High Spinal Anesthesia Enhances Anti-Inflammatory Responses in Patients Undergoing Coronary Artery Bypass Graft Surgery and Aortic Valve Replacement: Randomized Pilot Study.

BACKGROUND: Cardiac surgery induces many physiologic changes including major inflammatory and sympathetic nervous system responses. Here, we conducted a single-centre pilot study to generate hypotheses on the potential immune impact of adding high spinal anaesthesia to general anaesthesia during cardiac surgery in adults. We hypothesized that this strategy, previously shown to blunt the sympathetic response and improve pain management, could reduce the undesirable systemic inflammatory responses caused by cardiac surgery. METHODS: This prospective randomized unblinded pilot study was conducted on 14 patients undergoing cardiac surgery for coronary artery bypass grafting and/or aortic valve replacement secondary to severe aortic stenosis. The primary outcome measures examined longitudinally were serum pro-inflammatory (IL-6, IL-1b, CCL2), anti-inflammatory (IL-10, TNF-RII, IL-1Ra), acute phase protein (CRP, PTX3) and cardiovascular risk (sST2) biomarkers. RESULTS: The kinetics of pro- and anti-inflammatory biomarker was determined following surgery. All pro-inflammatory and acute phase reactant biomarker responses induced by surgical stress were indistinguishable in intensity and duration between control groups and those who also received high spinal anaesthesia. Conversely, IL-10 levels were markedly elevated in both intensity and duration in the group receiving high spinal anesthesia (p = 0.005). CONCLUSIONS: This hypothesis generating pilot study suggests that high spinal anesthesia can alter the net inflammatory response that results from cardiac surgery. In appropriately selected populations, this may add incremental benefit by dampening the net systemic inflammatory response during the week following surgery. Larger population studies, powered to assess immune, physiologic and clinical outcomes in both acute and longer term settings, will be required to better assess potential benefits of incorporating high spinal anesthesia. TRIAL REGISTRATION: ClinicalTrials.gov NCT00348920.

Assessment of donor heart viability during ex vivo heart perfusion.

Ex vivo heart perfusion (EVHP) may facilitate resuscitation of discarded donor hearts and expand the donor pool; however, a reliable means of demonstrating organ viability prior to transplantation is required. Therefore, we sought to identify metabolic and functional parameters that predict myocardial performance during EVHP. To evaluate the parameters over a broad spectrum of organ function, we obtained hearts from 9 normal pigs and 37 donation after circulatory death pigs and perfused them ex vivo. Functional parameters obtained from a left ventricular conductance catheter, oxygen consumption, coronary vascular resistance, and lactate concentration were measured, and linear regression analyses were performed to identify which parameters best correlated with myocardial performance (cardiac index: mL·min(-1)·g(-1)). Functional parameters exhibited excellent correlation with myocardial performance and demonstrated high sensitivity and specificity for identifying hearts at risk of poor post-transplant function (ejection fraction: R(2) = 0.80, sensitivity = 1.00, specificity = 0.85; stroke work: R(2) = 0.76, sensitivity = 1.00, specificity = 0.77; minimum dP/dt: R(2) = 0.74, sensitivity = 1.00, specificity = 0.54; tau: R(2) = 0.51, sensitivity = 1.00, specificity = 0.92), whereas metabolic parameters were limited in their ability to predict myocardial performance (oxygen consumption: R(2) = 0.28; coronary vascular resistance: R(2) = 0.20; lactate concentration: R(2) = 0.02). We concluded that evaluation of functional parameters provides the best assessment of myocardial performance during EVHP, which highlights the need for an EVHP device capable of assessing the donor heart in a physiologic working mode.

A whole blood-based perfusate provides superior preservation of myocardial function during ex vivo heart perfusion.

BACKGROUND: Ex vivo heart perfusion (EVHP) provides the opportunity to resuscitate unused donor organs and facilitates assessments of myocardial function that are required to demonstrate organ viability before transplantation. We sought to evaluate the effect of different oxygen carriers on the preservation of myocardial function during EVHP. METHODS: Twenty-seven pig hearts were perfused ex vivo in a normothermic beating state for 6 hours and transitioned into working mode for assessments after 1 (T1), 3 (T3), and 5 (T5) hours. Hearts were allocated to 4 groups according to the perfusate composition. Red blood cell concentrate (RBC, n = 6), whole blood (RBC+Plasma, n = 6), an acellular hemoglobin-based oxygen carrier (HBOC, n = 8), or HBOC plus plasma (HBOC+Plasma, n = 7) were added to STEEN Solution (XVIVO Perfusion, Goteborg, Sweden) to achieve a perfusate hemoglobin concentration of 40 g/liter. RESULTS: The perfusate composition affected the preservation of systolic (T5 dP/dtmax: RBC+Plasma = 903 ± 99, RBC = 771 ± 77, HBOC+Plasma = 691 ± 82, HBOC = 563 ± 52 mm Hg/sec; p = 0.047) and diastolic (T5 dP/dtmin: RBC+Plasma = -574 ± 48, RBC = -492 ± 63, HBOC+Plasma = -326 ± 32, HBOC = -268 ± 22 mm Hg/sec; p < 0.001) function, and the development of myocardial edema (weight gain: RBC+Plasma = 6.6 ± 0.9, RBC = 6.6 ± 1.2, HBOC+Plasma = 9.8 ± 1.7, HBOC = 16.3 ± 1.9 g/hour; p < 0.001) during EVHP. RBC+Plasma hearts exhibited less histologic evidence of myocyte damage (injury score: RBC+Plasma = 0.0 ± 0.0, RBC = 0.8 ± 0.3, HBOC+Plasma = 2.6 ± 0.2, HBOC = 1.75 ± 0.4; p < 0.001) and less troponin-I release (troponin-I fold-change T1-T5: RBC+Plasma = 7.0 ± 1.7, RBC = 13.1 ± 1.6, HBOC+Plasma = 20.5 ± 1.1, HBOC = 16.7 ± 5.8; p < 0.001). Oxidative stress was minimized by the addition of plasma to RBC and HBOC hearts (oxidized phosphatidylcholine compound fold-change T1-T5: RBC+Plasma = 1.83 ± 0.20 vs RBC = 2.31 ± 0.20, p < 0.001; HBOC+Plasma = 1.23 ± 0.17 vs HBOC = 2.80 ± 0.28, p < 0.001). CONCLUSIONS: A whole blood-based perfusate (RBC+Plasma) minimizes injury and provides superior preservation of myocardial function during EVHP. The beneficial effect of plasma on the preservation of myocardial function requires further investigation.

Off-label use of recombinant activated factor VII in surgical and non-surgical patients at 16 Canadian hospitals from 2007 to 2010 (Canadian Registry Report).

PURPOSE: Recombinant activated factor VII (rFVIIa) is a pro-hemostatic drug that is approved for treatment of bleeding in hemophilia patients, but it is frequently used off-label in non-hemophiliacs. The purpose of this study was to determine if the off-label use of rFVIIa is expanding and whether this poses a net harm to patients. METHODS: For this historical cohort study, data were collected on all non-hemophilia patients who received rFVIIa from 2007 to 2010 at 16 Canadian centres, and the pattern of use was examined. Logistic regression was used to determine the prognostic importance of severity of bleeding and the presence of an rFVIIa dose-effect relationship with major adverse events. RESULTS: One thousand three hundred seventy-eight patients received rFVIIa off-label, and 987 (72%) of these patients underwent cardiac surgery. The median [interquartile range] dose was 57 [36-85] µg·kg(-1). Usage increased from 2007 to 2008 (n = 341 and 380, respectively) but decreased in 2009 and 2010 (n = 350 and 307, respectively). Dose of rFVIIa and bleeding severity were associated with measured adverse events (P < 0.05). After adjusting for bleeding severity, dose was not associated with any of the adverse events. CONCLUSIONS: The off-label use of rFVIIa in Canada remains stable. Since severity of bleeding is prognostically important, the benefits of rapidly gaining control of bleeding that is non-responsive to conventional therapies may at times warrant the use of potent hemostatic drugs with established risk profiles, such as rFVIIa.

A cardioprotective preservation strategy employing ex vivo heart perfusion facilitates successful transplant of donor hearts after cardiocirculatory death.

BACKGROUND: Ex vivo heart perfusion (EVHP) has been proposed as a means to facilitate the resuscitation of donor hearts after cardiocirculatory death (DCD) and increase the donor pool. However, the current approach to clinical EVHP may exacerbate myocardial injury and impair function after transplant. Therefore, we sought to determine if a cardioprotective EVHP strategy that eliminates myocardial exposure to hypothermic hyperkalemia cardioplegia and minimizes cold ischemia could facilitate successful DCD heart transplantation. METHODS: Anesthetized pigs sustained a hypoxic cardiac arrest and a 15-minute warm ischemic standoff period. Strategy 1 hearts (S1, n = 9) underwent initial reperfusion with a cold hyperkalemic cardioplegia, normothermic EVHP, and transplantation after a cold hyperkalemic cardioplegic arrest (current EVHP strategy). Strategy 2 hearts (S2, n = 8) underwent initial reperfusion with a tepid adenosine-lidocaine cardioplegia, normothermic EVHP, and transplantation with continuous myocardial perfusion (cardioprotective EVHP strategy). RESULTS: At completion of EVHP, S2 hearts exhibited less weight gain (9.7 ± 6.7 [S2] vs 21.2 ± 6.7 [S1] g/hour, p = 0.008) and less troponin-I release into the coronary sinus effluent (4.2 ± 1.3 [S2] vs 6.3 ± 1.5 [S1] ng/ml; p = 0.014). Mass spectrometry analysis of oxidized pleural in post-transplant myocardium revealed less oxidative stress in S2 hearts. At 30 minutes after wean from cardiopulmonary bypass, post-transplant systolic (pre-load recruitable stroke work: 33.5 ± 1.3 [S2] vs 19.7 ± 10.9 [S1], p = 0.043) and diastolic (isovolumic relaxation constant: 42.9 ± 6.7 [S2] vs 65.2 ± 21.1 [S1], p = 0.020) function were superior in S2 hearts. CONCLUSION: In this experimental model of DCD, an EVHP strategy using initial reperfusion with a tepid adenosine-lidocaine cardioplegia and continuous myocardial perfusion minimizes myocardial injury and improves short-term post-transplant function compared with the current EVHP strategy using cold hyperkalemic cardioplegia before organ procurement and transplantation.

The effect of total spinal anesthesia on cardiac function in a large animal model of brain death.

Brain death (BD) causes cardiac dysfunction in organ donors, attributable to the catecholamine storm that occurs with raised intracerebral pressure (ICP). However the direct contribution of the spinal sympathetics has not been well described. We examined the effect of total spinal anesthesia (TSA) on cardiac function in a large animal model of BD. Eighteen pigs were allocated to 3 experimental groups: Group 1, the saline-treated control group; Group 2, TSA administered prior to BD; and Group 3, TSA administered 30 min after BD. Inflation of an intracerebral balloon-tipped catheter was used to induce BD. Ventricular function was assessed using a pressure-volume loop catheter and magnetic resonance imaging. Serum catecholamine levels were assessed with high performance liquid chromatography. Inflation of the intracerebral balloon-tipped catheter was associated with a dramatic rise in heart rate and blood pressure, along with increased concentrations of serum epinephrine and norepinephrine. This phenomenon was not observed in Group 2. In Group 1, there was a significant decline in contractility, whereas groups 2 and 3 saw no change. Group 2 had greater contractile reserve than groups 1 and 3. Our data demonstrate the central role of spinal sympathetics in the hemodynamic response to raised ICP. Further work is required to determine the utility of TSA in reversing cardiac dysfunction in BD donors.

Quantitative assessment of cardiac output and left ventricular function by noninvasive phase-contrast and cine MRI: validation study with invasive pressure-volume loop analysis in a swine model.

PURPOSE: To validate noninvasive cardiac output measurements of phase-contrast magnetic resonance imaging (PC-MRI) and cine MRI using an invasive pressure-volume (PV) loop technique on a swine model. MATERIALS AND METHODS: We compared three methods for evaluating cardiac function at rest and under pharmaceutical low-dose inotropic infusion conditions: 1) phase-contrast MRI, 2) cine MRI, and 3) PV loop relationship. These measurements were made in 14 domestic pigs under rest conditions. Identical MRI acquisitions and PV loop analysis were performed on six pigs from the same group that received an infusion of dobutamine 2.5 µg/kg/min. Cardiac outputs from all measurements were analyzed and compared using linear regression and Bland-Altman analysis. RESULTS: Noninvasive PC-MRI and cine MRI did not show any significant differences compared to an invasive PV loop technique for measurement of cardiac output under both rest (PC-MRI, cine MRI, and PV loop, 3.17 ± 0.45, 3.18 ± 0.61, 3.45 ± 0.41 L/min, respectively) and pharmaceutical low-dose inotropic infusion conditions (PC-MRI, cine MRI, and PV loop, 4.78 ± 0.53, 4.7 ± 0.6, 4.96 ± 0.48 L/min, respectively). Statistical analysis showed good agreement of cardiac output measurements at rest (R(2) = 0.83) and under low-dose inotropic infusion conditions (R(2) = 0.74) using PC-MRI and PV loop techniques. Cardiac output measurement using cine MRI and PV loop techniques also showed good agreement at rest (R(2) = 0.85) and under low-dose inotropic infusion conditions (R(2) = 0.76). Furthermore, cardiac outputs determined with the three modalities showed good agreement over a wide range of heart rates (90-180 bpm). CONCLUSION: MRI can provide a reliable, noninvasive measurement of cardiac output that can be carried out without the complications that are inherent with current invasive procedures.

Total spinal anesthesia for cardiac surgery: does it make a difference in patient outcomes?

BACKGROUND: Heart disease is a major cause of morbidity and mortality. While cardiac surgery is a viable treatment option, it is a potent physiological stressor. The surgical stress response may result in patient decompensation and negative patient outcomes. The goal of a novel anesthetic approach, which combines high spinal anesthesia with intrathecal morphine and general anesthesia (TSA), is to attenuate this stress response. PURPOSE: The primary purpose of this pilot study (n = 70) was to describe and compare the outcomes of TSA cardiac surgery with a matched control sample of patients who received the "standard general anesthetic" (GA). METHOD: A retrospective, descriptive, correlational design was used for a matched pair total sample of (n = 70). Following ethics approval, patient consents were obtained and chart review data collection was completed. FINDINGS: TSA patients were more likely to be extubated in the operating room (p < 0.0001) and also had significantly shorter overall duration of endotracheal intubation (p < 0.0008). During the initial 24 hours after surgery, the TSA group received significantly less morphine (p < 0.0001). The mean difference in postoperative hospital length of stay did not reach statistical significance. However, on average, the TSA group was discharged three days earlier than the GA group. CONCLUSION: This evidence highlights the clinical nursing relevance of the type of anesthesia on postoperative care and outcomes. The knowledge gained from these findings will help to enable the multidisciplinary critical care team to anticipate TSA patient outcomes and to facilitate the development of appropriate and effective evidence-based, patient-focused plans of care. This pilot study establishes sound rationale for subsequent larger prospective cohort research of the TSA patient population.

Comprehensive Canadian review of the off-label use of recombinant activated factor VII in cardiac surgery.

BACKGROUND: This observational study sought to identify the off-label use pattern of recombinant activated factor VII (rFVIIa) in cardiac surgery and to identify predictors of its effectiveness and risk. METHODS AND RESULTS: At 18 Canadian centers, 522 nonhemophiliac cardiac surgical patients received rFVIIa during the period 2003 through 2006; data were available, and retrospectively collected, on 503 patients. The median (quartile 1, quartile 3) units of red blood cells transfused from surgery to therapy and in the 24 hours after therapy were 8 (5, 12) and 2 (1, 5), respectively (P<0.0001). Mortality rate was 32%, and mortality or major morbidity rate was 44%. These rates were within expected ranges (mortality, 27% to 35%; mortality or morbidity, 39% to 48%), which were calculated with a separate cohort of cardiac surgical patients who did not receive rFVIIa used as reference. Independent predictors of complications included instability before therapy (multiple inotropes or intra-aortic balloon pump) and increasing red blood cell units transfused before and after therapy. Variables independently associated with nonresponse included abnormal coagulation parameters and >15 red blood cell units transfused before therapy. CONCLUSIONS: In Canada, rFVIIa is used primarily when standard interventions have failed to control bleeding. In this setting, rFVIIa is associated with reduced blood product transfusions and, after risk adjustment, does not appear to be associated with increased or decreased complication rates. The effectiveness of the drug may be enhanced if it is given early in the course of refractory blood loss in the setting of adequate amounts of circulating coagulation factors.

Roadblock to recovery: the surgical stress response.

Inadequately managed post-operative pain and the resulting surgical stress response (SSR) negatively affect patient outcomes. Critical care nurses need to understand that adequate pain management is critical to enabling patient recovery. A review of the physiology and pathophysiology of the SSR provides concrete evidence to substantiate the need for critical care nurses to prioritize nursing care that focuses on the prevention, early detection, and management of pain and the surgical stress response. Critical care nurses equipped with this evidence are capable of improving patient outcomes.

Low-dose intrathecal morphine does not delay early extubation after cardiac surgery.

PURPOSE: This study was designed to examine the efficacy of low-dose intrathecal morphine (ITM) on extubation times and pain control after cardiac surgery. METHODS: 43 patients undergoing elective cardiac surgery were enrolled in this prospective, randomized, double-blind placebo controlled trial. Patients were given a pre-induction dose of ITM (6 microg x kg(-1) per ideal body weight in 5 mL normal saline, group ITM) or 5 mL of intrathecal normal saline (group ITS). Anesthesia was induced with thiopental (3 mg x kg(-1)), sufentanil, midazolam and rocuronium. The total allowable doses of sufentanil and midazolam for the entire case were limited to 0.5 microg x kg(-1) and 0.045 mg x kg(-1) respectively. Anesthesia was maintained with isoflurane before and during cardiopulmonary bypass (CPB), and with propofol after CPB. In the postanesthesia care unit, patients received nurse-administered morphine followed by patient-controlled analgesia morphine. Serial visual analogue scale pain scores, morphine use, mini-mental state examinations and pulmonary function tests were measured for 48 hr. Patient satisfaction questionnaires were completed at the time of discharge. RESULTS: Mean times to extubation from the application of dressings were short and did not differ between groups (ITM = 41.4 +/- 33.0 min, ITS = 39.2 +/- 37.1 min). During the first 24 hr postoperatively, the ITM group had improved pain control and a lower iv morphine requirement than the control group, both at rest and during deep breathing. Both forced expiratory volume in one second and forced vital capacity were improved in the ITM group. There were no differences in spinal-related side effects or in the overall complication rates. Patient satisfaction was high in both groups. CONCLUSION: Low-dose ITM for cardiac surgery did not delay early extubation, but it improved postoperative analgesia and pulmonary function.

High spinal anesthesia for cardiac surgery: effects on beta-adrenergic receptor function, stress response, and hemodynamics.

BACKGROUND: This double-blind, randomized, controlled trial examined the effect of high-dose intrathecal bupivacaine in combination with general anesthesia on atrial beta-adrenergic receptor function, the stress response, and hemodynamics during coronary artery bypass graft surgery. METHODS: Thirty-eight patients were randomized to either control (n = 19) or intrathecal bupivacaine (ITB) groups (n = 19). Patients in the ITB group received 37.5 mg intrathecal hyperbaric bupivacaine before induction of general anesthesia. Control patients received an injection of local anesthetic into the skin and subcutaneous tissues (sham spinal). Comparisons were made between groups with respect to atrial receptor desensitization and down-regulation, in addition to circulating catecholamines and hemodynamics. RESULTS: In patients with cardiopulmonary bypass (CPB) times in excess of 1 h, the ITB group had significantly less atrial beta-receptor dysfunction, as measured by maximal isproteronol, 50% maximal isoproterenol, sodium fluoride-stimulated activity, and zinterol stimulation assays of adenylyl cyclase activity (P < or = 0.02) and beta-adrenergic receptor density (P = 0.02). Serum epinephrine, norepinephrine, and cortisol concentrations were significantly lower in the ITB group, independent of CPB times (P < 0.0001, P < 0.001, and P < 0.05, respectively). ITB patients had a higher cardiac index and a lower pulmonary vascular resistance index in the post-CPB time period (P < 0.01 and P < 0.05, respectively). In the pre-CPB period, mean arterial pressure and systemic vascular resistance index were significantly lower in the ITB group. CONCLUSIONS: High-dose intrathecal bupivacaine, when combined with general anesthesia, resulted in less beta-receptor dysfunction and a lower stress response during coronary artery bypass graft surgery.