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  • 1.
    Baker, Tim
    et al.
    Karolinska Univ Hosp, Dept Anaesthesia Intens Care & Surg Serv, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Div Anaesthesiol & Intens Care Med, Stockholm, Sweden.;Karolinska Inst, Dept Publ Hlth Sci, Global Hlth Hlth Syst & Policy, Stockholm, Sweden..
    Blixt, Jonas
    Karolinska Univ Hosp, Dept Anaesthesia Intens Care & Surg Serv, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Div Anaesthesiol & Intens Care Med, Stockholm, Sweden..
    Lugazia, Edwin
    Muhimbili Univ Hlth & Allied Sci, Dept Anaesthesia & Intens Care, Dar Es Salaam, Tanzania..
    Schell, Carl Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Sormland Cty Council, Nykoping Hosp, Dept Internal Med, Nykoping, Sweden..
    Mulungu, Moses
    Muhimbili Natl Hosp, Dept Anaesthesia & Intens Care, Dar Es Salaam, Tanzania..
    Milton, Anna
    Karolinska Univ Hosp, Dept Anaesthesia Intens Care & Surg Serv, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Div Anaesthesiol & Intens Care Med, Stockholm, Sweden..
    Castegren, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Eriksen, Jaran
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Dept Lab Med, Div Clin Pharmacol, Stockholm, Sweden..
    Konrad, David
    Karolinska Univ Hosp, Dept Anaesthesia Intens Care & Surg Serv, S-17176 Stockholm, Sweden.;Karolinska Inst, Dept Physiol & Pharmacol, Div Anaesthesiol & Intens Care Med, Stockholm, Sweden..
    Single Deranged Physiologic Parameters Are Associated With Mortality in a Low-Income Country2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 10, p. 2171-2179Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether deranged physiologic parameters at admission to an ICU in Tanzania are associated with in-hospital mortality and compare single deranged physiologic parameters to a more complex scoring system. Design: Prospective, observational cohort study of patient notes and admission records. Data were collected on vital signs at admission to the ICU, patient characteristics, and outcomes. Cutoffs for deranged physiologic parameters were defined a priori and their association with in-hospital mortality was analyzed using multivariable logistic regression. Setting: ICU at Muhimbili National Hospital, Dar es Salaam, Tanzania. Patients: All adults admitted to the ICU in a 15-month period. Measurements and Main Results: Two hundred sixty-nine patients were included: 54% female, median age 35 years. In-hospital mortality was 50%. At admission, 69% of patients had one or more deranged physiologic parameter. Sixty-four percent of the patients with a deranged physiologic parameter died in hospital compared with 18% without (p < 0.001). The presence of a deranged physiologic parameter was associated with mortality (adjusted odds ratio, 4.64; 95% CI, 1.95-11.09). Mortality increased with increasing number of deranged physiologic parameters (odds ratio per deranged physiologic parameter, 2.24 [1.53-3.26]). Every individual deranged physiologic parameter was associated with mortality with unadjusted odds ratios between 1.92 and 16.16. A National Early Warning Score of greater than or equal to 7 had an association with mortality (odds ratio, 2.51 [1.23-5.14]). Conclusion: Single deranged physiologic parameters at admission are associated with mortality in a critically ill population in a low-income country. As a measure of illness severity, single deranged physiologic parameters are as useful as a compound scoring system in this setting and could be termed danger signs. Danger signs may be suitable for the basis of routines to identify and treat critically ill patients.

  • 2.
    Borges, Joao Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L. V.
    Bergquist, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lucchetta, Luca
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Maripuu, Enn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Amato, Marcelo B. P.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lung Inflammation Persists After 27 Hours of Protective Acute Respiratory Distress Syndrome Network Strategy and Is Concentrated in the Nondependent Lung2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 5, p. E123-E132Article in journal (Refereed)
    Abstract [en]

    Objective: PET with [F-18]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which during lung inflammation mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. We aimed at studying the location and evolution of inflammation by PET imaging, relating it to morphology (CT), during the first 27 hours of application of protective-ventilation strategy as suggested by the Acute Respiratory Distress Syndrome Network, in a porcine experimental model of acute respiratory distress syndrome. Design: Prospective laboratory investigation. Setting: University animal research laboratory. Subjects: Ten piglets submitted to an experimental model of acute respiratory distress syndrome. Interventions: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. During 27 hours of controlled mechanical ventilation according to Acute Respiratory Distress Syndrome Network strategy, the animals were studied with dynamic PET imaging of [F-18]fluoro-2-deoxy-D-glucose at two occasions with 24-hour interval between them. Measurements and Main Results: [F-18]fluoro-2-deoxy-D-glucose uptake rate was computed for the total lung, four horizontal regions from top to bottom (nondependent to dependent regions) and for voxels grouped by similar density using standard Hounsfield units classification. The global lung uptake was elevated at 3 and 27 hours, suggesting persisting inflammation. In both PET acquisitions, nondependent regions presented the highest uptake (p = 0.002 and p = 0.006). Furthermore, from 3 to 27 hours, there was a change in the distribution of regional uptake (p = 0.003), with more pronounced concentration of inflammation in nondependent regions. Additionally, the poorly aerated tissue presented the largest uptake concentration after 27 hours. Conclusions: Protective Acute Respiratory Distress Syndrome Network strategy did not attenuate global pulmonary inflammation during the first 27 hours after severe lung insult. The strategy led to a concentration of inflammatory activity in the upper lung regions and in the poorly aerated lung regions. The present findings suggest that the poorly aerated lung tissue is an important target of the perpetuation of the inflammatory process occurring during ventilation according to the Acute Respiratory Distress Syndrome Network strategy.

  • 3.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Costa, Eduardo L V
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Widström, Charles
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Medical Physics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Amato, Marcelo
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Early inflammation mainly affects normally and poorly aerated lung in experimental ventilator-induced lung injury2014In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 42, no 4, p. e279-e287Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The common denominator in most forms of ventilator-induced lung injury is an intense inflammatory response mediated by neutrophils. PET with [F]fluoro-2-deoxy-D-glucose can be used to image cellular metabolism, which, during lung inflammatory processes, mainly reflects neutrophil activity, allowing the study of regional lung inflammation in vivo. The aim of this study was to assess the location and magnitude of lung inflammation using PET imaging of [F]fluoro-2-deoxy-D-glucose in a porcine experimental model of early acute respiratory distress syndrome.

    DESIGN: Prospective laboratory investigation.

    SETTING: A university animal research laboratory.

    SUBJECTS: Seven piglets submitted to experimental ventilator-induced lung injury and five healthy controls.

    INTERVENTIONS: Lung injury was induced by lung lavages and 210 minutes of injurious mechanical ventilation using low positive end-expiratory pressure and high inspiratory pressures. All animals were subsequently studied with dynamic PET imaging of [F]fluoro-2-deoxy-D-glucose. CT scans were acquired at end expiration and end inspiration.

    MEASUREMENTS AND MAIN RESULTS: [F]fluoro-2-deoxy-D-glucose uptake rate was computed for the whole lung, four isogravitational regions, and regions grouping voxels with similar density. Global and intermediate gravitational zones [F]fluoro-2-deoxy-D-glucose uptakes were higher in ventilator-induced lung injury piglets compared with controls animals. Uptake of normally and poorly aerated regions was also higher in ventilator-induced lung injury piglets compared with control piglets, whereas regions suffering tidal recruitment or tidal hyperinflation had [F]fluoro-2-deoxy-D-glucose uptakes similar to controls.

    CONCLUSIONS: The present findings suggest that normally and poorly aerated regions-corresponding to intermediate gravitational zones-are the primary targets of the inflammatory process accompanying early experimental ventilator-induced lung injury. This may be attributed to the small volume of the aerated lung, which receives most of ventilation.

  • 4.
    Borges, João Batista
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Senturk, Mert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Ahlgren, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Open Lung in Lateral Decubitus With Differential Selective Positive End-Expiratory Pressure in an Experimental Model of Early Acute Respiratory Distress Syndrome2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 10, p. e404-e411Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: After lung recruitment, lateral decubitus and differential lung ventilation may enable the titration and application of optimum-selective positive end-expiratory pressure values for the dependent and nondependent lungs. We aimed at compare the effects of optimum-selective positive end-expiratory pressure with optimum global positive end-expiratory pressure on regional collapse and aeration distribution in an experimental model of acute respiratory distress syndrome.

    DESIGN: Prospective laboratory investigation.

    SETTING: University animal research laboratory.

    SUBJECTS: Seven piglets.

    INTERVENTIONS: A one-hit injury acute respiratory distress syndrome model was established by repeated lung lavages. After replacing the tracheal tube by a double-lumen one, we initiated lateral decubitus and differential ventilation. After maximum-recruitment maneuver, decremental positive end-expiratory pressure titration was performed. The positive end-expiratory pressure corresponding to maximum dynamic compliance was defined globally (optimum global positive end-expiratory pressure) and for each individual lung (optimum-selective positive end-expiratory pressure). After new maximum-recruitment maneuver, two steps were performed in randomized order (15 min each): ventilation applying the optimum global positive end-expiratory pressure and the optimum-selective positive end-expiratory pressure. CT scans were acquired at end expiration and end inspiration.

    MEASUREMENTS AND MAIN RESULTS: Aeration homogeneity was evaluated as a nondependent/dependent ratio (percent of total gas content in upper lung/percent of total gas content in lower lung) and tidal recruitment as the difference in the percent mass of nonaerated tissue between expiration and inspiration. At the end of the 15-minute optimum-selective positive end-expiratory pressure, compared with the optimum global positive end-expiratory pressure, resulted in 1) decrease in the percent mass of collapse in the lower lung at expiratory CT (19% ± 15% vs 4% ± 5%; p = 0.03); 2) decrease in the nondependent/dependent ratio between the optimum global positive end-expiratory pressure-expiratory-CT and optimum-selective positive end-expiratory pressure-expiratory-CT (3.7 ± 1.2 vs 0.8 ± 0.5; p = 0.01); 3) decrease in the nondependent/dependent ratio between the optimum global positive end-expiratory pressure-inspiratory-CT and optimum-selective positive end-expiratory pressure-inspiratory-CT (2.8 ± 1.1 vs 0.6 ± 0.3; p = 0.01); and 4) less tidal recruitment (p = 0.049).

    CONCLUSIONS: After maximum lung recruitment, lateral decubitus and differential lung ventilation enabled the titration of optimum-selective positive end-expiratory pressure values for the dependent and the nondependent lungs, made possible the application of an optimized regional open lung approach, promoted better aeration distribution, and minimized lung tissue inhomogeneities.

  • 5.
    Broche, Ludovic
    et al.
    European Synchrotron Radiat Facil, Biomed Beamline ID17, Grenoble, France.;Univ Picardie Jules Verne, INSERM, Dept Pediat Pulmonol, U1105, Amiens, France.;Amiens Univ Hosp, Amiens, France..
    Perchiazzi, Gaetano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Porra, Liisa
    Univ Helsinki, Dept Phys, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Tannoia, Angela
    Univ Bari, Dept Emergency & Organ Transplant, Bari, Italy..
    Pellegrini, Mariangela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Derosa, Savino
    Univ Bari, Dept Emergency & Organ Transplant, Bari, Italy..
    Sindaco, Alessandra
    Univ Bari, Dept Emergency & Organ Transplant, Bari, Italy..
    Borges, João Batista
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Degrugilliers, Loic
    Univ Picardie Jules Verne, INSERM, Dept Pediat Pulmonol, U1105, Amiens, France.;Amiens Univ Hosp, Amiens, France..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Wexler, Anthony S.
    Univ Calif Davis, Dept Mech Engn, Davis, CA 95616 USA.;Univ Calif Davis, Environm Qual Lab, Davis, CA 95616 USA..
    Bravin, Alberto
    European Synchrotron Radiat Facil, Biomed Beamline ID17, Grenoble, France..
    Verbanck, Sylvia
    Univ Hosp UZ Brussel, Div Resp, Brussels, Belgium..
    Smith, Bradford J.
    Univ Vermont, Dept Med, Burlington, VT USA. European Synchrotron Radiat Facil, Grenoble, France..
    Bates, Jason H. T.
    Univ Vermont, Dept Med, Burlington, VT USA. European Synchrotron Radiat Facil, Grenoble, France..
    Bayat, Sam
    Univ Picardie Jules Verne, INSERM, Dept Pediat Pulmonol, U1105, Amiens, France.;Amiens Univ Hosp, Amiens, France..
    Dynamic Mechanical Interactions Between Neighboring Airspaces Determine Cyclic Opening and Closure in Injured Lung2017In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 4, p. 687-694Article in journal (Refereed)
    Abstract [en]

    Objectives: Positive pressure ventilation exposes the lung to mechanical stresses that can exacerbate injury. The exact mechanism of this pathologic process remains elusive. The goal of this study was to describe recruitment/derecruitment at acinar length scales over short-time frames and test the hypothesis that mechanical interdependence between neighboring lung units determines the spatial and temporal distributions of recruitment/derecruitment, using a computational model. Design: Experimental animal study. Setting: International synchrotron radiation laboratory. Subjects: Four anesthetized rabbits, ventilated in pressure controlled mode. Interventions: The lung was consecutively imaged at - 1.5-minute intervals using phase-contrast synchrotron imaging, at positive end expiratory pressures of 12, 9, 6, 3, and 0 cm H2O before and after lavage and mechanical ventilation induced injury. The extent and spatial distribution of recruitment/derecruitment was analyzed by subtracting subsequent images. In a realistic lung structure, we implemented a mechanistic model in which each unit has individual pressures and speeds of opening and closing. Derecruited and recruited lung fractions (F-derecruaed, F-recruited) were computed based on the comparison of the aerated volumes at successive time points. Measurements and Main Results: Alternative recruitment/derecruitment occurred in neighboring alveoli over short-time scales in all tested positive end-expiratory pressure levels and despite stable pressure controlled mode. The computational model reproduced this behavior only when parenchymal interdependence between neighboring acini was accounted for. Simulations closely mimicked the experimental magnitude of F-derecruited and F-recruited when mechanical interdependence was included, while its exclusion gave F-recruited values of zero at positive end -expiratory pressure greater than or equal to 3 cm H2O. Conclusions: These findings give further insight into the microscopic behavior of the injured lung and provide a means of testing protective-ventilation strategies to prevent recruitment/derecruitment and subsequent lung damage.

  • 6.
    Carlsson, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 3, p. 1031-e4Article in journal (Refereed)
    Abstract [en]

    Objective:

    To study whether a reduction of the endotoxin load, once a generalized inflammatory state has been established, reduces the inflammatory response and endotoxin-induced effects on circulation, hypoperfusion, and organ dysfunction.

    Design:

    Prospective parallel-grouped placebo-controlled randomized interventional experimental study.

    Setting:

    University research unit.

    Subjects:

    Healthy pigs.

    Interventions:

    The animals were subjected to a continuous endotoxin infusion rate of either 4.0 or 0.063 µg endotoxin × kg-1 × h-1 for 1, 2, or 6 hours. The 1- and 2-hour infusion groups represented the applied therapy by a reduction of the endotoxin load of 5/6 and 2/3, respectively.

    Measurements and Main Results:

    During a 6-hour experiment, laboratory and physiologic parameters were recorded hourly in 26 anesthetized and mechanically ventilated pigs. Primary end point was to detect differences in tumor necrosis factor-[alpha] (TNF-[alpha]) concentration during the last 3 hours of the experiment. Despite the early reduction of the endotoxin load, no effect on TNF-[alpha] concentration was observed. Similarly, in circulatory parameters, such as mean arterial pressure and oxygen delivery, and in platelet count and renal function, no effects were noted. However, there was some improvement in pulmonary compliance and function as determined by Pao2, Paco2, and pH. These changes were associated with slight improvements in leukocyte response and capillary leakage.

    Conclusions:

    Termination of the endotoxin infusion represents an incontestable model of endotoxin concentration reduction. Endotoxin elimination strategies applied at the TNF-[alpha] peak or later will have very little or no effect on TNF-[alpha]–mediated toxicity. Nevertheless, there was an effect on the leukocyte response that was associated with an improvement in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

  • 7.
    Da, Jiping
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Chen, Luni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Nitric oxied up-regulates the glucocorticoid receptor and blunts the inflammatory reaction in porcine endotoxin sepsis2007In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 35, no 1, p. 26-32Article in journal (Refereed)
    Abstract [en]

    Objectives: Nitric oxide inhibits the expression of many genes involved in inflammatory diseases. Glucocorticoids inhibit similar transcription factors. We hypothesized that there may be an interaction between nitric oxide and glucocorticoids, with the potential to enhance the anti-inflammatory effect when administered simultaneously. Design: Prospective, randomized, controlled study. Setting: Animal research laboratory. Subjects: A total of 45 anesthetized and mechanically ventilated pigs. Interventions: Lung and systemic injury was induced by intravenous infusion of endotoxin (lipopolysaccharide) for 6 hrs. After 2.5 hrs, one group received 3.5 mg/kg hydrocortisone, another group inhaled nitric oxide (30 ppm), and still another group received both steroid and nitric oxide. Control groups of healthy and endotoxin-exposed piglets were also studied. Measurements and Main Results: Central hemodynamics and gas exchange were measured. Detection of the glucocorticoid receptor and inflammatory markers in lung, liver, and kidney tissue were made by immunohistochemistry, and morphology was studied with light microscopy. Endotoxin infusion markedly reduced glucocorticoid receptor expression in lung, liver, and kidney and up-regulated activator protein-1 and the inflammatory markers nuclear factor-κB and tumor necrosis factor-a. When administered separately, steroids and nitric oxide had modest effect on the inflammatory response. However, nitric oxide up-regulated the glucocorticoid receptor expression. Simultaneous administration of steroids and nitric oxide attenuated the inflammatory response and almost preserved or restored normal histology of both lung and systemic organs. When the glucocorticoid receptor was blocked by a receptor antagonist (mifepristone, 600 mg) and inhaled nitric oxide was subsequently administered, no increase in the expression of the glucocorticoid receptor was seen. Conclusion: We suggest that up-regulation of glucocorticoid receptor expression by nitric oxide made steroid therapy more effective.

  • 8. Dankiewicz, Josef
    et al.
    Schmidbauer, Simon
    Nielsen, Niklas
    Kern, Karl B.
    Mooney, Michael R.
    Stammet, Pascal
    Riker, Richard R.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Seder, David
    Smid, Ondrej
    Sunde, Kjetil
    Soreide, Eldar
    Unger, Barbara T.
    Friberg, Hans
    Safety, Feasibility, and Outcomes of Induced Hypothermia Therapy Following In-Hospital Cardiac Arrest-Evaluation of a Large Prospective Registry2014In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 42, no 12, p. 2537-2545Article in journal (Refereed)
    Abstract [en]

    Objectives: Despite a lack of randomized trials, practice guidelines recommend that mild induced hypothermia be considered for comatose survivors of in-hospital cardiac arrest. This study describes the safety, feasibility, and outcomes of mild induced hypothermia treatment following in-hospital cardiac arrest. Design: Prospective, observational, registry-based study. Setting: Forty-six critical care facilities in eight countries in Europe and the United States reporting in the Hypothermia Network Registry and the International Cardiac Arrest Registry. Patients: A total of 663 patients with in-hospital cardiac arrest and treated with mild induced hypothermia were included between January 2004 and February 2012. Interventions: None. Measurements and Main Results: A cerebral performance category of 1 or 2 was considered a good outcome. At hospital discharge 41% of patients had a good outcome. At median 6-month follow-up, 34% had a good outcome. Among in-hospital deaths, 52% were of cardiac causes and 44% of cerebral cause. A higher initial body temperature was associated with reduced odds of a good outcome (odds ratio, 0.79; 95% CI, 0.68-0.92). Adverse events were common; bleeding requiring transfusion (odds ratio, 0.56; 95% CI, 0.31-1.00) and sepsis (odds ratio, 0.52; 95% CI, 0.30-0.91) were associated with reduced odds for a good outcome. Conclusions: In this registry study of an in-hospital cardiac arrest population treated with mild induced hypothermia, we found a 41% good outcome at hospital discharge and 34% at follow-up. Infectious complications occurred in 43% of cases, and 11% of patients required a transfusion for bleeding. The majority of deaths were of cardiac origin.

  • 9. Derde, Sarah
    et al.
    Hermans, Greet
    Derese, Inge
    Güiza, Fabian
    Hedström, Yvette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Wouters, Pieter J
    Bruyninckx, Frans
    Dʼhoore, André
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Van den Berghe, Greet
    Vanhorebeek, Ilse
    Muscle atrophy and preferential loss of myosin in prolonged critically ill patients2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 1, p. 79-89Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Muscle weakness contributes to prolonged rehabilitation and adverse outcome of critically ill patients. Distinction between a neurogenic and/or myogenic underlying problem is difficult using routine diagnostic tools. Preferential loss of myosin has been suggested to point to a myogenic component. We evaluated markers of muscle atrophy and denervation, and the myosin/actin ratio in limb and abdominal wall skeletal muscle, of prolonged critically ill patients and matched controls in relation to insulin therapy and known risk factors for intensive care unit-acquired weakness.

    DESIGN:

    Secondary analysis of two large, prospective, single-center randomized clinical studies.

    SETTING:

    University hospital surgical and medical intensive care unit.

    PATIENTS:

    Critically ill patients and matched controls.

    INTERVENTIONS:

    Intensive care unit patients had been randomized to blood glucose control to 80-110 mg/dL with insulin infusion or conventional glucose management, where insulin was only administered when glucose levels rose above 215 mg/dL.

    MEASUREMENTS AND MAIN RESULTS:

    As compared with controls, rectus abdominis and vastus lateralis muscle of critically ill patients showed smaller myofiber size, decreased mRNA levels for myofibrillar proteins, increased proteolytic enzyme activities, and a lower myosin/actin ratio, virtually irrespective of insulin therapy. Increased forkhead box protein O1 action may have played a role. Most alterations were more severe in patients treated with corticosteroids. Duration of corticosteroid treatment, independent of duration of intensive care unit stay or other risk factors, was a dominant risk factor for a low myosin/actin ratio. The immature acetylcholine receptor subunit γ mRNA expression was elevated in vastus lateralis, independent of the myosin/actin ratio.

    CONCLUSIONS:

    Both limb and abdominal wall skeletal muscles of prolonged critically ill patients showed downregulation of protein synthesis at the gene expression level as well as increased proteolysis. This affected myosin to a greater extent than actin, resulting in a decreased myosin/actin ratio. Muscle atrophy was not ameliorated by intensive insulin therapy, but possibly aggravated by corticosteroids.

  • 10. Derde, Sarah
    et al.
    Vanhorebeek, Ilse
    Ververs, Eric-Jan
    Vanhees, Ine
    Darras, Veerle M
    Van Herck, Erik
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Van den Berghe, Greet
    Increasing intravenous glucose load in the presence of normoglycemia: Effect on outcome and metabolism in critically ill rabbits2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 2, p. 602-611Article in journal (Refereed)
    Abstract [en]

    Objectives: Endocrine disturbances and a feeding-resistant wasting syndrome, characterized by a negative protein balance, promote delayed recovery and poor outcome of critical illness. Parenteral nutrition alone cannot counteract the hypercatabolic state, possibly in part as a result of aggravation of the hyperglycemic response to illness. In critically ill rabbits, we investigated the impact of varying amounts of intravenous glucose while maintaining normoglycemia on mortality, organ damage, and markers of catabolism/anabolism. Design: Prospective, randomized laboratory investigation. Setting: University animal and molecular laboratory. Subjects: Three-month-old male rabbits. Interventions: Critically ill rabbits were randomized into a fasting group, a standard parenteral nutrition group, and two groups receiving either intermediate or high additional physiological amounts of intravenous glucose while maintained normoglycemic with insulin. These groups were compared with a hyperglycemic group and healthy rabbits. Protein and lipid load was equal for all fed groups. Measurements and Main Results: Varying intravenous glucose load did not affect mortality or organ damage provided hyperglycemia was prevented. Fasted critically ill rabbits lost weight, which was attenuated by increasing intravenous glucose load. As compared with healthy rabbits, mRNA expression and/or activity of several ubiquitin-proteasome pathway components, cathepsin-L and calpain-1, was elevated in skeletal muscle of fasted critically ill rabbits. Intravenous feeding was able to counteract this response. Excessive glucose load and/or hyperglycemia, however, reduced the protective effect of feeding. Genes investigated in the diaphragm and myocardium revealed roughly a similar response. Except in the normoglycemic group with intermediate glucose load, circulating thyroid hormone and insulin-like growth factor-1 levels decreased, most pronounced in hyperglycemic rabbits. Conclusions: Increasing intravenous glucose infusion within the physiological range, while maintaining normoglycemia, was safe for organ function and survival of critically ill rabbits. Concomitantly, it reduced the catabolic responses as compared with fasting. Whether this has a beneficial effect on muscle function and mass remains to be investigated.

  • 11. Ehrhardt, Harald
    et al.
    Sindelar, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Rieger-Fackeldey, Esther
    Schaller, Peter
    Schulze, Andreas
    Sedin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Physiology and Medical Biophysics.
    Effects of the inspiratory pressure waveform during patient-triggered ventilation on pulmonary stretch receptor and phrenic nerve activity in cats2001In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 29, no 6, p. 1207-1214Article in journal (Refereed)
    Abstract [en]

    Objective:

    To examine the effects of square wave, sinusoidal, and linear inspiratory pressure waveforms during pressure-controlled assist/control ventilation on the firing pattern of pulmonary stretch receptors and phrenic nerve activity.

    Design:

    Experimental, comparative study.

    Setting:

    Research laboratory at a university biomedical center.

    Subjects:

    Nine anesthetized, endotracheally intubated young cats (2.5–3.4 kg).

    Intervention:

    With interposed periods of continuous positive airway pressure (0.2 kPa), each cat was exposed to periods of assist/control ventilation with three different pressure waveforms, where the peak inspiratory pressure (0.74 ± 0.13 kPa), end-expiratory pressure (0.2 ± 0.02 kPa), and tidal volume (14.9 ± 5.22 mL/kg) were kept constant. Preset controlled ventilator rate was set below the rate of spontaneous breathing, and the mechanical inflation time equaled the inspiratory time during spontaneous breathing on continuous positive airway pressure.

    Measurements and Main Results:

    Respiratory rate and arterial blood gases did not change between the three pressure waveforms during assist/control ventilation. Peak pulmonary stretch receptor activity was lower and mean phrenic nerve activity higher during continuous positive airway pressure than during assist/control ventilation (p < .05). Peak inspiratory pulmonary stretch receptor activity was the same with all three pressure waveforms (82 ± 17 impulses·sec-1) but occurred earlier with square wave than with sinusoidal or linear pressure waveforms (p < .05). The total number of impulses in the phrenic nerve activity burst was smaller with square wave than with the other two pressure waveforms (0.21 ± 0.17 vs. 0.33 ± 0.27 and 0.42 ± 0.30 arbitrary units;p < .05), and the phrenic nerve activity burst duration was shorter with square wave (1.10 ± 0.45 vs. 1.54 ± 0.36 and 1.64 ± 0.25 secs;p < .05).

    Conclusion:

    Square wave pressure waveform during pressure-controlled assist/control ventilation strongly inhibits spontaneous inspiratory activity in cats. One mechanism for this inhibition is earlier and sustained peak pulmonary stretch receptor activity during inspiration. These findings show that differences in inspiratory pressure waveforms influence the spontaneous breathing effort during assist/control ventilation in cats.

  • 12.
    Elf, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Outcome after traumatic brain injury improved by an organized secondary insult program and standardized neurointensive care2002In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 30, no 9, p. 2129-2134Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate today's refined neurosurgical intensive care of patients with traumatic brain injury after implementation of an organized secondary insult program focused on the importance of avoiding secondary brain damage together with a standardized treatment protocol system.

    DESIGN: Clinical observational patient study.

    PATIENTS: A total of 154 patients 16-79 yrs of age with acute head trauma and pathologic computed tomographic findings treated between 1996 and 1997.

    SETTING: Neurointensive care unit.

    INTERVENTIONS: None.

    MEASUREMENTS AND MAIN RESULTS: Good recovery was obtained in 44% of the patients, moderate disability in 35%, severe disability in 16%, and no patient remained in a vegetative state. Six percent of the patients died, but only two of these patients (1.3%) died as direct result of their head injury. When the results for patients with Glasgow Coma Scale motor scores of >or=4 were compared with the periods 1980-1981 (preneurosurgical intensive care) and 1987-1988 (basic neurosurgical intensive care), mortality had decreased from 40% in the first period to 27% in the second period and to 2.8% in the present series. Favorable outcome in the same group of patients had increased steadily from 40% in the first period, to 68% in the second period, and finally, to 84% in the present series.

    CONCLUSIONS: The main observation in this hospital series of traumatic brain injury patients was a low rate of death directly caused by head injury and a high rate of favorable outcome. The comparison of patients with Glasgow Coma Scale motor scores of >or=4 with the previously reported results from the same unit indicate that substantial improvement in outcome has been achieved.

  • 13.
    Gedeborg, Rolf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Silander, H C
    Ronne-Engström, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Adverse effects of high-dose epinephrine on cerebral blood flow during experimental cardiopulmonary resuscitation2000In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 28, no 5, p. 1423-1430Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To study the effects of high-dose epinephrine, compared with standard-dose epinephrine, on the dynamics of superficial cortical cerebral blood flow as well as global cerebral oxygenation during experimental cardiopulmonary resuscitation. We hypothesized that high-dose epinephrine might be unable to improve cerebral blood flow during cardiopulmonary resuscitation as compared with standard-dose epinephrine.

    DESIGN:

    Randomized controlled study.

    SETTING:

    University hospital research laboratory.

    SUBJECTS:

    A total of 20 male anesthetized piglets.

    INTERVENTIONS:

    Ventricular fibrillation was induced. A nonintervention interval of 8 mins was followed by open-chest cardiopulmonary resuscitation. The animals were randomized to receive repeated bolus injections of either 20 microg/kg (standard-dose group, n = 10) or 200 microg/kg (high-dose group, n = 10) of epinephrine.

    MEASUREMENTS AND MAIN RESULTS:

    Focal cortical cerebral blood flow was measured continuously by using laser Doppler flowmetry. The duration of blood flow increase was significantly shorter in the high-dose group after the second dose of epinephrine. In the high-dose group there was also a consistent tendency for lower peak levels and shorter duration of flow increase in response to repeated bolus doses of epinephrine. Cerebral oxygen extraction ratio was significantly lower in the high-dose group after administration of epinephrine.

    CONCLUSIONS:

    Repeated bolus doses of epinephrine 200 microg/kg, as compared with 20 microg/kg, do not improve superficial cortical cerebral blood flow during experimental open-chest cardiopulmonary resuscitation. High-dose epinephrine appears to induce vasoconstriction of cortical cerebral blood vessels resulting in redistribution of blood flow from superficial cortex. This might be one explanation for the failure of high-dose epinephrine to improve overall outcome in clinical trials.

  • 14.
    Gedeborg, Rolf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Thiblin, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    The impact of clinically undiagnosed injuries on survival estimates2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 2, p. 449-55Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: Missed injury diagnoses may cause potentially preventable deaths. To estimate the effect of clinically undiagnosed injuries on injury-specific survival estimates and the accuracy of an injury severity score. To also estimate the potentially preventable mortality attributable to these injuries. DESIGN, SETTING, AND PATIENTS:: In a nation-wide, population-based study, data were collected from all hospital admissions for injuries in Sweden between 1998 and 2004. We studied 8627 deaths in hospital among 598,137 incident hospital admissions. MEASUREMENTS AND MAIN RESULTS:: New specific-injury categories were added in 7.4% (95% confidence interval [CI] 6.8-8.0) of all deaths with an autopsy rate of 24.2%. It was estimated that this proportion would have increased to 25.1% (95% CI 23.0-27.2), if all deaths had been autopsied. The most pronounced effect of clinically undiagnosed injuries was found for internal organ injury in the abdomen or pelvis, where they reduced the estimated survival from 0.83 to 0.69 (95% CI for the difference: 0.09-0.20). Autopsy diagnoses also revealed substantial bias of survival estimates for vascular injuries in the thorax and crush injuries to the head. The performance of the International Classification of Diseases Injury Severity Score improved when autopsy diagnoses were added to hospital discharge diagnoses. The maximum proportion of injury deaths attributable to missed injuries was estimated to be 6.5%. CONCLUSIONS:: Maintaining a high autopsy rate and merging accurate hospital discharge data and autopsy data are effective ways to improve the accuracy of survival estimates and mortality prediction models, and to estimate mortality attributable to diagnostic failures.

  • 15.
    Halmin, Marit
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Chiesa, Flaminia
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Vasan, Senthil K.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Wikman, Agneta
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden..
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Pedersen, Ole Birger Vesterager
    Naestved Hosp, Dept Clin Immunol, Naestved, Denmark..
    Erikstrup, Christian
    Aarhus Univ Hosp, Dept Clin Immunol, DK-8000 Aarhus, Denmark..
    Nielsen, Kaspar Rene
    Aalborg Univ Hosp, Dept Clin Immunol, Aalborg, Denmark..
    Titlestad, Kjell
    Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense, Denmark..
    Ullum, Henrik
    Copenhagen Univ Hosp, Dept Clin Immunol, Copenhagen, Denmark..
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Edgren, Gustaf
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Epidemiology of Massive Transfusion: A Binational Study From Sweden and Denmark2016In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 44, no 3, p. 468-477Article in journal (Refereed)
    Abstract [en]

    Objective: There is an increasing focus on massive transfusion, but there is a paucity of comprehensive descriptions of the massively transfused patients and their outcomes. The objective of this study is to describe the incidence rate of massive transfusion, patient characteristics, and the mortality of massively transfused patients. Design: Descriptive cohort study. Setting: Nationwide study with data from Sweden and Denmark. Patients: The study was based on the Scandinavian Donations and Transfusions database, including all patients receiving 10 or more red cell concentrate transfusions in Sweden from 1987 and in Denmark from 1996. A total of 92,057 patients were included. Patients were followed until the end of 2012. Measurements and Main Results: Descriptive statistics were used to characterize the patients and indications. Post transfusion mortality was expressed as crude 30-day mortality and as long-term mortality using the Kaplan-Meier method and using standardized mortality ratios. The incidence of massive transfusion was higher in Denmark (4.5 per 10,000) than in Sweden (2.5 per 10,000). The most common indication for massive transfusion was major surgery (61.2%) followed by trauma (15.4%). Massive transfusion due to obstetrical bleeding constituted only 1.8%. The overall 5-year mortality was very high (54.6%), however with large differences between indication groups, ranging from 91.1% among those transfused for a malignant disease without surgery to 1.7% among patients transfused for obstetrical bleeding. The early standardized mortality ratios were high and decreased thereafter, but remained elevated throughout the time period. Conclusions: This large-scale study based on nationwide data from Sweden and Denmark describes the complete range of massive transfusion. We report a nonnegligible incidence and both a high absolute mortality and high standardized mortality ratio. The general pattern was similar for Sweden and Denmark, and we believe that similar patterns may be found in other high-resource countries. The study provides a relevant background for clinicians and researchers for designing future studies in this field.

  • 16.
    Hillered, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nonischemic energy metabolic crisis in acute brain injury2008In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 36, no 10, p. 2952-2953Article in journal (Refereed)
  • 17. Hostman, Staffan
    et al.
    Borges, Joao
    Engstrom, Joakim
    Suarez-Sipmann, Fernando
    Hedenstierna, Goran
    Larsson, Anders
    Is tham a useful adjunct to normalize ph during lung protective ventilation with permissive hypercapnia?2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 12, p. U63-U63Article in journal (Other academic)
  • 18.
    Howells, Tim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Smielewski, Peter
    Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Neurosurg Unit,Div Anaesthesia, Cambridge, England..
    Donnelly, Joseph
    Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Neurosurg Unit,Div Anaesthesia, Cambridge, England..
    Czosnyka, Marek
    Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Neurosurg Unit,Div Anaesthesia, Cambridge, England.;Warsaw Univ Technol, Inst Elect Syst, Warsaw, Poland..
    Hutchinson, Peter J. A.
    Univ Cambridge, Addenbrookes Hosp, Dept Clin Neurosci, Neurosurg Unit,Div Anaesthesia, Cambridge, England..
    Menon, David K.
    Univ Cambridge, Addenbrookes Hosp, Div Anaesthesia, Cambridge, England..
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Aries, Marcel J. H.
    Maastricht Univ, Med Ctr, Dept Crit Care, Maastricht, Netherlands..
    Optimal Cerebral Perfusion Pressure in Centers With Different Treatment Protocols2018In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 46, no 3, p. e235-e241Article in journal (Refereed)
    Abstract [en]

    Objectives: The three centers in this study have different policies regarding cerebral perfusion pressure targets and use of vasopressors in traumatic brain injury patients. The aim was to determine if the different policies affected the estimation of cerebral perfusion pressure which optimizes the strength of cerebral autoregulation, termed "optimal cerebral perfusion pressure." Design: Retrospective analysis of prospectively collected data. Setting: Three neurocritical care units at university hospitals in Cambridge, United Kingdom, Groningen, the Netherlands, and Uppsala, Sweden. Patients: A total of 104 traumatic brain injury patients were included: 35 each from Cambridge and Groningen, and 34 from Uppsala. Interventions: None. Measurements and Main Results: In Groningen, the cerebral perfusion pressure target was greater than or equal to 50 and less than 70mm Hg, in Uppsala greater than or equal to 60, and in Cambridge greater than or equal to 60 or preferably greater than or equal to 70. Despite protocol differences, median cerebral perfusion pressure for each center was above 70mm Hg. Optimal cerebral perfusion pressure was calculated as previously published and implemented in the Intensive Care Monitoring+ software by the Cambridge group, now replicated in the Odin software in Uppsala. Periods with cerebral perfusion pressure above and below optimal cerebral perfusion pressure were analyzed, as were absolute difference between cerebral perfusion pressure and optimal cerebral perfusion pressure and percentage of monitoring time with a valid optimal cerebral perfusion pressure. Uppsala had the highest cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Uppsala patients were older than the other centers, and age is positively correlated with cerebral perfusion pressure/optimal cerebral perfusion pressure difference. Optimal cerebral perfusion pressure was significantly lower in Groningen than in Cambridge. There were no significant differences in percentage of monitoring time with valid optimal cerebral perfusion pressure. Summary optimal cerebral perfusion pressure curves were generated for the combined patient data for each center. These summary curves could be generated for Groningen and Cambridge, but not Uppsala. The older age of the Uppsala patient cohort may explain the absence of a summary curve. Conclusions: Differences in optimal cerebral perfusion pressure calculation were found between centers due to demographics (age) and treatment (cerebral perfusion pressure targets). These factors should be considered in the design of trials to determine the efficacy of autoregulation-guided treatment.

  • 19.
    Iyer, Kartik K.
    et al.
    QIMR Berghofer Med Res Inst, Syst Neurosci Grp, Brisbane, Qld, Australia.;Univ Queensland, Fac Med & Biomed Sci, Sch Med, Brisbane, Qld 4072, Australia..
    Roberts, James A.
    QIMR Berghofer Med Res Inst, Syst Neurosci Grp, Brisbane, Qld, Australia..
    Hellström-Westas, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Wikstrom, Sverre
    Karlstad Cent Hosp, Dept Pediat, Karlstad, Sweden..
    Pupp, Ingrid Hansen
    Lund Univ, Inst Clin Sci, Dept Pediat, Lund, Sweden..
    Ley, David
    Lund Univ, Inst Clin Sci, Dept Pediat, Lund, Sweden..
    Breakspear, Michael
    QIMR Berghofer Med Res Inst, Syst Neurosci Grp, Brisbane, Qld, Australia.;Metro North Mental Hlth Serv, Brisbane, Qld, Australia..
    Vanhatalo, Sampsa
    Univ Helsinki, Cent Hosp, HUS Med Imaging Ctr, Dept Childrens Clin Neurophysiol, Helsinki, Finland.;Univ Helsinki, Helsinki, Finland.;Univ Cent Hosp, Childrens Hosp, Dept Pediat, Helsinki, Finland..
    Early Detection of Preterm Intraventricular Hemorrhage From Clinical Electroencephalography2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 10, p. 2219-2227Article in journal (Refereed)
    Abstract [en]

    Objectives: Intraventricular hemorrhage is a common neurologic complication of extremely preterm birth and leads to lifelong neurodevelopmental disabilities. Early bedside detection of intraventricular hemorrhage is crucial to enabling timely interventions. We sought to detect early markers of brain activity that preempt the occurrence of intraventricular hemorrhage in extremely preterm infants during the first postnatal days. Design: Cross-sectional study. Setting: Level III neonatal ICU. Patients: Twenty-five extremely preterm infants (22-28 wk gestational age). Measurements and Main Results: We quantitatively assessed electroencephalography in the first 72 hours of postnatal life, focusing on the electrical burst activity of the preterm. Cranial ultrasound was performed on day 1 (0-24 hr) and day 3 (48-72 hr). Outcomes were categorized into three classes: 1) no intraventricular hemorrhage (grade 0); 2) mild-moderate intraventricular hemorrhage (grades 1-2, i.e., germinal matrix hemorrhages or intraventricular hemorrhage without ventricular dilatation, respectively); and 3) severe intraventricular hemorrhage (grades 3-4, i.e., intraventricular hemorrhage with ventricular dilatation or intraparenchymal involvement). Quantitative assessment of electroencephalography burst shapes was used to preempt the occurrence and severity of intraventricular hemorrhage as detected by ultrasound. The shapes of electroencephalography bursts found in the intraventricular hemorrhage infants were significantly sharper (F = 13.78; p < 0.0001) and less symmetric (F = 6.91; p < 0.015) than in preterm infants without intraventricular hemorrhage. Diagnostic discrimination of intraventricular hemorrhage infants using measures of burst symmetry and sharpness yielded high true-positive rates (82% and 88%, respectively) and low false-positive rates (19% and 8%). Conventional electroencephalography measures of interburst intervals and burst counts were not significantly associated with intraventricular hemorrhage. Conclusions: Detection of intraventricular hemorrhage during the first postnatal days is possible from bedside measures of brain activity prior to ultrasound confirmation of intraventricular hemorrhage. Significantly, our novel automated assessment of electroencephalography preempts the occurrence of intraventricular hemorrhage in the extremely preterm. Early bedside detection of intraventricular hemorrhage holds promise for advancing individual care, targeted therapeutic trials, and understanding mechanisms of brain injury in neonates.

  • 20.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Experimental animal models of muscle wasting in intensive care unit patients2007In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 35, no 9, p. S484-S487Article in journal (Refereed)
    Abstract [en]

    The muscle wasting and loss of muscle function associated with critical illness and intensive care have significant negative consequences for weaning from the respirator, duration of hospital stay, and quality of life for long periods after hospital discharge. There is, accordingly, a significant demand for focused research aiming at improving our understanding of the mechanisms underlying the impaired neuromuscular function in intensive care unit (ICU) patients. However, the study of generalized muscle weakness in critically ill ICU patients is further complicated by the coexistence of multiple independent factors, such as different primary diseases, large variability in pharmacologic treatment, collection of muscle samples several weeks after admission to the ICU, and exposure to causative agents. This has led to the design of specific animal models mimicking ICU conditions. These models have often been used to study the mechanisms underlying the paralysis and muscle wasting associated with acute quadriplegic myopathy in ICU patients. This short review aims at presenting existing and recently introduced experimental animal models mimicking the conditions in the ICU (i.e., models designed to determine the mechanisms underlying the muscle wasting associated with ICU treatment).

  • 21.
    Lattuada, Marco
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Abdominal lymph flow in an endotoxin sepsis model: Influence of spontaneous breathing and mechanical ventilation2006In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, no 11, p. 2792-2798Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Lymph flow from the abdomen was investigated in a sepsis model. We also compared the effect on thoracic duct lymph flow of mechanical ventilation with different levels of positive end-expiratory pressure (PEEP) and spontaneous breathing with continuous positive airway pressure (CPAP). DESIGN: Experimental study. SETTING: Research laboratory in a university hospital. SUBJECTS: Thirty-two pigs. INTERVENTIONS: Animals were anesthetized. In study 1 (n = 18), an ultrasonic flow probe was put around the intact thoracic duct just caudal to the diaphragm, and animals were randomized to receive mechanical ventilation with a PEEP of 5 cm H2O or 15 cm H2O or breathed spontaneously in CPAP with a PEEP of 5 cm H2O. In study 2 (n = 6), the thoracic duct was cannulated and the cannula externalized through the abdominal wall for lymph collection; animals were then ventilated as in study 1. In all animals, endotoxin was infused at 15 μg/kg/hr for 2.5 hrs and then continued at 5 μg/kg/hr. In study 3, healthy (n = 4) and endotoxin-exposed (n = 4) pigs had intra-abdominal pressure increased to 27 cm H2O for 2 hrs by pneumoperitoneum. Lymph flow was measured as in study 1. MEASUREMENTS AND MAIN RESULTS: Lymph flow (mean ± se) was 2.5 ± 0.4 mL/min at baseline and increased to 3.9 ± 0.8 mL/min after 90 mins and 6.3 ± 1.6 mL/min after 150 mins (p < .005) of endotoxin exposure. PEEP 15 cm H2O decreased lymph flow in pigs with intact thoracic duct (flow probe recording) and in pigs with cannulated lymph duct when drained against the central venous pressure. However, when drained against atmospheric pressure, PEEP increased flow. Spontaneous breathing increased flow both in intact and in cannulated animals. CONCLUSIONS: Endotoxin increases lymph flow from the abdomen. Mechanical ventilation with high PEEP impedes lymph drainage and could increase lymph production. Spontaneous breathing increases flow and improves drainage of abdominal edema.

  • 22.
    Lennmyr, Fredrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Molnar, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebral effects of hyperglycemia in experimental cardiac arrest2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 8, p. 1726-1732Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the effects of cardiac arrest on cerebral perfusion and oxidative stress during hyperglycemia and normoglycemia. Design: Experimental animal model. Setting: University laboratory. Subjects: Triple-breed pigs (weight, 22-27 kg). Interventions: Thirty-three pigs were randomized and clamped at blood glucose levels of 8.5-10 mM (high) or 4-5.5 mM (normal) and thereafter subjected to alternating current-induced 12-min cardiac arrest followed by 8 mins of cardiopulmonary resuscitation and direct-current shock to restore spontaneous circulation. Measurements and Main Results: Hemodynamics, regional near-infrared light spectroscopy, regional venous HbO(2), and biochemical markers (Protein S100 beta, troponin I, F-2-isoprostanes reflecting oxidative stress and inflammation) were monitored and/or sampled throughout an observation period of 4 hrs. No significant differences were seen in hemodynamics or biochemical profile. The cerebral oxygenation by means of regional near-infrared light spectroscopy was higher in the hyperglycemic (H) than in the normal (N) group after restoration of spontaneous circulation (p < .05). However, tendencies toward increased protein S100 beta and 15-keto-dihydro-prostaglandin F-2 alpha were observed in the H group but were not statistically significant. Conclusions: The responses to 12-min cardiac arrest and cardiopulmonary resuscitation share large similarities during hyperglycemia and normoglycemia. The higher cerebral tissue oxygenation observed in the hyperglycemia needs to be confirmed and the phenomenon needs to be addressed in future studies.

  • 23.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Carlsson, Markus
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Algotsson, Lars
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 10, p. 2782-2790Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To evaluate whether the addition of tobramycin further compromises renal function in inflammatory response-induced acute kidney injury. Effective antibiotic treatment in septic shock is crucial for the outcome. The combination of aminoglycosides with different beta-lactam antibiotics offers a broad antimicrobial coverage, rapid bacterial killing, synergistic effects, and low antibiotic-induced endotoxin release. However, aminoglycosides have nephrotoxic effects that may aggravate sepsis-induced acute kidney injury.

    DESIGN:

    Prospective, randomized, placebo-controlled experimental study.

    SETTING:

    University research unit.

    SUBJECTS:

    Twenty-four healthy pigs.

    INTERVENTIONS:

    The animals were anesthetized and randomized to four groups. Groups I (n = 8) and II (n = 8) received endotoxin infusion for 6 hrs, whereas groups III (n = 4) and IV (n = 4) received saline. Groups I and III received 7 mg/kg of tobramycin 20 mins after the initiation of the protocol, whereas groups II and IV received saline.

    MEASUREMENTS AND MAIN RESULTS:

    The renal elimination rate of a bolus dose of cefuroxime was chosen as the primary end point. Renal function was also evaluated by urine output, creatinine clearance, plasma cystatin C, plasma urea, and urine NAG (N-acetyl-beta-D-glucoaminidase). After 3 hrs, there were significantly lower cefuroxime elimination rates in the two endotoxin groups than in the nonendotoxin groups. No difference in cefuroxime elimination rates between groups I and II could be detected at any time point. Similarly, there were changes indicating acute kidney injury in urine output, creatinine clearance, and plasma cystatin C in the endotoxin groups with no differences between groups I and II. Plasma urea and urine NAG did not differ between any of the groups.

    CONCLUSIONS:

    The result of this study does not lend any support to the hypothesis that a single dose of tobramycin enhances the risk of acute renal failure in cases with systemic inflammatory response-induced acute kidney injury.

  • 24.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue added to a hypertonic-hyperoncotic solution increases short-term survival in experimental cardiac arrest2006In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 34, no 11, p. 2806-2813Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Methylene blue (MB), a free-radical scavenger inhibiting the production and actions of nitric oxide, may counteract excessive vasodilatation induced by nitric oxide during cardiac arrest. Effects of MB in cardiac arrest and cardiopulmonary resuscitation were investigated. DESIGN: Randomized, prospective, laboratory animal study. SETTING: University animal research laboratory. SUBJECTS: A total of 63 piglets of both sexes. INTERVENTIONS: A pig model of extended cardiac arrest (12 mins of untreated cardiac arrest and 8 mins of cardiopulmonary resuscitation) was employed to assess the addition or no addition of MB to a hypertonic saline-dextran solution. These two groups (MB and hypertonic saline-dextran group [MB group] and hypertonic saline-dextran-only group) of 21 animals were each compared with a group receiving isotonic saline (n = 21). MEASUREMENTS AND MAIN RESULTS: Although the groups were similar in baseline values, 4-hr survival in the MB group was increased (p = .02) in comparison with the isotonic saline group. Hemodynamic variables were somewhat improved at 15 mins after restoration of spontaneous circulation in the MB group compared with the other two groups. The jugular bulb levels of 8-isoprostane-prostaglandin F2alpha and 15-keto-dihydro-prostaglandin F2alpha (indicators of peroxidation and inflammation) were significantly decreased in the MB group compared with the isotonic saline group. Significant differences were recorded between the three groups in levels of protein S-100beta (indicator of neurologic injury), with lower levels in the MB group compared with the isotonic saline and hypertonic saline-dextran-only groups. Troponin I and myocardial muscle creatine kinase isoenzyme arterial concentrations (indicators of myocardial damage) were also significantly lower in the MB group. CONCLUSIONS: MB co-administered with a hypertonic-hyperoncotic solution increased 4-hr survival vs. saline in an experimental porcine model of cardiac arrest and reduced oxidative, inflammatory, myocardial, and neurologic injury.

  • 25.
    Miclescu, Adriana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Martijn, Cécile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Methylene blue protects the cortical blood-brain barrier against ischemia/reperfusion-induced disruptions2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 11, p. 2199-2206Article in journal (Refereed)
    Abstract [en]

    Objectives: To investigate the effects of cardiac arrest and the reperfusion syndrome on blood-brain barrier permeability and evaluate whether methylene blue counteracts blood-brain barrier disruption in a pig model of controlled cardiopulmonary resuscitation. Design: Randomized, prospective, laboratory animal study. Setting: University-affiliated research laboratory. Subjects: Forty-five piglets. Interventions: Forty-five anesthetized piglets were subjected to cardiac arrest alone or 12-min cardiac arrest followed by 8 mins cardiopulmonary resuscitation. The first group (n = 16) was used to evaluate blood-brain barrier disruptions after untreated cerebral ischemia after 0, 15, or 30 mins after untreated cardiac arrest. The other two groups received either an infusion of saline (n = 10) or infusion of saline with methylene blue (n = 12) 1 min after the start of cardiopulmonary resuscitation and continued 50 mins after return of spontaneous circulation. In these groups, brains were removed for immunohistological analyses at 30, 60, and 180 mins after return of spontaneous circulation. Measurements and Main Results: An increase of injured neurons and albumin immunoreactivity was demonstrated with in-creasing duration of ischemia/reperfusion. Less blood-brain barrier disruption was observed in subjects receiving methylene blue as demonstrated by decreased albumin leakage (p<.01), water content (p<.05), and neuronal injury (p<.01). Methylene blue treatment reduced cerebral tissue nitrite/nitrate content (p<.05) and the number of inducible and neuronal nitric oxide synthase-activated cortical cells during administration (p<.01). Meanwhile, the number of cortical endothelial nitric oxide synthase-activated cells increased over time (p<.001). Conclusion: Cerebral tissue water content, blood-brain barrier permeability and neurologic injury were increased early in reperfusion after cardiac arrest. Methylene blue exerted neuroprotective effects against the brain damage associated with the ischemia/reperfusion injury and ameliorated the blood-brain barrier disruption by decreasing nitric oxide metabolites. (Crit Care Med 2010; 38: 2199-2206)

  • 26. Moa, Gunnar
    et al.
    Nilsson, Kjell
    Zetterström, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Jonsson, Lars O
    A new device för administration of nasal CPAP in the newborn1988In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 16, p. 1238-1242Article in journal (Refereed)
  • 27.
    Mutschler, Diana K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Eriksson, M. B.
    Wikström, B. G.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berggren-Kiiski, Ritva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lagrange, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nordgren, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Microdialysis-evaluated myocardial cyclooxygenase-mediated inflammation and early circulatory depression in porcine endotoxemia2003In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 31, no 6, p. 1780-1785Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the early myocardial biochemical inflammatory response with the microdialysis technique during porcine endotoxemia and to simultaneously monitor systemic hemodynamics.

    DESIGN: Prospective, randomized, placebo-controlled trial with parallel groups.

    SETTING: Animal research laboratory at the University Hospital of Uppsala, Sweden.

    SUBJECTS: Thirteen piglets aged 12-14 wks receiving general anesthesia.

    INTERVENTIONS: After thoracotomy and the insertion of microdialysis probes in standardized locations in the left ventricle of the heart and in the quadriceps muscle, seven pigs received a continuous infusion of endotoxin, initiating a severe endotoxemic shock. Six pigs received saline instead of endotoxin.

    MEASUREMENTS AND MAIN RESULTS: Endotoxemia caused a rapid and pronounced elevation of a metabolite obtained from prostaglandin degradation, 15-keto-dihydro-PGF(2alpha), in myocardial microdialysate fluid being specific of cyclooxygenase (COX)-mediated inflammation (p <.001 vs. saline-infused controls). Simultaneously, we observed a decrease in left ventricular stroke work index in the endotoxemic pigs (p <.01 vs. saline-infused controls). Endotoxemia did not alter 15-keto-dihydro-PGF(2alpha) levels in quadriceps muscle. Endotoxemia caused increases in taurine, hypoxanthine, and magnesium in myocardial microdialysate (p <.05 vs. saline-infused controls), whereas the contents of pyruvate, lactate, inosine, adenosine, and calcium were not significantly changed.

    CONCLUSION: Endotoxemia induced a myocardial COX-mediated inflammation without signs of ischemia. In parallel, a depletion of myocardial energy substrates and a deterioration in myocardial performance were seen.

  • 28. Nielsen, Niklas
    et al.
    Sunde, Kjetil
    Hovdenes, Jan
    Riker, Richard R.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Stammet, Pascal
    Nilsson, Fredrik
    Friberg, Hans
    Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia2011In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    Objectives:

    To investigate the association between adverse events recorded during critical care and mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia.

    Design:

    Prospective, observational, registry-based study.

    Setting:

    Twenty-two hospitals in Europe and the United States.

    Patients:

    Between October 2004 and October 2008, 765 patients were included. Interventions: None.

    Measurements and Main Results:

    Arrhythmias (7%-14%), pneumonia (48%), metabolic and electrolyte disorders (5%-37%), and seizures (24%) were common adverse events in the critical care period in cardiac arrest patients treated with therapeutic hypothermia, whereas sepsis (4%) and bleeding (6%) were less frequent. Sustained hyperglycemia (blood glucose >8 mmol/L for >4 hrs; odds ratio 2.3, 95% confidence interval 1.6-3.6, p < .001) and seizures treated with anticonvulsants (odds ratio 4.8, 95% confidence interval 2.9-8.1, p < .001) were associated with increased mortality in a multivariate model. An increased frequency of bleeding and sepsis occurred after invasive procedures (coronary angiography, intravascular devices for cooling, intra-aortic balloon pump), but bleeding and sepsis were not associated with increased mortality (odds ratio 1.0, 95% confidence interval 0.46-2.2, p = .91, and odds ratio 0.30, 95% confidence interval 0.12-0.79, p = .01, respectively).

    Conclusions:

    Adverse events were common after out-of-hospital cardiac arrest. Sustained hyperglycemia and seizures treated with anticonvulsants were associated with increased mortality. Bleeding and infection were more common after invasive procedures, but these adverse events were not associated with increased mortality in our study.

  • 29.
    Nilsson, Manja C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hambraeus-Jonon, Kristina
    Lattuada, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chen, Luni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Li, Ren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Alving, Kjell
    Wiklund, Peter
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fredén, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Distant effects of nitric oxide inhalation in endotoxemic pigs2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 1, p. 242-248Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Inhalation of nitric oxide (INO) has distant effects. By a blood- borne factor, INO down-regulates endogenous nitric oxide production in healthy pig lungs, resulting in vasoconstriction in lung regions not directly reached by INO. The aim of this study was to investigate whether INO has distant effects in endotoxemic pig lungs. The hypothesis was that INO down-regulates endogenous NO production in lung regions not reached by INO. DESIGN: Prospective, randomized animal study. SETTING: University hospital research laboratory. SUBJECTS: Twenty-two pairs of domestic pigs. INTERVENTIONS: Cross-circulation was established in 22 pairs of anesthetized pigs. Nine pairs received endotoxin (control group) and 13 pairs received endotoxin, with one pig inhaling NO (80 ppm) and one pig receiving blood from that pig (NO-blood recipient group). MEASUREMENTS AND MAIN RESULTS: NO in exhaled air, NO synthase activity in lung tissue, endothelin-1 in the blood, ETA and ETB receptor immunoreactivity in lung tissue, vital parameters, and blood gases were measured. Endotoxin per se increased NO in exhaled air by 100% compared to baseline (control group). In the NO-blood recipient group, i.e., pigs receiving blood from the NO-inhaling pigs, NO in exhaled air increased by 300% (p = .03). The Ca-dependent NO synthase activity was higher in these pigs (p = .02), indicating increased endogenous NO production. The ET B receptor immunoreactivity was higher in the NO-blood recipient group (p = .004). CONCLUSIONS: As opposed to findings in healthy pigs, INO in endotoxemic pigs causes an increase in endogenous NO production in lung regions not reached by INO. Increased NO production in nonventilated lung regions may cause vasodilatation, counteracting the INO-induced increase in blood flow to the ventilated lung regions.

  • 30. Nunnally, Mark E.
    et al.
    Jaeschke, Roman
    Bellingan, Geoffrey J.
    Lacroix, Jacques
    Mourvillier, Bruno
    Rodriguez-Vega, Gloria M.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Vassilakopoulos, Theodoros
    Weinert, Craig
    Zanotti-Cavazzoni, Sergio
    Buchman, Timothy G.
    Targeted temperature management in critical care: A report and recommendations from five professional societies2011In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 5, p. 1113-1125Article in journal (Refereed)
    Abstract [en]

    Objective: Representatives of five international critical care societies convened topic specialists and a nonexpert jury to review, assess, and report on studies of targeted temperature management and to provide clinical recommendations.

    Data Sources: Questions were allocated to experts who reviewed their areas, made formal presentations, and responded to questions. Jurors also performed independent searches. Sources used for consensus derived exclusively from peer-reviewed reports of human and animal studies.

    Study Selection: Question-specific studies were selected from literature searches; jurors independently determined the relevance of each study included in the synthesis.

    Conclusions and Recommendations: 1) The jury opines that the term "targeted temperature management" replace "therapeutic hypothermia."

    2) The jury opines that descriptors (e. g., "mild") be replaced with explicit targeted temperature management profiles.

    3) The jury opines that each report of a targeted temperature management trial enumerate the physiologic effects anticipated by the investigators and actually observed and/or measured in subjects in each arm of the trial as a strategy for increasing knowledge of the dose/duration/response characteristics of temperature management. This enumeration should be kept separate from the body of the report, be organized by body systems, and be made without assertions about the impact of any specific effect on the clinical outcome.

    4) The jury STRONGLY RECOMMENDS targeted temperature management to a target of 32 degrees C-34 degrees C as the preferred treatment (vs. unstructured temperature management) of out-of-hospital adult cardiac arrest victims with a first registered electrocardiography rhythm of ventricular fibrillation or pulseless ventricular tachycardia and still unconscious after restoration of spontaneous circulation (strong recommendation, moderate quality of evidence).

    5) The jury WEAKLY RECOMMENDS the use of targeted temperature management to 33 degrees C-35.5 degrees C (vs. less structured management) in the treatment of term newborns who sustained asphyxia and exhibit acidosis and/or encephalopathy (weak recommendation, moderate quality of evidence).

  • 31.
    Purins, Karlis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sedigh, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Molnar, Christian
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Lorant, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wennberg, Lars
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lewén, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Standardized experimental brain death model for studies of intracranial dynamics, organ preservation, and organ transplantation in the pig2011In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 39, no 3, p. 512-517Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: Brain death impairs organ function and outcome after transplantation. There is a need for a brain death model to allow studies of organ viability and preservation. For neurointensive care research, it is also of interest to have a relevant brain death model for studies of intracranial dynamics and evaluation of cerebral monitoring devices. Therefore, the objective was to develop a standardized clinically relevant brain death model. METHODS:: Six pigs of both sexes (10-12 wks old; mean weight, 24.5 ± 1.4 kg) were included. Mean arterial blood pressure, heart rate, intracranial pressure, intracranial compliance, cerebral perfusion pressure, and brain tissue oxygenation (BtiPo2) were recorded during stepwise elevation of intracranial pressure by inflation of an epidural balloon catheter with saline (1 mL/20 mins). Brain death criteria were decided to be reached when cerebral perfusion pressure was <0 mm Hg for 60 mins and at least 10 mL saline was inflated epidurally. BtiPo2 and arterial injections of microspheres were used for confirmation of brain death. RESULTS:: A gradual volume-dependent elevation of intracranial pressure was observed. After 10 mL of balloon infusion, mean intracranial pressure was 89.8 ± 9.7 (sd) mm Hg. Intracranial compliance decreased from 0.137 ± 0.069 mL/mm Hg to 0.007 ± 0.001 mL/mm Hg. The mean arterial pressure decreased and the heart rate increased when the intracranial volume was increased to between 5 and 6 mL. All animals showed cerebral perfusion pressure ≤0 after 7 to 10 mL of infusion. In all animals, the criteria for brain death with negative cerebral perfusion pressure and BtiPo2 ∼0 mm Hg were achieved. Only a negligible amount of microspheres were found in the cerebrum, confirming brain death. The kidneys showed small foci of acute tubular necrosis. CONCLUSIONS:: The standardized brain death model designed in pigs simulates the clinical development of brain death in humans with a classic pressure-volume response and systemic cardiovascular reactions. Brain death was convincingly confirmed.

  • 32. Reske, Andreas W.
    et al.
    Costa, Eduardo L. V.
    Reske, Alexander P.
    Rau, Anna
    Borges, Joao Batista
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Beraldo, Marcelo A.
    Gottschaldt, Udo
    Seiwerts, Matthias
    Schreiter, Dierk
    Petroff, David
    Kaisers, Udo X.
    Wrigge, Hermann
    Amato, Marcelo B. P.
    Bedside Estimation of Nonaerated Lung Tissue Using Blood Gas Analysis2013In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 41, no 3, p. 732-743Article in journal (Refereed)
    Abstract [en]

    Objectives: Studies correlating the arterial partial pressure of oxygen to the fraction of nonaerated lung assessed by CT shunt yielded inconsistent results. We systematically analyzed this relationship and scrutinized key methodological factors that may compromise it. We hypothesized that both physiological shunt and the ratio between PaO2 and the fraction of inspired oxygen enable estimation of CT shunt at the bedside. Design: Prospective observational clinical and laboratory animal investigations. Setting: ICUs (University Hospital Leipzig, Germany) and Experimental Pulmonology Laboratory (University of Sao Paulo, Brazil). Patients, Subjects and Interventions: Whole-lung CT and arterial blood gases were acquired simultaneously in 77 patients mechanically ventilated with pure oxygen. A subgroup of 28 patients was submitted to different FIO2. We also studied 19 patients who underwent repeat CT. Furthermore we studied ten pigs with acute lung injury at multiple airway pressures, as well as a theoretical model relating PaO2 and physiological shunt. We logarithmically transformed the PaO2/FIO2 to change this nonlinear relationship into a linear regression problem. Measurements and Main Results: We observed strong linear correlations between Riley's approximation of physiological shunt and CT shunt (R-2 = 0.84) and between logarithmically transformed PaO2/FIO2 and CT shunt (R-2 = 0.86), allowing us to construct a look-up table with prediction intervals. Strong linear correlations were also demonstrated within-patients (R-2 = 0.95). Correlations were significantly improved by the following methodological issues: measurement of PaO2/FIO2 during pure oxygen ventilation, use of logarithmically transformed PaO2/FIO2 instead of the "raw" PaO2/FIO2, quantification of nonaerated lung as percentage of total lung mass and definition of nonaerated lung by the [-200 to +100] Hounsfield Units interval, which includes shunting units within less opacified lung regions. Conclusion: During pure oxygen ventilation, logarithmically transformed PaO2/FIO2 allows estimation of CT shunt and its changes in patients during systemic inflammation. Relevant intrapulmonary shunting seems to occur in lung regions with CT numbers between [-200 and +100] Hounsfield Units.

  • 33.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bircher, N G
    Alexander, H
    Effects of intra-aortic balloon occlusion on hemodynamics during, and survival after cardiopulmonary resuscitation in dogs.1997In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 25, no 6, p. 1003-9Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the effect of balloon occlusion of the proximal descending aorta during cardiopulmonary resuscitation (CPR) on hemodynamics, restoration of spontaneous circulation, and 24-hr survival.

    DESIGN: Prospective, randomized, controlled trial.

    SETTING: Experimental laboratory in a university hospital.

    SUBJECTS: Eighteen anesthetized dogs. INTERVENTIONS; Catheters were placed for hemodynamic and blood gas monitoring. An aortic balloon catheter was placed with its tip just distal to the left subclavian artery. After 10 mins of ventricular fibrillation without CPR, 3 mins of Basic Life Support (chest compressions and ventilation with 100% oxygen) was followed by up to 30 mins of Advanced Cardiac Life Support with canine drug dosages. In the treatment group (n = 8), the intra-aortic balloon was inflated when Advanced Cardiac Life Support started and not deflated until shortly after restoration of spontaneous circulation. The control animals (n = 10) were treated with an identical resuscitation but without intra-aortic balloon occlusion.

    MEASUREMENTS AND MAIN RESULTS: In the treatment group, coronary perfusion pressure was greater during Advanced Cardiac Life Support (p = .026). Restoration of spontaneous circulation was more frequent (7/8 dogs) as compared with the control group (3/10 dogs) (p = .025). There was a trend toward greater 24-hr survival in the treatment group (5/8 dogs) than in the control group (3/10 dogs).

    CONCLUSIONS: Balloon occlusion of the proximal descending aorta during experimental CPR improves restoration of spontaneous circulation. Further laboratory and human studies are needed to determine the clinical efficacy of this technique.

  • 34.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Grenvik, A
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Blood flow and perfusion pressure during open-chest versus closed-chest cardiopulmonary resuscitation in pigs.1995In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, no 4, p. 715-25Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the blood flow and perfusion pressure differences observed during open- vs. closed-chest cardiopulmonary resuscitation (CPR), including the effects of epinephrine and sodium bicarbonate administration.

    DESIGN: Prospective, randomized, controlled trial.

    SETTING: Experimental animal laboratory in a university hospital.

    SUBJECTS: A total of 35 anesthetized piglets.

    INTERVENTIONS: After tracheostomy and insertion of arterial, right atrial, and pulmonary arterial catheters, thoracotomy was performed with placement of a pulmonary arterial flow probe and left atrial catheter. Ventricular fibrillation was induced and followed by 15 mins of either open-chest (n = 14) or closed-chest (n = 21) CPR. A 4-min infusion of 50 mmol of sodium bicarbonate or saline was added at the start of CPR. After 8 mins of CPR, 0.5 mg of epinephrine was given intravenously, and after 15 mins, direct current (DC) shocks were used to revert the heart to sinus rhythm.

    MEASUREMENTS AND MAIN RESULTS: Blood flow was studied using transit-time ultrasound flowmetry. In an extended group, intrathoracic pressure was measured for calculation of transmural pressure. Before epinephrine administration, mean pulmonary arterial flow (cardiac output) was reduced: a) during closed-chest CPR relatively more than pulmonary perfusion pressure but in proportion to systemic perfusion pressure; b) during open-chest CPR relatively less than pulmonary perfusion pressure but still in proportion to systemic perfusion pressure. Epinephrine administration temporarily increased systemic perfusion pressure during both closed- and open-chest CPR but temporarily decreased pulmonary perfusion pressure only during closed-chest CPR. After epinephrine administration, cardiac output temporarily decreased during both closed-and open-chest CPR.

    CONCLUSIONS: Open-chest CPR resulted in better cardiac output and systemic perfusion pressure than closed-chest CPR. However, cardiac output values obtained with both methods were much lower than previously reported. After epinephrine administration, cardiac output became extremely low with both methods.

  • 35.
    Rubertsson, Sten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Grenvik, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Zemgulis, Vitas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wiklund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Systemic perfusion pressure and blood flow before and after administration of epinephrine during experimental cardiopulmonary resuscitation1995In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 23, no 12, p. 1984-1996Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate instantaneous blood flow variations in the compression and relaxation phases of cardiopulmonary resuscitation (CPR) and the effect of epinephrine administration.

    DESIGN: Prospective, randomized, controlled trial.

    SETTING: Experimental laboratory in a university hospital.

    SUBJECTS: Twenty-two anesthetized piglets.

    INTERVENTIONS: A tracheostomy was performed and arterial, central venous, and pulmonary arterial catheters were inserted, followed by thoracotomy with placement of pulmonary arterial, aortic, and left anterior descending coronary arterial (extended study group) flow probes and a left atrial catheter. Ventricular fibrillation for 2 mins was followed by 10 mins of either open-chest (n = 10) or closed-chest (n = 12) CPR. Seven minutes after the initiation of CPR, all piglets received 0.5 mg of epinephrine iv; at 12 mins, direct current shocks were applied.

    MEASUREMENTS AND MAIN RESULTS: Open-chest CPR generated greater systemic perfusion pressure than closed-chest CPR, especially during the relaxation phase, resulting in greater mean blood flow. With both open- and closed-chest CPR, antegrade pulmonary arterial and aortic blood flow occurred during compression, whereas antegrade left anterior descending coronary arterial blood flow occurred during relaxation. During relaxation, retrograde flow was found in the pulmonary artery and aorta. During compression, retrograde flow was found in the left anterior descending coronary artery. The administration of epinephrine had the following effects: a) increased the systemic perfusion pressure more during open- than closed-chest CPR; b) increased the systemic relaxation perfusion pressure more than the compression perfusion pressure; c) decreased mean pulmonary arterial and aortic blood flow, but substantially increased the mean left anterior descending coronary artery blood flow; and d) reduced the retrograde flow in the left anterior descending coronary artery.

    CONCLUSIONS: Open-chest CPR generated greater systemic perfusion pressure and blood flow than closed-chest CPR. Epinephrine increased left anterior descending coronary artery blood flow but decreased total cardiac output, such that cerebral perfusion might be endangered. This problem will be studied separately.

  • 36.
    Røsjø, Helge
    et al.
    Akershus Univ Hosp, Div Med, Lorenskog, Norway.;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Ottesen, Anett H.
    Akershus Univ Hosp, Div Med, Lorenskog, Norway.;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.;Oslo Univ Hosp, Expt Med Res Inst, Oslo, Norway..
    Nygård, Ståle
    Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.;Univ Oslo, Bioinformat Core Facil, Oslo, Norway.;Oslo Univ Hosp, Oslo, Norway..
    Christensen, Geir
    Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.;Oslo Univ Hosp, Expt Med Res Inst, Oslo, Norway..
    Pettilä, Ville
    Univ Helsinki, Dept Intens Care Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Univ Bern, Univ Hosp Bern, Dept Intens Care Med, Bern, Switzerland..
    Linko, Rita
    Univ Helsinki, Dept Intens Care Med, Helsinki, Finland..
    Karlsson, Sari
    Tampere Univ Hosp, Dept Intens Care Med, Tampere, Finland..
    Varpula, Tero
    Univ Helsinki, Dept Intens Care Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Ruokonen, Esko
    Kuopio Univ Hosp, Intens Care Med, Kuopio, Finland..
    Omland, Torbjorn
    Akershus Univ Hosp, Div Med, Lorenskog, Norway.;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway..
    Prognostic Value of Secretoneurin in Critically III Patients With Infections2016In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 44, no 10, p. 1882-1890Article in journal (Refereed)
    Abstract [en]

    Objectives : Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. Design: Two prospective, observational studies. Setting: Twenty-four and twenty-five ICUs in Finland. Patients: A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). Interventions: None. Measurements and Main Results: We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was approximate to 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. Conclusions: Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections.

  • 37.
    Santos, Arnoldo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. CIBER Enfermedades Resp CIBERES, Madrid, Spain.; CNIC, Ctr Nacl Invest Cardiovasc Carlos 3, Madrid, Spain.
    Gomez-Peñalver, Eva
    Hosp Gen Villalba, Intens Care Unit, Villalba, Spain.
    Monge-Garcia, M Ignacio
    Hosp SAS, Intens Care Unit, Jerez de la Frontera, Spain.
    Retamal, Jaime
    Pontificia Univ Catolica Chile, Dept Med Intens, Santiago, Chile.
    Batista Borges, João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Univ Sao Paulo, Heart Inst InCor, Hosp Clin, Div Pulm, Sao Paulo, Brazil.
    Tusman, Gerardo
    Department of Anesthesia, Hospital Privado de Comunidad, Mar del Plata, Argentina.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. CIBER de enfermedades respiratorias (CIBERES), Madrid, Spain..
    Effects on Pulmonary Vascular Mechanics of Two Different Lung-Protective Ventilation Strategies in an Experimental Model of Acute Respiratory Distress Syndrome2017In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 11, p. e1157-e1164Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To compare the effects of two lung-protective ventilation strategies on pulmonary vascular mechanics in early acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: University animal research laboratory.

    SUBJECTS: Twelve pigs (30.8 ± 2.5 kg).

    INTERVENTIONS: Acute respiratory distress syndrome was induced by repeated lung lavages and injurious mechanical ventilation. Thereafter, animals were randomized to 4 hours ventilation according to the Acute Respiratory Distress Syndrome Network protocol or to an open lung approach strategy. Pressure and flow sensors placed at the pulmonary artery trunk allowed continuous assessment of pulmonary artery resistance, effective elastance, compliance, and reflected pressure waves. Respiratory mechanics and gas exchange data were collected.

    MEASUREMENTS AND MAIN RESULTS: Acute respiratory distress syndrome led to pulmonary vascular mechanics deterioration. Four hours after randomization, pulmonary vascular mechanics was similar in Acute Respiratory Distress Syndrome Network and open lung approach: resistance (578 ± 252 vs 626 ± 153 dyn.s/cm; p = 0.714), effective elastance, (0.63 ± 0.22 vs 0.58 ± 0.17 mm Hg/mL; p = 0.710), compliance (1.19 ± 0.8 vs 1.50 ± 0.27 mL/mm Hg; p = 0.437), and reflection index (0.36 ± 0.04 vs 0.34 ± 0.09; p = 0.680). Open lung approach as compared to Acute Respiratory Distress Syndrome Network was associated with improved dynamic respiratory compliance (17.3 ± 2.6 vs 10.5 ± 1.3 mL/cm H2O; p < 0.001), driving pressure (9.6 ± 1.3 vs 19.3 ± 2.7 cm H2O; p < 0.001), and venous admixture (0.05 ± 0.01 vs 0.22 ± 0.03, p < 0.001) and lower mean pulmonary artery pressure (26 ± 3 vs 34 ± 7 mm Hg; p = 0.045) despite of using a higher positive end-expiratory pressure (17.4 ± 0.7 vs 9.5 ± 2.4 cm H2O; p < 0.001). Cardiac index, however, was lower in open lung approach (1.42 ± 0.16 vs 2.27 ± 0.48 L/min; p = 0.005).

    CONCLUSIONS: In this experimental model, Acute Respiratory Distress Syndrome Network and open lung approach affected pulmonary vascular mechanics similarly. The use of higher positive end-expiratory pressures in the open lung approach strategy did not worsen pulmonary vascular mechanics, improved lung mechanics, and gas exchange but at the expense of a lower cardiac index.

  • 38.
    Santos, Arnoldo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Lucchetta, Luca
    Monge-Garcia, M Ignacio
    Batista Borges, João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Tusman, Gerardo
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    The Open Lung Approach Improves Pulmonary Vascular Mechanics in an Experimental Model of Acute Respiratory Distress Syndrome2017In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 3, p. e298-e305Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To test whether positive end-expiratory pressure consistent with an open lung approach improves pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressures in experimental acute respiratory distress syndrome.

    DESIGN: Experimental study.

    SETTING: Animal research laboratory.

    SUBJECTS: Ten pigs, 35 ± 5.2 kg.

    INTERVENTIONS: Acute respiratory distress syndrome was induced combining saline lung lavages with injurious mechanical ventilation. The positive end-expiratory pressure level resulting in highest compliance during a decremental positive end-expiratory pressure trial after lung recruitment was determined. Thereafter, three positive end-expiratory pressure levels were applied in a random order: hyperinflation, 6 cm H2O above; open lung approach, 2 cm H2O above; and collapse, 6 cm H2O below the highest compliance level. High fidelity pressure and flow sensors were placed at the main pulmonary artery for measuring pulmonary artery resistance (Z0), effective arterial elastance, compliance, and reflected pressure waves.

    MEASUREMENTS AND MAIN RESULTS: After inducing acute respiratory distress syndrome, Z0 and effective arterial elastance increased (from 218 ± 94 to 444 ± 115 dyn.s.cm and from 0.27 ± 0.14 to 0.62 ± 0.22 mm Hg/mL, respectively; p < 0.001), vascular compliance decreased (from 2.76 ± 0.86 to 1.48 ± 0.32 mL/mm Hg; p = 0.003), and reflected waves arrived earlier (0.23 ± 0.07 vs 0.14 ± 0.05, arbitrary unit; p = 0.002) compared with baseline. Comparing the three positive end-expiratory pressure levels, open lung approach resulted in the lowest: 1) Z0 (297 ± 83 vs 378 ± 79 dyn.s.cm, p = 0.033, and vs 450 ± 119 dyn.s.cm, p = 0.002); 2) effective arterial elastance (0.37 ± 0.08 vs 0.50 ± 0.15 mm Hg/mL, p = 0.04, and vs 0.61 ± 0.12 mm Hg/mL, p < 0.001), and 3) reflection coefficient (0.35 ± 0.17 vs 0.48 ± 0.10, p = 0.024, and vs 0.53 ± 0.19, p = 0.005), comparisons with hyperinflation and collapse, respectively.

    CONCLUSIONS: In this experimental setting, positive end-expiratory pressure consistent with the open lung approach resulted in the best pulmonary vascular mechanics compared with higher or lower positive end-expiratory pressure settings.

  • 39. Seder, David B.
    et al.
    Sunde, Kjetil
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Mooney, Michael
    Stammet, Pascal
    Riker, Richard R.
    Kern, Karl B.
    Unger, Barbara
    Cronberg, Tobias
    Dziodzio, John
    Nielsen, Niklas
    Neurologic Outcomes and Postresuscitation Care of Patients With Myoclonus Following Cardiac Arrest2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 5, p. 965-972Article in journal (Refereed)
    Abstract [en]

    Objectives: To evaluate the outcomes of cardiac arrest survivors with myoclonus receiving modern postresuscitation care. Design: Retrospective review of registry data. Setting: Cardiac arrest receiving centers in Europe and the United States from 2002 to 2012. Patients: Two thousand five hundred thirty-two cardiac arrest survivors 18 years or older enrolled in the International Cardiac Arrest Registry. Interventions: None. Measurements and Main Results: Eighty-eight percent of patients underwent therapeutic hypothermia and 471 (18%) exhibited myoclonus. Patients with myoclonus had longer time to professional cardiopulmonary resuscitation (8.6 vs 7.0 min; p < 0.001) and total ischemic time (25.6 vs 22.3 min; p < 0.001) and less often presented with ventricular tachycardia/ventricular fibrillation, a witnessed arrest, or had bystander cardiopulmonary resuscitation. Electroencephalography demonstrated myoclonus with epileptiform activity in 209 of 374 (55%), including status epilepticus in 102 of 374 (27%). Good outcome (Cerebral Performance Category 1-2) at hospital discharge was noted in 9% of patients with myoclonus, less frequently in myoclonus with epileptiform activity (2% vs 15%; p < 0.001). Patients with myoclonus with good outcome were younger (53.7 vs 62.7 yr; p < 0.001), had more ventricular tachycardia/ventricular fibrillation (81% vs 46%; p < 0.001), shorter ischemic time (18.9 vs 26.4 min; p = 0.003), more witnessed arrests (91% vs 77%; p = 0.02), and fewer "do-not-resuscitate" orders (7% vs 78%; p < 0.001). Life support was withdrawn in 330 of 427 patients (78%) with myoclonus and poor outcome, due to neurological futility in 293 of 330 (89%), at 5 days (3-8 d) after resuscitation. With myoclonus and good outcome, median ICU length of stay was 8 days (5-11 d) and hospital length of stay was 14.5 days (9-22 d). Conclusions: Nine percent of cardiac arrest survivors with myoclonus after cardiac arrest had good functional outcomes, usually in patients without associated epileptiform activity and after prolonged hospitalization. Deaths occurred early and primarily after withdrawal of life support. It is uncertain whether prolonged care would yield a higher percentage of good outcomes, but myoclonus of itself should not be considered a sign of futility.

  • 40.
    Skoglund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    The neurological wake-up test increases stress hormone levels in patients with severe traumatic brain injury2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 1, p. 216-222Article in journal (Refereed)
    Abstract [en]

    Objectives: The "neurological wake-up test" is needed to evaluate the level of consciousness in patients with severe traumatic brain injury. However, the neurological wake-up test requires interruption of continuous sedation and may induce a stress response and its use in neurocritical care is controversial. We hypothesized that the neurological wake-up test induces an additional biochemical stress response in patients with severe traumatic brain injury.

    Patients: Twenty-four patients who received continuous propofol sedation and mechanical ventilation after moderate to severe traumatic brain injury (Glasgow Coma Scale score <= 8; patient age 18-71 yrs old) were analyzed. Exclusion criteria were age <18 yrs old, ongoing pentobarbital infusion, or markedly increased intracranial pressure on interruption of continuous sedation.

    Design: Single-center prospective study. During postinjury days 1-8, 65 neurological wake-up tests were evaluated. Adrenocorticotrophic hormone, epinephrine, and norepinephrine levels in plasma and cortisol levels in saliva were analyzed at baseline (during continuous intravenous propofol sedation) and during neurological wake-up test. Data are presented using medians and 25th and 75th percentiles.

    Setting: The study was performed in a university hospital neurocritical care unit.

    Interventions: None.

    Measurements and Main Results: At baseline, adrenocorticotrophic hormone and cortisol levels were 10.6 (6.0-19.4) ng/L and 16.0 (10.7-31.8) nmol/L, respectively. Immediately after the neurological wake-up test, adrenocorticotrophic hormone levels increased to 20.5 (11.1-48.4) ng/L (p < .05) and cortisol levels in saliva increased to 24.0 (12.3-42.5) nmol/L (p < .05). The plasma epinephrine and norepinephrine levels increased from a baseline of 0.3 (0.3-0.6) and 1.6 (0.9-2.3) nmol/L, respectively, to 0.75 (0.3-1.4) and 2.8 (1.28-3.58) nmol/L, respectively (both p < .05).

    Conclusions: The neurological wake-up test induces a biochemical stress response in patients with severe traumatic brain injury. The clinical importance of this stress response remains to be established but should be considered when deciding the frequency and use of the neurological wake-up test during neurocritical care.

  • 41.
    Skoglund, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Enblad, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Wake-up test and stress hormone levels in patients with brain injury: A focus on mechanisms involved: Reply2012In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 40, no 6, p. 2002-2003Article in journal (Refereed)
  • 42.
    Skorup, Paul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Maudsdotter, Lisa
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Castegren, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model.2018In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses.

    DESIGN: Prospective, placebo-controlled interventional experimental study.

    SETTING: University research unit.

    SUBJECTS: Thirty-six healthy pigs administered Escherichia coli as a 3-hour infusion.

    INTERVENTIONS: After 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline.

    MEASUREMENTS AND MAIN RESULTS: Plasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation.

    CONCLUSIONS: Treatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model.

  • 43.
    Suarez-Sipmann, Fernando
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Borges, Joao Batista
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    How We Stretch the Lung Matters2013In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 41, no 4, p. 1153-1155Article in journal (Other academic)
  • 44.
    Suarez-Sipmann, Fernando
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Böhm, Stephan H.
    Tusman, Gerardo
    Pesch, Tanja
    Thamm, Oliver
    Reissmann, Hajo
    Reske, Andreas
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Use of dynamic compliance for open lung positive end-expiratory pressure titration in an experimental study2007In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 35, no 1, p. 214-221Article in journal (Refereed)
    Abstract [en]

    Objective: We tested whether the continuous monitoring of dynamic compliance could become a useful bedside tool for detecting the beginning of collapse of a fully recruited lung. Design: Prospective laboratory animal investigation. Setting: Clinical physiology research laboratory, University of Uppsala, Sweden. Subjects: Eight pigs submitted to repeated lung lavages. Interventions: Lung recruitment maneuver, the effect of which was confirmed by predefined oxygenation, lung mechanics, and computed tomography scan criteria, was followed by a positive end-expiratory pressure (PEEP) reduction trial in a volume control mode with a tidal volume of 6 mL/kg. Every 10 mins, PEEP was reduced in steps of 2 cm H2O starting from 24 cm H2O. During PEEP reduction, lung collapse was defined by the maximum dynamic compliance value after which a first measurable decrease occurred. Open lung PEEP according to dynamic compliance was then defined as the level of PEEP before the point of collapse. This value was compared with oxygenation (PaO2) and CT scans. Measurements and Main Results: PaO2 and dynamic compliance were monitored continuously, whereas computed tomography scans were obtained at the end of each pressure step. Collapse defined by dynamic compliance occurred at a PEEP of 14 cm H2O. This level coincided with the oxygenation-based collapse point when also shunt started to increase and occurred one step before the percentage of nonaerated tissue on the computed tomography exceeded 5%. Open lung PEEP was thus at 16 cm H2O, the level at which oxygenation and computed tomography scan confirmed a fully open, not yet collapsed lung condition. Conclusions: In this experimental model, the continuous monitoring of dynamic compliance identified the beginning of collapse after lung recruitment. These findings were confirmed by oxygenation and computed tomography scans. This method might become a valuable bedside tool for identifying the level of PEEP that prevents end-expiratory collapse.

  • 45.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Samonis, George
    Kofteridi, Diamantis R.
    The Role of Aerosolized Colistin in the Treatment of Ventilator-Associated Pneumonia: A Systematic Review and Metaanalysis2015In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 43, no 3, p. 527-533Article in journal (Refereed)
    Abstract [en]

    Objectives: The present meta-analysis and systematic review evaluated the efficacy and safety of aerosolized colistin as adjunctive therapy to IV antimicrobials or as monotherapy in the treatment of ventilator-associated pneumonia. Design: The databases of MEDLINE and Cochrane Library up to June 2013 and all reference lists of the included studies and relevant reviews were searched. Studies were eligible if the efficacy and safety of aerosolized colistin in the treatment of ventilator-associated pneumonia was evaluated. An overall effect estimate for all dichotomous data as an odds ratio with 95% CI was calculated by the Mantel-Haenszel or the DerSimonian and Laird method depending on the statistical heterogeneity. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to interpret the findings. Interventions: None. Measurements and Main Results: Sixteen studies fulfilled the inclusion criteria: eight were comparing adjunctive aerosolized versus IV colistin (seven observational cohort or case-control studies and one randomized trial) and were meta-analyzed, and eight were single arm and were only systematically reviewed. The Grading of Recommendations Assessment, Development, and Evaluation approach showed limitations of the study design and presence of inconsistency in most of the outcomes, but no obvious indirectness or imprecision of results reporting. Based on the above assessments, the quality of evidence presented for each outcome ranged from "very low" to "low:" A significant improvement in clinical response (odds ratio, 1.57; 95% CI, 1.14-2.15; p = 0.006; = 37%), microbiological eradication (odds ratio, 1.61; 95% CI, 1.11-2.35; p = 0.01; I-2= 0%), and infection-related mortality (odds ratio, 0.58; 95% CI, 0.34-0.96; p = 0.04; I-2 = 46%) was observed with the addition of aerosolized colistin to IV treatment, whereas the addition of aerosolized colistin did not affect overall mortality (odds ratio, 0.74; 95% CI, 0.54-1.01; p = 0.06; I-2 = 25%) or nephrotoxicity (odds ratio, 1.18; 95% CI, 0.76-1.83; p= 0.45; I-2= 0%). Conclusion: Based on the present results and awaiting further evidence from randomized trials, aerosolized colistin is associated with improved outcome in the treatment of ventilator-associated pneumonia although the level of evidence was low.

  • 46.
    Valachis, Antonis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Malarsjukhuset, Dept Oncol, Eskilstuna, Sweden.
    Samonis, George
    Univ Hosp Heraklion, Infect Dis Unit, Dept Internal Med, Iraklion, Greece..
    Kofteridis, Diamantis P.
    Univ Hosp Heraklion, Infect Dis Unit, Dept Internal Med, Iraklion, Greece..
    The Role of Aerolized Colistin in the Treatment of Hospital-Acquired Pneumonia: Experience of Multicenter From Turkey Reply2016In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 44, no 5, p. E304-E305Article in journal (Other academic)
  • 47.
    Villar, Jesus
    et al.
    Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.;Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain..
    Martin-Rodriguez, Carmen
    Hosp Gen Ciudad Real, Intens Care Unit, Ciudad Real, Spain..
    Dominguez-Berrot, Ana M.
    Complejo Asistencial Univ Leon, Intens Care Unit, Leon, Spain..
    Fernandez, Lorena
    Hosp Univ Rio Hortega, Intens Care Unit, Valladolid, Spain..
    Ferrando, Carlos
    Hosp Clin Univ, Dept Anesthesiol, Valencia, Spain..
    Soler, Juan A.
    Hosp Univ Morales Meseguer, Intens Care Unit, Murcia, Spain..
    Diaz-Lamas, Ana M.
    Hosp Univ A Coruna, Intens Care Unit, Coruna, Spain..
    Gonzalez-Higueras, Elena
    Hosp Virgen de La Luz, Intens Care Unit, Cuenca, Spain..
    Nogales, Leonor
    Hosp Clin Univ, Intens Care Unit, Valladolid, Spain..
    Ambros, Alfonso
    Hosp Gen Ciudad Real, Intens Care Unit, Ciudad Real, Spain..
    Carriedo, Demetrio
    Complejo Asistencial Univ Leon, Intens Care Unit, Leon, Spain..
    Hernandez, Monica
    Hosp Univ La Paz, Intens Care Unit, Madrid, Spain..
    Martinez, Domingo
    Hosp Univ Virgen de Arrixaca, Intens Care Unit, Murcia, Spain..
    Blanco, Jesus
    Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.;Hosp Univ Rio Hortega, Intens Care Unit, Valladolid, Spain..
    Belda, Javier
    Hosp Clin Univ, Dept Anesthesiol, Valencia, Spain..
    Parrilla, Dacil
    Hosp Univ NS Candelaria, Intens Care Unit, Santa Cruz De Tenerife, Spain..
    Suárez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain..
    Tarancon, Concepcion
    Hosp Virgen de la Concha, Intens Care Unit, Zamora, Spain..
    Mora-Ordonez, Juan M.
    Hosp Univ Carlos Haya, Intens Care Unit, Malaga, Spain..
    Blanch, Lluis
    Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.;Corp Sanitaria Parc Tauli, Crit Care Ctr, Sabadell, Spain..
    Perez-Mendez, Lina
    Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.;Hosp Univ NS Candelaria, Res Unit, Santa Cruz De Tenerife, Spain..
    Fernandez, Rosa L.
    Inst Salud Carlos III, CIBER Enfermedades Resp, Madrid, Spain.;Hosp Univ Dr Negrin, Res Unit, Las Palmas Gran Canaria, Spain..
    Kacmarek, Robert M.
    Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA.;Harvard Univ, Dept Anesthesia, Boston, MA 02115 USA..
    A Quantile Analysis of Plateau and Driving Pressures: Effects on Mortality in Patients With Acute Respiratory Distress Syndrome Receiving Lung-Protective Ventilation2017In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 45, no 5, p. 843-850Article in journal (Refereed)
    Abstract [en]

    Objectives: The driving pressure (plateau pressure minus positive end-expiratory pressure) has been suggested as the major determinant for the beneficial effects of lung-protective ventilation. We tested whether driving pressure was superior to the variables that define it in predicting outcome in patients with acute respiratory distress syndrome.

    Design: A secondary analysis of existing data from previously reported observational studies.

    Setting: A network of ICUs.

    Patients: We studied 778 patients with moderate to severe acute respiratory distress syndrome.

    Interventions: None.

    Measurements and Main Results: We assessed the risk of hospital death based on quantiles of tidal volume, positive end-expiratory pressure, plateau pressure, and driving pressure evaluated at 24 hours after acute respiratory distress syndrome diagnosis while ventilated with standardized lung-protective ventilation. We derived our model using individual data from 478 acute respiratory distress syndrome patients and assessed its replicability in a separate cohort of 300 acute respiratory distress syndrome patients. Tidal volume and positive end-expiratory pressure had no impact on mortality. We identified a plateau pressure cut-off value of 29 cm H2O, above which an ordinal increment was accompanied by an increment of risk of death. We identified a driving pressure cut-off value of 19 cm H2O where an ordinal increment was accompanied by an increment of risk of death. When we cross tabulated patients with plateau pressure less than 30 and plateau pressure greater than or equal to 30 with those with driving pressure less than 19 and driving pressure greater than or equal to 19, plateau pressure provided a slightly better prediction of outcome than driving pressure in both the derivation and validation cohorts (p < 0.0000001).

    Conclusions: Plateau pressure was slightly better than driving pressure in predicting hospital death in patients managed with lung-protective ventilation evaluated on standardized ventilator settings 24 hours after acute respiratory distress syndrome onset.

  • 48. Vistisen, Simon T
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Prediction of fluid responsiveness in acute respiratory distress syndrome patients ventilated with low tidal volume and high positive end-expiratory pressure2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 6, p. 2146-Article in journal (Refereed)
  • 49. Wilhelms, Susanne B.
    et al.
    Huss, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Plastic Surgery.
    Granath, Göran
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Sjöberg, Folke
    Assessment of incidence of severe sepsis in Sweden using different ways of abstracting International Classification of Diseases codes: Difficulties with methods and interpretation of results2010In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 38, no 6, p. 1442-1449Article in journal (Refereed)
    Abstract [en]

    Objective: To compare three International Classification of Diseases code abstraction strategies that have previously been reported to mirror severe sepsis by examining retrospective Swedish national data from 1987 to 2005 inclusive. Design: Retrospective cohort study. Setting: Swedish hospital discharge database. Patients: All hospital admissions during the period 1987 to 2005 were extracted and these patients were screened for severe sepsis using the three International Classification of Diseases code abstraction strategies, which were adapted for the Swedish version of the International Classification of Diseases. Two code abstraction strategies included both International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes, whereas one included International Classification of Diseases, Tenth Revision codes alone. Interventions: None. Measurements and Main Results: The three International Classification of Diseases code abstraction strategies identified 37,990, 27,655, and 12,512 patients, respectively, with severe sepsis. The incidence increased over the years, reaching 0.35 per 1000, 0.43 per 1000, and 0.13 per 1000 inhabitants, respectively. During the International Classification of Diseases, Ninth Revision period, we found 17,096 unique patients and of these, only 2789 patients (16%) met two of the code abstraction strategy lists and 14,307 (84%) met one list. The International Classification of Diseases, Tenth Revision period included 46,979 unique patients, of whom 8% met the criteria of all three International Classification of Diseases code abstraction strategies, 7% met two, and 84% met one only. Conclusions: The three different International Classification of Diseases code abstraction strategies generated three almost separate cohorts of patients with severe sepsis. Thus, the International Classification of Diseases code abstraction strategies for recording severe sepsis in use today provides an unsatisfactory way of estimating the true incidence of severe sepsis. Further studies relating International Classification of Diseases code abstraction strategies to the American College of Chest Physicians/Society of Critical Care Medicine scores are needed.

  • 50. Wrigge, Hermann
    et al.
    Zinserling, Jörg
    Muders, Thomas
    Vareimann, Dirk
    Günther, Ulf
    von der Groeben, Cornelius
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Hedenstierna, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Putensen, Christian
    Electrical impedance tomography compared with thoracic computed tomography during a slow inflation maneuver in experimental models of lung injury2008In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 36, no 3, p. 903-909Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To determine the validity of functional electric impedance tomography to monitor regional ventilation distribution in experimental acute lung injury, and to develop a simple electric impedance tomography index detecting alveolar recruitment. DESIGN: Randomized prospective experimental study. SETTING: Academic research laboratory. SUBJECTS: Sixteen anesthetized, tracheotomized, and mechanically ventilated pigs. INTERVENTIONS: Acute lung injury was induced either by acid aspiration (direct acute lung injury) or by abdominal hypertension plus oleic acid injection (indirect acute lung injury) in ten pigs. Six pigs with normal lungs were studied as a control group and with endotracheal suction-related atelectasis. After 4 hrs of mechanical ventilation, a slow inflation was performed. MEASUREMENTS AND MAIN RESULTS: During slow inflation, simultaneous measurements of regional ventilation by electric impedance tomography and dynamic computed tomography were highly correlated in quadrants of a transversal thoracic plane (r2 = .63-.88, p < .0001, bias <5%) in both direct and indirect acute lung injury. Variability between methods was lower in direct than indirect acute lung injury (11 +/- 2% vs. 18 +/- 3%, respectively, p < .05). Electric impedance tomography indexes to detect alveolar recruitment were determined by mathematical curve analysis of regional impedance time curves. Empirical tests of different methods revealed that regional ventilation delay, that is, time delay of regional impedance time curve to reach a threshold, correlated well with recruited volume as measured by CT (r2 = .63). Correlation coefficients in subgroups were r2 = .71 and r2 = .48 in pigs with normal lungs with and without closed suction related atelectasis and r2 = .79 in pigs subject to indirect acute lung injury, respectively, whereas no significant correlation was found in pigs undergoing direct acute lung injury. CONCLUSIONS: Electric impedance tomography allows assessment of regional ventilation distribution and recruitment in experimental models of direct and indirect acute lung injury as well as normal lungs. Except for pigs with direct acute lung injury, regional ventilation delay determined during a slow inflation from impedance time curves appears to be a simple index for clinical monitoring of alveolar recruitment.

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