A randomized clinical trial of ascorbic acid in open abdominal aortic aneurysm repair.

BACKGROUND: Open AAA repair is associated with ischaemia-reperfusion injury where systemic inflammation and endothelial dysfunction can lead to multiple organ injury including acute lung injury. Oxidative stress plays a role that may be inhibited by ascorbic acid. METHODS: A double blind, allocation concealed, randomized placebo-controlled trial was performed to test the hypothesis that a single bolus dose (2g) of intra-operative parenteral ascorbic acid would attenuate biomarkers of ischaemia-reperfusion injury in patients undergoing elective open AAA repair. RESULTS: Thirty one patients completed the study; 18 received placebo and 13 ascorbic acid. Groups were comparable demographically. Open AAA repair caused an increase in urinary Albumin:Creatinine Ratio (ACR) as well as plasma IL-6 and IL-8. There was a decrease in exhaled breath pH and oxygenation. Lipid hydroperoxides were significantly higher in the ascorbic acid group following open AAA repair. There were no other differences between the ascorbic acid or placebo groups up to 4 hours after removal of the aortic clamping. CONCLUSIONS: Open AAA repair caused an increase in markers of systemic endothelial damage and systemic inflammation. Administration of 2g parenteral ascorbic acid did not attenuate this response and with higher levels of lipid hydroperoxides post-operatively a pro-oxidant effect could not be excluded. TRIAL REGISTRATION: ISRCTN27369400.

Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial.

OBJECTIVE: To test whether simvastatin improves physiological and biological outcomes in patients undergoing esophagectomy. BACKGROUND: One-lung ventilation during esophagectomy is associated with inflammation, alveolar epithelial and systemic endothelial injury, and the development of acute lung injury (ALI). Statins that modify many of the underlying processes are a potential therapy to prevent ALI. METHODS: We conducted a randomized double-blind placebo-controlled trial in patients undergoing esophagectomy. Patients received simvastatin 80 mg or placebo enterally for 4 days preoperatively and 7 days postoperatively. The primary end point was pulmonary dead space (Vd/Vt) at 6 hours after esophagectomy or before extubation. Inflammation was assessed by plasma cytokines and intraoperative exhaled breath condensate pH; alveolar type 1 epithelial injury was assessed by plasma receptor for advanced glycation end products and systemic endothelial injury by the urine albumin-creatinine ratio. RESULTS: Thirty-nine patients were randomized; 8 patients did not undergo surgery and were excluded. Fifteen patients received simvastatin and 16 received placebo. There was no difference in Vd/Vt or other physiological outcomes. Simvastatin resulted in a significant decrease in plasma MCP-1 on day 3 and reduced exhaled breath condensate acidification. Plasma receptor for advanced glycation end products was significantly lower in the simvastatin-treated group, as was the urine albumin-creatinine ratio on day 7 postsurgery. ALI developed in 4 patients in the placebo group and no patients in the simvastatin group although this difference was not statistically significant (P=0.1). CONCLUSIONS: In this proof of concept study, pretreatment with simvastatin in esophagectomy decreased biomarkers of inflammation as well as pulmonary epithelial and systemic endothelial injury.

Fragmentation of neutral amino acids and small peptides by intense, femtosecond laser pulses.

High power femtosecond laser pulses have unique properties that could lead to their application as ionization or activation sources in mass spectrometry. By concentrating many photons into pulse lengths approaching the timescales associated with atomic motion, very strong electric field strengths are generated, which can efficiently ionize and fragment molecules without the need for resonant absorption. However, the complex interaction between these pulses and biomolecular species is not well understood. To address this issue, we have studied the interaction of intense, femtosecond pulses with a number of amino acids and small peptides. Unlike previous studies, we have used neutral forms of these molecular targets, which allowed us to investigate dissociation of radical cations without the spectra being complicated by the action of mobile protons. We found fragmentation was dominated by fast, radical-initiated dissociation close to the charge site generated by the initial ionization or from subsequent ultrafast migration of this charge. Fragments with lower yields, which are useful for structural determinations, were also observed and attributed to radical migration caused by hydrogen atom transfer within the molecule.

Femtosecond lasers for mass spectrometry: proposed application to catalytic hydrogenation of butadiene.

Mass spectra from the interaction of intense, femtosecond laser pulses with 1,3-butadiene, 1-butene, and n-butane have been obtained. The proportion of the fragment ions produced as a function of intensity, pulse length, and wavelength was investigated. Potential mass spectrometry applications, for example in the analysis of catalytic reaction products, are discussed.

Observation of Ultrafast Charge Migration in an Amino Acid.

We present the first direct measurement of ultrafast charge migration in a biomolecular building block - the amino acid phenylalanine. Using an extreme ultraviolet pulse of 1.5 fs duration to ionize molecules isolated in the gas phase, the location of the resulting hole was probed by a 6 fs visible/near-infrared pulse. By measuring the yield of a doubly charged ion as a function of the delay between the two pulses, the positive hole was observed to migrate to one end of the cation within 30 fs. This process is likely to originate from even faster coherent charge oscillations in the molecule being dephased by bond stretching which eventually localizes the final position of the charge. This demonstration offers a clear template for observing and controlling this phenomenon in the future.

Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care.

OBJECTIVE: Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients. DESIGN: Prospective observational cohort study. SETTING: Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. PATIENTS: Patients were recruited within 24 hrs of admission to the intensive care unit. INTERVENTIONS: The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol). MEASUREMENTS AND MAIN RESULTS: Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium-dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3-159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59-88%) and specificity of 98% (CI, 94-99%). CONCLUSIONS: In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity.

A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study).

RATIONALE: There is no effective pharmacological treatment for acute lung injury (ALI). Statins are a potential new therapy because they modify many of the underlying processes important in ALI. OBJECTIVES: To test whether simvastatin improves physiological and biological outcomes in ALI. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial in patients with ALI. Patients received 80 mg simvastatin or placebo until cessation of mechanical ventilation or up to 14 days. Extravascular lung water was measured using thermodilution. Measures of pulmonary and nonpulmonary organ function were assessed daily. Pulmonary and systemic inflammation was assessed by bronchoalveolar lavage fluid and plasma cytokines. Systemic inflammation was also measured by plasma C-reactive protein. MEASUREMENTS AND MAIN RESULTS: Sixty patients were recruited. Baseline characteristics, including demographics and severity of illness scores, were similar in both groups. At Day 7, there was no difference in extravascular lung water. By Day 14, the simvastatin-treated group had improvements in nonpulmonary organ dysfunction. Oxygenation and respiratory mechanics improved, although these parameters failed to reach statistical significance. Intensive care unit mortality was 30% in both groups. Simvastatin was well tolerated, with no increase in adverse events. Simvastatin decreased bronchoalveolar lavage IL-8 by 2.5-fold (P = 0.04). Plasma C-reactive protein decreased in both groups but failed to achieve significance in the placebo-treated group. CONCLUSIONS: Treatment with simvastatin appears to be safe and may be associated with an improvement in organ dysfunction in ALI. These clinical effects may be mediated by a reduction in pulmonary and systemic inflammation. Clinical trial registered with www.controlled-trials.com (ISRCTN70127774).

Extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury.

OBJECTIVES: Acute lung injury and the acute respiratory distress syndrome are characterized by noncardiogenic pulmonary edema, which can be assessed by measurement of extravascular lung water. Traditionally, extravascular lung water has been indexed to actual body weight (mL/kg). Because lung size is dependent on height rather than weight, we hypothesized indexing to predicted body weight may be a better predictor of mortality in acute lung injury/acute respiratory distress syndrome. DESIGN: Prospective observational cohort study. SETTING: A tertiary referral intensive care unit. PATIENTS: Patients were recruited within 48 hrs of fulfilling the American European Consensus Conference definition of acute lung injury/acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, severity of illness scores, and respiratory parameters were collected. Extravascular lung water was measured using the PiCCO system. This was indexed to actual and predicted body weight. Statistically significant predictors of mortality identified using single regressor logistic regression and additional variables known to be associated with outcome were entered into a multiple logistic regression analysis. Receiver operator characteristic curves were generated. Forty-four patients were recruited (septic 34%). Using single regressor logistic regression, six variables were statistically significantly related to mortality: Acute Physiology and Chronic Health Evaluation II, PaO2, PaO2/Fio2 ratio, oxygenation index, actual extravascular lung water, and predicted extravascular lung water. In multiple logistic regression analysis, predicted extravascular lung water but not actual extravascular lung water was a predictor of mortality with an odds ratio of 4.3 (95% confidence interval, 1.5-12.9) per sd. Although the area under the curve for predicted extravascular lung water (0.8; confidence interval, 0.65-0.94) was larger than for actual extravascular lung water (0.72; confidence interval, 0.53-0.91), this was not statistically significant (p = .12). A baseline predicted extravascular lung water value of 16 mL/kg predicted intensive care unit mortality with a sensitivity of 0.75 (confidence interval, 0.47-0.91) and specificity of 0.78 (confidence interval, 0.61-0.89). CONCLUSIONS: Early measurement of predicted extravascular lung water is a better predictor than actual extravascular lung water to identify patients at risk for death in acute lung injury/acute respiratory distress syndrome.

A protocol-driven model for the rapid initiation of stroke thrombolysis in the emergency department.

OBJECTIVE: To assess efficacy and safety of a 24-hour comprehensive protocol-driven model for rapid assessment and thrombolysis of stroke patients in the emergency department. DESIGN: Prospective open observational study. PARTICIPANTS AND SETTING: All patients with acute stroke presenting within 3 hours to the St Vincent's Hospital (Sydney) emergency department between 1 December 2004 and 30 July 2005. MAIN OUTCOME MEASURES: Proportion of patients treated, patient demographics, clinical outcome, adverse events and time to treatment parameters. RESULTS: 134 patients (100 stroke; 34 transient ischaemic attack) were admitted to the stroke unit during the study period. Of the 100 stroke patients, 40 presented within 3 hours of symptom onset. Fifteen patients had no contraindications and received intravenous thrombolysis. At 3 months, 10 patients (67%) were independent (modified Rankin score [mRS], 0-2) and seven (47%) had an excellent functional outcome (mRS < or = 1). Symptomatic intracranial haemorrhage was not observed. The median time from symptom onset to tissue plasminogen activator treatment was 155 minutes (range, 105-197 min). Median onset-to-door, door-to-computed tomography, and door-to-needle times were 48, 25, and 87 minutes, respectively. CONCLUSION: Rapid assessment of stroke in the emergency department according to a comprehensive protocol allows identification and treatment of acute ischaemic stroke patients eligible for thrombolysis.

Gastric perforation secondary to incarcerated hiatus hernia: an important differential in the diagnosis of central crushing chest pain.

Gastric perforation in association with incarceration of a hiatus hernia rarely features on a list of differential diagnoses of acute chest pain. A patient presented to the emergency department with acute chest pain characteristic of myocardial ischaemia. Several risk factors for ischaemic heart disease (IHD) were present. Investigations revealed normal cardiac enzymes and normal electrocardiography both initially and at 90 mins. A chest radiograph demonstrated the presence of a hiatus hernia. The patient was diagnosed with, and treated for, unstable angina. A troponin T test at 12 h post-admission was normal. The patient's clinical condition continued to deteriorate. The source of her pain was found to be gastric perforations in association with an incarcerated hiatus hernia. Her postoperative course was complicated by pulmonary and intra-abdominal sepsis necessitating admission to the intensive care unit where she remained for 23 days. This case highlights the challenge that non-cardiac chest pain presents to the acute care physician. Patients who present with risk factors for and symptoms consistent with a diagnosis of IHD may have non-cardiogenic pathology which can be life-threatening.

Out of hours non-contrast head CT scan interpretation by senior emergency department medical staff.

OBJECTIVE: To assess the accuracy of 'out of hours' (17.00-08.00 hours) non-contrast head computed tomography (NCHCT) scan interpretation by senior ED medical staff. METHODS: The study was undertaken in an inner-city tertiary hospital in Sydney. A sample of 315 consecutive 'out of hours' NCHCT scans was compiled from a log book in the Medical Imaging Department and randomized into 21 sets of 15 scans. The scans were reviewed by emergency physicians and registrars recruited for the study and their interpretations were compared with the formal radiologist report. RESULTS: Seven emergency physicians and 14 registrars took part in the study. Two hundred and eighty-seven ED interpretations were used in the 2 x 2 table analysis. The overall observed agreement was 0.67 (95% confidence interval [CI] 0.61-0.72), sensitivity 0.57 (95% CI 0.45-0.69), specificity 0.70 (95% CI 0.64-0.76) and kappa 0.24 (95% CI 0.13-0.36). There were 32 false negative interpretations including three small contre coup contusions and three subdural haemorrhages. CONCLUSION: 'Out of hours' NCHCT scan interpretation by senior ED medical staff is only correct two-thirds of the time. Further education for all senior ED staff is indicated to improve our accuracy. The safety of NCHCT scan interpretation by senior ED medical staff needs further study.

Real-time ultrasonographically-guided internal jugular vein catheterization in the emergency department increases success rates and reduces complications: a randomized, prospective study.

STUDY OBJECTIVE: We compare real-time ultrasonographic guidance and the traditional landmark technique for the insertion of internal jugular vein catheters in an emergency department (ED) setting. METHODS: This was a prospective, randomized, clinical study performed in a tertiary ED between August 2003 and May 2005 on patients requiring central venous access. Ultrasonographically guided catheters were inserted under real time using the Sonosite ultrasonographic system with a 10 to 5 MHz 38-mm linear array transducer. Standardized data were collected on operator experience, method of insertion, reason for central venous access, and comorbidities. Outcome measures included successful insertion of an internal jugular vein catheter, number of attempts, access times, and complications. RESULTS: One hundred thirty patients were enrolled. Cannulation of the internal jugular vein was successful in 61 of 65 patients (93.9%) using ultrasonography and in 51 of 65 patients (78.5%) using the landmark technique, a significant difference of 15.4% (P=.009, 95% confidence interval [CI] 3.8% to 27.0%). Fifty of 61 (82.0%) of the successful ultrasonographically guided catheters were inserted on the first attempt compared with 36 of 51 (70.6%) of the successful landmark catheters. Mean access times to venipuncture and successful insertion were 138 and 281 seconds by ultrasonographic guidance and 132 and 271 seconds by the landmark technique. There was a 10.8% complication rate, with 11 complications (16.9%) in the landmark group and 3 (4.6%) in the ultrasonographic group, a difference of 12.3% (95% CI 1.9% to 22.8%). CONCLUSION: Ultrasonographically guided internal jugular vein catheterization in the ED setting was associated with a higher successful insertion rate and a lower complications rate.