Filip Fredén - Academia.edu (original) (raw)

Papers by Filip Fredén

Acta Anaesthesiologica Scandinavica, Sep 4, 2015

Background: Burn injuries are associated with strong inflammation and risk of secondary sepsis wh... more Background: Burn injuries are associated with strong inflammation and risk of secondary sepsis which both may affect the function of the glucocorticoid receptor (GR). The aim of this study was to determine GR expression and binding capacity in leucocytes from patients admitted to a tertiary burn center. Methods: Blood was sampled from 13 patients on admission and days 7, 14 and 21, and once from 16 healthy subjects. Patients were grouped according to the extent of burn and to any sepsis on day 7. Expression and binding capacity of GR were determined as arbitrary units using flow cytometry. Results: GR expression and binding capacity were increased compared to healthy subjects in most circulating leucocyte subsets on admission irrespective of burn size. Patients with sepsis on day 7 displayed increased GR expression in T lymphocytes (51.8%, P < 0.01) compared to admission. There was a negative correlation between GR binding capacity in neutrophils and burn size after 14 days (P < 0.05). Conclusions: GR expression and binding capacity are increased in most types of circulating leucocytes of severely burned patients on their admission to specialized burn care. If sepsis is present after 1 week, it is associated with higher GR expression in T lymphocytes and NK cells. Editorial comments: what this article tells us This study shows that glucocorticoid receptor expression and binding capacity in leucocytes are higher in burn patients compared to healthy volunteers. If patients have sepsis at 1 week after burn injury, this expression increases further.

In patients affected by acute respiratory failure or acute respiratory distress syndrome (ARDS) t... more In patients affected by acute respiratory failure or acute respiratory distress syndrome (ARDS) the leading cause of death is failure of different vital organs other than the lungs, so called multiple organ dysfunction syndrome (MODS). The abdominal organs have a crucial role in the pathogenesis of this syndrome.There is a lack of knowledge regarding the mechanisms by which mechanical ventilation can affect the abdominal compartment. One hypothesis is that mechanical ventilation can interfere with abdominal fluid balance causing edema and inflammation.We addressed the question whether different levels of ventilatory support (mechanical ventilation with different levels of positive end-expiratory pressure, PEEP, and spontaneous breathing with or without PEEP) can influence abdominal edema and inflammation in both healthy and endotoxin-exposed animals.The effect on lymphatic drainage from the abdomen exerted by different degrees of ventilatory support was evaluated (paper I). We demonstrated that endotoxin increases abdominal lymph production, that PEEP and mechanical ventilation increase lymph production but also impede lymphatic drainage; spontaneous breathing improves lymphatic drainage from the abdomen.By adapting a non-invasive nuclear medicine imaging technique and validating it (paper II), we have been able to evaluate extravascular fluid accumulation (edema formation) in the abdomen over time (paper III) demonstrating that edema increases during endotoxemia, mimicking a sepsis-like condition, and that spontaneous breathing, compared to mechanical ventilation, reduces extravascular fluid. Pro-inflammatory cytokines TNF-α and IL-6 in intestinal biopsies are reduced during spontaneous breathing compared to mechanical ventilation.Abdominal edema results in increased intra-abdominal pressure (IAP): in paper IV we analyzed the effect of increased intra-abdominal pressure on the respiratory system. Pulmonary shunt fraction increased with high IAP both in healthy and LPS animals, resulting in decreased level of oxygenation. These changes are only partially reversible by reducing IAP.In conclusion, mechanical ventilation is a life-saving tool but the possible side effect at the extra-pulmonary level should be considered, and the introduction of some degree of spontaneous breathing when clinically possible is a suggested choice.

BJA: British Journal of Anaesthesia, Sep 1, 1996

I.v. administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME... more I.v. administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), not only reduces blood flow in a hypoxic lung region but also causes systemic vasoconstriction and a decrease in cardiac output. In this study, we delivered nebulized L-NAME 0.2-1 mg kg 91 to the left lower lobe of 10 anaesthetized pigs. The left lower lobe was made hypoxic by selective inhalation of 5% oxygen or collapsed by interrupted ventilation, or both. Inhalation of L-NAME reduced fractional blood flow to the left lower lobe from 5.3 (SD 3.1)% to 1.7 (1.4)% (P:0.05) in lobar hypoxia and from 6.0 (3.3) to 2.7 (2.7)% (P:0.05) in lobar collapse. These reductions were accompanied by a significant increase in. P 2 O a There were no significant changes in arterial pressure, cardiac output or heart rate. We have shown that selective inhalation of L-NAME reduced blood flow to a hypoxic or collapsed lung region without systemic effects. The possible role for nitric oxide synthase inhibition in reducing shunt during onelung ventilation, however, requires further study. (Br.

Formation of atelectasis, defined as reversible collapse of aerated lung, often occurs after indu... more Formation of atelectasis, defined as reversible collapse of aerated lung, often occurs after induction of anaesthesia with mechanical ventilation. As a consequence, there is a risk for hypoxemia, altered hemodynamics and impaired respiratory system mechanics. In certain situations, the risk for atelectasis formation is increased and its consequences may also be more difficult to manage. Anesthesia for bariatric surgery in morbidly obese patients and surgery requiring one-lung ventilation (OLV) with capnothorax are examples of such situations.In Paper I (30 patients with BMI > 40 kg/m2 scheduled for bariatric surgery) a recruitment maneuver followed by positive end-expiratory pressure (PEEP) reduced the amount of atelectasis and improved oxygenation for a prolonged period of time. PEEP or a recruitment maneuver alone did not reduce the amount of atelectasis.In paper II we investigated whether it is possible to predict respiratory function impairment in morbidly obese patients without pulmonary disease from a preoperative lung function test. Patients with mild signs of airway obstruction (reduced end-expiratory flow) in the preoperative spirometry developed less atelectasis during anaesthesia.In paper III we developed an experimental model of sequential OLV with capnothorax using electrical impedance tomography (EIT) that in real-time detected lung separation and dynamic changes in pulmonary ventilation and perfusion distributions. OLV to the left side caused a decrease in cardiac output, arterial oxygenation and mixed venous saturation.In paper IV we used our model of OLV with capnothorax and applied a CO2-insufflation pressure of 16 cm H2O. We demonstrated that a PEEP level of 12-16 cm H2O is needed for optimal oxygenation and lowest possible driving pressure without compromising hemodynamic variables. Thus, the optimal PEEP was closely related to the level of the capnothorax insufflation pressure. With insufficient PEEP, ventilation/perfusion mismatch in the ventilated lung and redistribution of blood flow to the non-ventilated lung occurred.

[Uppsala University] , Distributor, Almqvist & Wiksell International eBooks, 1997

Pulmonary blood flow in acute lung injury and regional Hypoxia: Effect of mudulating the nitric o... more Pulmonary blood flow in acute lung injury and regional Hypoxia: Effect of mudulating the nitric oxide - guanylate cyclase system.

Acta Anaesthesiologica Scandinavica, Aug 21, 2018

Background: One-lung ventilation (OLV) with induced capnothorax carries the risk of severely impa... more Background: One-lung ventilation (OLV) with induced capnothorax carries the risk of severely impaired ventilation and circulation. Optimal PEEP may mitigate the physiological perturbations during these conditions. Methods: Right-sided OLV with capnothorax (16 cm H 2 O) on the left side was initiated in eight anesthetized, muscle-relaxed piglets. A recruitment maneuver and a decremental PEEP titration from PEEP 20 cm H 2 O to zero end-expiratory pressure (ZEEP) was performed. Regional ventilation and perfusion were studied with electrical impedance tomography and computer tomography of the chest was used. Endexpiratory lung volume and hemodynamics were recorded and. Results: PaO 2 peaked at PEEP 12 cm H 2 O (49 ± 14 kPa) and decreased to 11 ± 5 kPa at ZEEP (P < 0.001). PaCO 2 was 9.5 ± 1.3 kPa at 20 cm H 2 O PEEP and did not change when PEEP step-wise was reduced to 12 cm H 2 O PaCO 2. At lower PEEP, PaCO 2 increased markedly. The ventilatory driving pressure was lowest at PEEP 14 cm H 2 O (19.6 ± 5.8 cm H 2 O) and increased to 38.3 ± 6.1 cm H 2 O at ZEEP (P < 0.001). When reducing PEEP below 12-14 cm H 2 O ventilation shifted from the dependent to the nondependent regions of the ventilated lung (P = 0.003), and perfusion shifted from the ventilated to the nonventilated lung (P = 0.02). Conclusion: Optimal PEEP was 12-18 cm H 2 O and probably relates to capnothorax insufflation pressure. With suboptimal PEEP, ventilation/perfusion mismatch in the ventilated lung and redistribution of blood flow to the nonventilated lung occurred.

Acta Anaesthesiologica Scandinavica, Jan 5, 2015

Background: Carbon dioxide insufflation into the pleural cavity, capnothorax, with one-lung venti... more Background: Carbon dioxide insufflation into the pleural cavity, capnothorax, with one-lung ventilation (OLV) may entail respiratory and hemodynamic impairments. We investigated the online physiological effects of OLV/capnothorax by electrical impedance tomography (EIT) in a porcine model mimicking the clinical setting. Methods: Five anesthetized, muscle-relaxed piglets were subjected to first right and then left capnothorax with an intra-pleural pressure of 19 cm H2O. The contra-lateral lung was mechanically ventilated with a double-lumen tube at positive end-expiratory pressure 5 and subsequently 10 cm H2O. Regional lung perfusion and ventilation were assessed by EIT. Hemodynamics, cerebral tissue oxygenation and lung gas exchange were also measured. Results: During right-sided capnothorax, mixed venous oxygen saturation (P = 0.018), as well as a tissue oxygenation index (P = 0.038) decreased. There was also an increase in central venous pressure (P = 0.006), and a decrease in mean arterial pressure (P = 0.045) and cardiac output (P = 0.017). During the left-sided capnothorax, the hemodynamic impairment was less than during the right side. EIT revealed that during the first period of OLV/ capnothorax, no or very minor ventilation on the right side could be seen (3 ± 3% vs. 97 ± 3%, right vs. left, P = 0.007), perfusion decreased in the non-ventilated and increased in the ventilated lung (18 ± 2% vs. 82 ± 2%, right vs. left, P = 0.03). During the second OLV/capnothorax period, a similar distribution of perfusion was seen in the animals with successful separation (84 ± 4% vs. 16 ± 4%, right vs. left). Conclusion: EIT detected in real-time dynamic changes in pulmonary ventilation and perfusion distributions. OLV to the left lung with right-sided capnothorax caused a decrease in cardiac output, arterial oxygenation and mixed venous saturation.

Expiratory Resistance Prevents Eccentric Diaphragm Contraction, Flow Limitation andLung Collapse

Scars, burns & healing, 2022

Introduction Burn injuries are a common traumatic injury. Large burns have high mortality requiri... more Introduction Burn injuries are a common traumatic injury. Large burns have high mortality requiring intensive care and accurate mortality predictions. To assess if machine learning (ML) could improve predictions, ML algorithms were tested and compared with the original and revised Baux score. Methods Admission data and mortality outcomes were collected from patients at Uppsala University Hospital Burn Centre from 2002 to 2019. Prognostic variables were selected, ML algorithms trained and predictions assessed by analysis of the area under the receiver operating characteristic curve (AUC). Comparison was made with Baux scores using DeLong test Results A total of 17 prognostic variables were selected from 92 patients. AUCs in leave-one-out cross-validation for a decision tree model, an extreme boosting model, a random forest model, a support-vector machine (SVM) model and a generalised linear regression model (GLM) were 0.83 (95% confidence interval [CI] = 0.72–0.94), 0.92 (95% CI = 0.84–1), 0.92 (95% CI = 0.84–1), 0.92 (95% CI = 0.84–1) and 0.84 (95% CI = 0.74–0.94), respectively. AUCs for the Baux score and revised Baux score were 0.85 (95% CI = 0.75–0.95) and 0.84 (95% CI = 0.74–0.94). No significant differences were observed when comparing ML algorithms with Baux score and revised Baux score. Secondary variable selection was made to analyse model performance. Conclusion This proof-of-concept study showed initial credibility in using ML algorithms to predict mortality in burn patients. The sample size was small and future studies are needed with larger sample sizes, further variable selections and prospective testing of the algorithms. Lay Summary Burn injuries are one of the most common traumatic injuries especially in countries with limited prevention and healthcare resources. To treat a patient with large burns who has been admitted to an intensive care unit, it is often necessary to assess the risk of a fatal outcome. Physicians traditionally use simplified scores to calculate risks. One commonly used score, the Baux score, uses age of the patient and the size of the burn to predict the risk of death. Adding the factor of inhalation injury, the score is then called the revised Baux score. However, there are a number of additional causes that can influence the risk of fatal outcomes that Baux scores do not take into account. Machine learning is a method of data modelling where the system learns to predict outcomes based on previous cases and is a branch of artificial intelligence. In this study we evaluated several machine learning methods for outcome prediction in patients admitted for burn injury. We gathered data on 93 patients at admission to the intensive care unit and our experiments show that machine learning methods can reach an accuracy comparable with Baux scores in calculating the risk of fatal outcomes. This study represents a proof of principle and future studies on larger patient series are required to verify our results as well as to evaluate the methods on patients in real-life situations.

Intensive Care Medicine, Apr 1, 1993

Objective: In acute respiratory failure, increased cardiac output (Qt) increases shunt (Qs/0t). W... more Objective: In acute respiratory failure, increased cardiac output (Qt) increases shunt (Qs/0t). We have tested if this is caused by: 1) a redistribution of blood flow towards edematous regions, or 2) a decrease of regional ventilation in the edematous region. Design: Oleic acid edema was induced in the left lower lobe (LLL) of 11 pigs. Qt was varied with bleeding and infusion of blood and dextran. Blood flow to the LLL was measured at low and high Qt with electromagnetic low probes in 6 animals and with a gamma camera in 5. In the gamma camera pigs regional ventilation was also measured. Measurements and results: 0t was increased by 45% (electromagnetic flow probes) and 7307o (gamma camera). Qs/0t increased from 24.9-31.3~ (/)<0.05) and from 17.6-28.8% (p < 0.001) respectively. No change in fractional perfusion of LLL could be seen, neither with flow probes nor with gamma camera. A decrease in ventilation of LLL, 2.6070, was observed when Qt was increased (p< 0.05). Conclusion: Theoretically a small decrease in ventilation can explain the increase in shunt, if regions with low ventilation/perfusion (VA/0) ratio are transformed to shunt. This is, however, unlikely since earlier studies have shown that blood flow is distributed either to regions with normal VA/0 ratio or to shunt regions. We conclude that the cardiac output dependent shunt is not caused by redistribution of blood flow between lobes or by decreased ventilation in the edematous region. We cannot exclude that blood flow is redistributed within the edematous lobe.

American Journal of Respiratory and Critical Care Medicine, May 15, 2020

Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying p... more Rationale: Tidal expiratory flow limitation (tidal-EFL) is not completely avoidable by applying positive end-expiratory pressure and may cause respiratory and hemodynamic complications in ventilated patients with lungs prone to collapse. During spontaneous breathing, expiratory diaphragmatic contraction counteracts tidal-EFL. We hypothesized that during both spontaneous breathing and controlled mechanical ventilation, external expiratory resistances reduce tidal-EFL. Objectives: To assess whether external expiratory resistances 1) affect expiratory diaphragmatic contraction during spontaneous breathing, 2) reduce expiratory flow and make lung compartments more homogeneous with more similar expiratory time constants, and 3) reduce tidal atelectasis, preventing hyperinflation. Methods: Three positive end-expiratory pressure levels and four external expiratory resistances were tested in 10 pigs after lung lavage. We analyzed expiratory diaphragmatic electric activity and respiratory mechanics. On the basis of computed tomography scans, four lung compartments-not inflated (atelectasis), poorly inflated, normally inflated, and hyperinflated-were defined. Measurements and Main Results: Consequently to additional external expiratory resistances, and mainly in lungs prone to collapse (at low positive end-expiratory pressure), 1) the expiratory transdiaphragmatic pressure decreased during spontaneous breathing by .10%, 2) expiratory flow was reduced and the expiratory time constants became more homogeneous, and 3) the amount of atelectasis at end-expiration decreased from 24% to 16% during spontaneous breathing and from 32% to 18% during controlled mechanical ventilation, without increasing hyperinflation. Conclusions: The expiratory modulation induced by external expiratory resistances preserves the positive effects of the expiratory brake while minimizing expiratory diaphragmatic contraction. External expiratory resistances optimize lung mechanics and limit tidal-EFL and tidal atelectasis, without increasing hyperinflation.

European Journal of Plastic Surgery, May 4, 2022

Scald is one type of burn that s often mentioned alone and occurs mostly in the paediatric popula... more Scald is one type of burn that s often mentioned alone and occurs mostly in the paediatric population. Inhaled steam is mostly cooled off in the airways, why thermal damage is rarely seen. A sudden exposure to hot steam/inhalation can cause a thermal inhalation injury. A scoping review was performed, with the aim to summarize all published papers in English, about steam-related injuries. The search was conducted using the PubMed® and Cochrane libraries on 19th of May 2021, without a set time period. Out of a total of 1186 identified records, 31 were chosen for review. Burns related to the contact with steam are generally rare and can be both minor and severe. The more severe cases related to steam exposure are mostly workplace accidents and the minor injuries reported in the literature are often related to steam inhalation therapy, especially in the paediatric population. This review describes the challenges that can be found dealing with patients suffering from cutaneous steam burns and/or steam inhalation injuries. A steam injury to the airways or the skin can be directly life-threatening and should be treated with caution. This type of injury can lead to acute respiratory insufficiency and sometimes death. A case of a male patient with extensive cutaneous steam burns and a steam inhalation injury who passed away after 11 days of treatment is also presented to illustrate this review.

Critical Care, Mar 7, 2022

Background: The ratio of partial pressure of arterial oxygen to inspired oxygen fraction (PaO 2 /... more Background: The ratio of partial pressure of arterial oxygen to inspired oxygen fraction (PaO 2 /F I O 2) during invasive mechanical ventilation (MV) is used as criteria to grade the severity of respiratory failure in acute respiratory distress syndrome (ARDS). During the SARS-CoV2 pandemic, the use of PaO 2 /F I O 2 ratio has been increasingly used in noninvasive respiratory support such as high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV). The grading of hypoxemia in non-invasively ventilated patients is uncertain. The main hypothesis, investigated in this study, was that the PaO 2 /F I O 2 ratio does not change when switching between MV, NIV and HFNC. Methods: We investigated respiratory function in critically ill patients with COVID-19 included in a single-center prospective observational study of patients admitted to the intensive care unit (ICU) at Uppsala University Hospital in Sweden. In a steady state condition, the PaO 2 /F I O 2 ratio was recorded before and after any change between two of the studied respiratory support techniques (i.e., HFNC, NIV and MV). Results: A total of 148 patients were included in the present analysis. We find that any change in respiratory support from or to HFNC caused a significant change in PaO 2 /F I O 2 ratio. Changes in respiratory support between NIV and MV did not show consistent change in PaO 2 /F I O 2 ratio. In patients classified as mild to moderate ARDS during MV, the change from HFNC to MV showed a variable increase in PaO 2 /F I O 2 ratio ranging between 52 and 140 mmHg (median of 127 mmHg). This made prediction of ARDS severity during MV from the apparent ARDS grade during HFNC impossible. Conclusions: HFNC is associated with lower PaO 2 /F I O 2 ratio than either NIV or MV in the same patient, while NIV and MV provided similar PaO 2 /F I O 2 and thus ARDS grade by Berlin definition. The large variation of PaO 2 /F I O 2 ratio indicates that great caution should be used when estimating ARDS grade as a measure of pulmonary damage during HFNC.

Anesthesiology, May 1, 1995

Scandinavian Cardiovascular Journal, 1999

Inhaled NO is reported to be less effective in patients with ARDS if cardiac output is high (&amp... more Inhaled NO is reported to be less effective in patients with ARDS if cardiac output is high (> 10 L/min). It has also been demonstrated that increased blood flow and increased shear stress cause an enhancement of endogenous NO production. In one-lung ventilation and regional hypoxia, nitric oxide (NO) delivered to the ventilated lung may decrease blood flow to the nonventilated lung and improve arterial oxygenation. So far, however, results have been divergent. The present study was performed with the hypothesis that inhaled NO would be less effective if cardiac output was increased. In the anaesthetized pig, hypoxia (5% O2) was induced in the left lower lobe. NO was delivered consecutively to the hypoxic lobe and to the other, oxygenated parts, of the lungs during continuous measurement of lobar blood flow and total lung blood flow. Bleeding and infusion of dextran caused variation in cardiac output. It was found that lobar hypoxia per se reduced lobar blood flow from 22.9+/-3.1% to 4.7+/-0.9% of cardiac output. An increase (3.2+/-0.3 L x min(-1)) and a decrease (2.2+/-0.2 L x min(-1)) in cardiac output did not alter the relative perfusion of the hypoxic lobe from baseline cardiac output (2.6+/-0.2 L x min(-1)) values. When NO was delivered to the hypoxic lobe, there was a marked increase in relative lobar perfusion to 19.0+/-2.9% during low cardiac output and 16.5+/-2.7% during high cardiac output without any significant difference between the two NO-induced increases of lobar perfusion. The increase in lobar perfusion tended to depend inversely on total pulmonary blood flow when cardiac output had been reduced by bleeding but without reaching statistical significance (r = -0.42, p > 0.05). The decrease in mean pulmonary artery pressure and PaO2 seen during NO inhalation to the hypoxic lobe did not correlate with the level of cardiac output. When NO was delivered to the oxygenated parts of the lungs, no significant effect on relative lobar perfusion or arterial oxygenation was observed, either at raised or at lowered cardiac output. The findings give no further evidence to show that variations in cardiac output alter the effect of NO inhalation.

Annals of burns and fire disasters, 2015