Prophylactic furosemide to prevent transfusion-associated circulatory overload: a randomized controlled study in rats.

Transfusion-associated circulatory overload (TACO) is the leading cause of transfusion related morbidity and mortality. The only treatment is empirical use of furosemide. Our aim was to investigate if furosemide can prevent TACO. A randomized controlled trial was performed using a previously validated two-hit rat model for TACO. Volume incompliance was induced (first hit) in anemic, anesthetized Lewis rats. Rats were randomized to placebo, low-dose (5 mg kg-1) or high-dose (15 mg kg-1) furosemide-administered prior to transfusion (second-hit) and divided over two doses. Primary outcome was change in left-ventricular end-diastolic pressure (∆LVEDP) pre- compared to post-transfusion. Secondary outcomes included changes in preload, afterload, contractility and systemic vascular resistance, as well as pulmonary outcomes. Furosemide treated animals had a significantly lower ∆LVEDP compared to placebo (p = 0.041), a dose-response effect was observed. ∆LVEDP in placebo was median + 8.7 mmHg (IQR 5.9-11), + 3.9 (2.8-5.6) in the low-dose and 1.9 (- 0.6 to 5.6) in the high-dose group. The effect of furosemide became apparent after 15 min. While urine output was significantly higher in furosemide treated animals (p = 0.03), there were no significant changes in preload, afterload, contractility or systemic vascular resistance. Furosemide rapidly and dose-dependently decreases the rise in hydrostatic pulmonary pressure following transfusion, essential for preventing TACO.

Differential effects of speed and volume on transfusion-associated circulatory overload: A randomized study in rats.

BACKGROUND AND OBJECTIVES: Transfusion-associated circulatory overload (TACO) is the primary cause of transfusion-related mortality. Speed and volume of transfusion are major risk factors. The aim of this study was to investigate the interaction of red blood cell (RBC) transfusion speed and volume on the development of TACO. MATERIALS AND METHODS: A validated model for TACO in anaemic Lewis rats with an acute myocardial infarction was used. The effect on pulmonary hydrostatic pressure of one, two or four units of packed RBCs transfused in either 30 or 60 min was evaluated (3.3-26.6 ml·kg-1 ·hr-1 ). Pulmonary capillary pressure was measured as left ventricular end-diastolic pressure (LVEDP). Cardiac stress biomarkers atrial natriuretic-peptide (ANP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured 1-h post-transfusion. RESULTS: Thirty animals were included (n = 5 per group). Transfusion of RBCs increased LVEDP in a volume-dependent manner (ΔLVEDP [mmHg]: -0.95, +0.50, +6.26, p < 0.001). Fast transfusion increased overall ΔLVEDP by +3.5 mmHg and up to +11.8 mmHg in the four units' group (p = 0.016). Doubling transfusion speed increased ΔLVEDP more than doubling volume in the larger volume groups. No difference in ANP or NT-proBNP were seen in high transfusion volume or groups. CONCLUSION: Transfusion volume dose-dependently increased LVEDP, with speed of transfusion rapidly elevating LVEDP at higher transfusion volumes. ANP and NT-proBNP were not impacted by transfusion volume or speed in this model. TACO is seen as purely volume overload, however, this study emphasizes that limiting transfusion speed, as a modifiable risk factor, might aid in preventing TACO.

Volume incompliance and transfusion are essential for transfusion-associated circulatory overload: a novel animal model.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is the predominant complication of transfusion resulting in death. The pathophysiology is poorly understood, but inability to manage volume is associated with TACO, and observational data suggest it is different from simple cardiac overload due to fluids. We developed a two-hit TACO animal model to assess the role of volume incompliance ("first-hit") and studied whether volume overload ("second-hit") by red blood cell (RBC) transfusion is different compared to fluids (Ringer's lactate [RL]). MATERIALS AND METHODS: Male adult Lewis rats were stratified into a control group (no intervention) or a first hit: either myocardial infarction (MI) or acute kidney injury (AKI). Animals were randomized to a second hit of either RBC transfusion or an equal volume of RL. A clinically relevant difference was defined as an increase in left ventricular end-diastolic pressure (ΔLVEDP) of +4.0 mm Hg between the RBC and RL groups. RESULTS: In control animals (without first hit) LVEDP was not different between infusion groups (Δ + 1.6 mm Hg). LVEDP increased significantly more after RBCs compared to RL in animals with MI (Δ7.4 mm Hg) and AKI (Δ + 5.4 mm Hg), respectively. Volume-incompliant rats matched clinical TACO criteria in 92% of transfused versus 25% of RL-infused animals, with a greater increase in heart rate and significantly higher blood pressure. CONCLUSION: To our knowledge, this is the first animal model for TACO, showing that a combination of volume incompliance and transfusion is essential for development of circulatory overload. This model allows for further testing of mechanistic factors as well as therapeutic approaches.

Incorporation of Daily Goals in Daily Care Planning Does Not Shorten Length of Stay in the Intensive Care Unit.

A strategy of defining and checking explicitly formulated patient-specific treatments targets or "daily goals" in the intensive care unit has been associated with improved communication. We investigated the effect of incorporation of daily goals into daily care planning on length of stay in the intensive care unit. Furthermore, the type of daily goals and deviations from daily goals in daily care with or without documented reason were evaluated. Four university hospitals in the Netherlands, of which 2 study "daily goal" hospitals and 2 control hospitals, participated in a prospective before-after study. During the before phase of the study, daily goals were formulated by the attending physician but kept blinded from doctors and nurses caring for the patient. During the after phase of the study, daily goals were integrated in the care plan for patients admitted to the 2 study hospitals but not for patients admitted to the control hospitals. The implementation of daily goals was, after case-mix correction, not associated with a change in intensive care unit length of stay. However, this study showed that an improved administrative discipline, that is, the recording of the reason why a daily goal or standard protocol was not accomplished, is in favor of the daily goal implementation.

The impact of changes in intensive care organization on patient outcome and cost-effectiveness-a narrative review.

The mortality rate of critically ill patients is high and the cost of the intensive (ICU) department is among the highest within the health-care industry. The cost will continue to increase because of the aging population in the western world. In the present review, we will discuss the impact of changes in ICU department organization on patient outcome and cost-effectiveness. The general perception that drug and treatment discoveries are the main drivers behind improved patient outcome within the health-care industry is in general not true. This is especially the case for the ICU department, in which the past decades' organizational changes were the main drivers behind the reduction of ICU mortality. These interventions were at the same time able to reduce cost, something which is rare for drug and treatment discoveries. The organization of the intensive care department has been changed over the past decades, resulting in better patient outcome and reduction of cost. Major changes are the implementation of the "closed format" and electronic patient record. Furthermore, we will present possible future options to improve the organization of the ICU department to further reduce mortality and cost such as pooling of dedicated ICU into mixed ICU and embedding business strategies such as lean and total quality management. Challenges are ahead as the ICU is taking up the largest share of national health-care expenditure, and with the aging of the population, this will continue to increase. Besides future improvements of organizational structures within the ICU, the focus should also be on the implementation of and compliance with proven beneficial organizational structures.

Timely individual audit and feedback significantly improves transfusion bundle compliance-a comparative study.

OBJECTIVE: To investigate the difference in effect on transfusion bundle compliance between two Audit and Feedback (A&F) strategies to implement the transfusion bundle. DESIGN AND SETTING: This implementation study was conducted in an ICU of a university hospital from May to December 2014. The ICU consists of two nursing teams containing 63 and 62 nurses. PARTICIPANTS: All ICU nurses participated in this study. INTERVENTION: Monthly A&F on team level versus a combination of monthly A&F on team level plus timely individual feedback. MEASUREMENTS: The primary outcome was bundle compliance. Compliance was measured after every single transfusion. RESULTS: Monthly A&F on team level with timely individual A&F significantly improves bundle compliance during implementation compared to monthly A&F on team level alone. The overall effect of compliance during the study period was significantly higher with an OR of 4.05 (95% confidence interval, CI: 1.62 to 10.08), P < 0.001. This indicates that when using the combined A&F strategy nurses are more likely to be compliant to the bundle than when monthly A&F was used alone. CONCLUSIONS: Compared to monthly team A&F alone, providing timely individual A&F plus monthly A&F on team level significantly improves the success of implementing a transfusion bundle on the ICU during the implementation period. Providing timely individual A&F plus monthly A&F on team level might also be effective for the implementation of other bundles in healthcare. Future research could elaborate on longer duration of the intervention, the use of information and computer technology to lower costs of the intervention, and to enhance sustainability.

Nurses versus physician-led interhospital critical care transport: a randomized non-inferiority trial.

PURPOSE: Regionalization and concentration of critical care increases the need for interhospital transport. However, optimal staffing of ground critical care transport has not been evaluated. METHODS: In this prospective, randomized, open-label, blinded-endpoint non-inferiority trial, critically ill patients on mechanical ventilation transported by interhospital ground critical care transport were randomized between transport staffed by a dedicated team comprising a critical care nurse and paramedic (nurses group) or a dedicated team including a critical care physician (nurses + physician group). The primary outcome was the number of patients with critical events, both clinical and technical, during transport. Clinical events included decrease in blood pressure, oxygen saturation, or temperature, blood loss, new cardiac arrhythmias, or death. Non-inferiority was assumed if the upper limit of the two-sided 90 % confidence interval (CI) for the between-group difference lies below the non-inferiority margin of 3 %. RESULTS: Of 618 eligible transported critically ill patients, 298 could be analyzed after randomization and allocation to the nurses group (n = 147) or nurses + physician group (n = 151). The percentages of patients with critical events were 16.3 % (24 incidents in 147 transports) in the nurses group and 15.2 % (23 incidents in 151 transports) in the nurses + physician group (difference 1.1 %, two-sided 90 % CI [-5.9 to 8.1]). Critical events occurred in both groups at a higher than the expected (0-1 %) rate. In the nurses group consultations for physician assistance were requested in 8.2 % (12 in 147 transports), all of which were performed prior to transport. CONCLUSIONS: The number of patients with critical events did not markedly differ between critical care transports staffed by a critical care nurse and paramedic compared to a team including a critical care physician. However, as a result of an unexpected higher rate of critical events in both groups recorded by an electronic health record, non-inferiority of nurse-led interhospital critical transport could not be established ( http://www.controlled-trials.com/ISRCTN39701540 ).

Guideline implementation powered by feedback and education improves manual hyperinflation performance.

AIM: To determine whether a literature-based guideline, powered by educational meetings and individual feedback, improves manual hyperinflation (MH) performance by intensive care unit (ICU) nurses. BACKGROUND: MH is frequently applied in intubated and mechanically ventilated ICU patients. MH is a complex intervention, and large variation in its performance has been found. MATERIALS AND METHODS: First, a literature-based guideline on MH was developed. The intervention consisted of education of this guideline and individual feedback. Before and 3 months after the intervention, ICU nurses performed MH maneuvers in a skills laboratory. Data collected included applied volumes, peak inspiratory flows (PIF) and peak expiratory flows (PEF), and the use of inspiratory holds. RESULTS: Eighty nurses participated. Decrease of PIF was not statistically significant. PEF increased from 52 ± 7 to 83 ± 23 L/min (P < 0·01). PIF to PEF ratio decreased from 1·4 [1·1-1·7] to 0·8 [0·6-1·1] (P < 0·01). Peak inspiratory pressures decreased from 40 ± 14 to 19 ± 6 cm H2 O (P < 0·01). The proportion of nurses applying inspiratory holds increased from 14% to 58%; use of rapid release of the resuscitation bag, considered mandatory, increased from 4% to 61%. CONCLUSION: Implementation of a literature-based guideline on MH, powered by educational meetings and individual feedback, improves MH performance by ICU nurses. RELEVANCE TO CLINICAL PRACTICE: If it is decided to practice MH in the care of the intubated and mechanical ventilated patient, a standardized, uniform performed MH procedure is a prerequisite.

Effect of transfusion of fresh frozen plasma on parameters of endothelial condition and inflammatory status in non-bleeding critically ill patients: a prospective substudy of a randomized trial.

INTRODUCTION: Much controversy exists on the effect of a fresh frozen plasma (FFP) transfusion on systemic inflammation and endothelial damage. Adverse effects of FFP have been well described, including acute lung injury. However, it is also suggested that a higher amount of FFP decreases mortality in trauma patients requiring a massive transfusion. Furthermore, FFP has an endothelial stabilizing effect in experimental models. We investigated the effect of fresh frozen plasma transfusion on systemic inflammation and endothelial condition. METHODS: A prospective predefined substudy of a randomized trial in coagulopathic non-bleeding critically ill patients receiving a prophylactic transfusion of FFP (12 ml/kg) prior to an invasive procedure. Levels of inflammatory cytokines and markers of endothelial condition were measured in paired samples of 33 patients before and after transfusion. The statistical tests used were paired t test or the Wilcoxon signed-rank test. RESULTS: At baseline, systemic cytokine levels were mildly elevated in critically ill patients. FFP transfusion resulted in a decrease of levels of TNF-α (from 11.3 to 2.3 pg/ml, P = 0.01). Other cytokines were not affected. FFP also resulted in a decrease in systemic syndecan-1 levels (from 675 to 565 pg/ml, P = 0.01) and a decrease in factor VIII levels (from 246 to 246%, P <0.01), suggestive of an improved endothelial condition. This was associated with an increase in ADAMTS13 levels (from 24 to 32%, P <0.01) and a concomitant decrease in von Willebrand factor (vWF) levels (from 474 to 423%, P <0.01). CONCLUSIONS: A fixed dose of FFP transfusion in critically ill patients decreases syndecan-1 and factor VIII levels, suggesting a stabilized endothelial condition, possibly by increasing ADAMTS13, which is capable of cleaving vWF. TRIAL REGISTRATIONS: Trialregister.nl NTR2262, registered 26 March 2010 and Clinicaltrials.gov NCT01143909, registered 14 June 2010.

Transfusion of fresh-frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME).

BACKGROUND: Prophylactic use of fresh-frozen plasma (FFP) is common practice in patients with a coagulopathy undergoing an invasive procedure. Evidence that FFP prevents bleeding is lacking, while risks of transfusion-related morbidity after FFP have been well demonstrated. We aimed to assess whether omitting prophylactic FFP transfusion in nonbleeding critically ill patients with a coagulopathy who undergo an intervention is noninferior to a prophylactic transfusion of FFP. STUDY DESIGN AND METHODS: A multicenter randomized open-label trial with blinded endpoint evaluation was performed in critically ill patients with a prolonged international normalized ratio (INR; 1.5-3.0). Patients undergoing placement of a central venous catheter, percutaneous tracheostomy, chest tube, or abscess drainage were eligible. Patients with clinically overt bleeding, thrombocytopenia, or therapeutic use of anticoagulants were excluded. Patients were randomly assigned to omitting or administering a prophylactic transfusion of FFP (12 mL/kg). Outcomes were occurrence of postprocedural bleeding complications, INR correction, and occurrence of lung injury. RESULTS: Due to slow inclusion, the trial was stopped before the predefined target enrollment was reached. Eighty-one patients were randomly assigned, 40 to FFP and 41 to no FFP transfusion. Incidence of bleeding did not differ between groups, with a total of one major and 13 minor bleedings (p = 0.08 for noninferiority). FFP transfusion resulted in a reduction of INR to less than 1.5 in 54% of transfused patients. No differences in lung injury scores were observed. CONCLUSION: In critically ill patients undergoing an invasive procedure, no difference in bleeding complications was found regardless whether FFP was prophylactically administered or not.

[A limited role for telemedicine on the Dutch intensive care]. / Beperkte rol voor telegeneeskunde op Nederlandse IC.

The use of telecommunication and information technology has evolved rapidly in many areas. However, it has not kept pace for the organisation of medicine. It can be expected that e-Health will revolutionise the landscape of medicine in the coming years. Due to a shortage of intensivists, with the 24/7 availability of an intensivist in less than 30% of ICUs, tele-ICU care has been introduced in the U.S. with proven beneficial effects on patient outcome and economics. This cannot be compared with the Dutch situation where there are short distances between hospitals, ubiquitous, excellent infrastructure for patient transport and a sufficient number of intensivists. Furthermore, an ICU is not only characterised by its own means in terms of human resources and equipment, but also by the 24/7 availability of other (critical) medical specialities in the hospital. The contribution of tele-ICU is therefore limited in the Netherlands but might play a role for second opinions and consultation for highly specialized expertise.

Heliox Improves Carbon Dioxide Removal during Lung Protective Mechanical Ventilation.

Introduction. Helium is a noble gas with low density and increased carbon dioxide (CO2) diffusion capacity. This allows lower driving pressures in mechanical ventilation and increased CO2 diffusion. We hypothesized that heliox facilitates ventilation in patients during lung-protective mechanical ventilation using low tidal volumes. Methods. This is an observational cohort substudy of a single arm intervention study. Twenty-four ICU patients were included, who were admitted after a cardiac arrest and mechanically ventilated for 3 hours with heliox (50% helium; 50% oxygen). A fixed protective ventilation protocol (6 mL/kg) was used, with prospective observation for changes in lung mechanics and gas exchange. Statistics was by Bonferroni post-hoc correction with statistical significance set at P < 0.017. Results. During heliox ventilation, respiratory rate decreased (25 ± 4 versus 23 ± 5 breaths min(-1), P = 0.010). Minute volume ventilation showed a trend to decrease compared to baseline (11.1 ± 1.9 versus 9.9 ± 2.1 L min(-1), P = 0.026), while reducing PaCO2 levels (5.0 ± 0.6 versus 4.5 ± 0.6 kPa, P = 0.011) and peak pressures (21.1 ± 3.3 versus 19.8 ± 3.2 cm H2O, P = 0.024). Conclusions. Heliox improved CO2 elimination while allowing reduced minute volume ventilation in adult patients during protective mechanical ventilation.

Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia.

INTRODUCTION: Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest. METHODS: A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined. RESULTS: In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C. CONCLUSIONS: Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest. TRIAL REGISTRATION: ClinicalTrials.gov NCT01020916, registered 25 November 2009.

Contribution of damage-associated molecular patterns to transfusion-related acute lung injury in cardiac surgery.

BACKGROUND: The incidence of transfusion-related acute lung injury (TRALI) in cardiac surgery patients is high and this condition contributes to an adverse outcome. Damage-associated molecular pattern (DAMP) molecules, HMGB1 and S100A12, are thought to mediate inflammatory changes in acute respiratory distress syndrome. We aimed to determine whether DAMP are involved in the pathogenesis of TRALI in cardiac surgery patients. MATERIALS AND METHODS: This was a secondary analysis of a prospective observational trial in cardiac surgery patients admitted to the Intensive Care Unit of a university hospital in the Netherlands. Fourteen TRALI cases were randomly matched with 32 transfused and non-transfused controls. Pulmonary levels of HMGB1, S100A12 and inflammatory cytokines (interleukins-1ß, -6, and -8 and tumour necrosis factor-α) were determined when TRALI evolved. In addition, systemic and pulmonary levels of soluble receptor for advanced glycation end products (sRAGE) were determined. RESULTS: HMGB1 expression and levels of sRAGE in TRALI patients did not differ from those in controls. There was a trend towards higher S100A12 levels in TRALI patients compared to the controls. Furthermore, S100A12 levels were associated with increased levels of markers of pulmonary inflammation, prolonged cardiopulmonary bypass, hypoxemia and duration of mechanical ventilation. CONCLUSION: No evidence was found that HMGB1 and sRAGE contribute to the development of TRALI. S100A12 is associated with duration of cardiopulmonary bypass, pulmonary inflammation, hypoxia and prolonged mechanical ventilation and may contribute to acute lung injury in cardiac surgery patients.

Utility of thromboelastography and/or thromboelastometry in adults with sepsis: a systematic review.

INTRODUCTION: Coagulation abnormalities are frequent in sepsis. Conventional coagulation assays, however, have several limitations. A surge of interest exists in the use of point-of-care tests to diagnose hypo- and hypercoagulability in sepsis. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched from 1 January 1980 to 31 December 2012. The search was limited to adults, and language was limited to English. Reference lists of retrieved articles were hand-searched for additional studies. Ongoing trials were searched on http://www.controlled-trials.com and http://www.clinicaltrials.gov. Studies addressing TEG/ROTEM measurements in adult patients with sepsis admitted to the ICU were considered eligible. RESULTS: Of 680 screened articles, 18 studies were included, of which two were randomized controlled trials, and 16 were observational cohort studies. In patients with sepsis, results show both hyper- and hypocoagulability, as well as TEG/ROTEM values that fell within reference values. Both hyper- and hypocoagulability were to some extent associated with diffuse intravascular coagulation. Compared with conventional coagulation tests, TEG/ROTEM can detect impaired fibrinolysis, which can possibly help to discriminate between sepsis and systemic inflammatory response syndrome (SIRS). A hypocoagulable profile is associated with increased mortality. The value of TEG/ROTEM to identify patients with sepsis who could possibly benefit from therapies interfering with the coagulation system could not be assessed, because studies addressing this topic were limited. CONCLUSION: TEG/ROTEM could be a promising tool in diagnosing alterations in coagulation in sepsis. Further research on the value of TEG/ROTEM in these patients is warranted. Given that coagulopathy is a dynamic process, sequential measurements are needed to understand the coagulation patterns in sepsis, as can be detected by TEG/ROTEM.

Mechanical ventilation with heliox in an animal model of acute respiratory distress syndrome.

BACKGROUND: Heliox has a lower density and higher diffusion capacity compared to oxygen-in-air. We hypothesized that heliox ventilation allows for a reduction in minute volume ventilation and inspiratory pressures needed for adequate gas exchange in an animal model of an acute lung injury. METHODS: After intratracheal instillation of lipopolysaccharide (10 mg/kg), adult rats were randomized to ventilation with either a gas mixture of helium/oxygen (50:50%) or oxygen/air (50:50%). They were mechanically ventilated according to the ARDSnet recommendations with tidal volumes of 6 ml/kg and monitored with a pneumotachometer. Bronchoalveolar lavage fluid was analyzed for markers of lung injury, and embedded lung sections were histologically scored for lung injury. RESULTS: Heliox limited the increase in driving pressures needed to achieve preset tidal volumes, with a concomitant decrease in loss of compliance. Heliox did neither allow for reduced minute volume ventilation in this model nor improve gas exchange. Also, heliox did not reduce lung injury. CONCLUSIONS: Heliox modestly improved respiratory mechanics but did not improve lung injury in this rat model of acute respiratory distress syndrome.

Methylprednisolone fails to attenuate lung injury in a mouse model of transfusion related acute lung injury.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality. Anecdotally, TRALI patients have been treated with corticosteroids. However, evidence for its therapeutic rationale in TRALI is lacking. We determined the effects of corticosteroids on lung injury in a "two-hit" mouse model of antibody-mediated TRALI. STUDY DESIGN AND METHODS: BALB/c mice were primed with lipopolysaccharide, after which TRALI was induced by injecting major histocompatibility complex (MHC)-I antibody against H2K(d) . Mice infused with phosphate-buffered saline served as controls. Simultaneously, one group of TRALI mice was infused with methylprednisolone (MPS; 2 mg/kg). Mice were supported by mechanical ventilation for 2 hours, after which bronchoalveolar lavage fluid (BALF) and lung homogenate were obtained. Statistics were obtained by one-way analysis of variance or Kruskal-Wallis. RESULTS: Injection of MHC-I antibodies resulted in TRALI, indicated by pulmonary edema and increased BALF levels of protein and the proinflammatory mediators macrophage inflammatory protein-2, keratinocyte-derived chemokine, and interleukin (IL)-6. Administration of MPS did not affect the amount of edema nor pulmonary protein and chemokine levels. MPS reduced systemic inflammatory reaction as well as IL-6 levels in the BALF. CONCLUSION: In a two-hit model of antibody-mediated TRALI, MPS attenuated the IL-6 host response, but failed to prevent the development of lung injury.

Heliox allows for lower minute volume ventilation in an animal model of ventilator-induced lung injury.

BACKGROUND: Helium is a noble gas with a low density, allowing for lower driving pressures and increased carbon dioxide (CO2) diffusion. Since application of protective ventilation can be limited by the development of hypoxemia or acidosis, we hypothesized that therefore heliox facilitates ventilation in an animal model of ventilator-induced lung injury. METHODS: Sprague-Dawley rats (N=8 per group) were mechanically ventilated with heliox (50% oxygen; 50% helium). Controls received a standard gas mixture (50% oxygen; 50% air). VILI was induced by application of tidal volumes of 15 mL kg(-1); lung protective ventilated animals were ventilated with 6 mL kg(-1). Respiratory parameters were monitored with a pneumotach system. Respiratory rate was adjusted to maintain arterial pCO2 within 4.5-5.5 kPa, according to hourly drawn arterial blood gases. After 4 hours, bronchoalveolar lavage fluid (BALF) was obtained. Data are mean (SD). RESULTS: VILI resulted in an increase in BALF protein compared to low tidal ventilation (629 (324) vs. 290 (181) µg mL(-1); p<0.05) and IL-6 levels (640 (8.7) vs. 206 (8.7) pg mL(-1); p<0.05), whereas cell counts did not differ between groups after this short course of mechanical ventilation. Ventilation with heliox resulted in a decrease in mean respiratory minute volume ventilation compared to control (123 ± 0.6 vs. 146 ± 8.9 mL min(-1), P<0.001), due to a decrease in respiratory rate (22 (0.4) vs. 25 (2.1) breaths per minute; p<0.05), while pCO2 levels and tidal volumes remained unchanged, according to protocol. There was no effect of heliox on inspiratory pressure, while compliance was reduced. In this mild lung injury model, heliox did not exert anti-inflammatory effects. CONCLUSIONS: Heliox allowed for a reduction in respiratory rate and respiratory minute volume during VILI, while maintaining normal acid-base balance. Use of heliox may be a useful approach when protective tidal volume ventilation is limited by the development of severe acidosis.

The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation.

Background. Mechanical ventilation (MV) has the potential to initiate ventilator-induced lung injury (VILI). The pathogenesis of VILI has been primarily studied in animal models using more or less injurious ventilator settings. However, we speculate that duration of MV also influences severity and character of VILI. Methods. Sixty-four healthy C57Bl/6 mice were mechanically ventilated for 5 or 12 hours, using lower tidal volumes with positive end-expiratory pressure (PEEP) or higher tidal volumes without PEEP. Fifteen nonventilated mice served as controls. Results. All animals remained hemodynamically stable and survived MV protocols. In both MV groups, PaO2 to FiO2 ratios were lower and alveolar cell counts were higher after 12 hours of MV compared to 5 hours. Alveolar-capillary permeability was increased after 12 hours compared to 5 hours, although differences did not reach statistical significance. Lung levels of inflammatory mediators did not further increase over time. Only in mice ventilated with increased strain, lung compliance declined and wet to dry ratio increased after 12 hours of MV compared to 5 hours. Conclusions. Deleterious effects of MV are partly dependent on its duration. Even lower tidal volumes with PEEP may initiate aspects of VILI after 12 hours of MV.