Cytokine modulation of Na(+)-dependent glutamine transport across the brush border membrane of monolayers of human intestinal Caco-2 cells.

Previous studies have demonstrated that Na(+)-dependent brush border glutamine transport is diminished in septic patients. To examine the potential regulation of this decreased transport by endotoxin, cytokines, or glucocorticoids, the human intestinal Caco-2 cell line was studied in vitro. Na(+)-dependent glutamine transport across the apical brush border membrane was assayed in confluent monolayers of differentiated cells that were 10 days old. Uptake of 50 microM glutamine was determined after a 12-hour incubation with varying doses (10 to 1000 U/mL) of tumor necrosis factor-alpha, interleukin-1, interleukin-6, interferon-gamma, and various combinations of these cytokines. Studies were also done in cells incubated with E. coli endotoxin (1 micrograms/mL) or dexamethasone (1 and 10 microM). Endotoxin, tumor necrosis factor, interleukin-1, and interleukin-6 alone and in combination did not significantly reduce Na(+)-dependent glutamine transport across the brush border of Caco-2 cells. Dexamethasone decreased glutamine transport by 20%, but this decrease was not apparent for 48 hours. Interferon consistently decreased glutamine transport by 30%; this was due to a reduction in carrier maximal transport velocity (3427 +/- 783 pmol/mg protein/minute in controls versus 2279 +/- 411 in interferon, p less than 0.05) rather than a change in Km (276 +/- 29 microM in controls versus 333 +/- 74 in interferon, p = not interferon + dexamethasone + tumor necrosis factor + interleukin-1 resulted in a 38% decrease in transport activity. Cytokines and glucocorticoids may work independently and synergistically in regulating Na(+)-dependent brush border glutamine transport in human intestinal cells. Whether these signal molecules play a central role in the cause of the diminished brush border glutamine transport that occurs in septic patients requires further study.     

Systemic steroid pretreatment improves cerebral protection after circulatory arrest.

BACKGROUND: This study evaluates whether systemic steroid pretreatment enhances neuroprotection during deep hypothermic circulatory arrest (DHCA) compared with steroid in cardiopulmonary bypass (CPB) prime. METHODS: Four-week-old piglets randomly placed into two groups (n = 5 per group) were given methylprednisolone (30 mg/kg) into the pump prime (group PP), or pretreated intravenously 4 hours before CPB (group PT). All animals underwent 100 minutes of DHCA (15 degrees C), were weaned off CPB, and were sacrificed 6 hours later. Postoperative changes in body weight, bioimpedance, and colloid oncotic pressure (COP) were measured. Cerebral trypan blue content, immunohistochemical evaluation of transforming growth factor-beta1 (TGF-beta1) expression, and caspase-3 activity were performed. RESULTS: Percentage weight gain (group PP 25.0% +/- 10.4% versus group PT 12.5% +/- 4.0%; p = 0.036), and percentage decrease in bioimpedance (PP 37.2% +/- 14.5% versus PT 15.6% +/- 7.9%; p = 0.019) were significantly lower, whereas postoperative COP was significantly higher in group PT versus group PP (PT 15.3 +/- 1.8 mm Hg versus PP 11.6 +/- 0.8 mm Hg; p = 0.003). Cerebral trypan blue (ng/g dry tissue) was significantly lower in group PT (PT 5.6 x 10(-3) +/- 1.1 x 10(-3) versus PP 9.1 x 10(-3) +/- 5.7 x 10(-4); p = 0.001). Increased TGF-beta1 expression and decreased caspase-3 activity were shown in group PT. CONCLUSIONS: Systemic steroid pretreatment significantly reduced total body edema and cerebral vascular leak and was associated with better immunohistochemical indices of neuroprotection after DHCA.     

Effect of polymer coating (poly 2-methoxyethylacrylate) of the oxygenator on hemostatic markers during cardiopulmonary bypass in children

OBJECTIVE: Heparin and other oxygenator coatings have been used in attempts to reduce hemostatic activation during cardiopulmonary bypass (CPB). This study evaluated whether an oxygenator coated with poly 2-methoxyethylacrylate (PMEA) (X-coating; Terumo Corporation, Tokyo, Japan) would cause less activation of coagulation and fibrinolytic systems during CPB in children than a noncoated oxygenator. DESIGN: Observational study. SETTING: University-affiliated children's hospital. PATIENTS: Twenty-six patients, 3 months to 5 years old, who underwent congenital heart surgery for repair of a ventricular septal defect, atrial septal defect, or both. INTERVENTIONS: Patients were divided into 2 age-matched groups based on the type of oxygenator used: a noncoated oxygenator (group NC) versus a PMEA-coated oxygenator (group C). MEASUREMENTS AND MAIN RESULTS: Blood samples for coagulation and fibrinolytic markers were compared before, during, and after CPB. Despite increases in thrombin generation markers (F1.2 and TAT) at certain times during CPB in group C compared to group NC, a comparison over all times during CPB were not statistically different between groups. Overall D-dimer concentrations during CPB were elevated in group C compared to group NC (p = 0.02). Active tPA and active PAI-1 were not different between groups during or after CPB. Group C had higher platelet counts (181,000 +/- 29,000) during CPB than group NC (155,000 +/- 57,000, p = 0.04) but not postoperatively. Twelve hours postoperatively, chest tube outputs were 8.8 +/- 3 mL/kg in group C and 19.1 +/- 12 mL/kg in group NC (p = 0.003). The corresponding outputs 24 hours after surgery were 12.4 +/- 3 mL/kg and 24 +/- 11 mL/kg, respectively (p = 0.005). CONCLUSIONS: Except for a somewhat higher platelet count during CPB, there was no indication that PMEA coating resulted in less activation of coagulation and fibrinolytic systems. The lower postoperative chest tube output observed after CPB with PMEA-coated oxygenators needs to be studied further.     

N-acetylcysteine reduces lung reperfusion injury after deep hypothermia and total circulatory arrest

OBJECTIVE: We hypothesized that the use of N-acetylcysteine would ameliorate the lung reperfusion injury observed after deep hypothermia and total circulatory arrest (DHTSA). METHODS: Experiments were carried out on 12 adult mongrel dogs of either sex weighing 25 to 30 kg. The animals were randomly divided into two groups of six animals each. All animals were cooled to an esophageal temperature of 15 degrees C during 30 minutes and underwent 60 minutes of DHTSA, followed by the reinstitution of cardiopulmonary bypass (CPB) and rewarming. Before rewarming, while 100 mL physiologic saline solution was added into the pump in group I, 50 mg/kg N-acetylcysteine(NAC) was given in group II. Heart rate, mean arterial pressure, pulmonary arterial pressure, left atrial pressure, central venous pressure, and cardiac output were recorded. To measure lung tissue malondialdehyde (MDA), water content and polymorphonuclear leukocytes (PMNs) count, lung tissue samples were taken before CPB and after weaning CPB. In addition, alveolar-arterial oxygen difference (AaDO(2))()for tissue oxygenation was calculated by obtaining arterial blood gas samples. Dynamic lung compliance (DLC) was measured before CPB and after CPB. RESULTS: MDA levels before CPB of 44.2 +/- 3.9 nmol/g tissue rose to 76.6 +/- 5.6 nmol/g tissue after weaning CPB in group I (p = 0.004). In group II also, the MDA levels increased from 43.5 +/- 4.2 to 57.4 +/- 5.6 nmol MDA/g tissue after weaning CPB (p = 0.006). The MDA increase in group II after CPB was found to be significantly lower than in group I (p = 0.006). The wet-to-dry lung weight ratio in the NAC group was 5.1 +/- 0.2, significantly less than in the control group (5.9 +/- 0.3), (p = 0.004). AaDO(2) significantly increased in the group I and II (p = 0.002 and p = 0.002, respectively); this elevation in group I was significant than in group II (p = 0.044). In histopathological examination, it was observed that neutrophil counts in the lung parenchyma rose significantly after CPB in both groups (p < 0.001). The increase in group I was significantly larger than group II (p < 0.001). CONCLUSIONS: Results represented in our study indicate that addition of NAC into the pump after DHTSA can reduce lung reperfusion injury.     

Effects of phentolamine on tissue perfusion in pediatric cardiac surgery

OBJECTIVE: To evaluate whether the deleterious effects of cardiopulmonary bypass (CPB) can be overcome by phentolamine-induced pharmacologic vasodilation in pediatric patients with congenital heart disease. DESIGN: Prospective, randomized, clinical study. SETTING: Single university hospital. PARTICIPANTS: Forty-three pediatric patients undergoing open cardiac surgery for repair of congenital heart disease. INTERVENTIONS: Patients were randomly allocated into two groups. Patients in group 1 (n = 22) received 0.2 mg/kg of phentolamine during the cooling and rewarming periods of CPB. Group 2 patients (n = 21) did not receive phentolamine. Temperature measurements (rectal [R], nasopharyngeal [N], and toe [P]) and serum lactate values were obtained before, during, and after CPB; systemic oxygen consumption was evaluated during CPB. MEASUREMENTS AND MAIN RESULTS: At the end of the CPB period and at the end of the operation, lactate values of group 1 (1.87+/-0.37 and 1.8+/-0.39 mmol/L, respectively) were significantly lower than values of group 2 (2.24+/-0.28 and 2.33+/-0.33 mmol/L; p < 0.05 and p < 0.05, respectively). At the beginning of the rewarming period N-R temperature gradients of group 1 (0.14 degrees C+/-0.92 degrees C) were lower than group 2 (-0.58 degrees C+/-1.84 degrees C) values (p < 0.05). Central-peripheral temperature gradients of group 1 obtained at the end of the CPB period (N-R = 2.18 degrees C+/-0.69 degrees C; N-P = 7.84 degrees C+/-1.54 degrees C; R-P = 5.66 degrees C+/-1.70 degrees C) were significantly lower than the values of group 2 (N-R = 2.80 degrees C+/-0.91 degrees C, N-P = 9.97 degrees C+/-2.02 degrees C; R-P = 7.18 degrees C+/-2.10 degrees C; p < 0.05; p < 0.001; p < 0.05). At the end of the operation values of group 1 (N-R = 0.48 degrees C+/-0.31 degrees C; N-P = 6.30 degrees C+/-1.23 degrees C; R-P = 5.82 degrees C+/-1.16 degrees C) were significantly lower than the values of group 2 (N-R = 0.94 degrees C+/-0.56 degrees C; N-P = 8.69 degrees C+/-0.28 degrees C; R-P = 7.75 degrees C+/-2.15 degrees C; p < 0.05; p < 0.001; p < 0.001). The systemic oxygen consumption values of group 1 were higher than group 2 (6.26+/-1.82 v 5.17+/-1.05 mL/min/kg; p < 0.05) after complete rewarming. Mean arterial pressure (MAP) values of group 1 (58.9+/-6.4 mmHg) were lower than group 2 (63.4+/-6.7 mmHg) at the period after CPB (p = 0.03). CONCLUSION: The results suggest that the use of phentolamine during CPB is associated with limited systemic anaerobic metabolism and more uniform body perfusion.     

Retrograde autologous priming: is it useful in elective on-pump coronary artery bypass surgery?

BACKGROUND: The effect of reduced cardiopulmonary bypass (CPB) prime volume by retrograde autologous priming (RAP) was studied. METHODS: Twenty patients undergoing elective coronary artery bypass grafting were randomized to either standard prime (SP) volume (1,602 +/- 202 mL crystalloid prime, n = 10) or RAP (395 +/- 150 mL). RAP was performed by draining crystalloid prime from the arterial and venous lines into a recirculation bag before CPB. Cardiac index, pulmonary vascular resistance index, systemic vascular resistance index, alveolar-arterial oxygen tension difference, pulmonary shunt fraction, extravascular lung water (EVLW), plasma colloid osmotic pressure (COP), crystalloid fluid balance, body weight, and clinical parameters were evaluated perioperatively. RESULTS: Demographic data and operative parameters were equal for patients in both groups. During CPB, COP was reduced by 55% in the SP group (9.8 +/- 2.0 vs 21.4 +/- 2.1 mm Hg) and by 41% in the RAP group (12.4 +/- 1.1 vs 20.9 +/- 1.8 mm Hg) (p = 0.008, SP vs RAP group). Compared with preoperatively, EVLW was unchanged in the RAP group 2 hours post-CPB, but it was elevated by 21% in the SP group (p = 0.002, SP vs RAP group). End-CPB crystalloid fluid balance was significantly reduced in the RAP group (1,857 +/- 521 vs 2,831 +/- 637 mL). Postoperative (day 2) weight gain in the SP group (1.5 +/- 1.2 kg, p = 0.021) was absent in the RAP group (0.1 +/- 0.9, NS). Postoperative time to full mobilization was shorter in the RAP group. Postpump cardio-respiratory function did not differ among groups. CONCLUSIONS: This small-scale pilot study indicates that by reducing crystalloid fluid administration and fall of COP during CPB, RAP reduces postpump EVLW accumulation and weight gain in uncomplicated coronary artery bypass graft patients with no associated effects on cardio-respiratory function.     

Complete prevention of myocardial stunning, contracture, low-reflow, and edema after heart transplantation by blocking neutrophil adhesion molecules during reperfusion.

This study tested the hypothesis that preventing neutrophil adhesion during reperfusion, by blocking either the neutrophil membrane CD18 integrin complex or its endothelial and myocyte ligand, intercellular adhesion molecule-1 (ICAM-1), would reduce myocardial inflammation and edema and improve reflow and ventricular function after heart preservation and transplantation. After cardioplegia and insertion of a left ventricular balloon, rabbit hearts were heterotopically transplanted into recipient rabbits either immediately (immediate, n = 12) or after preservation in 4 degrees C saline (3 hours of ischemia, n = 33). Forty-five minutes before reperfusion, recipients of preserved hearts received intravenous infusions of either saline (vehicle, n = 13), anti-CD18 monoclonal antibody (Mab) R15.7 (2 mg/kg) (anti-CD18, n = 10), or anti-ICAM-1 Mab R1.1 (2 mg/kg) (anti-ICAM, n = 10). During 3 hours of reperfusion the slope of the peak-systolic pressure-volume relation and its volume-axis intercept, the exponential elastic coefficient of the end-diastolic pressure-volume relation, the unstressed ventricular volume, and the time constant of the exponential left ventricular pressure decay after dP/dtmin were serially measured. Myocardial blood flow was measured with microspheres from which coronary vascular resistance was calculated. After explanation, the degree of myocardial inflammation, estimated by tissue neutrophil sequestration (myeloperoxidase assay) and myocardial water content were determined. Within each group no significant differences in measurements made at 1, 2, and 3 hours of reperfusion were noted. Compared with the immediate transplantation group, the vehicle group demonstrated a significant increase in myeloperoxidase activity (3380 +/- 456 versus 1712 +/- 552 microU/gm, p < 0.05), coronary vascular resistance (115.5 +/- 13.4 versus 70.5 +/- 10.6 U/gm, p < 0.05), and myocardial water content (79.8% +/- 0.4% versus 75.6% +/- 1.3%, p < 0.05), a significant decrease in unstressed ventricular volume (a leftward shift in the end-diastolic pressure-volume relation) (-0.49 +/- 0.24 versus 0.28 +/- 0.21 ml, p < 0.05), and a marked prolongation in exponential left ventricular pressure delay after dP/dtmin (156.64 +/- 3.81 versus 37.25 +/- 3.34 msec, p < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Phosphodiesterase type 4 inhibitor prevents acute lung injury induced by cardiopulmonary bypass in a rat model.

OBJECTIVES: Cardiopulmonary bypass (CPB) induces systemic inflammatory response with neutrophil activation and subsequent lung dysfunction. Rolipram, a selective phosphodiesterase type 4 inhibitor, blocks the decrease in levels of cyclic adenosine monophosphate associated with neutrophil activation. Here, we tested the protective effect of rolipram on CPB-induced lung injury in the rat. METHODS: Rats were divided into three groups: control (C), rolipram (R) and sham (S). In the C and R groups, animals underwent CPB at a flow rate of 60 ml/kg per min for 60 min followed by another 60-min observation, whereas the S group rats were sustained for 120 min only with median sternotomy and the placement of cannulae for CPB. Rolipram (40 microg/kg per min) was administered to the R group rats by continuous intravenous infusion from 10 min before the establishment of CPB to the end of the experiment. RESULTS: The R and S groups showed significantly higher mean arterial oxygen pressure and lower mean lung wet-to-dry weight ratio compared with those observed in the C group (R: 489+/-44 or S: 527+/-55 vs. C: 287+/-185, and R: 5.0+/-0.4 or S: 4.7+/-0.3 vs. C: 5.9+/-0.5, respectively; (P < 0.01). Although CD11b expression levels on circulating neutrophils in the C group doubled after CPB, those in the R and S groups remained almost the same (P = 0.0008). Intrapulmonary tumor necrosis factor-alpha concentrations (pg/microg protein) in the C group tended to be higher than those observed in the R and S groups (R: 5.2+/-2.1, S: 5.0+/-2.1 and C: 8.9+/-5.4; R vs. C: P = 0.09 and S vs. C: P = 0.08). Pathological study of lungs revealed that more alveolar hemorrhage and neutrophil accumulation were observed in the C group compared to the R and S groups. CONCLUSIONS: These results suggest that rolipram prevents acute lung injury via the inhibition of neutrophil activation during and after CPB in this setting of a rat model.     

Moderate versus deep hypothermia for the arterial switch operation--experience with 100 consecutive patients.

OBJECTIVES: To evaluate the impact of moderate versus deep perioperative hypothermia on postoperative morbidity in patients receiving the arterial switch operation (ASO). METHODS: One hundred consecutive patients received the ASO from 9/98 to 4/06 using temperature-corrected full-flow moderate (M>24 degrees C, n=51) or deep hypothermic cardiopulmonary bypass (CPB) (D <20 degrees C, n=49). Complex TGA morphology was present in 33 patients (M: 27.4%, D: 38.8%, n.s.). Median age was 9 days (M) versus 10 days (D) and body weight was 3.5+/-0.7 kg (M) versus 3.6+/-0.9 kg (D) (both p=n.s.). Follow-up was 3.7+/-2.1 years. RESULTS: Lowest perioperative rectal temperature was 25.3+/-1.1 degrees C (M) versus 19.0+/-0.8 degrees C (D), p<0.001. Intraoperative blood transfusion (M: 231+/-47 ml, D: 252+/-112 ml, p=0.04) and postoperative lactate level (M: 3.2+/-1.3 mmol/l, D: 3.8+/-2.4 mmol/l, p=0.02) were lower under moderate hypothermia. One patient (D) suffered myocardial ischemia, required ECMO support and died. All other patients were safely weaned from CPB using dopamine (M: 3.0 microg/kg min, D: 3.4 microg/kg min, n.s.) and dobutamine (M: 5.6 microg/kg min, D: 6.7 microg/kg min, p=0.048). Secondary chest closure was performed in 41% (M) versus 59% (D) (p=0.04). Patients were extubated after 89 h (M) versus 126 h (D) (p=0.03). Under moderate hypothermia ICU stay (M: 8.4+/-4.7 days, D: 12.0+/-13.8 days, p=0.03) and hospital stay (M: 12.8+/-6.8 days, D: 20.7+/-15.5 days, p=0.001) were shorter. Five-year freedom from reoperation was 97.0% for simple and 85.2% for complex TGA with RVOT reconstruction in 4/6 patients. CONCLUSIONS: The ASO under full-flow moderate compared to deep hypothermia was advantageous regarding length of procedure and primary chest closure rate. Moderate hypothermia seemed to be beneficial for pulmonary recovery, length of chest tube drainage treatment and inotropic support. No worse early or long-term effects of moderate hypothermia were found.     

Profound hypothermia (less than 10 degrees C) compared with deep hypothermia (15 degrees C) improves neurologic outcome in dogs after two hours' circulatory arrest induced to enable resuscitative surgery

Deaths from uncontrollable hemorrhage might be prevented by arresting the circulation under protective hypothermia to allow resuscitative surgery to repair these injuries in a bloodless field. We have shown previously that in hemorrhagic shock, circulatory arrest of 60 minutes under deep hypothermia (tympanic membrane temperature, Ttm = 15 degrees C) was the maximum duration of arrest that allowed normal brain recovery. We hypothesize that profound cerebral hypothermia (Ttm less than 10 degrees C) could extend the duration of safe circulatory arrest. In pilot experiments, we found that the cardiopulmonary system did not tolerate arrest at a core (esophageal) temperature (Tes) of less than 10 degrees C. Twenty-two dogs underwent 30-minute hemorrhagic shock (mean arterial pressure 40 mm Hg), rapid cooling by cardiopulmonary bypass (CPB), blood washout to a hematocrit of less than 10%, and circulatory arrest of 2 hours. In deep hypothermia group 1 (n = 10), Ttm was maintained at 15 degrees C during arrest. In profound hypothermia group 2 (n = 12), during cooling with CPB, the head was immersed in ice water, which decreased Ttm to 4 degrees-7 degrees C. The Tes was 10 degrees C in all dogs during arrest. Reperfusion and rewarming were by CPB for 2 hours. Controlled ventilation was to 24 hours, intensive care to 72 hours. In the 20 dogs that followed protocol, best neurologic deficit scores (0% = normal, 100% = brain death) at 24-72 hours were 23% +/- 19% in group 1 and 12% +/- 8% in group 2 (p = 0.15). Overall performance categories and histologic damage scores were significantly better in group 2 (p = 0.04 and p less than 0.001, respectively). We conclude that profound cerebral hypothermia with CPB plus ice water immersion of the head can extend the brain's tolerance of therapeutic circulatory arrest beyond that achieved with deep hypothermia.     

Equivalent eighteen-hour lung preservation with low-potassium dextran or Euro-Collins solution after prostaglandin E1 infusion.

Improved techniques of pulmonary preservation would help alleviate the critical shortage of donor organs in lung transplantation and would improve early graft function. A previous study demonstrated that cold pulmonary artery flush with low-potassium dextran solution was superior to Euro-Collins solution in preservation of canine lung allografts stored for 12 hours when no pulmonary vasodilator was used before donor lung flush. The present study was designed to determine whether donor pretreatment with prostaglandin E1 would affect the superiority of low-potassium dextran as a preservation solution. Prostaglandin E1 was infused (50 micrograms/min) in 12 donor dogs until potent vasodilation was demonstrated. Low-pressure pulmonary artery flush (50 ml/kg) with either Euro-Collins or low-potassium dextran solution (n = 6 for each group) was performed at 4 degrees C in a randomized, blinded fashion. Heart-lung blocks were extracted and stored at 4 degrees C for 18 hours before left lung allografting. Inflatable cuffs were placed around each pulmonary artery, allowing independent study of the native and transplanted lungs. All 12 recipient dogs survived the 3-day assessment period. Lungs flushed and stored in Euro-Collins or low-potassium dextran solution provided equivalent gas exchange function on day 0 (arterial oxygen tension: Euro-Collins 289 +/- 105 mm Hg versus low-potassium dextran 265 +/- 111 mm Hg; mean +/- standard error of the mean) and on day 3 (Euro-Collins 516 +/- 45 mm Hg versus low-potassium dextran 354 +/- 77 mm Hg; p = 0.10). Mean pulmonary artery pressures in the transplanted lung were not significantly different in the Euro-Collins and low-potassium dextran groups on day 0 (21.4 +/- 2 mm Hg versus 33.7 +/- 5 mm Hg, respectively; p = 0.09) or on day 3 (20.2 +/- 2.7 mm Hg versus 24.2 +/- 5.1 mm Hg, respectively; p = 0.50). We conclude that there was no advantage of low-potassium dextran over Euro-Collins as a flush solution in this 18-hour canine single lung allograft model in which prostaglandin E1 was administered before pulmonary artery flush.     

Comparing dual-stream and standard cardiopulmonary bypass in pigs

BACKGROUND: Dual-stream (DS) and standard cardiopulmonary bypass (CPB) were compared. METHODS: A DS catheter inserted into the distal ascending aorta across the arch pumps blood through an upper lumen (maximum 2.25 L/min) directed by a bloodstreaming baffle toward the arch vessels. A separate lower lumen pumps blood (maximum 3.75 L/min) into the aorta caudad to the inflated baffle. The baffle is flat and horizontal along the catheter. When the baffle is collapsed the heart or both lumens may perfuse all organs. For 30 minutes 8 randomized CPB pigs had corporeal cooling to 32 degrees C and for 30 minutes had rewarming to 36 degrees C. Eight randomized DS pigs had 25 degrees C upper lumen cooling for 60 minutes. Lower lumen blood flow was streamed at 32 degrees C for 30 minutes, then rewarmed to 36 degrees C for 30 minutes. RESULTS: The change in relative lower lumen to brain blood flow as determined by brain-counted microspheres (15 micron) injected into the ascending aorta was less for DS brains than controls during full flow (DS 63.4+/-129.5 versus CPB 2,585.4+/-250.8, p < 0.001), and when injected into the ejecting-heart left atrium just after weaning off only lower lumen blood flow (DS 250.8+/-297.3 versus CPB 1,159.1+/-782.3, p < 0.001). DS brain temperatures were lower at an equal pump-off core temperature of 36 degrees C+/-0.5 degrees C (DS 31.6 degrees C+/-3.2 degrees C versus CPB 36.5 degrees C+/-1.7 degrees C, p < 0.025). Jugular O2 saturations were not different. CONCLUSIONS: DS-CPB prioritizes pump-filtered separate cold blood flow to the brain over a blood-streaming baffle to wash away potentially surgery related air and particulate matter arising from the heart or ascending aorta.     

Electroplegia: an alternative to blood cardioplegia for arresting the heart during conventional (on-pump) cardiac operation

BACKGROUND: Aortic cross-clamping is contraindicated in patients with severe atherosclerosis of the ascending aorta, and administration of chemical cardioplegia may be cumbersome in these patients. In this study, we demonstrate an alternative method of achieving cardioplegia by electrical stimulation of the vagus nerve. METHODS: In anesthetized canines, the left anterior descending coronary artery was reversibly ligated for 90 minutes, followed by cardiopulmonary bypass (CPB) and randomization to three groups (n = 8 each): (1) BCP group: 1 hour of intermittent hypothermic (4 degrees C) blood cardioplegia infusion; (2) CPB group: 1 hour of CPB alone; (3) EP group (group receiving electroplegia): 1 hour of intermittent vagal stimulation (total of 60 20-second electrical stimuli at 40 Hz, 6 to 10 V) with adjunctive pyridostigmine (0.5 mg/kg), verapamil (50 microg/kg), and propranolol (80 microg/kg) to potentiate hyperpolarization and suppress ectopic escape beats. RESULTS: The EP group achieved consistent intervals of arrest with 3.8 +/- 1.2 escape beats per 20-second stimulation period. After 2 hours of reperfusion off CPB, the left anterior descending coronary artery segmental shortening was reduced from baseline in all groups, but the segmental shortening recovered to a greater extent in the EP group than in either the CPB or BCP group (2.4% +/- 1.4% versus -1.3% +/- 1.3% versus -4.0% +/- 0.8%, p < 0.05). Infarct size (TTC stain, percentage of area at risk) was comparable among groups (EP: 20.9% +/- 4.7%; CPB: 29.6% +/- 3.2%; BCP: 25.1% +/- 5.7%). Postischemic left anterior descending coronary artery endothelial function (percent maximum relaxation to acetylcholine) was depressed in the EP group (68.6% +/- 7.6% versus 102.3% +/- 6.4%, p < 0.05), but was comparable versus nonischemic circumflex function in the BCP group (77.1% +/- 11.9% versus 100.4% +/- 10.0%, p = 0.15) and the CPB group (93.8% +/- 6.6% versus 93.3% +/- 6.6%). CONCLUSIONS: Electroplegia achieves elective intermittent cardiac arrest, avoids hypothermia, chemical cardioplegia, and aortic cross-clamping, with physiological outcomes comparable to blood cardioplegia.     

The effects of two rewarming strategies on heat balance and metabolism after coronary artery bypass surgery with moderate hypothermia

BACKGROUND: Postoperative hypothermia is common in cardiac surgery with hypothermic cardiopulmonary bypass (CPB). This trial was designed to evaluate whether rewarming over the normal bladder temperature (over 37 degrees C) at the end of hypothermic CPB combined with passive heating methods after CPB might result in a better heat balance, lower energy expenditure (EE) and decrease of disturbances in oxygen balance compared to only rewarming the patients to a bladder temperature of 35-37 degrees C. METHODS: A prospective, randomized controlled clinical study was performed in 38 patients scheduled for elective coronary artery bypass surgery. Twenty patients (group C) were rewarmed to a bladder temperature of 35-37 degrees C at the end of hypothermic (28 degrees C) CPB. Eighteen patients (group W) were rewarmed to a bladder temperature of 37-38.5 degrees C. RESULTS: At the end of CPB, the bladder temperature was 36.2+/-0.7 degrees C (mean+/-SD) in group C and 37.9+/-0.5 degrees C in group W. After half an hour's stay in the ICU, the mean body temperature (MBT) was 35.1+/-0.6 degrees C in group C and 36.6+/-0.7 degrees C in group W. During the following five hours, MBT increased to 37.4+/-0.8 degrees C in group C and to 38.0+/-0.6 degrees C in the other group. The peak value of EE in the ICU was 1.73+/-0.44 (group C) vs 1.35+/-0.29 (W/kg) (group W) (P=0.003). EE was significantly (P=0.044) higher in group C than in the other group between 1.5 and 5.5 h in the ICU. The increased energy expenditure due to heat production was associated with an increase in O2 consumption (VO2) 61.6+/-30.4% vs 25.2+/-24.1%, (peak values) compared to the basal values of the two groups measured before anesthesia (between groups P<0.001). Between 1.5 and 5.5 h in the ICU, group C had significantly higher VO2 (P=0.026), CO2 production (P=0.017), venous pCO2 (P<0.001) and minute ventilation (p=0.014) than group W. Venous pH was lower (P<0.001) in group C. The peak value of oxygen extraction was also higher (P=0.045) in group C. On the other hand, the lowest value of venous oxygen saturation was higher (P=0.04) in group W. CONCLUSION: With rewarming the patients at the end of CPB to a bladder temperature of over 37 degrees C combined with passive heating methods after CPB, it was possible to decrease EE and VO2 compared to the control group (rewarmed to bladder temperature of 35-37 degrees C) after coronary artery bypass surgery with moderate hypothermia.     

The hemodynamic effects of phenoxybenzamine in neonates, infants, and children

STUDY OBJECTIVES: To evaluate the hemodynamic effects of the long-acting, alpha-adrenergic blocker, phenoxybenzamine, in children of different age groups. DESIGN: Retrospective chart review. SETTING: Tertiary-care, congenital cardiac surgery center. MEASUREMENTS: The data of 75 pediatric patients who received phenoxybenzamine while undergoing surgical repair of congenital heart defects on cardiopulmonary bypass (CPB) were studied. Patients were selected in three age groups: younger than one month (n = 25), one to 12 months (n = 25), and one to 5 years (n = 25). All patients received a full dose of phenoxybenzamine 1 mg/kg. Demographics, CPB duration, mean arterial pressure on CPB, mean flow on CPB (normalized to body surface area), and central-to-peripheral temperature gradients were recorded. Systemic vascular resistance index (SVRI) was calculated. MAIN RESULTS: Cardiopulmonary bypass duration was significantly longer in the age group of younger than 1 mo than in the older groups. Mean CPB flow/body surface area was similar in all children (3.45 +/- 0.9, 3.74 +/- 0.69, and 3.48 +/- 0.59 L/min/m2, respectively; P < 0.28). However, mean SVRI was significantly lower in children younger than 1 mo (997.3 +/- 233, 1196.9 +/- 394, and 1168.83 +/- 227 dynes/cm2m5; P < 0.04). Temperature gradient was significantly narrower in patients younger than one month than those who were one to 12 months and one to 5 years at the end of cooling (0.90 degrees C +/- 0.1 degrees C, 1.04 degrees C +/- 3.61 degrees C, 1.4 degrees C +/- 3.07 degrees C; P < 0.001) at end-rewarming and termination of CPB (4.58 degrees C +/- 2.36 degrees C, 6.23 degrees C +/- 4.17 degrees C, 7.32 degrees C +/- 3.46 degrees C; P < 0.02). Multivariate analysis showed that patient age was a significant variable affecting response to phenoxybenzamine, after adjusting for duration of CPB (P = 0.31), mean hematocrit on CPB (P = 0.86), and core cooling temperature (P = 0.34). CONCLUSION: The effect of phenoxybenzamine on SVRI, cooling, and rewarming on CPB varies with age as shown by more profound vasodilatation and narrower temperature gradients.     

Inducible nitric oxide production is an adaptation to cardiopulmonary bypass-induced inflammatory response

BACKGROUND: Cardiopulmonary bypass (CPB) increases nitric oxide (NO) production by the activation of NO synthases (NOS). However, the role of NO from inducible NOS (iNOS) in CPB-induced inflammatory response remains unclear. We examined the effect of a selective iNOS inhibitor, aminoguanidine, on CPB-induced inflammatory response in a rat-CPB model. METHODS: Adult Sprague-Dawley rats underwent 60 minutes of CPB (100 mL x kg(-1) x min(-1), 34 degrees C). Group A (n = 10) received 100 mg/kg of aminoguanidine intraperitoneally 30 minutes before the initiation of CPB, and group B (n = 10) served as controls. RESULTS: There were significant time-dependent changes in plasma interleukin (IL)-6, IL-8, nitrate + nitrite, the percentage ratio of nitrotyrosine to tyrosine (%NO2-Tyr, an indicator of peroxynitrite formation), and respiratory index (RI). Three hours after CPB termination, IL-6, IL-8, and RI were significantly higher in group A (IL-6, 397.5+/-80.6 pg/mL; IL-8, 26.99+/-6.57 ng/mL; RI, 1.87+/-0.31) than in group B (IL-6, 316.5+/-73.9 pg/mL, p <0.05; IL-8, 17.21+/-3.12 ng/mL, p < 0.01; RI, 1.57+/-0.24, p < 0.05) although nitrate + nitrite (31.8+/-4.1 micromol/L) and %NO2-Tyr (1.15%+/-0.20%) were significantly lower in group A than in group B (nitrate + nitrite, 50.2+/-5.0 micromol/L, p < 0.01; %NO2-Tyr, 1.46%+/-0.21%, p < 0.01). Western immunoblot analysis from lung tissue of group A identified marked iNOS inhibition without inhibiting endothelial-constitutive NOS, and neutrophil accumulation in the lung specimens was significantly greater in group A (6.5+/-0.7/alveoli) than in group B (4.4+/-0.4/alveoli, p < 0.01). CONCLUSIONS: These results suggest that NO production from iNOS may be an adaptive response for attenuating the CPB-induced inflammatory response.     

Effect of a human urinary protease inhibitor (Ulinastatin) on respiratory function in pediatric patients undergoing cardiopulmonary bypass

BACKGROUND: We performed this prospective randomized study to determine the effect of a human urinary protease inhibitor (Ulinastatin) on respiratory function in pediatric patients undergoing cardiopulmonary bypass. METHODS: Twenty-two children were included in this study. They were randomly allocated to 1 of the following groups; a control group (n=11) or a Ulinastatin group (n=11) in which patients received 5000 U/kg of Ulinastatin. Arterial blood samples were obtained before cardiopulmonary bypass (CPB), immediately after CPB, and 30 min after protamine administration, as well as 3 hours after and 18 hours after CPB, and Interleukin-8 and neutrophil elastase concentration were evaluated. RESULTS: CPB time and aortic clamp time did not differ between the groups. Interleukin 8 and neutrophil elastase concentrations before CPB increased significantly immediately after CPB, these concentrations did not differ between the groups. However, neutrophil elastase concentrations of a Ulinastatin group were significantly lower than that of a control group at 30 min after protamine administration (a Ulinastatin group: 1011.3+/-539.1 mg/ml, a control group: 1619.7+/-595.7 mg/ml, p<0.05) and A-aDO2 of a Ulinastatin group was significantly lower than that of a control group at 2 hours after CPB (a Ulinastatin group: 67.1+/-70.6 mmHg, a control group: 169.2+/-116.3 g, p<0.05). CONCLUSIONS: These results suggest that Ulinastatin suppresses the increase in neutrophil elastase and protects the respiratory function in pediatric patients undergoing cardiopulmonary bypass.     

Postoperative hyperthermia following off-pump versus on-pump coronary artery bypass surgery

OBJECTIVE: Hyperthermia is common in the first 24 hours following coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB). An inflammatory response to CPB is often implicated in the pathophysiology of this fever. Unlike CABG with CPB, the temperature pattern after off-pump CABG (OPCAB), where CPB is avoided, has not yet been described. The purpose of this study was to describe the postoperative temperature pattern following OPCAB and to compare it with that following on-pump cardiac surgery. DESIGN: Retrospective, observational study. SETTING: Tertiary care university hospital. PARTICIPANTS: Consenting patients undergoing CABG or OPCAB procedures. INTERVENTIONS: Observational. MEASUREMENTS AND MAIN RESULTS: Of the CABG patients, 89% had temperature elevations above 38 degrees C, versus 44% of the OPCAB patients (P = 0.04). Peak body temperature was higher in the on-pump patients (CABG 38.5 degrees C +/- 0.4 degrees C versus OPCAB 37.9 degrees C +/- 0.5 degrees C; P = 0.002), as was the area under the curve for temperatures greater than 38 degrees C (CABG 1.6 +/- 1.7 degrees C/hr versus OPCAB 0.4 +/- 1.2 degrees C/hr; P = 0.02). CONCLUSIONS: Off-pump CABG surgery patients experience less hyperthermia compared with on-pump CABG patients. The reasons for a lower incidence and severity of hyperthermia after OPCAB surgery are not known, but may be related to a reduced inflammatory response.     

Preoperative administration of steroids: influence on adhesion molecules and cytokines after cardiopulmonary bypass

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with tissue damage mediated by adhesion molecules and cytokines. Prebypass steroid administration may modulate the inflammatory response, resulting in improved postoperative recovery. METHODS: Fifty patients undergoing elective coronary operations under normothermic CPB were randomized into two groups: group A (n = 24) received intravenous methylprednisolone (10 mg/kg) 4 hours preoperatively, and group B (n = 26) served as controls. Cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin-2R [IL-2R], IL-6, IL-8), soluble adhesion molecules (sE-selectin, sICAM-1), C-reactive protein, and leukocytes were measured before steroid application, then 24 and 48 hours, and 6 days postoperatively. Adhesion molecules were measured by enzyme-linked immunosorbent assay, cytokines by chemiluminescent immunoassay. Postoperatively, hemodynamic measurements, inotropic agent requirements, blood loss, duration of mechanical ventilation, and intensive care unit stay were compared. RESULTS: Aortic cross-clamp and CPB time was similar in both groups. Prednisolone administration reduced postoperative levels of IL-6 (611 versus 92.7 pg/mL; p = 0.003), TNF-alpha (24.4 versus 11.0 pg/L, p = 0.02), and E-selectin (327 versus 107 ng/mL, p = 0.02). Postoperative recovery did not differ between groups. CONCLUSIONS: Preoperative administration of methylprednisolone blunted the increase of IL-6, TNF-alpha, and E-selectin levels after CPB but had no measurable effect on postoperative recovery.     

The release of systemic inflammatory mediators is independent of cardiopulmonary bypass temperature

OBJECTIVE: The aim of this study was to investigate the effect of systemic CPB temperature on the production of the key mediators of the systemic inflammatory response to coronary artery bypass graft (CABG) surgery. DESIGN: Randomized clinical study. SETTING: University hospital. PARTICIPANTS: Thirty patients undergoing first-time CABG surgery. INTERVENTIONS: The patients were randomized to hypothermic (32 degrees C, n = 15) or normothermic (36 degrees C, n = 15) CPB. MEASUREMENTS AND MAIN RESULTS: Plasma interleukin (IL)-6, IL-8, IL-10, C-reactive protein (CRP), cortisol, and neutrophils were measured the day before operation, at closure of the sternum, and 4, 16, and 44 hours later. The cytokine, CRP, cortisol, and neutrophil responses were independent of temperature during CPB with peak concentrations of IL-10 at closure of the sternum followed by IL-6, IL-8, cortisol, neutrophils, and finally CRP. A correlation between maximal plasma concentrations of IL-10 and cortisol was seen in both groups after surgery (p = 0.02). Drainage after surgery was lower after normothermic CPB (p=0.02), with no difference in the requirement for blood transfusion. All patients were discharged from the intensive care unit within 24 hours after surgery. CONCLUSIONS: The release of systemic inflammatory mediators after cardiac surgery was independent of mild hypothermia (32 degrees C) versus normothermia (36 degrees C) during CPB.