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.     

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.     

Atrial natriuretic factor and renal sodium excretion during ventilation with PEEP in hypervolemic dogs.

Controlled mandatory ventilation with positive end-expiratory pressure (PEEP) reduces renal sodium excretion. To examine whether atrial natriuretic factor (ANF) is involved in the renal response to alterations in end-expiratory pressure in hypervolemic dogs, experiments were performed on anesthetized dogs with increased blood volume. Changing from PEEP to zero end-expiratory pressure (ZEEP) increased sodium excretion by 145 +/- 61 from 310 +/- 61 mumol/min and increased plasma immunoreactive (ir) ANF by 104 +/- 27 from 136 +/- 21 pg/ml. Changing from ZEEP to PEEP reduced sodium excretion by 136 +/- 36 mumol/min and reduced plasma irANF by 98 +/- 22 pg/ml. To examine a possible causal relationship, ANF (6 ng.min-1.kg body wt-1) was infused intravenously during PEEP to raise plasma irANF to the same level as during ZEEP. Sodium excretion increased by 80 +/- 36 from 290 +/- 78 mumol/min as plasma irANF increased by 96 +/- 28 from 148 +/- 28 pg/ml. We conclude that alterations in end-expiratory pressure lead to great changes in plasma irANF and sodium excretion in dogs with increased blood volume. Comparison of the effects of altering end-expiratory pressure and infusing ANF indicates that a substantial part of the changes in sodium excretion during variations in end-expiratory pressure can be attributed to changes in plasma irANF.     

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.     

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.     

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)     

Positive end-expiratory pressure prevents lung mechanical stress caused by recruitment/derecruitment.

This study tests the hypotheses that a recruitment maneuver per se yields and/or intensifies lung mechanical stress. Recruitment maneuver was applied to a model of paraquat-induced acute lung injury (ALI) and to healthy rats with (ATEL) or without (CTRL) previous atelectasis. Recruitment was done by using 40-cmH(2)O continuous positive airway pressure for 40 s. Rats were, then, ventilated for 1 h at zero end-expiratory pressure (ZEEP) or positive end-expiratory pressure (PEEP; 5 cmH(2)O). Atelectasis was generated by inflating a sphygmomanometer around the thorax. Additional groups did not undergo recruitment but were ventilated for 1 h under ZEEP. Lung resistive and viscoelastic pressures and static elastance were computed before and immediately after recruitment, and at the end of 1 h of ventilation. Lungs were prepared for histology. Type III procollagen (PCIII) mRNA expression in lung tissue was analyzed by RT-PCR. Lung mechanics improved after recruitment in the CTRL and ALI groups. One hour of ventilation at ZEEP increased alveolar collapse, static elastance, and lung resistive and viscoelastic pressures. Alveolar collapse was similar in ATEL and ALI, and recruitment opened the alveoli in both groups. ALI showed higher PCIII expression than ATEL or CTRL groups. One hour of ventilation at ZEEP did not increase PCIII expression but augmented it significantly in the three groups when applied after recruitment. However, PEEP ventilation after recruitment avoided any increment in PCIII expression in all groups. In conclusion, recruitment followed by ZEEP was more deleterious in ALI than in mechanical ATEL, although ZEEP alone did not elevate PCIII expression. Ventilation with 5-cmH(2)O PEEP prevented derecruitment and aborted the increase in PCIII expression.     

Functional residual capacity and ventilation homogeneity in mechanically ventilated small neonates.

A modification of a computerized tracer gas (SF6) washout method was designed for serial measurements of functional residual capacity (FRC) and ventilation homogeneity in mechanically ventilated very-low-birth-weight infants with tidal volumes down to 4 ml. The method, which can be used regardless of the inspired O2 concentration, gave accurate and reproducible results in a lung model and good agreement compared with He dilution in rabbits. FRC was measured during 2-4 cmH2O of positive end-expiratory pressure (PEEP) in 15 neonates (700-1,950 g), most of them with mild-to-moderate respiratory distress syndrome. FRC increased with body weight and decreased (P less than 0.05) with increasing O2 requirement. Change to zero end-expiratory pressure caused an immediate decrease in FRC by 29% (P less than 0.01) and gave FRC (ml) = -1.4 + 17 x weight (kg) (r = 0.83). Five minutes after PEEP was discontinued (n = 12), FRC had decreased by a further 16% (P less than 0.01). The washout curves indicated a near-normal ventilation homogeneity not related to changes in PEEP. This was interpreted as evidence against the presence of large volumes of trapped alveolar gas.     

Effects of surfactant depletion on regional pulmonary metabolic activity during mechanical ventilation

Inflammation during mechanical ventilation is thought to depend on regional mechanical stress. This can be produced by concentration of stresses and cyclic recruitment in low-aeration dependent lung. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) allows for noninvasive assessment of regional metabolic activity, an index of neutrophilic inflammation. We tested the hypothesis that, during mechanical ventilation, surfactant-depleted low-aeration lung regions present increased regional (18)F-FDG uptake suggestive of in vivo increased regional metabolic activity and inflammation. Sheep underwent unilateral saline lung lavage and were ventilated supine for 4 h (positive end-expiratory pressure = 10 cmH(2)O, tidal volume adjusted to plateau pressure = 30 cmH(2)O). We used PET scans of injected (13)N-nitrogen to compute regional perfusion and ventilation and injected (18)F-FDG to calculate (18)F-FDG uptake rate. Regional aeration was quantified with transmission scans. Whole lung (18)F-FDG uptake was approximately two times higher in lavaged than in nonlavaged lungs (2.9 ± 0.6 vs. 1.5 ± 0.3 10(-3)/min; P < 0.05). The increased (18)F-FDG uptake was topographically heterogeneous and highest in dependent low-aeration regions (gas fraction 10-50%, P < 0.001), even after correction for lung density and wet-to-dry lung ratios. (18)F-FDG uptake in low-aeration regions of lavaged lungs was higher than that in low-aeration regions of nonlavaged lungs (P < 0.05). This occurred despite lower perfusion and ventilation to dependent regions in lavaged than nonlavaged lungs (P < 0.001). In contrast, (18)F-FDG uptake in normally aerated regions was low and similar between lungs. Surfactant depletion produces increased and heterogeneously distributed pulmonary (18)F-FDG uptake after 4 h of supine mechanical ventilation. Metabolic activity is highest in poorly aerated dependent regions, suggesting local increased inflammation.     

Hemodynamic, gas exchange, and hormonal consequences of LBPP during PEEP ventilation

Hemodynamic, gas exchange, and hormonal response induced by application of a 25- to 40-mmHg lower body positive pressure (LBPP), during positive end-expiratory pressure (PEEP; 14 +/- 2.5 cmH2O) were studied in nine patients with acute respiratory failure. Compared with PEEP alone, LBPP increased cardiac index (CI) from 3.57 to 4.76 l X min-1 X m-2 (P less than 0.001) in relation to changes in right atrial pressure (RAP) (11 to 16 mmHg; P less than 0.01). Cardiopulmonary blood volume (CPBV) measured in five patients increased during LBPP from 546 +/- 126 to 664 +/- 150 ml (P less than 0.01), with a positive linear relationship between changes in RAP and CPBV (r = 0.88; P less than 0.001). Venous admixture (Qva/QT) decreased with PEEP from 24 to 16% (P less than 0.001) but did not change with LBPP despite the large increase in CI, leading to a marked O2 availability increase (P less than 0.001). Although PEEP induced a significant rise in plasma norepinephrine level (NE) (from 838 +/- 97 to 1008 +/- 139 pg/ml; P less than 0.05), NE was significantly decreased by LBPP to control level (from 1,008 +/- 139 to 794 +/- 124 pg/ml; P less than 0.003). Plasma epinephrine levels were not influenced by PEEP or LBPP. Changes of plasma renin activity (PRA) paralleled those of NE. No change in plasma arginine vasopressin (AVP) was recorded. We concluded that LBPP increases venous return and CPBV and counteracts hemodynamic effects of PEEP ventilation, without significant change in Qva/QT. Mechanical ventilation with PEEP stimulates sympathetic activity and PRA apparently by a reflex neuronal mechanism, at least partially inhibited by the loading of cardiopulmonary low-pressure reflex and high-pressure baroreflex. Finally, AVP does not appear to be involved in the acute cardiovascular adaptation to PEEP.     

Different ventilation strategies alter surfactant responses in preterm rabbits.

The effect of ventilation strategy on in vivo function of different surfactants was evaluated in preterm rabbits delivered at 27 days gestational age and ventilated with either 0 cmH2O positive end-expiratory pressure (PEEP) at tidal volumes of 10-11 ml/kg or 3 cmH2O PEEP at tidal volumes of 7-8 ml/kg after treatment with one of four different surfactants: sheep surfactant, the lipids of sheep surfactant stripped of protein (LH-20 lipid), Exosurf, and Survanta. The use of 3 cmH2O PEEP decreased pneumothoraces in all groups except for the sheep surfactant group where pneumothoraces increased (P < 0.01). Ventilatory pressures (peak pressures - PEEP) decreased more with the 3 cmH2O PEEP, low-tidal-volume ventilation strategy for Exosurf-, Survanta-, and sheep surfactant-treated rabbits (P < 0.05), whereas ventilation efficiency indexes (VEI) improved only for Survanta- and sheep surfactant-treated rabbits with 3 cmH2O PEEP (P < 0.01). Pressure-volume curves for sheep surfactant-treated rabbits were better than for all other treated groups (P < 0.01), although Exosurf and Survanta increased lung volumes above those in control rabbits (P < 0.05). The recovery of intravascular radiolabeled albumin in the lungs and alveolar washes was used as an indicator of pulmonary edema. Only Survanta and sheep surfactant decreased protein leaks in the absence of PEEP, whereas all treatments decreased labeled albumin recoveries when 3 cmH2O PEEP was used (P < 0.05). These experiments demonstrate that ventilation style will alter a number of measurements of surfactant function, and the effects differ for different surfactants.     

Alterations to surfactant precede physiological deterioration during high tidal volume ventilation

Lung injury due to mechanical ventilation is associated with an impairment of endogenous surfactant. It is unknown whether this impairment is a consequence of or an active contributor to the development and progression of lung injury. To investigate this issue, the present study addressed three questions: Do alterations to surfactant precede physiological lung dysfunction during mechanical ventilation? Which components are responsible for surfactant's biophysical dysfunction? Does exogenous surfactant supplementation offer a physiological benefit in ventilation-induced lung injury? Adult rats were exposed to either a low-stretch [tidal volume (Vt) = 8 ml/kg, positive end-expiratory pressure (PEEP) = 5 cmH2O, respiratory rate (RR) = 54-56 breaths/min (bpm), fractional inspired oxygen (Fi(O2)) = 1.0] or high-stretch (Vt = 30 ml/kg, PEEP = 0 cmH2O, RR = 14-16 bpm, Fi(O2) = 1.0) ventilation strategy and monitored for either 1 or 2 h. Subsequently, animals were lavaged and the composition and function of surfactant was analyzed. Separate groups of animals received exogenous surfactant after 1 h of high-stretch ventilation and were monitored for an additional 2 h. High stretch induced a significant decrease in blood oxygenation after 2 h of ventilation. Alterations in surfactant pool sizes and activity were observed at 1 h of high-stretch ventilation and progressed over time. The functional impairment of surfactant appeared to be caused by alterations to the hydrophobic components of surfactant. Exogenous surfactant treatment after a period of high-stretch ventilation mitigated subsequent physiological lung dysfunction. Together, these results suggest that alterations of surfactant are a consequence of the ventilation strategy that impair the biophysical activity of this material and thereby contribute directly to lung dysfunction over time.     

Quantitative imaging of alveolar recruitment with hyperpolarized gas MRI during mechanical ventilation

The aim of this study was to assess the utility of (3)He MRI to noninvasively probe the effects of positive end-expiratory pressure (PEEP) maneuvers on alveolar recruitment and atelectasis buildup in mechanically ventilated animals. Sprague-Dawley rats (n = 13) were anesthetized, intubated, and ventilated in the supine position ((4)He-to-O(2) ratio: 4:1; tidal volume: 10 ml/kg, 60 breaths/min, and inspiration-to-expiration ratio: 1:2). Recruitment maneuvers consisted of either a stepwise increase of PEEP to 9 cmH(2)O and back to zero end-expiratory pressure or alternating between these two PEEP levels. Diffusion MRI was performed to image (3)He apparent diffusion coefficient (ADC) maps in the middle coronal slices of lungs (n = 10). ADC was measured immediately before and after two recruitment maneuvers, which were separated from each other with a wait period (8-44 min). We detected a statistically significant decrease in mean ADC after each recruitment maneuver. The relative ADC change was -21.2 ± 4.1 % after the first maneuver and -9.7 ± 5.8 % after the second maneuver. A significant relative increase in mean ADC was observed over the wait period between the two recruitment maneuvers. The extent of this ADC buildup was time dependent, as it was significantly related to the duration of the wait period. The two postrecruitment ADC measurements were similar, suggesting that the lungs returned to the same state after the recruitment maneuvers were applied. No significant intrasubject differences in ADC were observed between the corresponding PEEP levels in two rats that underwent three repeat maneuvers. Airway pressure tracings were recorded in separate rats undergoing one PEEP maneuver (n = 3) and showed a significant relative difference in peak inspiratory pressure between pre- and poststates. These observations support the hypothesis of redistribution of alveolar gas due to recruitment of collapsed alveoli in presence of atelectasis, which was also supported by the decrease in peak inspiratory pressure after recruitment maneuvers.     

Effects of ventilation on the surfactant system in sepsis-induced lung injury.

The present study examined the effects of mechanical ventilation, with or without positive end-expiratory pressure (PEEP), on the alveolar surfactant system in an animal model of sepsis-induced lung injury. Septic animals ventilated without PEEP had a significant deterioration in oxygenation compared with preventilated values (arterial PO(2)/inspired O(2) fraction 316 +/- 16 vs. 151 +/- 14 Torr; P < 0.05). This was associated with a significantly lower percentage of the functional large aggregates (59 +/- 3 vs. 72 +/- 4%) along with a significantly reduced function (minimum surface tension 17.7 +/- 1.8 vs. 11.8 +/- 3.8 mN/m) compared with nonventilated septic animals (P < 0.05). Sham animals similarly ventilated without PEEP maintained oxygenation, percent large aggregates and surfactant function. With the addition of PEEP, the deterioration in oxygenation was not observed in the septic animals and was associated with no alterations in the surfactant system. We conclude that animals with sepsis-induced lung injury are more susceptible to the harmful effects of mechanical ventilation, specifically lung collapse and reopening, and that alterations in alveolar surfactant may contribute to the development of lung dysfunction.     

Changes in Positive End-Expiratory Pressure Alter the Distribution of Ventilation within the Lung Immediately after Birth in Newborn Rabbits

Current recommendations suggest the use of positive end-expiratory pressures (PEEP) to assist very preterm infants to develop a functional residual capacity (FRC) and establish gas exchange at birth. However, maintaining a consistent PEEP is difficult and so the lungs are exposed to changing distending pressures after birth, which can affect respiratory function. Our aim was to determine how changing PEEP levels alters the distribution of ventilation within the lung. Preterm rabbit pups (28 days gestation) were delivered and mechanically ventilated with one of three strategies, whereby PEEP was changed in sequence; 0-5-10-5-0 cmH₂O, 5-10-0-5-0 cmH₂O or 10-5-0-10-0 cmH₂O. Phase contrast X-ray imaging was used to analyse the distribution of ventilation in the upper left (UL), upper right (UR), lower left (LL) and lower right (LR) quadrants of the lung. Initiating ventilation with 10PEEP resulted in a uniform increase in FRC throughout the lung whereas initiating ventilation with 5PEEP or 0PEEP preferentially aerated the UR than both lower quadrants (p<0.05). Consequently, the relative distribution of incoming V_T was preferentially directed into the lower lobes at low PEEP, primarily due to the loss of FRC in those lobes. Following ventilation at 10PEEP, the distribution of air at end-inflation was uniform across all quadrants and remained so regardless of the PEEP level. Uniform distribution of ventilation can be achieved by initiating ventilation with a high PEEP. After the lungs have aerated, small and stepped reductions in PEEP result in more uniform changes in ventilation.     

Right atrial pressure as measure of ventricular constraint in newborn lambs

Although the lungs and pericardium constrain the heart and limit cardiac output, no method exists to assess this constraint in sick newborns. We hypothesize that a useful estimate of ventricular constraint may be obtained by measuring right atrial pressure (P(RA)) in the newborn. To test this hypothesis, we measured P(RA), thoracic inferior vena caval pressure (P(IVC); saline-filled catheters), and ventricular constraint (pericardial pressure, P(PER); liquid-containing balloon) in 4-wk-old (neonatal, n = 12) and 3-day-old (newborn, n = 6) anesthetized lambs. The measurements were made while LV filling pressure was altered (0-20 mmHg) and while positive end-expiratory pressure (PEEP) was maintained at 2.5 or 15 cmH2O. In all of the lambs, a strong linear relationship (r) existed between P(RA) and P(PER) (P(RA) = 1.19 P(PER) + 0.0, r = 0.99) and between P(IVC) and P(PER) (P(IVC) = 1.24 P(PER) + 0.1, r = 0.99; PEEP of 2.5 cmH2O). Similar relationships were also observed with increased PEEP (P(RA) = 1.29 P(PER)-1.2, r = 0.98 and P(IVC) = 1.32 P(PER)-1.2, r = 0.97). Because P(RA) provides an accurate measure of ventricular constraint in the normal lamb, it may be a useful measure of ventricular constraint in the sick newborn.     

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.     

Effect of negative-pressure ventilation on lung water in permeability pulmonary edema

We have previously shown (Am. Rev. Respir. Dis. 136: 886-891, 1987) improved cardiac output in dogs with pulmonary edema ventilated with external continuous negative chest pressure ventilation (CNPV) using negative end-expiratory pressure (NEEP), compared with continuous positive-pressure ventilation (CPPV) using equivalent positive end-expiratory pressure (PEEP). The present study examined the effect on lung water of CNPV compared with CPPV to determine whether the increased venous return created by NEEP worsened pulmonary edema in dogs with acute lung injury. Oleic acid (0.06 ml/kg) was administered to 27 anesthetized dogs. Supine animals were then divided into three groups and ventilated for 6 h. The first group (n = 10) was treated with intermittent positive-pressure ventilation (IPPV) alone; the second (n = 9) received CNPV with 10 cmH2O NEEP; the third (n = 8) received CPPV with 10 cmH2O PEEP. CNPV and CPPV produced similar improvements in oxygenation over IPPV. However, cardiac output was significantly depressed by CPPV, but not by CNPV, when compared with IPPV. Although there were no differences in extravascular lung water (Qwl/dQl) between CNPV and CPPV, both significantly increased Qwl/dQl compared with IPPV (7.81 +/- 0.21 and 7.87 +/- 0.31 vs. 6.71 +/- 0.25, respectively, P less than 0.01 in both instances). CNPV and CPPV, but not IPPV, enhanced lung water accumulation in the perihilar areas where interstitial pressures may be most negative at higher lung volumes.     

The effect of conductive ventilation heterogeneity on diffusing capacity measurement.

It has long been assumed that the ventilation heterogeneity associated with lung disease could, in itself, affect the measurement of carbon monoxide transfer factor. The aim of this study was to investigate the potential estimation errors of carbon monoxide diffusing capacity (Dl(CO)) measurement that are specifically due to conductive ventilation heterogeneity, i.e., due to a combination of ventilation heterogeneity and flow asynchrony between lung units larger than acini. We induced conductive airway ventilation heterogeneity in 35 never-smoker normal subjects by histamine provocation and related the resulting changes in conductive ventilation heterogeneity (derived from the multiple-breath washout test) to corresponding changes in diffusing capacity, alveolar volume, and inspired vital capacity (derived from the single-breath Dl(CO) method). Average conductive ventilation heterogeneity doubled (P < 0.001), whereas Dl(CO) decreased by 6% (P < 0.001), with no correlation between individual data (P > 0.1). Average inspired vital capacity and alveolar volume both decreased significantly by, respectively, 6 and 3%, and the individual changes in alveolar volume and in conductive ventilation heterogeneity were correlated (r = -0.46; P = 0.006). These findings can be brought in agreement with recent modeling work, where specific ventilation heterogeneity resulting from different distributions of either inspired volume or end-expiratory lung volume have been shown to affect Dl(CO) estimation errors in opposite ways. Even in the presence of flow asynchrony, these errors appear to largely cancel out in our experimental situation of histamine-induced conductive ventilation heterogeneity. Finally, we also predicted which alternative combination of specific ventilation heterogeneity and flow asynchrony could affect Dl(CO) estimate in a more substantial fashion in diseased lungs, irrespective of any diffusion-dependent effects.