Effect of changes in inspired oxygen fraction on oxygen delivery during cardiac surgery: a substudy of the CARROT trial

When hemoglobin (Hb) is fully saturated with oxygen, the additional gain in oxygen delivery (DO2) achieved by increasing the fraction of inspired oxygen (FiO2) is often considered clinically insignificant. In this study, we evaluated the change in DO2, interrogated by mixed venous oxygen saturation (SvO2), in response to a change in FiO2 of 0.5 during cardiac surgery. When patients were hemodynamically stable, FiO2 was alternated between 0.5 and 1.0 in on-pump cardiac surgery patients (pilot study), and between 0.3 and 0.8 in off-pump coronary artery bypass grafting patients (substudy of the CARROT trial). After the patient had stabilized, a blood gas analysis was performed to measure SvO2. The observed change in SvO2 (ΔSvO2) was compared to the expected ΔSvO2 calculated using Fick's equation. A total 106 changes in FiO2 (two changes per patient; total 53 patients; on-pump, n = 36; off-pump, n = 17) were finally analyzed. While Hb saturation remained near 100% (on-pump, 100%; off-pump, mean [SD] = 98.1% [1.5] when FiO2 was 0.3 and 99.9% [0.2] when FiO2 was 0.8), SvO2 changed significantly as FiO2 was changed (the first and second changes in on-pump, 7.7%p [3.8] and 7.6%p [3.5], respectively; off-pump, 7.9%p [4.9] and 6.2%p [3.9]; all P < 0.001). As a total, regardless of the surgery type, the observed ΔSvO2 after the FiO2 change of 0.5 was ≥ 5%p in 82 (77.4%) changes and ≥ 10%p in 31 (29.2%) changes (mean [SD], 7.5%p [3.9]). Hb concentration was not correlated with the observed ΔSvO2 (the first changes, r = - 0.06, P = 0.677; the second changes, r = - 0.21, P = 0.138). The mean (SD) residual ΔSvO2 (observed - expected ΔSvO2) was 0%p (4). Residual ΔSvO2 was more than 5%p in 14 (13.2%) changes and exceeded 10%p in 2 (1.9%) changes. Residual ΔSvO2 was greater in patients with chronic kidney disease than in those without (median [IQR], 5%p [0 to 7] vs. 0%p [- 3 to 2]; P = 0.049). DO2, interrogated by SvO2, may increase to a clinically significant degree as FiO2 is increased during cardiac surgery, and the increase of SvO2 is not related to Hb concentration. SvO2 increases more than expected in patients with chronic kidney disease. Increasing FiO2 can be used to increase DO2 during cardiac surgery.ope

The efficacy of intramuscular ephedrine in preventing hemodynamic perturbations in patients with spinal anesthesia and dexmedetomidine sedation

Dexmedetomidine is used for sedation during spinal anesthesia. The sympatholytic effect of dexmedetomidine may exacerbate hypotension and bradycardia with spinal anesthesia. This study investigated the effects of prophylactic intramuscular injection of ephedrine in preventing hypotension and bradycardia occurring through combined use of spinal anesthesia and dexmedetomidine. One hundred sixteen patients scheduled for lower extremity orthopedic surgery were randomized into two groups receiving either ephedrine 20 mg intramuscularly or equivalent amount of 0.9% NaCl, both with dexmedetomidine and spinal anesthesia. The primary endpoint was the incidence of hemodynamic perturbations (hypotension or bradycardia event). The secondary endpoint was a rescue doses of ephedrine and atropine. The incidence of hemodynamic perturbations was significantly lower in the ephedrine group compared with to the saline group (26.3% versus 55.9%, p = 0.001). The rescue doses of atropine (0.09 ± 0.21 versus 0.28 ± 0.41, p = 0.001) and ephedrine (1.04 ± 2.89 versus 2.03 ± 3.25, p = 0.007) were also significantly lower in the ephedrine group. There was no differences in number of patients with hypertensive (7.0% versus 11.9%, p = 0.375) or tachycardia (1.8% versus 3.4% p = 0.581) episodes. The use of ephedrine intramuscular injections may be a safe and efficacious option in preventing hemodynamic perturbations in patients who received spinal anesthesia and sedation using dexmedetomidine.ope

Annexin A1 Bioactive Peptide Promotes Resolution of Neuroinflammation in a Rat Model of Exsanguinating Cardiac Arrest Treated by Emergency Preservation and Resuscitation

Neuroinflammation initiated by damage-associated molecular patterns, including high mobility group box 1 protein (HMGB1), has been implicated in adverse neurological outcomes following lethal hemorrhagic shock and polytrauma. Emergency preservation and resuscitation (EPR) is a novel method of resuscitation for victims of exsanguinating cardiac arrest, shown in preclinical studies to improve survival with acceptable neurological recovery. Sirtuin 3 (SIRT3), the primary mitochondrial deacetylase, has emerged as a key regulator of metabolic and energy stress response pathways in the brain and a pharmacological target to induce a neuronal pro-survival phenotype. This study aims to examine whether systemic administration of an Annexin-A1 bioactive peptide (ANXA1sp) could resolve neuroinflammation and induce sirtuin-3 regulated cytoprotective pathways in a novel rat model of exsanguinating cardiac arrest and EPR. Adult male rats underwent hemorrhagic shock and ventricular fibrillation, induction of profound hypothermia, followed by resuscitation and rewarming using cardiopulmonary bypass (EPR). Animals randomly received ANXA1sp (3 mg/kg, in divided doses) or vehicle. Neuroinflammation (HMGB1, TNFα, IL-6, and IL-10 levels), cerebral cell death (TUNEL, caspase-3, pro and antiapoptotic protein levels), and neurologic scores were assessed to evaluate the inflammation resolving effects of ANXA1sp following EPR. Furthermore, western blot analysis and immunohistochemistry were used to interrogate the mechanisms involved. Compared to vehicle controls, ANXA1sp effectively reduced expression of cerebral HMGB1, IL-6, and TNFα and increased IL-10 expression, which were associated with improved neurological scores. ANXA1sp reversed EPR-induced increases in expression of proapoptotic protein Bax and reduction in antiapoptotic protein Bcl-2, with a corresponding decrease in cerebral levels of cleaved caspase-3. Furthermore, ANXA1sp induced autophagic flux (increased LC3II and reduced p62 expression) in the brain. Mechanistically, these findings were accompanied by upregulation of the mitochondrial protein deacetylase Sirtuin-3, and its downstream targets FOXO3a and MnSOD in ANXA1sp-treated animals. Our data provide new evidence that engaging pro-resolving pharmacological strategies such as Annexin-A1 biomimetic peptides can effectively attenuate neuroinflammation and enhance the neuroprotective effects of EPR after exsanguinating cardiac arrest.ope

Dynamic Indices Fail to Predict Fluid Responsiveness in Patients Undergoing One-Lung Ventilation for Thoracoscopic Surgery

Thoracic surgery using CO2 insufflation maintains closed-chest one-lung ventilation (OLV) that may provide the necessary heart-lung interaction for the dynamic indices to predict fluid responsiveness. We studied whether pulse pressure variation (PPV) and stroke volume variation (SVV) can predict fluid responsiveness during thoracoscopic surgery. Forty patients were enrolled in the study. OLV was performed with a tidal volume of 6 mL/kg at a positive end-expiratory pressure of 5 cm H2O, while CO2 was insufflated to the contralateral side at 8 mm Hg. Patients whose stroke volume index (SVI) increased ≥15% after fluid challenge (7 mL/kg) were defined as fluid responders. The predictive ability of PPV and SVV on fluid responsiveness was investigated using the area under the receiver-operator characteristic curve (AUROC), which was also assessed according to the right or left lateral decubitus position considering the intrathoracic location of the right-sided superior vena cava. AUROCs of PPV and SVV for predicting fluid responsiveness were 0.65 (95% confidence interval 0.47-0.83, p = 0.113) and 0.64 (95% confidence interval 0.45-0.82, p = 0.147), respectively. The AUROCs of indices did not exhibit any statistical significance according to position. Dynamic indices of preload cannot predict fluid responsiveness during one-lung ventilation with CO2 gas insufflation.ope

Effect of prophylactic continuous infusion of isosorbide dinitrate on myocardial protection and hemodynamics in patients undergoing off-pump coronary bypass surgery.

BACKGROUND: Multi-vessel off-pump coronary bypass surgery (OPCAB) imposes cumulative myocardial ischemia/reperfusion injury, which may be attenuated by continuous infusion of nitrate. However, nitrate infusion and consequent decrease in preload may be hazardous during heart displacement which causes restrictive filling of the ventricles. Therefore, we evaluated the effect of nitrate infusion on myocardial protection and hemodynamics in patients undergoing OPCAB, in a prospective, randomized and controlled trial. METHODS: Fifty patients with stable angina and left ventricular ejection fraction >40% undergoing elective, isolated, multivessel OPCAB were enrolled. Patients were randomized equally to either continuous infusion of isosorbide dinitrate 0.5microg/kg/min or same amount of normal saline during the surgery. Operative data including hemodynamic variables, intraoperative ST segment changes and postoperative cardiac enzyme release (creatine kinase-MB, troponin T) were compared. RESULTS: Patients characteristic and operative data including ST segment changes and use of vasopressors were similar between the groups except the total amount of infused crystalloid during the surgery which was significantly higher in the nitrate group. Postoperative variables including cardiac enzyme release were also similar between the groups. CONCLUSIONS: Prophylactic continuous infusion of nitrate during OPCAB exerted no additional benefit in terms of myocardial protection. It also, was not associated with accentuated decrease in cardiac output during heart displacement, and the decrease in preload seems to have been nullified by modest increase in fluid therapy.ope

Effect of erythropoietin on the incidence of acute kidney injury following complex valvular heart surgery: a double blind, randomized clinical trial of efficacy and safety

INTRODUCTION: Recombinant human erythropoietin (EPO) is known to provide organ protection against ischemia-reperfusion injury through its pleiotropic properties. The aim of this single-site, randomized, case-controlled, and double-blind study was to investigate the effect of pre-emptive EPO administration on the incidence of postoperative acute kidney injury (AKI) in patients with risk factors for AKI undergoing complex valvular heart surgery. METHODS: We studied ninety-eight patients with preoperative risk factors for AKI. The patients were randomly allocated to either the EPO group (n = 49) or the control group (n = 49). The EPO group received 300 IU/kg of EPO intravenously after anesthetic induction. The control group received an equivalent volume of normal saline. AKI was defined as an increase in serum creatinine >0.3 mg/dl or >50% from baseline. Biomarkers of renal injury were serially measured until five days postoperatively. RESULTS: Patient characteristics and operative data, including the duration of cardiopulmonary bypass, were similar between the two groups. Incidence of postoperative AKI (32.7% versus 34.7%, P = 0.831) and biomarkers of renal injury including cystatin C and neutrophil gelatinase-associated lipocalin showed no significant differences between the groups. The postoperative increase in interleukin-6 and myeloperoxidase was similar between the groups. None of the patients developed adverse complications related to EPO administration, including thromboembolic events, throughout the study period. CONCLUSIONS: Intravenous administration of 300 IU/kg of EPO did not provide renal protection in patients who are at increased risk of developing AKI after undergoing complex valvular heart surgery.ope

Effects of intraoperative inspired oxygen fraction (FiO2 0.3 vs 0.8) on patients undergoing off-pump coronary artery bypass grafting: the CARROT multicenter, cluster-randomized trial

BACKGROUND: To maintain adequate oxygenation is of utmost importance in intraoperative care. However, clinical evidence supporting specific oxygen levels in distinct surgical settings is lacking. This study aimed to compare the effects of 30% and 80% oxygen in off-pump coronary artery bypass grafting (OPCAB). METHODS: This multicenter trial was conducted in three tertiary hospitals from August 2019 to August 2021. Patients undergoing OPCAB were cluster-randomized to receive either 30% or 80% oxygen intraoperatively, based on the month when the surgery was performed. The primary endpoint was the length of hospital stay. Intraoperative hemodynamic data were also compared. RESULTS: A total of 414 patients were cluster-randomized. Length of hospital stay was not different in the 30% oxygen group compared to the 80% oxygen group (median, 7.0 days vs 7.0 days; the sub-distribution hazard ratio, 0.98; 95% confidence interval [CI] 0.83-1.16; P = 0.808). The incidence of postoperative acute kidney injury was significantly higher in the 30% oxygen group than in the 80% oxygen group (30.7% vs 19.4%; odds ratio, 1.94; 95% CI 1.18-3.17; P = 0.036). Intraoperative time-weighted average mixed venous oxygen saturation was significantly higher in the 80% oxygen group (74% vs 64%; P < 0.001). The 80% oxygen group also had a significantly greater intraoperative time-weighted average cerebral regional oxygen saturation than the 30% oxygen group (56% vs 52%; P = 0.002). CONCLUSIONS: In patients undergoing OPCAB, intraoperative administration of 80% oxygen did not decrease the length of hospital stay, compared to 30% oxygen, but may reduce postoperative acute kidney injury. Moreover, compared to 30% oxygen, intraoperative use of 80% oxygen improved oxygen delivery in patients undergoing OPCAB. Trial registration ClinicalTrials.gov (NCT03945565; April 8, 2019). © 2023. The Author(s).ope

Effect of 6% Hydroxyethyl Starch 130/0.4 as a Priming Solution on Coagulation and Inflammation Following Complex Heart Surgery

PURPOSE: Prolonged duration of cardiopulmonary bypass aggravates the degree of inflammation and coagulopathy. We investigated the influence of 6% hydroxyethyl starch (HES) 130/0.4 on coagulation and inflammation compared with albumin when used for both cardiopulmonary bypass priming and perioperative fluid therapy in patients undergoing complex valvular heart surgery. MATERIALS AND METHODS: Fifty four patients were randomly allocated into albumin-HES, albumin-nonHES, and HES-HES groups. The cardiopulmonary bypass circuit was primed with 5% albumin in the albumin-HES and albumin-nonHES group, and with HES in the HES-HES group. As perioperative fluid, only plasmalyte was used in the albumin-nonHES group whereas HES was used up to 20 mL/kg in the albumin-HES and albumin-HES group. Serial assessments of coagulation profiles using the rotational thromboelastometry and inflammatory markers (tissue necrosis factor-α, interleukin-6, and interleukin-8) were performed. RESULTS: Patients' characteristics and the duration of cardiopulmonary bypass (albumin-HES; 137±34 min, HES-HES; 136±47 min, albumin-nonHES; 132±39 min) were all similar among the groups. Postoperative coagulation profiles demonstrated sporadic increases in clot formation time and coagulation time, without any differences in the actual amount of perioperative bleeding and transfusion requirements among the groups. Also, inflammatory markers showed significant activation after cardiopulmonary bypass without any differences among the groups. CONCLUSION: Even in the presence of prolonged duration of cardiopulmonary bypass, HES seemed to yield similar influence on the ensuing coagulopathy and inflammatory response when used for priming and perioperative fluid therapy following complex valvular heart surgery compared with conventional fluid regimen including albumin and plasmalyte.ope

Trendelenburg position with hip flexion as a rescue strategy to increase spinal anaesthetic level after spinal block

BACKGROUND: When the level achieved by a spinal anaesthetic is too low to perform surgery, patients are usually placed in the Trendelenburg position. However, cephalad spread of the hyperbaric spinal anaesthetics may be limited by the lumbar lordosis. The Trendelenburg position with the lumbar lordosis flattened by hip flexion was evaluated as a method to extend the analgesic level after the administration of hyperbaric local anaesthetic. METHODS: When the pinprick block level was lower than T10 5 min after intrathecal injection of hyperbaric bupivacaine (13 mg), patients were recruited to the study and randomly allocated to one of the two positions: the Trendelenburg position with hip flexion (hip flexion group, n = 20) and the Trendelenburg position without hip flexion (control group, n = 20). Each assigned position was maintained for 5 min and then patients were returned to the horizontal supine position. Spinal block level was assessed by pinprick, cold sensation, and modified Bromage scale at intervals for the following 150 min. RESULTS: The maximum level of pinprick and cold sensory block [median (range)] was higher in the hip flexion group [T4 (T8-C6) and T3 (T6-C2)] compared with the control group [T7 (T12-T4) and T5 (T11-T3)] (P < 0.001). The maximum motor blockade median (range) was not different between the two groups being 3 (3-3) in the hip flexion group vs 3 (0-3) in the control group. CONCLUSIONS: When the level of spinal anaesthesia is lower than required, flexion of the hips in the Trendelenburg position may be useful as a strategy attempt to increase the level of the block.ope

Remifentanil protects myocardium through activation of anti-apoptotic pathways of survival in ischemia-reperfused rat heart

Remifentanil is a commonly used opioid in anesthesia with cardioprotective effect in ischemia-reperfused (I/R) heart. We evaluated the influence of remifentanil on myocardial infarct size and expressions of proteins involved in apoptosis in I/R rat heart following various time protocols of remifentanil administration. Artificially ventilated anesthetized Sprague-Dawley rats were subjected to a 30 min of left anterior descending coronary artery occlusion followed by 2 h of reperfusion. Rats were randomly assigned to one of five groups; Sham, I/R only, remifentanil preconditioning, postconditioning and continuous infusion group. Myocardial infarct size, the phosphorylation of ERK1/2, Bcl2, Bax and cytochrome c and the expression of genes influencing Ca2+ homeostasis were assessed. In remifentanil-administered rat hearts, regardless of the timing and duration of administration, infarct size was consistently reduced compared to I/R only rats. Remifentanil improved expression of ERK1/2 and anti-apoptotic protein Bcl2, and expression of sarcoplasmic reticulum genes which were significantly reduced in the I/R rats only. Remifentanil reduced expression of pro-apoptotic protein, Bax and cytochrome c. These suggested that remifentanil produced cardioprotective effect by preserving the expression of proteins involved in anti-apoptotic pathways, and the expression of sarcoplasmic reticulum genes in I/R rat heart, regardless of the timing of administration.ope