ICU- and ventilator-free days with isoflurane or propofol as a primary sedative - A post- hoc analysis of a randomized controlled trial.

PURPOSE: To compare ICU-free (ICU-FD) and ventilator-free days (VFD) in the 30 days after randomization in patients that received isoflurane or propofol without receiving the other sedative. MATERIALS AND METHODS: A recent randomized controlled trial (RCT) compared inhaled isoflurane via the Sedaconda® anaesthetic conserving device (ACD) with intravenous propofol for up to 54 h (Meiser et al. 2021). After end of study treatment, continued sedation was locally determined. Patients were eligible for this post-hoc analysis only if they had available 30-day follow-up data and never converted to the other drug in the 30 days from randomization. Data on ventilator use, ICU stay, concomitant sedative use, renal replacement therapy (RRT) and mortality were collected. RESULTS: Sixty-nine of 150 patients randomized to isoflurane and 109 of 151 patients randomized to propofol were eligible. After adjusting for potential confounders, the isoflurane group had more ICU-FD than the propofol group (17.3 vs 13.8 days, p = 0.028). VFD for the isoflurane and propofol groups were 19.8 and 18.5 respectively (p = 0.454). Other sedatives were used more frequently (p < 0.0001) and RRT started in a greater proportion of patients in the propofol group (p = 0.011). CONCLUSIONS: Isoflurane via the ACD was not associated with more VFD but with more ICU-FD and less concomitant sedative use.

Prolonged sedation with sevoflurane in comparison to intravenous sedation in critically ill patients - A randomized controlled trial.

BACKGROUND: Volatile anesthetics are used more commonly for sedation in the intensive-care-unit (ICU). However, evidence for long-term use remains low. We therefore conducted a randomized-controlled trial comparing sevoflurane with intravenous sedation with particular focus on efficacy and safety. METHODS: In this prospective, randomized-controlled phase-IIb monocentric clinical-trial ICU patients requiring at least 48 h of sedation were randomized to receive sevoflurane (S) or propofol/midazolam (P). Sedation quality was monitored using the Richmond-Agitation-Sedation-Scale. Following termination of sedation, the time to spontaneous breathing and extubation, opioid consumption, hemodynamics, ICU and hospital length of stay (LOS) and adverse events were recorded. RESULTS: 79 patients were eligible to randomization. Sedation quality was comparable between sevoflurane (n = 39) and propofol (n = 40). However, the use of sevoflurane lead to a reduction in time to spontaneous breathing (26 min vs. 375 min, P < 0.001). Patients sedated with propofol had lower opioid requirements (remifentanil:400 µg/h vs. 500 µg/h, P = 0.007; sufentanil:40 µg/h vs. 30 µg/h, P = 0.007) while hemodynamics, LOS or the occurrence of adverse events did not differ. CONCLUSION: ICU patients sedated with sevoflurane >48 h may return to spontaneous breathing faster, while the quality of sedation is comparable to a propofol-based sedation regime. Sevoflurane might be considered to be safe for long-term sedation in this patient population, while being non-inferior compared to propofol.

Hemoadsorption in the critically ill-Final results of the International CytoSorb Registry.

The aim of the current paper is to summarize the results of the International CytoSorb Registry. Data were collected on patients of the intensive care unit. The primary endpoint was actual in-hospital mortality compared to the mortality predicted by APACHE II score. The main secondary endpoints were SOFA scores, inflammatory biomarkers and overall evaluation of the general condition. 1434 patients were enrolled. Indications for hemoadsorption were sepsis/septic shock (N = 936); cardiac surgery perioperatively (N = 172); cardiac surgery postoperatively (N = 67) and "other" reasons (N = 259). APACHE-II-predicted mortality was 62.0±24.8%, whereas observed hospital mortality was 50.1%. Overall SOFA scores did not change but cardiovascular and pulmonary SOFA scores decreased by 0.4 [-0.5;-0.3] and -0.2 [-0.3;-0.2] points, respectively. Serum procalcitonin and C-reactive protein levels showed significant reduction: -15.4 [-19.6;-11.17] ng/mL; -17,52 [-70;44] mg/L, respectively. In the septic cohort PCT and IL-6 also showed significant reduction: -18.2 [-23.6;-12.8] ng/mL; -2.6 [-3.0;-2.2] pg/mL, respectively. Evaluation of the overall effect: minimal improvement (22%), much improvement (22%) and very much improvement (10%), no change observed (30%) and deterioration (4%). There was no significant difference in the primary outcome of mortality, but there were improvements in cardiovascular and pulmonary SOFA scores and a reduction in PCT, CRP and IL-6 levels. Trial registration: ClinicalTrials.gov Identifier: NCT02312024 (retrospectively registered).

Therapeutic Plasma Exchanges in Combination with High-Dose Steroid-Induced Immunosuppression as an Ultima Ratio Therapy in Severe Coronavirus Disease 2019 (COVID-19): A Case-Series Report.

We present 2 cases of severe Covid-19 with comorbidities (arterial hypertension, obesity, diabetes mellitus) treated with membrane-based therapeutic plasma exchanges in combination with a short-term high-dose immunosuppressive therapy. The therapy has been initiated in an attempt to alleviate the prevalent cytokine storm and to prevent intubation and invasive mechanical ventilation, when a long-term nasal oxygen therapy with a maximum flow rate of 8L/min was insufficient to achieve an adequate oxygenation. Even though patient 2 had to be intubated after the 4th cycle of plasmapheresis due to the exhaustion of the respiratory muscles and the subsequent acquired sepsis with a microbiological evidence of a mixed bacterial-fungal infection, both patients showed a good response to treatment, including improvement of laboratory and radiological findings. To our knowledge, this combination of therapeutic plasma exchange with a high-dose steroid therapy has not been reported previously.

Hemoadsorption in 'Liver Indication'-Analysis of 109 Patients' Data from the CytoSorb International Registry.

BACKGROUND: Our aim is to report the results of the 'liver indication' subset of patients in the CytoSorb International Registry. METHODS: Structured data were recorded. Treatment characteristics and changes from T1 (start of hemoadsorption) to T2 (termination) were evaluated with a special focus on bilirubin, C-reactive protein, procalcitonin, interleukin-6, platelet levels, SOFA scores, mortality, and subjective assessment by the attending physicians. RESULTS: Until January 2021, from the total 1434 patients, 109 (age: 49.2 ± 17.1 years, 57.8% males) received treatment for hyperbilirubinemia. APACHE II-predicted mortality was 49.6 ± 26.8%. In the study, 91% of patients were alive at the termination of hemoadsorption and improvement was observed by the physicians in 75 cases. Overall, 65 (59.6%) patients died in the hospital, and 60 (55.0%) died in the ICU. Patients received a median of two treatments for a median of 43 h (interquartile range: 24-72 h) in total. Serum bilirubin levels reduced significantly to -4.6 (95% CI: -6.329 to -2.8) mg/dL. Thrombocytopenia was reported in four patients as an adverse event. CONCLUSIONS: We report the largest case series on hemoadsorption for 'liver indication' from the CytoSorb International Registry. The finding of significant bilirubin removal observed in our study could have substantial impact in designing and executing further studies on the effects of hemoadsorption in liver dysfunction, which are certainly warranted.

Inhaled isoflurane via the anaesthetic conserving device versus propofol for sedation of invasively ventilated patients in intensive care units in Germany and Slovenia: an open-label, phase 3, randomised controlled, non-inferiority trial.

BACKGROUND: Previous studies indicate that isoflurane could be useful for the sedation of patients in the intensive care unit (ICU), but prospective studies evaluating isoflurane's efficacy have been small. The aim of this study was to test whether the sedation with isoflurane was non-inferior to sedation with propofol. METHODS: This phase 3, randomised, controlled, open-label non-inferiority trial evaluated the efficacy and safety of up to 54 h of isoflurane compared with propofol in adults (aged ≥18 years) who were invasively ventilated in ICUs in Germany (21 sites) and Slovenia (three sites). Patients were randomly assigned (1:1) to isoflurane inhalation via the Sedaconda anaesthetic conserving device (ACD; Sedana Medical AB, Danderyd, Sweden; ACD-L [dead space 100 mL] or ACD-S [dead space 50 mL]) or intravenous propofol infusion (20 mg/mL) for 48 h (range 42-54) using permuted block randomisation with a centralised electronic randomisation system. The primary endpoint was percentage of time in Richmond Agitation-Sedation Scale (RASS) range -1 to -4, assessed in eligible participants with at least 12 h sedation (the per-protocol population), five or more RASS measurements, and no major protocol violations, with a non-inferiority margin of 15%. Key secondary endpoints were opioid requirements, spontaneous breathing, time to wake-up and extubation, and adverse events. Safety was assessed in all patients who received at least one dose. The trial is complete and registered with EudraCT, 2016-004551-67. FINDINGS: Between July 2, 2017, and Jan 12, 2020, 338 patients were enrolled and 301 (89%) were randomly assigned to isoflurane (n=150) or propofol (n=151). 146 patients (97%) in each group completed the 24-h follow-up. 146 (97%) patients in the isoflurane group and 148 (98%) of patients in the propofol group were included in the per-protocol analysis of the primary endpoint. Least-squares mean percentage of time in RASS target range was 90·7% (95% CI 86·8-94·6) for isoflurane and 91·1% (87·2-95·1) for propofol. With isoflurane sedation, opioid dose intensity was 29% lower than with propofol for the overall sedation period (0·22 [0·12-0·34] vs 0·32 [0·21-0·42] mg/kg per h morphine equivalent dose, p=0·0036) and spontaneous breathing was more frequent on day 1 (odds ratio [OR] 1·72 [1·12-2·64], generalised mixed linear model p=0·013, with estimated rates of 50% of observations with isoflurane vs 37% with propofol). Extubation times were short and median wake-up was significantly faster after isoflurane on day 2 (20 min [IQR 10-30] vs 30 min [11-120]; Cox regression p=0·0011). The most common adverse events by treatment group (isoflurane vs propofol) were: hypertension (ten [7%] of 150 vs two [1%] of 151), delirium (eight [5%] vs seven [5%]), oliguria (seven [5%] vs six [4%]), and atrial fibrillation (five [3%] vs four [3%]). INTERPRETATION: These results support the use of isoflurane in invasively ventilated patients who have a clinical need for sedation. FUNDING: Sedana Medical AB.

Adsorption therapy in critically ill with septic shock and acute kidney injury: a retrospective and prospective cohort study.

BACKGROUND: Haemoadsorption has been described as an effective way to control increased pro- and anti-inflammatory mediators ("cytokine storm") in septic shock patients. No prospective or randomised clinical study has yet confirmed these results. However, no study has yet prospectively specifically investigated patients in severe septic shock with sepsis-associated acute kidney injury (SA-AKI). Therefore, we aimed to examine whether haemoadsorption could influence intensive care unit (ICU) and hospital mortality in these patients. Furthermore, we examined the influence of haemoadsorption on length of stay in the ICU and therapeutic support. METHODS: Retrospective control group and prospective intervention group design in a tertiary hospital in central Europe (Germany). Intervention was the implementation of haemoadsorption for patients in septic shock with SA-AKI. 76 patients were included in this analysis. RESULTS: Severity of illness as depicted by APACHE II was higher in patients treated with haemoadsorption. Risk-adjusted ICU mortality rates (O/E ratios) did not differ significantly between the groups (0.80 vs. 0.83). We observed in patients treated with haemoadsorption a shorter LOS and shorter therapeutic support such as catecholamine dependency and duration of RRT. However, in multivariate analysis (logistic regression for mortality, competing risk for LOS), we found no significant differences between the two groups. CONCLUSIONS: The implementation of haemoadsorption for patients in septic shock with acute renal failure did not lead to a reduction in ICU or hospital mortality rates. Despite univariate analysis delivering some evidence for a shorter duration of ICU-related treatments in the haemoadsorption group, these results did not remain significant in multivariate analysis. Trial registration CytoSorb® registry https://clinicaltrials.gov/ct2/show/NCT02312024 . December 9, 2014. DATABASE: https://www.cytosorb-registry.org/ (registration for content acquisition is necessary).

[Severe Shock Symptoms Due to Ticagrelor Related Anaphylactoid Reaction Following ST Elevation Myocardial Infarction]. / Schwere Schocksymptomatik infolge anaphylaktoider Reaktion auf Ticagrelor.

BACKGROUND: Ticagrelor as a P2Y12 receptor antagonist is recommended in patients with acute coronary syndrome without a primary cardiosurgical therapy. Severe relevant side effects, especially anaphylactic reactions, have not yet been described in the current literature. CASE PRESENTATION: We describe the first documented case in the current literature with a severe anaphylaxis after ticagrelor in a 76-year-old male patient with ST-elevation myocardial infarction. The diagnosis seems to be objectivated by the observed time-related life-threatening event after repetitive administration of ticagrelor and the rapid stabilization after adequate anaphylactic treatment. CONCLUSION: This case should raise the awareness that a supposedly safe drug can still cause an anaphylactic shock.

Rational application of antibiotics-The influence of anaesthetists' gender on self-confidence and knowledge.

BACKGROUND: High rates of multiresistant pathogens require detailed knowledge about rational utilization of antibiotics. Many physicians consider themselves uncertain about the interpretation of microbiological diagnostics. We examined whether self-confidence, self-rated knowledge, and objective knowledge regarding the use of antibiotics are associated with gender. METHODS: For this survey study, in 2017, anaesthesiologists and residents of 16 anaesthetic departments in Germany were asked to complete the Multiinstitutional Reconnaissance of practice with Multiresistant bacteria (MR2) survey. It consists of 55 items evaluating self-confidence regarding the practical use of antibiotics (n = 6), self-rated theoretical knowledge (n = 16), and objective knowledge (n = 5). Their answers to these items in relation to their gender were analysed using Chi-square, Kruskal-Wallis-H-Tests, and unadjusted as well as adjusted logistic regression models. RESULTS: Six hundred eighty-four (response rate: 53.9 %) questionnaires were returned and were available for analysis. Female doctors (35.5 %) felt less self-confident (P < 0.001). Self-rated knowledge differed in overall mean (P = 0.014) and the unadjusted (odds ratio [OR]: 0.55; P = 0.013) but not in the adjusted logistic regression (OR: 0.84; P = 0.525). Objective knowledge differed after pooling questions (61.2% correct answers vs 65.4%, P = 0.01) but not with respect to single items and the adjusted logistic regression (OR: 0.83, P = 0.356). CONCLUSION: Less self-confidence and a lower self-rated knowledge were found in female anaesthetists; this is consistent to the gender phenomena observed by other researchers. Nevertheless, between the 2 groups objective knowledge did not differ significantly in any item.

Influence of different infracardial positions of central venous catheters in hemodynamic monitoring using the transpulmonal thermodilution method.

Hemodynamic measurements are often conducted by the transpulmonary thermodilution (TPTD)-based PiCCO(®)-system. This requires a central-venous (CVC) and a thermistor-tipped arterial catheter, usually placed in the femoral artery. In certain clinical situations, CVC devices have to be placed in the inferior vena cava. However, little is known about the influence of different CVC positions (i.e. ipsi- vs. contra-lateral to the arterial catheter) on the accuracy of the TPTD measurement results. In this prospective observational study surgical intensive care unit patients who had been inserted with CVCs either into the superior (CVCVCS) or the inferior vena cava (CVCinf) in addition to an arterial PiCCO(®)-catheter, were enrolled. Patients were then divided into two groups: Group I was provided with a CVC in the contralateral (CVCcontra) and Group II in the ipsilateral (CVCipsi) inferior vena cava. Thermodilution via injection of ice-cold saline was then performed via CVCsup and CVCinf. Bland-Altman analysis for cardiac index (CI), extra-vascular lung water index (EVLWI) and global end-diastolic volume index (GEDVI) were employed. Additional correction formulas for femorally assed parameters were determined. In a total of 28 patients, bias (limits of agreement) for measurements of CI in CVCcontra was found to be +0.2 (-0.4; +0.9) and +0.3 (-0.4; +1.0) L/min/m(2) in CVCipsi. GEDVI showed a bias of +274.8 (-47.3; +596.9) mL/m(2) in CVCcontra and +274.7 (-100.7; +650.1) mL/m(2) in CVCipsi. The mean EVLWI were 9.4 ± 4.3 mL/kg for EVLWIVCS and 10.7 ± 5.2 mL/kg for EVLWIinf. The LoA yielded at -3.4 and +6.1 mL/kg with a bias of +1.3 mL/kg. Percentage errors revealed clinically acceptable limits for CI and GEDVI, but not for EVLWI. Using TPTD via an infracardial central vein, measurements of CI showed high accuracy and precision while GEDVI measurements were precise with a lower accuracy, irrespective of the position of the infracardial CVC.

Efficiency and safety of inhalative sedation with sevoflurane in comparison to an intravenous sedation concept with propofol in intensive care patients: study protocol for a randomized controlled trial.

BACKGROUND: State of the art sedation concepts on intensive care units (ICU) favor propofol for a time period of up to 72 h and midazolam for long-term sedation. However, intravenous sedation is associated with complications such as development of tolerance, insufficient sedation quality, gastrointestinal paralysis, and withdrawal symptoms including cognitive deficits. Therefore, we aimed to investigate whether sevoflurane as a volatile anesthetic technically implemented by the anesthetic-conserving device (ACD) may provide advantages regarding 'weaning time', efficiency, and patient's safety when compared to standard intravenous sedation employing propofol. METHOD/DESIGN: This currently ongoing trial is designed as a two-armed, monocentric, randomized prospective phase II study including intubated intensive care patients with an expected necessity for sedation exceeding 48 h. Patients are randomly assigned to either receive intravenous sedation with propofol or sevoflurane employing the ACD. Primary endpoint is the comparison of the 'weaning time' defined as the time required from discontinuation of the sedating agent until sufficient spontaneous breathing occurs. Moreover, sedation depth evaluated by Richmond Agitation Sedation Scale and parameters of patient's safety (that is, vital signs, laboratory monitoring of organ function) as well as the duration of mechanical ventilation and overall stay on the ICU are analyzed and compared. An intention-to-treat analysis will be carried out with all patients for whom it will be possible to define a wake-up time. In addition, a per-protocol analysis is envisaged. Completion of patient recruitment is expected by the end of 2012. DISCUSSION: This clinical study is designed to evaluate the impact of sevoflurane during long-term sedation of critically ill patients on 'weaning time', efficiency, and patient's safety compared to the standard intravenous sedation concept employing propofol. TRIAL REGISTRATION: EudraCT2007-006087-30; ISRCTN90609144.

[Addicted anaesthetists]. / Berufliche Belastungen in der Anästhesiologie - Abhängigkeitssyndrome bei Anästhesisten.

Drug dependence of anaesthetists occurs more often than in other physicians, especially the noxious usage of common substances in anaesthesiology and pain management like opioids and anaesthetics. Opioids are the most frequent abusively taken medication followed by benzodiazepines, illegal drugs, Propofol and Ketamine. Determining for the behavioral pattern is the easy access to the drugs. Especially as some of the addictive-drugs (e. g. Propofol, Ketamine) are not underlying any release-control. Recent German surveys confirm the American figures. For the development of drug dependence many factors like biographic, social and genetic aspects as well as the substances and their potential itself are significant. Furthermore, the presence of many stimuli encourages the relapse-risk for addicted people despite earlier abstinence. At least 16% of all cases and 37% of the Propofol-addiction cases proceed deadly. American studies with structured therapy-, rehabilitation- and follow-up surveillance-programs show a positive prognosis for anaesthetists. In Germany it requires rethinking and the establishment of comparable therapy-offers and facilities.

Age-dependent effects of gradual decreases in cerebral perfusion pressure on the neurochemical response in swine.

OBJECTIVE: There is still a lack of knowledge on the age-dependent relation between a reduction in cerebral perfusion pressure (CPP) and compromised brain perfusion leading to excessive transmitter release and brain damage cascades. The hypothesis is that an age-dependent lower threshold of cerebral blood flow (CBF) autoregulation determines the amount and time course of transmitter accumulation. DESIGN AND SETTING: This was a prospective randomized, blinded animal study performed in a university laboratory involving eight newborn and 11 juvenile anesthetized pigs. INTERVENTION: Striatal dopamine, glutamate, glucose, and lactate were monitored by microdialysis. For CPP manipulation, the cisterna magna was infused with artificial cerebrospinal fluid to control intracranial pressure at the maintained arterial blood pressure (stepwise CPP decrease in 15-min stages to 50, 40, 30, and finally 0 mmHg). MEASUREMENTS AND MAIN RESULTS: Juvenile pigs showed a gradual decrease in CBF between 50 mmHg CPP (CPP-50) and 30 mmHg CPP (CPP-30), but a significant CBF reduction did not occur in newborn piglets until CPP-30 (P < 0.05). At CPP-30, brain oxidative metabolism was reduced only in juveniles, concomitantly with elevations in dopamine and glutamate levels (P < 0.05). In contrast, newborn piglets exhibited a delayed and blunted accumulated of transmitters and metabolites (P < 0.05). CONCLUSIONS: The lower limit of CBF autoregulation was associated with modifications in neurochemical parameters that clearly occurred before brain oxidative metabolism was compromised. Early indicators for mild to moderate hypoperfusion are elevated levels of lactate and dopamine, but elevated levels of glutamate appear to be an indicator of brain ischemia. The shift to the left of the lower autoregulatory threshold is mainly responsible for the postponed neurochemical response to decrements in the CPP in the immature brain.

High frequency oscillation, extracorporeal membrane oxygenation and pumpless arteriovenous lung assist in the management of severe ARDS.

BACKGROUND: The protective lung strategy for severe ARDS, has markedly decreased the associated morbidity and mortality. Sometimes, even the best instrumentation and therapeutic strategy may be insufficient, and extracorporeal gas exchange support is necessary. We describe a desperate case of ARDS, in which various modes of ventilation, combined with vigorous extracorporeal support, resulted in a successful outcome. CASE REPORT: A 35-year-old man, a heavy smoker, was admitted to the hospital because of lobar pneumonia. Despite wide spectrum antimicrobial therapy, he developed ARDS and was placed on a ventilator. Standard ventilation was ineffective and veno-venous ECMO was instituted. The extravascular lung water index (EVLWI) was extremely high (over 30 mL kg-1) and signs of a hyperdynamic circulation (CI 6.1 L m-2 min-1) were observed. Modification of the inotropic support and continuous infusion of furosemide resulted in normalisation of the hydration status, and over a week of ECMO therapy, the patient's general condition improved to the stage that he was scheduled to be weaned from extracorporeal treatment. On the 7th day however, he suddenly deteriorated. A lung CT-scan revealed bilateral pneumothoraces and diffuse pulmonary embolism. Three thoracic drains were inserted, but unfortunately, the drainage was complicated by massive bleeding and a subsequent thoracotomy. Two days later, a gastrointestinal haemorrhage occurred. Heparin dosage was reduced, and ECMO was discontinued and replaced with HFOV. This resulted in adequate oxygenation, however because of ineffective CO2 elimination, pumpless arteriovenous extracorporeal lung assist (PECLA) was instituted, allowing conventional ventilation to be resumed after 8 days. The further clinical course was complicated by persistent bilateral pneumothoraces, pleural effusion and Pseudomonas nosocomial infection. The man eventually recovered after 54 days in the ICU, and was transferred to a rehabilitation department. DISCUSSION AND CONCLUSION: ECMO has been recommended for severe ARDS since it avoids overdistension of the lungs and the use of high oxygen concentrations. Early institution of ECMO decreases mortality and morbidity in rapidly progressing ARDS. In the described case, ECMO was probably started too late, after volutrauma has already occurred. A combination of HFOV and PECLA may be recommended in selected cases, in which CO2 retention poses a serious problem.

State of the art: sedation concepts with volatile anesthetics in critically Ill patients.

The use of volatile anesthetics in the intensive care unit (ICU) has only been possible at great cost with the use of commercially available anesthesia systems. A new anesthetic-conserving device (AnaConDa) now facilitates, from a technical viewpoint, the routine use of volatile anesthetics in intensive care patients as part of prolonged sedation, using ICU ventilators. The volatile anesthetic is hereby applied continually via a syringe pump into a miniature vaporizer, which is integrated into the ventilator circuit in place of the usual respiratory filter. During expiration, the anesthetic exhaled by the patient enters the recirculation system, is predominantly stored in the active carbon layer of the anesthetic-conserving device, and redirected into the inspiratory air. At clinically relevant concentrations, more than 90% of the gas is recirculated in such a way. Aside from the possibility of using a central anesthetic gas scavenging system, the use of special passive residual gas filters, which can be connected to the expiratory outlet of the respirator machine, appears above all to be practical. The use of volatile anesthetics on the ICU could adopt a permanent position in various intensive care analgosedation concepts in future. It may be possible thereby to optimize the treatment process both in medical and economical terms.

Evaluation of a bedside monitor of regional CBF as a measure of CO2 reactivity in neurosurgical intensive care patients.

OBJECTIVE: Mild hyperventilation remains a key element in the management of elevated intracranial pressure. However, a harmful effect of hyperventilation on the development or deterioration of ischemic lesions has been shown in patients after severe head trauma. The objective of this study was to investigate the clinical feasibility and reliability of continuous monitoring of regional cerebral blood flow (rCBF) during mild hyperventilation using a thermodiffusion probe. CO2 reactivity was calculated. The measurement of the partial pressure of oxygen (PtiO2) in the cerebral tissue served as a reference parameter. METHODS: An intraparenchymal intracranial pressure sensor, a multiparameter probe for determining the partial pressure of cerebral gases (pHti, PtiO2, PtiCO2), and a thermodiffusion probe for measuring rCBF were used in 10 intensive care patients. All patients were analgosedated and received pressure-controlled mechanical ventilation. Controlled mild hyperventilation was carried out on 2 consecutive days. CO2 reactivity was determined in relation to both CBF and PtiO2. RESULTS: Controlled hyperventilation resulted in a rCBF reduction from 30+/-3 mL/100 g/min to 25+/-2.4 mL/100 g/min (-17%; P<0.05) on the first day of examination and 31+/-3.6 mL/100 g/min to 22+/-4.9 mL/100 g/min (-29%; P<0.05) on the second day. Likewise, mild hyperventilation resulted in a reduction of regional cerebral tissue oxygen partial pressure from 20+/-2.9 mm Hg to 15+/-4 (-25%; P<0.05) on the first day and 20+/-3.1 mm Hg to 14+/-1.5 mm Hg (-30%; P<0.05) on the second. CONCLUSIONS: Continuous monitoring of regional CBF, using an intraparenchymally placed thermodiffusion probe, seems to be a simple and safe bedside technique. The promise of reliably monitoring and interpreting additional parameters such as PtiO2 and PtiCO2 warrants further investigation.

Development and validation of an efficient HPLC method for quantification of voriconazole in plasma and microdialysate reflecting an important target site.

Voriconazole is a very potent antifungal agent used to treat serious fungal infections (candidiasis); it is also the therapy of choice for aspergillosis. After standard dosing, several factors affect exposure of voriconazole, resulting in large variability and demanding further elucidation of drug distribution. For measurements at the site of action, microdialysis is considered to be an outstanding minimally invasive method. For determination of voriconazole in microdialysate and human plasma a new, efficient, reliable, and robust HPLC assay using UV detection at 254 nm has been developed and validated. After simple sample preparation using acetonitrile for plasma and for microdialysate, 20 microL were injected and separated on an RP-18 column. The chromatographic run time was less than 4 min. Overall, the assay showed high precision (CV 93.9 to 99.5%) and accuracy (RE -96.7 to +107%) for both matrices. Of the 36 drug products typically co-administered with voriconazole, none except ambroxol interfered with its peak signal, and this interference was successfully managed. In summary, the method is highly suitable for application in (pre)clinical microdialysis studies, e.g., of critically ill patients with invasive mycoses.

Endothelin-1 and cerebral blood flow in a porcine model.

The purpose of the study was to investigate whether provoked changes of cerebral perfusion pressure and arterial carbon dioxide tension are able to influence the cerebral metabolism of endothelin-1 (ET-1) in a porcine model. Brain tissue oxygen tension, regional cerebral blood flow and mean arterial blood pressure were monitored in 10 healthy pigs during induced hyperventilation (HV), hypertension (HrT) and hypotension (HoT). ET-1 was determined in the arterial and cerebrovenous blood. Microdialysis samples (lactate, glucose and pyruvate) were taken from brain and subcutaneous tissue. A significant decrease (p<0.05) of the arterial ET-1 (1.46+/-0.33 fmol/mL) compared to the baseline (2.18+/-0.36 fmol/mL) was observed after the HoT-period. We detected a positive correlation between cerebrovenous ET-1 and extracellular cerebral glucose (0.68; p<0.05) after the baseline as well as a negative correlation of -0.81 (p<0.005) between the cerebrovenous ET-1 level and the extracellular cerebral lactate after the HoT-period. These data imply that with increasingly pathological changes of the cerebral metabolism endothelin becomes progressively more important in the regulation of cerebral vascular tone.

Recombinant factor VIIa reduces bleeding risk in patients on platelet aggregation inhibitors immediately prior to renal transplantation--a retrospective analysis.

BACKGROUND: Transplant surgery often requires an effective preoperative treatment which allows to reduce the risk of bleeding caused by platelet aggregation inhibitors without major delay. The use of recombinant activated coagulation factor VIIa (rFVIIa) may be a future treatment option in such patients. METHOD: Five patients with end-stage renal disease on treatment with platelet aggregation inhibitors (ASA, Plavix, Aggrenox), who were scheduled for renal transplantation and received a preoperative bolus of recombinant factor VIIa (rFVIIa, NovoSeven) in a dose of 3 kIU/kg (60 microg/kg), were retrospectively analyzed. Parameters of plasmatic coagulation as well as bleeding time were determined before as well as after the administration of rFVIIa. RESULTS: The initial median bleeding time was 7.3 min (range 6.2-14.6); after administration of rFVIIa it fell to 2.8 min (range 1.8-3.2). All patients had a good intraoperative hemostasis. None of the patients developed a hematoma requiring surgical treatment. The graft of all patients was homogeneously and well perfused, with a sufficient postoperative diuresis. CONCLUSION: The administration of rFVIIa prior to renal transplantation in patients on treatment with platelet aggregation inhibitors was effective and without major complications. Further studies should be performed in order to confirm our observations.