Glucocorticoid receptor expression and binding capacity in patients with burn injury.

BACKGROUND: Burn injuries are associated with strong inflammation and risk of secondary sepsis which both may affect the function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in leucocytes from patients admitted to a tertiary burn center. METHODS: Blood was sampled from 13 patients on admission and days 7, 14 and 21, and once from 16 healthy subjects. Patients were grouped according to the extent of burn and to any sepsis on day 7. Expression and binding capacity of GR were determined as arbitrary units using flow cytometry. RESULTS: GR expression and binding capacity were increased compared to healthy subjects in most circulating leucocyte subsets on admission irrespective of burn size. Patients with sepsis on day 7 displayed increased GR expression in T lymphocytes (51.8%, P < 0.01) compared to admission. There was a negative correlation between GR binding capacity in neutrophils and burn size after 14 days (P < 0.05). CONCLUSIONS: GR expression and binding capacity are increased in most types of circulating leucocytes of severely burned patients on their admission to specialized burn care. If sepsis is present after 1 week, it is associated with higher GR expression in T lymphocytes and NK cells.

Real-time ventilation and perfusion distributions by electrical impedance tomography during one-lung ventilation with capnothorax.

BACKGROUND: Carbon dioxide insufflation into the pleural cavity, capnothorax, with one-lung ventilation (OLV) may entail respiratory and hemodynamic impairments. We investigated the online physiological effects of OLV/capnothorax by electrical impedance tomography (EIT) in a porcine model mimicking the clinical setting. METHODS: Five anesthetized, muscle-relaxed piglets were subjected to first right and then left capnothorax with an intra-pleural pressure of 19 cm H2 O. The contra-lateral lung was mechanically ventilated with a double-lumen tube at positive end-expiratory pressure 5 and subsequently 10 cm H2 O. Regional lung perfusion and ventilation were assessed by EIT. Hemodynamics, cerebral tissue oxygenation and lung gas exchange were also measured. RESULTS: During right-sided capnothorax, mixed venous oxygen saturation (P = 0.018), as well as a tissue oxygenation index (P = 0.038) decreased. There was also an increase in central venous pressure (P = 0.006), and a decrease in mean arterial pressure (P = 0.045) and cardiac output (P = 0.017). During the left-sided capnothorax, the hemodynamic impairment was less than during the right side. EIT revealed that during the first period of OLV/capnothorax, no or very minor ventilation on the right side could be seen (3 ± 3% vs. 97 ± 3%, right vs. left, P = 0.007), perfusion decreased in the non-ventilated and increased in the ventilated lung (18 ± 2% vs. 82 ± 2%, right vs. left, P = 0.03). During the second OLV/capnothorax period, a similar distribution of perfusion was seen in the animals with successful separation (84 ± 4% vs. 16 ± 4%, right vs. left). CONCLUSION: EIT detected in real-time dynamic changes in pulmonary ventilation and perfusion distributions. OLV to the left lung with right-sided capnothorax caused a decrease in cardiac output, arterial oxygenation and mixed venous saturation.

Distant effects of nitric oxide inhalation in lavage-induced lung injury in anaesthetised pigs.

BACKGROUND: Inhalation of nitric oxide (INO) exerts both local and distant effects. INO in healthy pigs causes down-regulation of endogenous nitric oxide (NO) production and vasoconstriction in lung regions not reached by INO, especially in hypoxic regions, which augments hypoxic pulmonary vasoconstriction. In contrast, in pigs with endotoxemia-induced lung injury, INO causes increased NO production in lung regions not reached by INO. The aim of this study was to investigate whether INO exerts distant effects in surfactant-depleted lungs. METHODS: Twelve pigs were anaesthetised, and the left lower lobe (LLL) was separately ventilated. Lavage injury was induced in all lung regions, except the LLL. In six pigs, 40 ppm INO was given to the LLL (INO group), and the effects on endogenous NO production and blood flow in the lavage-injured lung regions were studied. Six pigs served as a control group. NO concentration in exhaled air (ENO), NO synthase (NOS) activity and cyclic guanosine monophosphate (cGMP) in lung tissue, and regional pulmonary blood flow were measured. RESULTS: The calcium (Ca(2+) )-dependent NOS activity was lower (P < 0.05) in the lavage-injured lung regions in the INO group than in the control group. There were no measurable differences between the groups for Ca(2+) -independent NOS activity, cGMP, ENO, or regional pulmonary blood flow. CONCLUSIONS: Regional INO did not increase endogenous NO production in lavage-injured lung regions not directly reached by INO, but instead down-regulated the constitutive calcium-dependent nitric oxide synthase activity, indicating that NO may inhibit its own synthesis.

Improved ventilation-perfusion matching with increasing abdominal pressure during CO(2) -pneumoperitoneum in pigs.

BACKGROUND: CO(2) -pneumoperitoneum (PP) is performed at varying abdominal pressures. We studied in an animal preparation the effect of increasing abdominal pressures on gas exchange during PP. METHODS: Eighteen anaesthetized pigs were studied. Three abdominal pressures (8, 12 and 16 mmHg) were randomly selected in each animal. In six pigs, single-photon emission computed tomography (SPECT) was used for the analysis of V/Q distributions; in another six pigs, multiple inert gas elimination technique (MIGET) was used for assessing V/Q matching. In further six pigs, computed tomography (CT) was performed for the analysis of regional aeration. MIGET, CT and central haemodynamics and pulmonary gas exchange were recorded during anaesthesia and after 60 min on each of the three abdominal pressures. SPECT was performed three times, corresponding to each PP level. RESULTS: Atelectasis, as assessed by CT, increased during PP and in proportion to abdominal pressure [from 9 ± 2% (mean ± standard deviation) at 8 mmHg to 15 ± 2% at 16 mmHg, P<0.05]. SPECT during increasing abdominal CO(2) pressures showed a shift of blood flow towards better ventilated areas. V/Q analysis by MIGET showed no change in shunt during 8 mmHg PP (9 ± 1.9% compared with baseline 9 ± 1.2%) but a decrease during 12 mmHg PP (7 ± 0.9%, P<0.05) and 16 mmHg PP (5 ± 1%, P<0.01). PaO(2) increased from 39 ± 10 to 52 ± 9 kPa (baseline to 16 mmHg PP, P<0.01). Arterial carbon dioxide (PCO(2) ) increased during PP and increased further with increasing abdominal pressures. CONCLUSION: With increasing abdominal pressure during PP perfusion was redistributed more than ventilation away from dorsal, collapsed lung regions. This resulted in a better V/Q match. A possible mechanism is enhanced hypoxic pulmonary vasoconstriction mediated by increasing PCO(2) .

No effect of metabolic acidosis on nitric oxide production in hypoxic and hyperoxic lung regions in pigs.

AIM: In the severely ill intensive care patients metabolic acidosis and hypoxia often co-exist. We studied the effects of metabolic acidosis on nitric oxide synthase (NOS) dependent and NOS independent nitric oxide (NO) production in hypoxic and hyperoxic lung (HL) regions in a pig model. METHODS: Eighteen healthy anaesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (LLL) and hyperoxic gas to the rest of the lung. Six pigs received HCl infusion (HCl group), six pigs received the non-specific NOS inhibitor N(ω) -nitro-l-arginine methyl ester (l-NAME) and HCl infusions (l-NAME + HCl group) and six pigs received buffered Ringer's solution (control group). NO concentration in exhaled air (ENO), NOS activity in lung tissue, and regional pulmonary blood flow were measured. RESULTS: Metabolic acidosis, induced by infusion of HCl, decreased the relative perfusion to the hypoxic LLL from 7 (3) [mean (SD)] to 3 (1) % in the HCl group (P < 0.01), and from 4 (1) to 1 (1) % in the l-NAME + HCl group (P < 0.05), without any measurable significant changes in ENO from hypoxic or HL regions There were no significant differences between the HCl and control groups for Ca(2+) -dependent (cNOS) or Ca(2+) -independent NOS (iNOS) activity in hypoxic or HL regions. CONCLUSIONS: Metabolic acidosis augmented the hypoxic pulmonary vasoconstriction, without any changes in pulmonary NOS dependent or NOS independent NO production. When acidosis was induced during ongoing NOS blockade, the perfusion of hypoxic lung regions was almost abolished, indicating acidosis-induced pulmonary vasoconstriction was not NO dependent.

Ventilation-perfusion distributions and gas exchange during carbon dioxide-pneumoperitoneum in a porcine model.

BACKGROUND: Carbon dioxide (CO2)-pneumoperitoneum (PP) of 12 mm Hg increases arterial oxygenation, but it also promotes collapse of dependent lung regions. This seeming paradox prompted the present animal study on the effects of PP on ventilation-perfusion distribution (V/Q) and gas exchange. METHODS: Fourteen anaesthetized pigs were studied. In seven pigs, single photon emission computed tomography (SPECT) was used for spatial analysis of ventilation and perfusion distributions, and in another seven pigs, multiple inert gas elimination technique (MIGET) was used for detailed analysis of V/Q matching. SPECT/MIGET and central haemodynamics and pulmonary gas exchange were recorded during anaesthesia before and 60 min after induction of PP. RESULTS: SPECT during PP showed no or only poorly ventilated regions in the dependent lung compared with the ventilation distribution during anaesthesia before PP. PP was accompanied by redistribution of blood flow away from the non- or poorly ventilated regions. V/Q analysis by MIGET showed decreased shunt from 9 (sd 2) to 7 (2)% after induction of PP (P<0.05). No regions of low V/Q were seen either before or during PP. Almost no regions of high V/Q developed during PP (1% of total ventilation). Pa(o2) increased from 33 (1.2) to 35.7 (3.2) kPa (P<0.01) and arterial to end-tidal Pco2 gradient (Pae'(co2) increased from 0.3 (0.1) to 0.6 (0.2) kPa (P<0.05). CONCLUSIONS: Perfusion was redistributed away from dorsal, collapsed lung regions when PP was established. This resulted in a better V/Q match. A possible mechanism is enhanced hypoxic pulmonary vasoconstriction.

Development of atelectasis and arterial to end-tidal PCO2-difference in a porcine model of pneumoperitoneum.

BACKGROUND: Intraperitoneal insufflation of carbon dioxide (CO2) may promote collapse of dependent lung regions. The present study was undertaken to study the effects of CO2-pneumoperitoneum (CO2-PP) on atelectasis formation, arterial oxygenation, and arterial to end-tidal PCO2-gradient (Pa-E'(CO2)). METHODS: Fifteen anaesthetized pigs [mean body weight 28 (SD 2) kg] were studied. Spiral computed tomography (CT) scans were obtained for analysis of lung tissue density. In Group 1 (n=5) mechanical ventilation (V(T)=10 ml kg (-1), FI(O2)=0.5) was applied, in Group 2 (n=5) FI(O2) was increased for 30 min to 1.0 and in Group 3 (n=5) negative airway pressure was applied for 20 s in order to enhance development of atelectasis. Cardiopulmonary and CT data were obtained before, 10, and 90 min after induction of CO2-PP at an abdominal pressure of 12 mmHg. RESULTS: Before CO2-PP, in Group 1 non-aerated tissue on CT scans was 1 (1)%, in Group 2 3 (2)% (P<0.05, compared with Group 1), and in Group 3 7 (3)% (P<0.05, compared with Group 1 and Group 2). CO2-PP significantly increased atelectasis in all groups. PaO2/FI(O2) fell and venous admixture ('shunt') increased in proportion to atelectasis during anaesthesia but CO2-PP had a varying effect on PaO2/FI(O2) and shunt. Thus, no correlation was seen between atelectasis and PaO2/FI(O2) or shunt when all data before and during CO2-PP were pooled. Pa-E'(CO2), on the other hand correlated strongly with the amount of atelectasis (r2=0.92). CONCLUSIONS: Development of atelectasis during anaesthesia and PP may be estimated by an increased Pa-E'(CO2).

One-lung ventilation induces hyperperfusion and alveolar damage in the ventilated lung: an experimental study.

BACKGROUND: One-lung ventilation (OLV) increases mechanical stress in the lung and affects ventilation and perfusion (V, Q). There are no data on the effects of OLV on postoperative V/Q matching. Thus, this controlled study evaluates the influence of OLV on V/Q distribution in a pig model using a gamma camera technique [single-photon emission computed tomography (SPECT)] and relates these findings to lung histopathology after OLV. METHODS: Eleven anaesthetized and ventilated pigs (V(T)=10 ml kg(-1), Fio2=0.40, PEEP=5 cm H2O) were studied. After lung separation, OLV and thoracotomy were performed in seven pigs (OLV group). During OLV and in a two-lung ventilation (TLV), control group (n=4) ventilation settings remained unchanged. SPECT with (81m)Kr (ventilation) and (99m)Tc-labelled macro-aggregated albumin (perfusion) was performed before, during, and 90 min after OLV/TLV. Finally, lung tissue samples were harvested and examined for alveolar damage. RESULTS: OLV affected ventilation and haemodynamic variables, but there were no differences between the OLV group and the control group before and after OLV/TLV. SPECT revealed an increase of perfusion in the dependent lung compared with baseline (49-56%), and a corresponding reduction of perfusion (51-44%) in non-dependent lungs after OLV. No perfusion changes were observed in the control group. This resulted in increased low V/Q regions and a shift of V/Q areas to 0.3-0.5 (10(-0.5)-10(-0.3)) in dependent lungs of OLV pigs and was associated with an increased diffuse alveolar damage score. CONCLUSIONS: OLV in pigs results in a substantial V/Q mismatch, hyperperfusion, and alveolar damage in the dependent lung and may thus contribute to gas exchange impairment after thoracic surgery.

Pulmonary vasoconstriction during regional nitric oxide inhalation: evidence of a blood-borne regulator of nitric oxide synthase activity.

BACKGROUND: Inhaled nitric oxide (INO) is thought to cause selective pulmonary vasodilation of ventilated areas. The authors previously showed that INO to a hyperoxic lung increases the perfusion to this lung by redistribution of blood flow, but only if the opposite lung is hypoxic, indicating a more complex mechanism of action for NO. The authors hypothesized that regional hypoxia increases NO production and that INO to hyperoxic lung regions (HL) can inhibit this production by distant effect. METHODS: Nitric oxide concentration was measured in exhaled air (NO(E)), NO synthase (NOS) activity in lung tissue, and regional pulmonary blood flow in anesthetized pigs with regional left lower lobar (LLL) hypoxia (fraction of inspired oxygen [FIO2] = 0.05), with and without INO to HL (FIO2 = 0.8), and during cross-circulation of blood from pigs with and without INO. RESULTS: Left lower lobar hypoxia increased exhaled NO from the LLL (NO(E)LLL) from a mean (SD) of 1.3 (0.6) to 2.2 (0.9) parts per billion (ppb) (P < 0.001), and Ca2+-dependent NOS activity was higher in hypoxic than in hyperoxic lung tissue (197 [86] vs. 162 [96] pmol x g(-1) x min(-1), P < 0.05). INO to HL decreased the Ca2+-dependent NOS activity in hypoxic tissue to 49 [56] pmol x g(-1) x min(-1) (P < 0.01), and NO(E)LLL to 2.0 [0.8] ppb (P < 0.05). When open-chest pigs with LLL hypoxia received blood from closed-chest pigs with INO, NO(E)LLL decreased from 2.0 (0.6) to 1.5 (0.4) ppb (P < 0.001), and the Ca2+-dependent NOS activity in hypoxic tissue decreased from 152 (55) to 98 (34) pmol x g(-1) x min(-1) (P = 0.07). Pulmonary vascular resistance increased by 32 (21)% (P < 0.05), but more so in hypoxic (P < 0.01) than in hyperoxic (P < 0.05) lung regions, resulting in a further redistribution (P < 0.05) of pulmonary blood flow away from hypoxic to hyperoxic lung regions. CONCLUSIONS: Inhaled nitric oxide downregulates endogenous NO production in other, predominantly hypoxic, lung regions. This distant effect is blood-mediated and causes vasoconstriction in lung regions that do not receive INO.

Endothelin-1 and nitric oxide synthase in short rebound reaction to short exposure to inhaled nitric oxide.

On withdrawal of inhalation of nitric oxide (INO) administered after lung injury, pulmonary artery pressure (PAP) and arterial oxygen tension (Pa(O(2))) may deteriorate more than before INO (rebound response). In this study, we investigated the possible roles of endothelin (ET)-1 and nitric oxide (NO) synthase (NOS) activity in the short rebound reaction to short-term inhalation of NO. Twenty-six anesthetized mechanically ventilated piglets were given endotoxin infusion. Twelve animals then received INO (30 parts per million) for two 30-min periods. Nine controls were not given NO. Measurements were made of blood gases and hemodynamic parameters, lung tissue ET-1 expression and NOS activity, and plasma ET-1 concentration. INO decreased PAP and increased Pa(O(2)), but INO withdrawal caused a short rebound reaction with an increase in PAP. Lung tissue expression and plasma concentration of ET-1 increased during INO, and plasma ET-1 increased further after its withdrawal. Activity of constitutive NOS decreased during INO, whereas that of inducible NOS was unchanged. Upregulation of ET-1 and downregulation of NOS activity may have influenced the short rebound reaction to short-term INO.

Pulmonary blood flow distribution in lobar hypoxia--influence of cardiac output and nitric oxide inhalation.

Inhaled NO is reported to be less effective in patients with ARDS if cardiac output is high (> 10 L/min). It has also been demonstrated that increased blood flow and increased shear stress cause an enhancement of endogenous NO production. In one-lung ventilation and regional hypoxia, nitric oxide (NO) delivered to the ventilated lung may decrease blood flow to the nonventilated lung and improve arterial oxygenation. So far, however, results have been divergent. The present study was performed with the hypothesis that inhaled NO would be less effective if cardiac output was increased. In the anaesthetized pig, hypoxia (5% O2) was induced in the left lower lobe. NO was delivered consecutively to the hypoxic lobe and to the other, oxygenated parts, of the lungs during continuous measurement of lobar blood flow and total lung blood flow. Bleeding and infusion of dextran caused variation in cardiac output. It was found that lobar hypoxia per se reduced lobar blood flow from 22.9+/-3.1% to 4.7+/-0.9% of cardiac output. An increase (3.2+/-0.3 L x min(-1)) and a decrease (2.2+/-0.2 L x min(-1)) in cardiac output did not alter the relative perfusion of the hypoxic lobe from baseline cardiac output (2.6+/-0.2 L x min(-1)) values. When NO was delivered to the hypoxic lobe, there was a marked increase in relative lobar perfusion to 19.0+/-2.9% during low cardiac output and 16.5+/-2.7% during high cardiac output without any significant difference between the two NO-induced increases of lobar perfusion. The increase in lobar perfusion tended to depend inversely on total pulmonary blood flow when cardiac output had been reduced by bleeding but without reaching statistical significance (r = -0.42, p > 0.05). The decrease in mean pulmonary artery pressure and PaO2 seen during NO inhalation to the hypoxic lobe did not correlate with the level of cardiac output. When NO was delivered to the oxygenated parts of the lungs, no significant effect on relative lobar perfusion or arterial oxygenation was observed, either at raised or at lowered cardiac output. The findings give no further evidence to show that variations in cardiac output alter the effect of NO inhalation.

Inhalation of a nitric oxide synthase inhibitor to a hypoxic or collapsed lung lobe in anaesthetized pigs: effects on pulmonary blood flow distribution.

I.v. administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), not only reduces blood flow in a hypoxic lung region but also causes systemic vasoconstriction and a decrease in cardiac output. In this study, we delivered nebulized L-NAME 0.2-1 mg kg-1 to the left lower lobe of 10 anaesthetized pigs. The left lower lobe was made hypoxic by selective inhalation of 5% oxygen or collapsed by interrupted ventilation, or both. Inhalation of L-NAME reduced fractional blood flow to the left lower lobe from 5.3 (SD 3.1)% to 1.7 (1.4)% (P < 0.05) in lobar hypoxia and from 6.0 (3.3) to 2.7 (2.7)% (P < 0.05) in lobar collapse. These reductions were accompanied by a significant increase in PaO2. There were no significant changes in arterial pressure, cardiac output or heart rate. We have shown that selective inhalation of L-NAME reduced blood flow to a hypoxic or collapsed lung region without systemic effects. The possible role for nitric oxide synthase inhibition in reducing shunt during one-lung ventilation, however, requires further study.

Nitric oxide modulation of pulmonary blood flow distribution in lobar hypoxia.

BACKGROUND: Nitric oxide, endogenously produced or inhaled, has been shown to play an important role in the regulation of pulmonary blood flow. The inhalation of nitric oxide reduces pulmonary arterial pressure in humans, and the blockade of endogenous nitric oxide production increases the pulmonary vascular response to hypoxia. This study was performed to investigate the hypothesis that intravenous administration of an nitric oxide synthase inhibitor and regional inhalation of nitric oxide can markedly alter the distribution of pulmonary blood flow during regional hypoxia. METHODS: Hypoxia (5% O2) was induced in the left lower lobe of the pig, and the blood flow to this lobe was measured with transit-time ultrasound. Nitric oxide was administered in the gas ventilating the hypoxic lobe and the hyperoxic lung regions with and without blockade of endogenous nitric oxide production by means of N omega-nitro-L-arginine methyl ester (L-NAME). RESULTS: Hypoxia in the left lower lobe reduced blood flow to that lobe to 27 +/- 3.9% (mean +/- SEM) of baseline values (P < 0.01). L-NAME caused a further reduction in lobar blood flow in all six animals to 12 +/- 3.5% and increased arterial oxygen tension (PaO2) (P < 0.01). Without L-NAME, the inhalation of nitric oxide (40 ppm) to the hypoxic lobe increased lobar blood flow to 66 +/- 5.6% of baseline (P < 0.01) and, with L-NAME, nitric oxide delivered to the hypoxic lobe resulted in a lobar blood flow that was 88 +/- 9.3% of baseline (difference not significant). When nitric oxide was administered to the hyperoxic lung regions, after L-NAME infusion, the blood flow to the hypoxic lobe decreased to 2.5 +/- 1.6% of baseline and PaO2 was further increased (P < 0.01). CONCLUSIONS: By various combinations of nitric oxide inhalation and intravenous administration of an nitric oxide synthase inhibitor, lobar blood flow and arterial oxygenation could be markedly altered during lobar hypoxia. In particular, the combination of intravenous L-NAME and nitric oxide inhalation to the hyperoxic regions almost abolished perfusion of the hypoxic lobe and resulted in a PaO2 that equalled the prehypoxic values. This possibility of adjusting regional blood flow and thereby of improving PaO2 may be of value in the treatment of patients undergoing one-lung ventilation and of patients with acute respiratory failure.

Dependence of shunt on cardiac output in unilobar oleic acid edema. Distribution of ventilation and perfusion.

OBJECTIVE: In acute respiratory failure, increased cardiac output (Qt) increases shunt (Qs/Qt). We have tested if this is caused by: 1) a redistribution of blood flow towards edematous regions, or 2) a decrease of regional ventilation in the edematous region. DESIGN: Oleic acid edema was induced in the left lower lobe (LLL) of 11 pigs. Qt was varied with bleeding and infusion of blood and dextran. Blood flow to the LLL was measured at low and high Qt with electromagnetic low probes in 6 animals and with a gamma camera in 5. In the gamma camera pigs regional ventilation was also measured. MEASUREMENTS AND RESULTS: Qt was increased by 45% (electromagnetic flow probes) and 73% (gamma camera). Qs/Qt increased from 24.9-31.3% (p < 0.05) and from 17.6-28.8% (p < 0.001) respectively. No change in fractional perfusion of LLL could be seen, neither with flow probes nor with gamma camera. A decrease in ventilation of LLL, 2.6%, was observed when Qt was increased (p < 0.05). CONCLUSION: Theoretically a small decrease in ventilation can explain the increase in shunt, if regions with low ventilation/perfusion (VA/Q) ratio are transformed to shunt. This is, however, unlikely since earlier studies have shown that blood flow is distributed either to regions with normal VA/Q ratio or to shunt regions. We conclude that the cardiac output dependent shunt is not caused by redistribution of blood flow between lobes or by decreased ventilation in the edematous region. We cannot exclude that blood flow is redistributed within the edematous lobe.