Increased ratio of P[v-a]CO2 to C[a-v]O2 without global hypoxia: the case of metformin-induced lactic acidosis.

The ratio of venoarterial CO2 tension to arteriovenous O2 content difference (P[v-a]CO2/C[a-v]O2) increases when lactic acidosis is due to inadequate oxygen supply (hypoxia); we aimed to verify whether it also increases when lactic acidosis develops because of mitochondrial dysfunction (dysoxia) with constant oxygen delivery. Twelve anaesthetised, mechanically ventilated pigs were intoxicated with IV metformin (4.0 to 6.4 g over 2.5 to 4.0 h). Saline and norepinephrine were used to preserve oxygen delivery. Lactate and P[v-a]CO2/C[a-v]O2 were measured every one or two hours (arterial and mixed venous blood). During metformin intoxication, lactate increased from 0.8 (0.6-0.9) to 8.5 (5.0-10.9) mmol/l (p < 0.001), even if oxygen delivery remained constant (from 352 ± 78 to 343 ± 97 ml/min, p = 0.098). P[v-a]CO2/C[a-v]O2 increased from 1.6 (1.2-1.8) to 2.3 (1.9-3.2) mmHg/ml/dl (p = 0.004). The intraclass correlation coefficient between lactate and P[v-a]CO2/C[a-v]O2 was 0.72 (p < 0.001). We conclude that P[v-a]CO2/C[a-v]O2 increases when lactic acidosis is due to dysoxia. Therefore, a high P[v-a]CO2/C[a-v]O2 may not discriminate hypoxia from dysoxia as the cause of lactic acidosis.

Antithrombin During Extracorporeal Membrane Oxygenation in Adults: National Survey and Retrospective Analysis.

The impact of antithrombin replacement during extracorporeal membrane oxygenation (ECMO) in adults remains unclear. This work comprises a survey, showing that antithrombin is routinely supplemented in many Italian ECMO-Centers, and a retrospective analysis on 66 adults treated with veno-venous ECMO and unfractionated heparin at our Institution. Twenty-four to 72 h after the beginning of ECMO, antithrombin activity was ≤70% in 47/66 subjects and activated partial thromboplastin time (aPTT) ratio was <1.5 in 20/66 subjects. Activated partial thromboplastin time ratio <1.5 was associated not with lower antithrombin activity (61 ± 17 vs. 63 ± 22%; p = 0.983) but with higher circulating level of C-reactive protein (23 ± 8 vs. 11 ± 9 mg/dl; p < 0.001). In 34 subjects who received antithrombin concentrate, antithrombin activity increased (from 54 ± 9 to 84 ± 13%; p < 0.001); the proportion of subjects with aPTT ratio ≥1.5 increased (from 21/34 [62%] to 31/34 [91%]; p = 0.004); heparin dosage remained constant (from 19 ± 7 to 19 ± 6 IU/kg/h; p = 0.543); and C-reactive protein decreased (from 17 ± 10 to 13 ± 9 mg/dl; p = 0.013). Among those with aPTT ratio <1.5, aPTT ratio remained <1.5 in 3 out of 13 subjects. Antithrombin is frequently supplemented during veno-venous ECMO although low antithrombin activity does not constantly impede, and antithrombin replacement does not constantly ensure, reaching the target aPTT ratio. Inflammation possibly affects the individual response to heparin.

Role of Strain Rate in the Pathogenesis of Ventilator-Induced Lung Edema.

OBJECTIVE: Lungs behave as viscoelastic polymers. Harms of mechanical ventilation could then depend on not only amplitude (strain) but also velocity (strain rate) of lung deformation. Herein, we tested this hypothesis. DESIGN: Laboratory investigation. SETTING: Animal unit. SUBJECTS: Thirty healthy piglets. INTERVENTIONS: Two groups of animals were ventilated for 54 hours with matched lung strains (ratio between tidal volume and functional residual capacity) but different lung strain rates (ratio between strain and inspiratory time). Individual strains ranged between 0.6 and 3.5 in both groups. Piglets ventilated with low strain rates had an inspiratory-to-expiratory time ratio of 1:2-1:3. Those ventilated with high strain rates had much lower inspiratory-to-expiratory time ratios (down to 1:9). Respiratory rate was always 15 breaths/min. Lung viscoelastic behavior, with ventilator setting required per protocol, was "quantified" as dynamic respiratory system hysteresis (pressure-volume loop [in Joules]) and stress relaxation (airway pressure drop during an end-inspiratory pause [in cm H2O]). Primary outcome was the occurrence of pulmonary edema within 54 hours. MEASUREMENTS AND MAIN RESULTS: On average, the two study groups were ventilated with well-matched strains (2.1 ± 0.9 vs 2.1 ± 0.9; p = 0.864) but different strain rates (1.8 ± 0.8 vs 4.6 ± 1.5 s; p < 0.001), dynamic respiratory system hysteresis (0.6 ± 0.3 vs 1.4 ± 0.8 J; p = 0.001), and stress relaxation (3.1 ± 0.9 vs 5.0 ± 2.3 cm H2O; p = 0.008). The prevalence of pulmonary edema was 20% among piglets ventilated with low strain rates and 73% among those ventilated with high strain rates (p = 0.010). CONCLUSIONS: High strain rate is a risk factor for ventilator-induced pulmonary edema, possibly because it amplifies lung viscoelastic behavior.

Lung anatomy, energy load, and ventilator-induced lung injury.

BACKGROUND: High tidal volume can cause ventilator-induced lung injury (VILI), but positive end-expiratory pressure (PEEP) is thought to be protective. We aimed to find the volumetric VILI threshold and see whether PEEP is protective per se or indirectly. METHODS: In 76 pigs (22 ± 2 kg), we examined the lower and upper limits (30.9-59.7 mL/kg) of inspiratory capacity by computed tomography (CT) scan at 45 cmH2O pressure. The pigs underwent a 54-h mechanical ventilation with a global strain ((tidal volume (dynamic) + PEEP volume (static))/functional residual capacity) from 0.45 to 5.56. The dynamic strain ranged from 18 to 100 % of global strain. Twenty-nine pigs were ventilated with end-inspiratory volumes below the lower limit of inspiratory capacity (group "Below"), 38 within (group "Within"), and 9 above (group "Above"). VILI was defined as death and/or increased lung weight. RESULTS: "Below" pigs did not develop VILI; "Within" pigs developed lung edema, and 52 % died before the end of the experiment. The amount of edema was significantly related to dynamic strain (edema 188-153 × dynamic strain, R (2) = 0.48, p < 0.0001). In the "Above" group, 66 % of the pigs rapidly died but lung weight did not increase significantly. In pigs ventilated with similar tidal volume adding PEEP significantly increased mortality. CONCLUSIONS: The threshold for VILI is the lower limit of inspiratory capacity. Below this threshold, VILI does not occur. Within these limits, severe/lethal VILI occurs depending on the dynamic component. Above inspiratory capacity stress at rupture may occur. In healthy lungs, PEEP is protective only if associated with a reduced tidal volume; otherwise, it has no effect or is harmful.

High positive end-expiratory pressure: only a dam against oedema formation?

INTRODUCTION: Healthy piglets ventilated with no positive end-expiratory pressure (PEEP) and with tidal volume (VT) close to inspiratory capacity (IC) develop fatal pulmonary oedema within 36 h. In contrast, those ventilated with high PEEP and low VT, resulting in the same volume of gas inflated (close to IC), do not. If the real threat to the blood-gas barrier is lung overinflation, then a similar damage will occur with the two settings. If PEEP only hydrostatically counteracts fluid filtration, then its removal will lead to oedema formation, thus revealing the deleterious effects of overinflation. METHODS: Following baseline lung computed tomography (CT), five healthy piglets were ventilated with high PEEP (volume of gas around 75% of IC) and low VT (25% of IC) for 36 h. PEEP was then suddenly zeroed and low VT was maintained for 18 h. Oedema was diagnosed if final lung weight (measured on a balance following autopsy) exceeded the initial one (CT). RESULTS: Animals were ventilated with PEEP 18 ± 1 cmH2O (volume of gas 875 ± 178 ml, 89 ± 7% of IC) and VT 213 ± 10 ml (22 ± 5% of IC) for the first 36 h, and with no PEEP and VT 213 ± 10 ml for the last 18 h. On average, final lung weight was not higher, and actually it was even lower, than the initial one (284 ± 62 vs. 347 ± 36 g; P = 0.01). CONCLUSIONS: High PEEP (and low VT) do not merely impede fluid extravasation but rather preserve the integrity of the blood-gas barrier in healthy lungs.

Lung stress and strain during mechanical ventilation: any difference between statics and dynamics?

OBJECTIVE: Tidal volume (VT) and volume of gas caused by positive end-expiratory pressure (VPEEP) generate dynamic and static lung strains, respectively. Our aim was to clarify whether different combinations of dynamic and static strains, resulting in the same large global strain, constantly produce lung edema. DESIGN: Laboratory investigation. SETTING: Animal unit. SUBJECTS: Twenty-eight healthy pigs. INTERVENTIONS: After lung computed tomography, 20 animals were ventilated for 54 hours at a global strain of 2.5, either entirely dynamic (VT 100% and VPEEP 0%), partly dynamic and partly static (VT 75-50% and VPEEP 25-50%), or mainly static (VT 25% and VPEEP 75%) and then killed. In eight other pigs (VT 25% and VPEEP 75%), VPEEP was abruptly zeroed after 36-54 hours and ventilation continued for 3 hours. MEASUREMENTS AND MAIN RESULTS: Edema was diagnosed when final lung weight (balance) exceeded the initial weight (computed tomography). Mortality, lung mechanics, gas exchange, pulmonary histology, and inflammation were evaluated. All animals ventilated with entirely dynamic strain (VT 825±424 mL) developed pulmonary edema (lung weight from 334±38 to 658±99 g, p<0.01), whereas none of those ventilated with mainly static strain (VT 237±21 mL and VPEEP 906±114 mL, corresponding to 19±1 cm H2O of positive end-expiratory pressure) did (from 314±55 to 277±46 g, p=0.65). Animals ventilated with intermediate combinations finally had normal or largely increased lung weight. Smaller dynamic and larger static strains lowered mortality (p<0.01), derangement of lung mechanics (p<0.01), and arterial oxygenation (p<0.01), histological injury score (p=0.03), and bronchoalveolar interleukin-6 concentration (p<0.01). Removal of positive end-expiratory pressure did not result in abrupt increase in lung weight (from 336±36 to 351±77 g, p=0.51). CONCLUSIONS: Lung edema forms (possibly as an all-or-none response) depending not only on global strain but also on its components. Large static are less harmful than large dynamic strains, but not because the former merely counteracts fluid extravasation.