Corrigendum: Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

[This corrects the article DOI: 10.3389/fimmu.2023.1230049.].

Iatrogenic air embolism: pathoanatomy, thromboinflammation, endotheliopathy, and therapies.

Iatrogenic vascular air embolism is a relatively infrequent event but is associated with significant morbidity and mortality. These emboli can arise in many clinical settings such as neurosurgery, cardiac surgery, and liver transplantation, but more recently, endoscopy, hemodialysis, thoracentesis, tissue biopsy, angiography, and central and peripheral venous access and removal have overtaken surgery and trauma as significant causes of vascular air embolism. The true incidence may be greater since many of these air emboli are asymptomatic and frequently go undiagnosed or unreported. Due to the rarity of vascular air embolism and because of the many manifestations, diagnoses can be difficult and require immediate therapeutic intervention. An iatrogenic air embolism can result in both venous and arterial emboli whose anatomic locations dictate the clinical course. Most clinically significant iatrogenic air emboli are caused by arterial obstruction of small vessels because the pulmonary gas exchange filters the more frequent, smaller volume bubbles that gain access to the venous circulation. However, there is a subset of patients with venous air emboli caused by larger volumes of air who present with more protean manifestations. There have been significant gains in the understanding of the interactions of fluid dynamics, hemostasis, and inflammation caused by air emboli due to in vitro and in vivo studies on flow dynamics of bubbles in small vessels. Intensive research regarding the thromboinflammatory changes at the level of the endothelium has been described recently. The obstruction of vessels by air emboli causes immediate pathoanatomic and immunologic and thromboinflammatory responses at the level of the endothelium. In this review, we describe those immunologic and thromboinflammatory responses at the level of the endothelium as well as evaluate traditional and novel forms of therapy for this rare and often unrecognized clinical condition.

Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs.

Introduction: Air embolism may complicate invasive medical procedures. Bubbles trigger complement C3-mediated cytokine release, coagulation, and platelet activation in vitro in human whole blood. Since these findings have not been verified in vivo, we aimed to examine the effects of air embolism in pigs on thromboinflammation. Methods: Forty-five landrace pigs, average 17 kg (range 8.5-30), underwent intravenous air infusion for 300 or 360 minutes (n=29) or served as sham (n=14). Fourteen pigs were excluded due to e.g. infections or persistent foramen ovale. Blood was analyzed for white blood cells (WBC), complement activation (C3a and terminal C5b-9 complement complex [TCC]), cytokines, and hemostatic parameters including thrombin-antithrombin (TAT) using immunoassays and rotational thromboelastometry (ROTEM). Lung tissue was analyzed for complement and cytokines using qPCR and immunoassays. Results are presented as medians with interquartile range. Results: In 24 pigs receiving air infusion, WBC increased from 17×109/L (10-24) to 28 (16-42) (p<0.001). C3a increased from 21 ng/mL (15-46) to 67 (39-84) (p<0.001), whereas TCC increased only modestly (p=0.02). TAT increased from 35 µg/mL (28-42) to 51 (38-89) (p=0.002). ROTEM changed during first 120 minutes: Clotting time decreased from 613 seconds (531-677) to 538 (399-620) (p=0.006), clot formation time decreased from 161 seconds (122-195) to 124 (83-162) (p=0.02) and α-angle increased from 62 degrees (57-68) to 68 (62-74) (p=0.02). In lungs from pigs receiving air compared to sham animals, C3a was 34 ng/mL (14-50) versus 4.1 (2.4-5.7) (p<0.001), whereas TCC was 0.3 CAU/mL (0.2-0.3) versus 0.2 (0.1-0.2) (p=0.02). Lung cytokines in pigs receiving air compared to sham animals were: IL-1ß 302 pg/mL (190-437) versus 107 (66-120), IL-6 644 pg/mL (358-1094) versus 25 (23-30), IL-8 203 pg/mL (81-377) versus 21 (20-35), and TNF 113 pg/mL (96-147) versus 16 (13-22) (all p<0.001). Cytokine mRNA in lung tissue from pigs receiving air compared to sham animals increased 12-fold for IL-1ß, 121-fold for IL-6, and 17-fold for IL-8 (all p<0.001). Conclusion: Venous air embolism in pigs activated C3 without a corresponding C5 activation and triggered thromboinflammation, consistent with a C3-dependent mechanism. C3-inhibition might represent a therapeutic approach to attenuate this response.

Air Bubbles Activate Complement and Trigger Hemostasis and C3-Dependent Cytokine Release Ex Vivo in Human Whole Blood.

Venous air embolism, which may complicate medical and surgical procedures, activates complement and triggers thromboinflammation. In lepirudin-anticoagulated human whole blood, we examined the effect of air bubbles on complement and its role in thromboinflammation. Whole blood from 16 donors was incubated with air bubbles without or with inhibitors of C3, C5, C5aR1, or CD14. Complement activation, hemostasis, and cytokine release were measured using ELISA and quantitative PCR. Compared with no air, incubating blood with air bubbles increased, on average, C3a 6.5-fold, C3bc 6-fold, C3bBbP 3.7-fold, C5a 4.6-fold, terminal complement complex sC5b9 3.6-fold, prothrombin fragments 1+2 (PTF1+2) 25-fold, tissue factor mRNA (TF-mRNA) 26-fold, microparticle tissue factor 6.1-fold, ß-thromboglobulin 26-fold (all p < 0.05), and 25 cytokines 11-fold (range, 1.5-78-fold; all p < 0.0001). C3 inhibition attenuated complement and reduced PTF1+2 2-fold, TF-mRNA 5.4-fold, microparticle tissue factor 2-fold, and the 25 cytokines 2.7-fold (range, 1.4-4.9-fold; all p < 0.05). C5 inhibition reduced PTF1+2 2-fold and TF-mRNA 12-fold (all p < 0.05). C5 or CD14 inhibition alone reduced three cytokines, including IL-1ß (p = 0.02 and p = 0.03). Combined C3 and CD14 inhibition reduced all cytokines 3.9-fold (range, 1.3-9.5-fold; p < 0.003) and was most pronounced for IL-1ß (3.2- versus 6.4-fold), IL-6 (2.5- versus 9.3-fold), IL-8 (4.9- versus 8.6-fold), and IFN-γ (5- versus 9.5-fold). Antifoam activated complement and was avoided. PTF1+2 was generated in whole blood but not in plasma. In summary, air bubbles activated complement and triggered a C3-driven thromboinflammation. C3 inhibition reduced all mediators, whereas C5 inhibition reduced only TF-mRNA. Combined C5 and CD14 inhibition reduced IL-1ß release. These data have implications for future mechanistic studies and possible pharmacological interventions in patients with air embolism.

Open chest and pericardium facilitate transpulmonary passage of venous air emboli.

BACKGROUND: Transpulmonary passage of air emboli can lead to fatal brain- and myocardial infarctions. We studied whether pigs with open chest and pericardium had a greater transpulmonary passage of venous air emboli than pigs with closed thorax. METHODS: We allocated pigs with verified closed foramen ovale to venous air infusion with either open chest with sternotomy and opening of the pleura and pericardium (n = 8) or closed thorax (n = 16). All pigs received a five-hour intravenous infusion of ambient air, starting at 4-6 mL/kg/h and increased by 2 mL/kg/h each hour. We assessed transpulmonary air passage by transesophageal M-mode echocardiography and present the results as median with inter-quartile range (IQR). RESULTS: Transpulmonary air passage occurred in all pigs with open chest and pericardium and in nine pigs with closed thorax (56%). Compared to pigs with closed thorax, pigs with open chest and pericardium had a shorter to air passage (10 minutes (5-16) vs. 120 minutes (44-212), P < .0001), a smaller volume of infused air at the time of transpulmonary passage (12 mL (10-23) vs.170 mL (107-494), P < .0001), shorter time to death (122 minutes (48-185) vs 263 minutes (248-300, P = .0005) and a smaller volume of infused air at the time of death (264 mL (53-466) vs 727 mL (564-968), P = .001). In pigs with open chest and, infused air and time to death correlated strongly (r = 0.95, P = .001). CONCLUSION: Open chest and pericardium facilitated the transpulmonary passage of intravenously infused air in pigs.

A successful new method for single left lobe recruitment.

Any gas will flow down the path of least resistance and highest compliance. This is a problem in the treatment of severe unilateral lung disease in the intensive care unit (ICU). Deep sedation interferes with the diaphragm's ability to distribute air into the lower lung. Spontaneous breathing in a conscious patient, in combination with mechanical ventilation via an endotracheal tube inserted into the left main stem bronchus, can recruit collapsed alveoli.

Lactate Gap: A Diagnostic Support in Severe Metabolic Acidosis of Unknown Origin.

Ethylene glycol poisoning is a medical emergency. The metabolites glycolate and glyoxylate give metabolic acidosis. Because of similar structure, these metabolites are misinterpreted as lactate by many point-of-care blood gas analyzers. The falsely high lactate values can lead to misdiagnosis, inappropriate laparotomies, and delayed antidotal therapy. As laboratory analyzers measure plasma lactate only, the difference or the "lactate gap" aids in early diagnosis. We present a patient with severe metabolic acidosis and elevated lactate levels on the point-of-care analyzer. A lactate gap supported the diagnosis of ethylene glycol poisoning. Hemodialysis and fomepizole treatment could be started immediately.

Gas Embolism During Hysteroscopic Surgery?: Three Cases and a Literature Review.

During a period of 1 month, 3 episodes of probable or actual venous air embolism occurred during hysteroscopic surgery. All patients developed the same symptoms of ventilatory and hemodynamic decompensation, beginning with a reduction in end-tidal carbon dioxide, arterial desaturation, and cyanosis on the upper trunk, and rapidly progressed to hypotension and 2 cardiac arrests. While entrainment of some air is common during hysteroscopy, life-threatening embolism is a rare but serious complication for which an anesthetist needs to be vigilant and prepared. If even a small drop in end-tidal carbon dioxide occurs, venous air embolism should be suspected and the operation should be discontinued.

Combined inhibition of C5 and CD14 efficiently attenuated the inflammatory response in a porcine model of meningococcal sepsis.

BACKGROUND: Fulminant meningococcal sepsis, characterized by overwhelming innate immune activation, mostly affects young people and causes high mortality. This study aimed to investigate the effect of targeting two key molecules of innate immunity, complement component C5, and co-receptor CD14 in the Toll-like receptor system, on the inflammatory response in meningococcal sepsis. METHODS: Meningococcal sepsis was simulated by continuous intravenous infusion of an escalating dose of heat-inactivated Neisseria meningitidis administered over 3 h. The piglets were randomized, blinded to the investigators, to a positive control group (n = 12) receiving saline and to an interventional group (n = 12) receiving a recombinant anti-CD14 monoclonal antibody together with the C5 inhibitor coversin. RESULTS: A substantial increase in plasma complement activation in the untreated group was completely abolished in the treatment group (p = 0.006). The following inflammatory mediators were substantially reduced in plasma in the treatment group: Interferon-γ by 75% (p = 0.0001), tumor necrosis factor by 50% (p = 0.01), Interleukin (IL)-8 by 50% (p = 0.03), IL-10 by 40% (p = 0.04), IL-12p40 by 50% (p = 0.03), and granulocyte CD11b (CR3) expression by 20% (p = 0.01). CONCLUSION: Inhibition of C5 and CD14 may be beneficial in attenuating the detrimental effects of complement activation and modulating the cytokine storm in patients with fulminant meningococcal sepsis.

Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis.

INTRODUCTION: Sepsis is an exaggerated and dysfunctional immune response to infection. Activation of innate immunity recognition systems including complement and the Toll-like receptor family initiate this disproportionate inflammatory response. The aim of this study was to explore the effect of combined inhibition of the complement component C5 and the Toll-like receptor co-factor CD14 on survival, hemodynamic parameters and systemic inflammation including complement activation in a clinically relevant porcine model of polymicrobial sepsis. METHODS: Norwegian landrace piglets (4 ± 0.5 kg) were blindly randomized to a treatment group (n = 12) receiving the C5 inhibitor coversin (OmCI) and anti-CD14 or to a positive control group (n = 12) receiving saline. Under anesthesia, sepsis was induced by a 2 cm cecal incision and the piglets were monitored in standard intensive care for 8 hours. Three sham piglets had a laparotomy without cecal incision or treatment. Complement activation was measured as sC5b-9 using enzyme immunoassay. Cytokines were measured with multiplex technology. RESULTS: Combined C5 and CD14 inhibition significantly improved survival (p = 0.03). Nine piglets survived in the treatment group and four in the control group. The treatment group had significantly lower pulmonary artery pressure (p = 0.04) and ratio of pulmonary artery pressure to systemic artery pressure (p < 0.001). Plasma sC5b-9 levels were significantly lower in the treatment group (p < 0.001) and correlated significantly with mortality (p = 0.006). IL-8 and IL-10 were significantly (p < 0.05) lower in the treatment group. CONCLUSIONS: Combined inhibition of C5 and CD14 significantly improved survival, hemodynamic parameters and inflammation in a blinded, randomized trial of porcine polymicrobial sepsis.

Massive Organ Inflammation in Experimental and in Clinical Meningococcal Septic Shock.

Fulminant meningococcal sepsis is characterized by a massive growth of bacteria in the circulation, regarded as the primary inflammatory site, with no specific solid organ focus. Here we aimed to study the local inflammatory response in organs using a porcine model of fulminant meningococcal septic shock challenged with exponentially increasing doses of heat inactivated Neisseria meningitidis. The results were compared with those obtained in organs post mortem from three patients with lethal meningococcal septic shock. Nine patients with lethal pneumococcal disease and 14 patients with sudden infant death syndrome served as controls. Frozen tissue were thawed, homogenized and prepared for quantification of bacterial DNA by real-time polymerase chain reaction, and key inflammatory mediators were measured by ELISA in the pig material and by multiplex in the human material. In addition, gene expression assayed by Affymetrix gene expression profiling was performed in the pig study. The porcine model revealed a major influx of N. meningitidis in lungs, liver, spleen, and kidneys accompanied with major production of cardinal inflammatory mediators including tumor necrosis factor, interleukin (IL)-1ß, IL-6, and IL-8, far exceeding the amount detected in blood. Genes encoding for these mediators revealed a similar profile. By comparing the wild-type with a lipopolysaccharide (LPS) deficient meningococcal strain, we documented that LPS was the dominant group of molecules inducing organ inflammation and was required for IL-8 production. IL-10 production was predominantly stimulated by non-LPS molecules. The massive organ inflammation in the porcine model was present in the three patients dying of meningococcal shock and differed markedly from the patients with lethal pneumococcal infections and sudden infant death syndrome. In conclusion, in meningococcal sepsis, a massive local inflammatory response occurs in specific organs.

Soluble CD14 is associated with markers of vascular dysfunction in bariatric surgery patients.

BACKGROUND: Chronic endotoxemia has been proposed to contribute to obesity-related complications. We aimed to investigate the potential impact of lipopolysaccharide (LPS) and subsequent monocyte activation measured as soluble CD14 (sCD14) on markers of vascular dysfunction in obese subjects undergoing bariatric surgery. METHODS: This was a prospective study of 49 obese patients and 17 controls, assessed by plasma levels of LPS, sCD14, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). RESULTS: Levels of ADMA were increased in obese subjects compared to controls, but were not significantly reduced after bariatric surgery. In obese subjects at baseline, there was a significant trend to increasing levels of ADMA and SDMA through tertiles of sCD14 and decreasing levels of both markers through tertiles of LPS. In models adjusting for age and gender, sCD14 but not LPS remained independently associated with ADMA and SDMA. For every 10% age- and gender-adjusted increase in sCD14, ADMA increased 0.031 µM (5.6%), whereas SDMA increased 0.039 µM (10.8%). CONCLUSIONS: Our results suggest that monocyte activation as measured by sCD14 is associated with obesity-related vascular dysfunction, whereas potential upstream triggers including microbial products should be investigated in future studies.

Fear of hypoglycemia in women and men with type 1 diabetes.

BACKGROUND: Severe hypoglycemia is a serious complication of type1 diabetes feared by many who have the disease. OBJECTIVES: The aim of this study was to investigate specific fears related to hypoglycemia in adults with type 1 diabetes and to investigate how aspects of fear of hypoglycemia may differ between genders. METHODS: A cross-sectional study with questionnaires sent to 636 patients with type 1 diabetes, aged 18-75 years, who attended the outpatient clinic at St. Olavs Hospital, Trondheim, Norway. Fears related to hypoglycemia were assessed using the Hypoglycemia Fear Survey II Worry subscale (HFS-II-Worry). RESULTS: The response rate was 70% (N = 445, 216 women and 229 men). The mean HFS-II-Worry score was higher in women than in men (2.46 [SD = 0.80] vs. 2.22 [SD = 0.74], respectively; p < .001). Women scored higher than men in all items in the HFS-II-Worry, and women's average scores were statistically significantly higher in 5 of the 18 items after correction for multiple comparisons. The largest gender differences in mean scores occurred in the items "low blood glucose interfering with important things," "becoming upset and difficult," "difficulty thinking clearly," and "feeling lightheaded or dizzy." In both women and men, the highest mean scores appeared in the worry items "become hypoglycemic while sleeping" and "not having food available." DISCUSSION: In this sample of Norwegian adults with type 1 diabetes, women expressed more concerns about hypoglycemia than men. The highest HFS-II-Worry scores occurred in the same items in women and men, but the largest gender differences in mean scores appeared across a variety of other items, some of which were related to social esteem.

Advantages of strain echocardiography in assessment of myocardial function in severe sepsis: an experimental study.

OBJECTIVES: Cardiovascular failure is an important feature of severe sepsis and mortality in sepsis. The aim of our study was to explore myocardial dysfunction in severe sepsis. DESIGN: Prospective experimental study. SETTING: Operating room at Intervention Centre, Oslo University Hospital. SUBJECTS: Eight Norwegian Landrace pigs. INTERVENTIONS: The pigs were anesthetized, a medial sternotomy performed and miniature sensors for wall-thickness measurements attached to the epicardium and invasive pressure monitoring established, and an infusion of Escherichia coli started. Hemodynamic response was monitored and myocardial strain assessed by echocardiography. MEASUREMENTS AND MAIN RESULTS: Left ventricular myocardial function was significantly reduced assessed by longitudinal myocardial strain (-17.2% ± 2.8% to -12.3% ± 3.2%, p = 0.04), despite a reduced afterload as expressed by the left ventricular end-systolic meridional wall stress (35 ± 13 to 18 ± 8 kdyn/cm, p = 0.04). Left ventricular ejection fraction remained unaltered (48% ± 7% to 49% ± 5%, p = 0.4) as did cardiac output (6.3 ± 1.3 to 5.9 ± 3 L/min, p = 0.7). The decline in left ventricular function was further supported by significant reductions in the index of regional work by pressure-wall thickness loop area (121 ± 45 to 73 ± 37 mm × mm Hg, p = 0.005). Left ventricular myocardial wall thickness increased in both end diastole (11.5 ± 2.7 to 13.7 ± 2.4 mm, p = 0.03) and end systole (16.1 ± 2.9 to 18.5 ± 1.8 mm, p = 0.03), implying edema of the left ventricular myocardial wall. Right ventricular myocardial function by strain was reduced (-24.2% ± 4.1% to -16.9% ± 5.7%, p = 0.02). High right ventricular pressures caused septal shift as demonstrated by the end-diastolic transseptal pressure gradient (4.1 ± 3.3 to -2.2 ± 5.8 mm Hg, p = 0.01). CONCLUSIONS: The present study demonstrates myocardial dysfunction in severe sepsis. Strain echocardiography reveals myocardial dysfunction before significant changes in ejection fraction and cardiac output and could prove to be a useful tool in clinical evaluation of septic patients.

Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model.

The complement and TLR systems are activated in sepsis, contributing to an unfavorable inflammatory "storm." Combined inhibition of these systems has been documented to efficiently attenuate the inflammatory responses induced by Gram-negative bacteria. In this study, we hypothesized that the combined inhibition would attenuate the inflammatory responses induced by Gram-positive bacteria. Staphylococcus aureus bacteria (strains Cowan and Wood), as well as S. aureus cell wall lipoteichoic acid (LTA), were incubated in thrombin-inhibited human whole blood. Complement was inhibited at the level of C3 and C5, and the TLRs by inhibiting CD14 and TLR2. Thirty-four inflammatory markers were measured by multiplex technology and flow cytometry. Thirteen markers increased significantly in response to Cowan and Wood, and 12 in response to LTA. Combined inhibition with the C3 inhibitor compstatin and the anti-CD14 Ab 18D11 significantly reduced 92 (Cowan, LTA) and 85% (Wood) of these markers. Compstatin alone significantly reduced 54 (Cowan), 38 (Wood), and 83% (LTA), whereas anti-CD14 alone significantly reduced 23, 15, and 67%, respectively. Further experiments showed that the effects of complement inhibition were mainly due to inhibition of C5a interaction with the C5a receptor. The effects on inhibiting CD14 and TLR2 were similar. The combined regimen was more efficient toward the bacterial effects than either complement or anti-CD14 inhibition alone. Complement was responsible for activation of and phagocytosis by both granulocytes and monocytes. Disrupting upstream recognition by inhibiting complement and CD14 efficiently attenuated S. aureus-induced inflammation and might be a promising treatment in both Gram-negative and Gram-positive sepsis.

Bradykinin analysis revived--a validated method for determination of its stable metabolite in whole blood by LC-MS/MS.

Investigation of bradykinin involvement in diseases like hereditary angioedema has been greatly hindered by its rapid metabolism and generation, induced by sampling. Because of this, reliable measurements of bradykinin have yet to be introduced in clinical practice. Prevention of bradykinin generation during sampling, and determination of the in vivo generated stable metabolite BK1-5, should allow a reliable indirect measure of bradykinin involvement. An LC-MS/MS method has been developed to determine BK1-5 in human whole blood. The method inactivates metabolizing enzymes with ethanol, followed by solid phase extraction (C18), separation (C8) and detection (linear ion trap) through the transitions 287.25→320.20 (y3, quantifier), 408.20 (b4, qualifier) for BK1-5, and 292.17→330.20 (y3, quantifier), 408.20 (b4, qualifier) for the heavy labelled internal standard. The method showed acceptable linearity (n=3, r(2)=0.994), intra-run precision (CV<15%), inter-run precision (CV<15%) and accuracy (CV<14%), without matrix effects. LLOQ was 265.5 pmol L(-1) and LOD was 35.4 pmol L(-1). The method was used on blood samples from patients with hereditary angioedema, where BK1-5 was measured during attacks and in remision. The samples showed elevated concentrations (up to 1.7 nmol L(-1) during attacks and 265.5 pmol L(-1) in remission) compared to healthy volunteers (<35.4 pmol L(-1)). This is the first time BK1-5 in hereditary angioedema patients has been measured.

Plasma lipopolysaccharide is closely associated with glycemic control and abdominal obesity: evidence from bariatric surgery.

OBJECTIVE: It is of vital importance to elucidate the triggering factors of obesity and type 2 diabetes to improve patient care. Bariatric surgery has been shown to prevent and even cure diabetes, but the mechanism is unknown. Elevated levels of lipopolysaccharide (LPS) predict incident diabetes, but the sources of LPS are not clarified. The objective of the current study was to evaluate the potential impact of plasma LPS on abdominal obesity and glycemic control in subjects undergoing bariatric surgery. RESEARCH DESIGN AND METHODS: This was a prospective observational study involving a consecutive sample of 49 obese subjects undergoing bariatric surgery and 17 controls. Main assessments were plasma LPS, HbA1c, adipose tissue volumes (computed tomography), and quantified bacterial DNA in adipose tissue compartments. RESULTS: Plasma levels of LPS were elevated in obese individuals compared with controls (P < 0.001) and were reduced after bariatric surgery (P = 0.010). LPS levels were closely correlated with HbA1c (r = 0.56; P = 0.001) and intra-abdominal fat volumes (r = 0.61; P < 0.001), but only moderately correlated with subcutaneous fat volumes (r = 0.33; P = 0.038). Moreover, there was a decreasing gradient (twofold) in bacterial DNA levels going from mesenteric via omental to subcutaneous adipose tissue compartments (P = 0.041). Finally, reduced LPS levels after bariatric surgery were directly correlated with a reduction in HbA1c (r = 0.85; P < 0.001). CONCLUSIONS: Our findings support a hypothesis of translocated gut bacteria as a potential trigger of obesity and diabetes, and suggest that the antidiabetic effects of bariatric surgery might be mechanistically linked to, and even the result of, a reduction in plasma levels of LPS.

"Fighting the system": families caring for ventilator-dependent children and adults with complex health care needs at home.

BACKGROUND: An increasing number of individuals with complex health care needs now receive life-long and life-prolonging ventilatory support at home. Family members often take on the role of primary caregivers. The aim of this study was to explore the experiences of families giving advanced care to family members dependent on home mechanical ventilation. METHODS: Using qualitative research methods, a Grounded Theory influenced approach was used to explore the families' experiences. A total of 15 family members with 11 ventilator-dependent individuals (three children and eight adults) were recruited for 10 in-depth interviews. RESULTS: The core category, "fighting the system," became the central theme as family members were asked to describe their experiences. In addition, we identified three subcategories, "lack of competence and continuity", "being indispensable" and "worth fighting for". This study revealed no major differences in the families' experiences that were dependent on whether the ventilator-dependent individual was a child or an adult. CONCLUSIONS: These findings show that there is a large gap between family members' expectations and what the community health care services are able to provide, even when almost unlimited resources are available. A number of measures are needed to reduce the burden on these family members and to make hospital care at home possible. In the future, the gap between what the health care can potentially provide and what they can provide in real life will rapidly increase. New proposals to limit the extremely costly provision of home mechanical ventilation in Norway will trigger new ethical dilemmas that should be studied further.

Home mechanical ventilation and specialised health care in the community: Between a rock and a hard place.

BACKGROUND: Home mechanical ventilation probably represents the most advanced and complicated type of medical treatment provisioned outside a hospital setting. The aim of this study was both to explore the challenges experienced by health care professionals in community health care services when caring for patients dependent on home mechanical ventilation, continual care and highly advanced technology, and their proposed solutions to these challenges. METHODS: Using qualitative research methods, a grounded theory influenced approach was used to explore the respondents' experiences and proposed solutions. A total of 34 multidisciplinary respondents from five different communities in Norway were recruited for five focus groups. RESULTS: The core category in our findings was what health care professionals in community health care services experience as "between a rock and a hard place," when working with hospitals, family members, and patients. We further identified four subcategories, "to be a guest in the patient's home," "to be accepted or not," "who decides," and "how much can we take." The main background for these challenges seems to stem from patients living and receiving care in their private homes, which often leads to conflicts with family members. These challenges can have a negative effect on both the community health caregivers' work environment and the community health service's provision of professional care. CONCLUSIONS: This study has identified that care of individuals with complex needs and dependent on home mechanical ventilation presents a wide range of immense challenges for community health care services. The results of this study point towards a need to define the roles of family caregivers and health care professionals and also to find solutions to improve their collaboration. The need to improve the work environment for caregivers directly involved in home-care also exists. The study also shows the need for more dialogue concerning eligibility requirements, rights, and limitations of patients in the provision and use of ventilatory support in private homes.

Dissecting the effects of lipopolysaccharides from nonlipopolysaccharide molecules in experimental porcine meningococcal sepsis.

OBJECTIVE: To dissect the in vivo responses to lipopolysaccharide compared with nonlipopolysaccharide structures of whole meningococci. DESIGN: Comparative experimental study. SETTING: University hospital with an animal intensive care unit and laboratory. SUBJECTS: Twenty-four anesthetized healthy Norwegian landrace pigs of 30 kg (+/- 2.5 kg) grouped into two test groups and one control group. INTERVENTIONS: Exponentially increasing numbers of Neisseria meningitidis H44/76 (NmLPS+) or a knockout mutant of H44/76 completely lacking lipopolysaccharide (NmLPS-) were infused intravenously to the pigs. MEASUREMENTS AND MAIN RESULTS: Physiological and hematologic parameters were continuously recorded and biochemical analyses were performed in batch after completion. Systemic vascular resistance, cardiac index and lactate changed significantly more in the NmLPS+ than in the NmLPS- group (p < .05). Mean pulmonary artery pressure increased early in the NmLPS+ and late in the NmLPS- group, but finally reached equally high values. Capillary leakage (fluid requirement, plasma albumin loss, organ wet/dry ratio) was more prominent in the NmLPS+ group (p < .05). Leukocytes were depleted in a highly lipopolysaccharide-dependent manner (p < .001). Thrombin-antithrombin complexes and plasminogen activator inhibitor-1 increased 2.5 to five times more in the NmLPS+ group (p < .05). Maximum cytokine concentrations in plasma were markedly higher in the NmLPS+ group (p < .05): tumor necrosis factor-alpha (40 times), interleukin-1beta (40 times), interleukin-6 (13 times), and interleukin-10 (four times). Interleukin-12 increased only in the NmLPS+ group. CONCLUSION: This large animal model, which simulates human disease well, confirms the potency of lipopolysaccharide but provides clear evidence that nonlipopolysaccharide molecules induce cardiovascular and hematologic changes quite similar to those caused by lipopolysaccharide. In general, 10- to 20-fold higher doses of the lipopolysaccharide-deficient mutant were required to induce the same degree of pathophysiological changes. Endotoxic activity of Gram-negative bacteria should no longer be attributed solely to the activity of lipopolysaccharide.