Julian Millo

Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia

Background: Fibrin deposition is a hallmark of pneumonia. To determine the kinetics of alterations in local coagulation and fibrinolysis in relation to ventilator associated pneumonia (VAP), a single centre prospective study of serial changes in pulmonary and systemic thrombin generation and fibrinolytic activity was conducted in patients at risk for VAP. Methods: Non-directed bronchial lavage (NBL) was performed on alternate days in patients expected to require mechanical ventilation for more than 5 days. A total of 28 patients were studied, nine of whom developed VAP. Results: In patients who developed VAP a significant increase in thrombin generation was observed in the airways, as reflected by a rise in the levels of thrombin-antithrombin complexes in NBL fluid accompanied by increases in soluble tissue factor and factor VIIa concentrations. The diagnosis of VAP was preceded by a decrease in fibrinolytic activity in NBL fluid. Indeed, before VAP was diagnosed clinically, plasminogen activator activity levels in NBL fluid gradually declined, which appeared to be caused by a sharp increase in NBL fluid levels of plasminogen activator inhibitor 1. Conclusion: VAP is characterised by a shift in the local haemostatic balance to the procoagulant side, which precedes the clinical diagnosis of VAP.

Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines.

Objective:This article aims to provide the first systematic review of enhanced recovery after surgery (ERAS) programs for esophagectomy and generate guidelines. Background:ERAS programs use multimodal approaches to reduce complications and accelerate recovery. Although ERAS is well established in colorectal surgery, experience after esophagectomy has been minimal. However, esophagectomy remains an extremely high-risk operation, commonly performed in patients with significant comorbidities. Consequently, ERAS may have a significant role to play in improving outcomes. No guidelines or reviews have been published in esophagectomy. Methods:We undertook a systematic review of the PubMed, EMBASE, and the Cochrane databases in July 2012. The literature was searched for descriptions of ERAS in esophagectomy. Components of successful ERAS programs were determined, and when not directly available for esophagectomy, extrapolation from related evidence was made. Graded recommendations for each component were then generated. Results:Six retrospective studies have assessed ERAS for esophagectomy, demonstrating favorable morbidity, mortality, and length of stay. Methodological quality is, however, low. Overall, there is little direct evidence for components of ERAS, with much derived from nonesophageal thoracoabdominal surgery. Conclusions:ERAS in principle seems logical and safe for esophagectomy. However, the underlying evidence is poor and lacking. Despite this, a number of recommendations for practice and research can be made.

TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P=0.02), sTNFRSF1A (P=0.005) and sTNFRSF1B (P=0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R=0.51, P<0.001; sTNFRSF1B R=0.53, P<0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study

BackgroundDespite consensus criteria, diagnosing acute lung injury, or its more severe form acute respiratory distress syndrome (ALI/ARDS) remains challenging. Adding objective measures, such as plasma levels of biological markers could facilitate recognition of ALI/ARDS. This study was designed to assess and compare the diagnostic accuracy of biological markers for ALI/ARDS with ventilator-associated pneumonia (VAP).MethodsWe performed serial measurements of Clara cell protein (CC16), soluble receptor for advanced glycation end products (sRAGE), surfactant protein D (SP-D) and Krebs von den Lungen (KL-6) in plasma of patients with VAP and mechanically ventilated control patients without VAP. ALI/ARDS was diagnosed using the criteria of the North-American European consensus conference.ResultsThirty-seven patients were enrolled - 22 patients with VAP and 15 control patients. Ten patients with pneumonia met the ALI/ARDS consensus criteria. Control patients never met these criteria. Plasma CC16 had a good diagnostic capacity for ALI/ARDS as shown by the receiver operating characteristic curve with an area under the curve of 0.91 (95% confidence interval (CI) 0.79 - 1.00; p < 0.001). Identification of ALI/ARDS patients by sudden increases in plasma CC16 of 30% or more yielded a sensitivity of 90% and a specificity of 92%. Of note, levels of CC16 increased 2 days before ALI/ARDS diagnosis. A cut-off level of 50 ng/ml SP-D yielded a specificity of 100% while the sensitivity was 70%. The area under the curve for SP-D was 0.80 (95% CI 0.58 - 1.00; p = 0.02). The diagnostic accuracies of KL-6 and sRAGE were low.ConclusionPlasma CC16 seems a potential biological marker for ALI/ARDS in patients with VAP. Plasma levels of sRAGE, SP-D and KL-6 have limited discriminative power for diagnosing ALI/ARDS in VAP.

Protein C in pneumonia

Pneumonia is characterised by a disturbed alveolar fibrin turnover which is the net result of activation of coagulation and attenuation of fibrinolysis.1,2 We have recently shown, in patients developing ventilator associated pneumonia (VAP), that suppression of fibrinolysis precedes the clinical diagnosis while procoagulant effects mainly occur afterwards.2 We have extended these findings by investigating the relationship in time between changes in the anticoagulant protein C (PC) pathway and VAP. Levels of PC, activated PC (APC), and soluble thrombomodulin (sTM) were measured in non-directed bronchial lavage fluid collected every other day from critically ill patients during mechanical ventilation. APC was measured with an enzyme capture assay using monoclonal antibody HAPC 1555 and chromogenic substrate Spectrozyme PCa (American Diagnostica, Greenwich, CT, USA);3 PC activity was measured with an amidolytic assay using chromogenic substrate S2366 (Chromogenix, Milan, Italy); and sTM was measured with an ELISA (Diagnostica Stago, Asnieres-sur-Seine, France). Serial data …

Manipulation of CD98 expression affects both trophoblast cell fusion and amino acid transport activity during syncytialization of human placental BeWo cells

The physiological importance of CD98 surface antigen in regulating placental trophoblast cell fusion and amino acid transport activity has been studied in parallel in a cell model of syncytialization (the cytotrophoblast cell line BeWo following increased intracellular cAMP by forskolin treatment) using antisense oligonucleotides. CD98 protein abundance (determined by Western blot) was decreased by 50 % following antisense oligonucleotide transfection. Transfection with antisense oligonucleotide altered the responses of BeWo to forskolin. Cell fusion (determined by a quantitative flow cytometry assay) was inhibited by 57 %, and both human chorionic gonadotropin secretion and L‐leucine influx through system L were suppressed. These findings show that CD98 is involved in the process of cell fusion necessary for syncytiotrophoblast formation and that during this physiologically important event, amino acid transport activity is also regulated through expression of this membrane protein.

Randomised double‐blind comparison of ondansetron and droperidol to prevent postoperative nausea and vomiting associated with patient‐controlled analgesia

In a randomised, double‐blind trial, we compared the use of ondansetron and droperidol for the prevention of nausea and vomiting after total abdominal hysterectomy, during patient‐controlled analgesia with morphine. One hundred and forty‐two patients were randomly allocated to one of two groups. All patients received a standardised general anaesthetic and postoperative analgesic regimen. One group received ondansetron 4 mg at induction of anaesthesia, and ondansetron 0.13 mg with each 1‐mg bolus dose of morphine. The other group received droperidol 0.5 mg at induction and droperidol 0.05 mg per 1‐mg bolus dose of morphine. Results were available for 137 patients. During the first 24 h after surgery, prophylaxis was successful in 26 of 66 patients given ondansetron (39%) compared with 36 of 71 patients given droperidol (51%). This difference was not statistically significant (Chi‐squared = 1.766, p = 0.18). We conclude that in the regimens studied, ondansetron is not more effective than droperidol at preventing postoperative nausea and vomiting.

The effect of formalizing enhanced recovery after esophagectomy with a protocol.

Enhanced recovery after surgery (ERAS) pathways aim to accelerate functional return and discharge from hospital. They have proven effective in many forms of surgery, most notably colorectal. However, experience in esophagectomy has been limited. A recent study reported significant reductions in pulmonary complications, mortality, and length of stay following the introduction of an ERAS protocol alone, without the introduction of any clinical changes. We instituted a similar change 16 months ago, introducing a protocol to provide a formal framework, for our existing postoperative care. This retrospective analysis compared outcome following esophagectomy for the 16 months before and 20 months after this change. Data were collected from prospectively maintained secure web-based multidisciplinary databases. Complication severity was classified using the Clavien-Dindo scale. Operative mortality was defined as death within 30 days of surgery, or at any point during the same hospital admission. Lower respiratory tract infection was defined as clinical evidence of infection, with or without radiological signs. Respiratory complications included lower respiratory tract infection, pleural effusion (irrespective of drainage), pulmonary collapse, and pneumothorax. Statistical analysis was performed using SPSS v21. One hundred thirty-two patients underwent esophagectomy (55 protocol group; 77 before). All were performed open. There were no differences between the two groups in terms of age, gender, operation, use of neoadjuvant therapy, cell type, stage, tumor site, or American Society of Anesthesiologists grade. Median length of stay was 14.0 days (protocol) compared with 12.0 before (interquartile range 9-19 and 9.5-15.5, respectively; P = 0.073, Mann-Whitney U-test). Readmission within 30 days of discharge occurred in five (9.26%) and six (8.19%; P = 1.000, Fishers exact test). There were four in-hospital deaths (3.03%): one (1.82%) and three (3.90%), respectively (P = 0.641). There were no differences in the severity of complications (P = non-significant; Pearsons chi-squared). There were no differences in the type of complications occurring in either group. The protocol was completed successfully by 26 (47.3%). No baseline factors were predictive of this. In contrast to previous studies, we did not demonstrate any improvement in outcome by formalizing our existing pathway using a written protocol. Consequently, improvements in short-term outcome from esophagectomy within ERAS would seem to be primarily due to improvements in components of perioperative care. Consequently, we would recommend that centers introducing new (or reviewing existing) ERAS pathways for esophagectomy focus on optimizing clinical aspects of such standardized pathways.

Bronchoalveolar levels of plasminogen activator inhibitor-1 and soluble tissue factor are sensitive and specific markers of pulmonary inflammation.

Sir: Activation of coagulation and inhibition of fibrinolysis are hallmarks of pulmonary inflammation. Changes in alveolar fibrin turnover have been reported in pneumonia [1, 2, 3] and acute respiratory distress syndrome (ARDS) [1]. Recently in Intensive Care Medicine El Sohl et al. [4] proposed plasminogen activator inhibitor (PAI)-1 as a biomarker of ARDS in patients with aspiration pneumonitis. They reported bronchoalveolar lavage fluid PAI-1 levels in 51 patients with witnessed aspiration who had a PaO2/FIO2 ratio lower than 300 mmHg for a period no less than 4 h from admission. PAI-1 antigen levels were more than five

Neurosciences intensive care medicine in initial neurosurgical training

The authors describe a novel 4-month clinical placement in neurosciences intensive care medicine (NICM) undertaken in the first specialty registrar (ST1) year of neurosurgical training as part of a clinical neurosciences themed training year. Neurosurgery is unique among British surgical specialties in having pioneered themed early years in run-through training to replace basic surgical training in general surgical specialties as part of Modernising Medical Careers. After describing events leading to the new neurosurgical training, the knowledge, skills and attitudes acquired in NICM are highlighted alongside discussion of logistic aspects and future directions from an inaugural experience.