Albumin and Cardioprotection in On-Pump Cardiac Surgery-A Post Hoc Analysis of a Randomized Trial.

OBJECTIVES: To study the quantitative potency of plasma albumin on cardioprotection in terms of creatinine kinase-myocardial band mass (CK-MBm) in on-pump cardiac surgery. DESIGN: Post hoc analysis of a double-blinded randomized clinical trial. SETTING: Single-center study in the Helsinki University Hospital. PARTICIPANTS: A total of 1,386 adult on-pump cardiac surgical patients. INTERVENTION: Administration of 4% albumin (n = 693) or Ringers acetate (n = 693) for cardiopulmonary bypass priming and volume replacement intraoperatively and postoperatively during the first 24 hours. MEASUREMENTS AND MAIN RESULTS: Albumin concentration was measured preoperatively and intraoperatively (after protamine administration), and CK-MBm on the first postoperative morning. Multivariate linear regression analyses were measured in the whole cohort and the Ringer group. Plasma albumin concentration did not differ between the groups preoperatively (Ringer v albumin: 38.3 ± 5.0 g/L v 38.6 ± 4.5 g/L; p = 0.171) but differed intraoperatively (29.5 ± 5.2 g/L v 41.5 ± 6.0 g/L; p < 0.001). Creatinine kinase-myocardial band mass was higher in the Ringer (32.0 ± 34.8 µg/L) than in the albumin group (24.3 ± 33.0 µg/L) (p < 0.001). Aortic cross-clamping time associated with CK-MBm in the whole cohort (standardized ß = 0.376 [95% CI 0.315-0.437], p < 0.001) and the Ringer group (ß = 0.363 [0.273-0.452]; p < 0.001). Albumin administration in the whole cohort (ß = -0.156 [-0.201 to -0.111]; p < 0.001) and high intraoperative albumin concentration in the Ringer group (ß = -0.07 [-0.140 to -0.003]; p = 0.04) associated with reduced CK-MBm. Compared with ischemia-induced increase in CK-MBm, albumin's potency to reduce CK-MBm was 41% in the whole cohort (ß-value ratio of -0.156/0.376) and 19% in the Ringer group (ß-value ratio of -0.07/0.363). CONCLUSION: Both endogenous and exogenous albumin appear to be cardioprotective regarding CK-MBm release in on-pump cardiac surgery.

Albumin Infusion and Blood Loss After Cardiac Surgery.

BACKGROUND: In the recent ALBICS (ALBumin In Cardiac Surgery) trial, 4% albumin used for cardiopulmonary bypass priming and volume replacement increased perioperative bleeding compared with Ringer acetate. In the present exploratory study, albumin-related bleeding was further characterized. METHODS: Ringer acetate and 4% albumin were compared in a randomized, double-blinded fashion in 1386 on-pump adult cardiac surgery patients. The study end points for bleeding were the Universal Definition of Perioperative Bleeding (UDPB) class and its components. RESULTS: The UDPB bleeding grades were higher in the albumin group than the Ringer group: "insignificant" (albumin vs Ringer: 47.5% vs 62.9%), "mild" (12.7% vs 8.9%), "moderate" (28.7% vs 24.4%), "severe" (10.2% vs 3.2%), and "massive" (0.9% vs. 0.6%; P < .001). Patients in the albumin group received red blood cells (45.2% vs 31.5%; odds ratio [OR], 1.80; 95% CI, 1.44-2.24; P < .001), platelets (33.3% vs 21.8%; OR, 1.79; 95% CI, 1.41-2.28; P < .001), and fibrinogen (5.6% vs 2.6%; OR, 2.24; 95% CI, 1.27-3.95; P < .05), and underwent resternotomy (5.3% vs 1.9%; OR, 2.95; 95% CI, 1.55-5.60, P < .001) more often than patients in the Ringer group. The strongest predictors of bleeding were albumin group allocation (OR, 2.18; 95% CI, 1.74-2.74) and complex (OR, 2.61; 95% CI, 2.02-3.37) and urgent surgery (OR, 1.63; 95% CI, 1.26-2.13). In interaction analysis, the effect of albumin on the risk of bleeding was stronger in patients on preoperative acetylsalicylic acid. CONCLUSIONS: Perioperative administration of albumin, compared with Ringer's acetate, resulted in increased blood loss and higher UDBP class. The magnitude of this effect was similar to the complexity and urgency of the surgery.

Zero-heat-flux thermometry over the carotid artery in assessment of core temperature in craniotomy patients.

Zero-heat-flux core temperature measurements on the forehead (ZHF-forehead) show acceptable agreement with invasive core temperature measurements but are not always possible in general anesthesia. However, ZHF measurements over the carotid artery (ZHF-neck) have been shown reliable in cardiac surgery. We investigated these in non-cardiac surgery. In 99 craniotomy patients, we assessed agreement of ZHF-forehead and ZHF-neck (3M™ Bair Hugger™) with esophageal temperatures. We applied Bland-Altman analysis and calculated mean absolute differences (difference index) and proportion of differences within ± 0.5 °C (percentage index) during entire anesthesia and before and after esophageal temperature nadir. In Bland-Altman analysis [mean (limits of agreement)], agreement with esophageal temperature during entire anesthesia was 0.1 (-0.7 to +0.8) °C (ZHF-neck) and 0.0 (-0.8 to +0.8) °C (ZHF-forehead), and, after core temperature nadir, 0.1 (-0.5 to +0.7) °C and 0.1 (-0.6 to +0.8) °C, respectively. In difference index [median (interquartile range)], ZHF-neck and ZHF-forehead performed equally during entire anesthesia [ZHF-neck: 0.2 (0.1-0.3) °C vs ZHF-forehead: 0.2 (0.2-0.4) °C], and after core temperature nadir [0.2 (0.1-0.3) °C vs 0.2 (0.1-0.3) °C, respectively; all p > 0.017 after Bonferroni correction]. In percentage index [median (interquartile range)], both ZHF-neck [100 (92-100) %] and ZHF-forehead [100 (92-100) %] scored almost 100% after esophageal nadir. ZHF-neck measures core temperature as reliably as ZHF-forehead in non-cardiac surgery. ZHF-neck is an alternative to ZHF-forehead if the latter cannot be applied.

Effect of 4% Albumin Solution vs Ringer Acetate on Major Adverse Events in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass: A Randomized Clinical Trial.

Importance: In cardiac surgery, albumin solution may maintain hemodynamics better than crystalloids and reduce the decrease in platelet count and excessive fluid balance, but randomized trials are needed to compare the effectiveness of these approaches in reducing surgical complications. Objective: To assess whether 4% albumin solution compared with Ringer acetate as cardiopulmonary bypass prime and perioperative intravenous volume replacement solution reduces the incidence of major perioperative and postoperative complications in patients undergoing cardiac surgery. Design, Setting, and Participants: A randomized, double-blind, single-center clinical trial in a tertiary university hospital during 2017-2020 with 90-day follow-up postoperatively involving patients undergoing on-pump coronary artery bypass grafting; aortic, mitral, or tricuspid valve surgery; ascending aorta surgery without hypothermic circulatory arrest; and/or the maze procedure were randomly assigned to 2 study groups (last follow-up was April 13, 2020). Interventions: The patients received in a 1:1 ratio either 4% albumin solution (n = 693) or Ringer acetate solution (n = 693) as cardiopulmonary bypass priming and intravenous volume replacement intraoperatively and up to 24 hours postoperatively. Main Outcomes and Measures: The primary outcome was the number of patients with at least 1 major adverse event: death, myocardial injury, acute heart failure, resternotomy, stroke, arrhythmia, bleeding, infection, or acute kidney injury. Results: Among 1407 patients randomized, 1386 (99%; mean age, 65.4 [SD, 9.9] years; 1091 men [79%]; 295 women [21%]) completed the trial. Patients received a median of 2150 mL (IQR, 1598-2700 mL) of study fluid in the albumin group and 3298 mL (IQR, 2669-3500 mL) in the Ringer group. The number of patients with at least 1 major adverse event was 257 of 693 patients (37.1%) in the albumin group and 234 of 693 patients (33.8%) in the Ringer group (relative risk albumin/Ringer, 1.10; 95% CI, 0.95-1.27; P = .20), an absolute difference of 3.3 percentage points (95% CI, -1.7 to 8.4). The most common serious adverse events were pulmonary embolus (11 [1.6%] in the albumin group vs 8 [1.2%] in the Ringer group), postpericardiotomy syndrome (9 [1.3%] in both groups), and pleural effusion with intensive care unit or hospital readmission (7 [1.0%] in the albumin group vs 9 [1.3%] in the Ringer group). Conclusions and Relevance: Among patients undergoing cardiac surgery with cardiopulmonary bypass, treatment with 4% albumin solution for priming and perioperative intravenous volume replacement solution compared with Ringer acetate did not significantly reduce the risk of major adverse events over the following 90 days. These findings do not support the use of 4% albumin solution in this setting. Trial Registration: ClinicalTrials.gov Identifier: NCT02560519.

Aerosol generation during general anesthesia is comparable to coughing: An observational clinical study.

BACKGROUND: Intubation, laryngoscopy, and extubation are considered highly aerosol-generating procedures, and additional safety protocols are used during COVID-19 pandemic in these procedures. However, previous studies are mainly experimental and have neither analyzed staff exposure to aerosol generation in the real-life operating room environment nor compared the exposure to aerosol concentrations generated during normal patient care. To assess operational staff exposure to potentially infectious particle generation during general anesthesia, we measured particle concentration and size distribution with patients undergoing surgery with Optical Particle Sizer. METHODS: A single-center observative multidisciplinary clinical study in Helsinki University Hospital with 39 adult patients who underwent general anesthesia with tracheal intubation. Mean particle concentrations during different anesthesia procedures were statistically compared with cough control data collected from 37 volunteers to assess the differences in particle generation. RESULTS: This study measured 25 preoxygenations, 30 mask ventilations, 28 intubations, and 24 extubations. The highest total aerosol concentration of 1153 particles (p)/cm³ was observed during mask ventilation. Preoxygenations, mask ventilations, and extubations as well as uncomplicated intubations generated mean aerosol concentrations statistically comparable to coughing. It is noteworthy that difficult intubation generated significantly fewer aerosols than either uncomplicated intubation (p = .007) or coughing (p = 0.006). CONCLUSIONS: Anesthesia induction generates mainly small (<1 µm) aerosol particles. Based on our results, general anesthesia procedures are not highly aerosol-generating compared with coughing. Thus, their definition as high-risk aerosol-generating procedures should be re-evaluated due to comparable exposures during normal patient care. IMPLICATION STATEMENT: The list of aerosol-generating procedures guides the use of protective equipments in hospitals. Intubation is listed as a high-risk aerosol-generating procedure, however, aerosol generation has not been measured thoroughly. We measured aerosol generation during general anesthesia. None of the general anesthesia procedures generated statistically more aerosols than coughing and thus should not be considered as higher risk compared to normal respiratory activities.

Endothelial glycocalyx during early reperfusion in patients undergoing cardiac surgery.

BACKGROUND: Experimental cardiac ischemia-reperfusion injury causes degradation of the glycocalyx and coronary washout of its components syndecan-1 and heparan sulfate. Systemic elevation of syndecan-1 and heparan sulfate is well described in cardiac surgery. Still, the events during immediate reperfusion after aortic declamping are unknown both in the systemic and in the coronary circulation. METHODS: In thirty patients undergoing aortic valve replacement, arterial concentrations of syndecan-1 and heparan sulfate were measured immediately before and at one, five and ten minutes after aortic declamping (reperfusion). Parallel blood samples were drawn from the coronary sinus to calculate trans-coronary gradients (coronary sinus-artery). RESULTS: Compared with immediately before aortic declamping, arterial syndecan-1 increased by 18% [253.8 (151.6-372.0) ng/ml vs. 299.1 (172.0-713.7) ng/ml, p < 0.001] but arterial heparan sulfate decreased by 14% [148.1 (135.7-161.7) ng/ml vs. 128.0 (119.0-138.2) ng/ml, p < 0.001] at one minute after aortic declamping. There was no coronary washout of syndecan-1 or heparan sulfate during reperfusion. On the contrary, trans-coronary sequestration of syndecan-1 occurred at five [-12.96 ng/ml (-36.38-5.15), p = 0.007] and at ten minutes [-12.37 ng/ml (-31.80-6.62), p = 0.049] after reperfusion. CONCLUSIONS: Aortic declamping resulted in extracardiac syndecan-1 release and extracardiac heparan sulfate sequestration. Syndecan-1 was sequestered in the coronary circulation during early reperfusion. Glycocalyx has been shown to degrade during cardiac surgery. Besides degradation, glycocalyx has propensity for regeneration. The present results of syndecan-1 and heparan sulfate sequestration may reflect endogenous restoration of the damaged glycocalyx in open heart surgery.

Early prolonged neutrophil activation in critically ill patients with sepsis.

We hypothesised that plasma concentrations of biomarkers of neutrophil activation and pro-inflammatory cytokines differ according to the phase of rapidly evolving sepsis. In an observational study, we measured heparin-binding protein (HBP), myeloperoxidase (MPO), IL-6 and IL-8 in 167 sepsis patients on intensive care unit admission. We prospectively used the emergence of the first sepsis-associated organ dysfunction (OD) as a surrogate for the sepsis phase. Fifty-five patients (of 167, 33%) developed the first OD > 1 h before, 74 (44%) within ± 1 h, and 38 (23%) > 1 h after intensive care unit admission. HBP and MPO were elevated at a median of 12 h before the first OD, remained high up to 24 h, and were not associated with sepsis phase. IL-6 and IL-8 rose and declined rapidly close to OD emergence. Elevation of neutrophil activation markers HBP and MPO was an early event in the evolution of sepsis, lasting beyond the subsidence of the pro-inflammatory cytokine reaction. Thus, as sepsis biomarkers, HBP and MPO were not as prone as IL-6 and IL-8 to the effect of sample timing.

Heparin Dose and Point-of-Care Measurements of Hemostasis in Cardiac Surgery-Results of a Randomized Controlled Trial.

OBJECTIVE: High heparin doses during cardiopulmonary bypass (CPB) have been suggested to reduce thrombin activation and consumption coagulopathy and consequently bleeding complications. The authors investigated the effect of a high heparin dose during CPB on point-of-care measurements of coagulation. The authors hypothesized that during CPB a high heparin dose compared with a lower heparin dose would reduce thrombin generation and platelet activation and tested whether this would be reflected in the results of rotational thromboelastometry (TEM) and platelet aggregation, measured with multiple electrode aggregometry (MEA). DESIGN: Prospective, randomized, controlled, open single-center study. SETTING: University teaching hospital. PARTICIPANTS: Sixty-three consecutive patients undergoing elective coronary artery bypass grafting with CPB were enrolled. INTERVENTIONS: Patients were randomly assigned to receive either a high (600 IU/kg, n = 32) or a low (300 IU/kg, n = 31) initial dose of heparin. Target levels of activated clotting time during CPB were >600 seconds in the high heparin dose group and >400 seconds in the low heparin dose group. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected (1) preoperatively after induction of anesthesia, (2) 10 minutes after aortic declamping, (3) 30 minutes after protamine administration, and (4) 3 hours after protamine administration. TEM and MEA were then measured. There was no difference in blood loss up to 18 hours postoperatively (median 735 mL for high dose v 610 mL for low dose; p < 0.056) or transfusions between the groups. Total median heparin dose (54,300 IU v 27,000 IU; p = 0.001) and median antifactor Xa levels during CPB (9.38 U/mL v 5.04 U/mL; p = 0.001) were greater in the high than in the low heparin dose group. However, neither TEM nor MEA results differed significantly between the groups. CONCLUSIONS: Compared with a lower dose of heparin during CPB, a high dose of heparin had little effect on the point-of-care measurements of hemostasis, TEM, and MEA. Based on the similarity of platelet and coagulation activity assessments, the higher heparin dose does not appear to offer benefit during CPB.

Effect and safety of 4% albumin in the treatment of cardiac surgery patients: study protocol for the randomized, double-blind, clinical ALBICS (ALBumin In Cardiac Surgery) trial.

BACKGROUND: In cardiac surgery with cardiopulmonary bypass (CPB), large amounts of fluids are administered. CPB priming with crystalloid solution causes marked hemodilution and fluid extravasation. Colloid solutions may reduce fluid overload because they have a better volume expansion effect than crystalloids. The European Medicines Agency does not recommend the use of hydroxyethyl starch solutions (HES) due to harmful renal effects. Albumin solution does not impair blood coagulation but the findings on kidney function are conflicting. On the other hand, albumin may reduce endothelial glycocalyx destruction and decrease platelet count during CPB. No large randomized, double-blind, clinical trials have compared albumin solution to crystalloid solution in cardiac surgery. METHODS/DESIGN: In this single-center, double-blind, randomized controlled trial comprising 1386 adult cardiac surgery patients, 4% albumin solution will be compared to Ringer's acetate solution in CPB priming and volume replacement up to 3200 mL during surgery and the first 24 h of intensive care unit stay. The primary efficacy outcome is the number of patients with at least one major adverse event (MAE) during 90 postoperative days (all-cause death, acute myocardial injury, acute heart failure or low output syndrome, resternotomy, stroke, major arrhythmia, major bleeding, infection compromising post-procedural rehabilitation, acute kidney injury). Secondary outcomes are total number of MAEs, incidence of major adverse cardiac events (MACE; cardiac death, acute myocardial injury, acute heart failure, arrhythmia), amount of each type of blood product transfused (red blood cells, fresh frozen plasma, platelets), total fluid balance at the end of the intervention period, total measured blood loss, development of acute kidney injury, days alive without mechanical ventilation in 90 days, days alive outside intensive care unit at 90 days, days alive at home at 90 days, and 90-day mortality. DISCUSSION: The findings of this study will provide new evidence regarding efficacy and safety of albumin solution in adult patients undergoing cardiac surgery with CPB. TRIAL REGISTRATION: EudraCT (clinicaltrialsregister.eu) 2015-002556-27 Registered 11 Nov 2016 and ClinicalTrials.gov NCT02560519. Registered 25 Sept 2015.

Reduction of Inflammation by High-Dose Methylprednisolone Does not Attenuate Oxidative Stress in Children Undergoing Bidirectional Glenn Procedure With or Without Aortic Arch or Pulmonary Arterial Repair.

OBJECTIVE: Corticosteroids attenuate an inflammatory reaction in pediatric heart surgery. Inflammation is a source of free oxygen radicals. Children with a cyanotic heart defect are prone to increased radical stress during heart surgery. The authors hypothesized that high-dose methylprednisolone reduces inflammatory reaction and thereby also oxidative stress in infants with a univentricular heart defect undergoing the bidirectional Glenn procedure. DESIGN: A double-blind, placebo-controlled, randomized clinical trial. SETTING: Operating room and pediatric intensive care unit of a university hospital. PARTICIPANTS: The study comprised 29 infants undergoing the bidirectional Glenn procedure with or without aortic arch or pulmonary arterial repair. INTERVENTIONS: After anesthesia induction, the patients received intravenously either 30 mg/kg of methylprednisolone (n = 15) or the same volume of saline as placebo (n = 14). MEASUREMENTS AND MAIN RESULTS: Plasma interleukin-6, interleukin-8, interleukin-10 (biomarkers of inflammation), and 8-hydroxydeoxyguanosine concentrations (a biomarker of oxidative stress) were measured at the following 4 time points: preoperatively, during cardiopulmonary bypass, after protamine administration, and 6 hours postoperatively. The study parameters did not differ between the study groups preoperatively. Methylprednisolone reduced the proinflammatory cytokines interleukin-6 and interleukin-8 and increased the anti-inflammatory cytokine interleukin-10 postoperatively. Despite reduced inflammation, there were no differences in 8-hydroxydeoxyguanosine between the methylprednisolone and placebo groups. CONCLUSIONS: The proinflammatory reaction and increase in free radical stress were not interrelated during congenital heart surgery in cyanotic infants with a univentricular heart defect undergoing the bidirectional Glenn procedure. High-dose methylprednisolone was ineffective in attenuating free radical stress.

Graft glycocalyx degradation in human liver transplantation.

OBJECTIVE: Ischaemia/reperfusion-injury degrades endothelial glycocalyx. Graft glycocalyx degradation was studied in human liver transplantation. METHODS: To assess changes within the graft, blood was drawn from portal and hepatic veins in addition to systemic samples in 10 patients. Plasma syndecan-1, heparan sulfate and chondroitin sulfate, were measured with enzyme-linked immunosorbent assay. RESULTS: During reperfusion, syndecan-1 levels were higher in graft caval effluent [3118 (934-6141) ng/ml, P = 0.005] than in portal venous blood [101 (75-121) ng/ml], indicating syndecan-1 release from the graft. Concomitantly, heparan sulfate levels were lower in graft caval effluent [96 (32-129) ng/ml, P = 0.037] than in portal venous blood [112 (98-128) ng/ml], indicating heparan sulfate uptake within the graft. Chondroitin sulfate levels were equal in portal and hepatic venous blood. After reperfusion arterial syndecan-1 levels increased 17-fold (P < 0.001) and heparan sulfate decreased to a third (P < 0.001) towards the end of surgery. CONCLUSION: Syndecan-1 washout from the liver indicates extensive glycocalyx degradation within the graft during reperfusion. Surprisingly, heparan sulfate was taken up by the graft during reperfusion. Corroborating previous experimental reports, this suggests that endogenous heparan sulfate might be utilized within the graft in the repair of damaged glycocalyx.

The origin of plasma neutrophil gelatinase-associated lipocalin in cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) is common after heart surgery. Neutrophil gelatinase-associated lipocalin (NGAL) is produced in injured kidney. NGAL has been used as an early plasma biomarker for AKI in patients undergoing heart surgery. Neutrophils contain all isoforms (25-kDa, 45-kDa and 145-kDa) but the kidney produces almost exclusively the 25-kDa isoform of NGAL. We investigated first, whether there is association between NGAL and neutrophil activation, and second whether activated neutrophils are a significant source of circulating NGAL in plasma in patients undergoing cardiac surgery. METHODS: Two separate patient cohorts were studied: 1) the "kinetic cohort" (n = 29) and 2) the "FINNAKI cohort" (n = 306). As NGAL is strictly co-localized with lactoferrin in neutrophils, NGAL and lactoferrin were measured with enzyme-linked immunosorbent assay in all patients. In sixty-one patients of the "FINNAKI cohort" Western blot was used to separate NGAL isoforms according to their molecular size. Mann-Whitney U, Kruskal-Wallis H, Pearson's and Spearman's tests were used as appropriate. RESULTS: There was strong intraoperative association between NGAL and lactoferrin at all four time-points in the "kinetic cohort". In the "FINNAKI cohort", NGAL and lactoferrin concentrations correlated preoperatively (R = 0.59, p < 0.001) and at admission to the intensive care unit (R = 0.69, p < 0.001). At admission to intensive care unit, concentrations of NGAL and lactoferrin were higher in AKI than in non-AKI patients (NGAL: p < 0.001; lactoferrin: p < 0.029). In Western blot analyses, neutrophil specific 45-kDa isoform (median 41% [IQR 33.3-53.1]) and mostly neutrophil derived 145-kDa isoform (median 53.5% [IQR 44.0-64.9%]) together represented over 90% of total NGAL in plasma. Potentially kidney derived NGAL isoform (25-kDa) accounted for only 0.9% (IQR 0.3 - 3.0%) of total NGAL in plasma. There were no statistically significant differences in the distribution of NGAL isomers between AKI and non-AKI patients. CONCLUSIONS: Plasma NGAL during cardiac surgery is associated with neutrophil activation. Based on molecular size, the majority of circulating NGAL is derived from neutrophils. Neutrophil activation is a confounding factor when interpreting increased plasma NGAL in cardiac surgery.

Glycocalyx Degradation and Inflammation in Cardiac Surgery.

OBJECTIVE: Experimental inflammation induces degradation of glycocalyx. The authors hypothesized that inflammation is an important determinant of glycocalyx degradation in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). DESIGN: A prospective observational study. SETTING: Operation theater and intensive care unit of a university hospital. PARTICIPANTS: Two separate prospective patient cohorts. INTERVENTIONS: Blood samples were collected at 5 perioperative time points in the trial cohort (30 patients) and only preoperatively in the preoperative cohort (35 patients). Plasma syndecan-1 (biomarker of glycocalyx degradation), interleukin-6 (IL-6), IL-8, and IL-10 were measured. MEASUREMENTS AND MAIN RESULTS: In the trial cohort, preoperative ranges were as follows: 0.8-198 ng/mL for syndecan-1; 0-902 pg/mL for IL-6; 0-314.9 pg/mL for IL-8, and 0-2,909 pg/mL for IL-10. Seven out of 30 patients were outliers in terms of plasma concentrations of syndecan-1 and all cytokines preoperatively. The increase of syndecan-1 was 2.7-fold, and those of IL-6 and IL-8 were both 2.5-fold. The increase of IL-10 was modest. Plasma syndecan-1 correlated with all cytokines preoperatively (IL-6: R = 0.66, p < 0.001; IL-8: R = 0.67, p = 0.001; IL-10: R = 0.73, p < 0.001) as well as at 6 hours postoperatively (IL-6: R = 0.49, p = 0.006; IL-8: R = 0.43, p = 0.02; IL-10: R = 0.41, p = 0.03) and on the postoperative morning (IL-6: R = 0.57, p = 0.001; IL-8: R = 0.37, p = 0.06; IL-10: R = 0.51, p = 0.005) but not intraoperatively. The preoperative findings of the trial cohort could be confirmed in the preoperative cohort. CONCLUSIONS: In patients undergoing cardiac surgery with CPB, inflammation in terms of proinflammatory cytokines IL-6 and IL-8 and anti-inflammatory cytokine IL-10 is associated with glycocalyx degradation measured as plasma syndecan-1 concentrations.

Heparin Binding Protein in Adult Heart Surgery.

BACKGROUND: Heparin binding protein (HBP) is released from neutrophilic secretory vesicles upon neutrophil adhesion on the endothelium. HBP mediates capillary hyperpermeability experimentally. In sepsis, HBP predicts organ dysfunction. Cardiopulmonary bypass induces neutrophil activation and hyperpermeability. We hypothesized that in cardiopulmonary bypass, HBP is released in the reperfused coronary circulation concomitantly with neutrophil adhesion. METHODS: In 30 patients undergoing aortic valve replacement, concomitant blood samples were drawn from the coronary sinus and arterial line before aortic cross-clamping and 5 minutes after reperfusion to calculate transcoronary differences. Plasma HBP concentrations, neutrophil markers lactoferrin and myeloperoxidase, myocardial injury marker heart-type fatty acid binding protein, and leukocyte differential counts were measured. RESULTS: Arterial HBP was 4.1 ng/mL (interquartile range [IQR], 3.6 to 5.3 ng/mL) preoperatively and 150.0 ng/mL (IQR, 108.2 to 188.6 ng/mL) after aortic declamping. HBP increased 39-fold, lactoferrin 16-fold, and myeloperoxidase fourfold during cardiopulmonary bypass. Before cardiopulmonary bypass, there were marginal transcoronary differences in HBP (1.4 ng/mL; IQR, -0.4 to 3.6 ng/mL; p = 0.001) and heart-type fatty acid binding protein (0.4 ng/mL; IQR, -0.04 to 3.5 ng/mL; p = 0.001) but not in the other indicators. During reperfusion, transcoronary HBP release (6.4 ng/mL; IQR, 1.8 to 13.7; ng/mL; p < 0.001) was observed concomitantly with transcoronary neutrophil sequestration (-0.14 × 109/L; IQR, -0.28 to 0.01 × 109/L; p = 0.001) and transcoronary heart-type fatty acid binding protein release (6.9 ng/mL; IQR, 3.0 to 25.8 ng/mL; p < 0.001). There were no transcoronary differences in lactoferrin or myeloperoxidase during reperfusion. CONCLUSIONS: Cardiopulmonary bypass results in substantial increase in circulating HBP. HBP is also released from the reperfused coronary circulation concomitantly with coronary neutrophil adhesion and myocardial injury. HBP may be one candidate for a humoral factor mediating capillary leak in cardiopulmonary bypass.

Heart-Type Fatty Acid Binding Protein and High-Dose Methylprednisolone in Pediatric Cardiac Surgery.

OBJECTIVES: Corticosteroids possess cardioprotection in experimental cardiac ischemia/reperfusion. The authors hypothesized that if cardioprotection of corticosteroids occured during pediatric cardiac surgery, then methylprednisolone used in cardiopulmonary bypass prime would reduce postoperative concentrations of heart-type fatty-acid-binding protein, a cardiac biomarker. DESIGN: A double-blind, placebo-controlled, randomized clinical trial. SETTING: Operating room and pediatric intensive care unit of a university hospital. PARTICIPANTS: Forty-five infants and young children undergoing ventricular or atrioventricular septal defect correction. INTERVENTIONS: The patients received one of the following: 30 mg/kg of methylprednisolone intravenously after anesthesia induction (n = 15), 30 mg/kg of methylprednisolone in cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS: Plasma heart-type fatty-acid-binding protein (hFABP) was measured. Preoperatively, hFABP did not differ among the study groups. Methylprednisolone administered preoperatively and in the cardiopulmonary bypass prime solution reduced hFABP by 44% (p = 0.010) and 38% (p = 0.033) 6 hours postoperatively. hFABP significantly correlated with concomitant troponin T after protamine administration (R = 0.811, p < 0.001) and 6 hours postoperatively (R = 0.806, p < 0.001). CONCLUSIONS: Methylprednisolone in cardiopulmonary bypass prime solution administered only a few minutes before cardiac ischemia confered cardioprotection of the same magnitude as preoperative methylprednisolone as indicated by hFABP concentrations. Rapid cardioprotective actions of corticosteroids in pediatric heart surgery observed previously experimentally may have occurred.

Novel Zero-Heat-Flux Deep Body Temperature Measurement in Lower Extremity Vascular and Cardiac Surgery.

OBJECTIVE: The aim of this study was to compare deep body temperature obtained using a novel noninvasive continuous zero-heat-flux temperature measurement system with core temperatures obtained using conventional methods. DESIGN: A prospective, observational study. SETTING: Operating room of a university hospital. PARTICIPANTS: The study comprised 15 patients undergoing vascular surgery of the lower extremities and 15 patients undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Zero-heat-flux thermometry on the forehead and standard core temperature measurements. MEASUREMENTS AND MAIN RESULTS: Body temperature was measured using a new thermometry system (SpotOn; 3M, St. Paul, MN) on the forehead and with conventional methods in the esophagus during vascular surgery (n = 15), and in the nasopharynx and pulmonary artery during cardiac surgery (n = 15). The agreement between SpotOn and the conventional methods was assessed using the Bland-Altman random-effects approach for repeated measures. The mean difference between SpotOn and the esophageal temperature during vascular surgery was+0.08°C (95% limit of agreement -0.25 to+0.40°C). During cardiac surgery, during off CPB, the mean difference between SpotOn and the pulmonary arterial temperature was -0.05°C (95% limits of agreement -0.56 to+0.47°C). Throughout cardiac surgery (on and off CPB), the mean difference between SpotOn and the nasopharyngeal temperature was -0.12°C (95% limits of agreement -0.94 to+0.71°C). Poor agreement between the SpotOn and nasopharyngeal temperatures was detected in hypothermia below approximately 32°C. CONCLUSIONS: According to this preliminary study, the deep body temperature measured using the zero-heat-flux system was in good agreement with standard core temperatures during lower extremity vascular and cardiac surgery. However, agreement was questionable during hypothermia below 32°C.

High-Dose Methylprednisolone Has No Benefit Over Moderate Dose for the Correction of Tetralogy of Fallot.

BACKGROUND: The optimal dose of methylprednisolone during pediatric open heart surgical procedures is unknown. This study compared the antiinflammatory and cardioprotective effects of high and lower doses of methylprednisolone in children undergoing cardiac operations. METHODS: Thirty children, between 1 and 18 months old and undergoing total correction of tetralogy of Fallot, were randomized in double-blind fashion to receive either 5 or 30 mg/kg of intravenous methylprednisolone after anesthesia induction. Plasma concentrations of methylprednisolone, interleukin-6 (IL-6), IL-8, and IL-10, troponin T, and glucose were measured at anesthesia induction before administration of the study drug, at 30 minutes on cardiopulmonary bypass (CPB), just after weaning from CPB, and at 6 hours after CPB. Troponin T and blood glucose were also measured on the first postoperative morning. RESULTS: Significantly higher methylprednisolone concentrations were measured in patients receiving 30 mg/kg of methylprednisolone at 30 minutes on CBP, after weaning from CPB and at 6 hours after CPB (p < 0.001). No differences were detected in IL-6, IL-8, IL-10, or troponin concentrations at any time point. Blood glucose levels were significantly higher in patients receiving 30 mg/kg of methylprednisolone at 6 hours after CPB (p = 0.04) and on the first postoperative morning (p = 0.02). CONCLUSIONS: Based on the measured concentrations of interleukins or troponin T, a 30 mg/kg dose of methylprednisolone during pediatric open heart operations does not offer any additional antiinflammatory or cardioprotective benefit over a 5 mg/kg dose. Higher dose of methylprednisolone exposes patients more frequently to hyperglycemia.

The Effect of Methylprednisolone on Plasma Concentrations of Neutrophil Gelatinase-Associated Lipocalin in Pediatric Heart Surgery.

OBJECTIVES: Plasma neutrophil gelatinase-associated lipocalin is a kidney injury marker used in pediatric heart surgery. Neutrophil gelatinase-associated lipocalin is also a constituent of specific granules of neutrophils. Corticosteroids are widely used in pediatric heart surgery. Methylprednisolone inhibits degranulation of neutrophil-specific granules. Use of corticosteroids has not been taken into account in studies of neutrophil gelatinase-associated lipocalin in pediatric heart surgery. We studied the influence of systemically administered methylprednisolone on plasma neutrophil gelatinase-associated lipocalin concentrations in pediatric heart surgery. DESIGN: Two separate double-blinded randomized trials. SETTING: PICU at a university-affiliated hospital. PATIENTS: Forty neonates undergoing open-heart surgery and 45 children undergoing ventricular and atrioventricular septal defect correction. INTERVENTIONS: First trial (neonate trial), 40 neonates undergoing open-heart surgery received either 30 mg/kg IV methylprednisolone (n = 20) or placebo (n = 20). Second trial (ventricular septal defect trial), 45 children undergoing ventricular or atrioventricular septal defect correction received one of the following: 30 mg/kg of methylprednisolone IV after anesthesia induction (n = 15), 30 mg/kg methylprednisolone in the cardiopulmonary bypass prime solution (n = 15), or placebo (n = 15). MEASUREMENTS AND MAIN RESULTS: Plasma neutrophil gelatinase-associated lipocalin and creatinine were measured in both series. Lactoferrin levels were measured as a marker of neutrophil-specific granules in the ventricular septal defect trial only. No differences in creatinine levels occurred between the groups of either trial. Preoperative, neutrophil gelatinase-associated lipocalin did not differ between the study groups of either trial. Preoperatively administered methylprednisolone in the neonate trial reduced neutrophil gelatinase-associated lipocalin by 41% at 6 hours postoperatively (p = 0.002). Preoperatively administered methylprednisolone in the ventricular septal defect trial reduced neutrophil gelatinase-associated lipocalin by 47% (p = 0.010) and lactoferrin by 52% (p = 0.013) 6 hours postoperatively. Lactoferrin levels in the ventricular septal defect trial correlated with neutrophil gelatinase-associated lipocalin (R = 0.492; p = 0.001) preoperatively and after weaning from cardiopulmonary bypass (R = 0.471; p = 0.001). CONCLUSIONS: Preoperatively administered methylprednisolone profoundly decreases plasma neutrophil gelatinase-associated lipocalin levels. Neutrophil gelatinase-associated lipocalin seems to originate to a significant extent from activated neutrophils. Preoperative methylprednisolone is a confounding factor when interpreting plasma neutrophil gelatinase-associated lipocalin levels as a kidney injury marker in pediatric heart surgery.

Effect of timing and route of methylprednisolone administration during pediatric cardiac surgical procedures.

BACKGROUND: We compared the antiinflammatory and cardioprotective effects of the two most common regimens of corticosteroid administration in pediatric cardiac surgical procedures: a single dose delivered either at anesthesia induction or by cardiopulmonary bypass (CPB) prime. METHODS: Forty-five children, aged between 1 and 18 months and undergoing ventricular septal or atrioventricular septal defect correction, were randomized in double-blind fashion into three groups. The anesthesia induction group received 30 mg/kg methylprednisolone intravenously after anesthesia induction, and the CPB-prime group received 30 mg/kg methylprednisolone by CPB circuit. The placebo group received saline solution. Plasma concentrations of methylprednisolone, interleukin (IL)-6, IL-8 and IL-10, and troponin were measured at anesthesia induction before the study drug, 30 minutes on CPB, after patients were weaned from CPB, and 6 hours after cessation of CPB. RESULTS: Equally high methylprednisolone concentrations were detected in both methylprednisolone groups, but the measured peak concentration occurred earlier in the induction group. Significantly lower IL-8 concentrations were observed just after patients were weaned from and 6 hours after CPB in the anesthesia induction group compared with the placebo (p = 0.002, p = 0.001) and prime groups (p = 0.003, p = 0.006). Significant reductions of troponin were detected in both methylprednisolone groups compared with placebo (induction, p = 0.001; prime, p = 0.002) 6 hours after patients were weaned from CPB. CONCLUSIONS: Methylprednisolone administration at anesthesia induction was superior in terms of antiinflammatory action. Methylprednisolone administration in CPB-prime only a few minutes before aortic cross-clamping and cardioplegia resulted in mean troponin reductions similar to those of administration at anesthesia induction. Corticosteroids may have direct cardioprotective properties, as reported in experimental studies.