Plasma and Lung Tissue Pharmacokinetics of Ceftaroline Fosamil in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass: an In Vivo Microdialysis Study.

Ceftaroline fosamil, a fifth-generation cephalosporin antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), is currently approved for the treatment of pneumonia and complicated skin and soft tissue infections. However, pharmacokinetics data on free lung tissue concentrations in critical patient populations are lacking. The aim of this study was to evaluate the pharmacokinetics of the high-dose regimen of ceftaroline in plasma and lung tissue in cardiac surgery patients during intermittent and continuous administration. Nine patients undergoing elective cardiac surgery on cardiopulmonary bypass were included in this study and randomly assigned to intermittent or continuous administration. Eighteen hundred milligrams of ceftaroline fosamil was administered intravenously as either 600 mg over 2 h every 8 h (q8h) (intermittent group) or 600 mg over 2 h (loading dose) plus 1,200 mg over 22 h (continuous group). Interstitial lung tissue concentrations were measured by in vivo microdialysis. Relevant pharmacokinetics parameters were calculated for each group. Plasma exposure levels during intermittent and continuous administration were comparable to those of previously published studies and did not differ significantly between the two groups. In vivo microdialysis demonstrated reliable and adequate penetration of ceftaroline into lung tissue during intermittent and continuous administration. The steady-state area under the concentration-time curve from 0 to 8 h (AUCss 0-8) and the ratio of AUCSS 0-8 in lung tissue and AUC in plasma (AUClung/plasma) were descriptively higher in the continuous group. Continuous administration of ceftaroline fosamil achieved a significantly higher proportion of time for which the free drug concentration remained above 4 times the minimal inhibitory concentration (MIC) during the dosing interval (% fT>4xMIC) than intermittent administration for pathogens with a MIC of 1 mg/liter. Ceftaroline showed adequate penetration into interstitial lung tissue of critically ill patients undergoing major cardiothoracic surgery, supporting its use for pneumonia caused by susceptible pathogens.

Effect of cardiopulmonary bypass on regional antibiotic penetration into lung tissue.

The use of cardiopulmonary bypass (CPB) during cardiac surgery causes regional ventilation-perfusion mismatch, contributing to regional disturbances in antibiotic penetration into lung tissue. Ventilation-perfusion mismatch is associated with postoperative pneumonia, a frequent and devastating complication after cardiac surgery. In this prospective clinical animal study, we performed in vivo microdialysis to determine the effect of CPB on regional penetration of levofloxacin (LVX) into lung tissue. Six pigs underwent surgery with CPB (CPB group), and another six pigs underwent surgery without CPB (off-pump coronary artery bypass grafting; OPCAB group). LVX (750 mg) was administered intravenously to all pigs immediately after surgery. For regional measurements of LVX in pulmonary concentrations, microdialysis probes were inserted in both lungs of each pig. Pigs were placed in the right lateral position. Time versus concentration profiles of unbound LVX were measured in the upper and lower lung tissue and plasma in all pigs. In all pigs, maximum concentrations (Cmax) of LVX were significantly lower in the upper lung than in the lower lung (OPCAB, P = 0.035; CPB, P < 0.001). Median Cmax of LVX showed a significant difference in the upper versus lower lung in the CPB group (P < 0.05). No significant difference was found in the median Cmax of LVX in the upper and the lower lung in the OPCAB group (P = 0.32). Our data indicate that CPB affects perioperative regional antibiotic penetration into lung tissue. Common clinical antibiotic dosing schemes should be reevaluated in patients undergoing coronary artery bypass grafting with CPB.

Lidocaine/tetracaine patch (Rapydan) for topical anaesthesia before arterial access: a double-blind, randomized trial.

BACKGROUND: Arterial catheterization is painful and is associated with patient stress and anxiety. Analgesia is usually provided by subcutaneous injection of local anaesthetic. An alternative is topical anaesthesia, such as Rapydan which is a novel topical anaesthetic patch containing 70 mg each of lidocaine and tetracaine. We therefore tested the hypothesis that Rapydan patch analgesia is non-inferior to subcutaneous local anaesthetic. METHODS: Ninety patients undergoing elective major cardiac surgery were included in this prospective, double-blind clinical trial. Patients were randomly assigned to receive either a lidocaine/tetracaine patch, followed by subcutaneous injection 0.5 ml of normal saline solution, or placebo patch with subsequent subcutaneous injection of 0.5 ml of lidocaine 1%. Pain during arterial catheterization using 100-mm-long visual analogue scale (VAS) was the primary outcome. Other outcomes were pain during anaesthetic/saline injection and plasma tetracaine concentrations. RESULTS: VAS pain scores during arterial puncture were comparable in both groups and Rapydan was non-inferior to subcutaneous lidocaine. Pain scores at the time of subcutaneous injection were significantly lower (better) in patients assigned to the lidocaine/tetracaine patch than to lidocaine (P=0.001). Plasma tetracaine concentrations never exceeded the detection limit of 25 ng ml(-1) at any time in any patient. CONCLUSIONS: Both the lidocaine/tetracaine patch and subcutaneous injection of lidocaine provided comparable pain control during arterial catheter insertion. Subcutaneous lidocaine caused discomfort during injection, whereas the lidocaine/tetracaine patch required placement 20 min before the procedure. Given adequate time, the patch provided better overall analgesia by obviating the need for subcutaneous infiltration.

[Quality of postoperative pain therapy in Austria: national survey of all departments of anesthesiology]. / Qualität der postoperativen Schmerztherapie in Österreich : Bundesweite Umfrage unter allen anästhesiologischen Abteilungen.

BACKGROUND: Despite increasingly sophisticated concepts of perioperative pain therapy, such as increased use of combined regional anesthesia techniques, the renaissance of ketamine and dipyrone or the use of oral opioids, no significant improvement has been achieved in postoperative pain therapy since 1995. About 300,000 of the approximately 700,000 patients undergoing major surgery each year in Austria experience moderate to severe postoperative pain. The aim of this study was therefore to assess the nationwide status of perioperative acute pain management in postoperative recovery rooms and surgical wards in order to identify potential areas for improvement. METHODS: In 2006 the directors of all Austrian anesthesiology departments (n=125, 100%) were contacted and asked to give detailed information on the status of acute pain management of each individual hospital in Austria using a standardized questionnaire. Data of each individual department were derived from quality control and self-assessment of each department. No patients were questioned. The return rate was 96% (n=120) due to intensive personal contact in cases of missing data. RESULTS: In this nationwide survey 120 anesthesiology departments participated together accounting for a total of 757,895 operations per year. Of the patients 63.6% were informed preoperatively on the available regimens of acute pain management. In 81% of patients perioperative pain therapy consisted of a multimodal therapeutic approach, 58.6% of the departments used international guidelines and 39.7% worked with international guidelines adapted to local requirements. In 88% of patients a detailed prescription for postoperative pain therapy was available when transferred to the surgical ward. Surgical wards were equipped with routine pain therapy protocols in 28% another 20% of wards had special pain therapy protocols for individual operations. In 22% of cases pain assessment was repeated 3-4 times per day and in 33.9% postoperative pain was assessed only once twice per day. Pain assessments were recorded in the patient charts in 60.7% of cases. If changes to the pain therapy regimen were required anesthesiologists were involved in only 14.3% of cases. In addition an acute pain service was available only in 39.2% of Austrian anesthesiology departments. CONCLUSIONS: Although the multimodal approach to acute pain therapy is widely used and standardized therapeutic regimens are well established in the majority of anesthesiology and surgical wards, there still remains room for improvement. Pain assessment is generally barely adequate and written documentation of pain assessment is missing almost completely. In addition, almost two thirds of hospitals in Austria are still lacking an acute pain service.

Randomized clinical trial comparing double-lumen tube and EZ-Blocker for single-lung ventilation.

BACKGROUND: In several clinical situations, lung separation and single-lung ventilation (SLV) is essential. In these cases, the double-lumen tube (DLT) is the most widely used device. Bronchial blocker such as Univent or Arndt Blocker serves as an alternative. The EZ-Blocker(®) (EZ; AnaesthetIQ B.V., Rotterdam, The Netherlands) is a new device promising to exceed clinical performance of DLT. The aim of this study was to assess the clinical performance of EZ in comparison with conventional left-sided DLT. METHODS: Forty adult patients undergoing elective thoracic surgery requiring thoracotomy and SLV were included in this study. The patients were randomly assigned to one of two groups: EZ (combined with conventional 7.5 or 8.5 mm single-lumen tube) or DLT (37 or 39 Fr left-sided DLT). Time for intubation procedure and time to verification of the correct position of EZ or DLT using fibreoptic bronchoscopy (FOB) were recorded. After surgery, a thoracic surgeon rated the quality of collapse of the lung (1-3 on a three-level scale). RESULTS: Time for intubation using DLT 85.5 (54.8) s was significantly faster (P<0.001) than using EZ 192 (89.7) s, whereas time for bronchoscopy was not significantly different (P=0.556). Conditions of surgery were rated equally [DLT 1.3 (0.6) vs EZ 1.4 (0.6), P=0.681]. CONCLUSIONS: Although time for intubation was longer with the EZ, the device proved to be an efficient and easy-to-use device. The EZ is a valuable alternative device to conventional DLT. Verification of the correct position of the EZ by FOB seems to be obligatory. This study was registered at http://www.clinicaltrials.gov (identifier: NCT01171560).

Results of open heart surgery in Jehovah's Witnesses patients.

AIM: The aim of this paper was to evaluate the results in patients from the religious community of Jehovah's Witnesses (JW) undergoing open heart surgery. METHODS: Between January 1998 and November 2007, 35 patients with a religious background of JW church underwent open heart surgery at the Department of Cardiothoracic Surgery, Medical University of Vienna (Austria). Eighteen patients underwent coronary artery bypass graft (CABG), 11 patients underwent valve surgery and 5 patients underwent combined procedures. One patient underwent isolated ascending aortic replacement. Five patients undergoing CABG were operated without cardiopulmonary bypass (CBP). RESULTS: Mean baseline hematocrit serum levels were 35.8+/-6.3%. The mean decrease of hematocrit serum levels was 20.0+/-21.1% after surgery. The mean decrease of hematocrit serum levels in patients undergoing CABG without CPB was 12.5+/-5.4% and 12.0+/-20.0% in patients after isolated valve replacement. One patient died during the operation. Four patients died in the postoperative period due to anemia. During follow-up, being 34.6+/-34.8 months to date, no cardiovascular related adverse event has been observed. CONCLUSIONS: The decrease of hematocrit serum levels is significantly characterizing the postoperative period of open heart surgery in JW. In patients undergoing CABG without CPB and in patients undergoing isolated valve replacement, decrease of hematocrit serum levels was lowest. Therefore, these techniques should be considered for first choice when appropriate. Furthermore, highly normal preoperative hematocrit serum levels and a meticulous surgical technique remain the mainstay of therapy in these patients.

Cannulation of the axillary artery: the decision between direct cannulation and cannulation via side graft.

BACKGROUND: The axillary artery has emerged as promising alternative cannulation site when the ascending aorta is unsuitable for cannulation. However, in order to minimize vascular injury, the decision to cannulate the artery directly or via graft has to be considered carefully. METHODS: Seventy patients underwent axillary artery cannulation during a two-year period. Indications for operation were acute aortic dissection type A in 25(36 %), ascending aortic or arch aneurysm in 32 (46 %), redo surgery in 6 (9 %), and severely atherosclerotic aorta in 3 (4.3 %) patients. Depending on the diameter of the vessel and the rigidity of the wall, the artery was either cannulated directly or via an 8-mm prosthetic Dacron graft. RESULTS: Direct cannulation was performed in 46 patients (66 %) and cannulation via graft in the remaining 24 patients (34 %). The complication rate associated with axillary artery cannulation was 3.8 %. These two patients developed retrograde type A dissection and further dissection into the descending aorta caused by forceful insertion of a 20-French cannula in a very elastic and small artery. CONCLUSIONS: Cannulation of the axillary artery is an attractive approach with a wide indication spectrum. However, the decision to cannulate directly or via graft should be based on the diameter and elasticity of the vessel, to minimize the complications of vascular injury and subsequent dissection.

Clonidine added to bupivacaine enhances and prolongs analgesia after brachial plexus block via a local mechanism in healthy volunteers.

BACKGROUND AND OBJECTIVE: The addition of clonidine to local anaesthetics enhances pain relief after peripheral nerve block, but the site of action is unproven. METHODS: Seven healthy volunteers underwent three brachial block procedures using bupivacaine 0.25% 1 mg kg(-1) + epinephrine 1:200,000 (=local analgesic) in a randomized, double-blind cross-over fashion: (a) control treatment: local analgesic with 0.9% sodium chloride solution for the block and an intramuscular injection of saline; (b) intramuscular treatment: local analgesic with 0.9% NaCl for block and an intramuscular injection of clonidine 2 microg kg(-1) and (c) block treatment: local analgesic with clonidine 2 microg kg(-1) for block and an intramuscular injection of saline. RESULTS: The onset and duration of complete blockade (sensory/motor/temperature) was evaluated in the four nerve regions of the hand and forearm. Additionally, sedation score, blood pressure, heart rate and plasma clonidine concentrations were determined. The median duration of complete sensory blockade was 270 min (range 0-600) for block treatment compared to 0 min (range 0-480) for intramuscular treatment (P < 0.05) and 0 min (range 0-180) for control treatment (P < 0.05). Motor and temperature blockade exhibited similar results. Administration of clonidine was associated with sedation and a decrease in heart rate and blood pressure independent of the route of administration. Plasma clonidine concentrations were lower for block compared to the intramuscular treatment. CONCLUSIONS: The admixture of clonidine to bupivacaine plus epinephrine prolongs and enhances brachial plexus blockade. Lower clonidine plasma concentrations for block treatment strongly suggest a local effect.

Endoluminal stent-graft placement in patients with acute aortic dissection type B.

OBJECTIVES: This study was performed to evaluate the feasibility, safety and effectiveness of endovascular stent-grafting in treating Stanford type B acute aortic dissection. We describe our first clinical experiences and initial results with stent-grafting across the primary entry tear in patients with acute aortic dissection type B. METHODS: Between March 2000 and August 2001, nine patients with acute type B dissection were treated endoluminally by stent-graft implantation. There were seven male and two female patients with a mean age of 63 years (between 48 and 85 years). In all nine patients aortic dissection was diagnosed by multislice computed tomography (CT) angiography. All nine patients had a maximal aortic diameter of 5.5 cm or more and recurrent pain, one patient showed hemoptysis. This patient with signs of a contained rupture was treated under emergency condition, the eight remaining patients were in hemodynamic stabile condition at the time of intervention. The GORE Excluder stent-graft system was used in eight patients (mean 1.8 stents/patient) and the TALENT stent-graft system in one patient, which were introduced transfemorally. RESULTS: The primary entry tear could be sealed successfully in all nine patients. Complete thrombosis of the false thoracic aortic lumen was obtained in two patients, in the remaining seven patients the false lumen was obliterated in the area of the thoracic aorta but perfused via re-entries in the abdominal region. No severe intraoperative complications occurred. One patient developed bilateral incomplete paraplegia with motor and sensory deficits affecting completely the right leg and partially the left leg, 14 h after intervention. A cerebrospinal fluid drainage was initiated by inserting a lumbar catheter. All nine patients, including the patient with the transient paraplegia, could be discharged from the hospital in excellent condition and without remaining neurologic deficits. Control CT scans showed a reduction of the false lumen from 2.34+/-0.58 to 0.7+/-0.44 cm and an increase of the true lumen from 1.56+/-0.5 to 4.10+/-0.6 cm in the thoracic aortic region. Mean ICU stay was 1.8 days, mean postoperative hospital stay was 7.6 days. CONCLUSIONS: Stent-grafting of acute type B dissections may represent a very effective and promising new method by closure of the primary entry tear, thereby minimizing the risk of rupture of the thoracic aorta and optimizing distal perfusion by decompression of the true lumen.

Different modes of degeneration in autologous and heterologous heart valve prostheses.

BACKGROUND AND AIM OF THE STUDY: This study was performed to elucidate the mechanism of primary tissue failure of bioprosthetic heart valves, which were fabricated from autologous pericardium (Autogenics). Results were compared with the degeneration pattern of heterologous pericardial bioprostheses. METHODS: Between March 1994 and December 1996, 87 Autogenics heart valves were implanted in the aortic position. Since then, 15 valves had to be explanted due to structural deterioration. The average implant period was 33+/-8 months. All explants were examined by gross morphological evaluation and X-ray analysis to identify the failure mode of these devices. In eight explanted autologous tissue valves and six explanted heterologous pericardial bioprostheses, exact morphological evaluation was performed by scanning electron microscopy, microscopic and immunohistochemical techniques. RESULTS: All autologous tissue valves failed due to cuspal tears localized at the commissures. Nocalcification could be detected by X-ray analysis and microscopic methods. Endothelial cell coverage was evident at the outflow surface of all autologous bioprostheses. Histological examination showed severe disintegration of the collagen fibers by insudated plasma proteins and erythrocytes, and the absence of the original fibroblasts. Collagen fibers were vigorously altered between the inner and outer stent of the Autogenics valve. In contrast, heterologous pericardial valves failed due to severe calcification of the cusps. Histological evaluation displayed invasion of macrophages and calcific deposits. The collagenous texture of the pericardial tissue was significantly better preserved compared with autologous tissue. CONCLUSION: High biocompatibility of autologous tissue valves is indicated by the absence of calcium deposits, macrophages and foreign body giant cells, and the presence of endothelial cell ingrowth. Severe disintegration of autologous tissue suggests that brief immersion in glutaraldehyde generates inadequate mechanical stability of bioprosthetic heart valve material. Heterologous valves exhibit low biocompatibility but superior preservation of the collagenous biomaterial.

Thoracic aortic aneurysms: treatment with endovascular self-expandable stent grafts.

BACKGROUND: This study was performed to evaluate the safety and feasibility of endovascular stent graft placement in the treatment of descending thoracic aortic aneurysms. METHODS: Between November 1996 and February 1999, endovascular stent graft repair was used in 21 patients. There were 5 women and 16 men with a mean age of 67 years (range, 41 to 87 years). An atherosclerotic aneurysm with a diameter of more than 6 cm was the indication for intervention in 19 patients (90.5%). In 2 patients (9.5%), a localized aortic dissection with a diameter of more than 6 cm was treated. In 71.4% (15 of 21) of patients, multiple stents were necessary for aneurysm exclusion. To allow safe deployment of the stent graft, preliminary subclavian-carotid artery transposition was performed in 9 patients (42.9%). Vascular access was achieved through a small incision in the abdominal aorta (n = 6), an iliac artery (n = 8), or a femoral artery (n = 7). Talent and Prograft stent grafts were used. RESULTS: Successful deployment of the endovascular stent grafts was achieved in all patients. Two patients died postoperatively (mortality rate, 9.5%), 1 of aneurysmal rupture and the other of impaired perfusion of the celiac axis. Repeat stenting was done in 3 patients because of intraoperative leakage. CONCLUSIONS: Endovascular stent graft repair is a promising and less invasive alternative to exclude the aneurysm from blood flow. This technique allows treatment of patients who are unsuitable for conventional surgical procedures. An exact definition of inclusion criteria and technical development of stent grafts should contribute to further improvements in clinical results.