Effect of therapeutic suggestions during general anaesthesia on postoperative pain and opioid use: multicentre randomised controlled trial.

OBJECTIVE: To investigate the effect of therapeutic suggestions played to patients through earphones during surgery on postoperative pain and opioid use. DESIGN: Blinded randomised controlled study. SETTING: Five tertiary care hospitals in Germany. PARTICIPANTS: 385 of 400 patients consecutively recruited from January to December 2018 who were to undergo surgery for 1-3 hours under general anaesthesia. In the per protocol analysis 191 patients were included in the intervention group and 194 patients in the control group. INTERVENTION: The intervention comprised an audiotape of background music and positive suggestions based on hypnotherapeutic principles, which was played repeatedly for 20 minutes followed by 10 minutes of silence to patients through earphones during general anaesthesia. Patients in the control group were assigned to a blank tape. MAIN OUTCOME MEASURES: The main outcome was dose of opioid administered by patient controlled analgesia or nurse controlled analgesia within the first postoperative 24 hours, based on regular evaluation of pain intensity on a numerical rating scale (range 0-10, with higher scores representing more severe pain). RESULTS: Compared with the control group, the intervention group required a significantly (P=0.002) lower opioid dose within 24 hours after surgery, with a median of 4.0 mg (interquartile range 0-8) morphine equivalents versus 5.3 (2-12), and an effect size (Cohen's d) of 0.36 (95% confidence interval 0.16 to 0.56). The number of patients who needed opioids postoperatively was significantly (P=0.001) reduced in the intervention group: 121 of 191 (63%, 95% confidence interval 45% to 70%) patients in the intervention group versus 155 of 194 (80%, 74% to 85%) in the control group. The number needed to treat to avoid postoperative opioids was 6. Pain scores were consistently and significantly lower in the intervention group within 24 hours after surgery, with an average reduction of 25%. No adverse events were reported. CONCLUSIONS: Therapeutic suggestions played through earphones during general anaesthesia could provide a safe, feasible, inexpensive, and non-drug technique to reduce postoperative pain and opioid use, with the potential for more general use. Based on the finding of intraoperative perception by a considerable number of patients, surgeons and anaesthetists should be careful about background noise and conversations during surgery. TRIAL REGISTRATION: German Clinical Trial Register DRKS00013800.

Meta-Analysis of Electroacupuncture in Cardiac Anesthesia and Intensive Care.

BACKGROUND: Acupuncture treatment has been employed in China for over 2500 years and it is used worldwide as analgesia in acute and chronic pain. Acupuncture is also used in general anesthesia (GA). The aim of this systematic review and meta-analysis was to assess the efficacy of electroacupuncture (EA) in addition to GA in patients undergoing cardiac surgery. METHODS: We searched 3 databases (Pubmed, Cochrane Library, and Web of Science-from 1965 until January 31, 2017) for randomized controlled trials (RCTs) including patients undergoing cardiac surgery and receiving GA alone or GA + EA. As primary outcomes, we investigated the association between GA + EA approach and the dosage of intraoperative anesthetic drugs administered, the duration of mechanical ventilation (MV), the postoperative dose of vasoactive drugs, the length of intensive care unit (ICU) and hospital stay, and the levels of troponin I and cytokines. RESULTS: The initial search yielded 477 citations, but only 7 prospective RCTs enrolling a total of 321 patients were included. The use of GA + EA reduced the dosage of intraoperative anesthetic drugs (P < .05), leading to shorter MV time (P < .01) and ICU stay (P < .05) as well as reduced postoperative dose of vasoactive drugs (P < .001). In addition, significantly lower levels of troponin I (P < .01) and tumor necrosis factor α (P < .01) were observed. CONCLUSION: The complementary use of EA for open-heart surgery reduces the duration of MV and ICU stay, blunts the inflammatory response, and might have protective effects on the heart. Our findings stimulate future RCT to provide definitive recommendations.

R-100 improves pulmonary function and systemic fluid balance in sheep with combined smoke-inhalation injury and Pseudomonas aeruginosa sepsis.

BACKGROUND: Septic shock is a major cause of death in intensive care units around the world . The aim of the study was to investigate whether the novel drug R-100 (a superoxide degradation catalyst and nitric oxide donor) improves pulmonary function in a sheep model of septic shock caused by Pseudomonas aeruginosa and smoke inhalation. METHODS: Eleven female sheep were prepared surgically and randomly assigned to a treatment group (n = 5) or a control group (n = 6) after inhalation of cooled cotton smoke and airway instillation of live P. aeruginosa (2.5 × 1011 CFU) by bronchoscope under deep anesthesia and analgesia. The treatment group received an intravenous infusion of a total of 80 mg/kg of R-100 diluted in 500 mL of 5% dextrose. The control group was given 500 mL of 5% dextrose. All animals received intravenous lactated Ringer's solution to maintain a hematocrit level at baseline ± 3%. Blood gas and hemodynamics were measured at baseline and then analyzed every 3 h during the 24-h study period. Results are expressed as mean ± SEM. RESULTS: The treated animals showed significant improvement in their pulmonary gas exchange (PaO2/FiO2 ratio at 24 h: 246 ± 29 vs. 90 ± 40 mmHg control, P < 0.05). Pulmonary arterial pressures were reduced in the treated group (24 h: 26 ± 1 vs. 30 ± 2 cm mmHg control, P < 0.05). The treated animals also had an improved total fluid balance after 24 h (190 ± 45/24 h mL vs. 595 ± 234/24 h mL control, P < 0.05). CONCLUSIONS: Treatment with R-100 improves pulmonary gas exchange and blood oxygenation, and prevents a fluid imbalance in sheep subjected to smoke inhalation and P. aeruginosa.

Moxifloxacin monotherapy versus combination therapy in patients with severe community-acquired pneumonia evoked ARDS.

BACKGROUND: We tested the hypothesis that moxifloxacin monotherapy is equally effective and safe as a betalactam antibiotic based combination therapy in patients with acute respiratory distress syndrome (ARDS) evoked by severe community acquired pneumonia (CAP). METHODS: In a retrospective chart review study of 229 patients with adult respiratory distress syndrome (ARDS) admitted to our intensive care unit between 2001 and 2011, 169 well-characterized patients were identified to suffer from severe CAP. Patients were treated with moxifloxacin alone, moxifloxacin in combination with ß-lactam antibiotics, or with another antibiotic regimen based on ß-lactam antibiotics, at the discretion of the admitting attending physician. The primary endpoint was 30-day survival. To assess potential drug-induced liver injury, we also analyzed biomarkers of liver cell integrity. RESULTS: 30-day survival (69% overall) did not differ (p = 0.89) between moxifloxacin monotherapy (n = 42), moxifloxacin combination therapy (n = 44), and other antibiotic treatments (n = 83). We found significantly greater maximum activity of aspartate transaminase (p = 0.048), alanine aminotransferase (p = 0.003), and direct bilirubin concentration (p = 0.01) in the moxifloxacin treated groups over the first 10-20 days. However, these in-between group differences faded over time, and no differences remained during the last 10 days of observation. CONCLUSIONS: In CAP evoked ARDS, moxifloxacin monotherapy and moxifloxacin combination therapy was not different to a betalactam based antibiotic regimen with respect to 30-day mortality, and temporarily increased markers of liver cell integrity had no apparent clinical impact. Thus, in contrast to the current S3 guidelines, moxifloxacin may also be safe and effective even in patients with severe CAP evoked ARDS while providing coverage of an extended spectrum of severe CAP evoking bacteria. However, further prospective studies are needed for definite recommendations.

Effects of Acupuncture in Anesthesia for Craniotomy: A Meta-Analysis.

BACKGROUND: Acupuncture treatment has been used in China for >2500 years, and at present it is used worldwide as a form of analgesia in patients with acute and chronic pain. Furthermore, acupuncture is regularly used not only as a single anesthetic technique but also as a supplement or in addition to general anesthesia (GA). OBJECTIVES: The aim of this systematic review and meta-analysis was to assess the level of evidence for the clinical use of acupuncture in addition to GA in patients undergoing craniotomy. DESIGN: This is a systematic review of randomized controlled trials with meta-analyses. DATA SOURCES: The literature search (PubMed, Cochrane Library, and Web of Science) yielded 56 citations, published between 1972 and March 01, 2015. No systematic review or meta-analyses on this topic matched our search criteria. Each article of any language was assessed and rated for the methodological quality of the studies, using the recommendation of the Oxford Centre for Evidence Based Medicine. Ten prospective randomized controlled clinical trials with a total of 700 patients were included. ELIGIBILITY CRITERIA: Included in the meta-analysis were studies that involved any craniotomy under GA compared with a combination of GA and acupuncture. Exclusion criteria were no acupuncture during surgery, no GA during surgery, only postoperative data available, animal studies, and low grade of evidence. RESULTS: The use of acupuncture significantly reduced the amount of volatile anesthetics during surgery (P<0.001) and led to faster extubation time (P=0.001) and postoperative patient recovery (P=0.003). In addition, significantly reduced blood levels of the brain tissue injury marker S100ß 48 hours after operation (P=0.001) and occurrence of postoperative nausea and vomiting (P=0.017) were observed. No patient studied suffered from awareness. CONCLUSIONS: The analysis suggests that the complementary use of acupuncture for craniotomy has additional analgesic effects, reduces the needed amount of volatile anesthetic, reduces the onset of postoperative nausea and vomiting, and might have protective effects on brain tissue. Our findings may stimulate future randomized controlled trials to provide definitive recommendations.

Bivalirudin for Alternative Anticoagulation in Extracorporeal Membrane Oxygenation: A Systematic Review.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) offers therapeutic options in refractory respiratory and/or cardiac failure. Systemic anticoagulation with heparin is routinely administered. However, in patients with heparin-induced thrombocytopenia or heparin resistance, the direct thrombin inhibitor bivalirudin is a valid option and has been increasingly used for ECMO anticoagulation. We aimed at evaluating its safety and its optimal dosing for ECMO. METHODS: Systematic web-based literature search of PubMed and EMBASE performed via National Health Service Library Evidence and manually, updated until January 30, 2016. RESULTS: The search revealed 8 publications relevant to the topic (5 case reports). In total, 58 patients (24 pediatrics) were reported (18 received heparin as control groups). Bivalirudin was used with or without loading dose, followed by infusion at different ranges (lowest 0.1-0.2 mg/kg/h without loading dose; highest 0.5 mg/kg/h after loading dose). The strategies for monitoring anticoagulation and optimal targets were dissimilar (activated partial thromboplastin time 45-60 seconds to 42-88 seconds; activated clotting time 180-200 seconds to 200-220 seconds; thromboelastography in 1 study). CONCLUSION: Bivalirudin loading dose was not always used; infusion range and anticoagulation targets were different. In this systematic review, we discuss the reasons for this variability. Larger studies are needed to establish the optimal approach with the use of bivalirudin for ECMO.

Isoproternenol increases vascular volume expansion and urinary output after a large crystalloid bolus in healthy volunteers.

BACKGROUND: The primary goal of fluid therapy is to maintain fluid homeostasis. Commonly used isotonic crystalloids are only marginally effective and contribute to fluid excess syndrome. In patients with decreased cardiovascular reserve, fluid therapy alone is not sufficient to maintain end-organ perfusion. Therefore, inotropes or vasoactive drugs are used to supplement fluid infusion. Recent animal data suggest that coinfusion of adrenergic agents modulate the distribution of fluid between the vascular and extravascular/interstitial compartments after a fluid bolus. We sought to determine if this effect would translate in humans by coadministering a ß-adrenergic agonist with fluid. METHODS: Nine healthy volunteers (aged 21-50 years) were randomly paired and received either a continuous isoproterenol infusion (ISO: 0.05 µg/kg per minute) or 0.9% saline (control [CON]) 30min prior to a 25 mL/kg 0.9% NaCl fluid bolus. Hemodynamics, ventricular volume and function, and microcirculatory determinants (capillary filtration coefficient and oncotic pressure) were measured. Vascular and extravascular volume and fluid balance were determined. RESULTS: Compared with CON, ISO significantly increased heart rate (CON: 64.2 ± 4.1 beats/min vs. ISO: 97.4 ± 5.7 beats/min) and cardiac output (CON: 4.4 ± 0.7 L/min vs. ISO: 10.2 ± 0.9) before fluid bolus. Isoproterenol significantly increased urinary output (ISO: 10.86 ± 1.95 vs. control: 6.53 ± 1.45 mL/kg) and reduced extravascular volume (7.98 ± 2.0 vs. 14.15 ± 1.1mL/kg). Isoproterenol prevented an increase in capillary filtration coefficient (1.74 ± 0.4 vs. 3.21 ± 0.4 mL/min per mmHg · 10). CONCLUSIONS: Isoproterenol, a nonselective ß-adrenergic agonist, augments vascular volume expansion and eliminates extravascular volume via enhanced diuresis, which may in part be due to enhanced endothelial barrier function.

Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia.

BACKGROUND: Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS. METHODS: Adult sheep (30-40 kg) were surgically prepared. After 5 days of recovery, ALI was induced with cotton smoke insufflation, followed by instillation of live Pseudomonas aeruginosa (2.5×10(11) CFU) into both lungs under isoflurane anaesthesia. Following the injury, sheep were ventilated, resuscitated with lactated Ringer's solution and studied for 24 h. The sheep were randomly allocated to receive one of the following treatments intravenously over 1 h in one of the following groups: (1) control, PlasmaLyte A, n=8; (2) lower dose hMSCs, 5×10(6) hMSCs/kg, n=7; and (3) higher-dose hMSCs, 10×10(6) hMSCs/kg, n=4. RESULTS: By 24 h, the PaO2/FiO2 ratio was significantly improved in both hMSC treatment groups compared with the control group (control group: PaO2/FiO2 of 97±15 mm Hg; lower dose: 288±55 mm Hg (p=0.003); higher dose: 327±2 mm Hg (p=0.003)). The median lung water content was lower in the higher-dose hMSC-treated group compared with the control group (higher dose: 5.0 g wet/g dry [IQR 4.9-5.8] vs control: 6.7 g wet/g dry [IQR 6.4-7.5] (p=0.01)). The hMSCs had no adverse effects. CONCLUSIONS: Human MSCs were well tolerated and improved oxygenation and decreased pulmonary oedema in a sheep model of severe ARDS. TRAIL REGISTRATION NUMBER: NCT01775774 for Phase 1. NCT02097641 for Phase 2.

Tiotropium bromide suppresses smoke inhalation and burn injury-induced ERK 1/2 and SMAD 2/3 signaling in sheep bronchial submucosal glands.

The effects of tiotropium bromide on ERK 1/2, SMAD 2/3 and NFκB signaling in bronchial submucosal gland (SMG) cells of sheep after smoke inhalation and burn injury (S + B) were studied. We hypothesized that tiotropium would modify intracellular signaling processes within SMG cells after injury. Bronchial tissues were obtained from uninjured (sham, n = 6), S + B injured sheep 48 h after injury (n = 6), and injured sheep nebulized with tiotropium (n = 6). The percentage (mean ± SD) of cells showing nuclear localization of phosphorylated ERK 1/2, pSMAD 2/3, and NFκB (p65) was determined by immunohistochemistry. Nuclear pERK 1/2 staining was increased in injured animals as compared to sham, (66 ± 20 versus 14 ± 9), p = 0.0022, as was nuclear pSMAD, 84 ± 10 versus 20 ± 10, p = 0.0022. There was a significant decrease in pERK 1/2 labeling in the tiotropium group compared to the injured group (31 ± 20 versus 66 ± 20, p = 0.013), and also a decrease in pSMAD labeling, 62 ± 17 versus 84 ± 10, p = 0.04. A significant increase for NFκB (p65) was noted in injured animals as compared to sham (73 ± 16 versus 7 ± 6, p = 0.0022). Tiotropium-treated animals showed decreased p65 labeling as compared to injured (35 ± 17 versus 74 ± 16, p = 0.02). The decrease in nuclear expression of pERK, pSMAD and NFκB molecules in SMG cells with tiotropium treatment is suggestive that their activation after injury is mediated in part through muscarinic receptors.

Transesophageal echocardiography in the management of burn patients.

A systematic review was conducted to assess the level of evidence for the use of transesophageal echocardiography (TEE) in the management of burn patients. We searched any article published before and including June 30, 2013. Our search yielded 118 total publications, 11 met the inclusion criteria of burn injury and TEE. Available studies published in any language were rated and included. At the present time, there are no available systematic reviews/meta-analyses published that met our search criteria. Only a small number of clinical trials, all with a limited number of patients were available. Therefore, a meta-analysis on outcome parameters was not performed. However, the major pathologic findings in burn patients were reduced left ventricular (LV) systolic and diastolic function, mitral valve vegetation, pulmonary hypertension, pericardial effusion, fluid overload, and right heart failure. The advantages of TEE include offering direct assessment of cardiac valve competency, myocardial contractility, and most importantly real time assessment of adequacy of hemodynamic resuscitation and preload in the acute phase of resuscitation, with minimal additional risk. TEE serves multiple diagnostic purposes and is being used to better understand the fluid status and cardiac physiology of the critically ill burn patient. Randomized controlled trials especially on fluid resuscitation and cardiac performance in acute burns are warranted to potentially further improve outcome.

Healing efficacy of sea buckthorn (Hippophae rhamnoides L.) seed oil in an ovine burn wound model.

To investigate the efficacy of sea buckthorn (SBT) seed oil - a rich source of substances known to have anti-atherogenic and cardioprotective activity, and to promote skin and mucosa epithelization - on burn wound healing, five adult sheep were subjected to 3rd degree flame burns. Two burn sites were made on the dorsum of the sheep and the eschar was excised down to the fascia. Split-thickness skin grafts were harvested, meshed, and fitted to the wounds. The autograft was placed on the fascia and SBT seed oil was topically applied to one recipient and one donor site, respectively, with the remaining sites treated with vehicle. The wound blood flow (LASER Doppler), and epithelization (ultrasound) were determined at 6, 14, and 21 days after injury. 14 days after grafting, the percentage of epithelization in the treated sites was greater (95 ± 2.2% vs. 83 ± 2.9%, p<0.05) than in the untreated sites. Complete epithelization time was shorter in both treated recipient and donor sites (14.20 ± 0.48 vs. 19.60 ± 0.40 days, p<0.05 and 13.40 ± 1.02 vs. 19.60 ± 0.50 days, p<0.05, respectively) than in the untreated sites, confirmed by ultrasound. In conclusion, SBT seed oil has significant wound healing activity in full-thickness burns and split-thickness harvested wounds.

A meta-analysis of analgesic and sedative effects of dexmedetomidine in burn patients.

Sedation for burn patients is provided by a variety of techniques determined usually by institutional preferences. The available pool of drugs has recently expanded to include dexmedetomidine (DEX), a α2-adrenergic receptor agonist with analgesic and sedative potential. Beneficial effects of DEX in burn patients have been described in many studies published over the last 5 years. The aim of this study is to perform a systematic review and meta-analysis of the available literature to determine the role of DEX for analgosedation of burn patients. We searched any article that matched the keywords "dexmedetomidine" and "burn", published before October 01, 2012. The methodological quality of studies was assessed using the recommendation of the Oxford Centre for Evidence Based Medicine (OCEBM). Our search yielded eleven total citations, of which four studies (266 patients) met the inclusion criteria of DEX for analgosedation in burn patients. There are no meta-analyses published that met our inclusion criteria. Even though there were only a small number of clinical trials available, the meta-analysis shows evidence for deeper and better sedation as well as for prevention of hypertension when using DEX as an adjunct during burn procedures. No evidence was found for reduced pain scores in this setting. The authors recommend the development of a prospective, randomized, controlled multicenter trial with an adequate number of patients to further elucidate the potentially beneficial effects of DEX for the management of burn patients.

Effect of bronchodilators on bronchial gland cell proliferation after inhalation and burn injury in sheep.

The objective of this study is to measure the temporal changes in bronchial submucosal gland (SMG) cell proliferation in sheep after smoke inhalation and burn (S+B) injury, and to assess the effect of bronchodilators on the proliferative response. Archived main bronchial airways from sheep after S+B injury were immunostained for Ki67, and the percentage of ciliated duct and SMG cells expressing nuclear localization of Ki67 was determined for uninjured sheep and in sheep 24, 48, 72, and 96 hours after injury. A semiquantitative measure of lining epithelial exfoliation was made for each tissue. Bronchial tissues from sheep at 48 hours after S+B injury that had been nebulized with albuterol or tiotropium bromide (tiotropium) were examined to assess the effect of bronchodilators on the proliferative response. At 48 through 96 hours after injury, both ciliated duct and SMG cell proliferation were significantly increased compared with that of uninjured animals and animals 24 hours after injury, P <.05. A small increase in proliferation was seen in the SMG cells of albuterol-treated sheep compared with nebulized saline controls, P = .048. SMG cells of tiotropium-treated animals showed a significant increase in Ki67 nuclear staining compared with their study controls, P = .001. Extensive injury to the lining epithelium is associated with a proliferative response in both ciliated duct and SMG cells 24 hours after injury. The increase in proliferation in sheep treated with bronchodilators suggests that therapies for inhalation injury modify the glandular proliferative response. Further study to assess the ability of bronchodilators to enhance epithelial repair is warranted.

Extracorporeal membrane oxygenation in burn and smoke inhalation injury.

A systematic review and meta-analysis was conducted to assess the level of evidence for the use of extracorporeal membrane oxygenation (ECMO) in hypoxemic respiratory failure resulting from burn and smoke inhalation injury. We searched any article published before March 01, 2012. Available studies published in any language were included. Five authors rated each article and assessed the methodological quality of studies using the recommendation of the Oxford Centre for Evidence Based Medicine (OCEBM). Our search yielded 66 total citations but only 29 met the inclusion criteria of burn and/or smoke inhalation injury. There are no available systematic reviews/meta-analyses published that met our inclusion criteria. Only a small number of clinical trials, all with a limited number of patients, were available. The overall data suggests that there is no improvement in survival for burn patients suffering acute hypoxemic respiratory failure, with the use of ECMO. ECMO run times of less than 200 h correlate with higher survival compared to 200 h or more. Scald burns show a tendency of higher survival than flame burns. In conclusion, the presently available literature is based on insufficient patient numbers; the data obtained and level of evidence generated are limited. The role of ECMO in burn and smoke inhalation injury is therefore unclear. However, ECMO technology and expertise have improved over the last decades. Further research on ECMO in burn and smoke inhalation injury is warranted.

Development of a long-term ovine model of cutaneous burn and smoke inhalation injury and the effects of early excision and skin autografting.

UNLABELLED: Smoke inhalation injury frequently increases the risk of pneumonia and mortality in burn patients. The pathophysiology of acute lung injury secondary to burn and smoke inhalation is well studied, but long-term pulmonary function, especially the process of lung tissue healing following burn and smoke inhalation, has not been fully investigated. By contrast, early burn excision has become the standard of care in the management of major burn injury. While many clinical studies and small-animal experiments support the concept of early burn wound excision, and show improved survival and infectious outcomes, we have developed a new chronic ovine model of burn and smoke inhalation injury with early excision and skin grafting that can be used to investigate lung pathophysiology over a period of 3 weeks. MATERIALS AND METHODS: Eighteen female sheep were surgically prepared for this study under isoflurane anesthesia. The animals were divided into three groups: an Early Excision group (20% TBSA, third-degree cutaneous burn and 36 breaths of cotton smoke followed by early excision and skin autografting at 24h after injury, n=6), a Control group (20% TBSA, third-degree cutaneous burn and 36 breaths of cotton smoke without early excision, n=6) and a Sham group (no injury, no early excision, n=6). After induced injury, all sheep were placed on a ventilator and fluid-resuscitated with Lactated Ringers solution (4 mL/% TBS/kg). At 24h post-injury, early excision was carried out to fascia, and skin grafting with meshed autografts (20/1000 in., 1:4 ratio) was performed under isoflurane anesthesia. At 48 h post-injury, weaning from ventilator was begun if PaO(2)/FiO(2) was above 250 and sheep were monitored for 3 weeks. RESULTS: At 96 h post-injury, all animals were weaned from ventilator. There are no significant differences in PaO(2)/FiO(2) between Early Excision and Control groups at any points. All animals were survived for 3 weeks without infectious complication in Early Excision and Sham groups, whereas two out of six animals in the Control group had abscess in lung. The percentage of the wound healed surviving area (mean ± SD) was 74.7 ± 7.8% on 17 days post-surgery in the Early Excision group. Lung wet-to-dry weight ratio (mean ± SD) was significantly increased in the Early Excision group vs. Sham group (p<0.05). The calculated net fluid balance significantly increased in the early excision compared to those seen in the Sham and Control groups. Plasma protein, oncotic pressure, hematocrit of % baseline, hemoglobin of % baseline, white blood cell and neutrophil were significantly decreased in the Early Excision group vs. Control group. CONCLUSIONS: The early excision model closely resembles practice in a clinical setting and allows long-term observations of pulmonary function following burn and smoke inhalation injury. Further studies are warranted to assess lung tissue scarring and measuring collagen deposition, lung compliance and diffusion capacity.

Nebulization with γ-tocopherol ameliorates acute lung injury after burn and smoke inhalation in the ovine model.

We hypothesize that the nebulization of γ-tocopherol (g-T) in the airway of our ovine model of acute respiratory distress syndrome will effectively improve pulmonary function following burn and smoke inhalation after 96 h. Adult ewes (n = 14) were subjected to 40% total body surface area burn and were insufflated with 48 breaths of cotton smoke under deep anesthesia, in a double-blind comparative study. A customized aerosolization device continuously delivered g-T in ethanol with each breath from 3 to 48 h after the injury (g-T group, n = 6), whereas the control group (n = 5) was nebulized with only ethanol. Animals were weaned from the ventilator when possible. All animals were killed after 96 h, with the exception of one untreated animal that was killed after 64 h. Lung g-T concentration significantly increased after g-T nebulization compared with the control group (38.5 ± 16.8 vs. 0.39 ± 0.46 nmol/g, P < 0.01). The PaO(2)/FIO(2) ratio was significantly higher after treatment with g-T compared with the control group (310 ± 152 vs. 150 ± 27.0, P < 0.05). The following clinical parameters were improved with g-T treatment: pulmonary shunt fraction, peak and pause pressures, lung bloodless wet-to-dry weight ratios (2.9 ± 0.87 vs. 4.6 ± 1.4, P < 0.05), and bronchiolar obstruction (2.0% ± 1.1% vs. 4.6% ± 1.7%, P < 0.05). Nebulization of g-T, carried by ethanol, improved pulmonary oxygenation and markedly reduced the time necessary for assisted ventilation in burn- and smoke-injured sheep. Delivery of g-T into the lungs may be a safe, novel, and efficient approach for management of acute lung injury patients who have sustained oxidative damage to the airway.

The Angiotensin-converting enzyme inhibitor captopril inhibits poly(adp-ribose) polymerase activation and exerts beneficial effects in an ovine model of burn and smoke injury.

We investigated the effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in a clinically relevant ovine model of smoke and burn injury, with special reference to oxidative stress and activation of poly(ADP-ribose) polymerase, in the lung and in circulating leukocytes. Female, adult sheep (28-40 kg) were divided into three groups. After tracheostomy and under deep anesthesia, both vehicle-control-treated (n = 5) and captopril-treated (20 mg/kg per day, i.v., starting 0.5 h before the injury) (n = 5) groups were subjected to 2 × 20%, third-degree burn injury and were insufflated with 48 breaths of cotton smoke. A sham group not receiving burn/smoke was also studied (n = 5). Animals were mechanically ventilated and fluid resuscitated for 24 h in the awake state. Burn and smoke injury resulted in an upregulation of ACE in the lung, evidenced by immunohistochemical determination and Western blotting. Burn and smoke injury resulted in pulmonary dysfunction, as well as systemic hemodynamic alterations. Captopril treatment of burn and smoke animals improved PaO2/FiO2 ratio and pulmonary shunt fraction and reduced the degree of lung edema. There was a marked increase in PAR levels in circulating leukocytes after burn/smoke injury, which was significantly decreased by captopril. The pulmonary level of ACE and the elevated pulmonary levels of transforming growth factor ß in response to burn and smoke injury were significantly decreased by captopril treatment. Our results suggest that the ACE inhibitor captopril exerts beneficial effects on the pulmonary function in burn/smoke injury. The effects of the ACE inhibitor may be related to the prevention of reactive oxygen species-induced poly(ADP-ribose)polymerase overactivation. Angiotensin-converting enzyme inhibition may also exert additional beneficial effects by inhibiting the expression of the profibrotic mediator transforming growth factor ß.

Burn and smoke injury activates poly(ADP-ribose)polymerase in circulating leukocytes.

The nuclear enzyme poly(ADP-ribose)polymerase (PARP) plays a significant role in the pathogenesis of various forms of critical illness. DNA strand breaks induced by oxidative and nitrative stress trigger the activation of PARP, and PARP, in turn, mediates cell death and promotes proinflammatory responses. Until recently, most studies focused on the role of PARP in solid organs such as heart, liver, and kidney. We investigated the effect of burn and smoke inhalation on the levels of poly(ADP-ribosylated) proteins in circulating sheep leukocytes ex vivo. Adult female merino sheep were subjected to burn injury (2× 20% each flank, 3 degrees) and smoke inhalation injury (insufflated with a total of 48 breaths of cotton smoke) under deep anesthesia. Arterial and venous blood was collected at baseline, immediately after the injury and 1 to 24 h after the injury. Leukocytes were isolated with the Histopaque method. The levels of poly(ADP-ribosyl)ated proteins were determined by Western blotting. The amount of reactive oxygen species was quantified by the OxyBlot method. To examine whether PARP activation continues to increase ex vivo in the leukocytes, blood samples were incubated at room temperature or at 37°C for 3 h with or without the PARP inhibitor PJ34. To investigate whether the plasma of burn/smoke animals may trigger PARP activation, burn/smoke plasma was incubated with control leukocytes in vitro. The results show that burn and smoke injury induced a marked PARP activation in circulating leukocytes. The activity was the highest immediately after injury and at 1 h and decreased gradually over time. Incubation of whole blood at 37°C for 3 h significantly increased poly(ADP-ribose) levels, indicative of the presence of an ongoing cell activation process. In conclusion, PARP activity is elevated in leukocytes after burn and smoke inhalation injury, and the response parallels the time course of reactive oxygen species generation in these cells.

Real-time myocardial contrast stress echocardiography using bolus application.

In myocardial contrast echocardiography (MCE), power modulation technique may quantify myocardial perfusion in real-time. However, constant infusion of the contrast agent (CA) complicates handling. This pilot study sought for the clinical feasibility of quantitative MCE by a CA bolus application during Adenosine stress echocardiography to diagnose coronary artery disease (CAD). Twenty-four consecutive patients (pts) with contemporary coronary angiography underwent rest and maximum Adenosine stress. Signal intensity could be calculated in 316/348 left ventricular (LV) segments (91%) (18-segment model). At rest, gamma-variate (alpha) as well as saturation function (beta) was not significantly different in healthy men (n = 268) as well as CAD pts (n = 48) (alpha: 0.34 s(-1) versus 0.40 s(-1), n.s.; beta: 0.31 s(-1) versus 0.35 s(-1), n.s.). During Adenosine infusion both values increased in healthy men (alpha: 0.34 +/- 0.37 s(-1) versus 0.44 +/- 0.45 s(-1), p < 0.05; beta: 0.31 +/- 0.33 s(-1) versus 0.40 +/- 0.40 s(-1), p < 0.01), but not in CAD (alpha: 0.40 +/- 0.35 s(-1) versus 0.29 +/- 0.29 s(-1), n.s.; beta: 0.35 +/- 0.32 s(-1) versus 0.27 +/- 0.30 s(-1), n.s.). Sensitivity of alpha/beta reserve