Differential proteomic profile of lumbar and ventricular cerebrospinal fluid.

BACKGROUND: Pathological cerebral conditions may manifest in altered composition of the cerebrospinal fluid (CSF). Although diagnostic CSF analysis seeks to establish pathological disturbances in the brain proper, CSF is generally sampled from the lumbar compartment for reasons of technical ease and ethical considerations. We here aimed to compare the molecular composition of CSF obtained from the ventricular versus the lumbar CSF compartments to establish a relevance for employing lumbar CSF as a proxy for the CSF bathing the brain tissue. METHODS: CSF was collected from 46 patients with idiopathic normal pressure hydrocephalus (iNPH) patients during their diagnostic workup (lumbar samples) and in connection with their subsequent CSF diversion shunt surgery (ventricular samples). The mass-spectrometry-based proteomic profile was determined in these samples and in addition, selected biomarkers were quantified with ELISA (S100B, neurofilament light (NfL), amyloid-ß (Aß40, Aß42), and total tau (T-tau) and phosphorylated tau (P-tau) forms). The latter analysis was extended to include paired porcine samples obtained from the lumbar compartment and the cerebromedullary cistern closely related to the ventricles. RESULTS: In total 1231 proteins were detected in the human CSF. Of these, 216 distributed equally in the two CSF compartments, whereas 22 were preferentially (or solely) present in the ventricular CSF and four in the lumbar CSF. The selected biomarkers of neurodegeneration and Alzheimer's disease displayed differential distribution, some with higher (S100B, T-tau, and P-tau) and some with lower (NfL, Aß40, Aß42) levels in the ventricular compartment. In the porcine samples, all biomarkers were most abundant in the lumbar CSF. CONCLUSIONS: The overall proteomic profile differs between the ventricular and the lumbar CSF compartments, and so does the distribution of clinically employed biomarkers. However, for a range of CSF proteins and biomarkers, one can reliably employ lumbar CSF as a proxy for ventricular CSF if or a lumbar/cranial index for the particular molecule has been established. It is therefore important to verify the compartmental preference of the proteins or biomarkers of interest prior to extrapolating from lumbar CSF to that of the ventricular fluid bordering the brain.

Cerebrospinal fluid osmolality cannot predict development or surgical outcome of idiopathic normal pressure hydrocephalus.

BACKGROUND: The etiology of idiopathic normal pressure hydrocephalus (iNPH) is currently unknown. With no visible obstructions, altered cerebrospinal fluid (CSF) dynamics may explain the accumulation of ventricular fluid. We hypothesized that elevated osmolality in the CSF of iNPH patients could potentiate formation of ventricular fluid and thereby cause the disease progression and/or predict the surgical outcome. To address this hypothesis, we determined the lumbar and ventricular CSF osmolality of iNPH patients at different disease stages and compared with lumbar CSF samples obtained from control subjects. METHODS: The osmolality of CSF was determined on a total of 35 iNPH patients at diagnosis and at the subsequent treatment with shunt surgery (n = 20) and compared with the CSF osmolality from 20 control subjects. Simultaneously collected lumbar and ventricular CSF samples from experimental pigs were used to evaluate the compatibility between CSF from different compartments. RESULTS: We found no evidence of increased osmolality in the CSF of iNPH patients upon diagnosis or at the time of shunt treatment months after the diagnosis, compared with control individuals. CSF tapped from the lumbar space could be used as a read-out for ventricular CSF osmolality, as these were similar in both the patient group and in experimental pigs. We further observed no correlation between the CSF osmolality in iNPH patients and their responsiveness to shunt surgeries. CONCLUSIONS: The osmolality of lumbar CSF is a reliable reflection of the ventricular CSF osmolality, and is not elevated in iNPH patients. iNPH therefore does not appear to arise as a function of osmotic imbalances in the CSF system and CSF osmolality cannot serve as a biomarker for iNPH or as a predictive tool for shunt responsiveness.

Validating an empiric sulfadiazine-trimethoprim dosage regimen for treatment of Escherichia coli and Staphylococcus delphini infections in mink (Neovison vison).

Antimicrobial agents are used extensively off-label in mink, as almost no agents are registered for this animal species. Pharmacokinetic (PK) and pharmacodynamic (PD) data are required to determine antimicrobial dosages specifically targeting mink bacterial pathogens. The aims of this study were to assess, in a PKPD framework, the empirical dosage regimen for a combination of trimethoprim (TMP) and sulfadiazine (SDZ) in mink, and secondarily to produce data for future setting of clinical breakpoints. TMP and SDZ PK parameters were obtained experimentally in 22 minks following IV or oral administration of TMP/SDZ (30 mg/kg, i.e. 5 mg/kg TMP and 25 mg/kg SDZ). fAUC/MIC with a target value of 24 hr was selected as the PKPD index predictive of TMP/SDZ efficacy. Using a modeling approach, PKPD cutoffs for TMP and SDZ were determined as 0.062 and 16 mg/L, respectively. By incorporating an anticipated potentiation effect of SDZ on TMP against Escherichia coli and Staphylococcus delphini, the PKPD cutoff of TMP was revised to 0.312 mg/L, which is above the tentative epidemiological cutoffs (TECOFF) for these species. The current empirical TMP/SDZ dosage regimen (30 mg/kg, PO, once daily) therefore appears adequate for treatment of wild-type E. coli and S. delphini infections in mink.

Kinetic gait analysis in healthy dogs and dogs with osteoarthritis: An evaluation of precision and overlap performance of a pressure-sensitive walkway and the use of symmetry indices.

In veterinary practice, a thorough gait examination is essential in the clinical workup of any orthopedic patient, including the large population of dogs with chronic pain as a result of osteoarthritis. The traditional visual gait examination is, however, a subjective discipline, and systems for kinetic gait analysis may potentially offer an objective alternative for gait assessment by the measurement of ground reaction forces. In order to avoid unnecessary testing of patients, a thorough, stepwise evaluation of the diagnostic performance of each system is recommended before clinical use for diagnostic purposes. The aim of the study was to evaluate the Tekscan pressure-sensitive walkway system by assessing precision (agreement between repetitive measurements in individual dogs) and overlap performance (the ability to distinguish dogs with lameness due to osteoarthritis from clinically healthy dogs). Direction of travel over the walkway was investigated as a possible bias. Symmetry indices are commonly used to assess lameness by comparing ground reaction forces across different combinations of limbs in each dog. However, SIs can be calculated in several different ways and specific recommendations for optimal use of individual indices are currently lacking. Therefore the present study also compared indices in order to recommend a specific index preferable for future studies of canine osteoarthritis. Forty-one clinically healthy dogs and 21 dogs with osteoarthritis were included in the study. High precision was demonstrated. The direction of travel over the walkway was excluded as a possible bias. A significant overlap was observed when comparing ground reaction forces measured in dogs with osteoarthritis compared to clinically healthy dogs. In some affected dogs, symmetry indices comparing contralateral limbs differed from clinically healthy dogs, but in general, the overlap performance was insufficient and, consequently, general use of this method for diagnostic purposes in dogs with osteoarthritis cannot be recommended.

The influence of norepinephrine and phenylephrine on cerebral perfusion and oxygenation during propofol-remifentanil and propofol-remifentanil-dexmedetomidine anaesthesia in piglets.

BACKGROUND: Vasopressors are frequently used to increase blood pressure in order to ensure sufficient cerebral perfusion and oxygenation (CPO) during hypotensive periods in anaesthetized patients. Efficacy depends both on the vasopressor and anaesthetic protocol used. Propofol-remifentanil total intravenous anaesthesia (TIVA) is common in human anaesthesia, and dexmedetomidine is increasingly used as adjuvant to facilitate better haemodynamic stability and analgesia. Little is known of its interaction with vasopressors and subsequent effects on CPO. This study investigates the CPO response to infusions of norepinephrine and phenylephrine in piglets during propofol-remifentanil and propofol-remifentanil-dexmedetomidine anaesthesia. Sixteen healthy female piglets (25-34 kg) were randomly allocated into a two-arm parallel group design with either normal blood pressure (NBP) or induced low blood pressure (LBP). Anaesthesia was induced with propofol without premedication and maintained with propofol-remifentanil TIVA, and finally supplemented with continuous infusion of dexmedetomidine. Norepinephrine and phenylephrine were infused in consecutive intervention periods before and after addition of dexmedetomidine. Cerebral perfusion measured by laser speckle contrast imaging was related to cerebral oxygenation as measured by an intracerebral Licox probe (partial pressure of oxygen) and transcranial near infrared spectroscopy technology (NIRS) (cerebral oxygen saturation). RESULTS: During propofol-remifentanil anaesthesia, increases in blood pressure by norepinephrine and phenylephrine did not change cerebral perfusion significantly, but cerebral partial pressure of oxygen (Licox) increased following vasopressors in both groups and increases following norepinephrine were significant (NBP: P = 0.04, LBP: P = 0.02). In contrast, cerebral oxygen saturation (NIRS) fell significantly in NBP following phenylephrine (P = 0.003), and following both norepinephrine (P = 0.02) and phenylephrine (P = 0.002) in LBP. Blood pressure increase by both norepinephrine and phenylephrine during propofol-remifentanil-dexmedetomidine anaesthesia was not followed by significant changes in cerebral perfusion. Licox measures increased significantly following both vasopressors in both groups, whereas the decreases in NIRS measures were only significant in the NBP group. CONCLUSIONS: Cerebral partial pressure of oxygen measured by Licox increased significantly in concert with the vasopressor induced increases in blood pressure in healthy piglets with both normal and low blood pressure. Cerebral oxygenation assessed by intracerebral Licox and transcranial NIRS showed opposing results to vasopressor infusions.

The effect of dexmedetomidine on cerebral perfusion and oxygenation in healthy piglets with normal and lowered blood pressure anaesthetized with propofol-remifentanil total intravenous anaesthesia.

BACKGROUND: During anaesthesia and surgery, in particular neurosurgery, preservation of cerebral perfusion and oxygenation (CPO) is essential for normal postoperative brain function. The isolated effects on CPO of either individual anaesthetic drugs or entire anaesthetic protocols are of importance in both clinical and research settings. Total intravenous anaesthesia (TIVA) with propofol and remifentanil is widely used in human neuroanaesthesia. In addition, dexmedetomidine is receiving increasing attention as an anaesthetic adjuvant in neurosurgical, intensive care, and paediatric patients. Despite the extensive use of pigs as animal models in neuroscience and the increasing use of both propofol-remifentanil and dexmedetomidine, very little is known about their combined effect on CPO in pigs with uninjured brains. This study investigates the effect of dexmedetomidine on CPO in piglets with normal and lowered blood pressure during background anaesthesia with propofol-remifentanil TIVA. Sixteen healthy female Danish pigs (crossbreeds of Danish Landrace, Yorkshire and Duroc, 25-34 kg) were used. Three animals were subsequently excluded. The animals were randomly allocated into one of two groups with either normal blood pressure (NBP, n = 6) or with induced low blood pressure (LBP, n = 7). Both groups were subjected to the same experimental protocol. Intravenous propofol induction was performed without premedication. Anaesthesia was maintained with propofol-remifentanil TIVA, and later supplemented with continuous infusion of dexmedetomidine. Assessments of cerebral perfusion obtained by laser speckle contrast imaging (LSCI) were related to cerebral oxygenation measures (PbrO2) obtained by an intracerebral Clark-type Licox probe. RESULTS: Addition of dexmedetomidine resulted in a 32% reduction in median PbrO2 values for the LBP group (P = 0.03), but no significant changes in PbrO2 were observed for the NBP group. No significant changes in LSCI readings were observed in either group between any time points, despite a 28% decrease in the LBP group following dexmedetomidine administration. Caval block resulted in a significant (P = 0.02) reduction in median MAP from 68 mmHg (range 63-85) at PCB to 58 mmHg (range 53-63) in the LBP group, but no significant differences in either PbrO2 or LSCI were observed due to this intervention (P = 0.6 and P = 0.3 respectively). CONCLUSIONS: Addition of dexmedetomidine to propofol-remifentanil TIVA resulted in a significant decrease in cerebral oxygenation (PbrO2) measurements in piglets with lowered blood pressure. Cerebral perfusion (LSCI) did not decrease significantly in this group. In piglets with normal blood pressure, no significant changes in cerebral perfusion or oxygenation were seen in response to addition of dexmedetomidine to the background anaesthesia.

Effect of propofol and remifentanil on cerebral perfusion and oxygenation in pigs: a systematic review.

The objective of this review is to evaluate the existing literature with regard to the influence of propofol and remifentanil total intravenous anaesthesia (TIVA) on cerebral perfusion and oxygenation in healthy pigs. Anaesthesia has influence on cerebral haemodynamics and it is important not only in human but also in veterinary anaesthesia to preserve optimal regulation of cerebral haemodynamics. Propofol and remifentanil are widely used in neuroanaesthesia and are increasingly used in experimental animal studies. In translational models, the pig has advantages compared to small laboratory animals because of brain anatomy, metabolism, neurophysiological maturation, and cerebral haemodynamics. However, reported effects of propofol and remifentanil on cerebral perfusion and oxygenation in pigs have not been reviewed. An electronic search identified 99 articles in English. Title and abstract screening selected 29 articles for full-text evaluation of which 19 were excluded with reasons. Of the 10 peer-reviewed articles included for review, only three had propofol or remifentanil anaesthesia as the primary study objective and only two directly investigated the effect of anaesthesia on cerebral perfusion and oxygenation (CPO). The evidence evaluated in this systematic review is limited, not focused on propofol and remifentanil and possibly influenced by factors of potential importance for CPO assessment. In one study of healthy pigs, CPO measures were within normal ranges following propofol-remifentanil anaesthesia, and addition of a single remifentanil bolus did not affect regional cerebral oxygen saturation (rSO2). Even though the pool of evidence suggests that propofol and remifentanil alone or in combination have limited effects on CPO in healthy pigs, confirmative evidence is lacking.