In vitro validation and characterization of pulsed inhaled nitric oxide administration during early inspiration.

PURPOSE: Admixture of nitric oxide (NO) to the gas inspired with mechanical ventilation can be achieved through continuous, timed, or pulsed injection of NO into the inspiratory limb. The dose and timing of NO injection govern the inspired and intrapulmonary effect site concentrations achieved with different administration modes. Here we test the effectiveness and target reliability of a new mode injecting pulsed NO boluses exclusively during early inspiration. METHODS: An in vitro lung model was operated under various ventilator settings. Admixture of NO through injection into the inspiratory limb was timed either (i) selectively during early inspiration ("pulsed delivery"), or as customary, (ii) during inspiratory time or (iii) the entire respiratory cycle. Set NO target concentrations of 5-40 parts per million (ppm) were tested for agreement with the yield NO concentrations measured at various sites in the inspiratory limb, to assess the effectiveness of these NO administration modes. RESULTS: Pulsed delivery produced inspiratory NO concentrations comparable with those of customary modes of NO administration. At low (450 ml) and ultra-low (230 ml) tidal volumes, pulsed delivery yielded better agreement of the set target (up to 40 ppm) and inspiratory NO concentrations as compared to customary modes. Pulsed delivery with NO injection close to the artificial lung yielded higher intrapulmonary NO concentrations than with NO injection close to the ventilator. The maximum inspiratory NO concentration observed in the trachea (68 ± 30 ppm) occurred with pulsed delivery at a set target of 40 ppm. CONCLUSION: Pulsed early inspiratory phase NO injection is as effective as continuous or non-selective admixture of NO to inspired gas and may confer improved target reliability, especially at low, lung protective tidal volumes.

Changes in hepatic blood flow during whole body hyperthermia.

PURPOSE: Changes in blood flow distribution are important for heat dispersion and for supportive therapeutic strategies such as simultaneous whole body hyperthermia (WBH) and administration of chemotherapy. The aim of this clinical study was to determine changes in hepatic blood flow during WBH for the treatment of metastatic cancer. MATERIALS AND METHODS: This observational clinical study was part of a phase I/II feasibility study of WBH. WBH was induced using a radiant heat device. Hepatic blood flow was estimated using indocyanine green clearance measurements. The plasma disappearance rate of indocyanine green (PDR-ICG) was recorded in percent/min. We used an invasive thermo-dye-dilution technique to estimate hepatic blood flow, cardiac output, and volume status. Mean arterial blood pressure was also measured invasively. To determine the effects of hyperthermia the measurements were performed at defined temperature points. RESULTS: In 10 of 22 treatments the PDR-ICG fell below normal values during hyperthermia, which represented a significant fall in hepatic blood flow. Cardiac output, volume status, and mean arterial blood pressure did not differ between patients whose liver blood flow was reduced and those whose liver blood flow remained unchanged. CONCLUSIONS: We observed distinct reductions in hepatic blood flow during WBH, which suggested a significant redistribution of blood flow away from the core during WBH. This was not mirrored by global circulatory parameters.

Inhalation of an endothelin receptor A antagonist attenuates pulmonary inflammation in experimental acute lung injury.

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg.kg(-1), ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in PaO2 (316 +/- 47 mm Hg vs. control 53 +/- 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% +/- 1% positive cells vs. control 12% +/- 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 +/- 1 pg.100 mg-1 wet weight vs. control 7 +/- 1 pg.100 mg(-1) wet weight, p < 0.05). Concentrations of TNF-alpha, IL-1beta, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.

Inhalation of the ETA receptor antagonist LU-135252 selectively attenuates hypoxic pulmonary vasoconstriction.

Endogenous endothelin (ET)-1 modulates hypoxic pulmonary vasoconstriction (HPV). Accordingly, intravenously applied ET(A) receptor antagonists reduce HPV, but this is accompanied by systemic vasodilation. We hypothesized that inhalation of an ET(A) receptor antagonist might act selectively on the pulmonary vasculature and investigated the effects of aerosolized LU-135252 in an experimental model of HPV. Sixteen piglets (weight: 25 +/- 1 kg) were anesthetized and mechanically ventilated at an inspiratory oxygen fraction (Fi(O(2))) of 0.3. After 1 h of hypoxia at Fi(O(2)) 0.15, animals were randomly assigned either to receive aerosolized LU-135252 as bolus (0.3 mg/kg for 20 min; n = 8, LU group), or to receive aerosolized saline (n = 8, controls). In all animals, hypoxia significantly increased mean pulmonary arterial pressure (32 +/- 1 vs. 23 +/- 1 mmHg; P < 0.01; means +/- SE) and increased arterial plasma ET-1 (0.52 +/- 0.04 vs. 0.37 +/- 0.05 fmol/ml; P < 0.01) compared with mild hyperoxia at Fi(O(2)) 0.3. Inhalation of LU-135252 induced a significant and sustained decrease in mean pulmonary arterial pressure compared with controls (LU group: 27 +/- 1 mmHg; controls: 32 +/- 1 mmHg; values at 4 h of hypoxia; P < 0.01). In parallel, mean systemic arterial pressure and cardiac output remained stable and were not significantly different from control values. Consequently, in our experimental model of HPV, the inhaled ET(A) receptor antagonist LU-135252 induced selective pulmonary vasodilation without adverse systemic hemodynamic effects.

Alteration of transthyretin microheterogeneity in serum of multiple trauma patients.

Transthyretin (TTR) which exists in various isoforms, is a valid marker for acute phase response and subclinical malnutrition. The aim of the study was to investigate the relationship between inflammation, oxidative stress and the occurrence of changes in microheterogeneity of TTR.A prospective, observational study at a level-I trauma center of a large urban medical university was performed. Patients were severely injured (n = 18; injury severity score (ISS): 34-66), and were observed within the first 24 hours of admittance and over the following days until day 20 after injury. 20 healthy subjects, matched by age and sex, were used as controls.TTR was enriched by immunoprecipitation. Microheterogeneity of TTR was determined by linear matrix assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Four major mass signals were observed for TTR representing native, S-cysteinylated, S-cysteinglycinylated and S-glutathionylated TTR. In the course of their ICU stay, 14 of the 18 patients showed a transient change in microheterogeneity in favour of the S-cysteinglycinylated form of TTR (p < 0.05 vs. controls). The occurrence of this variant was not associated with the severity of trauma or the intensity of the acute-phase response, but was associated with oxidative stress as evidenced by Trolox.Our results demonstrate that changes in microheterogeneity of TTR occur in a substantial number of ICU trauma patients. The diagnostic values of these changes remains to be elucidated. It is speculated that TTR modification may well be the mechanism underlying the morphological manifestation of amyloidose or Alzheimer's diseases in patients surviving multiple trauma.

Endothelin-1 influences the efficacy of inhaled nitric oxide in experimental acute lung injury.

Beneficial effects of inhaled nitric oxide (iNO) on arterial oxygenation in acute lung injury (ALI) suggest the presence of vasoconstriction in ventilated lung regions and this may be influenced by endothelin-1 (ET-1). We studied a possible interaction between ET-1 and iNO in experimental ALI. Sixteen piglets were anesthetized and mechanically ventilated (inspired O2 fraction, 1.0). After induction of ALI by surfactant depletion, animals were randomly assigned to either inhale 30 ppm NO (iNO group, n = 8), or to receive no further intervention (controls, n = 8). Measurements were performed during the following 4 hrs. In all animals, induction of ALI significantly decreased arterial oxygen tension (PaO2) from 569 +/- 15 (prelavage) to 58 +/- 3 mm Hg. Inhaled NO significantly increased PaO2 when compared with controls (iNO group: 265 +/- 51 mm Hg; controls: 50 +/- 4 mm Hg, values at 4 hrs, P < 0.01). Prelavage ET-1 plasma levels were comparable between groups (iNO: 0.74 +/- 0.03, controls: 0.71 +/- 0.03 fmol/ml, NS). During the protocol, the ET-1 levels increased and were different at 3 hrs (iNO: 0.93 +/- 0.06, controls: 1.25 +/- 0.09 fmol/ml; P < 0.05). PaO2 changes induced by iNO revealed a moderate and significant correlation with ET-1 plasma levels (R = 0.548, P = 0.001). Our data suggest that endogenous ET-1 production influences the efficacy of iNO in ALI. Furthermore, iNO reduced ET-1 plasma levels, possibly indicating anti-inflammatory properties of iNO in the early phase of ALI.

Goal-directed therapy of cardiac preload in induced whole-body hyperthermia.

OBJECTIVES: To optimize volume therapy during induced whole-body hyperthermia (WBH) < or = 42.2 degrees C, pulmonary capillary wedge pressure (PCWP) and intrathoracic blood volume index (ITBVI) were compared as goal parameters. DESIGN: Prospective clinical study. SETTING: ICU at university hospital. PATIENTS: Twenty-three patients with metastatic cancers. INTERVENTIONS: Radiant WBH in combination with induced hyperglycemia, hyperoxemia, and chemotherapy was applied. Volume therapy was directed to the PCWP (group A, 8 to 12 mm Hg [20 treatments]), or to ITBVI (group B, 800 to 1,100 mL/m2 [19 treatments]) following a standardized protocol. Goals other than PCWP and ITBVI were cardiac index of > 3.5 L/min/m2 and mean arterial pressure of > 55 mm Hg. MEASUREMENTS AND RESULTS: In addition to the primary goals PCWP and ITBVI, at defined temperatures, central venous pressure (CVP), extravascular lung water index, the number of infusions, and packed RBCs, as well as serum lactate level, norepinephrine dosage, and levels of liver enzymes, bilirubin, creatinine, and urea were measured. Patients in group A received a significantly greater mean (+/- SD) amount of crystalloids compared to those in group B (6,175 +/- 656 vs 3,947 +/- 375 mL, respectively) and required significantly lower dosages of vasoconstrictors compared with patients in group B. Except for the lower values of CVP in patients in group A during hyperthermia, all of the other hemodynamic and laboratory parameters showed no significant differences between the groups or stayed in a normal range. CONCLUSION: PCWP and ITBVI are useful parameters to assess preload in induced WBH. Differences in crystalloids and vasopressor dosages may suggest an appropriate ITBVI of > 1,100 mL/m2 for patients with good cardiopulmonary health under such extremely hypercirculatory conditions.

Stress induced changes in lymphocyte subpopulations and associated cytokines during whole body hyperthermia of 41.8-42.2 degrees C.

Extreme acute physical stress leads to transient impairment of T-lymphocytes, which are essential for tumor defence and prevention of infectious diseases. Radiant whole body hyperthermia (WBH) at 41.8-42.2 degrees C may enhance the efficacy of systemic chemotherapy in patients with advanced malignancies, but is associated with marked physical stress. Aim of this study was to demonstrate stress induced short-time effects on lymphocyte subpopulations and associated cytokines during WBH. Total leukocyte count, white blood cell differential blood count, lymphocyte subpopulations (T-helper-/T4-cells, T-suppressor-/T8-cells, natural-killer-/NK-cells, gammadelta-T-cells) as well as plasma levels of Interleukin(IL)-10, IL-12 and Interferon-gamma (IFN-gamma) were measured in ten patients treated with WBH and additional cytostatic chemotherapy. Blood samples were drawn before treatment, at three temperature points during WBH, and 24 h after start of treatment. Results were compared with those obtained from a control group consisting of six patients receiving chemotherapy alone. Numbers of T4-cells decreased significantly during WBH, while numbers of NK-cells and gammadelta-T-cells increased, resulting in transient impairments of total lymphocyte counts and T4/T8-ratio. IL-12 plasma levels as well as IFN-gamma/IL-10-ratio also decreased during WBH. No significant changes were found in T8-cells of WBH patients. Changes were reversible within 24 h and could not been found in control patients. Our results support the hypothesis that WBH combined with chemo therapy induces a strong but reversible anti-inflammatory stress response in cancer patients during therapy. Further studies are necessary to examine the pathophysiological details and to evaluate the meaning of these transient immunological changes for patient's outcome.