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Kai Arnell, Per Enblad, Tomas Wester and Jan Sjölin

Object

There are no randomized studies comparing the efficacy of different antibiotic regimens for the treatment of cerebrospinal fluid (CSF) shunt infections, and in the studies that have been reported, efficacy data are limited. The aim of this study was therefore to report the authors' experience using a specific protocol for the management of shunt infections in children. Standard treatment included a two-stage procedure involving externalization of the ventricular catheter in combination with intraventricular and systemic administration of antibiotic medication followed by shunt replacement. Intraventricular treatment consisted of daily instillations of vancomycin or gentamicin with trough concentrations held at high levels of 7 to 17 mg/L for both antibiotic agents.

Methods

During a 13-year study period, the authors treated 34 consecutive intraventricular shunt infections in 30 children. Infections with coagulase-negative staphylococci predominated, and Gram-negative bacterial infection occurred in five children. Ten of the children were initially treated with intravenous antibiotic therapy for at least 3 days, but this treatment did not sterilize the CSF. After externalization of the ventricular catheter, high-dose intraventricular treatment was given for a median of 8 days (range 3–17 days) before shunt replacement.

Results

The CSF was found to be sterile (cultures were negative for bacteria) in one of three, seven of eight, 20 of 20, and six of six cases after 1, 2, 3, and more than 3 days' treatment, respectively. In no case was any subsequent culture positive after a negative result had been obtained. Clinical symptoms resolved in parallel with the sterilization of the CSF. There were no relapses or deaths during the 6-month follow-up period, and there have been none as of April 2007.

Conclusions

Despite the ventricular catheter being left in place and the short duration of therapy, the treatment regimen described by the authors resulted in quick sterilization of the CSF, a low relapse rate, and survival of all patients in this series.

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Lennart Persson, Johann Valtysson, Per Enblad, Per-Erik Wärme, Kristina Cesarini, Anders Lewén and Lars Hillered

✓ The authors have developed a method for routine monitoring of disturbances in brain energy metabolism and extracellular levels of excitatory amino acids using intracerebral microdialysis in 10 patients with subarachnoid hemorrhage. Microdialysis was conducted for periods ranging from 6 to 11 days after ictus. Altogether, 16,054 chemical analyses from 1647 dialysate samples were performed. Concentrations of the energy-related substances lactate, pyruvate, glucose, and hypoxanthine were measured, and the lactate/pyruvate ratio was calculated. The excitatory amino acids glutamate and aspartate were measured. The microdialysis data were matched with computerized tomography findings, clinical course, and outcome. The results support the concepts that microdialysis is a promising tool for chemical monitoring of the human brain and that extracellular fluid levels of lactate, lactate/pyruvate ratio, glucose, hypoxanthine, and glutamate are useful markers of disturbances in brain energy metabolism in neurointensive care patients. These results have generated a working hypothesis that the pattern of these extracellular markers may help differentiate between various causes of energy perturbations, such as hypoxia and different degrees of ischemia. The correlation between the dialysate levels of excitatory amino acids and outcome supports the concept of glutamate receptor overactivation in acute human brain injury.

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Maria Zetterling, Lars Hillered, Per Enblad, Torbjörn Karlsson and Elisabeth Ronne-Engström

Object

The aim in the present investigation was to study the relation between brain interstitial and systemic blood glucose concentrations during the acute phase after subarachnoid hemorrhage (SAH). The authors also evaluated the effects of insulin administration on local brain energy metabolism.

Methods

Nineteen patients with spontaneous SAH were prospectively monitored with intracerebral microdialysis (MD). The relation between plasma glucose and MD-measured interstitial brain glucose concentrations as well as the temporal pattern of MD glucose, lactate, pyruvate, glutamate, and glycerol was studied for 7 days after SAH. Using a target plasma glucose concentration of 5–10 mmol/L, the effect of insulin injection was also evaluated.

Results

The mean (± SD) correlation coefficient between plasma glucose and MD glucose was 0.27 ± 0.27 (p = 0.0005), with a high degree of individual variation. Microdialysis glucose, the MD/plasma glucose ratio, and MD glutamate concentrations decreased in parallel with a gradual increase in MD pyruvate and MD lactate concentrations. There were no significant changes in the MD L/P ratio or MD glycerol levels. Insulin administration induced a decrease in MD glucose and MD pyruvate.

Conclusions

After SAH, there was a positive correlation between plasma and MD glucose concentrations with a high degree of individual variation. A gradual decline in MD glucose and the MD/plasma glucose ratio and an increase in MD pyruvate and MD lactate concentrations during the 1st week after SAH suggest a transition to a hyperglycolytic state with increased cerebral glucose consumption. The administration of insulin was related to a lowering of MD glucose and MD pyruvate, often to low levels even though plasma glucose values remained above 6 mmol/L. After SAH, the administration of insulin could impede the glucose supply of the brain.

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Peter Frykholm, Lars Hillered, Bengt Långström, Lennart Persson, Johann Valtysson and Per Enblad

Object. Changes in lactate and glucose levels in the brain may be used to monitor a dynamic ischemic process. The authors related extracellular concentrations of glucose and lactate to regional cerebral blood flow (rCBF) and cerebral metabolic rate of oxygen (CMRO2) in a model of ischemia.

Methods. Transient (2 hours) middle cerebral artery occlusion (MCAO) was performed in eight macaque monkeys. Extracellular measurements of glucose and lactate levels using microdialysis (two probes in each brain) and sequential positron emission tomography measurements were performed during MCAO and reperfusion. Glucose and lactate levels were related to rCBF and CMRO2 as well as the pathophysiological categories of severe ischemia and penumbra.

In probe regions characterized by severe ischemia, there were significant changes in glucose and lactate levels and the lactate/glucose ratio. In probe regions distinguished by penumbra, only lactate levels increased significantly and, in general, the changes were smaller and transient. This difference between severe ischemic and penumbral regions was significant for all microdialysis parameters.

There was a significant correlation between glucose, and CBF and CMRO2. Lactate concentration was correlated with CMRO2.

Conclusions. Extracellular glucose levels might be limited by rCBF, whereas lactate levels were more related to CMRO2. Lactate concentration is a better marker of irreversible ischemia than glucose concentration, although near-zero levels of glucose during MCAO probably signals near-complete cessation of rCBF. In situations with elevated lactate levels, glucose may help to discriminate between partial and severe ischemia.

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Sami Abu Hamdeh, Niklas Marklund, Anders Lewén, Tim Howells, Raili Raininko, Johan Wikström and Per Enblad

OBJECTIVE

Increased intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI) with diffuse axonal injury (DAI) is not well defined. This study investigated the occurrence of increased ICP and whether clinical factors and lesion localization on MRI were associated with increased ICP in patients with DAI.

METHODS

Fifty-two patients with severe TBI (median age 24 years, range 9–61 years), who had undergone ICP monitoring and had DAI on MRI, as determined using T2*-weighted gradient echo, susceptibility-weighted imaging, and diffusion-weighted imaging (DWI) sequences, were enrolled. The proportion of good monitoring time (GMT) with ICP > 20 mm Hg during the first 120 hours postinjury was calculated and associations with clinical and MRI-related factors were evaluated using linear regression.

RESULTS

All patients had episodes of ICP > 20 mm Hg. The mean proportion of GMT with ICP > 20 mm Hg was 5%, and 27% of the patients (14/52) spent more than 5% of GMT with ICP > 20 mm Hg. The Glasgow Coma Scale motor score at admission (p = 0.04) and lesions on DWI sequences in the substantia nigra and mesencephalic tegmentum (SN-T, p = 0.001) were associated with the proportion of GMT with ICP > 20 mm Hg. In multivariable linear regression, lesions on DWI sequences in SN-T (8% of GMT with ICP > 20 mm Hg, 95% CI 3%–13%, p = 0.004) and young age (−0.2% of GMT with ICP > 20 mm Hg, 95% CI −0.07% to −0.3%, p = 0.002) were associated with increased ICP.

CONCLUSIONS

Increased ICP occurs in approximately one-third of patients with severe TBI who have DAI. Age and lesions on DWI sequences in the central mesencephalon (i.e., SN-T) are associated with elevated ICP. These findings suggest that MR lesion localization may aid prediction of increased ICP in patients with DAI.

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Elham Rostami, Henrik Engquist, Timothy Howells, Ulf Johnson, Elisabeth Ronne-Engström, Pelle Nilsson, Lars Hillered, Anders Lewén and Per Enblad

OBJECTIVE

Delayed cerebral ischemia (DCI) following subarachnoid hemorrhage (SAH) is one of the major contributors to poor outcome. It is crucial to be able to detect early signs of DCI to prevent its occurrence. The objective of this study was to determine if low cerebral blood flow (CBF) measurements and pathological microdialysis parameters measured at the bedside can be observed early in patients with SAH who later developed DCI.

METHODS

The authors included 30 patients with severe SAH. The CBF measurements were performed at Day 0–3 after disease onset, using bedside xenon-CT. Interstitial glucose, lactate, pyruvate, glycerol, and glutamate were measured using microdialysis.

RESULTS

Nine of 30 patients developed DCI. Patients with DCI showed significantly lower global and regional CBF, and lactate was significantly increased in these patients. A high lactate/pyruvate ratio was also detected in patients with DCI.

CONCLUSIONS

Early low CBF measurements and a high lactate and lactate/pyruvate ratio may be early warning signs of the risk of developing DCI. The clinical value of these findings needs to be confirmed in larger studies.

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Niklas Marklund, Kaj Blennow, Henrik Zetterberg, Elisabeth Ronne-Engström, Per Enblad and Lars Hillered

Object

Damage to axons contributes to postinjury disabilities and is commonly observed following traumatic brain injury (TBI). Traumatic brain injury is an important environmental risk factor for the development of Alzheimer disease (AD). In the present feasibility study, the aim was to use intracerebral microdialysis catheters with a high molecular cutoff membrane (100 kD) to harvest interstitial total tau (T-tau) and amyloid beta 1–42 (Aβ42) proteins, which are important biomarkers for axonal injury and for AD, following moderate-to-severe TBI.

Methods

Eight patients (5 men and 3 women) were included in the study; 5 of the patients had a focal/mixed TBI and 3 had a diffuse axonal injury (DAI). Following the bedside analysis of the routinely measured energy metabolic markers (that is, glucose, lactate/pyruvate ratio, glycerol, and glutamate), the remaining dialysate was pooled and two 12-hour samples per day were used to analyze T-tau and Aβ42 by enzyme-linked immunosorbent assay from Day 1 up to 8 days postinjury.

Results

The results show high levels of interstitial T-tau and Aβ42 postinjury. Patients with a predominantly focal lesion had higher interstitial T-tau levels than in the DAI group from Days 1 to 3 postinjury (p < 0.05). In contrast, patients with DAI had consistently higher Aβ42 levels when compared with patients with focal injury.

Conclusions

These results suggest that monitoring of interstitial T-tau and Aβ42 by using microdialysis may be an important tool when evaluating the presence and role of axonal injury following TBI.

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Alan Hoffer and Warren R. Selman

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Carolina Samuelsson, Timothy Howells, Eva Kumlien, Per Enblad, Lars Hillered and Elisabeth Ronne-Engström

Object

The aim of this study was to explore the relationship between hemodynamics (intracranial and systemic) and brain tissue energy metabolism, and between hemodynamics and glutamate (Glt)-glutamine (Gln) cycle activity.

Methods

Brain interstitial levels of lactate, pyruvate, Glt, and Gln were prospectively monitored in the neurointensive care unit for more than 3600 hours using intracerebral microdialysis in 33 patients with subarachnoid hemorrhage (SAH). Intracranial pressure (ICP), mean arterial blood pressure, and cerebral perfusion pressure (CPP) were recorded using a digitalized system.

Results

Interstitial Gln and pyruvate correlated with CPP (r = 0.25 and 0.24, respectively). Intracranial pressure negatively correlated with Gln (r = −0.29) and the Gln/Glt ratio (r = –0.40). Levels of Gln and pyruvate and the Gln/Glt ratio were higher and levels of Glt and lactate and the lactate/pyruvate ratio were lower during periods of decreased ICP (≤ 10 mm Hg) as compared with values in periods of elevated ICP (> 10 mm Hg). In 3 patients, a poor clinical condition was attributed to high ICP levels (range 15–25 mm Hg). When CSF drainage was increased and the ICP was lowered to 10 mm Hg, there was an instantaneous sharp increase in interstitial Glt and pyruvate in these 3 patients.

Conclusions

Increasing interstitial Gln and pyruvate levels appear to be favorable signs associated with improved CPP and low ICP. The authors suggest that this pattern indicates an energy metabolic situation allowing augmented astrocytic energy metabolism with accelerated Glt uptake and Gln synthesis. Moreover, their data raised the question of whether patients with SAH and moderately elevated ICP (15–20 mm Hg) would benefit from CSF drainage at lower pressure levels than what is usually indicated in current clinical protocols.