Pain management after robot-assisted minimally invasive esophagectomy.

Background: Adequate pain control after open esophagectomy is associated with reduced complications, earlier recovery and higher patient satisfaction. While further developing surgical procedures like robot-assisted minimally invasive esophagectomy (RAMIE) it is relevant to adapt postoperative pain management. The primary question of this observational survey was whether one of the two standard treatments, thoracic epidural analgesia (TEA) or intravenous patient-controlled analgesia (PCA), is superior for pain control after RAMIE as the optimal pain management for these patients still remains unclear. Use of additional analgesics, changes in forced expiratory volume in 1 s (FEV1), postoperative complications and duration of intensive care and hospital stay were also analyzed. Methods: This prospective observational pilot study analyzed 50 patients undergoing RAMIE (postoperative PCA with piritramide or TEA using bupivacaine; each n = 25). Patient reported pain using the numeric rating scale score and differences in FEV1 using a micro spirometer were measured at postoperative day 1, 3 and 7. Additional data of secondary endpoints were collected from patient charts. Results: Key demographics, comorbidity, clinical and operative variables were equivalently distributed. Patients receiving TEA had lower pain scores and a longer-lasting pain relief. Moreover, TEA was an independent predictive variable for reduced length of hospital stay (HR -3.560 (95% CI: -6.838 to -0.282), p = 0.034). Conclusions: Although RAMIE leads to reduced surgical trauma, a less invasive pain therapy with PCA appears to be inferior compared to TEA in case of sufficient postoperative analgesia and length of hospital stay. According to the results of this observational pilot study analgesia with TEA provided better and longer-lasting pain relief compared to PCA. Further randomized controlled trials should be conducted to evaluate the optimal postoperative analgesic treatment for RAMIE.

Big data: Airway management at a university hospital over 16 years; a retrospective analysis.

PURPOSE: Little is known about the current practice of airway management in Germany and its development over the last decades. The present study was, therefore, designed to answer the following questions. Which airway management procedures have been performed over the last 16 years and how has the frequency of these procedures changed over time? Is there a relationship between patient characteristics or surgical specialisation and the type of airway management performed? METHODS: In the present study, we used our in-house data acquisition and accounting system to retrospectively analyse airway management data for all patients who underwent a surgical or medical procedure with anaesthesiological care at our tertiary care facility over the past 16 years. 340,748 airway management procedures were analysed by type of procedure, medical/surgical specialty, and type of device used. Logistic regression was used to identify trends over time. RESULTS: Oral intubation was the most common technique over 16 years (65.7%), followed by supraglottic airway devices (18.1%), nasal intubation (7.5%), mask ventilation (1.6%), tracheal cannula (1.3%), double lumen tube (0.7%), and jet ventilation (0.6%). On average, the odds ratio of using supraglottic airway devices increased by 17.0% per year (OR per year = 1.072, 95% CI = 1.071-1.088) while oral intubation rates decreased. In 2005, supraglottic airway devices were used in about 10% of all airway management procedures. Until 2020, this proportion steadily increased by 27%. Frequency of oral intubation on the other hand decreased and was about 75% in 2005 and 53% in 2020. Over time, second-generation supraglottic airway devices were used more frequently than first-generation supraglottic airway devices. While second-generation devices made up about 9% of all supraglottic airway devices in 2010, in 2020 they represented a proportion of 82%. The use of fibreoptic intubation increased over time in otorhinolaryngology and dental, oral, and maxillofacial surgery, but showed no significant trends over the entire 16-year period. CONCLUSION: Our data represent the first large-scale evaluation of airway management procedures over a long time. There was a significant upward trend in the use of supraglottic airway devices, with an increase in the use of second-generation masks while a decrease in oral intubations was observed.

Influence of intraoperative fluid replacement on ampicillin serum levels and surgical site infections.

BACKGROUND: Surgical site infections (SSI) occur despite antimicrobial prophylaxis and increase postoperative morbidity and mortality. This could be caused by an intraoperative decrease in antibiotic serum concentrations such as ampicillin after major abdominal surgery due to blood loss and fluid therapy, which possibly promotes SSI. This hypothesis was tested in the present study. METHODS: This pilot study was performed as a prospective observational trial between March 2018 and May 2019. Ampicillin/sulbactam was administered intravenously during anesthesia induction. Fluid replacement was guided based on hemodynamic variables, including analysis of pulse pressure variation. The primary outcome was ampicillin serum level (ASL), measured after administration and hourly within 4 hours. The incidence of SSI at hospital discharge was the secondary outcome. Linear mixed and logistic regression models were used for statistical analyses. RESULTS: After screening of 133 adult patients, 129 were enrolled, and 102 completed the study protocol. No correlation was found between the volume of intraoperative fluids and ASL, nor was any association found between ASL and SSI. Based on 5 SSI cases, SSI were associated with higher intraoperative fluid volume. ASL was sufficient to provide intraoperative coverage for all potential bacterial strains. CONCLUSION: Intraoperative fluid replacement had no effect on ASL up to 4 hours after ampicillin/sulbactam administration. SSI were within an acceptable range, indicating adequate antimicrobial prophylaxis, so intraoperative control of ASL does not seem necessary. In conclusion, contrary to our initial hypothesis, ASL is not influenced by volume turnover or blood loss during major surgery and therefore does not affect SSI.

Is 'anxiety sensitivity' predictive of postoperative nausea and vomiting?: A prospective observational study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is an extremely distressing side effect for patients. Despite PONV prophylaxis guided by well established scoring systems, the incidence of PONV is still high. OBJECTIVE: The aim of the current study was to investigate the predictive value of anxiety sensitivity as an additional independent risk factor for PONV in patients with an increased risk of PONV. DESIGN: A noninterventional, observational study. SETTING: A tertiary care university hospital. PATIENTS: Patients with an increased risk of PONV (i.e. female, nonsmoking) undergoing elective surgery (general, gynaecological, urological, musculoskeletal or neurosurgical) under general anaesthesia. MAIN OUTCOME MEASURES: The number of patients with anxiety sensitivity assessed pre-operatively with the Anxiety Sensitivity Index-3 questionnaire, the number of patients experiencing PONV, predictive value of anxiety sensitivity compared with other established risk factors for PONV. RESULTS: Some 41.5% of the patients experienced PONV within the first 24 h after surgery. In these patients increased anxiety sensitivity (Anxiety Sensitivity Index-3 score higher than seven points) was associated with a five-fold increase in the odds ratio (OR) for PONV. From the regression model, the risk of PONV was increased by lack of PONV prophylaxis (OR, 3.68), the postoperative administration of opioids (OR, 3.60) and patient age (OR, 1.03), but laparoscopic surgery did not increase the risk. CONCLUSION: In addition to the well established risk factors, anxiety sensitivity can help to predict the risk of PONV. It seems justifiable to add psychological factors such as anxiety sensitivity to PONV risk-scores. PONV prophylaxis should be considered when anxiety sensitivity is high. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01875120.

Noninvasive Hemodynamic Measurements During Neurosurgical Procedures in Sitting Position.

BACKGROUND: Neurosurgical procedures in sitting position need advanced cardiovascular monitoring. Transesophageal echocardiography (TEE) to measure cardiac output (CO)/cardiac index (CI) and stroke volume (SV), and invasive arterial blood pressure measurements for systolic (ABPsys), diastolic (ABPdiast) and mean arterial pressure (MAP) are established monitoring technologies for these kind of procedures. A noninvasive device for continuous monitoring of blood pressure and CO based on a modified Penaz technique (volume-clamp method) was introduced recently. In the present study the noninvasive blood pressure measurements were compared with invasive arterial blood pressure monitoring, and the noninvasive CO monitoring to TEE measurements. METHODS: Measurements of blood pressure and CO were performed in 35 patients before/after giving a fluid bolus and a change from supine to sitting position, start of surgery, and repositioning from sitting to supine at the end of surgery. Data pairs from the noninvasive device (Nexfin HD) versus arterial line measurements (ABPsys, ABPdiast, MAP) and versus TEE (CO, CI, SV) were compared using Bland-Altman analysis and percentage error. RESULTS: All parameters compared (CO, CI, SV, ABPsys, ABPdiast, MAP) showed a large bias and wide limits of agreement. Percentage error was above 30% for all parameters except ABPsys. CONCLUSION: The noninvasive device based on a modified Penaz technique cannot replace arterial blood pressure monitoring or TEE in anesthetized patients undergoing neurosurgery in sitting position.

Influence of Age on Cerebral Housekeeping Gene Expression for Normalization of Quantitative Polymerase Chain Reaction after Acute Brain Injury in Mice.

To prevent methodological errors of quantitative PCR (qPCR) normalization with reference genes is obligatory. Although known to influence gene expression, impact of age on housekeeping gene expression has not been determined after acute brain lesions such as traumatic brain injury (TBI). Therefore, expression of eight common control genes was investigated at 15 min, 24 h, and 72 h after experimental TBI in 2- and 21-month-old C57Bl6 mice. Expression of ß2-microglobulin (B2M), ß-actin (ActB), and porphobilinogen deaminase (PBGD) increased after TBI in both ages. ß2M demonstrated age-dependent differences and highest inter- and intragroup variations. Expression of cyclophilin A, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hypoxanthine ribosyltransferase (HPRT), S100B, and 18SrRNA remained stable. Cyclophilin A and HPRT demonstrated strongest inter- and intragroup stability. The data indicate that the expression of most but not all control genes is stable during aging. The correct choice of housekeeping genes is of key importance to ensure adequate normalization of qPCR data. With respect to insult and age, normalization strategies should consider cyclophilin A as a single normalizer. Normalization with two reference genes is recommended with cyclophilin A and HPRT in young mice and in mixed age studies and with cyclophilin A and GAPDH in old mice. In addition, the present study suggests not to use ß2-microglobulin, ß-actin or PBGD as single control genes because of strong regulation after CCI in 2- and 21-month-old mice.

Changes in cerebral oxygen saturation following prone positioning for orthopaedic surgery under general anaesthesia: a prospective observational study.

BACKGROUND: Prone positioning is often necessary in orthopaedic surgery. The prone position, however, may result in impaired cerebral venous drainage with a subsequent reduction in cerebral perfusion. As a consequence, cerebral hypoxia may occur with the potential for neurological impairment. OBJECTIVE: We assessed the changes in cerebral oxygen saturation with near-infrared spectroscopy using two different monitors after positioning the patient from supine to prone. DESIGN: Prospective observational study. SETTING: Primary Care University Hospital, from May 2010 to February 2011. PARTICIPANTS: Forty patients undergoing general anaesthetic procedures, of which 35 completed the investigation. Similar measurements were done in 35 volunteers, who were studied while awake. INTERVENTIONS: Near-infrared spectroscopy was measured throughout anaesthesia using INVOS (a trend monitor using two infrared wavelengths) for one hemisphere and FORE-SIGHT (a monitor using four wavelengths of laser light to calculate absolute oxygen saturation) for the other hemisphere in an alternate randomisation pattern. OUTCOME MEASUREMENTS: The primary outcome was a change in cerebral oxygen saturation of more than 5% during prone positioning. A comparison with the changes obtained in awake volunteers following similar positioning was also made. RESULTS: Cerebral oxygen saturation increased during prone positioning with INVOS 0.032% per minute (P < 0.01) and with FORE-SIGHT 0.032% per minute (P < 0.01) in anaesthetised patients. Awake volunteers showed an increase of 0.171% per minute (INVOS) and 0.082% per minute (FORE-SIGHT) during prone positioning. Comparison of INVOS with FORE-SIGHT showed a good association, with a gradient of 0.80% per 1% change (P < 0.01). CONCLUSION: Both monitors detected a small increase in cerebral oxygen saturation of less than 5% in patients undergoing orthopaedic surgery in the prone position and in awake volunteers. This small increase is of limited clinical relevance and prone positioning may be regarded as safe in terms of the maintenance of cerebral oxygen saturation. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01275898.

Anesthesia for euthanasia influences mRNA expression in healthy mice and after traumatic brain injury.

Tissue sampling for gene expression analysis is usually performed under general anesthesia. Anesthetics are known to modulate hemodynamics, receptor-mediated signaling cascades, and outcome parameters. The present study determined the influence of anesthetic paradigms typically used for euthanization and tissue sampling on cerebral mRNA expression in mice. Naïve mice and animals with acute traumatic brain injury induced by controlled cortical impact (CCI) were randomized to the following euthanasia protocols (n=10-11/group): no anesthesia (NA), 1 min of 4 vol% isoflurane in room air (ISO), 3 min of a combination of 5 mg/kg midazolam, 0.05 mg/kg fentanyl, and 0.5 mg/kg medetomidine intraperitoneally (COMB), or 3 min of 360 mg/kg chloral hydrate intraperitoneally (CH). mRNA expression of actin-1-related gene (Act1), FBJ murine osteosarcoma viral oncogene homolog B (FosB), tumor necrosis factor alpha (TNFα), heat shock protein beta-1 (HspB1), interleukin (IL)-6, tight junction protein 1 (ZO-1), IL-1ß, cyclophilin A, micro RNA 497 (miR497), and small cajal body-specific RNA 17 were determined by real-time polymerase chain reaction (PCR) in hippocampus samples. In naïve animals, Act1 expression was downregulated in the CH group compared with NA. FosB expression was downregulated in COMB and CH groups compared with NA. CCI reduced Act1 and FosB expression, whereas HspB1 and TNFα expression increased. After CCI, HspB1 expression was significantly higher in ISO, COMB, and CH groups, and TNFα expression was elevated in ISO and COMB groups. MiR497, IL-6, and IL-1ß were upregulated after CCI but not affected by anesthetics. Effects were independent of absolute mRNA copy numbers. The data demonstrate that a few minutes of anesthesia before tissue sampling are sufficient to induce immediate mRNA changes, which seem to predominate in the early-regulated gene cluster. Anesthesia-related effects on gene expression might explain limited reproduciblity of real-time PCR data between studies or research groups and should therefore be considered for quantitative PCR data.

Effects of levosimendan on hemodynamics, local cerebral blood flow, neuronal injury, and neuroinflammation after asphyctic cardiac arrest in rats.

OBJECTIVES: Despite advances in cardiac arrest treatment, high mortality and morbidity rates after successful cardiopulmonary resuscitation are still a major clinical relevant problem. The post cardiac arrest syndrome subsumes myocardial dysfunction, impaired microcirculation, systemic inflammatory response, and neurological impairment. The calcium-sensitizer levosimendan was able to improve myocardial function and initial resuscitation success after experimental cardiac arrest/cardiopulmonary resuscitation. We hypothesized that levosimendan exerts beneficial effects on cerebral blood flow, neuronal injury, neurological outcome, and inflammation 24 hours after experimental cardiac arrest/cardiopulmonary resuscitation. DESIGN: Laboratory animal study. SETTING: University animal research laboratory. SUBJECTS: Sixty-one male Sprague-Dawley rats. INTERVENTIONS: Animals underwent asphyxial cardiac arrest/cardiopulmonary resuscitation, randomized to groups with levosimendan treatment (bolus 12 µg/kg and infusion for 3 hr [0.3 µg/min/kg]) or vehicle (saline 0.9% bolus and infusion for 3 hr [equivalent fluid volume]). Cardiac index, local cerebral blood flow, and hemodynamic variables were measured for 180 minutes after cardiac arrest/cardiopulmonary resuscitation. Behavioral and neurological evaluations were conducted 24 hours after cardiac arrest/cardiopulmonary resuscitation. Furthermore, neuronal injury, expressed as Fluoro-Jade B-positive cells in the hippocampal formation, cortical and hippocampal inflammatory cytokine gene expression, and blood plasma interleukin-6 values were assessed. MEASUREMENTS AND MAIN RESULTS: Treatment with levosimendan reduced neuronal injury and improved neurological outcome after 24 hours of reperfusion and resulted in elevated cardiac index and local cerebral blood flow compared with vehicle after cardiac arrest/cardiopulmonary resuscitation. Mean arterial blood pressure was reduced during the early reperfusion period in the levosimendan group. Cortical and hippocampal inflammatory cytokine gene expression and blood plasma interleukin-6 levels were not influenced. CONCLUSIONS: Levosimendan increased cerebral blood flow after experimental cardiac arrest/cardiopulmonary resuscitation. This effect coincided with reduced neuronal injury and improved neurologic outcome. Findings seem to be independent of inflammatory effects because no effects by levosimendan on cerebral or systemic inflammation could be detected. In summary, levosimendan is a promising agent to improve neurological outcome after cardiac arrest/cardiopulmonary resuscitation.

2-Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF-1α response after traumatic brain injury in mice.

HIF-1α is pivotal for cellular homeostasis in response to cerebral ischemia. Pharmacological inhibition of HIF-1α may reduce secondary brain damage by targeting post-translational mechanisms associated with its proteasomal degradation and nuclear translocation. This study examined the neuroprotective effects of 2-methoxyestradiol (2ME2), the involved HIF-1α-dependent response, and alternative splicing in exon 14 of HIF-1α (HIF-1α∆Ex14) after traumatic brain injury (TBI) in mice. Intraperitoneal 2ME2 administration 30 min after TBI caused a dose-dependent reduction in secondary brain damage after 24 h. 2ME2 was physiologically tolerated, showed no effects on immune cell brain migration, and mitigated trauma-induced brain expression of neuropathologically relevant HIF-1α target genes encoding for Plasminogen activator inhibitor 1 and tumor necrosis factor alpha. Moreover, TBI-induced expression of pro-apoptotic BNIP3 was attenuated by 2ME2 treatment. Alternatively, spliced HIF-1α∆Ex14 was substantially up-regulated from 6 to 48 h after TBI. In vitro, nuclear location and gene transcription activity of HIF-1α∆Ex14 were impaired compared to full-length HIF-1α, but no effects on nuclear translocation of the transcriptional complex partner HIF-1ß were observed. This study demonstrates that 2ME2 confers neuroprotection after TBI. While the role of alternatively spliced HIF-1α∆Ex14 remains elusive, the in vivo data provide evidence that inhibition of a maladaptive HIF-1α-dependent response contributes to the neuroprotective effects of 2ME2. We examined neuroprotective effects of 2-methoxyestradiol (2ME2) and the hypoxia-inducible factor 1-α (HIF-1α) response following traumatic brain injury in mice. Early 2ME2 administration reduced the secondary brain damage and neuronal HIF-1α probably involving ubiquitin proteasome system-mediated degradation. The up-regulation of neuropathological HIF-1α target genes and pro-apoptotic BNIP3 protein was attenuated. We propose that the inhibition of a maladaptive HIF-1α response may contribute to 2ME2-mediated neuroprotection.

Robotic assisted prostatic surgery in the Trendelenburg position does not impair cerebral oxygenation measured using two different monitors: A clinical observational study.

BACKGROUND: Robotic assisted prostatic surgery is frequently used because of its reduced side-effects compared with conventional surgery. During surgery, an extreme Trendelenburg position and CO2 pneumoperitoneum are necessary, which may lead to cerebral oedema, can potentially reduce brain perfusion and therefore could impair cerebral oxygenation. Cerebral oxygen saturation can be measured non-invasively using near-infrared spectroscopy (NIRS). OBJECTIVE: The hypothesis of the present study was that steep Trendelenburg positioning during robotic assisted prostatic surgery impairs cerebral oxygen saturation measured using two different NIRS monitors. DESIGN: Clinical observational study. SETTING: Primary care university hospital, study period from March 2012 to February 2013. PATIENTS: A total of 29 patients scheduled for robotic assisted prostatic surgery in a steep Trendelenburg position. INTERVENTIONS: Cerebral oxygen saturation was measured throughout anaesthesia using the INVOS sensor (a trend monitor using two infrared wavelengths) for one hemisphere and the FORE-SIGHT sensor (a monitor using four wavelengths of laser light to calculate absolute oxygen saturation) for the other hemisphere in an alternate randomisation. MAIN OUTCOME MEASURE: Changes in cerebral oxygenation of more than 5% during surgery in the Trendelenburg position. RESULTS: The median duration of Trendelenburg positioning was 190 (interquartile range 130 to 230) min. Cerebral oxygen saturation decreased with INVOS from 74 ± 5% at baseline to a lowest value of 70 ± 4% with a slope of -0.0129 min(-1) (P < 0.01) and with FORE-SIGHT from 72 ± 5% at baseline to a nadir of 70 ± 3% with a slope of -0.008 min(-1) (P < 0.01). Comparing INVOS with FORE-SIGHT, there was a good association, with a slope of 0.86 ± 0.04 (P < 0.01). CONCLUSION: Both monitors showed a clinically irrelevant decrease in cerebral oxygen saturation of less than 5% over 4 h in a steep Trendelenburg position combined with CO2 pneumoperitoneum in patients undergoing robotic assisted prostatic surgery. This extreme positioning seems to be acceptable with regard to cerebral oxygenation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ID NCT01275898.

Influence of beach chair position on cerebral oxygen saturation: a comparison of INVOS and FORE-SIGHT cerebral oximeter.

BACKGROUND: Although beach chair position (BCP) is frequently used for shoulder surgery, a potentially detrimental influence on cerebral oxygenation is discussed. Therefore, the present study investigated changes in regional cerebral oxygen saturation (rSO2/StO2) during BCP comparing 2 different devices for near-infrared spectroscopy measurement. METHODS: Data were collected in 35 patients undergoing shoulder surgery in BCP and compared with a control group of 35 awake volunteers. The rSO2/StO2 was assessed using INVOS and FORE-SIGHT monitors. Mean arterial blood pressure (MAP), peripheral oxygen saturation (SpO2), PeCO2, FiO2, end-tidal sevoflurane concentration, and rSO2/StO2 were measured before positioning, during BCP, and in supine position after surgery. RESULTS: A decrease in rSO2/StO2 could be observed after BCP (INVOS: 76.1% supine vs. 66.7% BCP, P<0.001; FORE-SIGHT: 78.6% supine, 66.1% BCP, P<0.001), which was reversible in supine position. This decrease correlated with MAP during BCP, while in supine position no correlation was detected. In control group BCP did not influence rSO2/StO2. Changes detected with INVOS or FORE-SIGHT cerebral oximeter did not differ. CONCLUSION: BCP is associated with a decrease in rSO2/StO2 of 10% in anesthetized patients, which is reversible after repositioning. No changes occurred in supine position under general anesthesia as well as in awake subjects in BCP. This underlines the assumption that vasodilation by anesthetics in combination with BCP evoke a drop in rSO2/StO2. A strict hemodynamic management may be necessary to prevent desaturation events. Despite different technology used by the devices, the results of INVOS and FORE-SIGHT cerebral oximeters are comparable.

Anaesthetic techniques to prevent perioperative stroke.

PURPOSE OF REVIEW: Different techniques and interventions that can be used by an anaesthesiologist to minimize the perioperative stroke risk are summarized. RECENT FINDINGS: The most important risk factors for perioperative stoke are not modifiable, for example previous stroke or renal failure, but they can be used to identify patients with a high risk for perioperative stroke. The antiplatelet therapy should be continued in patients with a high risk for cardiovascular thrombosis. This might be true even for operations in which bleeding should be strictly avoided such as eye surgery. One of the most recent neuroprotective approaches is the remote ischaemic preconditioning. SUMMARY: Perioperative stroke increases morbidity and mortality of patients undergoing surgery and is therefore highly relevant. Neuromonitoring should be used to detect a deterioration of cerebral blood flow and oxygen supply immediately. Statins which are initiated at least 2 weeks before the operation can possibly reduce the perioperative stroke rate. Routinely taken statins should not be terminated and this is also true for ß-blockers. The cerebral perfusion pressure should be kept at baseline levels, whereas a mild hypercapnia theoretically could be beneficial. Hypoglycemia has to be avoided while treatment of high blood glucose levels should be started when they exceed 150 mg/dl. The anesthesia for patients with a high risk for stroke has always to be performed by an experienced anaesthesiologist who is able to individualize the therapeutic interventions.

Influence of age on brain edema formation, secondary brain damage and inflammatory response after brain trauma in mice.

After traumatic brain injury (TBI) elderly patients suffer from higher mortality rate and worse functional outcome compared to young patients. However, experimental TBI research is primarily performed in young animals. Aim of the present study was to clarify whether age affects functional outcome, neuroinflammation and secondary brain damage after brain trauma in mice. Young (2 months) and old (21 months) male C57Bl6N mice were anesthetized and subjected to a controlled cortical impact injury (CCI) on the right parietal cortex. Animals of both ages were randomly assigned to 15 min, 24 h, and 72 h survival. At the end of the observation periods, contusion volume, brain water content, neurologic function, cerebral and systemic inflammation (CD3+ T cell migration, inflammatory cytokine expression in brain and lung, blood differential cell count) were determined. Old animals showed worse neurological function 72 h after CCI and a high mortality rate (19.2%) compared to young (0%). This did not correlate with histopathological damage, as contusion volumes were equal in both age groups. Although a more pronounced brain edema formation was detected in old mice 24 hours after TBI, lack of correlation between brain water content and neurological deficit indicated that brain edema formation is not solely responsible for age-dependent differences in neurological outcome. Brains of old naïve mice were about 8% smaller compared to young naïve brains, suggesting age-related brain atrophy with possible decline in plasticity. Onset of cerebral inflammation started earlier and primarily ipsilateral to damage in old mice, whereas in young mice inflammation was delayed and present in both hemispheres with a characteristic T cell migration pattern. Pulmonary interleukin 1ß expression was up-regulated after cerebral injury only in young, not aged mice. The results therefore indicate that old animals are prone to functional deficits and strong ipsilateral cerebral inflammation without major differences in morphological brain damage compared to young.

Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma*.

OBJECTIVE: To investigate the regulation of the cerebral renin-angiotensin system and the effect of angiotensin II receptor type 1 inhibition on secondary brain damage, cerebral inflammation, and neurologic outcome after head trauma. DESIGN: The expression of renin-angiotensin system components was determined at 15 mins, 3 hrs, 6 hrs, 12 hrs, and 24 hrs after controlled cortical impact in mice. Angiotensin II receptor type 1 was inhibited using candesartan (0.1, 0.5, 1 mg/kg) after trauma to determine its effect on secondary brain damage, brain edema formation, and inflammation. The window of opportunity was tested by delaying angiotensin II receptor type 1 inhibition for 30 mins, 1 hr, 2 hrs, and 4 hrs. The long-term effect was tested by single and daily repeated treatment with candesartan for 5 days after controlled cortical impact. SETTING: University research laboratory. SUBJECTS: Male C57Bl/6N mice. INTERVENTIONS: Brain trauma by use of a controlled cortical impact device. MEASUREMENTS AND MAIN RESULTS: Expression of angiotensin II receptor type 1A decreased by 42% within 24 hrs after controlled cortical impact, whereas angiotensin II receptor type 1B expression increased to 220% between 6 and 12 hrs. Blockage of angiotensin II receptor type 1 with 0.1 mg/kg candesartan within 4 hrs of injury significantly reduced secondary brain damage (30 mins: 25 mm vs. vehicle: 41 mm) and improved neurologic function after 24 hrs but failed to reduce brain edema formation. Daily treatment with candesartan afforded sustained reduction of brain damage and improved neurologic function 5 days after traumatic brain injury compared with single and vehicle treatment. Inhibition of angiotensin II receptor type 1 significantly attenuated posttraumatic inflammation (interleukin-6: -56%; interleukin-1ß: -42%; inducible nitric oxide synthase: -36%; tumor necrosis factor-α: -35%) and microglia activation (vehicle: 163 ± 25/mm vs. candesartan: 118 ± 13/mm). Higher dosages (0.5 and 1 mg/kg) resulted in prolonged reduction in blood pressure and failed to reduce brain lesion. CONCLUSIONS: The results indicate that angiotensin II receptor type 1 plays a key role in the development of secondary brain damage after brain trauma. Inhibition of angiotensin II receptor type 1 with a delay of up to 4 hrs after traumatic brain injury effectively reduces lesion volume. This reduction makes angiotensin II receptor type 1 a promising therapeutic target for reducing cerebral inflammation and limiting secondary brain damage.

Influence of a brief episode of anesthesia during the induction of experimental brain trauma on secondary brain damage and inflammation.

It is unclear whether a single, brief, 15-minute episode of background anesthesia already modulates delayed secondary processes after experimental brain injury. Therefore, this study was designed to characterize three anesthesia protocols for their effect on molecular and histological study endpoints. Mice were randomly separated into groups that received sevoflurane (sevo), isoflurane (iso) or an intraperitoneal anesthetic combination (midazolam, fentanyl and medetomidine; comb) prior to traumatic brain injury (controlled cortical impact, CCI; 8 m/s, 1 mm impact depth, 3 mm diameter). Twenty-four hours after insult, histological brain damage, neurological function (via neurological severity score), cerebral inflammation (via real-time RT-PCR for IL6, COX-2, iNOS) and microglia (via immunohistochemical staining for Iba1) were determined. Fifteen minutes after CCI, the brain contusion volume did not differ between the anesthetic regimens (sevo = 17.9±5.5 mm(3); iso = 20.5±3.7 mm(3); comb = 19.5±4.6 mm(3)). Within 24 hours after injury, lesion size increased in all groups (sevo = 45.3±9.0 mm(3); iso = 31.5±4.0 mm(3); comb = 44.2±6.2 mm(3)). Sevo and comb anesthesia resulted in a significantly larger contusion compared to iso, which was in line with the significantly better neurological function with iso (sevo = 4.6±1.3 pts.; iso = 3.9±0.8 pts.; comb = 5.1±1.6 pts.). The expression of inflammatory marker genes was not significantly different at 15 minutes and 24 hours after CCI. In contrast, significantly more Iba1-positive cells were present in the pericontusional region after sevo compared to comb anesthesia (sevo = 181±48/mm(3); iso = 150±36/mm(3); comb = 113±40/mm(3)). A brief episode of anesthesia, which is sufficient for surgical preparations of mice for procedures such as delivering traumatic brain injury, already has a significant impact on the extent of secondary brain damage.

Effect of autologous blood transfusion on cerebral cytokine expression.

BACKGROUND: Autologous blood transfusion (ABT), for example, by means of cell saver equipment, is used to reduce the need for allogenic blood transfusion in patients with high perioperative blood loss. This study investigated the effect of blood/extracorporal surface interaction during withdrawal and retransfusion of shed autologous blood on cerebral inflammation in rats. Rats subjected to hypotension with cerebral ischemia served as positive controls. METHODS: Eighty-eight male Sprague-Dawley rats were anesthetized with sevoflurane, instrumented, and randomly assigned to the following groups: sham-operation (SHAM), autologous blood withdrawal/transfusion only (ABT), or bilateral carotid artery occlusion and autologous blood withdrawal/transfusion (BCAO/ABT). Inflammatory gene expression was investigated with real-time RT-polymerase chain reaction at 6, 12, and 24 hours after SHAM, ABT, or BCAO/ABT in brain hippocampal tissue. Naive rats were investigated as reference. RESULTS: ABT alone had no impact on hippocampal inflammatory gene expression, whereas after BCAO/ABT tumor necrosis factor-alpha (10.7 fold at 24 h), interleukin-1ß (2.1 fold at 6 h), interleukin-6 (35.7 fold at 24 h), COX-2 (9.3 fold at 6 h), and inducible nitric oxide synthase (3.4 fold at 24 h) increased compared with SHAM. CONCLUSIONS: ABT by itself did not provoke an inflammatory reaction in the healthy brain. However, in combination with cerebral ischemia the induction of a broad spectrum of inflammatory parameters indicates an inflammatory reaction of the hippocampus beginning after 6 hours and being most pronounced after 24 hours. Therefore, this study shows that cerebral inflammation is not induced by ABT after contact with extracorporal surfaces in rats.

Measurement of cortical microcirculation during intracranial aneurysm surgery by combined laser-Doppler flowmetry and photospectrometry.

BACKGROUND: Accidental vessel occlusion is one major risk of intracranial aneurysm surgery potentially causing cerebral ischemia. The intraoperative assessment of cerebral ischemia remains a technological challenge. OBJECTIVE: As a novel approach, cortical tissue integrity was monitored using simultaneous measurements of regional capillary-venous cerebral blood flow (rvCBF), oxygen saturation (Srvo2), and hemoglobin amount (rvHb) during aneurysm surgery. METHODS: Fifteen patients scheduled for aneurysm surgery of the anterior and posterior circulation were included. A fiber optic probe was placed on the cortex associated with the distal branch of the aneurysmatic vessel. Blinded measurements by combined laser-Doppler flowmetry (rvCBF) and photospectrometry (Srvo2, rvHb) were performed before and after surgical clipping or trapping of the aneurysm. Data were correlated with postoperative imaging and neurological outcome. RESULTS: Cortical measurements could be successfully performed in all patients. Significant increase (>25% change from baseline) or decrease (<25% change from baseline) of rvCBF, Srvo2, and rvHb was detectable in 33 to 46% of patients after surgical intervention. Severe decrease (>50% change from baseline) of all parameters or solitary of rvCBF was correlated to reduced cerebral perfusion and neurological deficits in 2 patients. CONCLUSION: Combined laser-Doppler flowmetry and photospectrometry provides real-time information on cortical microcirculation. Intraoperative alterations of parameters (rvCBF, Srvo2, rvHb) might reflect changes of cerebral tissue integrity during intracranial aneurysm surgery.

Postoperative nausea and vomiting in patients after craniotomy: incidence and risk factors.

OBJECT: The purpose of this study was to assess the incidence and risk factors of postoperative nausea and vomiting (PONV) after craniotomy because most available data about PONV in neurosurgical patients are retrospective in nature or derive from small prospective studies. METHODS: Postoperative nausea and vomiting was prospectively assessed within 24 hours after surgery in 229 patients requiring supratentorial or infratentorial craniotomy. To rule out the relevance of the neurosurgical procedure itself to the development of PONV, the observed incidence of vomiting was compared with the rate of vomiting predicted with a surgery-independent risk score (Apfel postoperative vomiting score). RESULTS: The overall incidence of PONV after craniotomy was 47%. Logistic regression identified female sex as a risk factor for postoperative nausea (OR 4.25, 95% CI 2.3-7.8) and vomiting (OR 2.62, 95% CI 1.4-4.9). Both the incidence of nausea (OR 3.76, 95% CI 2.06-6.88) and vomiting (OR 4.48, 95% CI 2.4-8.37) were increased in patients not receiving steroids. Postoperative nausea and vomiting occurred after infratentorial as well as after supratentorial procedures. The observed incidence of vomiting within 24 hours after surgery was higher (49%) than would be predicted with the Apfel surgery-independent risk score (31%; p = 0.0004). CONCLUSIONS: The overall incidence of PONV within 24 hours after craniotomy was approximately 50%. One possible reason is that intracranial surgeries pose an additional and independent risk factor for vomiting, especially in female patients. Patients undergoing craniotomy should be identified as high-risk patients for PONV.