Djo Hasan

Cardioprotection in Pigs by Exogenous Norepinephrine but not by Cerebral Ischemia–Induced Release of Endogenous Norepinephrine

Background and Purpose— Endogenous norepinephrine release induced by cerebral ischemia may lead to small areas of necrosis in normal hearts. Conversely, norepinephrine may be one of the mediators that limit myocardial infarct size by ischemic preconditioning. Because brief ischemia in kidneys or skeletal muscle limits infarct size produced by coronary artery occlusion, we investigated whether cardiac norepinephrine release during transient cerebral ischemia also elicits remote myocardial preconditioning. Methods— Forty-one crossbred pigs of either sex were assigned to 1 of 7 experimental groups, of which in 6 groups myocardial infarct size was determined after a 60-minute coronary occlusion and 120 minutes of reperfusion. One group served as control (no pretreatment), while the other groups were pretreated with either cerebral ischemia or an intracoronary infusion of norepinephrine. Results— In 10 anesthetized control pigs, infarct size was 84±3% (mean±SEM) of the area at risk after a 60-minute coronary occlusion and 120 minutes of reperfusion. Intracoronary infusion of 0.03 nmol/kg · min−1 norepinephrine for 10 minutes before coronary occlusion did not affect infarct size (80±3%; n=6), whereas infusion of 0.12 nmol/kg · min−1 limited infarct size (65±2%; n=7;P <0.05). Neither 10-minute (n=5) nor 30-minute (n=6) cerebral ischemia produced by elevation of intracranial pressure before coronary occlusion affected infarct size (83±4% and 82±3%, respectively). Myocardial interstitial norepinephrine levels tripled during cerebral ischemia and during low-dose norepinephrine but increased 10-fold during high-dose norepinephrine. Norepinephrine levels increased progressively up to 500-fold in the area at risk during the 60-minute coronary occlusion, independent of the pretreatment, while norepinephrine levels remained unchanged in adjacent nonischemic myocardium and arterial plasma. Conclusions— Cerebral ischemia preceding a coronary occlusion did not modify infarct size, which is likely related to the modest increase in myocardial norepinephrine levels during cerebral ischemia. The infarct size limitation by high-dose exogenous norepinephrine is not associated with blunting of the ischemia-induced increase in myocardial interstitial norepinephrine levels.

Effects of cerebral air embolism on brain metabolism in pigs.

Objectives – Cerebral air embolism was induced in pigs and changes in intracranial pressure (ICP), brain oxygen (PbrO2), brain carbon dioxide (PbrCO2), brain pH (brpH) and glucose, lactate and pyruvate levels were used to characterize this model.

Detection of optimal PEEP for equal distribution of tidal volume by volumetric capnography and electrical impedance tomography during decreasing levels of PEEP in post cardiac-surgery patients

Background Homogeneous ventilation is important for prevention of ventilator-induced lung injury. Electrical impedance tomography (EIT) has been used to identify optimal PEEP by detection of homogenous ventilation in non-dependent and dependent lung regions. We aimed to compare the ability of volumetric capnography and EIT in detecting homogenous ventilation between these lung regions. Methods Fifteen mechanically-ventilated patients after cardiac surgery were studied. Ventilator settings were adjusted to volume-controlled mode with a fixed tidal volume (Vt) of 6–8 ml kg−1 predicted body weight. Different PEEP levels were applied (14 to 0 cm H2O, in steps of 2 cm H2O) and blood gases, Vcap and EIT were measured. Results Tidal impedance variation of the non-dependent region was highest at 6 cm H2O PEEP, and decreased significantly at 14 cm H2O PEEP indicating decrease in the fraction of Vt in this region. At 12 cm H2O PEEP, homogenous ventilation was seen between both lung regions. Bohr and Enghoff dead space calculations decreased from a PEEP of 10 cm H2O. Alveolar dead space divided by alveolar Vt decreased at PEEP levels ≤6 cm H2O. The normalized slope of phase III significantly changed at PEEP levels ≤4 cm H2O. Airway dead space was higher at higher PEEP levels and decreased at the lower PEEP levels. Conclusions In postoperative cardiac patients, calculated dead space agreed well with EIT to detect the optimal PEEP for an equal distribution of inspired volume, amongst non-dependent and dependent lung regions. Airway dead space reduces at decreasing PEEP levels.

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

A feasibility study into adenosine triphosphate measurement in exhaled breath condensate: a potential bedside method to monitor alveolar deformation

Recent research suggested an important role for pulmonary extracellular adenosine triphosphate (ATP) in the development of ventilation-induced lung injury. This injury is induced by mechanical deformation of alveolar epithelial cells, which in turn release ATP to the extracellular space. Measuring extracellular ATP in exhaled breath condensate (EBC) may be a non-invasive biomarker for alveolar deformation. Here, we study the feasibility of bedside ATP measurement in EBC. We measured ATP levels in EBC in ten subjects before and after an exercise test, which increases respiratory parameters and alveolar deformation. EBC lactate concentrations were measured as a dilution marker. We found a significant increase in ATP levels in EBC (before 73 RLU [IQR 50–209] versus after 112 RLU [IQR 86–203]; p value 0.047), and the EBC ATP-to-EBC lactate ratio increased as well (p value 0.037). We present evidence that bedside measurement of ATP in EBC is feasible and that ATP levels in EBC increase after exercise. Future research should measure ATP levels in EBC during mechanical ventilation as a potential biomarker for alveolar deformation.

Excessive extracellular ATP desensitizes P2Y2 and P2X4 ATP receptors provoking surfactant impairment ending in ventilation-induced lung injury

Stretching the alveolar epithelial type I (AT I) cells controls the intercellular signaling for the exocytosis of surfactant by the AT II cells through the extracellular release of adenosine triphosphate (ATP) (purinergic signaling). Extracellular ATP is cleared by extracellular ATPases, maintaining its homeostasis and enabling the lung to adapt the exocytosis of surfactant to the demand. Vigorous deformation of the AT I cells by high mechanical power ventilation causes a massive release of extracellular ATP beyond the clearance capacity of the extracellular ATPases. When extracellular ATP reaches levels >100 μM, the ATP receptors of the AT II cells become desensitized and surfactant impairment is initiated. The resulting alteration in viscoelastic properties and in alveolar opening and collapse time-constants leads to alveolar collapse and the redistribution of inspired air from the alveoli to the alveolar ducts, which become pathologically dilated. The collapsed alveoli connected to these dilated alveolar ducts are subject to a massive strain, exacerbating the ATP release. After reaching concentrations >300 μM extracellular ATP acts as a danger-associated molecular pattern, causing capillary leakage, alveolar space edema, and further deactivation of surfactant by serum proteins. Decreasing the tidal volume to 6 mL/kg or less at this stage cannot prevent further lung injury.