Black swans and fat tails. / Sorte svaner og fete haler.

Economists use the terms black swans and fat-tailed distributions to describe rare, but high-impact events in areas ranging from the financial markets to climate change. We would do well to take such phenomena into account ­ including in medicine.

No change in plasma potassium concentration during 10 minutes of apnoea: An observational study on potential organ donors.

BACKGROUND: Acute acidosis can increase the plasma potassium concentration. However, data on the effects of acute respiratory acidosis on plasma potassium concentration are conflicting. This study aimed to determine whether acute respiratory acidosis induces an immediate increase in plasma potassium concentration. METHODS: This observational study was conducted on participants undergoing apnoea testing prior to final radiological examination, registered in an internal quality registry at Oslo University Hospital between 25 April 2013 and 1 May 2020. A total of 124 donors were assessed for inclusion. Sixteen donors with blood glucose concentrations exceeding 10 mmol L-1 were excluded; finally, data from 108 donors were included in the study. The apnoea test, which is a standard neurological test performed in potential organ donors prior to radiological confirmation of ceased brain circulation, induces respiratory acidosis. The arterial plasma potassium concentration, pH and PaCO2 before and after the apnoea test were compared. Statistical analysis was conducted using the paired t test. RESULTS: The pre-apnoea and post-apnoea mean plasma potassium concentrations were 3.79 (95% confidence intervals [CI] 3.70-3.87) and 3.79 mmol L-1 (95% CI 3.70-3.88), respectively. The mean difference was -0.002 mmol L-1 (95% CI -0.04 to 0.04); the difference was not significant. The pre-apnoea and post-apnoea mean pH were 7.39 and 7.21, respectively, and the mean difference was 0.175 (P < .01). The pre-apnoea and post-apnoea mean PaCO2 were 5.66 and 9.48 kPa, respectively, and the mean difference was -3.83 (P < .01). CONCLUSIONS: Acute respiratory acidosis does not lead to rapid changes in plasma potassium concentration during apnoea testing in potential organ donors.

Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.

BACKGROUND: Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. OBJECTIVES: To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. METHODS: Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. RESULTS: SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1ß and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. CONCLUSION: Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS.

Perfluorodecalin lavage of a longstanding lung atelectasis in a child with spinal muscle atrophy.

OBJECTIVE: Persistent lung atelectasis is difficult to treat and perfluorochemical (PFC) liquid may be an option for bronchioalveolar lavage (BAL). CASE REPORT: A 4-year-old girl with spinal muscle atrophy was admitted in respiratory failure. On admission, the X-ray confirmed the persistence of total right-sided lung atelectasis, which had been present for 14 months. She was endotracheally intubated and ventilated from the day of admission. BAL with normal saline was performed twice without improvement. Following failed extubation and being dependent on continuous respiratory support, a trial of BAL using PFC liquid (Perfluorodecalin HP) was carried out. The PFC was delivered through the endotracheal tube on three consecutive days. A loading dose of 3 ml/kg was administered, followed by a varying dose in order to more effectively lavage the lungs. She tolerated the procedure well the first 2 days, although there were no clinical signs of improvement in the atelectasis. Intentionally, higher inflation pressures were applied after PFC instillation on day 3. Chest X-ray then showed hazy infiltrates on her left lung and she required more ventilatory support. However, lung infiltrates cleared over the next 3 days. A tracheotomy was done 6 days after the last PFC instillation. She had a slow recovery and was successfully decanulated. Clinical improvement of lung function was seen including less need of BiPAP and oxygen. A chest CT scan showed then functional lung tissue appearing in the previous total atelectatic right lung. CONCLUSION: Lavage with PFC can safely be performed with a therapeutic effect in a child with unilateral total lung atelectasis.

Meconium induced IL-8 production and intratracheal albumin alleviated lung injury in newborn pigs.

We have recently shown that albumin added to meconium before intratracheal instillation in newborn pigs limits detrimental effect on the lungs and reduces increase of IL-8. The aim of this study was to test the effect of albumin instillation as rescue treatment in meconium aspiration syndrome (MAS). MAS was induced in hypoxic piglets by lung instillation of meconium (MAS I = 675 mg/kg, n=12; MAS II=540 mg/kg, n=14). Morbidity and mortality differed (MAS I, dead=7/12; MAS II, dead=5/14). MAS groups were randomized to postmeconium instillation of either bovine albumin (30%, 1.4 mL/kg; MAS I, n=6; MAS II, n=7) or isotonic saline (9 mg/mL, 1.4 mL/kg; MAS I, n=6; MAS II, n=7). The controls (n=4) were tested by sequential instillation of saline (9 mg/mL, 5 mL/kg) and albumin (30%, 1.4 mL/kg). Lung function and gas exchange deteriorated significantly after instillation of meconium [oxygenation index (OI): MAS I, +814%; MAS II, +386%; ventilation index (VI): MAS I, +256%; MAS II, +162%; compliance: MAS I, -53%; MAS II, -44%]. Increases of tracheal IL-8 correlated to deterioration of lung function were 10- (MAS I) and 5-fold (MAS II) (p <0.001). Lung compliance was higher in albumin instillation versus saline instillation (MAS I, p=0.008; MAS II, p=0.002). Albumin did not influence intergroup differences in IL-8, hemodynamics, OI, or VI. MAS-induced IL-8 increases correlated with deterioration of lung function (OI, VI, and compliance). Rescue treatment with albumin in meconium aspiration improved lung compliance in piglets and may represent a new therapeutic approach to MAS.

Complement activation reflects severity of meconium aspiration syndrome in newborn pigs.

Meconium aspiration syndrome (MAS) is a serious condition in newborns, associated with a poorly characterized inflammatory reaction. The aim of this study was to investigate a possible role for complement in pulmonary pathophysiology and systemic inflammation in experimental MAS. MAS was induced by instillation of meconium into the lungs of 12 hypoxic piglets. Six controls received saline under otherwise identical conditions. Hemo- and lung dynamics were recorded for 5 h. Plasma complement activation, revealed by the terminal sC5b-9 complex (TCC), and cytokines were measured by enzyme immunoassays. TCC increased substantially in MAS animals compared with controls (p <0.0005). The increase in TCC correlated with lung dysfunction: closely with oxygenation index (r=0.51, p <0.0001) and ventilation index (r=0.64, p < 0.0001) and inversely with lung compliance (r=-0.22, p=0.05). IL-1beta and tumor necrosis factor-alpha increased significantly in MAS animals compared with the controls (p=0.004 and 0.008, respectively). The cytokine increase occurred later than TCC and showed correlations with lung dysfunction similar to TCC. IL-10 did not discriminate between MAS animals and controls (p=0.32). Finally, the subgroup of MAS animals that died (n=5) had substantially higher TCC concentration compared with the surviving MAS animals (n=7; p <0.0005). TCC increased substantially in MAS and was closely correlated to lung dysfunction. Complement activation preceded cytokine release, which may suggest a primary role for complement in the pathophysiology of MAS.

Meconium is a potent activator of complement in human serum and in piglets.

Meconium aspiration syndrome (MAS) is a clinical condition in the newborn infant with a significant morbidity and mortality. The complex pathophysiology of MAS, leading to both pulmonary and systemic complications, is characterized by an incompletely understood inflammatory reaction. Treatment is symptomatic, mainly limited to airway cleaning and ventilatory support. In this study, we show for the first time that meconium is a potent activator of complement, a key mediator of inflammation. In vitro, meconium activated the alternative complement pathway in human umbilical cord serum as judged by a substantial increase in the alternative pathway convertase C3bBbP. The activation proceeded through C3 (C3bc) and the terminal C5-9 pathway (terminal SC5b-9 complement complex), whereas the classical and lectin pathways were not activated (C1rs-C1-inhibitor complexes and C4bc). The lipid fraction, containing, e.g. free fatty acids, and the water fraction, containing, e.g. bile acids, contributed equally to the complement activation. A blocking antibody to factor D (alternative pathway) completely inhibited the meconium-induced complement activation, whereas blocking antibodies to mannose-binding lectin (lectin pathway) and C2 (classical and lectin pathway) had no effect. In vivo, meconium induced systemic complement activation in a piglet model of MAS, paralleling the increase in lung dysfunction. In conclusion, meconium is a potent activator of the complement system both in vitro and in vivo. Complement may be important in the pathogenesis of MAS, and specific complement inhibition might be a possible treatment approach in MAS.

[Lung edema follows inspiratory stridor--another pitfall for the anesthesiologist]. / Etter inspiratorisk stridor følger lungeødem--nok en fallgruve for en anestesiolog.

BACKGROUND: Patients with heart failure or elevated intracranial pressure are at risk of developing lung oedema when anaesthesized. Lung oedema may develop in patients with airway obstructions as well. MATERIAL AND RESULTS: We refer to a four-year-old boy anaesthesized for elective adenotomia and paracentesis. After being extubated, he developed a moderate inspiratory stridor lasting for hours. Clinically he normalized in two hours on a therapy with oxygen in a mask with continuous positive airway pressure (CPAP) and finally bronchodilator therapy with epinephrine and salbutamol. Successive lung X-rays showed lung oedema almost normalizing in 48 hours. INTERPRETATION: The triggering mechanism of lung oedema in airway obstruction is the negative intrathoracal pressure generated because of forced inspiratory effort. This pressure is transformed to a negative interstitial hydrostatic pressure that according to Starling's hypothesis on capillary filtration may generate a lung oedema. We conclude that our patient with nasal polyps had a lowered threshold for developing lung oedema faced with postextubatory complications causing inspiratory stridor. Pathogenic mechanisms are discussed.

Endogenous tetrapeptide from neuroblastoma and new-born pig brain inhibits neuroblastoma cell growth in vitro.

Neuroblastoma, the most frequent malignant tumour in neonates and young children, has an unusual clinical behaviour, age being the most important single factor. This could indicate that some growth-regulating mechanism in lost, or changed, during the first years of life. In search for possible growth-modifying factors, we identified a tetrapeptide, acetyl-Asp-Gln-Tyr-GlyNH2, in extracts of neuroblastoma tissue, in neuroblastoma cell cultures and in new-born pig brain tissue. The purified native peptide as well as a synthetic peptide with the same structure decreases in vitro growth of neuroblastoma cells at a restricted, low (picomolar) range. The structure of the peptide as well as its dose-response characteristics, indicates that it belongs to a group of endogenous growth-modifying oligopeptides that previously have been isolated from other organs and tissues. A possible role for the new peptide in clinical medicine is discussed.