Effect of Recombinant Human Thrombomodulin on Ventilator-Induced Lung Injury in Septic Rats

Background: High tidal ventilation with inflammation causes ventilator-induced lung injury (VILI). We previously found that recombinant thrombomodulin (rTM) has a protective effect regarding non-septic VILI caused by high-tidal-volume (HV) ventilation with high oxygen levels. This study aimed to investigate the preventive effect of rTM on VILI caused by sepsis and HV ventilation. Methods: A total of 46 adult male rats were subcutaneously administered either 3mg/kg of rTM or saline. Twelve hours later, the rats were underwent cecal ligation and puncture (CLP). At 2 h after this procedure, the rats were placed on a ventilator set at either low tidal volume [(LV) 6 ml/kg] or high tidal volume (HV 35 ml/kg) ventilation for another 2 h. Results: After 2 h of mechanical ventilation, the PaO2 was significantly lower and BALF protein was significantly higher in HV rats than in LV rats. The rTM did not improve oxygenation or BALF protein levels. Also in HV rats, lung tissue interleukin-6 and monocyte chemotactic protein-1 mRNA levels were significantly higher in the rTM-treated rats.Conclusion: rTM does not improve oxygenation in a non-DIC, CLP-pretreated, high-tidal-ventilation rat model.

Effects of Ultralow-Tidal-Volume Ventilation under Veno-Venous Extracorporeal Membrane Oxygenation in a Porcine Model with Ventilator-Induced Lung Injury

Low-tidal-volume ventilation decreases mortality in acute respiratory distress syndrome (ARDS) patients. This study investigated the effects of ultralow tidal ventilation under veno-venous extracorporeal membrane oxygenator (ECMO) support in pigs with ARDS. Eight pigs were intubated and inoculated with methicillin-resistant Staphylococcus aureus through bronchoscopy. Ultralow tidal ventilation (3 mL/kg) under extracorporeal membrane oxygenator (ECMO) support was applied to one group and high tidal ventilation (15 mL/kg) was applied to another group to maintain comparable oxygenation for 12 h without ECMO support. Each group had similar arterial blood gas values and hemodynamic variables at baseline and during the experiment. The high-tidal-volume ventilation group showed a gradual decline in arterial oxygen levels, and repeated ANOVA showed significant differences in oxygenation change over time in the ultralow tidal ventilation group. Inflammatory cytokine levels in the bronchoalveolar lavage fluid and lung ultrasound scores were similar between two groups. Histologic analysis showed that both groups developed pneumonia after 12 h; however, the ultralow tidal ventilation group had a lower lung injury score assessed by the pathologist. We developed the first ultralow-tidal-volume ventilation porcine model under veno-venous ECMO support. The ultralow-tidal-volume ventilation strategy can mitigate mechanical ventilator-associated lung injury.

Unravelling the complexities of the first breaths of life

ABSTRACTRationaleThe transition to air-breathing at birth is a seminal respiratory event common to all humans, but the intrathoracic processes remain poorly understood.ObjectivesThe objectives of this prospective, observational study were to describe the spatiotemporal gas flow, aeration and ventilation patterns within the lung in term neonates undergoing successful respiratory transition.MethodsElectrical impedance tomography was used to image intrathoracic volume patterns for every breath until six minutes from birth in neonates born by elective cesearean section and not needing resuscitation. Breaths were classified by video data, and measures of lung aeration, tidal flow conditions and intrathoracic volume distribution calculated for each inflation.Measurements and Main results1401 breaths from 17 neonates met all eligibility and data analysis criteria. Stable functional residual capacity was obtained by median (IQR) 43 (21, 77) breaths. Breathing patterns changed from predominantly crying (80·9% first minute) to tidal breathing (65·3% sixth minute). From birth tidal ventilation was not uniform with the lung, favouring the right and non-dependent regions; p<0·001 versus left and dependent (mixed effects model). Initial crying created a unique pattern with delayed mid-expiratory gas flow associated with intrathoracic volume redistribution (pendelluft flow) within the lung. This preserved functional residual, especially within the dorsal and right regions.ConclusionsThe commencement of air-breathing at birth generates unique flow and volume states associated with marked spatiotemporal ventilation inhomogeneity not seen elsewhere in respiratory physiology. At birth neonates innately brake expiratory flow to defend functional residual capacity gains and redistribute gas to less aerated regions.At a Glance CommentaryScientific Knowledge on the SubjectBirth requires the rapid transition from a fluid-filled to aerated lung that is poorly understood. Limited human and animal studies suggest high intrathoracic pressure and flow states are required to attain functional residual capacity and support tidal ventilation.What this Study Adds to the FieldIn the first breath-by-breath imaging of the lungs of term neonates undergoing successful respiratory transition at birth we identified highly inhomogeneous, spatiotemporal aeration and ventilation patterns during. Crying at birth preserved functional residual capacity by allowing intrathoracic volume redistribution (pendelluft flow) within the lung. Newborns defend aeration from intrathoracic lung-fluid shifts at birth by innately braking expiratory flow using the glottis and diaphragm.

Synchronised inflations generate greater gravity dependent lung ventilation in neonates

ABSTRACTBackgroundSynchronising positive pressure inflations with an infant’s own breathing is considered lung protective, but the ventilation patterns within the intubated infant lung during synchronous and asynchronous inflations are unknown.ObjectiveTo describe the regional distribution patterns of tidal ventilation within the lung during mechanical ventilation that is synchronous or asynchronous with an infant’s own breathing effort.MethodsIntubated infants receiving synchronised mechanical ventilation at The Royal Children’s Hospital NICU were studied. During four 10-minute periods of routine care, regional distribution of tidal volume (VT; Electrical Impedance Tomography), delivered pressure and airway flow (Florian Respiratory Monitor) were measured for every inflation. Post hoc, each inflation was then classified as synchronous or asynchronous from video data of the ventilator screen, and the distribution of absolute VT and delivered ventilation characteristics determined.Results2749 inflations (2462 synchronous) were analysed in 19 infants; mean (SD) age 28 (30) day, GA 35 (5) weeks. Synchronous inflations were associated with a shorter respiratory cycle (p=0.004) and more homogenous VT (centre of ventilation) along the right (0%) to left (100%) lung plane; 45.3 (8.6)% vs 48.8 (9.4)% (uniform ventilation 46%). The gravity dependent centre of ventilation was a mean (95% CI) 2.1 (−0.5, 4.6)% more towards the dependent lung during synchronous inflations. Tidal ventilation relative to anatomical lung size was more homogenous during synchronised inflations in the dependent lung.ConclusionSynchronous mechanical ventilator lung inflations generate more gravity dependent lung ventilation and more uniform right to left ventilation than asynchronous inflations.What is the key question?To determine the contribution of spontaneous effort synchronised with positive inflation pressures on ventilation patterns within the neonatal lung.What is the bottom line?Synchronous lung inflations generate greater homogeneity of ventilation within the right and left lungs, and greater ventilation in the gravity dependent lung ventilation than asynchronous inflations.Why read on?Understanding the complex interactions occurring within the lung between mechanical and spontaneous inflations provides insights into the potential for lung protection and injury.

Revisiting atelectasis in lung units with low ventilation/perfusion ratios

Patients on high inspired O2 concentrations are at risk of atelectasis, a problem that has been quantitatively assessed using analysis of ratio of ventilation to perfusion (V̇a/Q̇) equations. This approach ignores the potential of the elastic properties of the lung to support gas exchange through “apneic” oxygenation in units with no tidal ventilation, and is based on an error in the conservation of mass equations. To fill this gap, we correct the error and compare the pressure drops associated with apneic gas exchange with the pressure differences that can be supported by lung recoil. We analyze a worst case scenario: a small test unit in the Weibel model A tree structure with zero tidal ventilation, 100% inspired O2, the rest of the lung being normally ventilated tidally. We first computed the gas flux to the (unventilated) test unit and estimated the associated pressure drops. We then computed the difference in local gas pressure relative to the surrounding lung that would cause the unit to collapse. We compared these two, and finally computed the degree of airway narrowing that would effect change from the stable (apneic gas exchange) regime to the unstable regime leading to collapse. We find that except under extreme conditions of loss of airway caliber exceeding roughly 90%, lung recoil is sufficient to maintain oxygenation through convective transport alone. We further argue that the fundamental V̇a/Q̇ equations are invalid in these circumstances, and that the issue of atelectasis in low V̇a/Q̇ will require modifications to account for this additional mode of gas exchange. NEW & NOTEWORTHY Breathing high concentrations of oxygen increases the likelihood of atelectasis because of oxygen absorption, which is thought to be inevitable in regions with relatively low ventilation/perfusion ratios. However, airspaces of the lung resist collapse because of the forces of interdependence, and can, with low or even zero active tidal ventilation, draw in an inspiratory flow of oxygen sufficient to replace the oxygen consumed, thus preventing collapse of airspaces served by all but the most narrowed airways.

Impact of positive pressure ventilation on mean systemic filling pressure in critically ill patients after death

Mean systemic filling pressure (Pms) defines the pressure measured in the venous-arterial system when the cardiac output is nil. Its estimation has been proposed in patients with beating hearts by building the venous return curve, using different pairs of right atrial pressure/cardiac output during mechanical ventilation. We raised the hypothesis according to which the Pms is altered by tidal ventilation and positive end-expiratory pressure (PEEP), which would challenge this extrapolation method based on cardiopulmonary interactions. We conducted a two-center, noninterventional, observational, and prospective study, using an arterial and a venous catheter to measure the pressure in the circulatory system at the time of death in critically ill, mechanically ventilated patients with a PEEP. Arterial (Part) and venous pressures (Pra) were recorded in five conditions: at end expiration and end inspiration with and without PEEP and finally once the ventilator was disconnected. Part and Pra did not differ in any experimental conditions. Tidal ventilation increased Pra and Part by 2.4 and 1.9 mmHg, respectively, whereas PEEP increased both values by 1.2 and 1 mmHg, respectively. After disconnection of the ventilator, Pra and Part were 10.0 ± 4.2 and 9.9 ± 4.2 mmHg, respectively. Pms increases during mechanical ventilation, with an effect of tidal ventilation and PEEP. This calls into question the validity of its evaluation in heart-beating patients using cardiopulmonary interactions during mechanical ventilation. NEW & NOTEWORTHY The physiology of the mean systemic filling pressure (Pms) is not well understood in human beings. This study is the first report of a tidal ventilation- and positive end-expiratory pressure-related increase in Pms in critically ill patients. The results challenge the utility and the value estimating Pms in heart-beating patients by reconstruction of the venous return curve using varying inflation pressures.