Assessment of spontaneous breathing during pressure controlled ventilation with superimposed spontaneous breathing using respiratory flow signal analysis.

Integrating spontaneous breathing into mechanical ventilation (MV) can speed up liberation from it and reduce its invasiveness. On the other hand, inadequate and asynchronous spontaneous breathing has the potential to aggravate lung injury. During use of airway-pressure-release-ventilation (APRV), the assisted breaths are difficult to measure. We developed an algorithm to differentiate the breaths in a setting of lung injury in spontaneously breathing ewes. We hypothesized that differentiation of breaths into spontaneous, mechanical and assisted is feasible using a specially developed for this purpose algorithm. Ventilation parameters were recorded by software that integrated ventilator output variables. The flow signal, measured by the EVITA® XL (Lübeck, Germany), was measured every 2 ms by a custom Java-based computerized algorithm (Breath-Sep). By integrating the flow signal, tidal volume (VT) of each breath was calculated. By using the flow curve the algorithm separated the different breaths and numbered them for each time point. Breaths were separated into mechanical, assisted and spontaneous. Bland Altman analysis was used to compare parameters. Comparing the values calculated by Breath-Sep with the data from the EVITA® using Bland-Altman analyses showed a mean bias of - 2.85% and 95% limits of agreement from - 25.76 to 20.06% for MVtotal. For respiratory rate (RR) RRset a bias of 0.84% with a SD of 1.21% and 95% limits of agreement from - 1.53 to 3.21% were found. In the cluster analysis of the 25th highest breaths of each group RRtotal was higher using the EVITA®. In the mechanical subgroup the values for RRspont and MVspont the EVITA® showed higher values compared to Breath-Sep. We developed a computerized method for respiratory flow-curve based differentiation of breathing cycle components during mechanical ventilation with superimposed spontaneous breathing. Further studies in humans and optimizing of this technique is necessary to allow for real-time use at the bedside.

Platelet and coagulation function before and after burn and smoke inhalation injury in sheep.

BACKGROUND: Smoke inhalation and burn injury remain a major source of morbidity and mortality. There is known dysregulation of hemostasis in burn patients, but either hypercoagulation or hypocoagulation states are reported. Sheep are an established animal model for studying burn pathology and provide robust data on hemostatic function at baseline and after injury. METHODS: After an IACUC-approved protocol, 15 sheep were anesthetized and subjected to a 40% full thickness burn with smoke inhalation. Blood was sampled at baseline, 1 day postinjury (early effects) and days 2, 3, and 4 (late effects) after injury. Assays at each timepoint assessed: hemostatic function by thromboelastography (TEG), platelet counts and function by flow cytometry and aggregometry, coagulation protein levels, and free hemoglobin. Data were analyzed by the Wilcoxon paired test (nonparametric) with significance set at less than 0.05. RESULTS: By 24 hours postinjury, platelet counts had dropped, whereas the percent activated platelets increased. Absolute platelet functional response to the agonist adenosine diphosphate (ADP) decreased, whereas response to collagen showed no significant difference. On a per platelet basis, ADP response was unchanged, whereas the collagen response was elevated. Prothrombin time and activated partial thromboplastin time were prolonged. TEG parameters decreased significantly from baseline. Fibrinogen and factor V were trending up; coagulation proteins ATIII, factors IX and X were decreased.Late effects were followed in six animals. At day 4, platelet counts remained depressed compared with baseline with a nadir at day 2; responses to agonist on a per platelet basis remained the same for ADP and stayed elevated for collagen. Platelets continued to have elevated activation levels. Fibrinogen and factor V remained significantly elevated, whereas TEG parameters and prothrombin time, factors IX and X returned to near baseline levels. CONCLUSION: Coagulation parameters and hemostasis are dysregulated in sheep after smoke inhalation and burn. By 24 hours, sheep were hypocoagulable and subsequently became hypercoagulable by day 4. These results suggest a three-stage coagulopathy in burn injuries with a known early consumptive hypercoagulable state which is followed by a relatively hypocoagulable state with increased bleeding risk and then a return to a relatively unknown hypercoagulability with increased susceptibility to thrombotic disorders.

Reciprocal Risk of Acute Kidney Injury and Acute Respiratory Distress Syndrome in Critically Ill Burn Patients.

OBJECTIVE: To evaluate the association between acute respiratory distress syndrome and acute kidney injury with respect to their contributions to mortality in critically ill patients. DESIGN: Retrospective analysis of consecutive adult burn patients requiring mechanical ventilation. SETTING: A 16-bed burn ICU at tertiary military teaching hospital. PATIENTS: Adult patients more than 18 years old requiring mechanical ventilation during their initial admission to our burn ICU from January 1, 2003, to December 31, 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total 830 patients were included, of whom 48.2% had acute kidney injury (n = 400). These patients had a 73% increased risk of developing acute respiratory distress syndrome after controlling for age, gender, total body surface area burned, and inhalation injury (hazard ratio, 1.73; 95% CI, 1.18-2.54; p = 0.005). In a reciprocal multivariate analysis, acute respiratory distress syndrome (n = 299; 36%) demonstrated a strong trend toward developing acute kidney injury (hazard ratio, 1.39; 95% CI, 0.99-1.95; p = 0.05). There was a 24% overall in-hospital mortality (n = 198). After adjusting for the aforementioned confounders, both acute kidney injury (hazard ratio, 3.73; 95% CI, 2.39-5.82; p < 0.001) and acute respiratory distress syndrome (hazard ratio, 2.16; 95% CI, 1.58-2.94; p < 0.001) significantly contributed to mortality. Age, total body surface area burned, and inhalation injury were also significantly associated with increased mortality. CONCLUSIONS: Acute kidney injury increases the risk of acute respiratory distress syndrome in mechanically ventilated burn patients, whereas acute respiratory distress syndrome similarly demonstrates a strong trend toward the development of acute kidney injury. Acute kidney injury and acute respiratory distress syndrome are both independent risks for subsequent death. Future research should look at this interplay for possible early interventions.

Acute Respiratory Distress Syndrome in Burn Patients: A Comparison of the Berlin and American-European Definitions.

The purpose of this study was to compare the Berlin definition to the American-European Consensus Conference (AECC) definition in determining the prevalence of acute respiratory distress syndrome (ARDS) and associated mortality in the critically ill burn population. Consecutive patients admitted to our institution with burn injury that required mechanical ventilation for more than 24 hours were included for analysis. Included patients (N = 891) were classified by both definitions. The median age, % TBSA burn, and injury severity score (interquartile ranges) were 35 (24-51), 25 (11-45), and 18 (9-26), respectively. Inhalation injury was present in 35.5%. The prevalence of ARDS was 34% using the Berlin definition and 30.5% using the AECC definition (combined acute lung injury and ARDS), with associated mortality rates of 40.9 and 42.9%, respectively. Under the Berlin definition, mortality rose with increased ARDS severity (14.6% no ARDS; 16.7% mild; 44% moderate; and 59.7% severe, P < 0.001). By contrast, under the AECC definition increased mortality was seen only for ARDS category (14.7% no ARDS; 15.1% acute lung injury; and 46.0% ARDS, P < 0.001). The mortality of the 22 subjects meeting the AECC, but not the Berlin definition was not different from patients without ARDS (P = .91). The Berlin definition better stratifies ARDS in terms of severity and correctly excludes those with minimal disease previously captured by the AECC.

Early Utilization of Extracorporeal CO2 Removal for Treatment of Acute Respiratory Distress Syndrome Due to Smoke Inhalation and Burns in Sheep.

INTRODUCTION: In thermally injured patients, inhalation injury is often associated with acute respiratory distress syndrome (ARDS), and is an independent predictor of increased morbidity and mortality. Extracorporeal CO2 removal (ECCO2R) therapy offers new possibilities in protective mechanical ventilation in ARDS patients. We performed an early application of ECCO2R in mild-to-moderate ARDS in sheep ventilated in BiPAP mode. Our aim was to investigate its effect on severity of the lung injury. MATERIAL AND METHODS: Non-pregnant farm-bred ewes (n = 15) were anesthetized and injured by a combination of wood-bark smoke inhalation and a 40% total body surface area full-thickness burn, and were observed for 72 h or death. The animals were randomized to a Hemolung group (n = 7) or a Control group (n = 8) at time of ARDS onset. ECCO2R was performed in the Hemolung group after onset of ARDS.Histopathology, CT scans, systemic and pulmonary variables, and CO2 removal were examined. RESULTS: Early application of ECCO2R therapy with Hemolung in spontaneously breathing sheep decreased PaCO2 significantly, while the device removed about 70  mL of CO2 per minute. This did not result in lower minute ventilation in the Hemolung group. Lungpathology and CT scans did not show a difference between groups. CONCLUSION: In an ovine model of ARDS due to smoke inhalation and burn injury, early institution of ECCO2R in spontaneously breathing animals was effective in removing CO2 and in reducing PaCO2. However, it had no effect on reducing the severity of lung injury or mortality. Further studies are necessary to detail the interaction between extracorporeal CO2 removal and pulmonary physiology.

Resuscitative endovascular balloon occlusion of the aorta (REBOA): Comparison with immediate transfusion following massive hemorrhage in swine.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is less invasive than emergency department thoracotomy for the treatment of massive hemorrhage. We evaluated the effects of REBOA on carotid blood flow (Qcarotid) in a porcine model of massive hemorrhage. We hypothesized that REBOA restores Qcarotid faster than reinfusion of blood. METHODS: Spontaneously breathing sedated Sinclair pigs underwent exponential hemorrhage of 65% total blood volume in 1 hour. They were randomized into three groups. Positive control (PC, n = 7) underwent immediate transfusion of shed blood. REBOA (n = 21) received a novel 7 Fr ER-REBOA catheter (Pryor Medical, Arvada, CO) placed into aortic Zone 1 via a femoral artery introducer for 30 minutes or 60 minutes, with transfusion either after deflation or midway through inflation. Negative control (n = 7) received no resuscitation. Qcarotid was recorded continuously using an ultrasonic flow probe. Survival and time between Qcarotid, min and both a stable maximal value (Qcarotid, max) and restoration of baseline flow (Qcarotid, new BL) were compared by Kaplan-Meier analysis. RESULTS: Median time to Qcarotid, max was 3.0 minutes in the REBOA group versus 9.6 minutes in the control group (p = 0.006). Median time to Qcarotid, new BL was 6.0 minutes in the REBOA group versus 20.5 minutes in the PC group (p = 0.11). Slope of the linear regression between Qcarotid, min and Qcarotid, new BL was 16.7 in REBOA and 10.4 in PC (p = 0.31). Four-hour survival was 95% (20 of 21) in the REBOA group versus 71% (5 of 7) in the PC group (p = 0.06) and 0% in the negative control group. CONCLUSION: REBOA resulted in the restoration of Qcarotid ("cerebrovascular resuscitation") at least as rapidly as retransfusion of shed blood, with equivalent 4-hour survival. Further studies of REBOA, to include mitigation of end-organ effects and longer follow-up, are needed.

Multivariate analysis of the volumetric capnograph for PaCO2 estimation.

PURPOSE: End-tidal CO2 (eTCO2) can be used to estimate the arterial CO2 (PaCO2) under steady-state conditions, but that relationship deteriorates during hemodynamic or respiratory instability. We developed a multivariate method to improve our ability to estimate the PaCO2, by using additional information contained in the volumetric capnograph (Vcap) waveform. We tested this approach using data from a porcine model of chest trauma/hemorrhage. METHODS: This experiment consisted of 3 stages: pre-injury, injury/resuscitation, and post-injury. In stage I, anesthetized pigs (n=26) underwent ventilator maneuvers (tidal volume and respiratory rate) to induce hypo-or hyper-ventilation. In stage II, pigs underwent either (A) unilateral pulmonary contusion, hemorrhage, and resuscitation (n=13); or (B) bilateral pulmonary contusion (n=13) followed by 30 min of monitoring. In stage III, the ventilator maneuvers were repeated. The following Vcap features were measured: eTCO2, phase 2 slope (p2m), phase 3 slope (p3m), and inter-breath interval. The data were fit to 2 models: (1) multivariate linear regression and (2) a machine-learning model (M5P). RESULTS: 1750 10-breath sets were analyzed. Univariate models employing eTCO2 alone were adequate during stages I and III. During stage II, mean error for the linear model was -8.44 mmHg (R(2)=0.14, P<0.001) and for M5P it was -5.98 mmHg (R(2)=0.13, P<0.01). By adding Vcap features, all models exhibited improvement. In stage II, the mean error of the linear model improved to -4.64 mmHg (R(2)=0.11, P<0.01), and that of the M5P model improved to -1.62 mmHg (R(2)=0.25, P<0.01). CONCLUSIONS: By incorporating Vcap waveform features, multivariate methods modestly improved PaCO2 estimation, especially during periods of hemodynamic and respiratory instability. Further work would be needed to produce a clinically useful CO2 monitoring system under these challenging conditions.

Evaluation of the Cytosorb™ Hemoadsorptive Column in a Pig Model of Severe Smoke and Burn Injury.

INTRODUCTION: Host inflammatory response to any form of tissue injury, including burn, trauma, or shock, has been well documented. After significant burns, cytokines can increase substantially within the first 24 h after injury and may contribute to subsequent organ failure. Hemoadsorption by cytokine-adsorbing columns may attenuate this maladaptive response, thereby improving outcomes. The aim of this study was to investigate the feasibility, technical safety, and efficacy of cytokine and myoglobin removal by early use of a cytokine absorbing column (CytoSorb) in a porcine model of smoke inhalation and burn injury. METHODS: Anesthetized female Yorkshire pigs (n = 15) were injured by wood bark smoke inhalation and a 40% total body surface area deep burn and observed for 72 h or death. The animals were randomized to hemoadsorption treatment (n = 9) or a sham group (n = 6) before injury. A 6-h hemoadsorption or sham session was performed on days one, two, and three. Serum cytokines (IL-1b, IL-6, IL-8, IL-10, TNF-alpha) and myoglobin were measured systemically, locally in bronchoalveolar lavage fluid and also in circulating blood before and after the adsorbing column to evaluate single pass clearance by the device. RESULTS: Hemoadsorption caused significant removal of IL-1b, IL-6, IL-10, and myoglobin across the device mainly during the first run, ranging from 22% for IL-6 to 29% for IL-1b and 41% removal rates for myoglobin after 15  min of treatment. Systemic cytokine or myoglobin serum concentrations did not change. CONCLUSIONS: In a porcine model of smoke and burn injury, hemoadsorption using the CytoSorb cartridge did not result in significant systemic or pulmonary reductions in the measured cytokines or myoglobin despite efficient transmembrane reductions. Further investigations are needed to optimize the efficiency of mediator clearance to affect both circulating levels and clinically relevant outcomes.

Automated inhaled nitric oxide alerts for adult extracorporeal membrane oxygenation patient identification.

BACKGROUND: Recently, automated alerts have been used to identify patients with respiratory failure based on set criteria, which can be gleaned from the electronic medical record (EMR). Such an approach may also be useful for identifying patients with severe adult respiratory distress syndrome (ARDS) who may benefit from extracorporeal membrane oxygenation (ECMO). Inhaled nitric oxide (iNO) is a common rescue therapy for severe ARDS which can be easily tracked in the EMR, and some patients started on iNO may have indications for initiating ECMO. This case series summarizes our experience with using automated electronic alerts for ECMO team activation focused particularly on an alert triggered by the initiation of iNO. METHODS: After a brief trial evaluation, our Smart Alert system generated an automated page and e-mail alert to ECMO team members whenever a nonzero value for iNO appeared in the respiratory care section of our EMR. If iNO was initiated for severe respiratory failure, a detailed evaluation by the ECMO team determined if ECMO was indicated. For those patients managed with ECMO, we tabulated baseline characteristics, indication for ECMO, and outcomes. RESULTS: From September 2012 to July 2013, 45 iNO alerts were generated on 42 unique patients. Six patients (14%) met criteria for ECMO. Of these, four were identified exclusively by the iNO alert. At the time of the alert, the median PaO2-to-FIO2 ratio was 64 mm Hg (range, 55-107 mm Hg), the median age-adjusted oxygenation index was 73 (range, 51-96), and the median Murray score was 3.4 (range, 3-3.75), indicating severe respiratory failure. Median time from iNO alert to ECMO initiation was 81 hours (range, -2-292 hours). Survival to hospital discharge was 83% in those managed with ECMO. CONCLUSION: Automated alerts may be useful for identifying patients with severe ARDS who may be ECMO candidates. LEVEL OF EVIDENCE: Diagnostic test, level V.

The noninvasive carbon dioxide gradient (NICO2G) during hemorrhagic shock.

Hemorrhagic shock (HS) is a setting in which both pulmonary and cutaneous perfusion may be impaired. The goals of this study were to evaluate the relationship between end-tidal (etCO2), transcutaneous (tPCO2), arterial carbon dioxide (PaCO2) and lactate during lethal HS and to assess the effect of progressive HS on those variables and on a new variable, the noninvasive CO2 gradient ([NICO2G] or the difference between tPCO2 and etCO2). Ten consciously sedated swine were hemorrhaged, by means of a computerized exponential protocol, of up to 80% estimated blood volume for 20 min. End-tidal carbon dioxide, tPCO2, PaCO2, and lactate measurements were taken at baseline and every 5 min thereafter, that is, after 25%, 44%, and 62% total blood volume hemorrhage (TBVH) and at cardiac arrest. Cardiac arrest occurred on average at 67% TBVH. Data were analyzed by linear regression and one-way repeated-measures analysis of variance and are presented as means ± SD. Forty-nine paired measurements were made. There was no overall relationship between NICO2 variables and PaCO2: PaCO2 vs. tPCO2 (r2 = 0.002, P = 0.78); PaCO2 vs. etCO2 (r2 = 0.0002, P = 0.93). Rather, NICO2G increased at each level of blood loss: 4.0 ± 24.9 at baseline, 6.3 ± 35.7 at 25% TBVH, 25.0 ± 37.6 at 44% TBVH, 55.0 ± 33.9 at 62% TBVH, and 70.0 ± 33.2 at cardiac arrest (P < 0.05). Similarly, tPCO2 increased and etCO2 decreased at each level. Linear regression of NICO2G and lactate showed a better correlation than was observed for the other two variables: NICO2G, r2 = 0.58; tPCO2, r2 = 0.46; etCO2, r2 = 0.26. During HS, NICO2 monitors lose accuracy for approximating the PaCO2 but gain usefulness as hemodynamic monitors. Also, by combining data from two different organ systems, NICO2G demonstrated improved correlation with lactate than did either etCO2 or tPCO2 alone.

Acute respiratory distress syndrome in wartime military burns: application of the Berlin criteria.

BACKGROUND: Acute respiratory distress syndrome (ARDS) prevalence and related outcomes in burned military casualties from Iraq and Afghanistan have not been described previously. The objective of this article was to report ARDS prevalence and its associated in-hospital mortality in military burn patients. METHODS: Demographic and physiologic data were collected retrospectively on mechanically ventilated military casualties admitted to our burn intensive care unit from January 2003 to December 2011. Patients with ARDS were identified in accordance with the new Berlin definition of ARDS. Subjects were categorized as having mild, moderate, or severe ARDS. Multivariate logistic regression identified independent risk factors for developing moderate-to-severe ARDS. The main outcome measure was the prevalence of ARDS in a cohort of patients burned as a result of recent combat operations. RESULTS: A total of 876 burned military casualties presented during the study period, of whom 291 (33.2%) required mechanical ventilation. Prevalence of ARDS in this cohort was 32.6%, with a crude overall mortality of 16.5%. Mortality increased significantly with ARDS severity: mild (11.1%), moderate (36.1%), and severe (43.8%) compared with no ARDS (8.7%) (p < 0.001). Predictors for the development of moderate or severe ARDS were inhalation injury (odds ratio [OR], 1.90; 95% confidence interval [CI], 1.01-3.54; p = 0.046), Injury Severity Score (ISS) (OR, 1.04; 95% CI, 1.01-1.07; p = 0.0021), pneumonia (OR, 198; 95% CI, 1.07-3.66; p = 0.03), and transfusion of fresh frozen plasma (OR, 1.32; 95% CI, 1.01-1.72; p = 0.04). Size of burn was associated with moderate or severe ARDS by univariate analysis but was not an independent predictor of ARDS by multivariate logistic regression (p > 0.05). Age, size of burn, and moderate or severe ARDS were independent predictors of mortality. CONCLUSION: In this cohort of military casualties with thermal injuries, nearly a third required mechanical ventilation; of those, nearly one third developed ARDS, and nearly one third of patients with ARDS did not survive. Moderate and severe ARDS increased the odds of death by more than fourfold and ninefold, respectively. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level III.

Extracorporeal gas exchange and spontaneous breathing for the treatment of acute respiratory distress syndrome: an alternative to mechanical ventilation?*.

OBJECTIVES: Venovenous extracorporeal gas exchange is increasingly used in awake, spontaneously breathing patients as a bridge to lung transplantation. Limited data are available on a similar use of extracorporeal gas exchange in patients with acute respiratory distress syndrome. The aim of this study was to investigate the use of extracorporeal gas exchange in awake, spontaneously breathing sheep with healthy lungs and with acute respiratory distress syndrome and describe the interactions between the native lung (healthy and diseased) and the artificial lung (extracorporeal gas exchange) in this setting. DESIGN: Laboratory investigation. SETTING: Animal ICU of a governmental laboratory. SUBJECTS: Eleven awake, spontaneously breathing sheep on extracorporeal gas exchange. INTERVENTIONS: Sheep were studied before (healthy lungs) and after the induction of acute respiratory distress syndrome via IV injection of oleic acid. Six gas flow settings (1-10 L/min), resulting in different amounts of extracorporeal CO2 removal (20-100% of total CO2 production), were tested in each animal before and after the injury. MEASUREMENTS AND MAIN RESULTS: Respiratory variables and gas exchange were measured for every gas flow setting. Both healthy and injured sheep reduced minute ventilation according to the amount of extracorporeal CO2 removal, up to complete apnea. However, compared with healthy sheep, sheep with acute respiratory distress syndrome presented significantly increased esophageal pressure variations (25 ± 9 vs 6 ± 3 cm H2O; p < 0.001), which could be reduced only with very high amounts of CO2 removal (> 80% of total CO2 production). CONCLUSIONS: Spontaneous ventilation of both healthy sheep and sheep with acute respiratory distress syndrome can be controlled via extracorporeal gas exchange. If this holds true in humans, extracorporeal gas exchange could be used in awake, spontaneously breathing patients with acute respiratory distress syndrome to support gas exchange. A deeper understanding of the pathophysiology of spontaneous breathing during acute respiratory distress syndrome is however warranted in order to be able to propose extracorporeal gas exchange as a safe and valuable alternative to mechanical ventilation for the treatment of patients with acute respiratory distress syndrome.

Pressure-guided positioning of bicaval dual-lumen catheters for venovenous extracorporeal gas exchange.

PURPOSE: Bicaval dual-lumen catheters allow for single-site cannulation venovenous extracorporeal gas exchange and facilitate early mobilization of patients. Using these catheters blood is drained from the superior and inferior venae cavae, pumped through a respiratory membrane, and returned into the right atrium. The insertion of these catheters is challenging as their correct positioning is fundamental to reduce recirculation and avoid severe complications. We describe here a new technique for the positioning of bicaval dual-lumen catheters. MATERIALS AND METHODS: The right internal jugular vein was percutaneously cannulated in nine sheep. The distance between skin and tricuspid valve was measured from the point of pressure change in the waveform of a Swan-Ganz catheter being retracted from the right ventricle into the right atrium. The atrium-tricuspid valve-ventricle axis was determined by observing the fluctuations of the tip of the Swan-Ganz entering the ventricle during fluoroscopy. A bicaval dual-lumen catheter was placed on the basis of these evaluations and connected to an extracorporeal respiratory support system. RESULTS: The position of the catheter was verified at necropsy approximately 18 h after insertion. In all cases the catheter was correctly placed, with the central port situated in front of the tricuspid valve. CONCLUSIONS: The described technique may help to position bicaval dual-lumen catheters for venovenous extracorporeal gas exchange without the use of transesophageal echocardiography or contrast media during fluoroscopy.