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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 pCO(2) difference ( increment pCO(2); 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 increment pCO(2) 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 increment pCO(2) levels between 96-h survivors and non-survivors. increment pCO(2) 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 increment pCO(2) and lactate, respectively. Our results do not support the use of increment pCO(2) 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.

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 hours 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. (Less)

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 (V-T) 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) cmH(2)0, plateau pressure was 20 cmH(2)0 (IQR = 17-23), driving pressure was 12 cmH(2)0 (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. Funding Agencies|Universita degli Studi di Genova; Swedish Research Council [Vetenskapsradet]; Swedish Heart-Lung Foundation; Stig and Ragna Gorthon Foundation; Knutsson Foundation; Laerdal Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Region Skane; Swedish National Health Service

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.

Additional file 1: Additional statistical analysis of subgroups population and association with outcome.

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.

BackgroundProenkephalin 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).ResultsOf 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.ConclusionPlasma 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.

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.Post hoc analysis of a prospective randomized study.Thirty-six ICUs in 10 countries.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.None.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).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.

We hypothesized that a targeted temperature of 33 °C as compared to that of 36 °C would increase survival and reduce the severity of circulatory shock in patients with shock on admission after out-of-hospital cardiac arrest (OHCA).The recently published Target Temperature Management trial (TTM-trial) randomized 939 OHCA patients with no difference in outcome between groups and no difference in mortality at the end of the trial in a predefined subgroup of patients with shock at admission. Shock was defined as a systolic blood pressure of90 mm Hg for30 min or the need of supportive measures to maintain a blood pressure ≥90 mmHg and/or clinical signs of end-organ hypoperfusion. In this post hoc analysis reported here, we further analyzed the 139 patients with shock at admission; all had been randomized to receive intervention at 33 °C (TTM33; n = 71) or 36 °C (TTM36; n = 68). Primary outcome was 180-day mortality. Secondary outcomes were intensive care unit (ICU) and 30-day mortality, severity of circulatory shock assessed by mean arterial pressure, serum lactate, fluid balance and the extended Sequential Organ Failure assessment (SOFA) score.There was no significance difference between targeted temperature management at 33 °C or 36 °C on 180-day mortality [log-rank test, p = 0.17, hazard ratio 1.33, 95 % confidence interval (CI) 0.88-1.98] or ICU mortality (61 vs. 44 %, p = 0.06; relative risk 1.37, 95 % CI 0.99-1.91). Serum lactate and the extended cardiovascular SOFA score were higher in the TTM33 group (p0.01).We found no benefit in survival or severity of circulatory shock with targeted temperature management at 33 °C as compared to 36 °C in patients with shock on admission after OHCA.

Further characterization of the post-cardiac arrest syndrome (PCAS) is essential to better understand the mechanisms resulting in injury and death. We investigated serial serum concentrations of the stress hormone c-terminal provasopressin (CT-proAVP or copeptin), the cardiac biomarker MR-proANP and a biomarker of oxidation injury, Peroxiredoxin 4 (Prx4) in patients treated with mild hypothermia (MHT) after cardiac arrest, and studied their association to the PCAS and long-term outcome.

Aim To investigate serial serum concentrations of procalcitonin (PCT) and C-reactive protein (CRP) in patients treated with mild hypothermia after cardiac arrest, and to study their association to severe infections, post cardiac arrest syndrome (PCAS) and long-term outcome. Methods Serum samples from cardiac arrest patients treated with mild hypothermia were collected serially at admission, 2, 6, 12, 24, 36, 48 and 72 h after cardiac arrest. PCT and CRP concentrations were determined and tested for association with three definitions of infection, two surrogate markers of PCAS (circulation-SOFA and time to return of spontaneous circulation (ROSC)) and cerebral performance category (CPC) at six months. Results Eighty-four patients were included. PCT displayed an earlier release pattern than CRP with a significant increase within 2 h, increasing further at 6 h and onwards in patients with poor outcome. CRP increased later and continued to rise during the study period. PCT was strongly associated with circulation-SOFA and time to ROSC, and predicted a poor neurologic outcome with high accuracy (area under the receiver operating characteristic curve of 0.88, 0.86 and 0.87 at 12, 24 and 48 h respectively). No association of PCT or CRP to infection was observed. Conclusion Our results suggest that PCT is released early after resuscitation following cardiac arrest, is associated with markers of PCAS but not with infection, and is an accurate predictor of poor outcome. Validation of these findings in larger studies is warranted.

To investigate whether early coronary angiography (CAG) after out-of-hospital cardiac arrest of a presumed cardiac cause is associated with improved outcomes in patients without acute ST elevation.

The role of cell adhesion molecules and transmigration of PMNs through the endothelial barrier is probably essential in intestinal ischemia and reperfusion (I/R)-induced gut barrier dysfunction. Although cytokines are released in I/R, it is unclear whether cytokines directly increase permeability or if this phenomenon requires both expression of cell adhesion molecules and PMN adhesion-activation. Endothelial barrier dysfunction plays an important role in the pathogenesis of multiple organ dysfunction syndrome, inducing gut barrier failure, but the mechanisms are not fully understood. The purpose of this study was to evaluate the potential therapeutic value of inhibition of platelet activating factor (PAF), intercellular adhesion molecule-1 (ICAM-1), and platelet endothelial cell adhesion molecule-1 (PECAM-1) in gut barrier dysfunction induced by intestinal I/R.A PAF antagonist (lexipafant, BB-882) and monoclonal antibodies against rat ICAM-1 (anti-ICAM-1-MAb) and PECAM-1 (anti-PECAM-1-MAb) were used in a model of gut barrier dysfunction caused by intestinal ischemia for 40 min and concomitant reperfusion for 12 h in the rat, and endothelial permeability, myeloperoxidase activity, interleukin-1beta and protease inhibitor levels were evaluated.The endothelial permeability and tissue leukocyte recruitment in the distal small intestine significantly increased in rats with I/R treated with saline. Proteolytic activity in plasma was evident by low levels of the three measured plasma protease inhibitors. These changes were, to different degrees, reduced by treatment with lexipafant, anti-ICAM-1-MAb, or anti-PECAM-1-MAb. Alterations in systemic levels of interleukin-1beta paralleled the changes found in gut barrier permeability and leukocyte trapping.Our results suggest that treatment with the PAF inhibitor lexipafant and monoclonal antibodies against ICAM-1 or, seemingly most efficient, PECAM-1 reduces the severity of I/R-associated intestinal dysfunction, associated with a decrease in systemic concentrations of IL-1beta local leukocyte recruitment, and partly restoring plasma protease inhibitor levels.

Aim To investigate plasma levels of the neutrophil-borne heparin-binding protein (HBP) in patients with induced hypothermia after cardiac arrest (CA), and to study any association to severity of organ failure, incidence of infection and neurological outcome. Methods This study included 84 patients with CA of mixed origin who were treated with hypothermia. Plasma samples from 7 time points during the first 72 h after return of spontaneous circulation (ROSC) were collected and analyzed for HBP with an ELISA. Outcomes were dichotomized: a cerebral performance category scale (CPC) of 1–2 at 6 months follow-up was considered a good outcome, a CPC of 3–5, a poor outcome. Patient data, including APACHE II and SOFA-scores were retrieved from the computerized system for quality assurance for intensive care. Results At 6 h and 12 h after CA, plasma levels of HBP were significantly higher among patients with a poor outcome. A receiver operated characteristics (ROC)-analysis yielded respective areas under curve (AUC) values of 0.68 and 0.70. This was similar to APACHE II and SOFA-score AUC values. There was a significant correlation between early elevated HBP-values and time to ROSC. HBP-levels were not higher in patients with infections at any time. Conclusions Elevated HBP is an early indicator of organ failure and poor neurological outcome after CA, independent of microbial infection, and should be further evaluated in prospective trials. The temporal profile of HBP is suggestive of a role in the pathogenesis of critical illness after CA.

BACKGROUND: Oxygen free radicals (OFRs), platelet activating factor (PAF), cell adhesion molecules, and transmigration of polymorphonuclear leukocytes through the gut barrier are probably all essential in the development of gut barrier dysfunction following intestinal ischemia and reperfusion (I/R). Pretreatment and early treatment of I/R with the OFRs-scavenger (NAC), the PAF inhibitor lexipafant, and monoclonal antibodies against the adhesion molecule PECAM-1 (anti-PECAM-1-Mab) have been reported to be effective in the prevention or recovery of gut barrier dysfunction and result in a decrease in cytokine levels. Less is known about the effect of treatment inserted during the late stage of I/R. The objective of this study was to evaluate the potential therapeutic value of single or combination therapy with NAC, lexipafant, and anti-PECAM-1-MAb administered late during intestinal I/R in the rat. METHODS: NAC, lexipafant, and anti-PECAM-1-MAb were administrated, alone or in combination, after 3 h of reperfusion following 40 min of superior mesenteric arterial ischemia in the rat. Intestinal endothelial and epithelial barrier permeability, myeloperoxidase (MPO) activity, interleukin-1 beta (IL-1 beta), and protease inhibitor levels were evaluated after 12 h of reperfusion. RESULTS: Intestinal endothelial and epithelial permeability significantly increased in rats with I/R and saline treatment. Proteolytic activity in plasma was indicated by low levels of the three measured plasma protease inhibitors. Intestinal mucosal MPO content increased significantly. These changes were, to different degrees, reduced by late inserted treatment with NAC, lexipafant, or anti-PECAM-1-MAb. Alterations in systemic levels of IL-1 beta paralleled the changes found in gut barrier permeability and leukocyte trapping. Systemic antithrombin III levels and increased barrier permeability in remote organs were partly restored, especially by multimodal therapy. CONCLUSION: Treatment with NAC, lexipafant, and/or monoclonal antibodies against PECAM-1, inserted at a later stage of I/R, reduced the severity of I/R-associated intestinal dysfunction and decreased the systemic concentrations of IL-1 beta, local leukocyte recruitment (MPO), and partly restored plasma protease inhibitor levels. (Less)