John Baier M.D.John Baier M.D.

University of ManitobaUniversity of Manitoba

Ventilation Strategies Ventilation Strategies and Experimental Lung and Experimental Lung

InjuryInjury

Role of Mechanical Ventilation Role of Mechanical Ventilation in Lung Injuryin Lung Injury

Mechanical ventilation is life saving but it also Mechanical ventilation is life saving but it also causes lung injurycauses lung injury

Evolution of ventilation techniques over the last 20 Evolution of ventilation techniques over the last 20 years years

Past PracticesPast Practices Current TrendsCurrent Trends

Low or normal arterial COLow or normal arterial CO2 2 Increasing tolerance for high or Increasing tolerance for high or very high arterial COvery high arterial CO2 2

Normal acid-base or alkalosisNormal acid-base or alkalosis Respiratory acidosisRespiratory acidosis

Larger tidal volumesLarger tidal volumes Small tidal volumesSmall tidal volumes

No PEEPNo PEEP Optimal PEEPOptimal PEEP

Ventilator induced Lung InjuryVentilator induced Lung Injury Ventilator induced lung injury (VLI) is similar to that induced Ventilator induced lung injury (VLI) is similar to that induced

by other meansby other means• different etiologies have similar cellular and biochemical different etiologies have similar cellular and biochemical

mechanisms mechanisms • VLI compounds lung injury induced by other meansVLI compounds lung injury induced by other means

VLIVLI• Membrane damageMembrane damage

Alveolar type II cell necrosisAlveolar type II cell necrosis• Exposure of underlying basement membraneExposure of underlying basement membrane• Activation of inflammationActivation of inflammation

Injury to pulmonary vascular bedInjury to pulmonary vascular bed• Increase in vascular permeabilityIncrease in vascular permeability• Interstitial and alveolar edemaInterstitial and alveolar edema• Protein leak into alveolar spaceProtein leak into alveolar space

Intra-alveolar activation of coagulation pathwaysIntra-alveolar activation of coagulation pathways Activation of inflammatory pathwaysActivation of inflammatory pathways

Ventilator induced Lung InjuryVentilator induced Lung Injury

• Inflammatory cell influx and activationInflammatory cell influx and activation NeutrophilsNeutrophils Alveolar macrophagesAlveolar macrophages Increase in cytokines, prostanoids, growth factorsIncrease in cytokines, prostanoids, growth factors

• Airway EffectsAirway Effects BronchospasmBronchospasm Cilliary dysfunctionCilliary dysfunction

Ways by which Ventilation Can Cause Ways by which Ventilation Can Cause release of Inflammatory Mediatorsrelease of Inflammatory Mediators

Stress failure of plasma membranes (necrosis)Stress failure of plasma membranes (necrosis)• Release of preformed mediatorsRelease of preformed mediators• Proinflammatory effects of cytosol released from Proinflammatory effects of cytosol released from

damaged cellsdamaged cells Stress failure of endothelial and epithelial barriersStress failure of endothelial and epithelial barriers

• Loss of compartmentalizationLoss of compartmentalization• Hemorrhage and accumulation of leukocytes in the Hemorrhage and accumulation of leukocytes in the

lungslungs Overdistention without tissue destructionOverdistention without tissue destruction Effects on the vasculature independent of stretch Effects on the vasculature independent of stretch

and ruptureand rupture• Increased intraluminal pressureIncreased intraluminal pressure• Increased shear stressIncreased shear stress

Mechanotransduction Mechanotransduction

Several studies have show that Several studies have show that mechanical stretching of cell layers can mechanical stretching of cell layers can • induce production of inflammatory mediatorsinduce production of inflammatory mediators• Alter NaAlter Na++ K K + + ATPase function (lung edema)ATPase function (lung edema)

Mechanical stretch stimulates MIP-2 in Mechanical stretch stimulates MIP-2 in fetal lung cellsfetal lung cells

Mourgeon et al: Am Journal Physiology (lung Cell Mol Physiol) 2000Mourgeon et al: Am Journal Physiology (lung Cell Mol Physiol) 2000

Primary fetal lung cells isolated from ratsPrimary fetal lung cells isolated from rats Cell grown on gelfoam spongesCell grown on gelfoam sponges Stretched by computer controlled solenoidsStretched by computer controlled solenoids Incubated with or without the presence of LPSIncubated with or without the presence of LPS

Mechanical stretch enhances LPS Mechanical stretch enhances LPS induced MIP-2 productioninduced MIP-2 production

Mechanical stretch of Mechanical stretch of the cells induced the cells induced production of MIP-2production of MIP-2

Greatly enhanced the Greatly enhanced the stimulatory effect of stimulatory effect of LPS on MIP-2 LPS on MIP-2 productionproduction

Cells in an organotypic culture were subjected to 2 or 5% unidirectional stretch for 4 h at 40 cycles/min in the absence (control; no stretch) and presence of LPS (100 ng/ml). MIP-2 concentrations in the culture medium were analyzed by ELISA. P < 0.0001 by 1-way ANOVA. * P < 0.05 compared with all other groups. # P < 0.05 vs. all control and LPS-only groups.

Fetal rat lung cells were subjected to 5% stretch for 4 h at different frequencies in the presence ( ) and absence of LPS (100 ng/ml; ). P < 0.0001 by 1-way ANOVA. * P < 0.05 compared with that of stretch only at 20 or 40 cycles/min

Ventilatory StrategiesVentilatory Strategies

HyperventilationHyperventilation• HypocapneaHypocapnea

PEEPPEEP HypoventilationHypoventilation

• Hypercarbia Hypercarbia

““therapeutic therapeutic hypercarbia”hypercarbia”

Hyperventilation and Hyperventilation and Lung InjuryLung Injury

““Too much of a good thing is Too much of a good thing is bad for you or Stretching it bad for you or Stretching it

too far!”too far!”

Why (or How) does Hyperventilation Why (or How) does Hyperventilation Cause Lung injury?Cause Lung injury?

Airleak SyndromesAirleak Syndromes Excessive stretchExcessive stretch Effects of low COEffects of low CO22

Effects of alkalosisEffects of alkalosis0

10

20

30

40

50

60

70

80

Per

cen

tag

e

No BPD BPD Deaths

Pneumothorax

PIE

All Airleaks

HSC Winnipeg Manitoba HSC Winnipeg Manitoba

1987-19881987-1988

HyperventilationHyperventilation

Effect of high tidal volumesEffect of high tidal volumes

Synergistic effect of high tidal volume Synergistic effect of high tidal volume and hyperoxia on lung injuryand hyperoxia on lung injury

Quin et al: Journal of Applied Physiology 2002Quin et al: Journal of Applied Physiology 2002

Ventilated rat modelVentilated rat model• Compared 2 tidal volumesCompared 2 tidal volumes

7 ml vs 20 ml kg7 ml vs 20 ml kg-1-1 • Extra dead space added to ETT tube to maintain Extra dead space added to ETT tube to maintain

PPaaCOCO22 at 30-40 torr (20 ml kg at 30-40 torr (20 ml kg-1 -1 group)group)

• RA vs 100% oxygenRA vs 100% oxygen

Large Tidal volume Ventilation is synergistic Large Tidal volume Ventilation is synergistic with hyperoxia to induce lung edemawith hyperoxia to induce lung edema

Ventilation with large Ventilation with large tidal volumes tidal volumes increased lung waterincreased lung water

Lung water was Lung water was further increased in further increased in the presence of the presence of hyperoxiahyperoxia

Lung water measured by lung wet-to-dry weight ratio in control, nonventilated rats; rats ventilated for 2 h at tidal volumes (VT) 7 or 20 ml/kg for 2 h and killed immediately after exposure; and rats ventilated for 2 h with VT 20 ml/kg and killed 6 and 24 h after ventilation. Open bars are rats on room air (RA), and solid bars are rats with hyperoxia (means ± SE). *P < 0.05 vs. control; P < 0.05 vs. VT 7 ml/kg RA; P < 0.05 vs. all other groups.

Large Tidal volume Ventilation is synergistic Large Tidal volume Ventilation is synergistic with hyperoxia to induce lung inflammationwith hyperoxia to induce lung inflammation

Ventilation with large tidal Ventilation with large tidal volumes increased lung MIP-volumes increased lung MIP-2 (analogous to IL-8 in the 2 (analogous to IL-8 in the human) and neutrophil human) and neutrophil influx.influx.

Neutrophil influx was further Neutrophil influx was further increased in the presence of increased in the presence of hyperoxiahyperoxia

Measurements of MIP-2 (A) and neutrophils (B) in BAL in control, nonventilated rats and rats ventilated for 2 h at 7 and 20 ml/kg and killed 6 h after ventilation. Open bars are rats on RA, and solid bars are rats on hyperoxia (means ± SE). *P < 0.05 vs. control, nonventilated animals; P < 0.05 vs. all other groups

HyperventilationHyperventilation

Effect of hypocarbiaEffect of hypocarbia

Hypocapnic alkalosis injures the lungHypocapnic alkalosis injures the lungLaffey et al: Am J Resp Crit Care Med 2000Laffey et al: Am J Resp Crit Care Med 2000

Isolated rabbit lungsIsolated rabbit lungs• Altered the inspired concentration of Altered the inspired concentration of

COCO22 to induce hypocapnic alkalosis to induce hypocapnic alkalosis FiCOFiCO2 2 of 0.06 (control) vs. 0.01 (alkalosis)of 0.06 (control) vs. 0.01 (alkalosis) FiOFiO2 2 constant (0.75)constant (0.75)

• VVTT 4 ml kg 4 ml kg-1-1 (PIP changes) (PIP changes)

• 2 experimental protocol2 experimental protocol 3 hour period of ventilation and perfusion3 hour period of ventilation and perfusion Warm ischemia - reperfusionWarm ischemia - reperfusion

Hypocapnic alkalosis induces increased Hypocapnic alkalosis induces increased pulmonary permeabilitypulmonary permeability

Mechanical ventilation Mechanical ventilation (3 hours) increased (3 hours) increased pulmonary capillary pulmonary capillary permeability (Kf,c) in permeability (Kf,c) in both control and both control and hypocapnic groups.hypocapnic groups.

Hypocapnic ventilation Hypocapnic ventilation was associated with a was associated with a much greater increase much greater increase in Kf,cin Kf,c

Kf,c before and after prolonged ventilation. Final Kf,c was significantly greater than baseline in both groups (*p < 0.05); the magnitude of the increase was significantly greater in the group with hypocapnia versus the control group ( p < 0.05).

Hypocapnic alkalosis reduces lung Hypocapnic alkalosis reduces lung compliancecompliance

Peak airway pressures Peak airway pressures required to maintain required to maintain tidal volume increased tidal volume increased over time in the over time in the hypocapnic group hypocapnic group compared to controlscompared to controls

Peak airway pressure [Paw] at baseline, before and after prolonged ventilation. Paw was significantly elevated in the group with hypocapnia (*p < 0.05) but not in the control group.

Hypocapnic alkalosis results in increased Hypocapnic alkalosis results in increased lung weightlung weight

Increase in lung weight after prolonged ventilation. Lung weight was significantly increased in the group with hypocapnia (*p < 0.05) but not in the control group

Deleterious effects of hypocapnea on Deleterious effects of hypocapnea on pulmonary reperfusion injurypulmonary reperfusion injury

Kf,c before and after IR injury. Kf,c was significantly increased following IR in the control group and the group with hypocapnia (*p < 0.05); the magnitude of the increase was significantly greater in the group with hypocapnia versus the control group ( p < 0.05).

Peak airway pressure (Paw) measured at baseline, before and immediately after IR injury, and at the end of the experiment. Paw was significantly increased following IR in the group with hypocapnia (*p < 0.05) but not in the control group

Summary thus farSummary thus far(what we have learned)(what we have learned)

High tidal volume ventilation induces lung injuryHigh tidal volume ventilation induces lung injury Alkalosis induces lung injuryAlkalosis induces lung injury Synergistic with other factors that induce lung Synergistic with other factors that induce lung

injuryinjury

Effects of PEEP on VLIEffects of PEEP on VLI

Effect of CPAP vs IMV with PEEP Effect of CPAP vs IMV with PEEP on lung injury in newbornon lung injury in newborn

Jobe et al Pediatr Res 2002Jobe et al Pediatr Res 2002

Preterm lamb modelPreterm lamb model• Studied spontaneous breathing with Studied spontaneous breathing with

CPAP 5 vs IMV with PEEP of 4CPAP 5 vs IMV with PEEP of 4• Ventilator rate fixed at 40 breaths/minVentilator rate fixed at 40 breaths/min

• PIP adjusted to give PCOPIP adjusted to give PCO22 of 40 mm Hg of 40 mm Hg TTinspinsp 0.7 sec 0.7 sec

Measured indices of lung injury and Measured indices of lung injury and inflammationinflammation

Blood pH and PCO2 values for the cord blood and for 120 min after birth. The pH and PCO2 values were different between the ventilation and CPAP groups at all times except for the cord blood values at 0 time (p < 0.05).

Deflation pressure-volume curves for the CPAP lambs and the ventilated lambs. All volumes between 10 and 40 cm H2O pressure are higher for the CPAP lungs than for the ventilated lungs (p < 0.05).

CPAP is associated with decreased CPAP is associated with decreased lung inflammationlung inflammation

Spontaneous Spontaneous breathing on CPAP breathing on CPAP was associated with was associated with decreased neutrophil decreased neutrophil influx and decreased influx and decreased HH22OO22 production production compared to IMVcompared to IMV

There were no There were no differences in differences in mononuclear cell mononuclear cell numbers or cytokine numbers or cytokine mRNA expressionmRNA expression

Role of PEEP in determining lung Role of PEEP in determining lung injuryinjury

Naik et al: AM J Resp Crit Care Med 2001Naik et al: AM J Resp Crit Care Med 2001

Preterm lamb modelPreterm lamb model• Delivered 126-132 daysDelivered 126-132 days• Treated with surfactant with rSP-CTreated with surfactant with rSP-C• 3 treatment groups3 treatment groups

No PEEPNo PEEP 4 cm H4 cm H220 PEEP0 PEEP 7 cm H7 cm H22O PEEPO PEEP

• FiOFiO22 and PIP adjusted to keep PaCO and PIP adjusted to keep PaCO22 50- 50-60 mm Hg60 mm Hg

Sequential measurements of PaCO2 and the tidal volumes. The ventilatory goals were to keep PaCO2 between 50 and 60 mm Hg, and the tidal volumes (VT) 10 ml/kg. There were no differences between the groups. The filled symbols indicate combined PaCO2 values and VT for both 2 h and 7 h ventilation groups

(A-C ) Ventilatory pressures measured as peak inspiratory pressure minus positive end-expiratory pressure (PIP   PEEP), PaO2/FIO2 ratios, and lung gas volumes at 40 cm H2O (V40) 2 h and 7 h. The ventilatory pressures required to achieve the target PaCO2 were lower for the 4 and 7 PEEP groups. The PaO2/FIO2 ratios were higher for the 4 and 7 PEEP groups. V40 with 0 PEEP had consistently lower lung volumes relative to 4 and 7 PEEP after both 2 h and 7 h ventilation. *p < 0.05 versus 4, 7 PEEP

Effect of PEEP on Inflammatory Effect of PEEP on Inflammatory markers of lung injurymarkers of lung injury

Ventilation increases Ventilation increases neutrophil influx and neutrophil influx and HH22002 2 activity in the activity in the lung. Optimal PEEP lung. Optimal PEEP moderates neutrophil moderates neutrophil influxinflux

Neutrophil counts (A) and total H2O2 activity (B) in alveolar wash fluid after 2 h ventilation. All ventilated groups had higher neutrophil counts relative to fetal controls. The 0 and 7 PEEP groups had elevated neutrophil counts relative to the 4 PEEP group. Total H2O2 activity in alveolar washes was increased in ventilated groups compared with unventilated fetal control. to < 0.05, control group versus all ventilated groups; *p < 0.05 versus 4 PEEP.

Effect of PEEP on Cytokine ExpressionEffect of PEEP on Cytokine Expression

IL-1 and IL-6 mRNA levels after 2 h and 7 h ventilation. IL-1 and IL-6 mRNAs were elevated in all ventilated groups relative to fetal control groups. Both IL-1 and IL-6 mRNA were significantly increased in 0 PEEP relative to 4 PEEP after both 2 h and 7 h ventilation. IL-1 and IL-6 mRNA decreased between 2 h and 7 h. tp < 0.05, control groups versus all ventilated groups, *p < 0.05 versus 4 PEEP, and #p < 0.05 versus 7 h ventilation. The inset shows representative RNase protection assay for IL-1 and IL-6 after 2 h ventilation

IL-8 and TNF- mRNA levels after 2 h and 7 h ventilation. IL-8 was increased in all ventilated groups relative to fetal controls. IL-8 was also significantly elevated in 0 PEEP compared with 4 PEEP after 7 h ventilation. TNF- was increased in all ventilated groups after 7 h ventilation relative to fetal control groups. The different PEEP levels did not influence TNF- mRNA levels. tp < 0.05 control groups versus all ventilated groups. *p < 0.05 versus 4 PEEP. **p < 0.05 control groups versus groups ventilated for 7 h. The insets show representative RNase protection assays for IL-8 and TNF- after 2 h ventilation.

Morphology of the lungs. (Morphology of the lungs. (AA) Representative ) Representative sections that were scored as 1 = collapsed. sections that were scored as 1 = collapsed. 2 = distended, and 3 = overdistended 2 = distended, and 3 = overdistended alveoli. All the panels were photographed at alveoli. All the panels were photographed at the same magnification. Original the same magnification. Original magnification: ×230. Scale bars = 100 µm. magnification: ×230. Scale bars = 100 µm. ((BB) Percentage fractional areas of alveolar ) Percentage fractional areas of alveolar inflation. The 0 PEEP group had more inflation. The 0 PEEP group had more collapsed alveoli compared with 4 and collapsed alveoli compared with 4 and 7 PEEP. 7 PEEP showed more overdistended 7 PEEP. 7 PEEP showed more overdistended alveoli compared with 0 PEEP. alveoli compared with 0 PEEP. * p < 0.05 versus 4 and 7 PEEP; * p < 0.05 versus 4 and 7 PEEP; tp < 0.05 versus 4 and 7 PEEP tp < 0.05 versus 4 and 7 PEEP

Ventilator Strategies and Lung InjuryVentilator Strategies and Lung InjuryTremblay et al J Clin. Invest. 1997Tremblay et al J Clin. Invest. 1997

Isolated rat lung modelIsolated rat lung model• Compared the effects of PEEP and high Compared the effects of PEEP and high

tidal volumes on cytokine production in tidal volumes on cytokine production in the presence of LPSthe presence of LPS

• 4 treatment groups4 treatment groups Control (C)Control (C) Moderate volume MV with PEEP (MVHP)Moderate volume MV with PEEP (MVHP) Moderate volume MV with zero PEEP (MVZP)Moderate volume MV with zero PEEP (MVZP) High Volume MV with zero PEEP (HVZP)High Volume MV with zero PEEP (HVZP)

Static Lung Compliance after 2 hrs of Static Lung Compliance after 2 hrs of ex vivoex vivo ventilation ventilation

Ventilation without Ventilation without PEEP or with high PEEP or with high volumes results in volumes results in decreased static decreased static compliancecompliance

Static compliance curves of the lungs prior to ex vivo ventilation and following 2 h of ex vivo ventilation. A significant rightward shift developed in both zero PEEP groups (P < 0.005 for MVZP, HVZP), whereas no shift was observed in the presence of 10 cm of PEEP for either saline- or LPS-treated lungs.

Ventilation strategy and Ventilation strategy and Inflammatory mediatorsInflammatory mediators

Cytokine Cytokine concentrations were concentrations were greatest in lungs greatest in lungs ventilated without ventilated without PEEP or with high PEEP or with high volumesvolumes

Effect of ventilation strategy on absolute lung lavage cytokine concentrations for the saline- injected groups. A similar trend was seen for all cytokines with lowest levels in the control group (C) and highest in HVZP. Despite similar end-expiratory distention, MVHP ventilation had significantly lower BAL cytokine concentrations than HVZP ventilation. *P < 0.05 vs. Control, MVHP, MVZP; P < 0.05 vs. Control, MVHP; §P < 0.05 vs. Control.

Ventilation strategy and Ventilation strategy and Inflammatory mediatorsInflammatory mediators

Cytokine Cytokine concentrations were concentrations were greatest in lungs greatest in lungs ventilated without ventilated without PEEP or with high PEEP or with high volumesvolumes

The pattern of lavage cytokines seen in response to ventilation strategy was similar to the saline-treated groups except for MIP-2, in which the control group (C) had comparable levels to the MVZP group (both increased significantly vs. the MVHP group). *P < 0.05 vs. Control, MVHP, MVZP; P < 0.05 vs. Control, MVHP; §P < 0.05 vs. Control; ¶P < 0.05 vs. MVHP.

Ratio of study group BAL cytokine concentrations relative to saline-treated controls. LPS ( ) pretreatment resulted in significantly increased levels of TNF for three of the ventilatory strategies (i.e., an approximately 5-fold increase for C, an approximately 30fold increase for MVHP, and an approximately 37-fold increase for MVZP) as compared to saline-treated (O) controls. LPS also increased levels of MIP-2 for all four ventilatory strategies, whereas no significant changes were seen with the other four cytokines assessed. As IL-6 and IFN were undetectable in saline-treated controls, an arbitrary value of 1 was assigned to allow comparison. *P < 0.05 vs. saline treated group

Ventilation strategy and Ventilation strategy and c-fosc-fos expression expression

Northern blot analysis of lung homogenate c-fos mRNA for the various ventilation strategies. Densitometric values for c-fos were standardized to 28S ribosomal RNA. A similar trend to that observed for the BAL cytokine concentrations was seen in both saline- and LPS-treated animals. The presence or absence of LPS was not found to make a significant difference in c-fos mRNA levels. *P < 0.05 vs. Control; P < 0.05 vs. MVHP.

Mechanical ventilation Mechanical ventilation increased expression increased expression of of c-fosc-fos which was which was enhanced by LPSenhanced by LPS

Ventilation with high Ventilation with high volumes or no PEEP volumes or no PEEP further increased further increased c-fosc-fos expression expression

Ventilation strategy and TNFVentilation strategy and TNF expression expression

Mechanical ventilation Mechanical ventilation increased expression increased expression of TNFof TNF which was which was enhanced by LPSenhanced by LPS

Ventilation with high Ventilation with high volumes or no PEEP volumes or no PEEP further increased TNFfurther increased TNF expression expression Northern blot analysis of lung homogenate TNF mRNA levels

for the various ventilation strategies. Densitometric values for TNF were standardized to 28S ribosomal RNA. TNF mRNA in the saline-treated animals increased for three of the ventilatory strategies as compared to the controls (§P < 0.05 vs. Control). In LPStreated animals, TNF mRNA was significantly greater for MVHP and MVZP as compared to controls or HVZP (*P < 0.05 vs. Control HVZP). Within ventilatory strategies, LPS was found to increase TNF mRNA for three of the four ventilation strategies used (C, MVHP, MVZP; P < 0.05).

Ventilation Strategy and Lung Edema Ventilation Strategy and Lung Edema formationformation

Ventilation with lower Ventilation with lower tidal volume reduces tidal volume reduces lung edema formationlung edema formation

Rate of pulmonary edema formation, measured as excess extravascular lung water/h, was significantly lower with lower tidal volume ventilation [*P < 0.05 compared with the 3-ml/kg group, P < 0.05 compared with the 6-ml/kg group, P < 0.05 compared with the 12-ml/kg positive end-expiratory pressure (PEEP) 5-cmH2O group]. All acid-injured rats (solid bars) had a significantly more extravascular lung water than did ventilated control rats instilled with saline instead of acid (open bars; P < 0.001 by ANOVA correction for multiple comparisons). Excess lung water did not differ among the control groups (P > 0.05). Sample water did not differ among the control groups (P > 0.05). Sample sizes: 12 ml/kg PEEP 10 cmH2O, n = 4; 12 ml/kg PEEP 5cm H2O, n = 8; 6 ml/kg PEEP 10 cmH2O, n = 13; 3 ml/kg PEEP 10 cmH2O, n = 12. Data are means ± SD.

Light photomicrographs of rat lungs ventilated with 3 ml/kg PEEP 10 cmHLight photomicrographs of rat lungs ventilated with 3 ml/kg PEEP 10 cmH22O (O (AA); 6 ml/kg ); 6 ml/kg PEEP 10 cmHPEEP 10 cmH22O (O (BB); 12 ml/kg PEEP 5 cmH); 12 ml/kg PEEP 5 cmH22O (O (CC); and 12 ml/kg PEEP 10 cmH); and 12 ml/kg PEEP 10 cmH22O (O (DD) after ) after lung acid injury. There was significantly more interstitial and alveolar edema after higher lung acid injury. There was significantly more interstitial and alveolar edema after higher tidal volume ventilation. Lung injury scores based on edema, hyaline membranes, septal tidal volume ventilation. Lung injury scores based on edema, hyaline membranes, septal thickening, inflammatory cell infiltration, and small airway epithelial injury were thickening, inflammatory cell infiltration, and small airway epithelial injury were significantly higher in rats ventilated with 12 ml/kg PEEP 10 cmH2O, although injury was significantly higher in rats ventilated with 12 ml/kg PEEP 10 cmH2O, although injury was patchy in all groups (original magnification, ×40; hematoxylin-eosin). patchy in all groups (original magnification, ×40; hematoxylin-eosin).

Summary thus farSummary thus far(what we have learned)(what we have learned)

High tidal volume ventilation induces lung injuryHigh tidal volume ventilation induces lung injury Alkalosis induces lung injuryAlkalosis induces lung injury Synergistic with other factors that induce lung Synergistic with other factors that induce lung

injuryinjury Lung injury is reduced by use of CPAP or PEEPLung injury is reduced by use of CPAP or PEEP

Hypercapnea may Hypercapnea may protect the lungprotect the lung

Wean, Wean, WeanWean, ,

WEANWEAN

Protective effects of hypercapnic Protective effects of hypercapnic acidosis on VLIacidosis on VLI

Sinclair et al: Am J Respir Crit Care Med 2002Sinclair et al: Am J Respir Crit Care Med 2002

Rabbit modelRabbit model• All ventilated with high VAll ventilated with high VT T ~ 25 ml/kg to induce ~ 25 ml/kg to induce

lung injury for 4 hourslung injury for 4 hours

• Randomized to eucapnia (PaRandomized to eucapnia (PaCOCO22 ~ 40 mm Hg ~ 40 mm Hg

or hypercapnia (Paor hypercapnia (PaCOCO22 80-100 mm Hg) 80-100 mm Hg)

Achieved by addition of COAchieved by addition of CO22 to inspired gas (4-5% vs to inspired gas (4-5% vs 12%)12%)

• Respiratory rate kept constant (32 Respiratory rate kept constant (32 breaths/min)breaths/min)

• FiOFiO22 kept constant 0.5 kept constant 0.5

Effects of hypercapnic acidosis on Effects of hypercapnic acidosis on oxygenation in ventilator induced lung injuryoxygenation in ventilator induced lung injury

Oxygenation was Oxygenation was better preserved in better preserved in hypercapnic acidosishypercapnic acidosis

Arterial partial pressure of oxygen as it varies over time between the two study groups. Solid squares = hypercapnic groupopen circles = eucapnic group. *p < 0.05 compared with time zero value within the same group.p < 0.05 compared with hypercapnic group at same time point.

Effects of hypercapnea on lung injury Effects of hypercapnea on lung injury indices in VILIindices in VILI

All four types of injury are reduced in the hypercapnic group, particularly PMN infiltration and hemorrhage. Black bars = hypercapnic group White bars = eucapnic group. p < 0.05.

Effects of hypercapnea on BAL indices in Effects of hypercapnea on BAL indices in ventilator induced lung injuryventilator induced lung injury

Hypercapnic acidosis Hypercapnic acidosis was associated with a was associated with a reduction in the reduction in the inflammatory infiltrate inflammatory infiltrate in BALin BAL

This was This was predominately due to predominately due to decrease in decrease in neutrophilsneutrophils

BAL fluid total and differential cell counts. Eucapnic animals had significantly more nucleated cells per ml, most of which were neutrophils, whereas fewer cells, predominately macrophages, were found in the hypercapnic group. p < 0.05.

Protective effects of hypercapnia in Protective effects of hypercapnia in pulmonary reperfusion injurypulmonary reperfusion injury

Laffey et al: Am J Respir Crit Care Med 2000Laffey et al: Am J Respir Crit Care Med 2000

Rabbit modelRabbit model FiCOFiCO22 altered to produce hypercapnea altered to produce hypercapnea

FiCOFiCO2 2 of 0.00 (control) vs. 0.06 (hypercapnea)of 0.00 (control) vs. 0.06 (hypercapnea)• Very high PVery high PaaCOCO22 (50-60 torr vs.100 torr) (50-60 torr vs.100 torr)

FiOFiO2 2 constant (0.75)constant (0.75)

• VVTT 6 ml kg 6 ml kg-1-1 , constant rate and PEEP , constant rate and PEEP• Experimental protocolExperimental protocol

Warm ischemia – reperfusion of left lung Warm ischemia – reperfusion of left lung • Ligature of left hilum followed by reperfusionLigature of left hilum followed by reperfusion

Hypercapnea improves pulmonary Hypercapnea improves pulmonary mechanics following reperfusion injurymechanics following reperfusion injury

Hypercapnic acidosis Hypercapnic acidosis was associated with was associated with improved pulmonary improved pulmonary mechanicsmechanics

Peak airway pressure (Paw). Paw was comparable in both groups at baseline; increased significantly in both groups following reperfusion; and was significantly lower in TH versus CON (*p < 0.05). (B) Static Inflation compliance. Compliance was comparable in both groups at baseline, and decreased significantly in both groups following IR. The final static lung compliance value was significantly greater in TH versus CON (*p < 0.05 versus baseline in both groups, and p < 0.05 TH versus CON). (C ) Dynamic expiratory compliance. Dynamic expiratory compliance was comparable in both groups at baseline and decreased significantly in both groups following reperfusion. The final value of dynamic lung compliance was significantly greater (and the decrement smaller) in TH versus CON (*p < 0.05). (D) Lung wet:dry ratio. The wet: dry ratio was significantly lower in TH versus CON (*p < 0.05).

Hypercapnea reduces inflammatory Hypercapnea reduces inflammatory mediators following reperfusion injurymediators following reperfusion injury

(A) The protein concentration in the BAL fluid was significantly lower in TH versus CON groups (*p < 0.05). (B) BALF TNF- was significantly lower in the TH versus CON groups (*p < 0.05). (C ) The lung tissue 8-Isoprostane concentration was lower in TH versus CON (*p < 0.05). (D). Lung tissue myeloperoxidase levels were similar in both groups.

Hypercapnic acidosis Hypercapnic acidosis was associated with a was associated with a reduction in reduction in inflammatory inflammatory mediators following mediators following reperfusion injuryreperfusion injury

Hypercapnea reduces oxidant injury and Hypercapnea reduces oxidant injury and Apotosis following reperfusion injuryApotosis following reperfusion injury

Hypercapnic acidosis Hypercapnic acidosis was associated with a was associated with a reduction in oxidant reduction in oxidant injury (nitration of injury (nitration of tyrosine) and tyrosine) and reduction in apoptosis reduction in apoptosis of lung cellsof lung cells

Control Hypercapnea

Protective effect of hypercapnia on Protective effect of hypercapnia on endotoxin induced lung injuryendotoxin induced lung injury

Laffey et al: Am J Resp Cir Care Med 2004Laffey et al: Am J Resp Cir Care Med 2004

Rat Model (adult)Rat Model (adult)• Mechanical ventilation Mechanical ventilation

FiOFiO22 0.30, V 0.30, VTT 4.5 ml kg 4.5 ml kg-1-1, 90 bpm, PEEP 2.5, 90 bpm, PEEP 2.5

• Hypercapnia induced by added COHypercapnia induced by added CO22 (FiCO (FiCO22 0.06)0.06)

• Therapeutic vs. prophylactic strategiesTherapeutic vs. prophylactic strategies• Intratracheal instillation of Intratracheal instillation of E coliE coli LPS LPS

Hypercapnia reduces lung inflammation Hypercapnia reduces lung inflammation following endotoxin installationfollowing endotoxin installation

Hypercapnic acidosis Hypercapnic acidosis was associated with a was associated with a reduction in lung reduction in lung inflammationinflammation

A) Control (B) Therapeutic hypercapnic acidosis

Oxygenation (lower A-a Oxygenation (lower A-a gradient) is maintained gradient) is maintained by therapeutic by therapeutic hypercapniahypercapnia

Lung compliance is Lung compliance is maintained by maintained by hypercapniahypercapnia

Hypercapnia improves lung function Hypercapnia improves lung function following endotoxin installationfollowing endotoxin installation

Caveats and ConcernsCaveats and Concerns

Therapeutic hypercapnia may not be as effective Therapeutic hypercapnia may not be as effective in surfactant deficiencyin surfactant deficiency

Rai et al: Rai et al: Pediatr Res 2004Pediatr Res 2004

• Surfactant depleted rabbits (saline lavage)Surfactant depleted rabbits (saline lavage) Compared high and normal COCompared high and normal CO22 (FiCO (FiCO2 2 0.12)0.12)

VVtt 12 mL/kg, 12 mL/kg, PEEP 0 cm HPEEP 0 cm H22O, and a rate of 19 breaths/min O, and a rate of 19 breaths/min vs. Vvs. Vtt 5 mL/kg, with PEEP 12.5 5 mL/kg, with PEEP 12.5 cm Hcm H22O and rate 52O and rate 52

• Found little differences between treatment groupsFound little differences between treatment groups Compliance, cytokine levels, oxygenationCompliance, cytokine levels, oxygenation

Caveats and ConcernsCaveats and Concerns What about the brain???What about the brain???

• Potential adverse effects of high COPotential adverse effects of high CO22 on incidence of IVH on incidence of IVH COCO22 increases cerebral blood flow increases cerebral blood flow

Van Hulst et al Van Hulst et al Clin Physiol Funct Imaging 2004Clin Physiol Funct Imaging 2004

• Effects of hypocapnia and hypercapnia on brain glucose Effects of hypocapnia and hypercapnia on brain glucose and lactate (pigs)and lactate (pigs)

Hypercapnia has no effectHypercapnia has no effect Hypocapnia decreased brain glucose and increased lactateHypocapnia decreased brain glucose and increased lactate

Kamper et al Kamper et al Acta Paediatr 2004Acta Paediatr 2004

• Similar survival and neurological outcome between Similar survival and neurological outcome between ELBW infants treated with early CPAP and permissive ELBW infants treated with early CPAP and permissive hypercapnia and those treated conventionallyhypercapnia and those treated conventionally

Summary Summary (what we have learned)(what we have learned)

High tidal volume ventilation induces lung injuryHigh tidal volume ventilation induces lung injury Alkalosis induces lung injuryAlkalosis induces lung injury Synergistic with other factors that induce lung Synergistic with other factors that induce lung

injuryinjury Lung injury is reduced by use of CPAP or PEEPLung injury is reduced by use of CPAP or PEEP

• Optimal PEEP strategiesOptimal PEEP strategies Hypercapnea protects the lung from injuryHypercapnea protects the lung from injury

• Protects lung against injury from other causesProtects lung against injury from other causes• Even when high tidal volumes are usedEven when high tidal volumes are used