There is no evidence that carbon dioxide-enriched oxygen before apnea affects the time to arterial desaturation, but it might improve cerebral oxygenation in anesthetized obese patients: a single-blinded randomized crossover trial.

PURPOSE: Carbon dioxide (CO2) increases cerebral perfusion. The effect of CO2 on apnea tolerance, such as after anesthesia induction, is unknown. This study aimed to assess if cerebral apnea tolerance can be improved in obese patients under general anesthesia when comparing O2/Air (95%O2) to O2/CO2 (95%O2/5%CO2). METHODS: In this single-center, single-blinded, randomized crossover trial, 30 patients 18-65 years, with body mass index > 35 kg/m2, requiring general anesthesia for bariatric surgery, underwent two apneas that were preceded by ventilation with either O2/Air or O2/CO2 in random order. After anesthesia induction, intubation, and ventilation with O2/Air or O2/CO2 for 10 min, apnea was performed until the cerebral tissue oxygenation index (TOI) dropped by a relative 20% from baseline (primary endpoint) or oxygen saturation (SpO2) reached 80% (safety abortion criterion). The intervention was then repeated with the second substance. RESULTS: The safety criterion was reached in all patients before cerebral TOI decreased by 20%. The time until SpO2 dropped to 80% was similar in the two groups (+ 6 s with O2/CO2, 95%CI -7 to 19 s, p = 0.37). Cerebral TOI and PaO2 were higher after O2/CO2 (+ 1.5%; 95%CI: from 0.3 to 2.6; p = 0.02 and + 0.6 kPa; 95%CI: 0.1 to 1.1; p = 0.02). CONCLUSION: O2/CO2 improves cerebral TOI and PaO2 in anesthetized bariatric patients. Better apnea tolerance could not be confirmed.

General Anesthetics in Cancer Surgery: Can Anesthesiologists Help the Patient with More than a Safe Sleep.

Most patients suffering from neoplastic diseases will at some point during their illness be approached surgically. Surgery itself may be unfortunately responsible for tumor proliferation and metastatic spread. With the perioperative period increasingly becoming a focus of research in anesthesia, anesthesiologists have looked at the chance to influence cancer progression based on their choice of anesthesia regimen and strategy. Many anesthetic agents have been investigated for their potential impact on the course of cancer disease. There is an abundance of retrospective studies and very few prospective ones that tackled this issue. The aim of this article is to review the current state of the evidence on general anesthesia involving volatile and intravenous agents as substrates, focusing on halogenated inhalational agents and propofol, to guide clinical decision making in assessments of the best practice for perioperative management of cancer surgery.

Inflammation reduces osteoblast cytotoxicity induced by diclofenac: An in vitro study.

BACKGROUND: Diclofenac and other NSAIDs are routinely used in the postoperative period. Their effect on fracture healing remains unclear and controversial. OBJECTIVE: The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of diclofenac on human osteoblasts. DESIGN: Laboratory in vitro study. SETTING: Institute of Physiology, Zurich, Center for Integrative Human Physiology, University of Zurich. MATERIALS: Monolayers of human osteoblasts. INTERVENTIONS: Exposure of human osteoblast monolayers to several concentrations of diclofenac, for different periods of time, with and without an artificially induced inflammatory process. MAIN OUTCOME MEASURES: Cell count, cell viability, cell proliferation and apoptosis. RESULTS: A concentration-mediated, time and exposure dependent cytotoxic effect of diclofenac-mediated apoptosis was observed. Stimulated inflammatory conditions seemed to reduce toxic effects. CONCLUSION: Cytotoxic effects of diclofenac are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to diclofenac cytotoxicity, especially in the presence of higher concentration and longer exposure time.

Perioperative omega-3 fatty acids fail to confer protection in liver surgery: Results of a multicentric, double-blind, randomized controlled trial.

BACKGROUND & AIMS: In a variety of animal models, omega-3 polyunsaturated fatty acids (Ω3-FAs) conferred strong protective effects, alleviating hepatic ischemia/reperfusion injury and steatosis, as well as enhancing regeneration after major tissue loss. Given these benefits along with its safety profile, we hypothesized that perioperative administration of Ω3-FAs in patients undergoing liver surgery may ameliorate the postoperative course. The aim of this study was to investigate the perioperative use of Ω3-FAs to reduce postoperative complications after liver surgery. METHODS: Between July 2013 and July 2018, we carried out a multicentric, double-blind, randomized, placebo-controlled trial designed to test whether 2 single intravenous infusions of Omegaven® (Ω3-FAs) vs. placebo may decrease morbidity. The primary endpoints were postoperative complications by severity (Clavien-Dindo classification) integrated within the comprehensive complication index (CCI). RESULTS: A total of 261 patients (132 in the Omegaven and 129 in the placebo groups) from 3 centers were included in the trial. Most cases (87%, n = 227) underwent open liver surgery and 56% (n = 105) were major resections (≥3 segments). In an intention-to-treat analysis including the dropout cases, the mortality rate was 4% and 2% in the Omegaven and placebo groups (odds ratio0.40;95% CI 0.04-2.51; p = 0.447), respectively. Any complications and major complications (Clavien-Dindo ≥ 3b) occurred in 46% vs. 43% (p = 0.709) and 12% vs. 10% (p = 0.69) in the Omegaven and placebo groups, respectively. The mean CCI was 17 (±23) vs.14 (±20) (p = 0.417). An analysis excluding the dropouts provided similar results. CONCLUSIONS: The routine perioperative use of 2 single doses of intravenous Ω3-FAs (100 ml Omegaven) cannot be recommended in patients undergoing liver surgery (Grade A recommendation). LAY SUMMARY: Despite strong evidence of omega-3 fatty acids having liver-directed, anti-inflammatory and pro-regenerative action in various rodent models, 2 single omega-3 fatty acid infusions given to patients before and during liver surgery failed to reduce complications. Because single omega-3 fatty acid infusions failed to confer liver protection in this trial, they cannot currently be recommended. TRIAL REGISTRATION: ClinicalTrial.gov: ID: NCT01884948; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

Sevoflurane preconditioning protects from posttransplant injury in mouse lung transplantation.

BACKGROUND: Although sevoflurane (Sevo) had been shown to ameliorate posttransplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from posttransplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters. MATERIALS AND METHODS: Three experimental approaches were used: (1) BALB/c mice were preconditioned for 2 h with Sevo or a fentanyl cocktail (Control; n = 10); (2) syngeneic (Syn) mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 h storage to mimic PGD (Syn-Tx, n = 12) versus controls (fentanyl cocktail); and (3) allogeneic (Allo) Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n = 12) versus controls (fentanyl cocktail). Syn-Tx grafts were harvested on Day 1, Allo-Tx grafts on Day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction). RESULTS: Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (P = 0.03) and a tendency toward lower levels of lung tissue messenger RNA for tumor necrosis factor-α. In Syn-Tx recipients, the Sevo group had histologically a tendency toward an attenuation of PGD and showed significantly lower levels of interleukin 6 (P = 0.01) in plasma, but higher levels of interleukin 10 (P < 0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (P = 0.03), fewer classical macrophages (F4/80+; P < 0.01), but more anti-inflammatory activated macrophages (M2, CD206+; P < 0.01). Functionally, the Sevo group had a tendency toward improved oxygenation. CONCLUSIONS: We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction of alternatively activated macrophages during AR. These promising data could set the base for using Sevo preconditioning in donor lungs for a human trial.

Which Anesthesia Regimen Is Best to Reduce Morbidity and Mortality in Lung Surgery?: A Multicenter Randomized Controlled Trial.

BACKGROUND: One-lung ventilation during thoracic surgery is associated with hypoxia-reoxygenation injury in the deflated and subsequently reventilated lung. Numerous studies have reported volatile anesthesia-induced attenuation of inflammatory responses in such scenarios. If the effect also extends to clinical outcome is yet undetermined. We hypothesized that volatile anesthesia is superior to intravenous anesthesia regarding postoperative complications. METHODS: Five centers in Switzerland participated in the randomized controlled trial. Patients scheduled for lung surgery with one-lung ventilation were randomly assigned to one of two parallel arms to receive either propofol or desflurane as general anesthetic. Patients and surgeons were blinded to group allocation. Time to occurrence of the first major complication according to the Clavien-Dindo score was defined as primary (during hospitalization) or secondary (6-month follow-up) endpoint. Cox regression models were used with adjustment for prestratification variables and age. RESULTS: Of 767 screened patients, 460 were randomized and analyzed (n = 230 for each arm). Demographics, disease and intraoperative characteristics were comparable in both groups. Incidence of major complications during hospitalization was 16.5% in the propofol and 13.0% in the desflurane groups (hazard ratio for desflurane vs. propofol, 0.75; 95% CI, 0.46 to 1.22; P = 0.24). Incidence of major complications within 6 months from surgery was 40.4% in the propofol and 39.6% in the desflurane groups (hazard ratio for desflurane vs. propofol, 0.95; 95% CI, 0.71 to 1.28; P = 0.71). CONCLUSIONS: This is the first multicenter randomized controlled trial addressing the effect of volatile versus intravenous anesthetics on major complications after lung surgery. No difference between the two anesthesia regimens was evident.

Clinical concentrations of morphine are cytotoxic on proliferating human fibroblasts in vitro.

BACKGROUND: Morphine and other opioids are routinely used systemically and as wound infusions in the postoperative period. Their effect on wound and fracture healing remains unclear. OBJECTIVE: The primary outcome was to assess the potential cytotoxicity of clinically relevant concentrations of morphine on human fibroblasts. DESIGN: Laboratory in-vitro study. SETTING: Institute of Physiology, Zurich Center for Integrative Human Physiology, University of Zurich. MATERIALS: Monolayers of human fibroblasts. INTERVENTION(S): Exposure of human fibroblast monolayers to several concentrations of morphine, for different periods of time, with and without an artificially induced inflammatory process. MAIN OUTCOME MEASURES: Cell count, cell viability, cell proliferation and apoptosis. RESULTS: A concentration, time and exposure-dependent cytotoxic effect of morphine-mediated apoptosis was observed. Simulated inflammatory conditions seemed to lessen toxic effects. CONCLUSION: Cytotoxic effects of morphine are exposure, time and concentration dependent. Simulating aspects of inflammatory conditions seems to increase resistance to morphine cytotoxicity especially in the presence of higher concentration and longer exposure times.

"A randomized, double-blind study of the effects of omega-3 fatty acids (Omegaven) on outcome after major liver resection".

BACKGROUND: The body is dependent on the exogenous supply of omega-3 polyunsaturated fatty acids (n3-PUFA). These essential fatty acids are key players in regulating metabolic signaling but also exert anti-inflammatory and anti-carcinogenic properties. The liver is a major metabolic organ involved in fatty acid metabolism. Under experimental conditions, n3-PUFA exert beneficial effect on hepatic steatosis, regeneration and inflammatory insults such as ischemic injury after surgery. Some of these effects have also been observed in human subjects. However, it is unclear whether perioperative administration of n3-PUFA is sufficient to protect the liver from ischemic injury. Therefore, we designed a randomized controlled trial (RCT) assessing n3-PUFA (pre-) conditioning strategies in patients scheduled for liver surgery. METHODS/DESIGN: The Omegaven trial is a multi-centric, double-blind, randomized, placebo- controlled trial applying two single doses of Omegaven or placebo on 258 patients undergoing major liver resection. Primary endpoints are morbidity and mortality one month after hospital discharge, defined by the Clavien- Dindo classification of surgical complications (Ann Surg 240(2):205-13, 2004) as well as the Comprehensive Complication Index (CCI) (Ann Surg 258(1):1-7, 2013). Secondary outcome variables include length of Intensive Care Unit (ICU) and hospital stay, postoperative liver function tests, fatty acid and eicosanoid concentration, inflammatory markers in serum and in liver tissue. An interim analysis is scheduled after the first 30 patients per randomization group. DISCUSSION: Long-term administration of n3-PUFA have a beneficial effect on metabolism and hepatic injury. Patients often require surgery without much delay, thus long-term n3-PUFA uptake is not possible. Also, lack of compliance may lead to incomplete n3-PUFA substitution. Hence, perioperative Omegaven™ may provide an easy and controllable way to ensure hepaative application of tic protection. TRIAL REGISTRATION: ClinicalTrial.gov: ID: NCT01884948 , registered June 14, 2013; Institution Ethical Board Approval: KEK-ZH-Nr. 2010-0038; Swissmedic Notification: 2012DR3215.

Intrathecal hyperbaric 2% prilocaine versus 0.4% plain ropivacaine for same-day arthroscopic knee surgery: a prospective randomized double-blind controlled study.

BACKGROUND: Short-duration spinal anesthesia is a good option for ambulatory knee surgery. Hyperbaric 2% prilocaine has short onset and rapid recovery times and, therefore, may be well suited in this setting. The aim of this study was to compare the times to reach motor block, motor block resolution, and discharge from the postanesthesia care unit (PACU) between hyperbaric 2% prilocaine and 0.4% plain ropivacaine. METHODS: In this prospective randomized double-blind study, 140 patients (ages 18-80 yr and American Society of Anesthesiologists physical status I-II) scheduled for elective unilateral arthroscopic knee surgery lasting < 45 min were allocated to either 3 mL of 2% prilocaine (60 mg) or 3 mL of 0.4% plain ropivacaine (12 mg). Time to reach complete recovery of motor block, time to reach criteria for discharge, as well as side effects up to 48 hr after discharge were recorded. RESULTS: The median (interquartile range [IQR]) time to recovery from the motor block was faster in the 2% prilocaine group compared with the 0.4% ropivacaine group (180 [169-240] min vs 240 [180-300] min, respectively; median difference, 60 min, 95% confidence interval (CI), 23 to 97 min; P = 0.036). The median [IQR] time to reach discharge criteria was similar between the two groups (330 [295-365] min vs, 335 [290-395] min; median difference 5 min, 95% CI, -25 to 35 min; P = 0.330). The incidence of side effects was low and similar in both groups. No case of transient neurologic symptoms occurred in either group. CONCLUSION: The recovery of motor block was faster after intrathecal administration of hyperbaric 2% prilocaine compared with 0.4% plain ropivacaine; however, discharge time was similar between the two groups. Both drugs showed a similar risk profile.

Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial.

OBJECTIVES: : To elucidate the possible organ-protective effect of pharmacological postconditioning in patients undergoing liver resection with inflow occlusion. BACKGROUND: : Inflow occlusion reduces blood loss during liver transection in selected patients but is potentially harmful due to ischemia-reperfusion injury. Preventive strategies include the use of repetitive short periods of ischemia interrupted by a reperfusion phase (intermittent clamping), application of a short period of ischemia before transection (ischemic preconditioning), or pharmacological preconditioning before transection. Whether intervention after resection (postconditioning) may confer protection is unknown. METHODS: : A 3 arm, prospective, randomized trial was designed for patients undergoing liver resection with inflow occlusion to compare the effects of pharmacological postconditioning with the volatile anesthetic agent sevoflurane (n = 48), intermittent clamping (n = 50), or no protective intervention (continuous inflow occlusion, n = 17). Endpoints included peak serum aspartate transaminase level, postoperative complications, and hospital stay. All patients were intravenously anesthetized with propofol. In patients with postconditioning, propofol infusion was stopped upon reperfusion and replaced with sevoflurane for 10 minutes. RESULTS: : Compared with the control group, both postconditioning (P = 0.044) and intermittent clamping (P = 0.015) significantly reduced aspartate transaminase levels. The risk of complications was significantly decreased by postconditioning, odds ratio, 0.08 [95% confidence interval (CI), 0.02-0.36; P = 0.001]) and intermittent clamping, odds ratio, 0.50 [95% CI, 0.26-0.96; P = 0.038], compared with controls. Both interventions reduced length of hospital stay, postconditioning -4 days [95% CI, -6 to -1; P = 0.009], and intermittent clamping -2 days, [95% CI, -4 to 0; P = 0.019]. CONCLUSIONS: : Pharmacological postconditioning reduces organ injury and postoperative complications. This easily applicable strategy should be used in patients with prolonged continuous inflow occlusion.

Bronchoaspiration: incidence, consequences and management.

Aspiration is defined as the inhalation of oropharyngeal or gastric contents into the lower respiratory tract. Upon injury, epithelial cells and alveolar macrophages secrete chemical mediators, attracting and activating neutrophils, which in turn release proteases and reactive oxygen species, degrading the alveolocapillary unit. Aspiration can lead to a range of diseases such as infectious pneumonia, chemical pneumonitis or respiratory distress syndrome with significant morbidity and mortality. It occurs in approximately 3-10 per 10 000 operations with an increased incidence in obstetric and paediatric anaesthesia. Patients are most at risk during induction of anaesthesia and extubation, in particular in emergency situations. The likelihood of significant aspiration can be reduced by fasting, pharmacological intervention and correct anaesthetic management using a rapid sequence induction. Treatment of acid aspiration is by suctioning after witnessed aspiration; antibiotics are indicated in patients with aspiration pneumonia only. Steroids are not proven to improve outcome or reduce mortality. Patients with acute lung injury requiring mechanical ventilation should be ventilated using lung protective strategies with low tidal volumes and low plateau pressure values, attempting to limit peak lung distension and end-expiratory collapse.

Intraoperative adverse events during irreversible electroporation-a call for caution.

BACKGROUND: Irreversible electroporation is increasingly used for treatment of solid tumors, but safety data remain scarce. This study aimed to describe intraoperative adverse events associated with irreversible electroporation in patients undergoing solid tumor ablation. METHODS: We analyzed demographic and intraoperative data for patients (n = 43) undergoing irreversible electroporation for hepato-pancreato-biliary and retroperitoneal malignancies (2012 to 2015). Adverse events were defined as cardiac, surgical, or equipment-related. RESULTS: Adverse events (n = 20, 47%) were primarily cardiac (90%, n = 18), including blood pressure elevation (77%, n = 14/18) and arrhythmia (16%, n = 7/43). All but one was managed medically, 1 patient with arrhythmia required termination of ablation. Bleeding and technical problems with the equipment occurred in 1 patient each. Multivariable analysis revealed previous cardiovascular disease and needle placement close to the celiac trunk associated with increased likelihood for cardiac events. CONCLUSIONS: Intraoperative cardiac adverse events are common during irreversible electroporation but rarely impair completion of the procedure.

Late Post-Conditioning with Sevoflurane after Cardiac Surgery--Are Surrogate Markers Associated with Clinical Outcome?

INTRODUCTION: In a recent randomized controlled trial our group has demonstrated in 102 patients that late post-conditioning with sevoflurane performed in the intensive care unit after surgery involving extracorporeal circulation reduced damage to cardiomyocytes exposed to ischemia reperfusion injury. On the first post-operative day the sevoflurane patients presented with lower troponin T values when compared with those undergoing propofol sedation. In order to assess possible clinical relevant long-term implications in patients enrolled in this study, we performed the current retrospective analysis focusing on cardiac and non-cardiac events during the first 6 months after surgery. METHODS: All patients who had successfully completed the late post-conditioning trial were included into this follow-up. Our primary and secondary endpoints were the proportion of patients experiencing cardiac and non-cardiac events, respectively. Additionally, we were interested in assessing therapeutic interventions such as initiation or change of drug therapy, interventional treatment or surgery. RESULTS: Of 102 patients analyzed in the primary study 94 could be included in this follow-up. In the sevoflurane group (with 41 patients) 16 (39%) experienced one or several cardiac events within 6 months after cardiac surgery, in the propofol group (with 53 patients) 19 (36%, p=0.75). Four patients (9%) with sevoflurane vs. 7 (13%) with propofol sedation had non-cardiac events (p=0.61). While a similar percentage of patients suffered from cardiac and/or non-cardiac events, only 12 patients in the sevoflurane group compared to 20 propofol patients needed a therapeutic intervention (OR: 0.24, 95% CI: 0.04-1.43, p=0.12). A similar result was found for hospital admissions: 2 patients in the sevoflurane group had to be re-admitted to the hospital compared to 8 in the propofol group (OR 0.23, 95% CI: 0.04-1.29, p=0.10). CONCLUSIONS: Sevoflurane does not seem to provide protection with regard to the occurrence of cardiac and non-cardiac events in the 6-month period following cardiac surgery with the use of extracorporeal circulation. However, there was a clear trend towards fewer interventions (less need for treatment, fewer hospital admissions) associated with sevoflurane post-conditioning in patients experiencing any event. Such results might encourage launching large multicenter post-conditioning trials with clinical outcome defined as primary endpoint.

Conditioning With Sevoflurane in Liver Transplantation: Results of a Multicenter Randomized Controlled Trial.

BACKGROUND: During times of organ scarcity and extended use of liver grafts, protective strategies in transplantation are gaining importance. We demonstrated in the past that volatile anesthetics such as sevoflurane attenuate ischemia-reperfusion injury during liver resection. In this randomized study, we examined if volatile anesthetics have an effect on acute graft injury and clinical outcomes after liver transplantation. METHODS: Cadaveric liver transplant recipients were enrolled from January 2009 to September 2012 at 3 University Centers (Zurich/Sao Paulo/Ghent). Recipients were randomly assigned to propofol (control group) or sevoflurane anesthesia. Postoperative peak of aspartate transaminase was defined as primary endpoint, secondary endpoints were early allograft dysfunction, in-hospital complications, intensive care unit, and hospital stay. RESULTS: Ninety-eight recipients were randomized to propofol (n = 48) or sevoflurane (n = 50). Median peak aspartate transaminase after transplantation was 925 (interquartile range, 512-3274) in the propofol and 1097 (interquartile range, 540-2633) in the sevoflurane group. In the propofol arm, 11 patients (23%) experienced early allograft dysfunction, 7 (14%) in the sevoflurane one (odds ratio, 0.64 (0.20 to 2.02, P = 0.45). There were 4 mortalities (8.3%) in the propofol and 2 (4.0%) in the sevoflurane group. Overall and major complication rates were not different. An effect on clinical outcomes was observed favoring the sevoflurane group (less severe complications), but without significance. CONCLUSIONS: This first multicenter trial comparing propofol with sevoflurane anesthesia in liver transplantation shows no difference in biochemical markers of acute organ injury and clinical outcomes between the 2 regimens. Sevoflurane has no significant added beneficial effect on ischemia-reperfusion injury compared to propofol.

Platypnea-orthodeoxia syndrome in the elderly treated by percutaneous patent foramen ovale closure: a case series and literature review.

BACKGROUND: Platypnea-orthodeoxia syndrome (POS) is a rare clinical phenomenon, associating normal oxygen saturation in a supine position and arterial hypoxemia in an upright position. This pathology can be secondary to an intracardiac shunt, a pulmonary vascular shunt or a ventilation-perfusion mismatch. Cardiac POS occurs in the presence of a right-to-left cardiac shunt, most commonly through a patent foramen ovale (PFO). METHODS AND RESULTS: From our single-center prospective database of percutaneous PFO closure we identified five patients (4 females, mean age: 77 ± 11 years) out of 224 (2.2%) patients with a PFO who presented with a POS of cardiac origin. Transthoracic and transoesophageal echocardiographic examinations revealed the underlying mechanisms of POS and the diagnosis was confirmed by right-and-left cardiac catheterization (RLC) and by measuring serial blood oxygen saturation in the pulmonary veins and left atrium in supine and upright positions. PFO was associated with atrial septal aneurysm and a persistent prominent Eustachian valve in 3 patients. All patients underwent a successful percutaneous PFO closure without any immediate or subsequent complications (mean follow-up of 24 ± 18 months). Immediately after the procedure, mean arterial oxygen saturation improved from 83% ± 3 to 93% ± 2 in an upright position and symptoms disappeared. CONCLUSION: POS is a rare and under-diagnosed pathology that must be actively investigated in the presence of position-dependent hypoxemia. The diagnostic work-up must exclude other causes of hypoxemia and confirm the intracardiac shunt using either contrast echocardiography or RLC. For cardiac POS, percutaneous PFO closure is a safe and effective technique that immediately relieves orthodeoxia and patient symptoms.

Poor responsiveness to antiplatelet drugs in acute coronary syndromes: clinical relevance and management.

Cardiovascular diseases are the most common cause of mortality and morbidity in Western countries, accounting for more than 40% of total mortality. An optimal pharmacological management in these patients is of major importance and antiplatelet agents remain the cornerstone of acute coronary syndrome (ACS) therapy at hospital admission and during percutaneous coronary interventions (PCI). The recently described poor biological responses to aspirin and clopidogrel have been source of major concern, especially in era of drug eluting stent implantation. Indeed, insufficient platelet inhibition at the time of PCI has been consistently associated with an increased risk of complications and recurrence of ischemic events. Despite the lack of uniformly accepted definitions of aspirin and clopidogrel poor response, we sought to describe the current evidence and gaps in knowledge. While trials on the potential benefit of an increased antiplatelet maintenance dose after PCI have shown only marginal benefits, the strengthening of the initial antiplatelet regimens by additional loading doses of clopidogrel, by the administration of glycoprotein IIb/IIIa receptor inhibitors or phosphodiesterase inhibitors might further improve outcomes during ACS and PCI in patients with poor responsiveness to conventional dual antiplatelet therapy. Overall, tailoring the antiplatelet treatment on the basis of the individual biological response improves the short-term outcome after PCI. New and more potent antiplatelet drugs may overcome the clinical consequences of the poor response to antiplatelet agents.

Lack of in vivo function of osteopontin in experimental anti-GBM nephritis.

Osteopontin (Opn) is a potent chemoattractant for mononuclear cells that is upregulated in various inflammatory states of the kidney. Opn is believed to contribute to mononuclear cell infiltration and renal injury. The importance of Opn was examined in vivo in rapidly progressive glomerulonephritis in Opn knockout mice. Glomerulonephritis was induced by intravenous injection of rabbit anti-mouse glomerular basement membrane antiserum in mice that had been presensitized to rabbit IgG. Immunologic responsiveness to rabbit IgG (assessed by cutaneous delayed-type hypersensitivity and antibody titers) showed no significant difference between wild-type and Opn -/- mice. Proteinuria was also similar in both groups. Glomerular crescent formation was not different in Opn +/+ and -/- groups (26 +/- 6% versus 29 +/- 7%). Tubulointerstitial infiltration was assessed qualitatively and showed no significant difference between the two genotypes. Formation of thrombi in the glomerular capillaries on a scale from 0 to 3 also showed no significant difference (1.3 +/- 0.3 for Opn +/+ and 1.4 +/- 0.3 for Opn -/- mice). Northern blot analysis of total kidney RNA showed a 5.1-fold increase of Opn expression in Opn +/+ mice compared with untreated controls and the absence of expression in Opn -/- mice, as expected. Regulated upon activation, normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1 mRNA levels were also markedly upregulated with no significant difference between the two strains, excluding compensatory overexpression of these two chemokines in Opn -/- mice. It is concluded that the known upregulation of Opn in murine anti-glomerular basement membrane nephritis does not significantly contribute to the glomerular and tubulointerstitial mononuclear cell infiltration in this model.