. Outcomes of the patients in the treatment group improved. CONCLUSIONS: The results of the study support the hypothesis that normobaric hyperoxia in patients with severe TBI improves the indices of brain oxidative metabolism. Based on these data further mechanistic studies and a prospective randomized controlled trial are warranted.

High level of extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure

OBJECT: Disturbed ionic and neurotransmitter homeostasis are now recognized as probably the most important mechanisms contributing to the development of secondary brain swelling after traumatic brain injury (TBI). Evidence obtained in animal models indicates that posttraumatic neuronal excitation by excitatory amino acids leads to an increase in extracellular potassium, probably due to ion channel activation. The purpose of this study was therefore to measure dialysate potassium in severely head injured patients and to correlate these results with measurements of intracranial pressure (ICP), patient outcome, and levels of dialysate glutamate and lactate, and cerebral blood flow (CBF) to determine the role of ischemia in this posttraumatic ion dysfunction. METHODS: Eighty-five patients with severe TBI (Glasgow Coma Scale Score < 8) were treated according to an intensive ICP management-focused protocol. All patients underwent intracerebral microdialyis. Dialysate potassium levels were analyzed using flame photometry, and dialysate glutamate and dialysate lactate levels were measured using high-performance liquid chromatography and an enzyme-linked amperometric method in 72 and 84 patients, respectively. Cerebral blood flow studies (stable xenon computerized tomography scanning) were performed in 59 patients. In approximately 20% of the patients, dialysate potassium values were increased (dialysate potassium > 1.8 mM) for 3 hours or more. A mean amount of dialysate potassium greater than 2 mM throughout the entire monitoring period was associated with ICP above 30 mm Hg and fatal outcome, as were progressively rising levels of dialysate potassium. The presence of dialysate potassium correlated positively with dialysate glutamate (p < 0.0001) and lactate (p < 0.0001) levels. Dialysate potassium was significantly inversely correlated with reduced CBF (p = 0.019). CONCLUSIONS: Dialysate potassium was increased after TBI in 20% of measurements. High levels of dialysate potassium were associated with increased ICP and poor outcome. The simultaneous increase in dialysate potassium, together with dialysate glutamate and lactate, supports the concept that glutamate induces ionic flux and consequently increases ICP, which the authors speculate may be due to astrocytic swelling. Reduced CBF was also significantly correlated with increased levels of dialysate potassium. This may be due to either cell swelling or altered vasoreactivity in cerebral blood vessels caused by higher levels of potassium after trauma. Additional studies in which potassium-sensitive microelectrodes are used are needed to validate these ionic events more clearly.

Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure

Early impaired cerebral blood flow (CBF) after severe head injury (SHI) leads to poor brain tissue oxygen delivery and lactate accumulation. The purpose of this investigation was to elucidate the relationship between CBF, local dialysate lactate (lact(md)) and dialysate glucose (gluc(md)), and brain tissue oxygen levels (PtiO2) under arterial normoxia. The effect of increased brain tissue oxygenation due to high fractions of inspired oxygen (FiO2) on lact(md) and CBF was explored. A total of 47 patients with SHI were enrolled in this studies (Glasgow Coma Score [GCS] < 8). CBF was first assessed in 40 patients at one time point in the first 96 hours (27 +/- 28 hours) after SHI using stable xenon computed tomography (Xe-CT) (30% inspired xenon [FiXe] and 35% FiO2). In a second study, sequential double CBF measurements were performed in 7 patients with 35% FiO2 and 60% FiO2, respectively, with an interval of 30 minutes. In a subsequent study, 14 patients underwent normobaric hyperoxia by increasing FiO2 from 35 +/- 5% to 60% and then 100% over a period of 6 hours. This was done to test the effect of normobaric hyperoxia on lact(md) and brain gluc(md), as measured by local microdialysis. Changes in PtiO2 in response to changes in FiO2 were analyzed by calculating the oxygen reactivity. Oxygen reactivity was then related to the 3-month outcome data. The levels of lact(md) and gluc(md) under hyperoxia were compared with the baseline levels, measured at 35% FiO2. Under normoxic conditions, there was a significant correlation between CBF and PtiO2 (R = 0.7; P < .001). In the sequential double CBF study, however, FiO2 was inversely correlated with CBF (P < .05). In the 14 patients undergoing the 6-hour 100% FiO2 challenge, the mean PtiO2 levels increased to 353 (87% compared with baseline), although the mean lact(md) levels decreased by 38 +/- 16% (P < .05). The PtiO2 response to 100% FiO2 (oxygen reactivity) was inversely correlated with outcome (P < .01). Monitoring PtiO2 after SHI provides valuable information about cerebral oxygenation and substrate delivery. Increasing arterial oxygen tension (PaO2) effectively increased PtiO2, and brain lact(md) was reduced by the same maneuver.

High extracellular potassium and its correlates after severe head injury: relationship to high intracranial pressure

Disturbed ionic and neurotransmitter homeostasis are now recognized to be probably the most important mechanisms contributing to the development of secondary brain swelling after traumatic brian injury (TBI). Evidence obtained from animal models indicates that posttraumatic neuronal excitation via excitatory amino acids leads to an increase in extracellular potassium, probably due to ion channel activation. The purpose of this study was therefore to measure dialysate potassium in severely head injured patients and to correlate these results with intracranial pressure (ICP), outcome, and also with the levels of dialysate glutamate, lactate, and cerebral blood flow (CBF) so as to determine the role of ischemia in this posttraumatic ionic dysfunction. Eighty-five patients with severe TBI (Glasgow Coma Scale score < 8) were treated according to an intensive ICP management-focused protocol. All patients underwent intracerebral microdialyis. Dialysate potassium levels were analyzed by flame photometry, as were dialysate glutamate and dialysate lactate levels, which were measured using high-performance liquid chromatography and an enzyme-linked amperometric method in 72 and 84 patients respectively. Cerebral blood flow studies (stable Xenon--computerized tomography scanning) were performed in 59 patients. In approximately 20% of the patients, potassium values were increased (dialysate potassium > 1.8 mmol). Mean dialysate potassium (> 2 mmol) was associated with ICP above 30 mm Hg and fatal outcome. Dialysate potassium correlated positively with dialysate glutamate (p < 0.0001) and lactate levels (p < 0.0001). Dialysate potassium was significantly inversely correlated with reduced CBF (p = 0.019). Dialysate potassium was increased after TBI in 20% of measurements. High levels of dialysate potassium were associated with increased ICP and poor outcome. The simultaneous increase of potassium, together with dialysate glutamate and lactate, supports the hypothesis that glutamate induces ionic flux and consequently increases ICP due to astrocytic swelling. Reduced CBF was also significantly correlated with increased levels of dialysate potassium. This may be due to either cell swelling or altered potassium reactivity in cerebral blood vessels after trauma.

Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury.

BACKGROUND: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology. METHODS: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS RESULTS: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >or= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained 128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained CONCLUSIONS: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI.

Magnetic resonance imaging signs of presumed elevated intracranial pressure in dogs.

The aim of this study was to describe magnetic resonance imaging (MRI) findings associated with presumed elevated intracranial pressure (ICP) in dogs and to evaluate whether MRI could be used to discriminate between dogs with and without elevated ICP. Of 91 dogs that underwent cranial MRI examination, 18 (19.8%) were diagnosed with elevated ICP based on neurological examination, fundoscopy and transcranial Doppler ultrasonography. The MRI findings that showed the strongest association with elevated ICP were mass effect (odds ratio [OR], 78.5), caudal transtentorial herniation (OR, 72.0), subfalcine herniation (OR, 45.6), perilesional oedema (OR, 34.0), displacement of the lamina quadrigemina (OR, 27.7) and effacement of the cerebral sulci (OR, 27.1). The presence of any two or more of the following MRI findings identified elevated ICP with a sensitivity of 72% and a specificity of 96%: compression of the suprapineal recess, compression of the third ventricle, compression of the fourth ventricle, effacement of the cerebral sulci and caudal transposition of the lamina quadrigemina. In conclusion, there is an association between MRI findings and elevated ICP in dogs; therefore, MRI might be useful to discriminate between dogs with and without elevated ICP.

Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model?

Background Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia. Methods Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher’s exact test, repeated measurements were assessed with the Friedman’s test; the baseline values were tested using Mann–Whitney U test and the difference of results of repeated measures were compared. Results In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold. Conclusion In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

The Effect of Increasing Intracranial Pressure on Ocular Vestibular-Evoked Myogenic Potential Frequency Tuning.

OBJECTIVE Ocular vestibular-evoked myogenic potentials (oVEMPs) represent extraocular muscle activity in response to vestibular stimulation. The authors sought to investigate whether posture-induced increase of the intracranial pressure (ICP) modulated oVEMP frequency tuning, that is, the amplitude ratio between 500-Hz and 1000-Hz stimuli. DESIGN Ten healthy subjects were enrolled in this study. The subjects were positioned in the horizontal plane (0 degree) and in a 30-degree head-downwards position to elevate the ICP. In both positions, oVEMPs were recorded using 500-Hz and 1000-Hz air-conducted tone bursts. RESULTS When tilting the subject from the horizontal plane to the 30-degree head-down position, oVEMP amplitudes in response to 500-Hz tone bursts distinctly decreased (3.40 μV versus 2.06 μV; p < 0.001), whereas amplitudes to 1000 Hz were only slightly diminished (2.74 μV versus 2.48 μV; p = 0.251). Correspondingly, the 500/1000-Hz amplitude ratio significantly decreased when tilting the subjects from 0- to 30-degree inclination (1.59 versus 1.05; p = 0.029). Latencies were not modulated by head-down position. CONCLUSIONS Increasing ICP systematically alters oVEMPs in terms of absolute amplitudes and frequency tuning characteristics. oVEMPs are therefore in principle suited for noninvasive ICP monitoring.

Desempenho Manual do Membro Superior Ipsilesional em Indivíduos com Acidente Vascular Encefálico

Introdução: nos pacientes que sofreram um Acidente Vascular Encefálico são incididos programas de reabilitação que visam principalmente o hemicorpo contralesional, negligenciando o lado ipsilesional. Porém, estão descritas alterações sensitivas e motoras do membro superior ipsilesional neste grupo populacional. Objetivo: avaliar os défices de sensibilidade, destreza grossa e fina e força de preensão da mão ipsilesional em indivíduos com diagnóstico de Acidente Vascular Encefálico, comparando o sexo, o hemisfério cerebral onde se localiza a lesão, a fase aguda e crónica, tendo como referência um grupo controlo. Metodologia: este estudo observacional de carácter analítico transversal foi constituído por 34 indivíduos em que 18 deles tem diagnóstico de Acidente Vascular Encefálico e 16 sem défices neurológicos. A avaliação foi iniciada com um questionário para recolha de informações dos participantes e de seguida foram aplicados instrumentos de avaliação num só momento com o mesmo examinador. Para avaliar a sensibilidade foi usado o Moving Touch-Pressure Test, para a força o Dinamómetro Baseline®, na avaliação da destreza grossa o Teste Caixa e Blocos e por fim a destreza fina com o Purdue Pegboard Test. Estatisticamente recorreu-se ao teste T-student para amostras independentes com nível de significância de 0,05. Resultados: verificou-se que o membro superior ipsilesional dos indivíduos que sofreram um AVE apresenta um défice na força de preensão manual com nível se significância de p=0,001, e de p=0,000 para a destreza fina e grossa e sensibilidade, quando comparados com um grupo controlo. Constatou-se também que no grupo de indivíduos com diagnóstico de Acidente Vascular Encefálico, o sexo masculino obteve melhores resultados em todos os parâmetros avaliados. Observou-se ainda que tanto os homens como as mulheres após sofrerem um Acidente Vascular Encefálico apresentam défices funcionais na mão ipsilesional, mas no entanto os homens apresentam apenas alterações na destreza grossa (p=0,017) e na força (p=0,001). Na comparação dos hemisférios cerebrais lesados e das fases aguda e crónica do AVE verificou-se que não houve diferenças significativas. Conclusão: Existem défices no membro superior ipsilesional após Acidente Vascular Encefálico, sendo então pertinente a sua inclusão em programas de reabilitação, podendo assim melhorar a qualidade de vida dos indivíduos com esta patologia.

L-ornithine phenylacetate attenuates increased arterial and extracellular brain ammonia and prevents intracranial hypertension in pigs with acute liver failure.

Hyperammonemia is a feature of acute liver failure (ALF), which is associated with increased intracranial pressure (ICP) and brain herniation. We hypothesized that a combination of L-ornithine and phenylacetate (OP) would synergistically reduce toxic levels of ammonia by (1) L-ornithine increasing glutamine production (ammonia removal) through muscle glutamine synthetase and (2) phenylacetate conjugating with the ornithine-derived glutamine to form phenylacetylglutamine, which is excreted into the urine. The aims of this study were to determine the effect of OP on arterial and extracellular brain ammonia concentrations as well as ICP in pigs with ALF (induced by liver devascularization). ALF pigs were treated with OP (L-ornithine 0.07 g/kg/hour intravenously; phenylbutyrate, prodrug for phenylacetate; 0.05 g/kg/hour intraduodenally) for 8 hours following ALF induction. ICP was monitored throughout, and arterial and extracellular brain ammonia were measured along with phenylacetylglutamine in the urine. Compared with ALF + saline pigs, treatment with OP significantly attenuated concentrations of arterial ammonia (589.6 +/- 56.7 versus 365.2 +/- 60.4 mumol/L [mean +/- SEM], P= 0.002) and extracellular brain ammonia (P= 0.01). The ALF-induced increase in ICP was prevented in ALF + OP-treated pigs (18.3 +/- 1.3 mmHg in ALF + saline versus 10.3 +/- 1.1 mmHg in ALF + OP-treated pigs;P= 0.001). The value of ICP significantly correlated with the concentration of extracellular brain ammonia (r(2) = 0.36,P< 0.001). Urine phenylacetylglutamine levels increased to 4.9 +/- 0.6 micromol/L in ALF + OP-treated pigs versus 0.5 +/- 0.04 micromol/L in ALF + saline-treated pigs (P< 0.001).Conclusion:L-Ornithine and phenylacetate act synergistically to successfully attenuate increases in arterial ammonia, which is accompanied by a significant decrease in extracellular brain ammonia and prevention of intracranial hypertension in pigs with ALF.