Low-volume ventilation causes peripheral airway injury and increased airway resistance in normal rabbits.

Lung mechanics and morphometry of 10 normal open-chest rabbits (group A), mechanically ventilated (MV) with physiological tidal volumes (8-12 ml/kg), at zero end-expiratory pressure (ZEEP), for 3-4 h, were compared with those of five rabbits (group B) after 3-4 h of MV with a positive end-expiratory pressure (PEEP) of 2.3 cmH(2)O. Relative to initial MV on PEEP, MV on ZEEP caused a progressive increase in quasi-static elastance (+36%) and airway (Rint; +71%) and viscoelastic resistance (+29%), with no change in the viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control levels, whereas Rint remained elevated (+22%). On PEEP, MV had no effect on lung mechanics. Gas exchange on PEEP was equally preserved in groups A and B, and the lung wet-to-dry ratios were normal. Both groups had normal alveolar morphology, whereas only group A had injured respiratory and membranous bronchioles. In conclusion, prolonged MV on ZEEP induces histological evidence of peripheral airway injury with a concurrent increase in Rint, which persists after restoration of normal end-expiratory volumes. This is probably due to cyclic opening and closing of peripheral airways on ZEEP.     

Mechanical ventilation-induced pneumoprotein CC-16 vascular transfer in rats: effect of KGF pretreatment

After air-blood barrier injury, "pneumoproteins" specific to lung epithelial distal airspaces reaching the bloodstream are putative markers of lung hyperpermeability. The contribution of mechanical ventilation (MV) to this leakage is unknown. To explore this issue, 16-kDa Clara cell protein (CC-16) concentration was quantified in bronchoalveolar lavages (BALFs) and/or sera of rats first exposed either to ambient air or to 48 h of hyperoxia-induced acute lung injury and then ventilated for 2 h according to one of the following strategies: 1) spontaneous ventilation (SV), 2) very-low-volume high PEEP (VLVHP, where PEEP is positive end-expiratory pressure), 3) low-volume zero PEEP, 4) moderate-volume low PEEP, and 5) high-volume zero PEEP (HVZP). Results show that total proteins in BALFs increased with time and MV, with little impact from hyperoxia preexposure. CC-16 content decreased in BALFs but increased in the bloodstream during MV, suggesting intravascular leakage. Lung overdistension may result either from high-volume (HVZP) or high-PEEP (VLVHP) MV, and it was the most potent inducer of CC-16 leakage (P < 0.05 vs. SV). In the VLVHP group, pretreatment with keratinocyte growth factor was efficient in reducing blood CC-16 transfer.     

Hormonal interactions and renal function during mechanical ventilation and ANF infusion in humans

To investigate the influence of atrial natriuretic factor (ANF) on renal function during mechanical ventilation (MV), we examined the renal and hormonal responses to synthetic human ANF infusion in eight patients during MV with zero (ZEEP) or 10 cmH2O positive end-expiratory pressure (PEEP). Compared with ZEEP, MV with PEEP was associated with a reduction in diuresis (V) from 208 +/- 51 to 68 +/- 11 ml/h (P less than 0.02), in natriuresis (UNa) from 12.4 +/- 3.3 to 6.2 +/- 2.1 mmol/h (P less than 0.02), and in fractional excretion of sodium (FENa) from 1.07 +/- 0.02), 0.21 to 0.67 +/- 0.17% (P less than 0.02) and with an increase in plasma renin activity (PRA) from 4.83 +/- 1.53 to 7.85 +/- 3.02 ng.ml-1.h-1 (P less than 0.05). Plasma ANF levels markedly decreased during PEEP in four patients but showed only minor changes in the other four patients, and mean plasma ANF levels did not change (163 +/- 33 pg/ml during ZEEP and 126 +/- 30 pg/ml during PEEP). Glomerular filtration rate and renal plasma flow were unchanged. Infusion of ANF (5 ng.kg-1.min-1) during PEEP markedly increased V and UNa by 110 +/- 61 and 107 +/- 26%, respectively, whereas PRA decreased from 7.85 +/- 3.02 to 4.40 +/- 1.5 ng.ml-1.min-1 (P less than 0.05). In response to a 10 ng.kg-1.min-1 ANF infusion, V increased to 338 +/- 79 ml/h during ZEEP but only to 134 +/- 45 ml/h during PEEP (P less than 0.02), whereas UNa increased, respectively, to 23.8 +/- 5.3 and 11.3 +/- 3.3 mmol/h (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of ANF in the acute antidiuresis during PEEP ventilation

To investigate the potential role of natriuretic factor (ANF) on changes on renal excretory function in response to increased intrathoracic pressure, seven patients were studied during three successive 60-min periods of 1) mechanical ventilation (MV) and zero end-expiratory pressure (ZEEP), 2) MV with 12 cmH2O positive end-expiratory pressure (PEEP), and 3) MV with the same level of PEEP while lower-body positive pressure (LBPP) was applied to restore venous return and increase central blood volume without fluid loading. Hemodynamics, renal excretory function parameters, and plasma immunoreactive atrial natriuretic factor (irANF) levels were recorded at the end of each period. Compared with ZEEP, PEEP induced a significant reduction of diuresis (from 134 +/- 17 to 59 +/- 13 ml/h, P less than 0.01) and natriuresis (from 8.37 +/- 3.5 to 3.83 +/- 2 mmol/h, P less than 0.01), whereas plasma irANF fell from 520 +/- 292 to 155 +/- 40 pg/ml (P less than 0.01) and transmural right atrial pressure decreased from 3.9 +/- 0.5 to 2.4 +/- 0.3 mmHg (P less than 0.01). Opposite changes were observed during application of LBPP, which restored diuresis and plasma irANF to near control ZEEP values, despite continuation of PEEP. Changes in renal excretory function parameters thus paralleled changes in right atrial pressure and plasma irANF. We suggest that changes in plasma irANF in response to hemodynamic variations induced by changes in intrathoracic pressure may contribute to alterations of renal excretory function during PEEP.     

Positive end expiratory pressure in patients with acute respiratory distress syndrome – The past,present and future

Though well studied, acute respiratory distress syndrome (ARDS) is still not fully understood. Mechanical ventilation (MV) has been a key treatment for ARDS. However, the optimal ventilation settings of basic MV parameters are still significantly debated. Only recently, were low tidal volumes shown to have lower mortality rates among ARDS patients.Despite over two decades of study, no standardisation of therapy or approach to MV appears on the horizon. This problem is likely due to the heterogeneity of the ARDS patient and ARDS affected lung. Currently, external MV parameters are set to try and treat an internal condition. There is no way to determine if more harm than good is being done. Hence, there is a tradeoff in between the risk of and benefit. What is required a method to assess that tradeoff and thus the potential risk.The use of positive end expiratory pressure (PEEP) and tidal volume has been identified as key ventilation parameters when treating ARDS patients. Although the impact of both parameters has been studied extensively, only the use of low tidal volumes has been conclusively determined. In contrast, the application of PEEP is still widely disputed.This review discusses two different approaches to ventilation management and the impact on optimal PEEP. The first approach examines the use of imaging techniques to determine regional lung mechanics. In the past, computed tomography (CT) was seen as a way to optimise PEEP, but the risks associated with it have limited it to a research tool. Newer methods such as lung ultrasound and electrical impedance tomography (EIT) seem to offer a less riskier approach to assessing regional mechanics.The second approach examines model-based approaches to ventilation management. Models that take ventilation data and depict a physical picture offer the potential to assess the risks on a patient-specific basis. Models offer the benefit of creating an approach to a highly heterogeneously and patient-specific problem in a non-invasive manner. Given the added dynamic of a patient's evolution over time, a highly patient-specific approach is typical and also what is required. Although both approaches can potentially be used to help with clinical decision making with regard to PEEP, they both pose advantages and disadvantages. The use of a given approach will depend on the individual needs of each clinic. Although not currently deployed in the clinic, model-based methods represent a novel methodology in treating ARDS patients. Thus, model-based approaches represent a “state of possible” rather than currently practiced methods, and require further clinical validation before justifying their use in the clinic.     

Effects of positive end-expiratory pressure on hepatic blood flow and performance

Positive end-expiratory pressure (PEEP) may impair extrapulmonary organ function. However, the effects of PEEP on the liver are unclear. We tested the hypothesis that at a constant cardiac output (CO), PEEP does not induce changes in hepatic blood flow (QL) and parenchymal performance. In splenectomized, close-chested canine preparations (group I, n = 6), QL was derived as hepatic outflow using electromagnetic flow probes (QLemf), and hepatic performance was defined by extraction and clearance of indocyanine green (ICG). In a noninvasive model (group II, n = 7), the effects of PEEP on hepatic performance alone were similarly analyzed. Measurements were taken during intermittent positive-pressure ventilation (IPPV1), after addition of 10 cmH2O PEEP to IPPV (PEEP1), during continued PEEP but after return of CO to IPPV1 levels by intravascular volume infusions (PEEP2), and after removal of both PEEP and excess blood volume (IPPV2). Phasic inspiratory decreases in QLemf present during positive-pressure ventilation were not increased during either PEEP1 or PEEP2. Mean QLemf decreased proportionately with CO during PEEP1 (P less than 0.05), but was restored to IPPV1 levels in a parallel fashion with CO during PEEP2. The ICG pharmacokinetic responses to PEEP were complex, with differential effects on extraction and clearance. Despite this, hepatic performance was not imparied in either group. we conclude that global QL reductions during PEEP are proportional to PEEP-induced decreases in CO and are preventable by returning CO to pre-PEEP levels by intravascular volume infusions. However, covarying changes in blood volume and hepatic outflow resistance may independently modulate hepatic function.     

Dependence of lung injury on inflation rate during low-volume ventilation in normal open-chest rabbits.

Lung mechanics and morphometry were assessed in two groups of nine normal open-chest rabbits mechanically ventilated (MV) for 3-4 h at zero end-expiratory pressure (ZEEP) with physiological tidal volumes (Vt; 11 ml/kg) and high (group A) or low (group B) inflation flow (44 and 6.1 ml x kg(-1) x s(-1), respectively). Relative to initial MV on positive end-expiratory pressure (PEEP; 2.3 cmH(2)O), MV on ZEEP increased quasi-static elastance and airway and viscoelastic resistance more in group A (+251, +393, and +225%, respectively) than in group B (+180, +247, and +183%, respectively), with no change in viscoelastic time constant. After restoration of PEEP, quasi-static elastance and viscoelastic resistance returned to control, whereas airway resistance, still relative to initial values, remained elevated more in group A (+86%) than in group B (+33%). In contrast, prolonged high-flow MV on PEEP had no effect on lung mechanics of seven open-chest rabbits (group C). Gas exchange on PEEP was equally preserved in all groups, and the lung wet-to-dry ratios were normal. Relative to group C, both groups A and B had an increased percentage of abnormal alveolar-bronchiolar attachments and number of polymorphonuclear leukocytes in alveolar septa, the latter being significantly larger in group A than in group B. Thus prolonged MV on ZEEP with cyclic opening-closing of peripheral airways causes alveolar-bronchiolar uncoupling and parenchymal inflammation with concurrent, persistent increase in airway resistance, which are worsened by high-inflation flow.     

Cytokine release, small airway injury, and parenchymal damage during mechanical ventilation in normal open-chest rats.

Lung morpho-functional alterations and inflammatory response to various types of mechanical ventilation (MV) have been assessed in normal, anesthetized, open-chest rats. Measurements were taken during protective MV [tidal volume (Vt) = 8 ml/kg; positive end-expiratory pressure (PEEP) = 2.6 cmH(2)O] before and after a 2- to 2.5-h period of ventilation on PEEP (control group), zero EEP without (ZEEP group) or with administration of dioctylsodiumsulfosuccinate (ZEEP-DOSS group), on negative EEP (NEEP group), or with large Vt (26 ml/kg) on PEEP (Hi-Vt group). No change in lung mechanics occurred in the Control group. Relative to the initial period of MV on PEEP, airway resistance increased by 33 +/- 4, 49 +/- 9, 573 +/- 84, and 13 +/- 4%, and quasi-static elastance by 19 +/- 3, 35 +/- 7, 248 +/- 12, and 20 +/- 3% in the ZEEP, NEEP, ZEEP-DOSS, and Hi-Vt groups. Relative to Control, all groups ventilated from low lung volumes exhibited histologic signs of bronchiolar injury, more marked in the NEEP and ZEEP-DOSS groups. Parenchymal and vascular injury occurred in the ZEEP-DOSS and Hi-Vt groups. Pro-inflammatory cytokine concentration in the bronchoalveolar lavage fluid (BALF) was similar in the Control and ZEEP group, but increased in all other groups, and higher in the ZEEP-DOSS and Hi-Vt groups. Interrupter resistance was correlated with indexes of bronchiolar damage, and cytokine levels with vascular-alveolar damage, as indexed by lung wet-to-dry ratio. Hence, protective MV from resting lung volume causes mechanical alterations and small airway injury, but no cytokine release, which seems mainly related to stress-related damage of endothelial-alveolar cells. Enhanced small airway epithelial damage with induced surfactant dysfunction or MV on NEEP can, however, contribute to cytokine production.     

Effects of mechanical ventilation at low lung volume on respiratory mechanics and nitric oxide exhalation in normal rabbits.

Lung mechanics, exhaled NO (NOe), and TNF-alpha in serum and bronchoalveolar lavage fluid were assessed in eight closed and eight open chest, normal anesthetized rabbits undergoing prolonged (3-4 h) mechanical ventilation (MV) at low volume with physiological tidal volumes (10 ml/kg). Relative to initial MV on positive end-expiratory pressure (PEEP), MV at low volume increased lung quasi-static elastance (+267 and +281%), airway (+471 and +382%) and viscolelastic resistance (+480 and +294%), and decreased NOe (-42 and -25%) in closed and open chest rabbits, respectively. After restoration of PEEP, viscoelastic resistance returned to control, whereas airway resistance remained elevated (+120 and +31%) and NOe low (-25 and -20%) in both groups of rabbits. Elastance remained elevated (+23%) only in closed-chest animals, being associated with interstitial pulmonary edema, as reflected by increased lung wet-to-dry weight ratio with normal albumin concentration in bronchoalveolar lavage fluid. In contrast, in 16 additional closed- and open-chest rabbits, there were no changes of lung mechanics or NOe after prolonged MV on PEEP only. At the end of prolonged MV, TNF-alpha was practically undetectable in serum, whereas its concentration in bronchoalveolar lavage fluid was low and similar in animals subjected or not subjected to ventilation at low volume (62 vs. 43 pg/ml). These results indicate that mechanical injury of peripheral airways due to their cyclic opening and closing during ventilation at low volume results in changes in lung mechanics and reduction in NOe and that these alterations are not mediated by a proinflammatory process, since this is expressed by TNF-alpha levels.     

Dependence of lung injury on surface tension during low-volume ventilation in normal open-chest rabbits.

To evaluate the role of pulmonary surfactant in the prevention of lung injury caused by mechanical ventilation (MV) at low end-expiratory volumes, lung mechanics and morphometry were assessed in three groups of eight normal, open-chest rabbits ventilated for 3-4 h at zero end-expiratory pressure (ZEEP) with physiological tidal volumes (Vt = 10 ml/kg). One group was left untreated (group A); the other two received surfactant intratracheally (group B) or aerosolized dioctylsodiumsulfosuccinate (group C) before MV on ZEEP. Relative to initial MV on positive end-expiratory pressure (PEEP; 2.3 cmH(2)O), quasi-static elastance (Est) and airway (Rint) and viscoelastic resistance (Rvisc) increased on ZEEP in all groups. After restoration of PEEP, only Rint (124%) remained elevated in group A, only Est (36%) was significantly increased in group B, whereas in group C, Est, Rint, and Rvisc were all markedly augmented (274, 253, and 343%). In contrast, prolonged MV on PEEP had no effect on lung mechanics of eight open-chest rabbits (group D). Lung edema developed in group C (wet-to-dry ratio = 7.1), but not in the other groups. Relative to group D, both groups A and C, but not B, showed histological indexes of bronchiolar injury, whereas all groups exhibited an increased number of polymorphonuclear leukocytes in alveolar septa, which was significantly greater in group C. In conclusion, administration of exogenous surfactant largely prevents the histological and functional damage of prolonged MV at low lung volumes, whereas surfactant dysfunction worsens the functional alterations, also because of edema formation and, possibly, increased inflammatory response.     

Quantification of compensatory processes of postnatal hypoxia in newborn piglets applying short-term nonlinear dynamics analysis

Background

Acute Respiratory Distress Syndrome (ARDS) patients require mechanical ventilation (MV) for breathing support. Patient-specific PEEP is encouraged for treating different patients but there is no well established method in optimal PEEP selection.

Methods

A study of 10 patients diagnosed with ALI/ARDS whom underwent recruitment manoeuvre is carried out. Airway pressure and flow data are used to identify patient-specific constant lung elastance (E _lung ) and time-variant dynamic lung elastance (E _drs ) at each PEEP level (increments of 5cmH ₂ O), for a single compartment linear lung model using integral-based methods. Optimal PEEP is estimated using E _lung versus PEEP, E _drs -Pressure curve and E _drs Area at minimum elastance (maximum compliance) and the inflection of the curves (diminishing return). Results are compared to clinically selected PEEP values. The trials and use of the data were approved by the New Zealand South Island Regional Ethics Committee.

Results

Median absolute percentage fitting error to the data when estimating time-variant E _drs is 0.9% (IQR = 0.5-2.4) and 5.6% [IQR: 1.8-11.3] when estimating constant E _lung . Both E _lung and E _drs decrease with PEEP to a minimum, before rising, and indicating potential over-inflation. Median E _drs over all patients across all PEEP values was 32.2 cmH ₂ O/l [IQR: 26.1-46.6], reflecting the heterogeneity of ALI/ARDS patients, and their response to PEEP, that complicates standard approaches to PEEP selection. All E _drs -Pressure curves have a clear inflection point before minimum E _drs , making PEEP selection straightforward. Model-based selected PEEP using the proposed metrics were higher than clinically selected values in 7/10 cases.

Conclusion

Continuous monitoring of the patient-specific E _lung and E _drs and minimally invasive PEEP titration provide a unique, patient-specific and physiologically relevant metric to optimize PEEP selection with minimal disruption of MV therapy.     

Hemodynamic effects of PEEP applied as a ramp in normo-, hyper-, and hypovolemia

Nonlinear hemodynamic responses on positive end-expiratory pressure (PEEP) have been attributed to a rise of mean central venous pressure (Pcv), to compensatory cardiovascular control mechanisms, and to the occurrence of a lung stretch depressor reflex above a threshold lung stretch. We tested the hypothesis that the contribution of each of these mechanisms is dependent on the preexisting volemic load. PEEP was applied as a continuous rise (ramp) in piglets in three different volemic loads. In the normovolemic circulation cardiac output (CO) decreased nonlinearly in three phases during the PEEP ramp up to 15 cmH2O. CO decreased gradually in phase I, followed by a sharp decrease in phase II between a PEEP of 3 and 9 cmH2O and again a more gradual decrease in phase III up to a PEEP of 15 cmH2O. Heart rate (HR) and mean aortic pressure (PaO) also decreased during phase II, indicating the predominance of a lung stretch depressor reflex. In the hypervolemic circulation (loading 15 ml . kg-1 dextran) only phases I and II were observed with the onset of phase II at a higher level of PEEP (6 cmH2O). More lung stretch appeared to be necessary to elicit the lung stretch depressor reflex. In the hypovolemic circulation (hemorrhage 15 ml . kg-1) CO decreased linearly, Pao was stable after an initial decrease, and HR increased continuously, indicating a predominance of cardiovascular compensatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)     

On-line monitoring of intrinsic PEEP in ventilator-dependent patients.

Measurement of the intrinsic positive end-expiratory pressure (PEEP(i)) is important in planning the management of ventilated patients. Here, a new recursive least squares method for on-line monitoring of PEEP(i) is proposed for mechanically ventilated patients. The procedure is based on the first-order model of respiratory mechanics applied to experimental measurements obtained from eight ventilator-dependent patients ventilated with four different ventilatory modes. The model PEEP(i) (PEEP(i,mod)) was recursively constructed on an inspiration-by-inspiration basis. The results were compared with two well-established techniques to assess PEEP(i): end-expiratory occlusion to measure static PEEP(i) (PEEP(i, st)) and change in airway pressure preceding the onset of inspiratory airflow to measure dynamic PEEP(i) (PEEP(i,dyn)). PEEP(i, mod) was significantly correlated with both PEEP(i,dyn) (r = 0.77) and PEEP(i,st) (r = 0.90). PEEP(i,mod) (5.6 +/- 3.4 cmH(2)O) was systematically >PEEP(i,dyn) and PEEP(i,st) (2.7 +/- 1.9 and 8.1 +/- 5.5 cmH(2)O, respectively), in all the models without external PEEP. Focusing on the five patients with chronic obstructive pulmonary disease, PEEP(i,mod) was significantly correlated with PEEP(i,st) (r = 0.71), whereas PEEP(i,dyn) (r = 0.22) was not. When PEEP was set 5 cmH(2)O above PEEP(i,st), all the methods correctly estimated total PEEP, i.e., 11.8 +/- 5.3, 12.5 +/- 5.0, and 12.0 +/- 4.7 cmH(2)O for PEEP(i,mod), PEEP(i,st), and PEEP(i,dyn), respectively, and were highly correlated (0.97-0.99). We interpreted PEEP(i,mod) as the lower bound of PEEP(i,st) and concluded that our method is suitable for on-line monitoring of PEEP(i) in mechanically ventilated patients.     

Influence of cyclic AMP on the growth response and anaerobic metabolism of carbon monoxide in Rhodocyclus gelatinosus

Rhodocyclus gelatinosus strain 1 (str. 1), a photoheterotrophic bacterium, used CO as an energy substrate under anaerobic CO/light conditions, and exhibited a diauxic growth response when CO was removed from the culture. Changes in the level of cyclic AMP which occurred in cells during diauxie suggested that the cyclic nucleotide operated as an intracellular control molecule. During CO/light-phase growth, intracellular cyclic AMP was 30 pmol/mg protein, and, as str. 1 adapted for photosynthetic growth after removal of CO, intracellular cyclic AMP levels decreased to 9 pmol/mg protein. Reexposure of a light culture to CO induced synthesis of CO oxidation activity (measured as CO:MV oxidoreductase). If 10 mM cyclic AMP was added with CO, the rate of synthesis of CO:MV oxidoreductase activity increased 25-fold, and str. 1 produced 1,230 units of activity (nmol CO oxidized min^-1 mg^-1 protein) after only 1 h. With cyclic AMP and no CO, no incerease in CO oxidation activity was seen. Appearance of CO oxidation activity in str. 1 represented de novo protein synthesis and was blocked with chloramphenicol. In addition to stimulating formation of CO oxidative activity, a high level of cyclic AMP in str. 1 during growth with CO appeared to influence photometabolism negatively by repressing bacteriochlorophyll formation.Abbreviations Bchl a bacteriochlorophyll a - MV methyl viologen - CO MV oxidoreductase, carbon monoxide: methyl viologen oxidoreductase     

Regulation of anaerobic carbon monoxide oxidation activity in Rhodocyclus gelatinosus

Rhodocyclus gelatinosus grows anaerobically at the expense of carbon monoxide (CO). The CO-oxidation system was substrate-induced and in CO/light, cells grew at an exponential rate with ever increasing amounts of CO:MV oxidoreductase activity (the measure of CO oxidation). Once strain 1 reached a high cell density, the concentration of CO became limiting and gas oxidation activity suddenly decreased. Cell growth continued unaffected. To help explain this, it appeared that strain 1 variably used both CO oxidation and photometabolism to support growth in CO/light. Light intensity determined the upper limit of amounts of CO:MV oxidoreductase in a culture, while intermediate amounts were regulated by CO concentration. Thus, in darkness, cells produced the maximum CO oxidation activity, whereas in growth-saturating light, the minimum limit occurred. The lower the levels of CO:MV oxidoreductase in cells, the greater the content of bacteriochlorophyll. In this manner, strain 1 grew with a generation time of 6.7 independent of light intensity.     

Proton interactions with hemes a and a3 in bovine heart cytochrome c oxidase

Three forms of cytochrome c oxidase, fully oxidized CcO (CcO-O), oxidized CcO complexed with cyanide (CcO.CN), and mixed valence CcO, in which both heme a(3) and Cu(B) are reduced and stabilized by carbon monoxide (MV.CO), were investigated by optical spectroscopy, MCD, and stopped-flow for the pH sensitivity of spectral features. In the pH range between pH 5.7 and 9.0, both heme a and heme a(3) in CcO-O interact with a single protolytic group. From the variation of the position of the Soret peak with changes in pH, a pK(a) of 6.6 +/- 0.2 was determined for this group. The pH sensitivity of heme a(3) is lost in the CcO.CN complex, and only heme a responds to pH changes. In MV.CO the spectra of both hemes are almost independent of pH between 5.7 and 11.0. The stoichiometry of proton uptake in the conversion of CcO-O both to MV.CO and to fully reduced CcO was determined between pH 5.8 and pH 8.2. Formation of MV.CO from CcO-O was accompanied by the uptake of approximately two protons, and this value was almost independent of pH. Full reduction of oxidized CcO was associated with the uptake of approximately 2 H(+) at basic pH, and this value increases with decreasing pH. On the basis of these proton uptake measurements, it is concluded that the pK(a) of the group is independent of the redox state of CcO. It is suggested that Glu60 of subunit II, located at the entrance of the proton conducting K-channel, is the protolytic residue that interacts with both hemes through a hydrogen-bonding network.     

Aggravation of myocardial dysfunction by injurious mechanical ventilation in LPS-induced pneumonia in rats

Background

Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI) and may thereby contribute to fatal multiple organ failure. We tested the hypothesis that injurious MV of lipopolysaccharide (LPS) pre-injured lungs induces myocardial inflammation and further dysfunction ex vivo, through calcium (Ca²⁺)-dependent mechanism.

Materials and methods

N = 35 male anesthetized and paralyzed male Wistar rats were randomized to intratracheal instillation of 2 mg/kg LPS or nothing and subsequent MV with lung-protective settings (low tidal volume (V_t) of 6 mL/kg and 5 cmH₂O positive end-expiratory pressure (PEEP)) or injurious ventilation (high V_t of 19 mL/kg and 1 cmH₂O PEEP) for 4 hours. Myocardial function ex vivo was evaluated in a Langendorff setup and Ca²⁺ exposure. Key mediators were determined in lung and heart at the mRNA level.

Results

Instillation of LPS and high V_t MV impaired gas exchange and, particularly when combined, increased pulmonary wet/dry ratio; heat shock protein (HSP)70 mRNA expression also increased by the interaction between LPS and high V_t MV. For the heart, C-X-C motif ligand (CXCL)1 and Toll-like receptor (TLR)2 mRNA expression increased, and ventricular (LV) systolic pressure, LV developed pressure, LV +dP/dt_max and contractile responses to increasing Ca²⁺ exposure ex vivo decreased by LPS. High V_t ventilation aggravated the effects of LPS on myocardial inflammation and dysfunction but not on Ca²⁺ responses.

Conclusions

Injurious MV by high V_t aggravates the effects of intratracheal instillation of LPS on myocardial dysfunction, possibly through enhancing myocardial inflammation via pulmonary release of HSP70 stimulating cardiac TLR2, not involving Ca²⁺ handling and sensitivity.     

Combination of constant-flow and continuous positive-pressure ventilation in canine pulmonary edema

Constant-flow ventilation (CFV) maintains alveolar ventilation without tidal excursion in dogs with normal lungs, but this ventilatory mode requires high CFV and bronchoscopic guidance for effective subcarinal placement of two inflow catheters. We designed a circuit that combines CFV with continuous positive-pressure ventilation (CPPV; CFV-CPPV), which negates the need for bronchoscopic positioning of CFV cannula, and tested this system in seven dogs having oleic acid-induced pulmonary edema. Addition of positive end-expiratory pressure (PEEP, 10 cmH2O) reduced venous admixture from 44 +/- 17 to 10.4 +/- 5.4% and kept arterial CO2 tension (PaCO2) normal. With the innovative CFV-CPPV circuit at the same PEEP and respiratory rate (RR), we were able to reduce tidal volume (VT) from 437 +/- 28 to 184 +/- 18 ml (P less than 0.001) and elastic end-inspiratory pressures (PEI) from 25.6 +/- 4.6 to 17.7 +/- 2.8 cmH2O (P less than 0.001) without adverse effects on cardiac output or pulmonary exchange of O2 or CO2; indeed, PaCO2 remained at 35 +/- 4 Torr even though CFV was delivered above the carina and at lower (1.6 l.kg-1.min-1) flows than usually required to maintain eucapnia during CFV alone. At the same PEEP and RR, reduction of VT in the CPPV mode without CFV resulted in CO2 retention (PaCO2 59 +/- 8 Torr). We conclude that CFV-CPPV allows CFV to effectively mix alveolar and dead spaces by a small bulk flow bypassing the zone of increased resistance to gas mixing, thereby allowing reduction of the CFV rate, VT, and PEI for adequate gas exchange.     

Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction

Positive end-expiratory pressure (PEEP) has generally been withheld from the treatment of patients with chronic airflow obstruction (CAO), in view of the risk of hyperinflation and lack of documented benefit. We studied 10 mechanically ventilated patients with exacerbated CAO and air trapping to determine the impact of PEEP on lung mechanics, alveolar pressure, and the work of breathing. PEEP levels of 5 and 10 cmH2O were applied to patients whose end-expiratory alveolar pressures were documented to be positive when breathing against ambient pressure (the auto-PEEP effect). All patients were studied under two conditions: every breath machine assisted (AMV) and every breath machine controlled (paralyzed, CMV). PEEP improved expiratory resistance without substantially increasing peak static pressure. Inspiratory resistance remained unchanged. The difference between the end-expiratory values of alveolar and central airway pressure narrowed as PEEP increased. Adding PEEP improved the effective triggering sensitivity of the ventilator, diminished ventilatory drive, and reduced the mechanical work of breathing during the machine-assisted ventilatory cycle. Our results indicate that low levels of PEEP may improve lung mechanics and reduce the effort required of mechanically ventilated patients with severe airflow obstruction, without substantially increasing the hazards of hyperinflation.