[Quality of results of therapy of acute respiratory failure : changes over a period of two decades]. / Ergebnisqualität der Therapie des akuten Lungenversagens : Veränderungen über einen Zeitraum von 2 Jahrzehnten.

Progress in intensive care (ICU) treatment of acute respiratory distress syndrome (ARDS) over the last 20 years includes the introduction of extracorporeal membrane oxygenation (ECMO) for CO2 removal and the widespread use of evidence-based lung-protective ventilatory strategies. Little is known, however, about whether these changes have resulted in improvements in short-term and long-term outcome of acute respiratory distress syndrome (ARDS) within the two decades after introduction. In a retrospective study 167 long-term survivors of severe ARDS who were transferred to the clinic for anesthesiology of the University of Munich, Campus Großhadern by means of specialized intensive care unit (ICU) transport teams and treated over a period of 20 years (1985-2005) were evaluated to investigate whether significant improvements in outcome as a consequence of the above mentioned progress in ARDS therapy have occurred. The ARDS patient cohort studied was characterized with regard to demographic variables, initial acute physiology and chronic health evaluation (APACHE) II score, duration of ICU treatment, the duration of mechanical ventilation and mortality. Data on long-term outcome were collected in a subcohort (n = 125) of patients who responded to mailed questionnaires and included health-related quality of life (HRQL, SF-36 questionnaire), symptoms of post-traumatic stress disorder (PTSD), traumatic memories from ICU treatment (PTSS-10 instrument) and current state of employment. During the observation period no significant changes regarding patient age (39 ± 16 years, mean ± SD), disease severity on admission to the ICU (APACHE II scores 22 ± 5), duration of ICU treatment (47 ± 39 days) or duration of mechanical ventilation (39 ± 38 days) were found. Overall ICU mortality during the two decades was 37.3 % (range 25.0 %-38.1 %) between 1995 and 2001 and a non-significant increase in values between 36.8 % and 58.3 % during the time interval from 2002 und 2005. The paO2/FIO2-ratio on ICU admittance improved significantly between 1990 and 2000 (69 ± 5 between 1990 and 1994 versus 101 ± 12 between 1995 and 2000, p < 0.01) and remained nearly unchanged thereafter. Long-term outcome was evaluated on average 5.0 ± 3.1 years after discharge from the ICU. During the time period between 1985 and 1994 survivors of ARDS showed significant impairments in all 8 categories of the SF-36 HRQL instrument when compared to an age and sex-matched normal population with maximal differences regarding physical function (z = -1.01), general health perception (z = -1.17) and mental health (z = -1.3). Patients who were treated from 1995 to 2005 were still impaired in 7 out of 8 categories of HRQL but reported significantly better mental health (49.6 ± 16.5 vs. 68.6 ± 17.8, p < 0,01) and better physical function than individuals from the previous decade (49.6 ± 16.5 vs. 73.4 ± 27.5, p = 0,03). The difference of mental health was no longer significant when compared to a healthy age and sex matched control group (p = 0.14) but the difference in physical function still was (z = -0.48, p < 0.01). The incidence of severe post-traumatic stress defined as a PTSS-10 score ≥ 35 was 20.4 % and remained unchanged throughout the 2 decades of observation. The PTSS-10 scores correlated with the number of traumatic memories present (r = 0.43, p < 0.01, n = 125). More than 50 % of long-term survivors were able to return to full time work with no significant changes during the 2 decades of observation. The introduction of new modalities of ARDS treatment were associated with higher paO2/FIO2-ratios on ICU admittance but had no effect on short-term outcomes including duration of ICU therapy, mechanical ventilation or mortality. The ARDS patients are still at risk for post-traumatic stress and persistent impairments in HRQL. Apart from some improvements in HRQL, the outcome of ARDS therapy remained largely unchanged during two decades.

Effects of exercise stress on the endocannabinoid system in humans under field conditions.

The effects of physical exercise stress on the endocannabinoid system in humans are almost unexplored. In this prospective study, we investigated in a crossover design and under field conditions at different altitudes the effects of physical exercise on the endocannabinoid system (ECS) in 12 trained healthy volunteers. For determination of alterations on the ECS three different protocols were analyzed: Protocol A (physical exercise at lower altitude) involved strenuous hiking below 2,100 m, whereas Protocol B (physical exercise by active ascent to high altitude) involved hiking up to 3,196 m, an accommodation at the cottage and a descent the next day. Protocol C (passive ascent) included a helicopter ascent to 3,196 m, an overnight stay at this altitude and a flight back to the base camp the following day. The cumulative hiked altitude in Protocol A and B was comparable (~1,650 m). The blood EC concentrations of anandamide increased significantly in Protocol A/B from baseline (T0) 0.12 ± 0.01/0.16 ± 0.02 (mean ± SEM) to 0.27 ± 0.02/0.42 ± 0.02 after exercise (T1) (p < 0.05). Anandamide levels in Protocol C remained stable at 0.20 ± 0.02. We conclude that the ECS is activated upon strenuous exercise whereas the combination with hypoxic stress further increases its activity. The reduced partial pressure of oxygen at high altitude alone did not affect this system. In summary, physical exercise activates the endocannabinoid system, whereas the combination with high altitude enhances this activation. This discloses new perspectives to adaptation mechanisms to physical exercise.

Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery.

BACKGROUND: The endocannabinoid system (ECS) is an endogenous signalling system which includes the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and specific G-protein-coupled endocannabinoid receptors (CB1 and CB2). Recent studies have described important roles of the peripheral ECS in human atherosclerosis, cardiometabolic disorders, heart failure, and systemic inflammation. We sought to study changes in plasma endocannabinoid concentrations during cardiac surgery (CS) under general anaesthesia with isoflurane/sufentanil, and during cardiopulmonary bypass (CPB). METHODS: We studied 30 patients undergoing CS with CPB. All patients received midazolam and sufentanil for induction and isoflurane and sufentanil for maintenance of general anaesthesia. Blood samples were drawn before and after induction of general anaesthesia, after the beginning of surgery, during and after weaning from CPB, and after admission to intensive care unit (ICU) after surgery. Endocannabinoid measurements were performed by HPLC-tandem mass spectrometry. RESULTS: Induction of general anaesthesia led to a significant decline in plasma AEA concentrations [from mean (sd) 0.39 (0.03) to 0.27 (0.03) ng ml(-1), P<0.01]. CPB induced a pronounced increase in 2-AG concentrations [from 112.5 (163.5) to 321.0 (120.4) ng ml(-1), P<0.01], whereas AEA concentrations remained persistently low until admission to the ICU. 2-AG concentrations returned to preoperative values after surgery. CONCLUSIONS: General anaesthesia with isoflurane significantly reduces plasma AEA concentrations. This could be a consequence of stress reduction after loss of consciousness. The significant increase in 2-AG after initiation of CPB may be part of an inflammatory response. These findings suggest that anaesthesia and surgery have differential effects on the ECS which could have substantial clinical consequences.

A beta-adrenergic antagonist reduces traumatic memories and PTSD symptoms in female but not in male patients after cardiac surgery.

BACKGROUND: Epinephrine enhances emotional memory whereas beta-adrenoceptor antagonists (beta-blockers, BBs) impair it. However, the effects of BB administration on memory are sex dependent. Therefore, we predicted differential effects of epinephrine and the BB metoprolol given to male and female patients after cardiac surgery (CS) on traumatic memories and post-traumatic stress disorder (PTSD) symptoms. METHOD: We performed a prospective observational study and determined the number of standardized traumatic memories (NTRM) and PTSD symptom intensity in cardiac surgical patients at 1 day before surgery, and at 1 week and 6 months after the procedure. PTSD symptoms and NTRM were quantified using validated questionnaires. Metoprolol could be administered any time post-operatively. RESULTS: Baseline NTRM was not significantly different between male (n=95) and female patients (n=33). One week after CS, the NTRM in male patients was significantly higher. Metoprolol had no significant effect in either sex. At 6 months, females with metoprolol (n=18) showed a significantly lower NTRM and significantly lower PTSD symptom scores than females without BBs (n=15, p=0.02). By contrast, the totally administered dosage of epinephrine correlated with NTRM in males (r=0.33, p<0.01) but not in females (r=0.21, p=0.29). CONCLUSIONS: beta-Adrenergic stimulation with epinephrine enhances memory for adverse experiences in males but not in females whereas beta-blockade selectively reduces memory for post-operative adverse events and PTSD symptoms in females.

Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report.

The complex regional pain syndrome (CRPS) is a disabling neuropathic pain condition that may develop following injuries of the extremities. The pathogenesis of this syndrome is not clear; however, it includes complex interactions between the nervous and the immune system resulting in chronic inflammation, pain and trophic changes. This interaction may be mediated by chronic stress which is thought to activate the endogenous cannabinoid (endocannabinoid) system (ECS). We conducted an open, prospective, comparative clinical study to determine plasma level of the endocannabinoid anandamide by high-performance liquid chromatography and a tandem mass spectrometry system in 10 patients with CRPS type I versus 10 age- and sex-matched healthy controls. As compared to healthy controls, CRPS patients showed significantly higher plasma concentrations of anandamide. These results indicate that the peripheral ECS is activated in CRPS. Further studies are warranted to evaluate the role of the ECS in the limitation of inflammation and pain.

Risk and outcome analysis of renal replacement therapies in patients after cardiac surgery with pre-operatively normal renal function.

Peri-operative acute renal failure requiring renal replacement therapy is common (5-30%) after cardiac surgery and associated with a mortality of approximately 50%. Pre-operative renal impairment seems to be the most important risk factor for frank postoperative renal failure. To help evaluate the risk factors, we conducted a prospective observational trial of 1574 consecutive patients with normal pre-operative renal function (creatinine < 110 micromol.l(-1)). Renal failure was defined as the need for renal replacement therapy. After univariate analysis of previously described risk factors, those who differed significantly between patients with or without renal failure were enrolled into a multivariate classification and regression tree (CART) statistical model that identifies the most 'predictive' risk factors and creates a ranked list of these. In patients with pre-operatively normal renal function, a serum level of lactate > 1.1 mmol.l(-1) in the first 24 h after the operation was the strongest predictor for the development of renal failure.

Pathogenesis of SIV pneumonia: selective replication of viral genotypes in the lung.

Lymphocytic interstitial pneumonia of HIV-infected individuals and SIV pneumonia of macaques are both characterized by diffuse infiltration of the lungs with lymphocytes, plasma cells, and macrophages. This study was undertaken to determine whether there are specific, macrophage-tropic genotypes that selectively replicate in the lung of macaques with SIV pneumonia, as in SIV encephalitis. Using a rapid, reproducible SIV/macaque model of AIDS, 11 pig-tailed macaques were intravenously inoculated with an immunosuppressive viral strain, SIV/DeltaB670, and a macrophage-tropic molecule clone, SIV/17E-Fr, and euthanized at 3 months postinoculation. All 11 macaques had severe (6 macaques) or moderate (5 macaques) pneumonia. To identify the viral genotypes that were replicating in the lung parenchyma, bronchoalveolar lavage (BAL) cells, and peripheral blood mononuclear cells (PBMC) of each macaque, RNA was isolated and the SIV env V1 region was amplified, cloned, and sequenced. Lung homogenates and BAL cells contained a more limited repertoire of viral genotypes than PBMC. SIV/17E-Fr was the major genotype in the lungs of 5 macaques and in BAL cells of 6 macaques. The remainder of the macaques had SIV/17E-Fr and the macrophage-tropic strains of SIV/DeltaB670 clones 2 and 12. In contrast, SIV/17E-Fr was the predominant strain in the PBMC of only 3 of 11 macaques. The viral strain that predominated in PBMC was rarely the strain that predominated in the lungs (only 3 of 11 macaques). The severity of pulmonary lesions did not correlate with the levels of viral RNA in lung homogenates or in plasma. However, when only SIV/17E-Fr was expressed in the lung, the viral load in the lung was significantly higher (P = 0.016) than when SIV/DeltaB670 was present alone or in combination with SIV/17E-Fr. These data suggest that SIV pneumonia is associated with selective replication of specific macrophage-tropic genotypes in the lung and that SIV/17E-Fr has a selective advantage for replication in the lung.

Identification and comparison of eleven rhesus macaque chemokine receptors.

Both simian and human immunodeficiency viruses (SIV and HIV) utilize chemokine receptors, with or without CD4, as portals for entry into susceptible cells. In this report, we present the cloning and comparison of 11 rhesus macaque chemokine receptors and receptor-like proteins (CCR1, CCR2b, CCR3, CCR5, CCR8, CXCR4, STRL33, GPR1, GPR15, APJ, and CRAM-A/B), the human counterparts of which have been previously shown to be utilized by SIV for entry.

Samarium-153 for intravascular irradiation therapy with liquid-filled balloons to prevent restenosis: acute and long-term results in a hypercholesterolemic rabbit restenosis model.

BACKGROUND: It has been shown that irradiation with either beta and gamma sources inhibit neointimal formation. Samarium-153 ((153)Sm) is an isotope with 0.8 MeV, subdivided in three different beta energies and 103 keV of gamma energy. This compound has been tested and used in humans for palliation of pain from bone metastases. The aim of the present study was to evaluate the feasibility and efficacy of brachytherapy with (153)Sm-filled balloon to inhibit neointimal formation in rabbits after balloon overstretch injury. METHODS: Nineteen rabbits underwent balloon injury in their iliac arteries. In 12 animals (control), oversized balloons filled with saline solution were inflated up to 5 atm for a period of 5 min. In 7 rabbits, the same procedure was performed but using balloons filled with (153)Sm. In all cases, both iliac arteries were treated. The prescribed radiation dose was 15 Gy at 1 mm depth. After 30 days, the animals were sacrificed and their arterial segments were analyzed. Radiation exposure at the animal chest to the table and at a distance of 1 m from the table was measured. RESULTS: Histopathologic analysis showed a striking reduction in the amount of neointima in the irradiated arteries compared with control vessels (0.36+/-0.21 vs. 1.07+/-0.56 mm(2), P<.01). The dose delivered to the animal chest was 21.5 mR/h, whereas only 1.9 mR/h was measured at the table and virtually no radiation could be detected at a distance of 1 m from the table. CONCLUSIONS: Brachytherapy with (153)Sm was feasible with minimal personnel exposure radiation and effectively inhibited neointimal formation in this experimental model. These results warrant further experimental and clinical investigations.

Molecular and biological characterization of a neurovirulent molecular clone of simian immunodeficiency virus.

To identify the molecular determinants of neurovirulence, we constructed an infectious simian immunodeficiency virus (SIV) molecular clone, SIV/17E-Fr, that contained the 3' end of a neurovirulent strain of SIV, SIV/17E-Br, derived by in vivo virus passage. SIV/17E-Fr is macrophage tropic in vitro and neurovirulent in macaques. In contrast, a molecular clone, SIV/17E-Cl, that contains the SU and a portion of the TM sequences of SIV/17E-Br is macrophage tropic but not neurovirulent. To identify the amino acids that accounted for the replication differences between SIV/17E-Fr and SIV/17E-Cl in primary macaque cells in vitro, additional infectious molecular clones were constructed. Analysis of these recombinant viruses revealed that changes in the TM portion of the envelope protein were required for the highest level of replication in primary macaque macrophages and brain cells derived from the microvessel endothelium. In addition, a full-length Nef protein is necessary for optimum virus replication in both of these cell types. Finally, viruses expressing a full-length Nef protein in conjunction with the changes in the TM had the highest specific infectivity in a sMAGI assay. Thus, changes in the TM and nef genes between SIV/17E-Cl and SIV/17E-Fr account for replication differences in vitro and correlate with replication in the central nervous system in vivo.

Pathogenesis of simian immunodeficiency virus encephalitis: viral determinants of neurovirulence.

To examine the relationship between macrophage tropism and neurovirulence, macaques were inoculated with two recombinant hybrid viruses derived from the parent viruses SIVmac239, a lymphocyte-tropic, non-neurovirulent clone, and SIV/17E-Br, a macrophage-tropic, neurovirulent virus strain. The first recombinant, SIV/17E-Cl, contained the portion of the env gene that encodes the surface glycoprotein and a short segment of the transmembrane glycoprotein of SIV/17E-Br in the backbone of SIVmac239. Unlike SIVmac239, SIV/17E-Cl replicated productively in macrophages, demonstrating that sequences in the surface portion of env determine macrophage tropism. None of five macaques inoculated with SIV/17E-Cl developed simian immunodeficiency virus (SIV) encephalitis. The second recombinant, SIV/17E-Fr, which contained the entire env and nef genes and the 3' long terminal repeat of SIV/17E-Br in the SIVmac239 backbone, was also macrophage tropic. Six of nine macaques inoculated with SIV/17E-Fr developed SIV encephalitis ranging from mild to moderate in severity, indicating a significant (P = 0.031) difference in the neurovirulence of the two recombinants. In both groups of macaques, CD4+ cell counts declined gradually during infection and there was no significant difference in the rate of the decline between the two groups of macaques. This study demonstrated that macrophage tropism alone is not sufficient for the development of neurological disease. In addition, it showed that while sequences in the surface portion of the envelope gene determine macrophage tropism, additional sequences derived from the transmembrane portion of envelope and/or nef confer neurovirulence.

Pathogenesis of ovine lentiviral encephalitis: derivation of a neurovirulent strain by in vivo passage.

The lentiviruses of sheep replicate almost exclusively in macrophages and cause chronic interstitial pneumonia, arthritis, and mastitis, but only rarely encephalitis. This study was undertaken to determine whether a non-neurovirulent field strain of ovine lentivirus isolated from joint fluid that replicated productively in lung and joint macrophages could be adapted to enter and replicate in the brain and cause encephalitis. The field isolate was passed seven times sequentially by intracerebral inoculation of sheep. The neuroadapted strain of virus caused severe encephalitis typical of visna in four of four sheep inoculated intracerebrally. The virus replicated to high titers in the brains of these animals and in cultured microglia. The inflammatory response in the brain was characterized by intense infiltrates of macrophages and CD8+ and CD4+ T cells. Many of the perivascular macrophages demonstrated TNF-alpha expression and there was upregulation of MHC Class II antigen expression on both inflammatory cells and endothelium. Inoculation of this neuroadapted virus into the bone marrow of three animals resulted in persistent infection and cell-associated viremia, but not encephalitis. Virus was not detected in brains from these animals, indicating that the virus was not neuroinvasive. These data suggest that neuroinvasiveness and neurovirulence are separate pathogenic determinants, both of which are required for the development of encephalitis during natural infection.

Cross-protective immune responses induced in rhesus macaques by immunization with attenuated macrophage-tropic simian immunodeficiency virus.

The simian immunodeficiency virus (SIV) macaque model of AIDS has provided a valuable system with which to investigate vaccine approaches for protection against human immunodeficiency virus type 1 (HIV-1) infection. In particular, the ability of macaques persistently infected with attenuated infectious molecular clones of SIV to resist challenge with the pathogenic parental swarm has conclusively demonstrated that protective immunity can be achieved by immunization prior to exposure. The breadth of these protective responses and the immunological correlates of protection, however, have not been identified. In addition, vaccine studies have mainly employed lymphocyte-tropic strains of HIV-1 and SIV. Recent studies have implicated macrophage-tropic strains in the transmission of HIV-1 and have suggested that these virus strains should be examined in vaccine strategies. Macrophage-tropic viruses may confer additional advantages in the induction of protective immunity by replication in antigen-presenting cells. In this study, the immune response of rhesus macaques inoculated with an attenuated macrophage-tropic recombinant of SIVmac239 (SIV/17E-Cl) was evaluated with respect to protective immunity by heterologous challenge at various times after infection. Vigorous type-specific neutralizing-antibody responses restricted to SIV/17E-Cl were evident by 2 weeks postinfection. By 7 months, however, cross-reactive neutralizing antibodies emerged which neutralized not only SIV/17E-Cl but also the heterologous primary isolate SIV/DeltaB670. Challenge of SIV/17E-Cl-infected monkeys with SIV/DeltaB670 at various times postinfection demonstrated that protective responses were associated with the appearance of cross-reactive neutralizing antibodies. Furthermore, passive transfer of sera from SIV/17E-Cl-infected animals passively protected two of four naive recipients.

Development of transgenic sheep that express the visna virus envelope gene.

The ovine lentiviruses cause encephalitis, pneumonia, and arthritis in sheep worldwide. Visna virus is a prototype of this family and the pathogenesis and molecular biology of the virus has been well characterized. The envelope proteins of visna virus are responsible for binding of virus to host cells and for causing cell fusion. The surface glycoprotein also elicits cellular and humoral immune responses to the virus, the former being thought to be responsible for eliminating infected cells as well as causing inflammatory lesions. In this study, transgenic sheep were constructed that expressed the envelope genes of visna virus under the control of the visna LTR to investigate the role of the env gene in the pathogenesis of lentiviral disease in its natural host. Three transgenic lambs were identified that contain the env transgene and express the envelope glycoproteins. These transgenic animals have remained healthy and expression of the viral gene has had no obvious deleterious effect. Expression of the visna envelope protein was demonstrated by cell fusion mediated by the envelope gene as well as by immunoprecipitation of the envelope proteins with monoclonal antibodies and immunofluorescence analyses of Env protein in cells. The target cell for visna virus replication in infected animals is the monocyte/macrophage. In natural infection, the level of viral gene expression in these cells increases with cell maturation. In the transgenic sheep, monocytes did not express the envelope glycoproteins until they differentiated into macrophages in vitro. Expression of the env mRNA in macrophages was quantitated by an RNase protection assay. In addition to expression in macrophages, the transgene was expressed by fibroblasts isolated from skin of the transgenic sheep. Expression of both the Env and Rev proteins was detected by immunoprecipitation and immunofluorescence. Two of the three lambs responded immunologically to the expression of the transgene by producing binding antibodies to the envelope glycoproteins. Thus, these transgenic sheep provide a model to study whether a lentivirus glycoprotein will prevent infection or modulate disease in its natural host after virus challenge.

Analysis of envelope changes acquired by SIVmac239 during neuroadaption in rhesus macaques.

Nucleotide sequence analyses of the env genes of two neurotropic variants of SIVmac239 were performed to determine whether molecular changes in these genes could be correlated with neurotropism. Biological characterization of virus from the infectious molecular clone of SIVmac239 had shown that it is highly lymphocyte-tropic and poorly macrophage-tropic. This virus failed to replicate in the brain after intracerebral inoculation, but passage of this virus in macaques resulted in development of viral variants that had acquired cell tropism for macrophages and were neurovirulent (D. P. Sharma, M. C. Zink, H. Anderson, R. J. Adams, J. E. Clements, S. V. Joag, and O. Narayan, J. Virol., 66, 3550-3556, 1992). The neurotropic virus SIVmac239/R71 was obtained from the brain of a monkey after the third in vivo passage of SIVmac239. Inoculation of this virus into another macaque leads to CNS disease and the isolation of another neurotropic virus SIVmac239/17E. The viral env sequences obtained by polymerase chain reaction amplification directly from DNA obtained from the brain of R71 and 17E macaques had a limited number of changes dispersed throughout the env gene when compared to the parental virus, SIVmac239. The most important finding was that there was a common set of nucleotide changes in the env gene of both R71 and 17E. This suggested that viruses containing these changes had a selective growth advantage in the brain and were the predominant species present in the central nervous system of macaques R71 and 17E. Analysis of individual clones containing the R71 env gene revealed that different env genes were present, but all had the changes that were conserved in both R71 and 17E but not present in the original lymphocyte-tropic parental virus, SIVmac239. Construction of an infectious recombinant virus containing the tat, rev, and env genes from 17E and the remainder of the genome from the parental virus SIVmac239 resulted in a virus that had the macrophage-tropism of 17E virus isolated from brain. This demonstrates that the env gene of 17E confers the cellular tropism of the virus on the parental virus, SIVmac239.

Lamellar body depletion in dogs undergoing pulmonary artery occlusion.

We have investigated the relationship between pulmonary artery occlusion (PAO) and the surfactant system of the lung by studying the ultrastructural responses of type II alveolar pneumocytes to PAO of 4-12 h duration in 16 mongrel dogs. In six of these animals, the occluded lung was allowed to reperfuse for 6 h before killing and in four animals subjected to PAO of 4 h duration, the occluded lung was ventilated with 5% CO2 balance air. PAO by itself resulted in a dramatic 80% reduction in the volumetric density of lamellar bodies (LB) in the type II cells. This resulted predominantly from a decrese in volume of the individual LB. Although reperfusion was associated with an increase in LB volume density toward normal, 6 h of reperfusion was insufficient to re-establish normal type II cellular morphology. Ventilation of the occluded lung with 5% CO2 prevented LB depletion indicating that alveolar CO2 tension may affect the release and/or synthesis of LB in type II pneumocytes.

Effects of isoproterenol on distribution of perfusion in embolized dog lungs.

In 19 mechanically venilated, anesthetized dogs, autologous venous thrombi were formed in the inferior vena cava and subsequently released. Serial perfusion lung scintigrams revealed the postembolic distribution of pulmonary blood flow before, during, and after the infusion of isoproterenol at 2.2 micrograms/min. Isoproterenol failed to restore perfusion to embolically occluded regions. When reperfusion occurred it was attributable to clot resolution. Gas exchange and hemodynamic measurements obtained in seven thromboembolized animals showed no scan evidence of reperfusion during the isoproterenol infusion. After embolization, cardiac output increased from 1.7 to 2.6 liter/min (p less than 0.05), and PvO2 from 38.0 to 45.3 mm Hg (p less than 0.05). Shunt fraction remained unchanged. The postembolic infusion of isoproterenol was associated with a further increase in cardiac output to 3.6 liter/min (p less than 0.01), an elevation in PvO2 to 50.7 mm Hg, along with a decrease in pulmonary vascular resistance from the postembolic mean of 448 to 246 dynes.sec.cm-5 (p less than 0.05). Perfusion defects following acute pulmonary thromboembolization are not altered by the infusion of the potent pulmonary vasodilator, isoproterenol. Infusion of this drug following thromboembolization may have potential therapeutic benefit by reducing pulmonary vascular resistance, increasing cardiac output, and elevating the mixed-venous oxygen tension.