Study protocol: NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC trial): a randomised controlled trial

Introduction Congenital heart disease (CHD) is a major cause of infant mortality. Many infants with CHD require corrective surgery with most operations requiring cardiopulmonary bypass (CPB). CPB triggers a systemic inflammatory response which is associated with low cardiac output syndrome (LCOS), postoperative morbidity and mortality. Delivery of nitric oxide (NO) into CPB circuits can provide myocardial protection and reduce bypass-induced inflammation, leading to less LCOS and improved recovery. We hypothesised that using NO during CPB increases ventilator-free days (VFD) (the number of days patients spend alive and free from invasive mechanical ventilation up until day 28) compared with standard care. Here, we describe the NITRIC trial protocol. Methods and analysis The NITRIC trial is a randomised, double-blind, controlled, parallel-group, two-sided superiority trial to be conducted in six paediatric cardiac surgical centres. One thousand three-hundred and twenty infants <2 years of age undergoing cardiac surgery with CPB will be randomly assigned to NO at 20 ppm administered into the CPB oxygenator for the duration of CPB or standard care (no NO) in a 1:1 ratio with stratification by age (<6 and ≥6 weeks), single ventricle physiology (Y/N) and study centre. The primary outcome will be VFD to day 28. Secondary outcomes include a composite of LCOS, need for extracorporeal membrane oxygenation or death within 28 days of surgery; length of stay in intensive care and in hospital; and, healthcare costs. Analyses will be conducted on an intention-to-treat basis. Preplanned secondary analyses will investigate the impact of NO on host inflammatory profiles postsurgery. Ethics and dissemination The study has ethical approval (HREC/17/QRCH/43, dated 26 April 2017), is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12617000821392) and commenced recruitment in July 2017. The primary manuscript will be submitted for publication in a peer-reviewed journal. Trial registration number ACTRN12617000821392.</p

Modified Glucose-Insulin-Potassium Regimen Provides Cardioprotection With Improved Tissue Perfusion in Patients Undergoing Cardiopulmonary Bypass Surgery

Background Laboratory studies demonstrate glucose-insulin-potassium (GIK) as a potent cardioprotective intervention, but clinical trials have yielded mixed results, likely because of varying formulas and timing of GIK treatment and different clinical settings. This study sought to evaluate the effects of modified GIK regimen given perioperatively with an insulin-glucose ratio of 1:3 in patients undergoing cardiopulmonary bypass surgery. Methods and Results In this prospective, randomized, double-blinded trial with 930 patients referred for cardiac surgery with cardiopulmonary bypass, GIK (200 g/L glucose, 66.7 U/L insulin, and 80 mmol/L KCl) or placebo treatment was administered intravenously at 1 mL/kg per hour 10 minutes before anesthesia and continuously for 12.5 hours. The primary outcome was the incidence of in-hospital major adverse cardiac events including all-cause death, low cardiac output syndrome, acute myocardial infarction, cardiac arrest with successful resuscitation, congestive heart failure, and arrhythmia. GIK therapy reduced the incidence of major adverse cardiac events and enhanced cardiac function recovery without increasing perioperative blood glucose compared with the control group. Mechanistically, this treatment resulted in increased glucose uptake and less lactate excretion calculated by the differences between arterial and coronary sinus, and increased phosphorylation of insulin receptor substrate-1 and protein kinase B in the hearts of GIK-treated patients. Systemic blood lactate was also reduced in GIK-treated patients during cardiopulmonary bypass surgery. Conclusions A modified GIK regimen administered perioperatively reduces the incidence of in-hospital major adverse cardiac events in patients undergoing cardiopulmonary bypass surgery. These benefits are likely a result of enhanced systemic tissue perfusion and improved myocardial metabolism via activation of insulin signaling by GIK. Clinical Trial Registration URL: clinicaltrials.gov. Identifier: NCT01516138

Aspects of leucocyte and fat filtration during cardiac surgery

Na een hartoperatie treden vaak door het hele lichaam ontstekingsreacties op. Door het bloed tijdens de operatie te filteren, lopen patiënten minder risico op beschadigingen in longen, hart en hersenen, ontdekte Hans de Vries. Tijdens een hartoperatie neemt de hart-longmachine een aantal lichaamsfuncties over. Deze machine vormt door zijn grote contactoppervlak met het bloed van de patiënt een enorme prikkel voor stollings- en ontstekingsreacties. De ontstekingen kunnen het hele lichaam treffen en zorgen daar voor weefselbeschadigingen. Een sleutelrol in dit schadelijke proces spelen witte bloedlichaampjes (leukocyten) en vetdeeltjes die tijdens de operatie in de bloedbaan komen. De Vries experimenteerde met twee filters die respectievelijk leukocyten en vetdeeltjes uit het bloed verwijderen. Hij ontdekte dat er minder ontstekingsreacties en weefselbeschadigingen optreden wanneer de leukocyten worden gefilterd uit het restbloed van de hart-longmachine. De patiënten blijken dan na de operatie een betere longfunctie te hebben. Het filter vangt overigens niet alle leukocyten weg; het verwijdert vooral de geactiveerde, ziekmakende witte bloedlichaampjes. Ook een vetdeeltjesfilter zorgt voor minder ontstekingsreacties. Voor de patiënten had dit echter geen merkbare gevolgen. Vermoedelijk laat de effectiviteit van dit filter nog te wensen over.

Intraoperative fluid restriction in pancreatic surgery : a double blinded randomised controlled trial

Background : Perioperative fluid restriction in a variety of operations has shown improvement of: complications, recovery of gastrointestinal function and length of stay (LOS). We investigated effects of crystalloid fluid restriction in pancreatic surgery. Our hypothesis: enhanced recovery of gastrointestinal function. Methods : In this double-blinded randomized trial, patients scheduled to undergo pancreatoduodenectomy (PD) were randomized: standard (S: 10ml/kg/hr) or restricted (R:5ml/kg/hr) fluid protocols. Primary endpoint: gastric emptying scintigraphically assessed on postoperative day 7. Results : In 66 randomized patients, complications and 6-year survival were analyzed. 54 patients were analyzed in intention to treat: 24 S-group and 30 R-group. 32 patients actually underwent a PD and 16 patients had a palliative gastrojejunostomy bypass operation in the full protocol analysis. The median gastric emptying time (T1/2) was 104 minutes (S-group, 95% confidence interval: 74-369) versus 159 minutes (R-group, 95% confidence interval: 61-204) (P = 0.893, NS). Delayed gastric emptying occurred in 10 patients in the S-group and in 13 patients in the R-group (45% and 50%, P = 0.779, NS). The primary outcome parameter, gastric emptying time, did not show a statistically significant difference between groups. Conclusion : A fluid regimen of 10ml/kg/hr or 5ml/kg/hr during pancreatic surgery did not lead to statistically significant differences in gastric emptying. A larger study would be needed to draw definite conclusions about fluid restriction in pancreatic surgery

Cardiopulmonary Predicators of Dysfunctional Ventilator Weaning Response after Coronary Artery Bypass Graft

Although the majority of coronary artery bypass graft (CABG) surgery patients are extubated within 6 to 8 hours following surgery, 20% to 40% of patients remain intubated 12 hours after surgery due to dysfunctional ventilator weaning response (DVWR). DVWR associated with increased morbidity and mortality (30% to 43%) following CABG surgery. Finding significant antecedence to predict DVWR could help to identify and prevent the complications from DVWR after CABG surgery. Literature review revealed that there is an association between cardiopulmonary indicators (CPI) and DVWR after CABG surgery. Cardiopulmonary indicators are the selected hemodynamic parameters that have an association with DVWR. The association of CPI with DVWR may be used to predict DVWR. Therefore, this study set out to find a predictive model for DVWR using CPI and significant antecedence. The purposes of this research study were to describe the characteristics of CPI among patients with normal ventilator weaning response (NVWR) and dysfunctional ventilator weaning response (DVWR) after coronary artery bypass graft (CABG) surgery, to find the differences in characteristics of cardiopulmonary indicators between patients with NVWR and DVWR after CABG surgery, and to build a prediction model for DVWR with significant antecedence. A retrospective case control study with time series design was utilized. An inclusion criteria guided purposive sampling technique was used to recruit 300 subjects from a retrospective audit of electronic medical records of patients who underwent CABG surgery between May 2003 and February 2006. Among the 300 subjects, 100 subjects constituted the case group and 200 constituted the control group. This study utilized descriptive and inferential statistical analysis, which was performed through SAS programs including PROC UNIVARIATE, PROC FREQ, PROC GLM, PROC REG, PROC MIXED REPEATED MEASURE ANOVA, and PROC LOGISTIC. The study included such demographic variables as age and sex and clinical variables COPD, CHF, renal failure, number of grafts, and BSA, which were used for the description of the study sample as well as included in the analysis as covariates. The outcome variables of this study were DVWR and NVWR. The independent variable of the study was CPI, which included heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO), respiratory rate (RR), mixed venous oxygen saturation (SVO2), oxygen saturation (SPO2), pulmonary artery diastolic pressure (PAD) and pulmonary artery systolic pressure (PASP). An hourly time series measurement of selected CPI for 12 consecutive hours after CABG surgery was used to predict DVWR. Findings revealed that several antecedence including COPD, CHF, MAP, RR, CO, PAD, and PASP were significantly associated with DVWR. In addition, findings revealed that the odds in favor of DVWR for patients with COPD were 5.466 times higher as compared to patients without COPD, holding all other variables constant. The odds in favor of DVWR for patients with CHF were 3.930 times higher than for patients without CHF, holding all other variables constant. The odds in favor of DVWR for patients with decrease 10mm/Hg mean MAP were 1.915 times the probability of NVWR, holding all other variables constant. This implies that hypotension increases risk of developing DVWR after CABG surgery. The odds in favor of DVWR for patients with decrease 5 points of mean RR were 2.978 times the probability of NVWR, holding all other variables constant. This implies that patients with lower RR are at risk of developing DVWR after CABG surgery. The odds in favor of DVWR for patients with decrease in mean CO by 2 points were 1.943 times the probability of NVWR, holding all other variables constant. This implies that patients with low CO are at the risk of developing DVWR after CABG surgery. The odds in favor of DVWR for patients with increase in mean PAD by 5mm/hg were 3.640 times the probability of NVWR, holding all other variables constant. This implies that patients with high PAD pressure are at risk of developing DVWR after CABG surgery. The odds in favor of DVWR for patients with decrease in mean PASP by 10mm/hg were 3.053 times the probability of NVWR, holding all other variables constant. This implies that the patients with low PASP are at risk of developing DVWR after CABG surgery. In conclusion, the results of this study revealed significant antecedence to predict DVWR after CABG surgery, including COPD, CHF, MAP, RR, CO, PAD, and PASP. Therefore, this study concluded that the above-mentioned significant antecedence may be used to predict DVWR after CABG surgery in critical care. The implications from the conclusion are that the weaning protocols after CABG surgery may be tailored using these significant predictors. In addition, the study findings imply that patients with a history of COPD and CHF have significant risk of developing DVWR after CABG surgery. Therefore, this researcher recommends that weaning criteria be developed considering the above risk factors for high risk patients

Comparison of spectral entropy and bispectral index electroencephalography in coronary artery bypass graft surgery

OBJECTIVE: The study's aim was to compare response entropy (RE) and state entropy (SE) with bispectral index (BIS) electroencephalography (EEG) as an alternative cerebral monitoring tool in patients scheduled for coronary artery bypass graft surgery. DESIGN: Prospective, observational single-center study. SETTING: University hospital. PARTICIPANTS: Thirty patients undergoing coronary artery bypass graft surgery receiving remifentanil-propofol anesthesia. INTERVENTIONS: Surgery was performed with cardiopulmonary bypass (CPB) and cardiac arrest in 15 patients, with CPB without cardiac arrest in 9 patients and without CPB in 6 patients. MEASUREMENTS AND MAIN RESULTS: RE, SE, BIS, burst suppression ratio (BSR), and frontal electromyography (f-EMG) were detected simultaneously. RE and SE compared favorably with BIS and their correlations were strong (r(2) = 0.6, r(2) = 0.55, respectively). The mean bias of RE and BIS was -1.8, but limits of agreement were high (+20.5/-24.1). RE and SE tended to be lower than the BIS values in the CPB subgroups. The detection of BSR was similar with RE and SE and the BIS. A strong correlation existed between BIS and f-EMG (r(2) = 0.62) in contrast to RE (r(2) = 0.45) and SE (r(2) =0.39). BIS monitoring was significantly more disturbed than RE and SE with 9.1% +/-10.9% and 0.1% +/- 0.2% of the total anesthesia time, respectively. Neither implicit nor explicit memory was shown. CONCLUSION: RE and SE are comparable with the BIS but showed significantly less interference from f-EMG and superior resistance against artifacts. Thus, spectral entropy is more suitable than the BIS during propofol-remifentanil anesthesia in cardiac surgery patients

Transpulmonary thermodilution: its role in assessment of lung water and pulmonary edema

Tissue edema, in particular pulmonary edema, increasingly is recognized as a perioperative complication affecting outcome. Management strategies directed at avoiding excessive fluid administration, reducing inflammatory response, and decreasing capillary permeability commonly are advocated in perioperative care protocols. In this review, transpulmonary thermodilution (TPTD) as a bedside tool to quantitatively monitor lung water accumulation and optimize fluid therapy is examined. Furthermore, the roles of TPTD as an early detector of fluid accumulation before the development of overt pulmonary edema and in risk stratification are explored. In addition, the ability of TPTD to provide insight into the etiology of pulmonary edema, specifically differentiating hydrostatic versus increased pulmonary capillary permeability, is emerging as an aid in therapeutic decision-making. The combination of hemodynamic and lung water data afforded by TPTD offers unique benefits for the care of high-risk perioperative patients

Fat contamination of pericardial suction blood and its influence on in vitro capillary-pore flow properties in patients undergoing routine coronary artery bypass grafting

AbstractObjective: Neurologic dysfunction after cardiopulmonary bypass might be due to arterial microembolization. Pericardial suction blood is a possible source of embolic material. Our aim was to determine the capillary-pore flow ability of pericardial suction blood. Methods: Pericardial suction blood from patients undergoing coronary bypass was collected, and pericardial suction blood and venous blood were sampled at the end of cardiopulmonary bypass and before reinfusion of pericardial suction blood. Pericardial suction blood was (n = 10) or was not (n = 10) prefiltered through a 30-μm cardiotomy screen filter before capillary in vitro analysis. Additionally, in 8 patients the plasma viscosity was measured, and in 5 of these patients, pericardial suction blood capillary deposits were evaluated by using a microscopy-imprint method and fat staining. Capillary flow was tested through 5-μm pore membranes. Tested components were plasma, plasma-eliminated whole-blood resuspension, and leukocyte/plasma-eliminated erythrocyte resuspension. Initial filtration rate and clogging slope expressed the blood-to-capillary interaction. Results: The plasma-flow profile of pericardial suction blood was highly impaired, with a 47% reduction in initial filtration rate (P <.001) and a 142% steeper clogging slope flow deceleration (P <.01). This difference was not due to a change in pericardial suction blood viscosity, such as by free hemoglobin, which corresponded to 5.7% of the erythrocytes. There were no differences in resuspended whole blood or erythrocytes. The cardiotomy filter had no effect. Microscopy suggested the presence of capillary fat deposits in pericardial suction blood that were not seen with venous plasma (P <.05). The pericardial suction blood volume was 458 ± 42 mL and contained 95.6 ± 9.3 g/L hemoglobin. Conclusions: The pericardial suction blood plasma capillary flow function was highly impaired by liquid fat. Pericardial suction blood hemoglobin appears worth recovering after fat removal, despite profound hemolysis.J Thorac Cardiovasc Surg 2002;124:377-8

Absence of reflex vascular responses from the intrapulmonary circulation in anaesthetised dogs

The aim of this investigation was to determine whether reflex cardiovascular responses were obtained to localised distension of the intrapulmonary arterial and venous circulations in a preparation in which the stimuli to other major reflexogenic areas were controlled and the lung was shown to possess reflex activity. Dogs were anaesthetised with [alpha]-chloralose, artificially ventilated, the chests widely opened and a cardiopulmonary bypass established. The intrapulmonary region of the left lung was isolated and perfused through the left pulmonary artery and drained through cannulae in the left pulmonary veins via a Starling resistance. Intrapulmonary arterial and venous pressures were controlled by the rate of inflow of blood and the pressure applied to the Starling resistance. Pressures to the carotid, aortic and coronary baroreceptors and heart chambers were controlled. Responses of vascular resistance were assessed from changes in perfusion pressures to a vascularly isolated hind limb and to the remainder of the subdiaphragmatic circulation (flows constant). The reactivity of the preparation was demonstrated by observing decreases in vascular resistance to large step changes in carotid sinus pressure (systemic vascular resistance decreased by -40 ± 5 %), chemical stimulation of lung receptors by injection into the pulmonary circulation of veratridine or capsaicin (resistance decreased by -32 ± 4 %) and, in the four dogs tested, increasing pulmonary stroke volume to 450 ml (resistance decreased by -24 ± 6 %). However, despite this evidence that the lung was innervated, increases in intrapulmonary arterial pressure from 14 ± 1 to 43 ± 3 mmHg or in intrapulmonary venous pressure from 5 ± 2 to 34 ± 2 mmHg or both did not result in any consistent changes in systemic or limb vascular resistances. In two animals tested, however, there were marked decreases in efferent phrenic nerve activity. These results indicate that increases in pressure confined to the intrapulmonary arterial and venous circulations do not cause consistent reflex vascular responses, even though the preparation was shown to be reflexly active and the lung was shown to be innervated