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Large-volume therapeutic phlebotomy is the mainstay of hemochromatosis treatment and offers an opportunity to investigate the hemodynamic changes during acute hypovolemia. An otherwise healthy 64-year-old male with hemochromatosis participated. On nine separate visits, 1000 mL therapeutic phlebotomy was performed. On one occasion, pre- and post-phlebotomy orthostatic challenge with 27° reverse Trendelenburg position was administered. Mean arterial pressure, heart rate, and stroke volume were measured continuously during the procedures. The patient's tolerance to the interventions was continuously evaluated. The procedures were well tolerated by the patient. Mean arterial pressure was maintained during hemorrhage and following phlebotomy in both supine and reverse Trendelenburg positions, primarily through an increase in heart rate and systemic vascular resistance. The present study found that 1000 mL therapeutic phlebotomy in a patient with hemochromatosis may be acceptably and safely used to model hemorrhage. The approach demonstrates high clinical applicability and ethically robustness in comparison with volunteer studies., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Acute poisoning caused by inhalation of carbon monoxide and other toxic substances is the primary cause of death in fires and may occur without signs of external injury. Life-threatening symptoms may arise immediately, as in cyanide poisoning, or over a longer period, as in carbon monoxide poisoning. Severe inhalation injury may also occur independently of systemic poisoning and should always be suspected in patients with soot on their face and in the respiratory tract, or hoarseness and wheezing.

Background: Acute fire smoke inhalation injury involves inflammatory mediators whose roles are poorly understood. We carried out a prospective observational study of fire smoke victims to identify clinical and biochemical markers that may predict pulmonary dysfunction and investigated possible correlations between dysfunction and cytokines in bronchoalveolar lavage (BAL) fluid and blood., Methods: Forty patients with respiratory and/or neurological symptoms following acute fire smoke inhalation had pulmonary function tests and blood gas analyses performed on admission, at discharge, and after 3 months. Cytokines were measured using BioPlex/XMap technology., Results: On admission, 30 (75%) patients had dyspnea. Patients presenting with bronchial wheezing (n = 14) had significantly lower PEF (201 l/min, 82-360) than non-wheezing patients (406 l/min, 100-683) (n = 16, P = 0.03). Bronchial wheezing predicted need for ICU treatment with OR = 93.3 at 95% CI (P < 0.001) and was associated with gas exchange impairment, with mean p a O 2 /FiO 2 ratio 34.4 (11.8-49.8) kPa on admission and 21.3 (8.3-44.5) kPa 48 h later. Blood HbCO also predicted ICU treatment, with OR = 1.58 at 95% CI (P < 0.001). Serum CRP, IL-6, IL-8, and MCP-1 were significantly higher in wheezing patients after 12-24 h compared with non-wheezing patients and study controls. Cytokine levels were still elevated after 3 months. BAL fluid had significantly higher levels of IL-8, MCP-1, IL-1β, and G-CSF compared with healthy controls., Conclusion: In victims of fire smoke inhalation, pulmonary wheezing predicts inflammation, pulmonary dysfunction, respiratory failure, and need for intensive care., (© 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Introduction: Removal of pulmonary secretions in mechanically ventilated patients usually requires suction with closed catheter systems or flexible bronchoscopes. Manual ventilation is occasionally performed during such procedures if clinicians suspect inadequate ventilation. Suctioning can also be performed with the ventilator entirely disconnected from the endotracheal tube (ETT). The aim of this study was to investigate if these two procedures generate negative airway pressures, which may contribute to atelectasis., Methods: The effects of device insertion and suctioning in ETTs were examined in a mechanical lung model with a pressure transducer inserted distal to ETTs of 9 mm, 8 mm and 7 mm internal diameter (ID). A 16 Fr bronchoscope and 12, 14 and 16 Fr suction catheters were used at two different vacuum levels during manual ventilation and with the ETTs disconnected., Results: During manual ventilation with ETTs of 9 mm, 8 mm and 7 mm ID, and bronchoscopic suctioning at moderate suction level, peak pressure (P PEAK ) dropped from 23, 22 and 24.5 cm H 2 O to 16, 16 and 15 cm H 2 O, respectively. Maximum suction reduced P PEAK to 20, 17 and 11 cm H 2 O, respectively, and the end-expiratory pressure fell from 5, 5.5 and 4.5 cm H 2 O to -2, -6 and -17 cm H 2 O. Suctioning through disconnected ETTs (open suction procedure) gave negative model airway pressures throughout the duration of the procedures., Conclusions: Manual ventilation and open suction procedures induce negative end-expiratory pressure during endotracheal suctioning, which may have clinical implications in patients who need high PEEP (positive end-expiratory pressure)., Competing Interests: Competing interests: None declared.

Background: The insertion of suction devices through endotracheal tubes (ETTs) increases airway resistance and the subsequent suctioning may reduce airway pressures and facilitate atelectasis. The aim of this study was to investigate how airway pressures and tidal volumes change when different combinations of suction equipment and ETT sizes are used, and to what extent unfavorable effects can be ameliorated by choice of ventilator settings., Methods: A mechanical ventilator was connected to a lung model by ETTs of 9 mm, 8 mm or 7 mm internal diameter (ID) with a pressure transducer inserted distal to the ETT. The effects of suction procedures with bronchoscope and closed catheter systems were investigated during pressure controlled ventilation (PCV) and volume controlled ventilation (VCV). In each mode, the effects of changes in inspiration:expiration (I:E) ratio, trigger sensitivity and suction pressure were examined., Results: The variables that contributed most to negative model airway pressures and loss of tidal volume during suctioning were (in descending order); 1) Small-size ETTs (7-8 mm ID) combined with large diameter suction devices (14-16 Fr); 2) inverse I:E ratio ventilation (in VCV); 3) negative ventilator trigger sensitivity; and 4) strong suction pressure. The pressure changes observed distal to the ETTs were not identical to those detected by the ventilator., Conclusions: Negative model airway pressure was induced by suctioning through small-size ETTs. The most extreme pressure and volume changes were ameliorated when conventional ventilator settings were used, such as PCV mode with short inspiration time and a trigger function sensitive to flow changes.

Background: Early intramedullary nailing (IMN) of long bone fractures in severely injured patients has been evaluated as beneficial, but has also been associated with increased inflammation, multi organ failure (MOF) and morbidity. This study was initiated to evaluate the impact of primary femoral IMN on coagulation-, fibrinolysis-, inflammatory- and cardiopulmonary responses in polytraumatized patients., Methods: Twelve adult polytraumatized patients with femoral shaft fractures were included. Serial blood samples were collected to evaluate coagulation-, fibrinolytic-, and cytokine activation in arterial blood. A flow-directed pulmonary artery (PA) catheter was inserted prior to IMN. Cardiopulmonary function parameters were recorded peri- and postoperatively. The clinical course of the patients and complications were monitored and recorded daily., Results: Mean Injury Severity Score (ISS) was 31 ± 2.6. No procedure-related effect of the primary IMN on coagulation- and fibrinolysis activation was evident. Tumor necrosis factor alpha (TNF-α) increased significantly from 6 hours post procedure to peak levels on the third postoperative day. Interleukin-6 (IL-6) increased from the first to the third postoperative day. Interleukin-10 (IL-10) peaked on the first postoperative day. A procedure-related transient hemodynamic response was observed on indexed pulmonary vascular resistance (PVRI) two hours post procedure. 11/12 patients developed systemic inflammatory response syndrome (SIRS), 7/12 pneumonia, 3/12 acute lung injury (ALI), 3/12 adult respiratory distress syndrome (ARDS), 3/12 sepsis, 0/12 wound infection., Conclusion: In the polytraumatized patients with femoral shaft fractures operated with primary IMN we observed a substantial response related to the initial trauma. We could not demonstrate any major additional IMN-related impact on the inflammatory responses or on the cardiopulmonary function parameters. These results have to be interpreted carefully due to the relatively few patients included., Trial Registration: ClinicalTrials.gov: NCT00981877.

Introduction: Operations in trauma patients represent a second insult and the extent of the surgical procedures influences the magnitude of the inflammatory response. Our hypothesis was that a reamer-irrigator-aspirator (RIA) system would cause a lesser inflammatory response than traditional reaming (TR)., Materials and Methods: Coagulation, fibrinolysis and cytokine responses were studied in Norwegian landrace pigs during and after intramedullary nailing (IMN) with two different reaming systems using ELISA and chromogenic peptide substrate assays. The TR (n=8) and the RIA (n=7) reaming systems were compared to a control group (n=7). The animals were followed for 72 h. Arterial, mixed venous and femoral vein blood were withdrawn simultaneously peroperatively and until 2 h after the nail was inserted for demonstration of local, pulmonary and systemic activation of the cascade systems. At 6 h, 24 h, 48 h and 72 h postoperatively arterial blood samples were withdrawn., Results: Significantly procedure-related increased levels were found for thrombin-antithrombin (TAT) and tissue plasminogen activator (t-PA) in the TR group and TAT in the RIA group. The local and the pulmonary activation of coagulation and fibrinolysis were more pronounced in the TR than in the RIA group, the difference reached significance for plasminogen activator inhibitor-1 (PAI-1) (arterial blood). The cytokine response, mainly represented by IL-6 increase, was more pronounced in the TR than the RIA group, and was significant for IL-6 in femoral vein blood. The arterial levels of IL-6 exceeded the mixed venous levels indicating an additional pulmonary activation of IL-6. Two animals in the TR group, who died of pulmonary embolism (PE) prior to planned study end point, had a more pronounced response compared to the rest of the TR group., Conclusion: A procedure-related coagulation and fibrinolytic response was demonstrated in both reaming groups, with more pronounced response in the TR than in the RIA group. Elevated levels of cytokines were demonstrated related to reaming and nailing, with significantly higher IL-6 levels in the TR than in the RIA group., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background and Objectives: In fresh blood, tissue hypoxia increases microcirculatory acidosis, which enhances erythrocyte O(2) unloading and increases the amount of available O(2). Storage of erythrocytes increases the HbO(2) affinity and reduces O(2) unloading. We examined the development of the affinity change during a period of 5 weeks of storage by present blood bank standards, and investigated to what extent acidosis offsets the affinity change., Materials and Methods: Blood from volunteer donors was processed and stored as erythrocyte concentrates (EC). At 2-5 day intervals, EC were drawn from the bags and suspended in plasma and crystalloids to an Hb ≈ 10 g/dL. The suspensions were adjusted to give a pH of 7.40, 7.10, 6.80 or 6.30 and equilibrated with different gas mixtures to SO(2) 0, 25, 50, 75 and 100%. Measurements of the PO(2)/SO(2) pairs at each pH were used to calculate the position of the HbO(2) curve and its P(50) value., Results: A significant leftward shift in the HbO(2) curve was established after 1 week of storage; after 2.5 weeks only minor further changes were observed. Acidification right-shifted the HbO(2) curve, after 2.5 weeks of storage the curve at pH 7.10 was similar to that for fresh blood at pH 7.40. Calculations of extractable O(2) showed that the left-shifted HbO(2) curve of stored EC could be advantageous at a low arterial PO(2)., Conclusions: The rightward shift of the HbO(2) curve due to acidosis is well maintained in stored erythrocytes, a moderate pH decrease offsets the storage-induced increased HbO(2) affinity.

Bronchoscope insertion through an endotracheal tube increases airflow resistance. Constant tidal volume (T(v)) ventilation can be maintained by augmenting the inspiratory pressure, but increased outflow resistance cannot be compensated for. Air trapping distal to the tube may lead to higher airway pressures in volume controlled (VC) mode and reduced T(v) in pressure controlled (PC) mode. Increased end-expiratory airway pressures will not be detected by ventilator pressure sensors. In mechanically ventilated and sedated patients, the effects of bronchoscope insertion on intrabronchial pressures were recorded by a pressure transducer distal to the endoscope. In half of the patients, the ventilator was set in VC mode prior to bronchoscope insertion, keeping the previous T(v) constant. In the other half the ventilator was set in PC mode, keeping previous peak inspiratory pressures constant. All patients underwent sequences of VC-PC-VC or PC-VC-PC ventilation with two-minute intervals between mode-changes. In VC mode, bronchoscope insertion increased peak airway pressure from 29 cmH2O (22 to 43) to 41 cmH2O (36 to 49) (P = 0.012) and end-expiratory airway pressure from 11 cmH2O (6 to 18) to 22.5 cmH2O (15 to 30) (P = 0.012). There were no significant changes in T(v), P(a)CO2 or P(a)O2 after two minutes. In PC mode, peak airway pressure was unchanged and end-expiratory airway pressure increased from 9.5 cmH2O (7 to 10) to 10.5 cmH2O (9 to 18) (P = 0.017). Median T(v) was reduced from 673 ml (585 to 800) to 450 ml (408 to 560) (P = 0.012); median P(a)CO2 increased from 5.7 kPa to 6.5 kPa (P = 0.012). Using distal measurement, positive end-expiratory airway pressure increased markedly in VC mode but only marginally in PC mode after bronchoscope insertion.

Introduction: Intramedullary orthopaedic procedures may increase the intramedullary pressure (IMP) and thereby cause intravasation of bone marrow contents. In recent studies by the authors the reamer-irrigator-aspirator (RIA) has been demonstrated to reduce IMP and coagulation-, fibrinolysis- and cytokine responses, but did not prove any significant difference in cardiopulmonary function parameters or numbers of emboli when compared to a traditional reaming (TR) system. The correlations between IMP increase, regardless type of reamer, and inflammatory- and coagulation responses, pulmonary embolization, and cardiopulmonary alterations have, however, not previously been analyzed in this material. Our hypothesis was that a lower IMP would result in reduced occurrence of pulmonary embolization, reduced inflammatory-and coagulation responses, as well as reduced cardiopulmonary alterations., Materials and Methods: Twenty-eight young Norwegian landrace pigs were exposed to femoral intramedullary reaming, with either the TR (n = 10) or the RIA (n = 10) system, or used as controls (n = 8). IMP was recorded during reaming and nailing. Serial blood samples for demonstration of coagulation-, fibrinolysis-, and cytokine activation were withdrawn peroperatively and until 72 hours post nail insertion. Circulatory and pulmonary effects were monitored peroperatively and until two hours postoperatively. The animals were sacrificed 72 hours post nail insertion and lung tissue biopsies were harvested and examined for lung emboli., Results and Conclusions: A strong correlation between increased IMP and increased coagulation-and cytokine responses was found. The number of emboli was not significantly correlated to IMP, but was strongly correlated to changes in the coagulation- and cytokine responses. No clinical relevant correlations were observed between increased IMP or numbers of lung emboli and changes in hemodynamic- or pulmonary function parameters. A correlation between coagulation activation and cytokine activation was observed. This study confirms the connection between increased IMP, increased coagulation activation and the magnitude of pulmonary emboli in a model evaluating the effects of intramedullary reaming of intact pig femora. In this model, the lowering of IMP during reaming, as obtained with RIA, reduced the magnitude of and the effects of bone marrow extravasation., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Intramedullary reaming and nailing increases intramedullary pressure. This may cause intravasation of bone marrow contents, leading to bone marrow embolization and altered cardiopulmonary function. Possible beneficial effects of attenuation of the intramedullary pressure increase by the use of a reamer-irrigator-aspirator (RIA) system were studied with the hypothesis that the RIA technique would cause lower numbers of pulmonary embolisms (PEs) and lesser cardiopulmonary affection than traditional reaming (TR)., Material and Methods: Intramedullary reaming and nailing was performed in intact femora of young Norwegian landrace pigs using either a standard intramedullary nailing technique (n = 8) or a RIA technique (n = 7). The hemodynamic and pulmonary effects were investigated during the reaming and nailing procedure and for 2 hours postoperatively. The animals were killed after 72 hours, and the lung/carcass weight ratio and the numbers of PEs were investigated., Results and Conclusion: The pattern of the procedure-related hemodynamic and pulmonary effects did not differ significantly between the RIA and the TR groups. The RIA group had lower numbers (ns) of embolisms per square centimeter lung area than the TR group. After reaming with the TR device, two animals died of PEs, the first postoperative day. The patients with femoral shaft fracture and additional cardiopulmonary injury or preexisting reduced cardiopulmonary function, however, need special attention, and the use of RIA may, in these cases, represent a better operative alternative with a lesser operative burden.

Background: Acute respiratory failure has an annual incidence of 20-75/100,000 and is the most common reason for admittance to an intensive care unit. A common cause is acute inflammatory changes in lung tissue. The article reviews clinical, etiological, pathophysiological and therapeutic aspects of acute respiratory failure, with an emphasis on failure secondary to proinflammatory processes., Material and Methods: This paper is not based on a comprehensive literature review, but on the clinical and scientific experience of the author, literature from a private archive and a limited Medline search., Results: Acute respiratory failure can be precipitated by agents and/or trauma that damage the lungs directly. Serious infections and tissue damage located in other parts of the body can also cause respiratory failure. In these cases, the blood transports activated blood cells and proinflammatory agents to the lungs where they induce secondary tissue inflammation. The resulting respiratory failure is often serious. Mortality is in the range 30-50 %., Interpretation: No specific treatment is available for secondary tissue inflammation; it usually resolves when the precipitating injuries or disease processes are healed. Positive pressure ventilation can prevent serious hypoxemia from causing additional damage to affected tissue. With modern treatment in an intensive care unit only 10-15 % of the deaths are caused by the respiratory failure per se, most deaths are caused by failure of several additional organs (multiorgan failure).

Background: Previous studies have indicated that alterations in blood glucose and/or insulin levels modify the inflammatory response. The purpose of this study was to elucidate whether increased levels of glucose and/or insulin influence the activation pattern of blood leucocytes and their production of cytokines in vitro., Methods: Venous blood was obtained from eight healthy male volunteers after an overnight fast. Glucose and/or insulin were added to aliquots of whole blood to increase the blood glucose concentration by 5 or 20 mmol/l and/or the insulin concentration by 6 or 30 nmol/l, respectively, before stimulation with E. coli lipopolysaccharide (LPS) at concentrations of 10, 100 or 1000 ng/ml. The samples were subsequently incubated at 37 degrees C for 6 h before cytokine measurements. After centrifugation the levels of interleukins (IL)-1beta, IL-6, IL-8, IL-10 and tumour necrosis factor (TNF)-alpha were measured in plasma using enzyme-linked immuno-sorbent assays. The results were compared with cytokine levels in parallel control samples to which only identical amounts of LPS were added., Results: The LPS-stimulated production of IL-1beta was significantly reduced by on average 26% in samples to which glucose 20 mmol/l was added; addition of insulin and/or glucose 5 mmol/l had no apparent effect on the IL-1beta production at any LPS concentration. The levels of IL-6, IL-8, IL-10 and TNF-alpha were not manifestly altered by addition of glucose and/or insulin at any LPS concentration., Conclusion: A substantial increase in blood glucose concentration changed the IL-1beta production, but not the production of other cytokines, in response to LPS stimulation.

In a 20-year-old woman with known asthma, anaphylactic bronchospasm induced a grave combined respiratory and metabolic acidosis (pH(a) 6.66) with marked hypoxaemia (S(a)O(2) 45%). The beneficial effects of the rightward shift of the oxyhaemoglobin dissociation curve on tissue O(2) unloading at such pH was more than offset by the negative effect on S(a)O(2) at the reduced P(a)O(2) (7.0 kPa) found in this patient. This case illustrates the detrimental effect of grave acidosis on arterial blood oxygen content at subnormal P(a)O(2) values, the beneficial effect of a supranormal P(a)O(2) on the S(a)O(2) in such patients, and the rapid remission rate of life-threatening acidosis and blood lactate after adequate ventilation and tissue oxygenation were secured. The initial treatment of the patient and clinically relevant considerations are discussed.

We describe an unusual case of acute myocardial infarction (AMI) and cardiogenic shock in a 25-year-old woman. After coronary revascularization, a thyrotoxic storm developed and the patient's cardiac failure changed into a hyperdynamic circulation without obvious changes in the patient's vital signs. This report will focus on three issues: (1) the benefit of advanced hemodynamic monitoring in circulatory unstable patients, (2) the confounding effects of untreated hyperthyroidism on the circulation, and (3) previous cancer treatment as a cause of AMI in young persons.

Increased nitrogen monoxide (NO) concentrations change leukocyte function under a multitude of experimental conditions. NO inhalation is an experimental treatment for lung failure and exposes leukocytes to increased NO concentrations during passage through the lungs. To investigate whether short-term NO inhalation induces lasting changes in the function of circulating human leukocytes, venous blood samples were drawn from eight healthy male volunteers before and at the end of a 35-min period of breathing 40 ppm NO in 30% O(2). The leukocytes in the samples were subsequently analyzed for NO-induced changes in expression of cell surface molecules, generation of reactive oxygen species (ROS), and cytokine production by flow cytometry and ELISA techniques. The results were (1) NO inhalation changed neither the baseline nor the Escherichia coli lipopolysaccharide (LPS)-induced expression of the cell adhesion molecules CD11a, CD11b, CD11c, and CD62L (l-selectin) on neutrophilic granulocytes (PMN) or monocytes (Mo). The expression of CD14 and HLA-DR was also unchanged. (2) The generation of ROS in response to activation with phorbol myristate acetate increased in PMN after NO inhalation; an increase in Mo did not reach significance. (3) Baseline and LPS-stimulated production of IL-1beta decreased after NO inhalation, while the LPS-stimulated production of TNF-alpha increased. No changes in IL-6 production were detected., (Copyright 2000 Academic Press.)

To gather further information about the effects on blood platelet activation of in vivo exposure to nitric oxide (NO), platelet reactivity was studied in blood from healthy, non-smoking male volunteers before and after 30 min inhalation of 40 ppm NO. Whole blood was stimulated in vitro with adenosine diphosphate or thrombin receptor activation peptide (TRAP-6). In an ex vivo perfusion model, non-anticoagulated blood was exposed to immobilised collagen at arterial blood flow conditions (2600 s(-1)). Blood samples from both the in vitro and ex vivo experiments were stained with fluorochrome-labelled Annexin-V and antibodies against CD42a, CD45, CD49b, CD61, CD62P and fibrinogen, and analysed with a three-colour flow cytometry technique. NO inhalation reduced the platelet activation response to adenosine diphosphate (ADP) stimulation by decreasing platelet-platelet aggregation, alpha-granule release and platelet-leukocyte conjugate formation. TRAP-stimulated platelet activation, collagen-induced platelet activation and thrombus growth was unaffected by NO inhalation. We therefore suggest an ADP receptor inhibitor mode of action of inhaled NO, selective on the newly suggested G protein- and phospholipase C-coupled P2Y1 receptor. Our results demonstrate that blood platelet activation in healthy subjects is modulated by inhalation of NO in therapeutically relevant doses, although the clinical impact of our findings remains unclear.

Objectives: To determine the oxyhemoglobin dissociation curve in blood with pH of approximately 6.3 due to metabolic and superimposed respiratory acidosis, and to evaluate the oxygen delivery capacity of the blood under these circumstances., Design: In vitro study., Setting: A blood gas laboratory in a university institute for respiratory physiology., Subjects: Heparinized normal human blood., Interventions: The oxyhemoglobin dissociation curve was determined by measuring PO2, pH, PCO2, and hemoglobin oxygen saturation at 37 degrees C in mixtures of blood from two reservoirs, both prepared by titration with lactic acid to a pH of 6.3 during tonometry with gases containing 4.2% CO2 and high and low oxygen percentages, respectively. For determination of the effect of additional increases in PCO2, the reservoir blood thus produced was prepared by further tonometry with gases containing 12.8% CO2 and the same oxygen percentages., Measurements and Main Results: With the same degree of lactic acidosis (blood lactate concentration of 52 mmol/L), the position of the oxyhemoglobin dissociation curve was the same for blood with PCO2 of 30 torr (4 kPa) and pH of 6.295 and for blood with PCO2 of 90 torr (12 kPa) and pH of 6.165. During tonometry with a gas with PCO2 of 30 torr (4 kPa) and PO2 of 20 torr (2.7 kPa) and addition of increasing amounts of lactic acid, leading to a stepwise change in pH from 6.7 to 6.0, hemoglobin oxygen saturation decreased with decreasing pH from 6.7 to 6.4, but remained the same at a pH of between 6.4 and 6.0. The measured rightward shift of the oxyhemoglobin dissociation curve at such a low pH was clearly less pronounced than that calculated using commonly applied equations, in particular, at the lowest pH. The beneficial effects of the rightward shift of the oxyhemoglobin dissociation curve on the estimates of extractable oxygen at a given venous PO2 decrease with decreasing pH, and disappear rapidly when the Pao2 is reduced below normal., Conclusions: The acidemia-induced rightward shift of the oxyhemoglobin dissociation curve does not increase further at a pH < 6.4, and is, at such extreme acidemia, less pronounced than calculated by the commonly used equations. To obtain optimal tissue oxygenation in patients with severe circulatory failure and extreme metabolic acidosis, Pao2 should be > 250 torr (> 33.3 kPa).

The general symptoms of upper airway obstruction are described, as well as the specific symptoms expected to be found in various conditions that cause such obstruction. An algorithm, intended primarily for general practitioners and other physicians who seldom confront such problems, describes the procedures for establishing an unobstructed airway in different situations. It also outlines the interventions necessary to ensure adequate oxygenation and ventilation when such procedures fail. Special emphasis is placed on the use of emergency tracheotomy, or oxygenation by means of cricothyreoid membrane puncture, as an alternative to emergency intubation by unskilled physicians.

E. coli LPS was infused (1 microgram/kg to 5 mg/kg over 30 min) to spontaneously breathing rabbits, and their arterial blood pressure (ABP), blood leukocyte count and blood gases were observed for 2.5-3.5 h. Pulmonary vascular and airway function were subsequently evaluated in vitro by comparing weight changes, fluid filtration rates, pulmonary vascular resistance (PVR) and airway pressures in their isolated, blood-perfused lungs with those in lungs from untreated rabbits. Lung preparations from both groups of animals were then exposed to autologous zymosan-activated plasma (ZAP) or n-formyl-methionyl-leucyl-phenylalanine (FMLP) and perfused for 2 more hours. LPS addition to isolated rabbit leukocytes increased cell aggregation; cell chemiluminescence after activation with FMLP was also enhanced. Infusion of 1-5 mg/kg LPS decreased the count of all types of leukocytes and caused a metabolic acidosis (BE < -8 mmol), but no decrease in ABP. PAO2-Pao2 increased by about 2.0 kPa. No vascular permeability increase was detected in the lungs of these animals during subsequent in vitro perfusion. Addition of ZAP or FMLP during perfusion markedly increased the PVR in lungs from LPS animals, but did not induce major microvascular leakage. No significant differences in edema between lungs from LPS-treated and control animals were found by microscopy.

Unlabelled: Generation of reactive oxygen intermediates by activated polymorphonuclear neutrophil granulocytes plays an important role in development of microcirculatory injury. The effect of the beta 2-adrenergic receptor agonists (beta 2-agonists) isoprenaline and terbutaline on the chemiluminescence or oxygen consumption of human granulocytes in response to activation with n-formyl-methionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate (PMA) was examined. The beta 2-agonist effect on activated cell aggregation and volume change was examined as well. As E. Coli lipopolysaccharide and FMLP may prime granulocytes for enhanced generation of reactive oxygen intermediates in response to other activators, the effect of beta 2-agonists on the priming effect of these agents was also investigated., Results: 1) Optimal concentrations of beta 2-agonists decrease the human granulocyte generation of reactive oxygen intermediates in response to activation with FMLP by 40-60%, without affecting the response to PMA. 2) beta 2-Agonists modify the priming effect of FMLP on activation with PMA, but do not interfere with the priming effect of E. Coli lipopolysaccharide on activation with FMLP. 3) Isoprenaline have different effects on generation of reactive oxygen intermediates and cell aggregation in FMLP-activated granulocytes. 4) High concentrations of isoprenaline and terbutaline have contrasting non-specific effects on the chemiluminescence, but not on the oxygen consumption, of activated granulocytes.

Polymorphonuclear neutrophil granulocytes (PMN) may contribute to the lung injury induced by nonpulmonary infections with gram-negative bacteria. The direct effect of E. coli lipopolysaccharide (LPS) on isolated human PMN or mixed leukocytes (ML), as well as the priming effect of preincubating cells with LPS, was examined in assays measuring the maximal rate of oxygen consumption (OC), cell chemiluminescence (CHML), and aggregation (AGG). LPS, 1-10 micrograms/ml, caused no acute response in PMN or ML suspended in Fisher's-HEPES medium with BSA (FHA), but increased both CHML and AGG of cells suspended in autologous plasma. Preincubation in FHA with LPS, 1 microgram/ml, for more than 15 min increased the OC of PMN activated with zymosan-activated plasma (ZAP) or n-formyl-methionyl-leu-cyl-phenylalanine (FMLP) by more than 100%. A similar increase in the CHML of such cells was seen after FMLP, but not after ZAP. ZAP, however, primed the CHML response of the cells to subsequent activation with FMLP more than did preincubation with LPS. Previous exposure to both agents had an additive effect. Preincubation of PMN with LPS decreased the time interval from addition of phorbol myristate acetate (PMA) to peak OC response, but less so than previous activation with FMLP. Neither agent affected the maximal rate of OC after addition of PMA. LPS also increased the PMN aggregation induced by ZAP and FMLP, but not by PMA. Cells preincubated with LPS, 0.01 microgram/ml, increased their CHML in response to FMLP if suspended in Krebs-Ringer balanced salt solution, but not if suspended in FHA. Such preincubation had no effect on OC of similarly activated cells in any of the media.

In man, about half the intravascular granulocytes are not freely circulating, but temporarily sequestered ('marginated'), so that they cannot be retrieved by bleeding. Where and how the sequestration occurs is not settled and is the subject of the present report. Isolated autologous rabbit granulocytes, labelled with two different 99mTc methods, were reinjected and followed with external scintigraphy. Intraarterial as well as intravenous injection led to rapid accumulation of radioactivity over the lungs. This finding was corroborated and extended by similar experiments, where the labelled cells had firstly been passed through an intermediary rabbit host to remove altered cells, i.e. cells damaged, 'primed' (pre-activated), or activated. In the final autologous host about two thirds of the label rapidly localized to the lungs and liver, and a few per cent to the spleen (which is very small in the rabbit). Even though more than half of the intermediary rabbit's calculated blood volume was removed, the blood sample contained only a few per cent of the rabbit's radioactivity; consequently, many of the labelled leucocytes had marginated during the bleeding. The proportional distribution of radioactivity over lungs, spleen, kidneys, and the rest of the intermediary animal was not markedly changed by this exsanguination, but there was a 4-20% decrease over the liver. Taken together, our findings indicate that normal granulocytes marginate in lungs, liver, and spleen--apparently explicable by the effects of cell size, vessel diameter, cell stiffness (visco-elastic properties) and size of the arterio-venous hydrostatic pressure difference. The liver and spleen seemed to play additional roles, since radioactivity over these organs decreased much slower than expected from reported blood half-times of intact and slightly damaged rabbit granulocytes. This led to a suggestion that macrophages exposed to blood normally phagocytose apoptotically dying granulocytes.

In 16 patients undergoing major vascular surgery, study was made of variations in white blood cell populations, cortisol concentration, pulmonary vascular resistance and intrapulmonary shunting. Six hours post-operatively the number of circulating lymphocytes and the relative proportion of T-lymphocytes were significantly reduced. During and after operation the relative proportion of T-suppressor cells rose from 20.5 to 44.8% of all lymphocytes. There was corresponding fall in T-helper cells. The proportion of lymphocytes with surface-bound Ig (B-lymphocytes) did not alter during surgery. No correlation was found between the number of circulating white blood cells and the haemodynamic parameters. Intrapulmonary shunting, which was increased already before operation, remained unchanged during and after surgery. Cortisol levels increased significantly and peaked 6 hours postoperatively. Significant correlations were found between cortisol levels and reduction in total number of lymphocytes and in percentage of T-lymphocytes. The study thus demonstrated significant changes in white blood cell populations following major vascular surgery and indicated a correlation between lymphocyte concentration and cortisol level.

The immune system, defending our organism against infections, can also cause disease. Anaesthetics may impair immunological defence by modifying the number and functions of immunocompetent cells, including the polymorphonuclear leucocytes (PMN). We have studied the effects of thiopentone, ketamine and morphine on some stimulated PMN responses that presumably reflect their microbicidal activity, i.e. oxygen consumption, aggregation, and volume increase. Stimulators were N-formyl-methionyl-leucyl-phenylalanine (FMLP, affecting cells via specific membrane receptors) and phorbol-myristate-acetate (PMA, activating protein kinase C, thereby short-cutting intramembraneous steps in normal signal transmission, and presumably provoking near-maximal cell responses with the dose applied). Preincubation of PMN with low doses of thiopentone enhanced oxygen consumption in unstimulated cells as well as in response to FMLP, but not PMA. FMLP-stimulated volume and aggregation responses were not detectably affected. The highest concentration of thiopentone depressed both oxygen uptake and volume/aggregation responses in FMLP-stimulated PMN. The amount of oxygen consumed after PMA stimulation was not affected, but both the onset of increased consumption and the maximal response were delayed. The two other drugs investigated, ketamine and morphine, did not appreciably affect oxygen consumption or aggregation by PMN: neither the baseline values nor those obtained after FMLP or PMA stimulation.

Increased numbers of polymorphonuclear granulocytes (PMN) in the airways, as measured by PMN content in bronchial lavage fluid (P less than 0.01), were found 3 h postoperatively in ten patients undergoing surgery for lumbar aortic aneurysms. An increase in plasma levels of the complement split product C3dg from 6 (0-19) AU/ml preoperatively to 20 (13-50) AU/ml 3 h after surgery (P less than 0.01), indicates an activation of the complement cascade. These changes were not accompanied by increased elastase activity in the bronchial lavage fluid or by major changes in pulmonary blood gas exchange or vascular resistance, indicating that massive PMN activation, analogous to that proposed in adult respiratory distress syndrome (ARDS) had not taken place. In conclusion, complement system activation and migration of PMN into the airways, as seen in connection with major vascular surgery, does not seem to contribute to ARDS-type pulmonary dysfunction.

Interstitial fluid pressure was measured in nine isolated perfused rabbit lungs with the servonull micropipette method. Bevelled glass micropipettes, with tip diameter 2-6 micrometers (o.d.) were inserted 2-6 mm into the left lung. At alveolar pressures of 3 to 5 cm H2O we found mean interstitial fluid pressures of 1.0 (SD 1.0) and 1.6 (SD 1.0) cm H2O relative to pleural pressure in the upper (n = 19) and lower (n = 21) lobes respectively. The vertical distance between the measuring sites in the upper and lower lobes was about 3 cm. Net filtration caused by elevated left atrial pressure caused practically no change in interstitial fluid pressure. Increased alveolar pressure either increased or decreased interstitial fluid pressure. The measured pressures probably represent interstitial fluid pressure in alveolar junctions or in the interstitium around small pulmonary arteries or veins. We conclude that interstitial fluid pressure in these sites is between alveolar and pleural pressure, and that it is only moderately affected by changes in alveolar pressure. The interstitial compliance appears to be high and there seem to be little or no vertical gradients in interstitial fluid pressure within the lung.

The effects of complement activation on pulmonary vascular permeability are disputed. In rabbit lungs perfused with autologous blood, zymosan activated plasma (ZAP) induced a moderate increase in pulmonary vascular resistance (PVR), but did not detectably change the vascular permeability within 2 h. The stronger neutrophil granulocyte (PMN) activator, phorbol myristate acetate (PMA), usually gave larger PVR increases and also increased pulmonary vascular permeability. Lungs from neutropenic animals, similarly perfused and given PMA, showed unchanged PVR reactions but had no apparent increase in vascular permeability. Lungs perfused with cell-free medium and given PMA displayed modest PVR increases, and no measurable permeability change. The lung preparatory procedure itself markedly influenced leukocyte circulation. Exsanguination of lung donors decreased the concentration of circulating PMN significantly, and they virtually disappeared from the perfusate within minutes after start of lung perfusion. PMN-mediated effects must therefore have been caused by cells already sequestered in the lungs. We conclude that ZAP does not induce an increased pulmonary vascular permeability in isolated, perfused rabbit lungs, in contrast to PMA. The permeability effects of PMA appear to be PMN dependent.

The ability of two polymorphonuclear granulocyte (PMN) activators, Zymosan activated plasma (ZAP) and Phorbol myristate acetate (PMA), to induce an adult respiratory distress syndrome (ARDS) type lung injury was compared in awake and anaesthetized rabbits. The preparatory procedure itself decreased the concentrations of circulating PMN and lymphocytes in anaesthetized animals. ZAP acutely lowered the number of circulating leukocytes due to a fall in PMN only, this was followed by a rebound. Both effects were more marked in awake than in anaesthetized animals. PMA caused a virtual disappearance of both PMN and lymphocytes from the blood. There was no rebound, and no difference between anaesthetized and awake animals. The activators caused equal increases in pulmonary arterial pressure (about 0.67 kPa) initially. This was followed by a return to baseline in ZAP animals, but a further increase in those given PMA. Increased airway pressure (0.4 kPa) was seen only in the PMA group; PaO2 decreased only in awake rabbits given PMA. Both activators, as well as the preparatory procedure itself, caused PMN accumulations in the alveolar septa, septal thickening, and modest perivascular edema with intact tissue architecture. PMA caused the most marked changes. Wet/dry lung weight ratios were only moderately increased. In conclusion, ZAP and PMA had different effects on circulating leukocytes, but gave nearly the same degree of PMN accumulation in the lungs. The modest edema indicated some increased microvascular leakage, but a fully developed ARDS-type lung injury did not occur.

The amount of reactive oxygen intermediates (ROI) generated by activated polymorphonuclear neutrophils (PMN), as well as the closeness of contact between PMN and vessel wall, may determine whether PMN activators will induce the adult respiratory distress syndrome. We examined the ROI-generating and aggregating effects of zymosan activated plasma (ZAP), phorbol myristate acetate (PMA) and n-formyl-methionyl-leucyl-phenylalanine (FMLP), on isolated human and rabbit PMN. PMA, after a short lag phase, induced a large and long-lasting increase in ROI generation. The initial peak response was higher and more rapid in human than in rabbit cells. The reaction to FMLP occurred almost instantaneously, but was much weaker than that to PMA, and ROI generation returned to near baseline in less than 10 min. No species difference was seen. ZAP caused an FMLP-like ROI response in human cells, whereas no response was observed in rabbit PMN. PMN aggregation was induced by all three activators, most markedly by PMA. No species difference was detected for PMA; FMLP gave a stronger aggregation of rabbit than of human PMN, however, while the opposite was true for ZAP. In conclusion, ZAP was a potent stimulus for PMN aggregation, but had modest (or no) effects on the production of ROI. Marked differences between human and rabbit PMN responses were observed.