Antimicrobial Drug Penetration Is Enhanced by Lung Tissue Inflammation and Injury.

Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into lung tissue.Objectives: To determine and compare tissue and BAL fluid concentrations of ceftaroline fosamil and linezolid in a model of unilateral acute lung injury in pigs and to evaluate whether dose adjustment is necessary to reach sufficient antimicrobial concentrations in injured lung tissue.Methods: After induction of unilateral acute lung injury, ceftaroline fosamil and linezolid were administered intravenously. Drug concentrations were measured in lung tissue through microdialysis and in blood and BAL fluid samples during the following 8 hours. The primary endpoint was the tissue concentration area under the concentration curve in the first 8 hours (AUC0-8 h) of the two antimicrobial drugs.Measurements and Main Results: In 10 pigs, antimicrobial drug concentrations were higher in inflamed and injured lung tissue compared with those in uninflamed and uninjured lung tissue (median ceftaroline fosamil AUC0-8 h [and interquartile range] = 26.7 mg ⋅ h ⋅ L-1 [19.7-39.0] vs. 16.0 mg ⋅ h ⋅ L-1 [13.6-19.9], P = 0.02; median linezolid AUC0-8 h 76.0 mg ⋅ h ⋅ L-1 [68.1-96.0] vs. 54.6 mg ⋅ h ⋅ L-1 [42.7-60.9], P = 0.01), resulting in a longer time above the minimal inhibitory concentration and in higher peak concentrations and dialysate/plasma ratios. Penetration into BAL fluid was excellent for both antimicrobials, but without left-to-right differences (ceftaroline fosamil, P = 0.78; linezolid, P = 1.00).Conclusions: Tissue penetration of two commonly used antimicrobial drugs for pneumonia is enhanced by early lung tissue inflammation and injury, resulting in longer times above the minimal inhibitory concentration. Thus, lung tissue inflammation ameliorates antimicrobial drug penetration during the acute phase.

Unilateral acute lung injury in pig: a promising animal model.

BACKGROUND: Acute lung injury (ALI) occurs in 23% unilateral. Models of unilateral ALI were developed and used previously without clearly demonstrating the strictly unilateral nature and severity of lung injury by the key parameters characterizing ALI as defined by the American Thoracic Society (ATS). Thus, the use of unilateral ALI remained rare despite the innovative approach. Therefore, we developed a unilateral model of ALI and focused on the crucial parameters characterizing ALI. This model can serve for direct comparisons between the injured and intact lungs within single animals, thus, reducing the number of animals required for valid experimental conclusions. METHODS: We established the model in nine pigs, followed by an evaluation of key parameters in six pigs (main study). Pigs were ventilated using an adapted left double-lumen tube for lung separation and two ventilators. ALI was induced in the left lung with cyclic rinsing (NaCl 0.9% + Triton® X-100), after which pigs were ventilated for different time spans to test for the timing of ALI onset. Ventilatory and metabolic parameters were evaluated, and bronchoalveolar lavage (BAL) was performed for measurements of inflammatory mediators. Finally, histopathological specimens were collected and examined in respect of characteristics defining the lung injury score (LIS) as suggested by the ATS. RESULTS: After adjustments of the model (n = 9) we were able to induce strictly left unilateral ALI in all six pigs of the evaluation study. The median lung injury score was 0.72 (IQR 0.62-0.79) in the left lung vs 0.14 (IQR 0.14-0.16; p < 0.05) in the right lung, confirming unilateral ALI. A significant and sustained drop in pulmonary compliance (Cdyn) of the left lung occurred immediately, whereas Cdyn of the right lung remained unchanged (p < 0.05). BAL fluid concentrations of interleukin-6 and -8 were increased in both lungs. CONCLUSIONS: We established a model of unilateral ALI in pigs, confirmed by histopathology, and typical changes in respiratory mechanics and an inflammatory response. This thoroughly evaluated model could serve as a basis for future studies and for comparing pathophysiological and pharmacological changes in the uninjured and injured lung within the same animal.

Hemolysis Index Correlations with Plasma-Free Hemoglobin and Plasma Lactate Dehydrogenase in Critically Ill Patients under Extracorporeal Membrane Oxygenation or Mechanical Circulatory Support-A Single-Center Study.

Monitoring for thrombosis and hemolysis is crucial for patients under extracorporeal or mechanical circulatory support, but it can be costly. We investigated correlations between hemolysis index (HI) and plasma-free hemoglobin (PFH) levels on one hand, and between the HI and plasma lactate dehydrogenase (LDH) levels on the other, in critically ill patients with and without extracorporeal or mechanical circulatory support. Additionally, we calculated the cost reductions if monitoring through HI were to replace monitoring through PFH or plasma LDH. In a single-center study, HI was compared with PFH and plasma LDH levels in blood samples taken for routine purposes in critically ill patients with and without extracorporeal or mechanical circulatory support. A cost analysis, restricted to direct costs associated with each measurement, was made for an average 10-bed ICU. This study included 147 patients: 56 patients with extracorporeal or mechanical circulatory support (450 measurements) and 91 patients without extracorporeal or mechanical circulatory support (562 measurements). The HI correlated well with PFH levels (r = 0.96; p < 0.01) and poorly with plasma LDH levels (r = 0.07; p < 0.01) in patients with extracorporeal or mechanical circulatory support. Similarly, HI correlated well with PFH levels (r = 0.97; p < 0.01) and poorly with plasma LDH levels (r = -0.04; p = 0.39) in patients without extracorporeal or mechanical circulatory support. ROC analyses demonstrated a strong performance of HI, with the curve indicating excellent discrimination in the whole cohort (area under the ROC of 0.969) as well as in patients under ECMO or mechanical circulatory support (area under the ROC of 0.988). Although the negative predictive value of HI for predicting PFH levels > 10 mg/dL was high, its positive predictive value was found to be poor at various cutoffs. A simple cost analysis showed substantial cost reduction if HI were to replace PFH or plasma LDH for hemolysis monitoring. In conclusion, in this cohort of critically ill patients with and without extracorporeal or mechanical circulatory support, HI correlated well with PFH levels, but poorly with plasma LDH levels. Given the high correlation and substantial cost reductions, a strategy utilizing HI may be preferable for monitoring for hemolysis compared to monitoring strategies based on PFH or plasma LDH. The PPV of HI, however, is unacceptably low to be used as a diagnostic test.

Effects of lung inflammation and injury on pulmonary tissue penetration of meropenem and vancomycin in a model of unilateral lung injury.

OBJECTIVE: The timing and dosing of antimicrobial therapy are key in the treatment of pneumonia in critically ill patients. It is uncertain whether the presence of lung inflammation and injury affects tissue penetration of intravenously administered antimicrobial drugs. The effects of lung inflammation and injury on tissue penetration of two antimicrobial drugs commonly used for pneumonia were determined in an established model of unilateral lung injury. METHODS: Unilateral lung injury was induced in the left lung of 13 healthy pigs through cyclic rinsing; the right healthy lung served as control. Infusions of meropenem and vancomycin were administered and concentrations of these drugs in lung tissue, blood, and epithelial lining fluid (ELF) were compared over a period of 6 h. RESULTS: Median vancomycin lung tissue concentrations and penetration ratio were higher in inflamed and injured lungs compared with uninflamed and uninjured lungs (AUC0-6h: P = 0.003 and AUCdialysate/AUCplasma ratio: P = 0.003), resulting in higher AUC0-24/MIC. Median meropenem lung tissue concentrations and penetration ratio in inflamed and injured lungs did not differ from that in uninflamed and uninjured lungs (AUC0-6: P = 0.094 and AUCdialysate/AUCplasma ratio: P = 0.173). The penetration ratio for both vancomycin and meropenem into ELF was similar in injured and uninjured lungs. CONCLUSION: Vancomycin penetration into lung tissue is enhanced by acute inflammation and injury, a phenomenon barely evident with meropenem. Therefore, inflammation in lung tissue influences the penetration into interstitial lung tissue, depending on the chosen antimicrobial drug. Measurement of ELF levels alone might not identify the impact of inflammation and injury.

Resident performance in basic perioperative transesophageal echocardiography: Comparing 3 teaching methods in a randomized controlled trial.

BACKGROUND: Training in transesophageal echocardiography (TEE) is based on hands-on training in the operating room, which is time consuming and therefore limits its experience among anesthesiologists. Medical simulations have been successfully used for training of invasive procedures in many areas.This paper compares the difference in effectiveness of teaching the 11 basic TEE views using either e-learning, simulation based training or hands-on training in the operating room in 3 groups of residents. METHODS: We included 51 anesthesia and intensive care residents of all training levels but no prior training in echocardiography in this prospective randomized single-center study.Residents received a tutorial about theoretical knowledge followed by 2 practical study sessions either by e-learning using an online simulator (www.pie.med.utoronto.ca/TEE), with the simulation mannequin (CAE Vimedix Simulator) or in the operating room. Both, a theoretical multiple choice test (0-50 points) and a practical exam test (0-110 points) on the simulation mannequin had to be completed.The primary endpoint was the post-training scores in the practical and theoretical exams after all training sessions. RESULTS: Residents received significantly higher test scores in both practical and theoretical examinations after training with the simulation mannequin (108.41 ±â€Š2.09, 40.6 ±â€Š5.23, n = 17) compared with e-learning (106.88 ±â€Š4.53, 36 ±â€Š4.76, n = 17) or hands-on training (106.82 ±â€Š2.01, 34.94 ±â€Š4.72, n = 17). CONCLUSIONS: Simulation based TEE training provides more effective training than other teaching methods. It is therefore especially suitable for the initial stages of TEE training to acquire psychomotor skills and knowledge of echo-anatomy.

Translation of ERC resuscitation guidelines into clinical practice by emergency physicians.

PURPOSE: Austrian out-of-hospital emergency physicians (OOHEP) undergo mandatory biannual emergency physician refresher courses to maintain their licence. The purpose of this study was to compare different reported emergency skills and knowledge, recommended by the European Resuscitation Council (ERC) guidelines, between OOHEP who work regularly at an out-of-hospital emergency service and those who do not currently work as OOHEP but are licenced. METHODS: We obtained data from 854 participants from 19 refresher courses. Demographics, questions about their practice and multiple-choice questions about ALS-knowledge were answered and analysed. We particularly explored the application of therapeutic hypothermia, intraosseous access, pocket guide use and knowledge about the participants' defibrillator in use. A multivariate logistic regression analysed differences between both groups of OOHEP. Age, gender, years of clinical experience, ERC-ALS provider course attendance and the self-reported number of resuscitations were control variables. RESULTS: Licenced OOHEP who are currently employed in emergency service are significantly more likely to initiate intraosseous access (OR = 4.013, p < 0.01), they initiate mild-therapeutic hypothermia after successful resuscitation (OR = 2.550, p < 0.01) more often, and knowledge about the used defibrillator was higher (OR = 2.292, p < 0.01). No difference was found for the use of pocket guides.OOHEP who have attended an ERC-ALS provider course since 2005 have initiated more mild therapeutic hypothermia after successful resuscitation (OR = 1.670, p <0.05) as well as participants who resuscitated within the last year (OR = 2.324, p < 0.01), while older OOHEP initiated mild therapeutic hypothermia less often, measured per year of age (OR = 0.913, p <0.01). CONCLUSION: Licenced and employed OOHEP implement ERC guidelines better into clinical practice, but more training on life-saving rescue techniques needs to be done to improve knowledge and to raise these rates of application.

Comparing three CPR feedback devices and standard BLS in a single rescuer scenario: a randomised simulation study.

BACKGROUND: Efficiently performed basic life support (BLS) after cardiac arrest is proven to be effective. However, cardiopulmonary resuscitation (CPR) is strenuous and rescuers' performance declines rapidly over time. Audio-visual feedback devices reporting CPR quality may prevent this decline. We aimed to investigate the effect of various CPR feedback devices on CPR quality. METHODS: In this open, prospective, randomised, controlled trial we compared three CPR feedback devices (PocketCPR, CPRmeter, iPhone app PocketCPR) with standard BLS without feedback in a simulated scenario. 240 trained medical students performed single rescuer BLS on a manikin for 8min. Effective compression (compressions with correct depth, pressure point and sufficient decompression) as well as compression rate, flow time fraction and ventilation parameters were compared between the four groups. RESULTS: Study participants using the PocketCPR performed 17±19% effective compressions compared to 32±28% with CPRmeter, 25±27% with the iPhone app PocketCPR, and 35±30% applying standard BLS (PocketCPR vs. CPRmeter p=0.007, PocketCPR vs. standard BLS p=0.001, others: ns). PocketCPR and CPRmeter prevented a decline in effective compression over time, but overall performance in the PocketCPR group was considerably inferior to standard BLS. Compression depth and rate were within the range recommended in the guidelines in all groups. CONCLUSION: While we found differences between the investigated CPR feedback devices, overall BLS quality was suboptimal in all groups. Surprisingly, effective compression was not improved by any CPR feedback device compared to standard BLS. All feedback devices caused substantial delay in starting CPR, which may worsen outcome.

Acute hyponatremia after cardioplegia by histidine-tryptophane-ketoglutarate--a retrospective study.

BACKGROUND: Hyponatremia is the most common electrolyte disorder in hospitalized patients and is known to be associated with increased mortality. The administration of antegrade single-shot, up to two liters, histidine-tryptophane-ketoglutarate (HTK) solution for adequate electromechanical cardiac arrest and myocardial preservation during minimally invasive aortic valve replacement (MIAVR) is a standard procedure. We aimed to determine the impact of HTK infusion on electrolyte and acid-base balance. METHODS: In this retrospective analysis we reviewed data on patient characteristics, type of surgery, arterial blood gas analysis during surgery and intra-/postoperative laboratory results of patients receiving surgery for MIAVR at a large tertiary care university hospital. RESULTS: A total of 25 patients were included in the study. All patients were normonatremic at start of surgery. All patients developed hyponatremia after administration of HTK solution with a significant drop of serum sodium of 15 mmol/L (p < 0.01). Measured osmolality did not change during all times of surgery compared to start of surgery (p = 0.28 - p = 0.79), indicating isotonic hyponatremia. After administration of HTK solution pH fell significantly due to development of metabolic acidosis. CONCLUSIONS: Acute hyponatremia during cardioplegia with HTK solution is isotonic and should probably not be corrected without presence of hypotonicity as confirmed by measurement of serum osmolality.

Single rescuer exertion using a mechanical resuscitation device: a randomized controlled simulation study.

OBJECTIVES: The goal of this experimental study was to investigate rescuer exertion when using "Animax," a manually operated hand-powered mechanical resuscitation device (MRD) for cardiopulmonary resuscitation (CPR), compared to standard basic life support (BLS). METHODS: This was a prospective, open, randomized, crossover simulation study. After being trained, 80 medical students with substantial knowledge in BLS performed one-rescuer CPR using either the MRD or the standard BLS for 12-minute intervals in random order. The main outcome parameter was the heart rate pressure product (RPP) as an index of cardiac work. Secondary outcome parameters were physical exhaustion quantified by the Borg scale (measurement of perceived exertion), Nine Hole Peg Test (NHPT; measurement of fine motor skills), and capillary lactate concentration during testing. RESULTS: While no significant difference could be found for the RPP, a significantly increased mean heart rate during the final minute of standard BLS compared to the MRD was found (139 ± 22 beats/min vs. 135 ± 26 beats/min, p = 0.027). By contrast, subjective exertion using the MRD was rated significantly higher on the Borg scale (15.1 ± 2.4 vs. 14.6 ± 2.6, p = 0.027). Mean serum lactate concentration was significantly higher when the MRD was used compared to standard BLS (3.4 ± 1.5 mmol/L vs. 2.1 ± 1.3 mmol/L, p ≤ 0.001). CONCLUSIONS: Use of the MRD leads to a RPP of the rescuers comparable to standard BLS. These findings suggest that there is no clinically relevant reduction of exertion if this MRD is used by a single rescuer. If this kind of MRD is used for CPR, frequent changeovers with a second rescuer should be considered as the guidelines suggest for standard CPR.

A manually powered mechanical resuscitation device used by a single rescuer: a randomised controlled manikin study.

PURPOSE: The goal of this randomized, open, controlled crossover manikin study was to compare the performance of "Animax", a manually operated hand-powered mechanical resuscitation device (MRD) to standard single rescuer basic life support (BLS). METHODS: Following training, 80 medical students performed either standard BLS or used an MRD for 12 min in random order. We compared the quality of chest compressions (effective compressions, compression depth and rate, absolute hands-off time, hand position, decompression), and of ventilation including the number of gastric inflations. An effective compression was defined as a compression performed with correct depth, hand position and decompression. RESULTS: The use of the MRD resulted in a significantly higher number of effective compressions compared to standard BLS (67 ± 34 vs. 41 ± 34%, p<0.001). In a comparison with standard BLS, the use of the MRD resulted in less absolute hands-off time (264 ± 57 vs. 79 ± 40 s, p<0.001) and in a higher minute-volume (1.86 ± 0.7 vs. 1.62 ± 0.7 l, p=0.020). However, ventilation volumes were below the 2005 ERC guidelines for both methods. Gastric inflations occurred only in 0 ± 0.1% with the MRD compared to 3 ± 7% during standard BLS (p<0.001). CONCLUSION: Single rescuer cardio-pulmonary resuscitation with the manually operated MRD was superior to standard BLS regarding chest compressions in this simulation study. The MRD delivered a higher minute-volume but did not achieve the recommended minimal volume. Further clinical studies are needed to test the MRD's safety and efficacy in patients.