Risk of malignant disease in 1-year sepsis survivors, a registry-based nationwide follow-up study.

BACKGROUND: Cancer and sepsis share risk factors, and sepsis patients may have impaired immune response and increased morbidity long after intensive care. This study aimed to assess whether sepsis survivors are at increased risk for cancer. Our objective was to assess the incidence of new cancer in 1-year sepsis survivors and test the hypothesis that it is higher than that of the general population. METHODS: We obtained data on ICU admissions of adult patients from Swedish Intensive care registry (SICR) from 2005 to 2017. We included patients with an explicit ICD-10 code for sepsis for the primary ICU admission. We obtained data on cancer diagnoses (2001-2018), death (2005-2018) and emigration (2005-2018) from Cancer and Cause of death and National Patient Registry databases of the National Board of Health and Welfare; age and sex-specific cancer incidence rates in Sweden from NORDCAN registry from 2006 to 2018. One-year survivors formed the final cohort, that was followed for new cancer diagnoses until death, emigration, or end of 2018, whichever came first. The main outcome measure was standardized incidence rate ratio (SIR) to compare the incidence of cancer in 1-year sepsis survivors to that in the general population (NORDCAN). We also performed several sensitivity analyses. RESULTS: In a cohort of 18,550 1-year survivors, 75,427 person years accumulated during a median follow-up (FU) of 3.36 years (IQR 1.72-5.86), 6366 (34.3%) patients died, and 1625 (8.8%) patients were diagnosed with a new cancer after a median FU of 2.51 (IQR 1.09-4.48) years. The incidence ratio of any new cancer over the whole FU was 1.31 (95% CI 1.23-1.40) for men and 1.74 (95% CI 1.61-1.88) for women. The difference in incidence rates persisted in several sensitivity analyses. The SIRs were highest in cancers of gastrointestinal tract, genital organs, and skin. CONCLUSION AND RELEVANCE: Compared to general population, incidence of cancer is increased in 1-year sepsis survivors. Variation in the findings depending on follow-up time suggests that factors other than sepsis alone are involved. Surveillance for malignant disease may be warranted in sepsis survivors.

Oxygen saturation in intraosseous sternal blood measured by CO-oximetry and evaluated non-invasively during hypovolaemia and hypoxia - a porcine experimental study.

PURPOSE: This study intended to determine, and non-invasively evaluate, sternal intraosseous oxygen saturation (SsO2) and study its variation during provoked hypoxia or hypovolaemia. Furthermore, the relation between SsO2 and arterial (SaO2) or mixed venous oxygen saturation (SvO2) was investigated. METHODS: Sixteen anaesthetised male pigs underwent exsanguination to a mean arterial pressure of 50 mmHg. After resuscitation and stabilisation, hypoxia was induced with hypoxic gas mixtures (air/N2). Repeated blood samples from sternal intraosseous cannulation were compared to arterial and pulmonary artery blood samples. Reflection spectrophotometry measurements by a non-invasive sternal probe were performed continuously. RESULTS: At baseline SaO2 was 97.0% (IQR 0.2), SsO2 73.2% (IQR 19.6) and SvO2 52.3% (IQR 12.4). During hypovolaemia, SsO2 and SvO2 decreased to 58.9% (IQR 16.9) and 38.1% (IQR 12.5), respectively, p < 0.05 for both, whereas SaO2 remained unaltered (p = 0.44). During hypoxia all saturations decreased; SaO2 71.5% (IQR 5.2), SsO2 39.0% (IQR 6.9) and SvO2 22.6% (IQR 11.4) (p < 0.01), respectively. For hypovolaemia, the sternal probe red/infrared absorption ratio (SQV) increased significantly from baseline (indicating a reduction in oxygen saturation) + 5.1% (IQR 7.4), p < 0.001 and for hypoxia + 19.9% (IQR 14.8), p = 0.001, respectively. CONCLUSION: Sternal blood has an oxygen saturation suggesting a mixture of venous and arterial blood. Changes in SsO2 relate well with changes in SvO2 during hypovolaemia or hypoxia. Further studies on the feasibility of using non-invasive measurement of changes in SsO2 to estimate changes in SvO2 are warranted.

A comparison of impact of comorbidities and demographics on 60-day mortality in ICU patients with COVID-19, sepsis and acute respiratory distress syndrome.

Severe Coronavirus disease 2019 (COVID-19) is associated with several pre-existing comorbidities and demographic factors. Similar factors are linked to critical sepsis and acute respiratory distress syndrome (ARDS). We hypothesized that age and comorbidities are more generically linked to critical illness mortality than a specific disease state. We used national databases to identify ICU patients and to retrieve comorbidities. The relative importance of risk factors for 60-day mortality was evaluated using the interaction with disease group (Sepsis, ARDS or COVID-19) in logistic regression models. We included 32,501 adult ICU patients. In the model on 60-day mortality in sepsis and COVID-19 there were significant interactions with disease group for age, sex and asthma. In the model on 60-day mortality in ARDS and COVID-19 significant interactions with cohort were found for acute disease severity, age and chronic renal failure. In conclusion, age and sex play particular roles in COVID-19 mortality during intensive care but the burden of comorbidity was similar between sepsis and COVID-19 and ARDS and COVID-19.

Surgical Removal of a Detached Mitral Valve Repair Clip to Resolve Cardiogenic Shock.

Transcatheter edge-to-edge mitral valve repair (TEER) with a clip device relieves symptoms and improves outcomes in patients not suitable for open heart surgery. Here, we present a patient in whom ventricular arrhythmias developed as a result of clip embolization shortly after TEER. He underwent successful emergent surgical clip removal and mitral valve replacement. (Level of Difficulty: Advanced.).

Effects of extensive bleeding in pigs on laboratory biomarkers.

BACKGROUND: During hemorrhage and resuscitation, clinical and laboratory monitoring is useful to guide further management. However, acute changes in the biochemistry due to blood loss and subsequent crystalloid fluid resuscitation have not been fully studied. MATERIALS AND METHODS: Twelve anesthetized, juvenile pigs were used. Atraumatic exsanguination, corresponding to a total blood loss of 40%, was performed through a catheter and completed 2 h after initiation of the experiment. Arterial samples were analyzed by point-of-care testing and venous samples were analyzed. Oxygen delivery was calculated. RESULTS: Shortly after 40% hemorrhage and concomitant fluid supplementation, there were significant reductions in arterial hemoglobin and hematocrit (approximately 25%, respectively). Oxygen delivery was less than half of the baseline value. Lactate in arterial blood was more than doubled after 40% exsanguination. On average, no other clinically significant changes in any of the analytes were observed, but interindividual dispersion was pronounced. CONCLUSIONS: Acute exsanguination was associated with decreased hemoglobin and hematocrit levels and increased lactate levels but limited effects on the other biomarkers that were studied. Increased levels of biomarkers in severely bleeding patients could indicate tissue damage and the source should be further investigated.

The swedish covid-19 intensive care cohort: Risk factors of ICU admission and ICU mortality.

BACKGROUND: Several studies have recently addressed factors associated with severe Coronavirus disease 2019 (COVID-19); however, some medications and comorbidities have yet to be evaluated in a large matched cohort. We therefore explored the role of relevant comorbidities and medications in relation to the risk of intensive care unit (ICU) admission and mortality. METHODS: All ICU COVID-19 patients in Sweden until 27 May 2020 were matched to population controls on age and gender to assess the risk of ICU admission. Cases were identified, comorbidities and medications were retrieved from high-quality registries. Three conditional logistic regression models were used for risk of ICU admission and three Cox proportional hazards models for risk of ICU mortality, one with comorbidities, one with medications and finally with both models combined, respectively. RESULTS: We included 1981 patients and 7924 controls. Hypertension, type 2 diabetes mellitus, chronic renal failure, asthma, obesity, being a solid organ transplant recipient and immunosuppressant medications were independent risk factors of ICU admission and oral anticoagulants were protective. Stroke, asthma, chronic obstructive pulmonary disease and treatment with renin-angiotensin-aldosterone inhibitors (RAASi) were independent risk factors of ICU mortality in the pre-specified primary analyses; treatment with statins was protective. However, after adjusting for the use of continuous renal replacement therapy, RAASi were no longer an independent risk factor. CONCLUSION: In our cohort oral anticoagulants were protective of ICU admission and statins was protective of ICU death. Several comorbidities and ongoing RAASi treatment were independent risk factors of ICU admission and ICU mortality.

A nationwide study of the long-term prevalence of dementia and its risk factors in the Swedish intensive care cohort.

BACKGROUND: Developing dementia is feared by many for its detrimental effects on cognition and independence. Experimental and clinical evidence suggests that sepsis is a risk factor for the later development of dementia. We aimed to investigate whether intensive care-treated sepsis is an independent risk factor for a later diagnosis of dementia in a large cohort of intensive care unit (ICU) patients. METHODS: We identified adult patients admitted to an ICU in 2005 to 2015 and who survived without a dementia diagnosis 1 year after intensive care admission using the Swedish Intensive Care Registry, collecting data from all Swedish general ICUs. Comorbidity, the diagnosis of dementia and mortality, was retrieved from the Swedish National Patient Registry, the Swedish Dementia Registry, and the Cause of Death Registry. Sepsis during intensive care served as a covariate in an extended Cox model together with age, sex, and variables describing comorbidities and acute disease severity. RESULTS: One year after ICU admission 210,334 patients were alive and without a diagnosis of dementia; of these, 16,115 (7.7%) had a diagnosis of sepsis during intensive care. The median age of the cohort was 61 years (interquartile range, IQR 43-72). The patients were followed for up to 11 years (median 3.9 years, IQR 1.7-6.6). During the follow-up, 6312 (3%) patients were diagnosed with dementia. Dementia was more common in individuals diagnosed with sepsis during their ICU stay (log-rank p < 0.001), however diagnosis of sepsis during critical care was not an independent risk factor for a later dementia diagnosis in an extended Cox model: hazard ratio (HR) 1.01 (95% confidence interval 0.91-1.11, p = 0.873). Renal replacement therapy and ventilator therapy during the ICU stay were protective. High age was a strong risk factor for later dementia, as was increasing severity of acute illness, although to a lesser extent. However, the severity of comorbidities and the length of ICU and hospital stay were not independent risk factors in the model. CONCLUSION: Although dementia is more common among patients treated with sepsis in the ICU, sepsis was not an independent risk factor for later dementia in the Swedish national critical care cohort. TRIAL REGISTRATION: This study was registered a priori with the Australian and New Zeeland Clinical Trials Registry (registration no. ACTRN12618000533291 ).

Mortality after Severe Sepsis and Septic Shock in Swedish Intensive Care Units 2008-2016-A nationwide observational study.

BACKGROUND: Recent studies have reported substantially decreased hospital mortality for sepsis, but data are scarcer on outcomes after hospital discharge. We studied mortality up to 1 year in Swedish intensive care unit (ICU) patients with and without sepsis. METHODS: Demographic and medical data for all registered adult general ICU patients admitted between 01-01-2008 and 30-09-2016 were retrieved from the Swedish Intensive Care Registry and linked with the National Patient Register for comorbidity data and the Cause of Death Register for death dates. The population was divided in two cohorts; (a) Patients with a diagnosis of severe sepsis or septic shock and (b) All other ICU patients. Crude yearly mortality was calculated, and logistic regression was used to analyse predictors of mortality. RESULTS: 28 886 sepsis and 221 941 nonsepsis ICU patients were identified. In the sepsis cohort, in 2008 unadjusted mortality was 32.6% at hospital discharge, 32.7% at 30 days, 39% at 90 days and 46.8% at 365 days. In 2016, mortality was 30.5% at hospital discharge, 31.9% at 30 days and 38% at 90 days. Mortality at 365 days was 45.3% in 2015. Corresponding nonsepsis mortality was 15.4%, 16.2%, 20% and 26% in 2008 and 15.6%, 17.1%, 20.7% and 26.7% in 2016/2015. No consistent decrease in odds of mortality was seen in the adjusted analysis. CONCLUSIONS: Mortality in severe sepsis and septic shock is high, with more than one in three patients not surviving three months after ICU admission, and adjusted mortality has not decreased convincingly in Sweden 2008-2016. TRIAL REGISTRATION: The study was registered prospectively, ClinicalTrials.gov ID: NCT03489447.

Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock.

BACKGROUND: Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding whether and which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited. METHODS: Twelve anesthetized pigs were sampled from IO, venous, and arterial accesses during stable circulation and after hemorrhage corresponding to 20% and 40% of the blood volume. Samples were analyzed for blood gases and acid-base status, electrolytes, hematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), and creatine kinase (CK). RESULTS: Average differences of blood gases and acid-base parameters, sodium, creatinine, hematocrit, ALT, and γ-GT and between IO and venous samples were small at baseline and after hemorrhage while differences for lactate and glucose increased with hypovolemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolemia. Dispersions of differences were often large. CONCLUSIONS: Average levels of blood gases, acid base parameters, hematocrit, CK, AST, γ-GT, creatinine, and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.

The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study.

BACKGROUND: Intraosseous (IO) access is a recommended method when venous access cannot be rapidly established in an emergency. Experimental data suggest that major hemorrhage and catecholamine administration both reduce bone marrow blood flow. We studied the uptake of gentamicin as a tracer substance administered IO following adrenaline administration in hemorrhagic shock and in cardiac arrest. METHODS: Twenty anesthetized pigs underwent hemorrhage corresponding to 50% of the blood volume. They then received injections of either; adrenaline IO (n = 5), saline IO n = 5), adrenaline IO during cardiac arrest and cardiopulmonary resuscitation (CPR, n = 5), or intravenous adrenaline. The injections were followed by an injection of gentamicin by the same route. Doses and volumes were equivalent among the groups. In all animals, mixed venous antibiotic concentrations were analyzed at 5, 15 and 30 min after administration. RESULTS: Mean (SD) plasma gentamicin concentrations (mg x L- 1) at 5 min were 26.4 (2.3) in the group with previous IO adrenaline administration, 26.6 (4.5) in the IO saline group, 31. 2 (12) in the IO adrenaline + CPR group and 23 (4.5) in the IV group. Concentrations in the CPR group were significantly higher than the others. CONCLUSIONS: No impairment of drug uptake with IO administration after recent IO adrenaline exposure was demonstrable in this shock model.

Analysis of thromboelastography, PT, APTT and fibrinogen in intraosseous and venous samples-an experimental study.

BACKGROUND: Laboratory analysis of coagulation is often important in emergencies. If vascular access is challenging, intraosseous catheterization may be necessary for treatment. We studied the analysis of coagulation parameters in intraosseous aspirate during stable conditions and after major haemorrhage in a porcine model. METHODS: Ten anesthetized pigs received central venous and intraosseous catheters and samples were taken for analysis of thromboelastography (TEG), prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen concentration. Analyses were repeated after removal of 50 % of the calculated blood volume and resuscitation with crystalloid. Intraosseous and venous values were compared. RESULTS: Bleeding and resuscitation resulted in haemodilution and hypotension. Median TEG reaction time was shorter in intraosseous than in venous samples before (1.6 vs 4.6 min) and after (1.6 vs 4.7 min) haemodilution. Median maximal amplitude was smaller in intraosseous samples at baseline (68.3 vs 76.4 mm). No major differences were demonstrated for the other TEG parameters. The intraosseous samples often coagulated in vitro, making analysis of PT, APTT and fibrinogen difficult. After haemodilution, TEG maximal amplitude and α-angle, and fibrinogen concentration, were decreased and PT increased. DISCUSSION: The intraosseous samples were clinically hypercoagulable and the TEG demonstrated a shortened reaction time. The reason for this may hypothetically be found in the composition of the IO aspirate or in the sampling technique. After 50 % haemorrhage and haemodilution, a clinically relevant decrease in fibrinogen concentration and a lower TEG maximal amplitude were observed. CONCLUSIONS: Although the sample is small, these data indicate that intraosseous samples are hypercoagulable, which may limit their usefulness for coagulation studies. Major haemodilution only moderately affected the studied parameters.

Evaluation of intraosseous sampling for measurements of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatinine kinase, gamma-glutamyl transferase and lactate dehydrogenase.

BACKGROUND: Intraosseous (IO) access can be established faster than a venous or arterial access when there is an urgent need for rapid initiation of treatment. The access can also be used to draw marrow samples. The aim of the present study was to evaluate the potential use of IO samples for enzyme determinations using a porcine model. MATERIALS AND METHODS: Bilateral tibial intraosseous cannulae and an arterial catheter were used for blood sampling from five healthy anesthetized pigs. Samples were collected at baseline and thereafter hourly for 6 h and analyzed for alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, creatinine kinase, gamma-glutamyl transferase and lactate dehydrogenase. RESULTS: Creatinine kinase, lactate dehydrogenase and alkaline phosphatase levels decreased over time. The differences between IO and arterial sampling were limited for all studied markers. CONCLUSION: The correlation between marrow and blood analysis for liver function tests and CK is sufficiently accurate in an emergency situation.

[Intraosseous sampling can be valuable in emergency situations]. / Intraosseös provtagning kan vara värdefull i akuta lägen.

Intraosseous administration of fluids and drugs is valuable when vascular access is difficult to achieve. Intraosseous needles are useful tools in such cases. Sampling of aspirates through such needles have raised concern regarding the possibility that aspirated bone marrow particles could damage analysis equipment. We recommend that point-of-care equipment should be used as far as possible when intraosseous aspirates are analyzed. This is especially relevant when whole blood (i.e. blood gases) is analyzed.When centrifuged, possibly occurring bone marrow particles are deposited in the pellet, whereas the supernatant essentially corresponds to plasma. We have successfully analyzed creatinine, morphine and troponin in such samples. Leucocytes and platelets, which are formed in the bone marrow, may cause falsely elevated values when intraosseous aspirates are analyzed. The risk of hemolysis, and its potential effect on certain analyses, should be considered.

Troponin I can be Determined in Intraosseous Aspirates in a Porcine Shock Model.

BACKGROUND: Determination of troponin I may be important in the management of the critically ill patient. In medical emergencies, especially when vascular access is difficult to achieve, the use of intraosseous (10) needles is recommended. We aimed to perform a descriptive study, aiming to elucidate whether IO needles can be used to evaluate troponin I in a porcine model of human shock. METHODS: Eight pigs were anesthetized and challenged with a 6 hours continuous intravenous infusion of E. coli endotoxin. An IO needle (EZ-IO®) was inserted in the proximal tibia of each pig. Circulatory variables were monitored and troponin I was sampled from arterial and venous blood and also from bone marrow aspirates. RESULTS: Circulatory deterioration developed in all endotoxemic animals, which was reflected by a profound deterioration of left ventricular stroke work index. Troponin I levels were nearly identical in both arterial, venous, and IO samples during the first hour of endotoxemia. At 1 hour, all mean troponin I levels had more than doubled as compared to baseline. The troponin I levels continued to increase over time and were markedly elevated versus baseline levels during the 2nd and 6th hours, regardless of sampling site. At 3 hours, IO troponin I reached a plateau, whereas troponin I in both arterial and venous blood continued to increase. CONCLUSIONS: This investigation has shown that troponin I can be analyzed in bone marrow aspirates in a shock model. This may be useful in medical emergencies, where cardiac damage is suspected to be involved. The levels of IO troponin I increased during the first 3 hours of shock, after which it remained at a high level. During this initial period there was, in parallel, a progressive circulatory deterioration.

Intraosseous samples can be used for creatinine measurements--an experimental study in the anaesthetised pig.

BACKGROUND: Intraosseous (IO) access is a valuable tool in prehospital locations and in emergency departments when other forms of vascular access are unavailable. Creatinine is often used for dose adjustment of drugs that may be administered through intraosseous cannulae. We aimed to study the possibility of analysing creatinine in intraosseous samples and study the accuracy and precision of such measurements. METHODS: Eight pigs with endotoxin induced septic shock were sampled hourly for six hours and analysed for plasma creatinine. Samples were collected from arterial, venous, and IO cannulae. RESULTS: There was an increase in creatinine values during the later part of the experiment. The coefficients of variation between the three sampling sites were less than 10% at all sampling times. CONCLUSIONS: Based on our findings intraosseous samples can be used for creatinine determination in emergency settings.

Intraosseous samples can be used for opioid measurements--an experimental study in the anaesthetized pig.

AIM: The intraosseous route provides access to the systemic circulation in an emergency situation when other forms of vascular access are unavailable and there is an urgent need for fluid or drug therapy. The intraosseous access has also been used for collecting samples for laboratory testing. A question that may arise in an unconscious or severely exhausted patient is whether this condition is caused by an unknown drug. We aimed to evaluate whether intraosseous samples could be used to measure opioids and to study the accuracy and precision of such measurements. METHODS: Five healthy, anaesthetized pigs were treated with a continuous morphine infusion as part of the anaesthesia procedure. Samples for morphine testing were collected hourly for 6 h from two tibial intraosseous cannulae and a central venous catheter. RESULTS: The differences in morphine concentrations between the two tibial intraosseous cannulae were less than 10% in 32/33 times. The values were also relatively stable over time. CONCLUSION: Our findings suggest that intraosseous samples can be used for the analysis of opioids if an IV route is not available.

Analysis of intraosseous samples using point of care technology--an experimental study in the anaesthetised pig.

BACKGROUND: Intraosseous access is an essential method in emergency medicine when other forms of vascular access are unavailable and there is an urgent need for fluid or drug therapy. A number of publications have discussed the suitability of using intraosseous access for laboratory testing. We aimed to further evaluate this issue and to study the accuracy and precision of intraosseous measurements. METHODS: Five healthy, anaesthetised pigs were instrumented with bilateral tibial intraosseous cannulae and an arterial catheter. Samples were collected hourly for 6h and analysed for blood gases, acid base status, haemoglobin and electrolytes using an I-Stat point of care analyser. RESULTS: There was no clinically relevant difference between results from left and right intraosseous sites. The variability of the intraosseous sample values, measured as the coefficient of variance (CV), was maximally 11%, and smaller than for the arterial sample values for all variables except SO2. For most variables, there seems to be some degree of systematic difference between intraosseous and arterial results. However, the direction of this difference seems to be predictable. CONCLUSION: Based on our findings in this animal model, cartridge based point of care instruments appear suitable for the analysis of intraosseous samples. The agreement between intraosseous and arterial analysis seems to be good enough for the method to be clinically useful. The precision, quantified in terms of CV, is at least as good for intraosseous as for arterial analysis. There is no clinically important difference between samples from left and right tibia, indicating a good reproducibility.