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Background: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans., Methods: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays., Results: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0-6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180-679 mL) autologous plasma, the concentration of cTn in participants' blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8-168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7-295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0-44.9) to 52.7 mL/min (95% CI, 42.2-57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2-95.0)., Conclusions: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury., Competing Interests: Dr Bundgaard received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Amgen, Sanofi, BMS, and MSD. Dr Bundgaard owns stock or stock options in Novo Nordic. Dr Kamstrup reported a grant from Gangsted Fonden outside the present work. P.R.K. reported consulting fees from Novartis and Silence Therapeutics. Dr Kamstrup reported payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Physicians’ Academy for Cardiovascular Education, Novartis, and PCSK9 Forum. Dr Frikke-Schmidt reported grants or contracts outside the present work from Lundbeck Foundation, The Danish Heart Foundation, and Sygeforsikringen Denmark Research Fund. Dr Kjærgaard reports a grant or contract from Novo Nordisk Foundation outside the present work. Dr Holmvang reported personal payment or honoraria for lectures from Boehringer Ingelheim and payment or honoraria to her institution for lectures from Bayer. Dr Holmvang reported receiving support for travel from Abbott to her institution. Dr Bor reported receiving honoraria for a lecture from Bristol-Myers. Dr Thygesen reported participation on the Data Safety Monitoring Board of DANBLOCK (Danish Trial of Beta Blocker Treatment After Myocardial Infarction Without Reduced Ejection Fraction) and REDUCE (Randomized Evaluation of Decreased Usage of Betablockers After Myocardial Infarction in the SWEDEHEART Registry). Dr Jaffe reported royalties or licenses and stock or stock options to RCE Technologies; consulting fees from Abbott, Roche, Beckman-Coulter, Radiometer, Siemens, Ortho Diagnostics, Spinship, and LuminaRx; and support for attending meetings and/or travel from the American Association for Clinical Chemistry. Dr Dahl reporting receiving payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Grifols and Ciesi to himself and support for attending ERS Congress 2022 from Grifols.

Background: To assess the effect of targeting higher or lower blood pressure during postresucitation intensive care among comatose patients with out-of-hospital cardiac arrest with a history of heart failure., Methods: The BOX trial (Blood Pressure and Oxygenation Targets After Out-of-Hospital Cardiac Arrest) was a randomized, controlled, double-blinded, multicenter study comparing titration of vasopressors toward a mean arterial pressure (MAP) of 63 versus 77 mm Hg during postresuscitation intensive care. Patients with a history of heart failure were included in this substudy. Pulmonary artery catheters were inserted shortly after admission. History of heart failure was assessed through chart review of all included patients. The primary outcome was cardiac index during the first 72 hours. Secondary outcomes were left ventricular ejection fraction, heart rate, stroke volume, renal replacement therapy and all-cause mortality at 365 days., Results: A total of 134 patients (17% of the BOX cohort) had a history of heart failure (patients with left ventricular ejection fraction, ≤40%: 103 [77%]) of which 71 (53%) were allocated to a MAP of 77 mm Hg. Cardiac index at intensive care unit arrival was 1.77±0.11 L/min·m -2 in the MAP63-group and 1.78±0.17 L/min·m -2 in the MAP77, P =0.92. During the next 72 hours, the mean difference was 0.15 (95% CI, -0.04 to 0.35) L/min·m -2 ; P group =0.22. Left ventricular ejection fraction and stroke volume was similar between the groups. Patients allocated to MAP77 had significantly elevated heart rate (mean difference 6 [1-12] beats/min, P group =0.03). Vasopressor usage was also significantly increased ( P =0.006). At 365 days, 69 (51%) of the patients had died. The adjusted hazard ratio for 365 day mortality was 1.38 (0.84-2.27), P =0.20 and adjusted odds ratio for renal replacement therapy was 2.73 (0.84-8.89; P =0.09)., Conclusions: In resuscitated patients with out-of-hospital cardiac arrest with a history of heart failure, allocation to a higher blood pressure target resulted in significantly increased heart rate in the higher blood pressure-target group. However, no certain differences was found for cardiac index, left ventricular ejection fraction or stroke volume., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099., Competing Interests: Disclosures None.

Background: Acute kidney injury (AKI) represents a common and serious complication to out-of-hospital cardiac arrest. The importance of post-resuscitation care targets for blood pressure and oxygenation for the development of AKI is unknown., Methods: This is a substudy of a randomized 2-by-2 factorial trial, in which 789 comatose adult patients who had out-of-hospital cardiac arrest with presumed cardiac cause and sustained return of spontaneous circulation were randomly assigned to a target mean arterial blood pressure of either 63 or 77 mm Hg. Patients were simultaneously randomly assigned to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao 2 ) of 9 to 10 kPa or a liberal oxygenation target of a Pao 2 of 13 to 14 kPa. The primary outcome for this study was AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) classification in patients surviving at least 48 hours (N=759). Adjusted logistic regression was performed for patients allocated to high blood pressure and liberal oxygen target as reference., Results: The main population characteristics at admission were: age, 64 (54-73) years; 80% male; 90% shockable rhythm; and time to return of spontaneous circulation, 18 (12-26) minutes. Patients allocated to a low blood pressure and liberal oxygen target had an increased risk of developing AKI compared with patients with high blood pressure and liberal oxygen target (84/193 [44%] versus 56/187 [30%]; adjusted odds ratio, 1.87 [95% CI, 1.21-2.89]). Multinomial logistic regression revealed that the increased risk of AKI was only related to mild-stage AKI (KDIGO stage 1). There was no difference in risk of AKI in the other groups. Plasma creatinine remained high during hospitalization in the low blood pressure and liberal oxygen target group but did not differ between groups at 6- and 12-month follow-up., Conclusions: In comatose patients who had been resuscitated after out-of-hospital cardiac arrest, patients allocated to a combination of a low mean arterial blood pressure and a liberal oxygen target had a significantly increased risk of mild-stage AKI. No difference was found in terms of more severe AKI stages or other kidney-related adverse outcomes, and creatinine had normalized at 1 year after discharge., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03141099., Competing Interests: Disclosures None.

Background and Objectives: EEG is widely used for prediction of neurologic outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explored the association between EEG and neurofilament light (NfL) as a marker of neuroaxonal injury, evaluated whether highly malignant EEG patterns are reflected by high NfL levels, and explored the association of EEG backgrounds and EEG discharges with NfL., Methods: We performed a post hoc analysis of the Target Temperature Management After Out-of-Hospital Cardiac Arrest trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours postarrest. Patients who awoke or died prior to 36 hours postarrest were excluded. EEG experts blinded to clinical information classified EEG background, amount of discharges, and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NfL after trial completion. The highest available concentration at 48 or 72 hours postarrest was used., Results: A total of 262/939 patients with EEG and NfL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NfL levels than patients with malignant patterns and NfL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI 1.4-6.1 and 6.5-26.2, respectively; effect size 0.47; p < 0.001). Both background and the amount of discharges were independently strongly associated with NfL levels ( p < 0.001). The EEG background had a stronger association with NfL levels than EEG discharges (R 2 = 0.30 and R 2 = 0.10, respectively). NfL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression, and suppression, respectively: 2.26-18.06, 3.91-41.71, and 5.74-41.74; effect size 0.30; p < 0.001 for all). NfL levels did not differ between suppression and burst suppression. Superimposed discharges were only associated with higher NfL levels if the EEG background was continuous., Discussion: Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NfL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NfL may be useful to better identify patients misclassified by single methods., Trial Registration Information: ClinicalTrials.gov NCT01020916., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Patients experiencing out-of-hospital cardiac arrest who remain comatose after initial resuscitation are at high risk of morbidity and mortality attributable to the ensuing post-cardiac arrest syndrome. Systemic inflammation constitutes a major component of post-cardiac arrest syndrome, and IL-6 (interleukin-6) levels are associated with post-cardiac arrest syndrome severity. The IL-6 receptor antagonist tocilizumab could potentially dampen inflammation in post-cardiac arrest syndrome. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest of a presumed cardiac cause and thereby potentially mitigate organ injury., Methods: Eighty comatose patients with out-of-hospital cardiac arrest were randomly assigned 1:1 in a double-blinded placebo-controlled trial to a single infusion of tocilizumab or placebo in addition to standard of care including targeted temperature management. Blood samples were sequentially drawn during the initial 72 hours. The primary end point was the reduction in C-reactive protein response from baseline until 72 hours in patients treated with tocilizumab evaluated by mixed-model analysis for a treatment-by-time interaction. Secondary end points (main) were the marker of inflammation: leukocytes; the markers of myocardial injury: creatine kinase myocardial band, troponin T, and N-terminal pro B-type natriuretic peptide; and the marker of brain injury: neuron-specific enolase. These secondary end points were analyzed by mixed-model analysis., Results: The primary end point of reducing the C-reactive protein response by tocilizumab was achieved since there was a significant treatment-by-time interaction, P <0.0001, and a profound effect on C-reactive protein levels. Systemic inflammation was reduced by treatment with tocilizumab because both C-reactive protein and leukocyte levels were markedly reduced, tocilizumab versus placebo at 24 hours: -84% [-90%; -76%] and -34% [-46%; -19%], respectively, both P <0.001. Myocardial injury was also reduced, documented by reductions in creatine kinase myocardial band and troponin T; tocilizumab versus placebo at 12 hours: -36% [-54%; -11%] and -38% [-53%; -19%], respectively, both P <0.01. N-terminal pro B-type natriuretic peptide was similarly reduced by active treatment; tocilizumab versus placebo at 48 hours: -65% [-80%; -41%], P <0.001. There were no differences in survival or neurological outcome., Conclusions: Treatment with tocilizumab resulted in a significant reduction in systemic inflammation and myocardial injury in comatose patients resuscitated from out-of-hospital cardiac arrest. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03863015.

Background: Thirty-day mortality in ST-elevation myocardial infarction (STEMI) patients is primarily driven by cardiogenic shock (CS). High neutrophil counts and high neutrophil/lymphocyte ratios (NLR) have previously been associated with mortality in STEMI patients; however, there is only sparse knowledge regarding their association with CS., Purpose: We sought to assess the associations between neutrophil count and NLR with the development of CS as well as 30-day mortality in STEMI patients., Methods: Patients admitted with STEMI at two tertiary Heart Centres throughout 1 year were included in the study and stratified into quartiles according to the level of leukocyte count upon admission. The primary endpoint was development of CS both before (early CS) and after leaving the catheterization laboratory (late CS). The secondary endpoint was all-cause 30-day mortality., Results: A total of 1,892 STEMI patients were included, whereof 194 (10%) developed CS while 122 (6.4%) died within 30 days. Patients in the highest quartile of neutrophils (OR: 2.54; 95% CI: 1.40-4.60; P = 0.002) and NLR (OR: 3.64; 95% CI: 2.02-6.54; P<0.0001) were at increased risk of developing late CS compared with patients in the lower quartiles, whereas there was no risk difference across quartiles regarding development of early CS. Both biomarkers correlated strongly to an increased 30-day mortality (plogrank<0.0001) and, moreover, a high level of neutrophils was independently associated with 30-day mortality (HR: 1.95; 95% CI: 1.25-3.03; P = 0.003)., Conclusion: High levels of neutrophils and a high NLR upon admission for STEMI were independently associated with an increased risk of developing late CS and, additionally, both biomarkers showed association to 30-day mortality.

Aims: The diagnosis of cardiogenic shock depends on clinical signs of poor perfusion and low blood pressure. Lactate concentration will increase with poor tissue perfusion, and it has prognostic value in cardiogenic shock patients. We sought to assess the prognostic value of lactate concentration in subjects admitted with suspected ST-elevation myocardial infarction (STEMI)., Methods and Results: In 2,094 (93%) out of 2,247 consecutive suspected STEMI-subjects, lactate concentration was measured on admission. The prognostic value of lactate concentration on 30-day mortality was assessed in addition to clinical signs of peripheral hypoperfusion, systolic blood pressure (sBP), and left ventricular ejection fraction (LVEF) in multivariable models.Lactate concentration added prognostic information beyond signs of peripheral hypoperfusion, sBP, and LVEF, and was independently associated with 30-day mortality (hazard ratio [95% confidence interval] 1.11 [1.07-1.14], P < 0.0001). Lactate also provided predictive information on 30-day mortality to the combination of signs of peripheral hypoperfusion, sBP, and LVEF (area under the receiver-operating characteristics curve = 0.88 vs. 0.83, P < 0.0001)., Conclusions: In conclusion, admission lactate concentration in suspected STEMI-subjects contains prognostic information on 30-day mortality when added to variables used in cardiogenic shock-definition. We recommend lactate measurement in STEMI-subjects, especially when signs of compromised hemodynamics are present.

Background: Mortality in ST-elevation myocardial infarction (STEMI) patients developing cardiogenic shock (CS) during hospitalization is high. Catecholamines, ischemia, and inflammation (parameters present in CS) affect the endothelium. We hypothesized that plasma level of biomarkers reflecting endothelial damage would be associated with CS and mortality., Methods: In 96% of 1467 consecutive patients with suspected STEMI, biomarkers reflecting endothelial cell- (soluble thrombomodulin, sTM) and glycocalyx- (syndecan-1) damage were measured on admission. Patients were stratified by CS development or not. CS-Patients were substratified by CS on admission (admission-CS), CS developed in the catheterization laboratory (cath. lab.-CS), or late CS., Results: STEMI patients with admission-CS (n = 85) and cath.lab.-CS (n = 25) had higher levels of sTM and syndecan-1 compared with no-CS patients (n = 1,299). Late CS-patients (n = 58) had higher levels of sTM (median (25th; 75th percentile) 8.8 (7.0; 11.6) vs. 7.4 (6.0; 9.0) ng/mL, P = 0.0004) but not Syndecan-1 (P = 0.26) compared with no-CS patients. sTM was, however, not independently associated with late CS development (OR (95% CI) 1.07 (0.99-1.16), P = 0.09). Patients with the highest level of sTM and syndecan-1 had the highest 30-day mortality (Plogrank<0.0001). However, neither sTM nor Syndecan-1 was independently associated with 30-day mortality (HR (95% CI) sTM: 1.06 (0.996-1.12), P = 0.07; Syndecan-1: 1.04 (0.99-1.08), P = 0.12)., Conclusion: Patients with suspected STEMI patients and admission-CS/cath.lab.-CS had elevated admission levels of sTM and Syndecan-1 compared with no CS patients. Patients developing late CS had higher sTM plasma concentration compared with patients without shock. However, the biomarker levels were not independently associated with late CS and mortality.

Objectives: No double-blinded clinical trials have investigated optimal mean arterial pressure targets in the ICU. The aim of this study was to develop and validate a method for blinded investigation of mean arterial pressure targets in patients monitored with arterial catheter in the ICU., Design: Prospective observational study (substudy A) and prospective, randomized, controlled clinical study (substudy B)., Setting: ICU, Department of Cardiology, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark., Patients: Adult patients resuscitated from out-of-hospital cardiac arrest., Interventions: Standard blood pressure measuring modules were offset to display 10% lower or higher blood pressure values. We then: 1) confirmed this modification in vivo by comparing offset to standard modules in 22 patients admitted to the ICU. Thereafter we 2) verified the method in two randomized, clinical trials, each including 50 out-of-hospital cardiac arrest patients, where the offset of the blood pressure module was blinded to the treating staff., Measurements and Main Results: Substudy A showed that the expected separation of blood pressure measurements was achieved with an excellent correlation of the offset and standard modules (R = 0.997). Bland-Altman plots showed no bias of modified modules over a clinically relevant range of mean arterial pressure. The primary endpoint of the clinical trials was between-group difference of norepinephrine dose needed to achieve target mean arterial pressure. Trial 1 aimed at a 10% difference between groups in mean arterial pressure (targets: 65 and 72 mm Hg, respectively) and demonstrated a separation of 5 ± 1 mm Hg (p < 0.001). The difference in norepinephrine dose was not significantly different (0.03 ± 0.03 µg/kg/min; p = 0.42). Trial 2 aimed at a 20% difference between groups in mean arterial pressure (targets: 63 and 77 mm Hg, respectively). Separation was 12 ± 1 mm Hg (p < 0.01) in mean arterial pressure and 0.07 ± 0.03 µg/kg/min (p < 0.01) in norepinephrine dose., Conclusions: The present method is feasible and robust and provides a platform for double-blinded comparison of mean arterial pressure targets in critically ill patients.

Background: Estimation of cardiac output (CO) is essential in the treatment of circulatory unstable patients. CO measured by pulmonary artery catheter thermodilution is considered the gold standard but carries a small risk of severe complications. Stroke volume and CO can be measured by transesophageal echocardiography (TEE), which is widely used during cardiac surgery. We hypothesized that Doppler-derived CO by 3-dimensional (3D) TEE would agree well with CO measured with pulmonary artery catheter thermodilution as a reference method based on accurate measurements of the cross-sectional area of the left ventricular outflow tract., Methods: The primary aim was a systematic comparison of CO with Doppler-derived 3D TEE and CO by thermodilution in a broad population of patients undergoing cardiac surgery. A subanalysis was performed comparing cross-sectional area by TEE with cardiac computed tomography (CT) angiography. Sixty-two patients, scheduled for elective heart surgery, were included; 1 was subsequently excluded for logistic reasons. Inclusion criteria were coronary artery bypass surgery (N = 42) and aortic valve replacement (N = 19). Exclusion criteria were chronic atrial fibrillation, left ventricular ejection fraction below 0.40 and intracardiac shunts. Nineteen randomly selected patients had a cardiac CT the day before surgery. All images were stored for blinded post hoc analyses, and Bland-Altman plots were used to assess agreement between measurement methods, defined as the bias (mean difference between methods), limits of agreement (equal to bias ± 2 standard deviations of the bias), and percentage error (limits of agreement divided by the mean of the 2 methods). Precision was determined for the individual methods (equal to 2 standard deviations of the bias between replicate measurements) to determine the acceptable limits of agreement., Results: We found a good precision for Doppler-derived CO measured by 3D TEE, but although the bias for Doppler-derived CO by 3D compared to thermodilution was only 0.3 L/min (confidence interval, 0.04-0.58), there were wide limits of agreement (-1.8 to 2.5 L/min) with a percentage error of 55%. Measurements of cross-sectional area by 3D TEE had low bias of -0.27 cm (confidence interval, -0.45 to -0.08) and a percentage error of 18% compared to cardiac CT angiography., Conclusions: Despite low bias, the wide limits of agreement of Doppler-derived CO by 3D TEE compared to CO by thermodilution will limit clinical application and can therefore not be considered interchangeable with CO obtained by thermodilution. The lack of agreement is not explained by lack of agreement of the 3D technique.

Objectives: To investigate the effects of the glucagon-like peptide-1 analog exenatide on blood glucose, lactate clearance, and hemodynamic variables in comatose, resuscitated out-of-hospital cardiac arrest patients., Design: Predefined post hoc analyzes from a double-blind, randomized clinical trial., Setting: The ICU of a tertiary heart center., Patients: Consecutive sample of adult, comatose patients undergoing targeted temperature management after out-of-hospital cardiac arrest from a presumed cardiac cause, irrespective of the initial cardiac rhythm., Interventions: Patients were randomized 1:1 to receive 6 hours and 15 minutes of infusion of either 17.4 μg of the glucagon-like peptide-1 analog exenatide (Byetta; Lilly) or placebo within 4 hours from sustained return of spontaneous circulation. The effects of exenatide were examined on the following prespecified covariates within the first 6 hours from study drug initiation: lactate level, blood glucose level, heart rate, mean arterial pressure, and combined dosage of norepinephrine and dopamine., Measurements and Main Results: The population consisted of 106 patients receiving either exenatide or placebo. During the first 6 hours from study drug initiation, the levels of blood glucose and lactate decreased 17% (95% CI, 8.9-25%; p = 0.0004) and 21% (95% CI, 6.0-33%; p = 0.02) faster in patients receiving exenatide versus placebo, respectively. Exenatide increased heart rate by approximately 10 beats per minute compared to placebo (p < 0.0001). There was no effect of exenatide on other hemodynamic variables., Conclusions: In comatose out-of-hospital cardiac arrest patients, infusion with exenatide lowered blood glucose and resulted in increased clearance of lactate as well as increased heart rate. The clinical importance of these physiologic effects remains to be investigated.

Background: The aim of this study was to describe out-of-hospital cardiac arrest (OHCA) survivors' ability to participate in activities of everyday life and society, including return to work. The specific aim was to evaluate potential effects of cognitive impairment., Methods and Results: Two hundred eighty-seven OHCA survivors included in the TTM trial (Target Temperature Management) and 119 matched control patients with ST-segment-elevation myocardial infarction participated in a follow-up 180 days post-event that included assessments of participation, return to work, emotional problems, and cognitive impairment. On the Mayo-Portland Adaptability Inventory-4 Participation Index, OHCA survivors (n=270) reported more restricted participation In everyday life and in society (47% versus 30%; P <0.001) compared with ST-segment-elevation myocardial infarction controls (n=118). Furthermore, 27% (n=36) of pre-event working OHCA survivors (n=135) compared with 7% (n=3) of pre-event working ST-segment-elevation myocardial infarction controls (n=45) were on sick leave (odds ratio, 4.9; 95% confidence interval, 1.4-16.8; P =0.01). Among the OHCA survivors assumed to return to work (n=135), those with cognitive impairment (n=55) were 3× more likely (odds ratio, 3.3; 95% confidence interval, 1.2-9.3; P =0.02) to be on sick leave compared with those without cognitive impairment (n=40; 36%, n=20, versus 15%, n=6). For OHCA survivors, the variables that were found most predictive for a lower participation were depression, restricted mobility, memory impairment, novel problem-solving difficulties, fatigue, and slower processing speed., Conclusions: OHCA survivors reported a more restricted societal participation 6 months post-arrest, and their return to work was lower compared with ST-segment-elevation myocardial infarction controls. Cognitive impairment was significantly associated with lower participation, together with the closely related symptoms of fatigue, depression, and restricted mobility. These predictive variables may be used during follow-up to identify OHCA survivors at risk of a less successful recovery that may benefit from further support and rehabilitation., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01946932., (© 2018 American Heart Association, Inc.)

Objectives: Dysglycemia and glycemic variability are associated with poor outcomes in critically ill patients. Targeted temperature management alters blood glucose homeostasis. We investigated the association between blood glucose concentrations and glycemic variability and the neurologic outcomes of patients randomized to targeted temperature management at 33°C or 36°C after cardiac arrest., Design: Post hoc analysis of the multicenter TTM-trial. Primary outcome of this analysis was neurologic outcome after 6 months, referred to as "Cerebral Performance Category.", Setting: Thirty-six sites in Europe and Australia., Patients: All 939 patients with out-of-hospital cardiac arrest of presumed cardiac cause that had been included in the TTM-trial., Interventions: Targeted temperature management at 33°C or 36°C., Measurements and Main Results: Nonparametric tests as well as multiple logistic regression and mixed effects logistic regression models were used. Median glucose concentrations on hospital admission differed significantly between Cerebral Performance Category outcomes (p < 0.0001). Hyper- and hypoglycemia were associated with poor neurologic outcome (p = 0.001 and p = 0.054). In the multiple logistic regression models, the median glycemic level was an independent predictor of poor Cerebral Performance Category (Cerebral Performance Category, 3-5) with an odds ratio (OR) of 1.13 in the adjusted model (p = 0.008; 95% CI, 1.03-1.24). It was also a predictor in the mixed model, which served as a sensitivity analysis to adjust for the multiple time points. The proportion of hyperglycemia was higher in the 33°C group compared with the 36°C group., Conclusion: Higher blood glucose levels at admission and during the first 36 hours, and higher glycemic variability, were associated with poor neurologic outcome and death. More patients in the 33°C treatment arm had hyperglycemia.

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients., Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 μg exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days., Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2-6.7] mmol/L versus 7.3 [6.2-8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups., Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791., (© 2016 American Heart Association, Inc.)

Objectives: Atrial fibrillation has been associated with increased mortality in the general population and mixed populations of critical ill. Atrial fibrillation can also affect patients during post-cardiac arrest care. We sought to assess the prognostic implications of atrial fibrillation following out-of-hospital cardiac arrest, including relation to the level of targeted temperature management., Design: A post hoc analysis of a prospective randomized trial., Setting: Thirty-six ICUs., Patients: We included 897 (96%) of the 939 comatose out-of-hospital cardiac arrest survivors from the targeted temperature management trial (year, 2010-2013) with data on heart rhythm on day 2., Interventions: Targeted temperature management at 33°C or 36°C., Measurements and Main Results: Endpoints included cumulative proportion of atrial fibrillation following out-of-hospital cardiac arrest and 180-day all-cause mortality and specific death causes stratified by atrial fibrillation. Atrial fibrillation on day 2 was used as primary endpoint analyses to exclude effects of short-term atrial fibrillation related to resuscitation and initial management. The cumulative proportions of atrial fibrillation were 15% and 11% on days 1 and 2, respectively. Forty-three percent of patients with initial atrial fibrillation the first day were reported with sinus rhythm on day 2. No difference was found between the groups treated with targeted temperature management at 33°C and 36°C. Patients affected by atrial fibrillation had significantly higher 180-day mortality (atrial fibrillation: 66% vs no-atrial fibrillation: 43%; plogrank < 0.0001 and unadjusted hazard ratio, 1.75 [1.35-2.30]; p < 0.0001). The association between atrial fibrillation and higher mortality remained significant (adjusted hazard ratio, 1.34 [1.01-1.79]; p < 0.05) adjusted for potential confounders. Atrial fibrillation was independently associated with increased risk of cardiovascular death and multiple-organ failure (adjusted hazard ratio, 2.07 [1.39-3.09]; p < 0.001), whereas no association with higher risk of death from cerebral causes was found., Conclusions: Atrial fibrillation was independently associated with higher mortality, primarily driven by cardiovascular causes and multiple-organ failure, and may thus identify a vulnerable subpopulation. Whether treatment to prevent atrial fibrillation is associated with an improved prognosis remains to be established.

Objective: To identify reliable predictors of outcome in comatose patients after cardiac arrest using a single routine EEG and standardized interpretation according to the terminology proposed by the American Clinical Neurophysiology Society., Methods: In this cohort study, 4 EEG specialists, blinded to outcome, evaluated prospectively recorded EEGs in the Target Temperature Management trial (TTM trial) that randomized patients to 33°C vs 36°C. Routine EEG was performed in patients still comatose after rewarming. EEGs were classified into highly malignant (suppression, suppression with periodic discharges, burst-suppression), malignant (periodic or rhythmic patterns, pathological or nonreactive background), and benign EEG (absence of malignant features). Poor outcome was defined as best Cerebral Performance Category score 3-5 until 180 days., Results: Eight TTM sites randomized 202 patients. EEGs were recorded in 103 patients at a median 77 hours after cardiac arrest; 37% had a highly malignant EEG and all had a poor outcome (specificity 100%, sensitivity 50%). Any malignant EEG feature had a low specificity to predict poor prognosis (48%) but if 2 malignant EEG features were present specificity increased to 96% (p < 0.001). Specificity and sensitivity were not significantly affected by targeted temperature or sedation. A benign EEG was found in 1% of the patients with a poor outcome., Conclusions: Highly malignant EEG after rewarming reliably predicted poor outcome in half of patients without false predictions. An isolated finding of a single malignant feature did not predict poor outcome whereas a benign EEG was highly predictive of a good outcome., (© 2016 American Academy of Neurology.)

Objectives: Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C., Design: Post hoc analysis of a prospective randomized study., Setting: Thirty-six ICUs in 10 countries., Patients: We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013., Interventions: Targeted temperature management at 33°C and 36°C., Measurements and Main Results: Endpoints were 180-day mortality and unfavorable neurologic function (cerebral performance category 3-5). Patients were stratified by target temperature and minimum heart rate during targeted temperature management (< 50, 50-59, and ≥ 60 beats/min [reference]) at 12, 20, and 28 hours after randomization. Heart rates less than 50 beats/min and 50-59 beats/min were recorded in 132 (30%) and 131 (29%) of the 33°C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (< 50 beats/min = 32%, 50-59 beats/min = 43%, and ≥ 60 beats/min = 60%; p(log-rank) < 0.0001). Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratio(adjusted) = 0.50 [0.34-0.74; p < 0.001]) and lower odds of unfavorable neurologic outcome (odds ratio(adjusted) = 0.38 [ 0.21-0.68; p < 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation, and lactate at admission. Similar, albeit less strong, independent associations of lower heart rates and favorable outcome were found in patients treated with targeted temperature management at 36°C., Conclusions: This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia during targeted temperature management at 33°C may thus be a novel, early marker of favorable outcome.

Objectives: Whole-body ischemia during out-of-hospital cardiac arrest triggers immediate activation of inflammatory systems leading to a sepsis-like syndrome. The aim was to investigate the association between level of systemic inflammation and mortality in survivors after out-of-hospital cardiac arrest treated with targeted temperature management., Design: Post hoc analysis., Setting: Single-center study of a prospective multicenter randomized study., Patients: One hundred sixty-nine patients (99%) with available blood samples out of 171 patients included in the Target Temperature Management trial, randomly assigning patients to targeted temperature management at 33°C or 36°C., Intervention: None., Measurements and Main Results: At baseline and 24, 48, and 72 hours after out-of-hospital cardiac arrest, blood samples were obtained and screened for a battery of inflammatory markers. Level of interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, interleukin-12, interleukin-13, tumor necrosis factor-α, interferon-γ, C-reactive protein, and procalcitonin were measured. Mortality at 30 days was evaluated by Cox analysis, and the predictive capability of inflammatory markers was evaluated by area under the curve. Level of all inflammatory markers changed significantly within 72 hours after out-of-hospital cardiac arrest (all p values<0.001), but only procalcitonin levels showed overall differences between nonsurvivors and survivors (p=0.0002). At baseline, interleukin-6 was independently associated with mortality, whereas both interleukin-6 levels (hazard ratio=1.23 [1.01-1.49]; p=0.04) and procalcitonin levels (hazard ratio=1.20 [1.03-1.39]; p=0.02) 24 hours after out-of-hospital cardiac arrest were associated with 30-day mortality with no interactions between targeted temperature management group and levels of interleukin-6 (p=0.25) or procalcitonin (p=0.85). None of the other inflammatory markers were independently associated with mortality. Area under the curve for procalcitonin and interleukin-6, 24 hours after out-of-hospital cardiac arrest, were 0.74 and 0.63, respectively., Conclusions: Level of inflammation, assessed by interleukin-6 and procalcitonin, was independently associated with increased mortality with the highest discriminative value obtained 24 hours after out-of-hospital cardiac arrest. Interventions aiming at decreasing level of inflammation as a way to improve outcome may be investigated in future studies.

Background: Studies have found higher survival rates after out-of-hospital cardiac arrest and admission to tertiary heart centers. The aim was to examine the level-of-care at tertiary centers compared with nontertiary hospitals and the association with outcome after out-of-hospital cardiac arrest., Methods and Results: Consecutive out-of-hospital cardiac arrest patients (n=1078) without ST-segment-elevation myocardial infarction admitted to tertiary centers (54%) and nontertiary hospitals (46%) were included (2002-2011). Patient charts were reviewed focusing on level-of-care and comorbidity. Survival to discharge differed significantly with 45% versus 24% of patients discharged alive (P<0.001), and after adjustment for prognostic factors admissions to tertiary centers were still associated with lower 30-day mortality (hazard ratio, 0.78 [0.64-0.96; P=0.02]), independent of comorbidity. The adjusted odds of predefined markers of level-of-care were higher in tertiary centers: admission to intensive care unit (odds ratio [OR], 1.8 [95% confidence interval, 1.2-2.5]), temporary pacemaker (OR, 6.4 [2.2-19]), vasoactive agents (OR, 1.5 [1.1-2.1]), acute (<24 hours) and late coronary angiography (OR, 10 [5.3-22] and 3.8 [2.5-5.7]), neurophysiological examination (OR, 1.8 [1.3-2.6]), and brain computed tomography (OR, 1.9 [1.4-2.6]), whereas no difference in therapeutic hypothermia was noted. Patients at tertiary centers were more often consulted by a cardiologist (OR, 8.6 [5.0-15]), had an echocardiography (OR, 2.8 [2.1-3.7]), and survivors more often had implantable cardioverter defibrillator's implanted (OR, 2.1 [1.2-3.6])., Conclusions: Admissions to tertiary centers were associated with significantly higher survival after out-of-hospital cardiac arrest in patients without ST-segment-elevation myocardial infarction in the Copenhagen area even after adjustment for prognostic factors including comorbidity. Level-of-care seems higher in tertiary centers both in the early phase, during the intensive care unit admission, and in the workup before discharge. The varying level-of-care may contribute to the survival difference; however, differences in comorbidity do not seem to matter significantly., (© 2015 American Heart Association, Inc.)

Background: Target temperature management is recommended as a neuroprotective strategy after out-of-hospital cardiac arrest. Potential effects of different target temperatures on cognitive impairment commonly described in survivors have not been investigated sufficiently. The primary aim of this study was to evaluate whether a target temperature of 33°C compared with 36°C was favorable for cognitive function; the secondary aim was to describe cognitive impairment in cardiac arrest survivors in general., Methods and Results: Study sites included 652 cardiac arrest survivors originally randomized and stratified for site to temperature control at 33°C or 36°C within the Target Temperature Management trial. Survival until 180 days after the arrest was 52% (33°C, n=178/328; 36°C, n=164/324). Survivors were invited to a face-to-face follow-up, and 287 cardiac arrest survivors (33°C, n=148/36°C, n=139) were assessed with tests for memory (Rivermead Behavioural Memory Test), executive functions (Frontal Assessment Battery), and attention/mental speed (Symbol Digit Modalities Test). A control group of 119 matched patients hospitalized for acute ST-segment-elevation myocardial infarction without cardiac arrest performed the same assessments. Half of the cardiac arrest survivors had cognitive impairment, which was mostly mild. Cognitive outcome did not differ (P>0.30) between the 2 temperature groups (33°C/36°C). Compared with control subjects with ST-segment-elevation myocardial infarction, attention/mental speed was more affected among cardiac arrest patients, but results for memory and executive functioning were similar., Conclusions: Cognitive function was comparable in survivors of out-of-hospital cardiac arrest when a temperature of 33°C and 36°C was targeted. Cognitive impairment detected in cardiac arrest survivors was also common in matched control subjects with ST-segment-elevation myocardial infarction not having had a cardiac arrest., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01946932., (© 2015 American Heart Association, Inc.)

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.

Background: Cardiovascular dysfunction is common after out-of-hospital cardiac arrest as part of the postcardiac arrest syndrome, and hypothermia may pose additional impact on hemodynamics. The aim was to investigate systemic vascular resistance index (SVRI), cardiac index, and myocardial performance at a targeted temperature management of 33°C (TTM33) versus 36°C (TTM36)., Methods and Results: Single-center substudy of 171 patients included in the Target Temperature Management Trial (TTM Trial) randomly assigned to TTM33 or TTM36 for 24 hours after out-of-hospital cardiac arrest. Mean arterial pressure ≥65 mm Hg and central venous pressure of 10 to 15 mm Hg were hemodynamic treatment goals. Hemodynamic evaluation was performed by serial right heart catheterization and transthoracic echocardiography. Primary end point was SVRI after 24 hours of cooling and secondary end points included mean SVRI, cardiac index, systolic function, and lactate levels. The TTM33 group had a significant increase in SVRI compared with TTM36 (2595; 95% confidence interval, 2422-2767) versus 1960 (95% confidence interval, 1787-2134) dynes m(2)/s per cm(5); P<0.0001, respectively) after 24 hours of cooling with an overall difference of 556 dynes m(2)/s per cm(5) (P(group) <0.0001). TTM33 was associated with decreased cardiac index (-0.4 L/min per m(2); P(group) <0.0001), decreased heart rate (P(group)=0.01), and stroke volume index (P(group)=0.004) compared with TTM36. Left ventricular ejection fraction (P=0.39) and peak systolic myocardial velocity (P=0.62) did not differ between TTM groups. Lactate levels were significantly higher in the TTM33 group (P=0.0008)., Conclusions: Targeted temperature management at 33°C with target mean arterial pressure ≥65 mm Hg is associated with increased SVRI and lower cardiac index because of lower heart rate with unaffected left ventricular systolic function compared with 36°C., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01020916., (© 2014 American Heart Association, Inc.)

Background: Left ventricular diastolic dysfunction (DD) is common after myocardial infarction (MI) despite preservation of left ventricular ejection fraction, yet it remains unclear how or whether DD affects cardiac hemodynamics with stress., Methods and Results: Invasive hemodynamic exercise testing was performed in 46 patients with a recent MI and left ventricular ejection fraction >45% and in 10 healthy volunteers. MI patients were enrolled prospectively and divided into those with DD (MI+DD; left atrial volume index >34 mL/m(2) and diastolic E/e' ratio>8; n=35) and those without DD (MI-DD; left atrial volume index <34 mL/m(2) and E/e' ratio<8; n=11). All underwent a supine cycle ergometer test with simultaneous right heart catheterization and echocardiography. At rest, 10 patients in MI+DD (29%) had pulmonary capillary wedge pressure >15 (14±4 mm Hg), whereas none of the MI-DD (10±2 mm Hg) or controls (9±2 mm Hg) displayed pulmonary capillary wedge pressure elevation (P=0.03). During exercise, an abnormal rise in pulmonary capillary wedge pressure (>25 mm Hg) was observed in 94% of MI+DD (36±6 mm Hg) compared with 36% of MI-DD (24±6 mm Hg) and none of the controls (16±6 mm Hg; P<0.0001). Exercise right atrial pressure was the highest in MI+DD followed by MI-DD and control (15±5 versus 9±4 versus 7±5 mm Hg; P<0.001), whereas no difference in cardiac index was found between groups., Conclusions: In post-MI patients with preserved ejection fraction and left ventricular DD, cardiac output with exercise is maintained at the expense of substantially increased filling pressure. DD and loss of diastolic reserve may promote progression from stage B to stage C heart failure after MI.

Background: Surgical site infections and disruption of sutured tissue are frequent complications following surgery. We aimed to assess risk factors predictive of tissue and wound complications in open gastrointestinal surgery., Methods: Data from 4855 unselected patients undergoing open gastrointestinal surgery from 1995 through 1998 were recorded in a clinical database and validated. The database embraced variables related to patient history, preoperative clinical condition, operative findings and severity, and the surgeon's training. Variables predictive of surgical site infection and dehiscence of sutured tissue within 30 days after surgery were assessed by multiple logistic regression analysis., Results: Following elective operation, the incidence of tissue and wound complications was 6% compared with 16% in emergency surgery (P < 0.001). These complications resulted in prolonged hospitalization in 50% of the patients and a 3-fold higher risk of reoperation but not increased mortality. Factors associated with complications following elective operations were smoking, comorbidity, and perioperative blood loss. Following emergency operations, male gender, peritonitis, and multiple operations were predictors of complications. Irrespective of elective or emergency surgery, the type of operation was a predictor of complications., Conclusion: Factors known to affect the process of tissue and wound healing are independently associated with tissue and wound complications following gastrointestinal surgery.

Dendritic cells (DCs) loaded with antigens can effectively stimulate host immune responses to syngeneic tumors, but there is considerable controversy as to which forms of antigen-loading are most immunogenic. Here, the authors compared immunotherapeutic reactivities of DCs loaded with a variety of antigen preparations. Because DC maturation stages affect their capacities of antigen processing and presentation, two DC populations were used for the current analysis: in vivo Flt-3 ligand-induced mature DCs and in vitro bone marrow-derived DCs, which were less mature. To facilitate a direct comparison, the LacZ gene-transduced B16 melanoma model system was used, where beta-galactosidase served as the surrogate tumor-rejection antigen. DC loading strategies included pulsing with the beta-galactosidase protein, H-2K restricted peptide, tumor cell lysate, and irradiated tumor cells and fusion of DCs with tumor cells. Our results demonstrated that electrofusion of DCs and tumor cells generated a therapeutic vaccine far superior to other methods of DC loading. For the treatment of 3-day established pulmonary tumor nodules, a single intranodal vaccination plus IL-12 resulted in a significant reduction of metastatic nodules, while other DC preparations were only marginally effective. Immunotherapy mediated by the fusion cells was tumor antigen-specific. Consistent with their therapeutic activity, fusion hybrids were the most potent stimulators to induce specific IFN-gamma secretion from immune T cells. Furthermore, fusion cells also stimulated a small amount of IL-10 production from immune T cells. However, this IL-10 secretion was also induced by other DC preparations and did not correlate with in vivo therapeutic reactivity.

Recent studies have identified a unique population of CD4+CD25+ regulatory T cells that is crucial for the prevention of spontaneous autoimmune diseases. Further studies demonstrated that depletion of CD4+CD25+ T cells enhances immune responses to nonself antigens. Because immune responses to malignant tumors are weak and ineffective, depletion of regulatory T cells has been reported to result in tumor regression. In the current study, using the weakly immunogenic MCA205 sarcoma and the poorly immunogenic B16/BL6/D5 (D5) melanoma, depletion of CD4+CD25+ T cells by the administration of anti-CD25 monoclonal antibodies (mAb), PC61 induced some tumor growth retardation, but all mice eventually succumbed to tumors. In our laboratory, immunotherapy by the transfer of tumor-immune T cells has demonstrated potent antitumor effects. A reliable source of tumor-reactive T cells has been lymph nodes (LN) draining progressive tumors. Therapeutic effector T cells can be generated by in vitro activation of draining LN cells with anti-CD3 mAb followed by culture in interleukin-2. In this system, PC61 mAb depletion of CD4+CD25+ T cells before or on day 8 of tumor growth resulted in increased sensitization in the draining LN. The therapeutic efficacy of activated tumor-draining LN cells from mAb depleted mice increased approximately three fold while maintaining specificity when tested in adoptive immunotherapy of established pulmonary metastases. Specific interferon-gamma secretion by LN T cells from mice treated with PC61 mAb 1 day before tumor inoculation increased significantly. However, this increase was not demonstrated with LN T cells from mice treated on day 8 despite their enhanced therapeutic reactivities. Our results indicate that although the antitumor immunity enhanced by the depletion of CD4+CD25+ T cells is insufficient to eradicate tumors, it augments the sensitization of immune T cells in the draining LN, thus, facilitating adoptive immunotherapy.

In a study of 545 patients who underwent vagotomies for repair of duodenal ulcers, 62 patients (11%) were found to have inadequately reduced pentapeptide and/or insulin-stimulated acid secretions three months after operation. The ulcers recurred in 14 patients within three to nine years (mean: four years) (23%, 95% confidence limits: 13-35). Postoperative acid production and acid reduction were equal in patients with and without ulcer recurrence. The patients who did not develop recurrent ulcers had significantly lower preoperative pentapeptide peak acid outputs and significantly shorter preoperative histories of ulcers than patients whose ulcers recurred.

From 1968 to 1978, 37 men and 14 women, with a median age of 43 years, were operated on for a pancreatic pseudocyst. Alcohol abuse was the dominating cause in 65% of the patients. Internal drainage (medium risk patients) was carried out in 76%, external drainage (high risk patients) in 12%, and pancreatic resection (low risk patients) in 12% of the patients. The hospital mortality rate was 14%. The patients who died were significantly older than those discharged from the hospital alive. At the time of follow-up (1--11 years, median: 4 years) after operation, a further 13% had died. Thirty per cent of the alcoholic and none of the nonalcoholic patients had severe pain at follow-up examination. Evaluated by their ability to work and pain, the late results were poorer for the alcoholics who continued drinking, better for alcoholics who had stopped drinking and best for nonalcoholics.