Validation of cardiac output monitoring based on uncalibrated pulse contour analysis vs transpulmonary thermodilution during off-pump coronary artery bypass grafting.

BACKGROUND: Cardiac output monitoring, as a part of a goal-directed haemodynamic management, has been shown to improve perioperative outcome in high-risk patients undergoing major surgical interventions. However, thorough validation of cardiac output monitoring devices in different clinical conditions is warranted. The aim of our study was to compare the reliability of a novel system for cardiac index (CI) monitoring based on uncalibrated pulse contour analysis (UPCA) with transpulmonary thermodilution (TPTD) during off-pump coronary artery bypass grafting (OPCAB). METHODS: Twenty patients undergoing elective OPCAB were enrolled into the study. CI measured by means of UPCA (CIUPCA) was validated against CI determined with TPTD technique (CITPTD). Parallel measurements of CI were performed at nine stages during the surgery and after operation. We assessed the accuracy and the precision of individual values and the agreement of trends of changes in CI. RESULTS: Totally, 180 pairs of data were collected. There was a significant correlation between CIUPCA and CITPTD (ρ=0.836, P<0.01). According to a Bland-Altman analysis, the mean bias between the methods was -0.14 litre min(-1) m(-2) with limits of agreement of ±0.82 litre min(-1) m(-2) and a percentage error of 31%. A polar plot trend analysis revealed acceptable angular bias (-0.54°), increased radial limits of agreement (±52.7°), and decreased polar concordance rate (74%). CONCLUSIONS: In OPCAB, UPCA provides accurate and precise CI measurements compared with TPTD. However, the ability of this method to follow trends in cardiac output is poor. CLINICAL TRIAL REGISTRATION: NCT01773720 (ClinicalTrials.gov).

The effects of methylene blue on ovine post-pneumonectomy pulmonary oedema.

BACKGROUND: We recently reported that post-pneumonectomy pulmonary oedema (PPO) occurs after ventilating the remaining lung with excessive tidal volumes. Studies in small animals have indicated that nitric oxide (NO) release increases in hyper-inflated lungs, but confirmatory evidence from larger animals is still lacking. We hypothesized that PPO could be prevented by methylene blue (MB), an inhibitor of NO synthase. METHODS: Sheep were subjected to a right-sided pneumonectomy (PE) and randomly assigned to a protectively ventilated group ((PROTV group, n=7) with tidal volumes of 6 ml/kg at 20 inflations/min and a positive end-expiratory pressure (PEEP) of 2 cmH(2)O, and two groups undergoing 'injurious ventilation' (INJV) with tidal volumes of 12 ml/kg and zero end-expiratory pressure (ZEEP), a control group (INJV group, n=7) and a treatment group subjected to MB 1 h after PE (INJV+MB group, n=7). Haemodynamic variables, lung mechanics, blood gases and plasma nitrites and nitrates (NOx) were determined. RESULTS: PE reduced pulmonary blood volume, extravascular lung water (EVLWI) and quasistatic lung compliance in all groups, in parallel with a rise in peak airway pressure (P<0.05). In the INJV group, pulmonary arterial pressure, EVLWI and pulmonary vascular permeability index increased and arterial oxygenation decreased towards cessation of the experiments. These changes were not antagonized by MB. Plasma NOx increased in all the groups compared with baseline, but with no intergroup difference. CONCLUSION: MB did not reduce PPO and accumulation of NOx in sheep subjected to ventilation with excessive tidal volumes and ZEEP.

Radiographic lung density assessed by computed tomography is associated with extravascular lung water content.

BACKGROUND: We hypothesized that in acute lung injury (ALI), the volume of pulmonary tissue with aqueous density, as determined by spiral computed tomography (CT), is associated with extravascular lung water content. Our aim was to compare tissue volume index, as assessed by CT, before and after oleic acid-induced ALI, with extravascular lung water indexes (EVLWI), determined with single transpulmonary thermodilution (EVLWI(STD)), thermal-dye dilution (EVLWI(TDD)), and postmortem gravimetry (EVLWI(G)). METHODS: Seven instrumented sheep received an intravenous infusion of oleic acid 0.08 ml/kg (OA group) and four animals had vehicle only (Control group). The day before, and immediately after the experiment, sheep were anesthetized to undergo quantitative CT examinations during a short breath hold. Hemodynamics, oxygenation, EVLWI(STD), and EVLW(TDD) were registered. Linear regression analysis was used to assess the relationships between EVLWI(STD), EVLW(TDD), EVLWI(G), and lung tissue volume index (TVI(CT)) determined with CT. RESULTS: In the OA group, total lung volume increased compared with Controls. Poorly and non-aerated lung volumes increased a 3.6- and 4.9-fold, respectively, and TVI(CT) almost doubled. EVLWI(STD), EVLWI(TDD), and TVI(CT) were associated significantly with EVLWI(G) (r=0.85, 0.90, and 0.88, respectively; P<0.001). TVI(CT) deviated from the reference EVLWI(G) values to the greatest extent with a mean bias +/- 2SD of 4.0 +/- 6.0 ml/kg. CONCLUSIONS: In ovine oleic acid-induced ALI, lung tissue volume, as assessed by quantitative CT, is in close agreement with EVLWI, as determined by indicator dilution methods and postmortem gravimetry, but overestimates lung fluid content.

Single transpulmonary thermodilution and continuous monitoring of central venous oxygen saturation during off-pump coronary surgery.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCAB) requires thorough monitoring of hemodynamics and oxygen transport. Our aim was to find out whether therapeutic guidance during and after OPCAB, using an algorithm based on advanced monitoring, influences perioperative hemodynamic and fluid management as well as the length of post-operative ICU and hospital stay. METHODS: Patients were randomized into two groups of hemodynamic monitoring: the conventional monitoring (CM) group (n=20) and the advanced monitoring (AM) group (n=20). In the CM group, therapy was guided by central venous pressure, mean arterial pressure (MAP) and heart rate (HR), and in the AM group by the intrathoracic blood volume index, MAP, HR, central venous oxygen saturation (ScvO(2)) and cardiac index (CI). The measurements were performed before and during surgery, and at 2, 4 and 6 h post-operatively. RESULTS: In the AM group, colloids and dobutamine were given more frequently and were accompanied by increments in ScvO(2), CI and oxygen delivery compared with baseline. The percentage of ephedrine administration was higher in the CM group. The algorithm guided by AM decreased time until achieving the status of 'fit for ICU discharge' and post-operative hospital stay by 15% and 25%, respectively. CONCLUSIONS: A goal-directed algorithm based on advanced hemodynamic monitoring and continuous measurement of ScvO(2) facilitates early detection and correction of hemodynamic changes and influences the strategy for fluid therapy that can improve the course of post-operative period after coronary artery bypass grafting on the beating heart.

[Assessment of current methods quantitating extravascular lung water and pulmonary aeration in inhomogeneous lung injury: an experimental study].

BACKGROUND: Single transpulmonary thermodilution (STTD) is a widely recognized technique for the quantification of extravascular lung water (EVLW). However, the accuracy of STTD can be substantially reduced in acute lung lesion (ALL) characterized by inhomogeneous distribution of edematous zones and major ventilation-perfusion mismatch. Quantitative computed tomography (CT) may be a helpful clinical adjunct allowing an assessment of pulmonary gas and tissue content. The purpose of the study was to compare the tissue volume index, as estimated by spiral CT (TVICT), with EVLW indices determined with STTD (EVLWISTTD), thermal-dye dilution (EVLWITDD), and postmortem gravimetry (EVLWIG) before and after oleic acid-induced ALL in sheep. MATERIALS: Eleven yearling sheep were randomly assigned to either an oleic acid (OA) group receiving an infusion of OA in a dose of 0.08 ml/kg i.v. or to a control group. The day before and immediately after the experiment, sheep underwent CT examinations. Pulmonary and systemic hemodynamics, oxygenation, EVLWISTTD and EVLWITDD were recorded. Linear regression analysis was used to assess the relationships between EVLWISTTD, EVLWITDD, EVLWIG, and TVICT (syngo PulmpCT, Siemens, Germany). RESULTS: OA caused 5- and 7-fold increments in poorly and nonaerated lung volumes, respectively, and increased total lung volume and TVICT, EVLWISTTD, EVLWITDD, and TVICT demonstrated a close agreement with EVLWIG (r = 0.86, 0.90, and 0.97, respectively; p < 0.001). TVICT overestimated reference EVLWIG values to the greatest extent. CONCLUSION: In a sheep model of OA-induced ALL, pulmonary tissue volume as estimated by quantitative CT closely correlates with EVLWI measured by dilutional methods and postmortem gravimetry.

Single transpulmonary thermodilution in off-pump coronary artery bypass grafting: haemodynamic changes and effects of different anaesthetic techniques.

BACKGROUND: Off-pump coronary artery bypass grafting (OPCAB) can be associated with severe cardiovascular changes, thus requiring advanced haemodynamic monitoring. Our aim was to investigate the feasibility of transpulmonary single thermodilution (STD) combined with pulse-contour analysis, a newly introduced method for cardiovascular monitoring, for assessment of changes in haemodynamics during different anaesthetic techniques in OPCAB. METHODS: Thirty-six patients scheduled for elective OPCAB were randomized to receive anaesthesia either with midazolam, propofol or isoflurane, in addition to fentanyl and pipecuronium. After catheterization of the femoral artery, haemodynamic parameters were assessed using STD and pulse-contour analysis. The measurements were performed after induction of anaesthesia, during surgery and at 2, 4 and 6 h post-operatively. RESULTS: At the end of surgery, the global ejection fraction decreased by 29% and 19% in the midazolam and the propofol groups, respectively, (P < 0.05) but remained unchanged in the isoflurane group. Moreover, in the isoflurane group, the left ventricular contractility index was higher and the mean arterial pressure (MAP) and the systemic vascular resistance index (SVRI) decreased in comparison with pre-operative values. Post-operatively, the cardiac index (CI) and the cardiac function index (CFI) increased in all groups (P < 0.05). The peri-operative requirement for ephedrine and nitroglycerin increased in the propofol and the midazolam groups, respectively (P < 0.05). CONCLUSION: During OPCAB, STD and pulse-contour analysis displayed changes in preload, myocardial function and afterload that gave valuable guidance for the conduct of anaesthesia, fluid management, and the administration of vasoactive agents. As assessed using STD, isoflurane within the present dose range appears to maintain myocardial performance and vascular tone better than midazolam or propofol.

[Monitoring of extravascular lung water in patients with severe sepsis]. / Monitoring vnesosudistoi vody legkikh u bol'nykh s tiazhelym sepsisom.

The key objective of the case study was the possibility to monitor the extravascular lung water (EVLW) in severe cases. Twelve mechanically ventilated patients with severe sepsis complicated by septic shock and by an acute lung injury (ALI) were involved in the prospective study. The measurements, performed on days 1 and 3 after the onset of sepsis, comprised hemodynamics, EVLW as assessed by Pulsion PiCCO method, blood gases and severity scores. The EVLW correlated significantly with lung injury score (r = 0.46), oxygenation (r = -0.46) and with pulmonary compliance (r = -0.58) versus the central venous pressure. The EVLW and lung injury scores were found to be essentially higher in non-survivors on day 3. The clinical situations, described in the present article, are indicative of a potential EVLW value applicable to sepsis treatment. Finally, the monitoring of EVLW is a useful tool in the purpose-oriented therapy of sepsis-induced ALI; moreover, the method has an important prognostic value.

Methylene blue reduces pulmonary oedema and cyclo-oxygenase products in endotoxaemic sheep.

The authors recently demonstrated that methylene blue (MB), an inhibitor of the nitric oxide (NO) pathway, reduces the increments in pulmonary capillary pressure, lung lymph flow and protein clearance in endotoxaemic sheep. In the present study, the authors examined whether MB influences pulmonary haemodynamics and accumulation of extravascular lung water (EVLW) by mechanisms other than the NO pathway. Sixteen awake, chronically-instrumented sheep randomly received either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty minutes later, all sheep received an intravenous infusion of Escherichia coli endotoxin 1 microg x kg(-1) for 20 min and either an intravenous infusion of MB 2.5 mg x kg(-1) x h(-1) or isotonic saline for 6 h. MB markedly attenuated the endotoxin-induced pulmonary hypertension and right ventricular failure, and reduced the accumulation of EVLW. Moreover, MB reduced the increments in plasma thromboxane B2 and 6-keto-prostaglandin F1alpha, and abolished the febrile response. However, MB had no effect on the changes in circulating neutrophils, serum hyaluronan, and total haemolytic activity of the alternative complement pathway. The authors conclude that in sheep, methylene blue attenuates the endotoxin-induced pulmonary hypertension and oedema, at least in part, by inhibiting the cyclo-oxygenase products of arachidonic acid. This is a novel effect of methylene blue in vivo.

Continuously infused methylene blue modulates the early cardiopulmonary response to endotoxin in awake sheep.

BACKGROUND: In endotoxemia and septic shock, enhanced generation of endogenous nitric oxide (NO) contributes to myocardial depression, hypotension, and derangement of gas exchange. We hypothesized that continuous infusion of methylene blue (MB), an inhibitor of the NO pathway, would counteract these effects in endotoxemic sheep. METHODS: Twenty-one sheep were anesthetized and instrumented for a chronic study with vascular catheters. On the day of the experiment, 18 conscious animals randomly received either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty minutes later, sheep received a 20-min intravenous infusion of Escherichia coli endotoxin 1 microg x kg(-1) and either an intravenous infusion of MB 2.5 mg x kg(-1) x h(-1) or isotonic saline, respectively, for 5 h. In addition, 3 animals were exposed to the same dose of MB alone. RESULTS: MB reduced the early endotoxin-induced declines in stroke volume, left ventricular stroke work and cardiac indices, and prevented mean arterial pressure from falling. Moreover, MB ameliorated the increases in pulmonary arterial pressure and pulmonary vascular resistance index. In addition, MB reduced the increments in venous admixture and AaPO2, decreased the falls in PaO2, SaO2, and oxygen delivery, and maintained oxygen consumption. MB also prevented the rises in body temperature and plasma nitrites and nitrates, and delayed the elevation of plasma lactate. When given alone to healthy sheep, MB transiently reduced plasma lactate and PaO2, and increased AaPO2. CONCLUSION: In ovine endotoxemia, continuously infused MB counteracts the early myocardial dysfunction and derangement of hemodynamics and gas exchange.

Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study.

OBJECTIVE: To evaluate the effects of continuous infusion of methylene blue (MB), an inhibitor of the nitric oxide pathway, on hemodynamics and organ functions in human septic shock. DESIGN: Prospective, randomized, controlled, open-label, pilot study. SETTING: Multidisciplinary intensive care unit of a university hospital. PATIENTS: Twenty patients with septic shock diagnosed <24 hrs before randomization. INTERVENTIONS: Patients were randomized 1:1 to receive either MB (MB group, n = 10) or isotonic saline (control group, n = 10), adjunctive to conventional treatment. MB was administered as an intravenous bolus injection (2 mg/kg), followed 2 hrs later by infusion at stepwise increasing rates of 0.25, 0.5, 1, and 2 mg/kg/hr that were maintained for 1 hr each. During infusion, mean arterial pressure was maintained between 70 and 90 mm Hg, while attempting to reduce concurrent adrenergic support. MEASUREMENTS AND MAIN RESULTS: Hemodynamics and organ function variables were assessed over a 24-hr period, and the survival rate at day 28 was noted. Infusion of MB prevented the stroke volume and the left-ventricular stroke work indexes from falling and increased mean arterial pressure. Compared with the control group, MB reduced the requirement for norepinephrine, epinephrine, and dopamine by as much as 87%, 81%, and 40%, respectively. Oxygen delivery remained unchanged in the MB group and decreased in the control group. MB also reduced the body temperature and the plasma concentration of nitrates/nitrites. Leukocytes and organ function variables such as bilirubin, alanine aminotransferase, urea, and creatinine were not significantly affected. Platelet count decreased in both groups. Five patients treated with MB survived vs. three patients receiving conventional treatment. CONCLUSIONS: In human septic shock, continuously infused MB counteracts myocardial depression, maintains oxygen transport, and reduces concurrent adrenergic support. Infusion of MB appears to have no significant adverse effects on the selected organ function variables.

Methylene blue reduces lung fluid filtration during the early phase of endotoxemia in awake sheep.

OBJECTIVE: To determine whether methylene blue (MB), an inhibitor of soluble guanylate cyclase and nitric oxide synthase, alters lung hemodynamics and fluid filtration after endotoxin in sheep. DESIGN: Prospective, randomized, controlled experimental study with repeated measurements. SETTING: University animal laboratory. SUBJECTS: Eight yearling, awake sheep. INTERVENTIONS: Sheep were instrumented for a chronic study with vascular and lung lymph catheters. In two experiments, separated by 1 wk of recovery, the animals received intravenously either an injection of MB 10 mg/kg or a corresponding volume of 0.9% sodium chloride as pretreatment. Thirty minutes later, sheep received a bolus injection of Escherichia coli endotoxin 1 microg/kg, followed by either an infusion of MB 2.5 mg/kg/hr or a corresponding volume of 0.9% sodium chloride for 5 hrs. MEASUREMENTS AND MAIN RESULTS: MB decreased the early phase endotoxin-induced rises in pulmonary capillary pressure and pulmonary vascular resistance. MB also reduced the increments in lung lymph flow (QL) and protein clearance (CL) as well as the rightward shift of the permeability-surface area product (PS). In addition, MB diminished the decrease in cardiac output, stabilized mean arterial pressure, and precluded the rise in plasma and lung lymph cyclic guanosine 3'-5' monophosphate. However, during the late phase, MB-treated sheep presented with a faster rise in QL with no difference in CL and PS from the endotoxemic controls. CONCLUSIONS: During the early phase of endotoxemia in sheep, MB attenuates lung injury by decreasing the enhanced lung fluid filtration as a result of reduced pulmonary capillary pressure and permeability. However, MB does not counteract the late phase increase in lung fluid filtration.

Effects of adenosine on extravascular lung water content in endotoxemic pigs.

OBJECTIVE: To investigate whether adenosine protects against endotoxin-induced increments in extravascular lung water content. DESIGN: Prospective, randomized, animal study. SETTING: University research laboratory. SUBJECTS: Twenty-one anesthetized juvenile pigs. INTERVENTIONS: The animals were divided into two groups subjected to endotoxin infusion: Endotoxin alone (n = 7), or endotoxin combined with adenosine infusion (n = 7) administered during the whole experimental period. Two other groups were exposed to anesthesia alone (n = 4) or adenosine infusion alone (n = 3), respectively. MEASUREMENTS AND MAIN RESULTS: Central hemodynamic variables and extravascular lung water, as assessed by the thermal dye dilution double indicator technique, were monitored. Plasma endothelin-1 concentrations were measured hourly. Extravascular lung water increased significantly in response to endotoxemia (p <.001) along with an increase in pulmonary microvascular pressure (P(mv) [p <.01]). Although the Pmv increased less in endotoxemic animals exposed to adenosine infusion, no intergroup difference was found. From 4 through 6 hrs, adenosine-treated pigs displayed only half of the extravascular lung water content of nontreated animals (p <.01). The latter did not differ from that of anesthetized controls receiving anesthesia or adenosine alone. Adenosine administered alone had no effect on P(mv). In pigs receiving adenosine alone, extravascular lung water content reached nadir after 3 hrs. In both endotoxin groups, plasma endothelin-1 concentration increased two-fold, peaking 4-6 hrs after the start of endotoxin infusion (p <.001). CONCLUSIONS: The endotoxin-induced increase in lung extravascular water was hampered by intravenously infused adenosine in the presence of a nonsignificantly reduced microvascular pressure. This leaves reduced microvascular permeability the most likely reason for the beneficial effect of adenosine.

Effect of aminoguanidine on lung fluid filtration after endotoxin in awake sheep.

It has been suggested that enhanced generation of nitric oxide by inducible nitric oxide synthase (iNOS) may contribute to acute lung injury. We hypothesized that aminoguanidine (AG), a proposed selective inhibitor of iNOS, would alter pulmonary hemodynamics, fluid filtration, and gas exchange after endotoxin in chronically instrumented awake sheep. Eighteen sheep were randomly assigned to receive either AG (10 mg/kg + 1 mg/kg/h), or NaCl 0.9% intravenously for 4 h, beginning 2 h after injection of Escherichia coli endotoxin (1 microgram/kg). After endotoxin, pulmonary artery pressure (Ppa), capillary pressure (Pc), and vascular resistance index (PVRI) rose concomitantly with six-fold increments in lung lymph flow (Q L) and protein clearance (CL). Extravascular lung water (EVLW) doubled, as assessed with the thermal dye dilution technique; Pa(O(2)) decreased, AaPO(2) and venous admixture (Q S/Q T) increased. After AG, Q L and CL increased further by approximately 30%, whereas EVLW remained unchanged, despite an additional increase in Pc. Ppa, PVRI, and systemic vascular resistance index rose, whereas cardiac index and pulmonary blood volume index declined. In addition, Pa(O(2)) rose, and AaPO(2) and Q S/Q T decreased. We conclude that in endotoxemic sheep, AG improves gas exchange and increases Q L and CL, whereas EVLW remains unchanged in spite of enhanced Pc. Apparently, increased lymphatic drainage prevents EVLW from rising after AG.

Inhaled nitric oxide reduces lung fluid filtration after endotoxin in awake sheep.

We studied the effect on lung fluid filtration of 37.6 ppm inhaled nitric oxide (NO) imposed for 1 h 2.5 h after endotoxin in seven awake sheep, with seven control subjects. The effects of NO on the longitudinal distribution of pulmonary vascular resistance (PVR) before and after endotoxin were specifically addressed in six sheep. Following endotoxin, sheep developed respiratory distress; PaO2, the alveolar-arterial oxygen tension difference (AaPO2) and venous admixture (Q S/Q T) changed significantly, as did the pulmonary artery pressure (Ppa), PVR, and lung lymph flow (Q L). Inhaled NO reduced Ppa and PVR by 50%; Q L decreased from 7.8 +/- 0.34 ml/15 min to 4.7 +/- 0.80 ml/15 min (mean +/- SEM), and lymph protein clearance from 4.9 +/- 0.18 ml/15 min to 3.6 +/- 0.75 ml/15 min. Lymph/plasma protein concentration ratio (L/P) increased from 0.63 +/- 0.016 to 0.72 +/- 0.006, concomitant with the decrease in Q L. The L/P - Q L relationships shifted from left, at baseline, to the right during endotoxemia, as did the permeability surface product (PS) isolines. The rightward shift was significantly less in the NO group. Inhaled NO significantly improved PaO2, AaPO2, and Q S/Q T, reduced the increase in pulmonary microwedge pressure back to baseline and decreased upstream and downstream PVR at 3.0 through 4. 0 h. We conclude that, in sheep, inhaled NO reduces lung fluid filtration by decreasing microvascular pressure and apparently also by declining the enhanced microvascular permeability during the late phase of endotoxemia.

Methylprednisolone attenuates airway and vascular responses induced by reactive oxygen species in isolated, plasma-perfused rat lungs.

The effects of methylprednisolone (MP) on the acute airway and pulmonary vascular responses induced by reactive oxygen species (ROS) were investigated in isolated, plasma-perfused rat lungs. ROS were generated by adding xanthine oxidase and hypoxanthine to the perfusate. MP was administered in 3 different ways: 1. Added to the perfusate (1 mg*ml-1) 5 min prior to xanthine oxidase and hypoxanthine, 2. Given as intraperitoneal injections (40 mg*kg-1) to lung donor rats 12 and 2 hours prior to the experiments, or 3. Combining 1 and 2. The lungs were perfused at constant volume inflow (15 ml*min-1). Pulmonary arterial pressure and transpulmonary pressure were followed for 30 min after addition of xanthine oxidase and hypoxanthine. ROS induced a powerful, acute broncho- and vasoconstriction, which was inhibited by addition of MP to the perfusate. Pretreatment with MP also inhibited the vascular and airway responses. Adding MP to the perfusate of pretreated lungs further reduced the ROS-induced smooth muscle constriction. In conclusion, MP inhibits vasoconstriction and bronchoconstriction induced by ROS in isolated rat lungs.

Nitric oxide and nitroglycerin reversal of pulmonary vasoconstriction induced by alpha-activation during exercise.

We have previously shown in sheep that pulmonary vascular resistance decreases rapidly after the onset of constant exercise, followed by a slower and smaller second vasodilation. The second phase is partly regulated by alpha- and beta-adrenoceptor activation. We examined the effect of inhaled nitric oxide (NO; 40 ppm) and intravenous nitroglycerin on beta-adrenergic blockade-induced pulmonary vasoconstriction during exercise. In paired studies, we exercised eight sheep at a constant rate of 4 miles per hour for 4 min on a treadmill and measured the hemodynamic response during beta-blockade (propranolol, 1 mg i.v.) with and without 40 ppm inhaled NO or continuous infusion of nitroglycerin (3.2-4.0 micrograms.kg-1.min-1). beta-Blockade resulted in a higher pulmonary vascular resistance during steady-state exercise (40-240 s) than in the unblocked state; reduction in pulmonary vascular resistance during the second phase of exercise was smaller with beta-blockade (13-16%) than with control exercise (26-30%). Inhaled NO and nitroglycerin reversed the beta-blockade-related pulmonary vasoconstriction to the levels of control exercise. Inhaled NO and intravenous nitroglycerin also reversed the pulmonary vasoconstriction produced by intravenous phenylephrine at rest. We conclude that exogenous NO, delivered by gas inhalation or via nitroso compounds, opposes and fully reverses alpha-receptor-activated pulmonary vasoconstriction during exercise in sheep.

Extracorporeal membrane oxygenation (ECMO) as lung or heart assist.

Extracorporeal membrane oxygenation (ECMO) may serve as extracorporeal lung assist (ECLA) in patients with acute respiratory failure (ARF) or as extracorporeal heart assist (ECHA) in patients with low output syndrome (LOS) after open heart surgery. From 1988 to 1992 seven patients underwent ECMO in our hospital; four suffered from ARF and three from LOS. Various bypass techniques were employed. Two ARF patients, aged 58 and 18 years, had veno-venous bypass; in the latter, ECMO was reinstituted as a veno-arterial bypass one week after weaning. In a three-year-old boy, the ECMO outflow tubing was primarily connected to the pulmonary artery, and shortly afterwards relocated to the common carotid artery. In a 31-year-old man with ARF, and three LOS patients, a 56-year-old woman, and two men aged 68 and 70 years, ECMO was veno-arterial with direct access to the ascending aorta. A heparin-coated system was used, and all but one patient, who was treated with warfarin, received a daily low dose of heparin, which was withdrawn after from one to nine days. Six patients were weaned off ECMO after 4.5 to 21 days. Three ARF patients recovered completely; the child died. In one LOS patient, ECMO was withdrawn due to a poor general condition. Two others were weaned off ECMO and the intra-aortic balloon pump, and the inotropic support was significantly reduced, but both died of multiple system organ failure. Although no firm conclusions can be drawn from these few case reports, the heparin-coated system used as ECLA appears promising, whereas ECHA seems to imply a poor prognosis in patients who are not candidates for cardiac transplantation.

Acute alveolar hypoxia increases endothelin-1 release but decreases release of calcitonin gene-related peptide in isolated perfused rat lungs.

The release and vascular effects of calcitonin gene-related peptide (CGRP) and endothelin-1 (ET-1) during acute alveolar hypoxia (O2 2%) were examined in isolated blood-perfused rat lungs. In 10 lungs, repeatedly ventilated with hypoxic gas for 5 min, samples from effluent blood were taken during hypoxia and analysed for plasma levels of CGRP-like immunoreactivity (-LI) and ET-1-LI. The plasma levels of ET-1-LI were significantly (p < 0.05) increased in hypoxic lungs (5.5 +/- 0.5 pmol l-1) compared with normoxic controls (3.7 +/- 0.56 pmol l-1). Plasma levels of CGRP-LI were significantly (p < 0.01) lower in hypoxic lungs (43.9 +/- 2.9 pmol l-1) than in normoxic controls (55.5 +/- 4.0 pmol l-1). No significant correlation was seen between perfusate peptide levels and pulmonary artery pressure (Ppa) during ventilation with normoxic or hypoxic gas. Infusion of the CGRP receptor blocker, CGRP, did not influence either the baseline Ppa or the development of the hypoxic pulmonary vasoconstriction response (HPV). In lungs undergoing HPV, 2 nmol l-1 ET-1 added to the perfusate, significantly reduced the hypoxic pressor response by 14 +/- 3% (p < 0.05), while addition of 200 nmol l-1 ET-1 caused no significant changes in HPV. CGRP 2 nmol l-1 caused no significant attenuation of HPV (8.9%), while 200 nmol l-1 CGRP significantly reduced HPV by 16 +/- 5% (p < 0.05). To conclude: acute alveolar hypoxia changes release of CGRP and ET-1 to the perfusate in isolated rat lungs. The results further suggest that CGRP and ET-1 are not involved in the development and regulation of the hypoxic pulmonary vasoconstriction response.