Hepcidin, in contrast to heparin binding protein, does not portend acute kidney injury in patients with community acquired septic shock.

BACKGROUND: Acute kidney injury (AKI) is a common and severe complication in patients treated at an Intensive Care Unit (ICU). The pathogenesis of AKI has been reported to involve hypoperfusion, diminished oxygenation, systemic inflammation, and damage by increased intracellular iron concentration. Hepcidin, a regulator of iron metabolism, has been shown to be associated with sepsis and septic shock, conditions that can result in AKI. Heparin binding protein (HBP) has been reported to be associated with sepsis and AKI. The aim of the present study was to compare serum hepcidin and heparin binding protein (HBP) levels in relation to AKI in patients admitted to the ICU. METHODS: One hundred and forty patients with community acquired illness admitted to the ICU within 24 hours after first arrival to the hospital were included in the study. Eighty five of these patients were diagnosed with sepsis and 55 with other severe non-septic conditions. Logistic and linear regression models were created to evaluate possible correlations between circulating hepcidin and heparin-binding protein (HBP), stage 2-3 AKI, peak serum creatinine levels, and the need for renal replacement therapy (RRT). RESULTS: During the 7-day study period, 52% of the 85 sepsis and 33% of the 55 non-sepsis patients had been diagnosed with AKI stage 2-3 already at inclusion. The need for RRT was 20% and 15%, respectively, in the groups. Hepcidin levels at admission were significantly higher in the sepsis group compared to the non-sepsis group but these levels did not significantly correlate to the development of stage 2-3 AKI in the sepsis group (p = 0.189) nor in the non-sepsis group (p = 0.910). No significant correlation between hepcidin and peak creatinine levels, nor with the need for RRT was observed. Stage 2-3 AKI correlated, as expected, significantly with HBP levels at admission in both groups (Odds Ratio 1.008 (CI 1.003-1.014, p = 0.005), the need for RRT, as well as with peak creatinine in septic patients. CONCLUSION: Initial serum hepcidin, and HBP levels in patients admitted to the ICU are biomarkers for septic shock but in contrast to HBP, hepcidin does not portend progression of disease into AKI or a later need for RRT. Since hepcidin is a key regulator of iron metabolism our present data do not support a decisive role of initial iron levels in the progression of septic shock into AKI.

Plasma glial fibrillary acidic protein and tau: predictors of neurological outcome after cardiac arrest.

BACKGROUND: The purpose was to evaluate glial fibrillary acidic protein (GFAP) and total-tau in plasma as predictors of poor neurological outcome after out-of-hospital (OHCA) and in-hospital cardiac arrest (IHCA), including comparisons with neurofilament light (NFL) and neuron-specific enolase (NSE). METHODS: Retrospective multicentre observational study of patients admitted to an intensive care unit (ICU) in three hospitals in Sweden 2014-2018. Blood samples were collected at ICU admission, 12 h, and 48 h post-cardiac arrest. Poor neurological outcome was defined as Cerebral Performance Category 3-5 at 2-6 months after cardiac arrest. Plasma samples were retrospectively analysed for GFAP, tau, and NFL. Serum NSE was analysed in clinical care. Prognostic performances were tested with the area under the receiver operating characteristics curve (AUC). RESULTS: Of the 428 included patients, 328 were OHCA, and 100 were IHCA. At ICU admission, 12 h and 48 h post-cardiac arrest, GFAP predicted neurological outcome after OHCA with AUC (95% CI) 0.76 (0.70-0.82), 0.86 (0.81-0.90) and 0.91 (0.87-0.96), and after IHCA with AUC (95% CI) 0.77 (0.66-0.87), 0.83 (0.74-0.92) and 0.83 (0.71-0.95). At the same time points, tau predicted outcome after OHCA with AUC (95% CI) 0.72 (0.66-0.79), 0.75 (0.69-0.81), and 0.93 (0.89-0.96) and after IHCA with AUC (95% CI) 0.61 (0.49-0.74), 0.68 (0.56-0.79), and 0.77 (0.65-0.90). Adding the change in biomarker levels between time points did not improve predictive accuracy compared to the last time point. In a subset of patients, GFAP at 12 h and 48 h, as well as tau at 48 h, offered similar predictive value as NSE at 48 h (the earliest time point NSE is recommended in guidelines) after both OHCA and IHCA. The predictive performance of NFL was similar or superior to GFAP and tau at all time points after OHCA and IHCA. CONCLUSION: GFAP and tau are promising biomarkers for neuroprognostication, with the highest predictive performance at 48 h after OHCA, but not superior to NFL. The predictive ability of GFAP may be sufficiently high for clinical use at 12 h after cardiac arrest.

Central venous stenosis after subclavian versus internal jugular dialysis catheter insertion (CITES) in adults in need of a temporary central dialysis catheter: study protocol for a two-arm, parallel-group, non-inferiority randomised controlled trial.

BACKGROUND: The right internal jugular vein is currently recommended for temporary central dialysis catheters (tCDC) based on results from previous studies showing a lower incidence of central vein stenosis compared to the subclavian vein. Data is however conflicting, and there are several advantages when the subclavian route is used for tCDCs. This prospective, controlled, randomised, non-inferiority study aims to compare the incidence of post-catheterisation central vein stenosis between the right subclavian and the right internal jugular routes. METHODS: Adult patients needing a tCDC will be included from several hospitals and randomised to either subclavian or internal jugular vein catheterisation with a silicone tCDC. Inclusion continues until 50 patients in each group have undergone a follow-up CT venography. The primary outcome is the incidence of post-catheterisation central vein stenosis detected by a CT venography performed 1.5 to 3 months after removal of the tCDC. Secondary outcomes include between-group comparisons of (I) the patients' experience of discomfort and pain, (II) any dysfunction of the tCDC during use, (III) catheterisation success rate and (IV) the number of mechanical complications. Furthermore, the ability to detect central vein stenosis by a focused ultrasound examination will be evaluated using the CT venography as golden standard. DISCUSSION: The use of the subclavian route for tCDC placement has largely been abandoned due to older studies with various methodological issues. However, the subclavian route offers several advantages for the patient. This trial is designed to provide robust data on the incidence of central vein stenosis after silicone tCDC insertion in the era of ultrasound-guided catheterisations. TRIAL REGISTRATION: Clinicaltrials.gov; NCT04871568. Prospectively registered on May 4, 2021.

Hypothermia versus normothermia after out-of-hospital cardiac arrest; the effect on post-intervention serum concentrations of sedatives and analgesics and time to awakening.

BACKGROUND: This study investigated the association of two levels of targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) with administered doses of sedative and analgesic drugs, serum concentrations, and the effect on time to awakening. METHODS: This substudy of the TTM2-trial was conducted at three centers in Sweden, with patients randomized to either hypothermia or normothermia. Deep sedation was mandatory during the 40-hour intervention. Blood samples were collected at the end of TTM and end of protocolized fever prevention (72 hours). Samples were analysed for concentrations of propofol, midazolam, clonidine, dexmedetomidine, morphine, oxycodone, ketamine and esketamine. Cumulative doses of administered sedative and analgesic drugs were recorded. RESULTS: Seventy-one patients were alive at 40 hours and had received the TTM-intervention according to protocol. 33 patients were treated at hypothermia and 38 at normothermia. There were no differences between cumulative doses and concentration and of sedatives/analgesics between the intervention groups at any timepoint. Time until awakening was 53 hours in the hypothermia group compared to 46 hours in the normothermia group (p = 0.09). CONCLUSION: This study of OHCA patients treated at normothermia versus hypothermia found no significant differences in dosing or concentration of sedatives or analgesic drugs in blood samples drawn at the end of the TTM intervention, or at end of protocolized fever prevention, nor the time to awakening.

Veno-arterial CO2 difference and lactate for prediction of early mortality after cardiac arrest.

Patients admitted to intensive care after cardiac arrest are at risk of circulatory shock and early mortality due to cardiovascular failure. The aim of this study was to evaluate the ability of the veno-arterial pCO2 difference (∆pCO2 ; central venous CO2 - arterial CO2 ) and lactate to predict early mortality in postcardiac arrest patients. This was a pre-planned prospective observational sub-study of the target temperature management 2 trial. The sub-study patients were included at five Swedish sites. Repeated measurements of ∆pCO2 and lactate were conducted at 4, 8, 12, 16, 24, 48, and 72 h after randomization. We assessed the association between each marker and 96-h mortality and their prognostic value for 96-h mortality. One hundred sixty-three patients were included in the analysis. Mortality at 96 h was 17%. During the initial 24 h, there was no difference in ∆pCO2 levels between 96-h survivors and non-survivors. ∆pCO2 measured at 4 h was associated with an increased risk of death within 96 h (adjusted odds ratio: 1.15; 95% confidence interval [CI]: 1.02-1.29; p = .018). Lactate levels were associated with poor outcome over multiple measurements. The area under the receiving operating curve to predict death within 96 h was 0.59 (95% CI: 0.48-0.74) and 0.82 (95% CI: 0.72-0.92) for ∆pCO2 and lactate, respectively. Our results do not support the use of ∆pCO2 to identify patients with early mortality in the postresuscitation phase. In contrast, non-survivors demonstrated higher lactate levels in the initial phase and lactate identified patients with early mortality with moderate accuracy.

Plasma neurofilament light is a predictor of neurological outcome 12 h after cardiac arrest.

BACKGROUND: Previous studies have reported high prognostic accuracy of circulating neurofilament light (NfL) at 24-72 h after out-of-hospital cardiac arrest (OHCA), but performance at earlier time points and after in-hospital cardiac arrest (IHCA) is less investigated. We aimed to assess plasma NfL during the first 48 h after OHCA and IHCA to predict long-term outcomes. METHODS: Observational multicentre cohort study in adults admitted to intensive care after cardiac arrest. NfL was retrospectively analysed in plasma collected on admission to intensive care, 12 and 48 h after cardiac arrest. The outcome was assessed at two to six months using the Cerebral Performance Category (CPC) scale, where CPC 1-2 was considered a good outcome and CPC 3-5 a poor outcome. Predictive performance was measured with the area under the receiver operating characteristic curve (AUROC). RESULTS: Of 428 patients, 328 (77%) suffered OHCA and 100 (23%) IHCA. Poor outcome was found in 68% of OHCA and 55% of IHCA patients. The overall prognostic performance of NfL was excellent at 12 and 48 h after OHCA, with AUROCs of 0.93 and 0.97, respectively. The predictive ability was lower after IHCA than OHCA at 12 and 48 h, with AUROCs of 0.81 and 0.86 (p ≤ 0.03). AUROCs on admission were 0.77 and 0.67 after OHCA and IHCA, respectively. At 12 and 48 h after OHCA, high NfL levels predicted poor outcome at 95% specificity with 70 and 89% sensitivity, while low NfL levels predicted good outcome at 95% sensitivity with 71 and 74% specificity and negative predictive values of 86 and 88%. CONCLUSIONS: The prognostic accuracy of NfL for predicting good and poor outcomes is excellent as early as 12 h after OHCA. NfL is less reliable for the prediction of outcome after IHCA.

Prognostic accuracy of head computed tomography for prediction of functional outcome after out-of-hospital cardiac arrest: Rationale and design of the prospective TTM2-CT-substudy.

Background: Head computed tomography (CT) is a guideline recommended method to predict functional outcome after cardiac arrest (CA), but standardized criteria for evaluation are lacking. To date, no prospective trial has systematically validated methods for diagnosing hypoxic-ischaemic encephalopathy (HIE) on CT after CA. We present a protocol for validation of pre-specified radiological criteria for assessment of HIE on CT for neuroprognostication after CA. Methods/design: This is a prospective observational international multicentre substudy of the Targeted Hypothermia versus Targeted Normothermia after out-of-hospital cardiac arrest (TTM2) trial. Patients still unconscious 48 hours post-arrest at 13 participating hospitals were routinely examined with CT. Original images will be evaluated by examiners blinded to clinical data using a standardized protocol. Qualitative assessment will include evaluation of absence/presence of "severe HIE". Radiodensities will be quantified in pre-specified regions of interest for calculation of grey-white matter ratios (GWR) at the basal ganglia level. Functional outcome will be dichotomized into good (modified Rankin Scale 0-3) and poor (modified Rankin Scale 4-6) at six months post-arrest. Prognostic accuracies for good and poor outcome will be presented as sensitivities and specificities with 95% confidence intervals (using pre-specified cut-offs for quantitative analysis), descriptive statistics (Area Under the Receiver Operating Characteristics Curve), inter- and intra-rater reliabilities according to STARD guidelines. Conclusions: The results from this prospective trial will validate a standardized approach to radiological evaluations of HIE on CT for prediction of functional outcome in comatose CA patients.The TTM2 trial and the TTM2 CT substudy are registered at ClinicalTrials.gov NCT02908308 and NCT03913065.

Hepcidin discriminates sepsis from other critical illness at admission to intensive care.

Initial differential diagnosis and prognosis for patients admitted to intensive care with suspected sepsis remain arduous. Hepcidin has emerged as a potential biomarker for sepsis. Here we report data on the relevance of levels of hepcidin versus other biomarkers as a diagnostic and prognostic tool for sepsis. 164 adult patients admitted to the intensive care unit (ICU) within 24 h upon arrival to the hospital were included. Blood samples collected daily for seven consecutive days and hepcidin levels, heparin binding protein (HBP) levels and standard biomarkers were determined. Blood cultures were initiated at inclusion. Clinical scores were evaluated daily and mortality after 28- and 180-days was recorded. One hundred of the patients were found to fulfil the criteria for sepsis whereas 64 did not. Hepcidin levels at admission were significantly higher in the septic than in the non-septic patients. In septic patients hepcidin levels declined significantly already at 24 h followed by a steady decline. A significant negative correlation was observed between hepcidin levels and SAPS 3 in patients with sepsis. Hepcidin levels at inclusion were significantly higher among septic patients that survived 180-days and predicted mortality. Our data show that hepcidin levels are indicative of sepsis in patients admitted to the ICU and has a prognostic value for mortality.

Influence of temperature management at 33 °C versus normothermia on survival in patients with vasopressor support after out-of-hospital cardiac arrest: a post hoc analysis of the TTM-2 trial.

BACKGROUND: Targeted temperature management at 33 °C (TTM33) has been employed in effort to mitigate brain injury in unconscious survivors of out-of-hospital cardiac arrest (OHCA). Current guidelines recommend prevention of fever, not excluding TTM33. The main objective of this study was to investigate if TTM33 is associated with mortality in patients with vasopressor support on admission after OHCA. METHODS: We performed a post hoc analysis of patients included in the TTM-2 trial, an international, multicenter trial, investigating outcomes in unconscious adult OHCA patients randomized to TTM33 versus normothermia. Patients were grouped according to level of circulatory support on admission: (1) no-vasopressor support, mean arterial blood pressure (MAP) ≥ 70 mmHg; (2) moderate-vasopressor support MAP < 70 mmHg or any dose of dopamine/dobutamine or noradrenaline/adrenaline dose ≤ 0.25 µg/kg/min; and (3) high-vasopressor support, noradrenaline/adrenaline dose > 0.25 µg/kg/min. Hazard ratios with TTM33 were calculated for all-cause 180-day mortality in these groups. RESULTS: The TTM-2 trial enrolled 1900 patients. Data on primary outcome were available for 1850 patients, with 662, 896, and 292 patients in the, no-, moderate-, or high-vasopressor support groups, respectively. Hazard ratio for 180-day mortality was 1.04 [98.3% CI 0.78-1.39] in the no-, 1.22 [98.3% CI 0.97-1.53] in the moderate-, and 0.97 [98.3% CI 0.68-1.38] in the high-vasopressor support groups with regard to TTM33. Results were consistent in an imputed, adjusted sensitivity analysis. CONCLUSIONS: In this exploratory analysis, temperature control at 33 °C after OHCA, compared to normothermia, was not associated with higher incidence of death in patients stratified according to vasopressor support on admission. Trial registration Clinical trials identifier NCT02908308 , registered September 20, 2016.

Ventilatory settings in the initial 72 h and their association with outcome in out-of-hospital cardiac arrest patients: a preplanned secondary analysis of the targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2) trial.

PURPOSE: The optimal ventilatory settings in patients after cardiac arrest and their association with outcome remain unclear. The aim of this study was to describe the ventilatory settings applied in the first 72 h of mechanical ventilation in patients after out-of-hospital cardiac arrest and their association with 6-month outcomes. METHODS: Preplanned sub-analysis of the Target Temperature Management-2 trial. Clinical outcomes were mortality and functional status (assessed by the Modified Rankin Scale) 6 months after randomization. RESULTS: A total of 1848 patients were included (mean age 64 [Standard Deviation, SD = 14] years). At 6 months, 950 (51%) patients were alive and 898 (49%) were dead. Median tidal volume (VT) was 7 (Interquartile range, IQR = 6.2-8.5) mL per Predicted Body Weight (PBW), positive end expiratory pressure (PEEP) was 7 (IQR = 5-9) cmH20, plateau pressure was 20 cmH20 (IQR = 17-23), driving pressure was 12 cmH20 (IQR = 10-15), mechanical power 16.2 J/min (IQR = 12.1-21.8), ventilatory ratio was 1.27 (IQR = 1.04-1.6), and respiratory rate was 17 breaths/minute (IQR = 14-20). Median partial pressure of oxygen was 87 mmHg (IQR = 75-105), and partial pressure of carbon dioxide was 40.5 mmHg (IQR = 36-45.7). Respiratory rate, driving pressure, and mechanical power were independently associated with 6-month mortality (omnibus p-values for their non-linear trajectories: p < 0.0001, p = 0.026, and p = 0.029, respectively). Respiratory rate and driving pressure were also independently associated with poor neurological outcome (odds ratio, OR = 1.035, 95% confidence interval, CI = 1.003-1.068, p = 0.030, and OR = 1.005, 95% CI = 1.001-1.036, p = 0.048). A composite formula calculated as [(4*driving pressure) + respiratory rate] was independently associated with mortality and poor neurological outcome. CONCLUSIONS: Protective ventilation strategies are commonly applied in patients after cardiac arrest. Ventilator settings in the first 72 h after hospital admission, in particular driving pressure and respiratory rate, may influence 6-month outcomes.

Influence of circulatory shock at hospital admission on outcome after out-of-hospital cardiac arrest.

Hypotension after cardiac arrest could aggravate prolonged hypoxic ischemic encephalopathy. The association of circulatory shock at hospital admission with outcome after cardiac arrest has not been well studied. The objective of this study was to investigate the independent association of circulatory shock at hospital admission with neurologic outcome, and to evaluate whether cardiovascular comorbidities interact with circulatory shock. 4004 adult patients with out-of-hospital cardiac arrest enrolled in the International Cardiac Arrest Registry 2006-2017 were included in analysis. Circulatory shock was defined as a systolic blood pressure below 90 mmHg and/or medical or mechanical supportive measures to maintain adequate perfusion during hospital admission. Primary outcome was cerebral performance category (CPC) dichotomized as good, (CPC 1-2) versus poor (CPC 3-5) outcome at hospital discharge. 38% of included patients were in circulatory shock at hospital admission, 32% had good neurologic outcome at hospital discharge. The adjusted odds ratio for good neurologic outcome in patients without preexisting cardiovascular disease with circulatory shock at hospital admission was 0.60 [0.46-0.79]. No significant interaction was detected with preexisting comorbidities in the main analysis. We conclude that circulatory shock at hospital admission after out-of-hospital cardiac arrest is independently associated with poor neurologic outcome.

Circulating dipeptidyl peptidase 3 on intensive care unit admission is a predictor of organ dysfunction and mortality.

BACKGROUND: Our aim was to investigate the prognostic potential of circulating dipeptidyl peptidase 3 (cDPP3) to predict mortality and development of organ dysfunction in a mixed intensive care unit (ICU) population, and for this reason, we analysed prospectively collected admission blood samples from adult ICU patients at four Swedish hospitals. Blood samples were stored in a biobank for later batch analysis. The association of cDPP3 levels with 30-day mortality and Sequential Organ Failure Assessment (SOFA) scores on day two was investigated before and after adjustment for the simplified acute physiology score III (SAPS-3), using multivariable (ordinal) logistic regression. The predictive power of cDPP3 was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Of 1978 included consecutive patients in 1 year (2016), 632 fulfilled the sepsis 3-criteria, 190 were admitted after cardiac arrest, and 157 because of trauma. Admission cDPP3 was independently (of SAPS-3) associated with 30-day mortality with odds ratios of 1.45 (95% confidence interval (CI) 1.28-1.64) in the entire ICU population, 1.30 (95% CI 1.08-1.57) in the sepsis subgroup and 2.28 (95% CI 1.50-3.62) in cardiac arrest. For trauma, there was no clear association. Circulating DPP3 alone was a moderate predictor of 30-day mortality with AUROCs of 0.68, 0.62, and 0.72 in the entire group, the sepsis subgroup, and the cardiac arrest subgroup, respectively. By adding cDPP3 to SAPS-3, AUROC improved for the entire group, the sepsis subgroup, and the cardiac arrest subgroup (p = 0.023). CONCLUSION: Circulating DPP3 on admission is a SAPS-3 independent prognostic factor of day-two organ dysfunction and 30-day mortality in a mixed ICU population and needs further evaluation.

Plasma proenkephalin A 119-159 on intensive care unit admission is a predictor of organ failure and 30-day mortality.

BACKGROUND: Proenkephalin A 119-159 (penKid) has been suggested as a marker of renal failure and poor outcome. We aimed to investigate the association of penKid on ICU admission with organ dysfunction and mortality in a mixed ICU population. In this retrospective, observational study, admission penKid levels from prospectively collected blood samples of consecutive patients admitted to four Swedish ICUs were analysed. The association of penKid with day-two sequential organ failure assessment (SOFA) scores and 30-day mortality was investigated using (ordinal) logistic regression. The predictive power of penKid for 30-day mortality and dialysis was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: Of 1978 included patients, 632 fulfilled the sepsis 3-criteria, 190 had a cardiac arrest, and 157 had experienced trauma. Admission penKid was positively associated with 30-day mortality with an odds ratio of 1.95 (95% confidence interval 1.75-2.18, p < 0.001), and predicted 30-day mortality in the entire ICU population with an AUC of 0.71 (95% confidence interval 0.68-0.73) as well as in the sepsis, cardiac arrest and trauma subgroups (AUCs of 0.61-0.84). Correction for admission plasma creatinine revealed that penKid correlated with neurological dysfunction. CONCLUSION: Plasma penKid on ICU admission is associated with day-two organ dysfunction and predictive of 30-day mortality in a mixed ICU-population, as well as in sepsis, cardiac arrest and trauma subgroups. In addition to being a marker of renal dysfunction, plasma penKid is associated with neurologic dysfunction in the entire ICU population, and cardiovascular dysfunction in sepsis.

Plasma proenkephalin A 119-159 and dipeptidyl peptidase 3 on admission after cardiac arrest help predict long-term neurological outcome.

BACKGROUND: A large proportion of adult survivors of cardiac arrest have a poor neurological outcome. Guidelines recommend multimodal neuro-prognostication no earlier than 72-96 h after cardiac arrest. There is great interest in earlier prognostic markers, including very early markers at admission. The novel blood biomarkers proenkephalin A 119-159 (penKid), bioactive adrenomedullin (bio-ADM) and circulating dipeptidyl peptidase 3 (cDPP3) have not been previously investigated for the early prognosis of cardiac arrest survivors. METHODS: This multicentre observational study included adult survivors of cardiac arrest admitted to intensive care at four Swedish intensive care units (ICUs) during 2016. Blood samples were collected at ICU admission and batch analysed. The association between admission plasma penKid, bio-ADM and cDPP3 and poor long-term neurological outcome, according to the Cerebral Performance Category (CPC) scale, was assessed by binary logistic regression. Their prognostic performance was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 190 patients were included, of which 136 patients had suffered out-of-hospital and 54 patients in-hospital cardiac arrest. Poor long-term neurological outcome was associated with elevated admission plasma concentrations of penKid and cDPP3, but not with bio-ADM. The association for penKid, but not for cDPP3, remained after adjusting for clinical cardiac arrest variables with prognostic value (time to return of spontaneous circulation (ROSC), initial rhythm, admission Glasgow coma scale (GCS) motor score and absence of pupillary reflexes). The prognostic performance of above mentioned clinical cardiac arrest variables alone was very good with an AUC of 0.90 (95% confidence interval, CI, 0.86-0.95), but improved further with the addition of penKid resulting in an AUC of 0.93 (95% CI 0.89-0.97, p < 0.026). Plasma penKid and cDPP3 alone provided moderate long-term prognostic information with AUCs of 0.70 and 0.71, respectively. CONCLUSION: After cardiac arrest, admission plasma levels of penKid and cDPP3, but not bio-ADM, predicted long-term neurological outcome. When added to clinical cardiac arrest variables, penKid further improved prognostic performance.

Circulating bioactive adrenomedullin as a marker of sepsis, septic shock and critical illness.

BACKGROUND: Biomarkers can be of help to understand critical illness and to identify and stratify sepsis. Adrenomedullin is a vasoactive hormone, with reported prognostic and potentially therapeutic value in sepsis. The primary aim of this study was to investigate the association of circulating bioactive adrenomedullin (bio-ADM) levels at intensive care unit (ICU) admission with mortality in sepsis patients and in a general ICU population. Secondary aims included the association of bio-ADM with organ failure and the ability of bio-ADM to identify sepsis. METHODS: In this retrospective observational study, adult patients admitted to one of four ICUs during 2016 had admission bio-ADM levels analysed. Age-adjusted odds ratios (OR) with 95% CI for log-2 transformed bio-ADM, and Youden's index derived cut-offs were calculated. The primary outcome was 30-day mortality, and secondary outcomes included the need for organ support and the ability to identify sepsis. RESULTS: Bio-ADM in 1867 consecutive patients were analysed; 632 patients fulfilled the sepsis-3 criteria of whom 267 had septic shock. The median bio-ADM in the entire ICU population was 40 pg/mL, 74 pg/mL in sepsis patients, 107 pg/mL in septic shock and 29 pg/mL in non-septic patients. The association of elevated bio-ADM and mortality in sepsis patients and the ICU population resulted in ORs of 1.23 (95% CI 1.07-1.41) and 1.22 (95% CI 1.12-1.32), respectively. The association with mortality remained after additional adjustment for lactate in sepsis patients. Elevated bio-ADM was associated with an increased need for dialysis with ORs of 2.28 (95% CI 2.01-2.59) and 1.97 (95% CI 1.64-2.36) for the ICU population and sepsis patients, respectively, and with increased need of vasopressors, OR 1.33 (95% CI 1.23-1.42) (95% CI 1.17-1.50) for both populations. Sepsis was identified with an OR of 1.78 (95% CI 1.64-1.94) for bio-ADM, after additional adjustment for severity of disease. A bio-ADM cut-off of 70 pg/mL differentiated between survivors and non-survivors in sepsis, but a Youden's index derived threshold of 108 pg/mL performed better. CONCLUSIONS: Admission bio-ADM is associated with 30-day mortality and organ failure in sepsis patients as well as in a general ICU population. Bio-ADM may be a morbidity-independent sepsis biomarker.

Sepsis is underreported in Swedish intensive care units: A retrospective observational multicentre study.

BACKGROUND: Sepsis is a common indication for admission to the intensive care unit (ICU). Since definitions vary across studies, comparisons of prevalence and outcomes have been challenging. We aimed to compare sepsis according to ICU discharge codes with sepsis according to Sepsis-3 criteria and to investigate the epidemiology of sepsis in the ICU. We hypothesized that sepsis using discharge codes is underreported. METHODS: Adult ICU admissions to four ICUs in Sweden between 2015 and 2017 were screened for sepsis according to the Sepsis-3 criteria. Medical records were reviewed and data extracted from the Swedish Intensive Care Registry. RESULTS: Of 5990 adult ICU patients, 28% fulfilled the Sepsis-3 criteria on admission, but only 31% of them had sepsis as the registered main diagnosis at ICU discharge. Of the 1654 Sepsis-3 patients, 38% met the septic shock criteria. The Sepsis-3 in-hospital mortality was 26% compared to 33% in patients with septic shock. The incidence rate for ICU-treated sepsis was 81 cases per 100 000 person-years. One in four had a positive blood culture, and 44% were culture negative. CONCLUSION: This large Swedish multicentre study showed that 28% of adult ICU patients fulfilled the Sepsis-3 criteria, but only one third of them had sepsis according to ICU discharge codes. We could confirm our hypothesis, that sepsis is severely underreported in Swedish ICUs, and we conclude that discharge codes should not be used for quality control or research purposes.

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

BACKGROUND: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest. METHODS: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score. RESULTS: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001. CONCLUSION: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure. TRIAL REGISTRATION: Clinical Trials, NCT01020916. Registered November 26, 2009.

Functional outcomes associated with varying levels of targeted temperature management after out-of-hospital cardiac arrest - An INTCAR2 registry analysis.

INTRODUCTION: Targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) has been recommended in international guidelines since 2005. The TTM-trial published in 2013 showed no difference in survival or neurological outcome for patients randomised to 33 °C or 36 °C, and many hospitals have changed practice. The optimal utilization of TTM is still debated. This study aimed to analyse if a difference in temperature goal was associated with outcome in an unselected international registry population. METHODS: This is a retrospective observational study based on a prospective registry - the International Cardiac Arrest Registry 2. Patients were categorized as receiving TTM in the lower range at 32-34 °C (TTM-low) or at 35-37 °C (TTM-high). Primary outcome was good functional status defined as cerebral performance category (CPC) of 1-2 at hospital discharge and secondary outcome was adverse events related to TTM. A logistic regression model was created to evaluate the independent effect of temperature by correcting for clinical and demographic factors associated with outcome. RESULTS: Of 1710 patients included, 1242 (72,6%) received TTM-low and 468 (27,4%) TTM-high. In patients receiving TTM-low, 31.3% survived with good outcome compared to 28.8% in the TTM-high group. There was no significant association between temperature and outcome (p = 0.352). In analyses adjusted for baseline differences the OR for a good outcome with TTM-low was 1.27, 95% CI (0.94-1.73). Haemodynamic instability leading to discontinuation of TTM was more common in TTM-low. CONCLUSIONS: No significant difference in functional outcome at hospital discharge was found in patients receiving lower- versus higher targeted temperature management.

The Combination of Biomarkers for Prognostication of Long-Term Outcome in Patients Treated with Mild Hypothermia After Out-of-Hospital Cardiac Arrest-A Pilot Study.

To explore if the brain biomarker neuron-specific enolase (NSE) in combination with a biomarker for stress; CT-proAVP (copeptin), oxidation; peroxiredoxin 4 (Prx4), inflammation; procalcitonin (PCT), or with biomarkers from the heart; midregional proatrial natriuretic peptide (MR-proANP), or troponin T (TnT) can improve the prognostic accuracy of long-term outcome after out-of-hospital cardiac arrest (OHCA). Serum samples from cardiac arrest patients, treated at 33°C for 24 hours, were collected serially at 12, 24, and 48 hours after cardiac arrest. The concentration of the investigated biomarkers was measured using stored samples, and long-term outcome was evaluated by the cerebral performance category (CPC) at 6 months. Poor outcome was defined as CPC 3-5. Sixty-two patients with OHCA of presumed cardiac cause were included. NSE had best prognostic accuracy for poor outcome at 48 hours with a receiver operating characteristic area under curve (AUC) of 0.94 (95% confidence interval [CI] 0.87-1). The combination of NSE with TnT, both at 48 hours, increased the AUC to 0.98 (95% CI 0.95-1, likelihood ratio [LR] test p-value 0.07, net reclassification index [NRI] <0.001); NSE and MR-proANP, both at 12 hours, yielded an AUC of 0.91 (95% CI 0.80-1, LR test p-value 0.0014, NRI p-value 0.003); NSE at 48 hours with MR-proANP at 12 hours yielded an AUC of 0.97 (95% CI 0.92-1, LR test p-value 0.055, NRI p-value 0.04). This pilot study suggests that a combination of biomarkers with NSE could be beneficial for improving early prognostication of long-term outcome following OHCA.

Hemodynamics and vasopressor support during targeted temperature management at 33°C Versus 36°C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial*.

OBJECTIVE: To investigate the hemodynamic profile associated with different target temperatures and to assess the prognostic implication of inotropic/vasopressor support and mean arterial pressure after out-of-hospital cardiac arrest. There is a lack of information how different target temperatures may affect hemodynamics. DESIGN: Post hoc analysis of a prospective randomized study. SETTING: Thirty-six ICUs in 10 countries. PATIENTS: Nine hundred twenty patients (97%) with available vasopressor data out of 950 patients from the Target Temperature Management trial randomly assigned patients to a targeted temperature management at 33 °C or 36 °C. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure, heart rate, and lactate were registered at prespecified time points. The population was stratified according to cardiovascular Sequential Organ Failure Assessment = 4 defining the high vasopressor group and cardiovascular Sequential Organ Failure Assessment less than or equal to 3 defining the low vasopressor group. The targeted temperature management 33 (TTM33) group had a hemodynamic profile with lower heart rate (-7.0 min(-1) [95% confidence limit, -8.7, -5.1]; p(group) < 0.0001), similar mean arterial pressure (-1.1 mm Hg [95% confidence limit, -2.3, 0.2]; p(group) = 0.10), and increased lactate (0.6 mmol/L [95% confidence limit, 0.3, 0.8]; p(group) < 0.0001) compared with the targeted temperature management 36 (TTM36) group. A cardiovascular Sequential Organ Failure Assessment score = 4 was recorded in 54% versus 45%, p = 0.03 in the TTM33 and the TTM36 group, respectively. The high vasopressor group carried a 53% mortality rate when compared with a 34% in the low vasopressor group, p(log-rank) less than 0.0001, with an adjusted hazard ratio of 1.38 (95% CI, 1.11-1.71; p = 0.004). There was no interaction between vasopressor group and allocated target temperature group (p = 0.40). An inverse relationship between mean arterial pressure and mortality was identified (p = 0.0008). CONCLUSIONS: Targeted temperature management at 33 °C was associated with hemodynamic alterations with decreased heart rate, elevated levels of lactate, and need for increased vasopressor support compared with targeted temperature management at 36 °C. Low mean arterial pressure and need for high doses of vasopressors were associated with increased mortality independent of allocated targeted temperature management.