Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study.

BACKGROUND: Receiving an allogeneic transfusion may be an independent predictor of mortality for patients undergoing cardiac surgery. Furthermore, these patients utilize 15% of all donated blood in the UK. In our unit, 80% of patients undergoing complex non-coronary cardiac surgery requiring cardiopulmonary bypass (CPB) receive an allogeneic transfusion. Activated recombinant FVII (rFVIIa) may be effective in reducing this need for transfusion. METHODS: Twenty patients undergoing complex cardiac surgery were randomized to receive rFVIIa or placebo after CPB and reversal of heparin. RESULTS: Two patients in the rFVIIa group received 13 units of allogeneic red cells and coagulation products compared with eight patients receiving 105 units of allogeneic red cells and coagulation products in the placebo group (relative risk of any transfusion 0.26; confidence interval 0.07-0.9; P=0.037). The groups did not differ for adverse events. CONCLUSION: Despite major limitations (underpowered study and prone to type I error), we have shown that rFVIIa significantly reduces the need for allogeneic transfusion in complex non-coronary cardiac surgery without causing adverse events.

Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage.

BACKGROUND: The transfusion of allogeneic red blood cells and allogeneic coagulation products is associated with risk to the patient and the depletion of an increasingly scarce resource. This prospective, randomized, double-blind, placebo-controlled trial investigated practices to avoid transfusion in patients undergoing first-time cardiac surgery. METHODS: Patients were randomized to one of three treatment groups: an aprotinin group, a tranexamic acid group, and a control group receiving normal saline. Intra-operative cell salvage was used for all patients. The primary outcomes were the number of patients exposed to allogeneic red blood cells, allogeneic coagulation products or any allogeneic transfusion (allogeneic red blood cells and/or allogeneic coagulation products). RESULTS: Patients were 2.5 times more likely to receive any allogeneic transfusion in the tranexamic group than in the aprotinin group (21 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with tranexamic acid was 0.43 (95% confidence interval 0.21-0.86; P=0.019). Patients in the control group were four times more likely to receive any allogeneic transfusion when compared with the aprotinin group (37 patients out of 60 compared with nine out of 60, respectively). The relative risk of any allogeneic transfusion comparing aprotinin with control was 0.24 (95% confidence interval 0.13-0.46; P<0.001). CONCLUSIONS: When used in addition to intra-operative cell salvage, aprotinin is the most efficacious pharmacological therapy for reducing patient exposure to any allogeneic transfusion during first-time cardiac surgery.

Myocardial oxygen consumption during dobutamine infusion in endotoxemic pigs.

PURPOSE: Dobutamine infusion is used to increase whole-body oxygen delivery in septic patients to satisfy unmet oxygen demand of hypoxic tissues. However, dobutamine infusion also increases myocardial work and myocardial oxygen consumption. Our goal was to determine the importance of this effect as a fraction of the increase in whole-body oxygen consumption, in a porcine model of septic shock. MATERIALS AND METHODS: Four hours after a 50 microg/kg infusion of Escherichia coli endotoxin (0111: B4, Sigma) in eight anesthetized pigs, whole-body oxygen delivery and myocardial oxygen delivery and consumption were calculated from blood flow and arterial and venous oxygen content measurements. We directly measured whole-body oxygen consumption by analysis of inhaled and exhaled gases using a metabolic cart. Then dobutamine 10 and 20 microg/kg/min was infused and measurements were repeated. RESULTS: Dobutamine infusion increased whole-body oxygen delivery but did not increase metabolic cart measured whole-body oxygen consumption. Dobutamine infusion of 10 and 20 microg/kg/min increased myocardial oxygen consumption by 7.0 +/- 0.6 (80 +/-10%) and 12.0 +/- 2.0 mL O2/min (142 +/- 30%), respectively (P < .01). CONCLUSIONS: In this porcine model of sepsis, dobutamine infusion significantly increases myocardial oxygen consumption. Because whole-body oxygen consumption does not change, dobutamine infusion may fail to increase and may decrease oxygen consumption by other organs.

Platelet-activating factor antagonism improves ventricular contractility in endotoxemia.

OBJECTIVES: Endotoxin stimulates platelet-activating factor production and also causes a decrease in myocardial contractility within a few hours in animal models of sepsis. Platelet-activating factor by itself decreases left ventricular contractility. We investigated whether platelet-activating factor contributes substantially to the decrease in left ventricular contractility seen in sepsis. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Twenty-two juvenile, cross-bred pigs. INTERVENTIONS: Anesthetized pigs were pretreated with a platelet-activating factor receptor antagonist (L-659,989) or vehicle (control), and then treated with endotoxin or saline (control). Hemodynamics and left ventricular pressures (Millar catheter) and volumes (conductance catheter) were measured. Left ventricular contractility was assessed using the slope, or maximum elastance (Emax), of the end-systolic pressure-volume relationship. MEASUREMENTS AND MAIN RESULTS: In the control/endotoxin group, 4 hrs after endotoxin administration, Emax had decreased by 41 +/- 4% (p < .05) and mean arterial pressure had decreased by 32 +/- 3% (p < .05). In the L-659,989/endotoxin group, the decreases in Emax (26 +/- 2%, p < .05) and mean arterial pressure (16 +/- 7%) were significantly attenuated compared with the control/endotoxin group (p < .05). CONCLUSIONS: We conclude that platelet-activating factor plays a modest but statistically significant role in the early decrease in left ventricular contractility after endotoxin administration. Inhibition of platelet-activating factor during sepsis might be beneficial for left ventricular mechanics and hemodynamics.

Nitric oxide synthase inhibition partially prevents decreased LV contractility during endotoxemia.

Decreased contractility of myocytes after cytokine exposure can be prevented by nitric oxide synthase inhibition. Whether this is true in an intact animal model of sepsis is unknown. Anesthetized pigs were pretreated with saline or a nitric oxide synthase inhibitor, N omega-nitro-L-arginine, and then treated with saline or endotoxin. We measured hemodynamics and left ventricular pressures (Millar catheter) and volumes (conductance catheter). Left ventricular contractility was assessed using the slope (E(max)) of the end-systolic pressure-volume relationship. Four hours after endotoxin infusion, E(max) had decreased by 44 +/- 5% (P < 0.05) and mean arterial pressure had decreased by 30 +/- 10% (P < 0.05). Pretreatment with N omega-nitro-L-arginine significantly reduced the decrease in E(max) to 28 +/- 3% (P < 0.05) and prevented the decrease in mean arterial pressure. However, it also raised pulmonary arterial pressure. We conclude that nitric oxide contributes to the early decrease in left ventricular contractility after endotoxin in the intact animal. However, the vascular effects of nitric oxide synthase inhibition increase right and left ventricular afterloads, which were detrimental to cardiac function.

Decreased left ventricular contractility during porcine endotoxemia is not prevented by ibuprofen.

OBJECTIVE: We investigated whether ibuprofen could prevent early decrease in left ventricular contractility that occurs during porcine endotoxemia. DESIGN: Prospective, randomized, controlled animal study. SETTING: University research laboratory. SUBJECTS: Adolescent crossbred pigs (n = 28). INTERVENTIONS: Anesthetized pigs were instrumented to measure hemodynamics and left ventricular pressures (using a Millar catheter) and volumes (using a conductance catheter). Pigs were then treated in four groups, according to pretreatment using ibuprofen (15 mg/kg) or saline and subsequent treatment using endotoxin (0111:B4, 50 microg/kg) or saline. MEASUREMENTS AND MAIN RESULTS: Measurements of hemodynamics and left ventricular pressures and volumes were repeated after pretreatment with ibuprofen (or saline in controls), and at hourly intervals for 4 hrs after the start of endotoxin or control saline infusions. Left ventricular contractility was primarily assessed using the slope of the end-systolic pressure-volume relationship. Data were analyzed, using a repeated-measures analysis of variance. The slope of the end-systolic pressure-volume relationship was decreased at 4 hrs by 41 +/- 9% in the saline/endotoxin group (p < .05) and by 36 +/- 14% in the ibuprofen/endotoxin group (p < .05), so that ibuprofen pretreatment had no significant effect on the decrease in left ventricular contractility. Mean arterial pressure decreased in the saline/endotoxin group by 23 +/- 12% at 1 hr (p < .05) and by 35 +/- 12% (p < .05) at 4 hrs. Ibuprofen significantly reduced the decrease in mean arterial pressure (2 +/- 6% increased at 1 hr, and 17 +/- 12% decreased at 4 hrs, both p<.05 compared with saline/endotoxin). Cardiac output increased by 25% (p < .05) in the first hour, but then decreased to be slightly (NS) below baseline at 4 hrs in both endotoxin groups. Mean pulmonary arterial pressure was increased in the saline/endotoxin group by 154 +/- 52% (p < .05) at 30 mins and by 118 +/- 40% (p < .05) at 4 hrs. Ibuprofen prevented the very acute increase in pulmonary arterial pressure (increased by 11 +/- 33% at 30 mins, p < .05 compared with saline/endotoxin) and significantly reduced the pulmonary hypertension at 4 hrs (increased by 70 +/- 25%, p < .05 compared with both baseline and saline/endotoxin). CONCLUSIONS: We conclude that products of the cyclooxygenase pathway do not play a major role in the early decrease in left ventricular contractility after endotoxin. However, ibuprofen may have a role in reducing the other cardiovascular effects of sepsis.

Prolonged leukocyte transit time in coronary microcirculation of endotoxemic pigs.

We quantified the timing and extent of leukocyte retention by the coronary microcirculation in a pig model of hyperdynamic sepsis in three ways. First, the transmyocardial leukocyte gradient was determined as coronary blood flow (calibrated ultrasonic flow probe) multiplied by the difference between leukocyte counts in the aorta and coronary sinus. Measurements were taken at 1-min intervals for 30 min and then at 3-min intervals for 45 min in anesthetized pigs exposed to either endotoxin (50 micrograms/kg iv over 30 min) (n = 7) or vehicle (n = 7). Second, postmortem morphometric analysis was used to quantitate the number and location of retained myocardial leukocytes. Finally, myocardial capillary transit time of leukocytes was calculated from the above measures. In the endotoxin group 2.1 +/- 0.8 x 10(9) leukocytes/100 g wet wt were retained in the coronary circulation, primarily in capillaries. This resulted in 111 +/- 37 (P < 0.05) times as many leukocytes in the coronary microcirculation than predicted from the arterial leukocyte concentration. Myocardial capillary transit time of leukocytes was prolonged to 39.1 +/- 20.6 s (P < 0.05) in the endotoxin group versus 5.0 +/- 1.4 s in the control group. We conclude that, after endotoxin infusion in a pig model of hyperdynamic sepsis, myocardial leukocyte transit is slowed, leading to the retention of large numbers of leukocytes in the coronary microcirculation.

Anti-tumor necrosis factor-alpha prevents decreased ventricular contractility in endotoxemic pigs.

It is not known how the decrease in left ventricular contractility following endotoxin exposure is mediated, or whether this decrease is preventable by antibodies to tumor necrosis factor-alpha (TNF alpha). Four groups of six anesthetized and instrumented pigs were pretreated with ovine polyclonal antibody to human TNF alpha (anti-TNF alpha), nonspecific IgG, or saline, and then treated with either endotoxin or saline. We measured hemodynamics and left ventricular pressures (Millar catheter) and volumes (conductance catheter). Left ventricular contractility was assessed using the slope (Emax) of the end-systolic pressure-volume relationship. Four hours after the start of endotoxin infusion in the nonspecific IgG pretreated group, Emax had decreased by 44 +/- 6% (p < 0.05), mean arterial pressure had decreased from 115 +/- 7 mm Hg to 70 +/- 10 mm Hg (p < 0.05), and cardiac output was rapidly decreasing after an initial increase (p < 0.05). Anti-TNF alpha significantly reduced the decrease in Emax (11 +/- 9%, p < 0.05), and the systemic hypotension (108 +/- 15 mm Hg to 99 +/- 6 mm Hg, p < 0.05), at 4 h, and prevented the late decrease in cardiac output. This suggests that TNF alpha is an important early mediator in sepsis leading to decreased left ventricular contractility.

Amrinone increases ventricular contractility and diastolic compliance in endotoxemia.

Systolic and diastolic dysfunction occur during human septic shock, and sensitivity to beta-adrenergic agents is reduced. We sought to determine whether amrinone, an inotropic agent independent of beta-receptors, increases left-ventricular contractility or diastolic compliance after endotoxin infusion. We measured left-ventricular volume (using a conductance catheter) and pressure (using a Millar catheter) before and after administering amrinone (4.5 mg/kg i.v., then 10 micrograms/kg/min) to six endotoxemic and seven control pigs. The slope of the end-systolic pressure-volume relationship, Ees, was used as the primary measure of contractility. Diastolic stiffness was characterized using stiffness parameters taken from pressure-volume relationships (k) and from pressure-volume strain relationships. Amrinone increased Ees from a median of 10.4 mm Hg/ml (interquartile range, 7.2 to 12.3) to 16.4 (13.7 to 18.6) (p < 0.05) in the endotoxin group (p < 0.05). Amrinone decreased diastolic stiffness (k) in the endotoxin group by 35 +/- 18% (p < 0.05). Amrinone did not significantly change Ees or k in the control group. Mean arterial pressure decreased after endotoxin infusion from 117 +/- 23 mm Hg to 76.5 +/- 14.9 mm Hg (p < 0.05), and decreased further after amrinone to 62.0 +/- 14.8 mm Hg (p < 0.05). We conclude that in this model of sepsis, amrinone may beneficially increase systolic contractility and diastolic compliance, but may dangerously decrease an already low mean arterial pressure.

Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs.

Why the myocardial oxygen extraction ratio (ERm) is decreased during septic shock in humans is unknown. Therefore, we calculated ERm in 15 anesthetized pigs by measuring arterial and coronary venous oxygen content. We measured myocardial lactate flux, myocardial contractility, and global myocardial blood flow and its distribution. After baseline measurements, animals received either saline (n = 6) or 50 micrograms/kg of endotoxin (n = 9). Measurements were repeated for 4 h. After endotoxin, ERm decreased from 67 +/- 12% at baseline to 36 +/- 10% (P < 0.01) at 1 h and 54 +/- 10% (P < 0.05) at 4 h, associated with an increased myocardial blood flow that was heterogeneous. Neither myocardial oxygen nor lactate consumption decreased in the endotoxin group, and changes in left ventricular contractility were not correlated with changes in ERm. We conclude that the decrease in ERm after endotoxin infusion is due to both increased blood flow and mismatching between myocardial oxygen delivery and demand. Impaired myocardial oxygen extraction capacity during sepsis did not cause global myocardial tissue hypoxia.

Functional characteristics of pediatric veno-venous hemofiltration.

OBJECTIVE: To evaluate the functional characteristics of continuous veno-venous hemofiltration in a pediatric size animal model. DESIGN: Prospective trial. SETTING: Animal laboratory at a large university-affiliated medical center. SUBJECTS: Four-week old lambs (weight 12.2 +/- 1.3 kg). INTERVENTIONS: Veno-venous hemofiltration was performed in anesthetized lambs (n = 5, 12.2 +/- 1.3 kg) using a standard pediatric hemofilter and pumped blood and ultrafiltrate. We compared postdilution, predilution, and hemofiltration with counterflow dialysis. MEASUREMENTS AND MAIN RESULTS: At net ultrafiltrate flows of 200, 400, and 600 mL/hr, we measured system pressures and urea clearance. Stable blood flow could reproducibly be achieved up to 140 mL/min (10 mL/kg/min); at higher flow demand, tubing collapse occurred. At blood flow rates of 5 to 10 mL/kg/min, ultrafiltrate flow of 1 mL/kg/min would create negative filter compartment pressure but consistently less negative than -500 mm Hg. During postdilution, predilution, and counterflow dialysis, urea clearance was virtually equal to ultrafiltrate flow. There was no increase in urea clearance when adding predilution or dialysis to basic postdilution. CONCLUSIONS: Veno-venous hemofiltration, using small filters and circuits in a pediatric size animal, can achieve stable blood flow up to 10 mL/kg/min. At this flow, ultrafiltrate flow of 1 mL/kg/min can produce a urea clearance of 1 mL/kg/min while keeping filter compartment pressure above maximal recommended negative pressures. Addition of dialysis in this nonuremic model did not increase urea clearance.

Bicarbonate does not increase left ventricular contractility during L-lactic acidemia in pigs.

Lactic acidosis decreases left ventricular contractility, but whether bicarbonate increases left ventricular contractility during lactic acidosis in vivo is controversial. Therefore, we measured hemodynamics and left ventricular mechanics before and after bicarbonate administration during L-lactic acid infusion in 15 anesthetized pigs. The pigs were beta-blocked and atrially paced to minimize indirect effects of acidosis on contractility. We measured mean arterial pressure, left ventricular end-diastolic pressure, thermodilution cardiac output, left ventricular pressure (Miller catheter), and left ventricular volume (three orthogonal pairs of ultrasonic crystals). Left ventricular contractility was assessed primarily using the slope (Emax) of the end-systolic pressure-volume relationship. While PCO2 was kept constant, 0.2 M L-lactic acid was infused, which reduced arterial pH to 7.05 +/- 0.06. Animals were then randomized to receive either 1 M NaHCO3 (n = 8), which increased pH to 7.45 +/- 0.11, or an equivalent amount of 1 M NaCl (n = 7). Bicarbonate decreased mean arterial pressure (105 +/- 20 to 95 +/- 39 mm Hg, p < 0.05) but did not increase cardiac output. These effects were not significantly different from the effects of saline. Bicarbonate did not significantly increase Emax (4.2 +/- 0.8 to 4.9 +/- 0.8 mm Hg/ml) and was indistinguishable from saline (5.0 +/- 0.7 to 5.2 +/- 0.7 mm Hg/ml). We conclude that bicarbonate infusion does not directly increase left ventricular contractility during lactic acidemia in pigs within this pH range.

Operating characteristics of pediatric continuous arteriovenous hemofiltration in an animal model.

Continuous arteriovenous hemofiltration (CAVH) is an increasingly popular technique in the care of critically ill children. The operating characteristics of the available circuits are largely unknown. Prior to introducing CAVH into our pediatric intensive care unit, we investigated the performance of three CAVH circuits: CAVH with postfilter dilution, CAVH with prefilter dilution (CAVHpre) and CAVH with dialysis counterflow. Using a neonatal lamb model, we measured filter blood flow (QB), ultrafiltrate rate (QU), arterial, venous and ultrafiltrate compartment pressures, oncotic pressure, plus urea levels in blood and ultrafiltrate fluid for the three CAVH circuit designs. Transmembrane pressure and urea clearance were calculated for various values of QB after varying a clamp on the arterial side of the circuit. The major finding, applicable to all circuits, was the wide variability of QB. Constant attention was required in order to obtain a consistent QB. Fluid clearance was effective with all three circuits. Urea clearance averaged 5-10 ml/min and was principally dependent on QU and independent of QB. The addition of dialysis counterflow did not increase urea clearance. The most convenient circuit we tested was CAVHpre, but the problem of unstable QB is common to all unpumped arteriovenous filtrate circuits. It is a major limiting factor in the practical application of this technology to critically ill children.