Clinical evaluation of leukocyte-depleted blood cardioplegia for pediatric open heart operation

Background. Blood cardioplegia (BCP) is widely used for myocardial protection during open heart operation. However, BCP may have a chance to induce neutrophil-mediated myocardial injury during aortic cross-clamping. We clinically evaluated the myocardial protective effect of leukocyte-depleted blood cardioplegia (LDBCP) for initial and intermittent BCP administration in pediatric patients.

Methods. Fifty patients undergoing open heart operation for congenital heart disease between January 1997 and March 1999 were reviewed. Twenty-five were administered LDBCP for myocardial protection during ischemic periods (LDBCP group), and the remaining 25 were given BCP without leukocyte depletion (BCP group).

Results. The difference in plasma concentrations of malondialdehyde between coronary sinus effluent blood and arterial blood just after reperfusion in the LDBCP group (1.68 ± 0.56 μmol/L) was significantly lower than that in the BCP group (2.35 ± 0.62 μmol/L; p < 0.01). The LDBCP group showed significantly lower plasma concentrations of human heart fatty acid-binding protein at 50 minutes after reperfusion (LDBCP group, 103.5 ± 38.7 IU/L; BCP group, 144.8 ± 48.8 IU/L; p < 0.01) and the peak value of creatine kinase-MB during the first 24 postoperative hours (LDBCP group, 17.0 ± 8.5 IU/L; BCP group, 26.0 ± 11.6 IU/L; p < 0.01) than did the BCP group. The maximum dose of catecholamine was significantly smaller in the LDBCP group (LDBCP group, 3.20 ± 2.18 μg · kg⁻¹ · min⁻¹; BCP group, 5.60 ± 2.83 μg · kg⁻¹· min⁻¹; p < 0.01).

Conclusions. These results suggest the usefulness of LDBCP for protection from the myocardial injury that can be induced by BCP administration during aortic cross-clamping.     

S100β correlates with neurologic complications after aortic operation using circulatory arrest

Background. Astrocyte protein S100β is a potential serum marker for neurologic injury. The goals of this study were to determine whether elevated serum S100β correlates with neurologic complications in patients requiring hypothermic circulatory arrest (HCA) during thoracic aortic repair, and to determine the impact of retrograde cerebral perfusion (RCP) on S100β release in this setting.

Methods. Thirty-nine consecutive patients underwent thoracic aortic repairs during HCA; RCP was used in 25 patients. Serum S100β was measured preoperatively, after cardiopulmonary bypass, and 24 hours postoperatively.

Results. Neurologic complications occurred in 3 patients (8%). These patients had higher postbypass S100β levels (7.17 ± 1.01 μg/L) than those without neurologic complications (3.63 ± 2.31 μg/L, p = 0.013). Patients with S100β levels of 6.0 μg/L or more had a higher incidence of neurologic complications (3 of 7, 43%) compared with those who had levels less than 6.0 μg/L (0 of 30, p = 0.005). Retrograde cerebral perfusion did not affect S100β release.

Conclusions. Serum S100β levels of 6.0 μg/L or higher after HCA correlates with postoperative neurologic complications. Using serum S100β as a marker for brain injury, RCP does not provide improved cerebral protection over HCA alone.     

Brief pretreatment of radial artery conduits with phenoxybenzamine prevents vasoconstriction long term

Background. Radial artery bypass conduits are prone to early vasospasm or “string sign” with use of vasopressor therapy intraoperatively and postoperatively, causing increased resistance in coronary artery grafts. Current intraoperative treatment with papaverine fails to provide sustained inhibition of vasoconstriction. We tested the hypothesis that a 30-minute pretreatment of radial artery segments with the -adrenergic antagonist phenoxybenzamine (PB) or the putative protein phosphatase 2,3-butadione monoxime (BDM) attenuates vasoconstriction induced by the vasopressors phenylephrine or norepinephrine for as long as 48 hours compared with papaverine.

Methods. Canine radial arteries were harvested, incubated in control buffer or solutions of papaverine 10⁻⁶ M, BDM 10⁻⁶ M or phenoxybenzamine 10⁻⁶ M for 30 minutes, washed, and stored in drug-free culture medium for 2, 24, or 48 hours. After storage, constriction was induced by norepinephrine at incremental concentrations ranging from 0.7 to 3.5 μmol/L or by phenylephrine (0.300 to 1.5 μmol/L) with or without the inhibitors, and the degree of vasoconstriction was quantified in organ chambers. Responses to norepinephrine or phenylephrine were compared to constriction with receptor-independent potassium chloride KC1 (30 mmol/L).

Results. Maximum responses to phenylephrine and norepinephrine were comparable at 2, 24, and 48 hours after harvest in the control group (phenylephrine: 67% ± 4%, 62% ± 6%, 65% ± 6% of KC1 response; norepinephrine: 75% ± 4%, 62% ± 1%, 58% ± 7%, respectively). Papaverine failed to attenuate constriction to phenylephrine and norepinephrine 2, 24, or 48 hours posttreatment. Pretreatment with BDM did not reduce vasoconstriction responses to phenylephrine or norepinephrine 2 hours after incubation but did reduce constriction responses thereafter. In contrast, phenoxybenzamine completely attenuated constriction to both phenylephrine (19% ± 8%, 1% ± 4%, −12% ± 4%) and norepinephrine (7.1% ± 1%, −5% ± 5%, −20% ± 5%) at 2, 24, and 48 hours posttreatment, respectively. Phenoxybenzamine did not alter endothelial function relative to controls at any time point.

Conclusions. Thirty-minute pretreatment of RA conduits with 10⁻⁶ M phenoxybenzamine completely inhibits vasoconstriction to phenylephrine and norepinephrine for as long as 48 hours. Soaking radial artery grafts briefly in phenoxybenzamine solution before implantation may be effective in preventing postoperative vasospasm caused by two common -adrenergic agonists used in postoperative hemodynamic management.     

The Brain Uses Mostly Dissolved Oxygen During Profoundly Hypothermic Cardiopulmonary Bypass

Background. During profoundly hypothermic cardiopulmonary bypass, cerebral venous oxygen saturation increases (eg, to 98% at 15°C). We reanalyzed results of clinical studies to learn why.

Methods. One hundred sixty-eight cerebral oxygen transport measurements were available from 96 infants and children undergoing profoundly hypothermic cardiopulmonary bypass during repair of congenital heart defects.

Results. Dissolved oxygen accounted for 2% to 17% of arterial oxygen content, depending on the arterial oxygen partial pressure and hemoglobin concentration. The fraction of the cerebral metabolic rate for oxygen obtained from dissolved oxygen depended on pump flow, temperature, hemoglobin concentration, and arterial oxygen partial pressure (all p < 10⁻³). For “full-flow” cardiopulmonary bypass, temperatures less than 18°C, and arterial oxygen partial pressure measurements more than 180 mm Hg, the mean ± standard deviation of the fraction of cerebral metabolic rate for oxygen obtained from dissolved oxygen equaled 77% ± 19%.

Conclusions. Dissolved oxygen satisfies most of the brain's oxygen requirements during profound hypothermic cardiopulmonary bypass. This result reflects four properties of profound hypothermic cardiopulmonary bypass: (1) increases in hemoglobin's oxygen affinity due to profound hypothermia (which impairs oxygen transfer from hemoglobin to cerebral tissue), (2) use of hemodilution, (3) use of high arterial oxygen partial pressure, and (4) low cerebral metabolic rate of oxygen.     

Hemodynamic effects of inspired carbon dioxide after the Norwood procedure

Background. Mortality in the early postoperative period after the Norwood procedure remains substantial. Inspired carbon dioxide (CO₂) has been suggested to improve hemodynamic status in this setting. Inspired CO₂ can be delivered by one of two strategies, ie, with or without an accompanying increase in minute ventilation. The hemodynamic effects of these two strategies have not previously been studied in a controlled fashion.

Methods. Seventeen infants (median age, 9 days; range, 4 to 49 days) undergoing Norwood procedures were prospectively enrolled in this crossover study. Patients were studied while sedated, paralyzed, and mechanically ventilated 1 day to 6 days after operation. The inspired oxygen fraction was kept constant (mean value, 0.24 ± 0.01). Measurements were made at five time points: 1 = baseline; 2 = inspired CO₂ with increased ventilation; 3 = baseline; 4 = inspired CO₂ alone; and 5 = baseline. Mixed venous oxygen saturation was monitored using indwelling lines in the superior vena cava.

Results. Inspired CO₂ with increased ventilation produced a rise in mean airway pressure with no change in arterial CO₂ tension or pH. This strategy had no effect on hemodynamic status or oxygen delivery. Inspired CO₂ alone produced a rise in arterial CO₂ tension and a fall in arterial pH (respiratory acidosis). This strategy resulted in significant improvement in both variables of systemic oxygen delivery: mixed venous oxygen saturation increased from 48% ± 2% to 56% ± 2% (p < 0.05), and arteriovenous oxygen saturation difference decreased from 3% ± 2% to 26% ± 2% (p < 0.05).

Conclusions. Inspired CO₂ after the Norwood procedure can improve oxygen delivery. This improvement occurs only if minute ventilation is kept constant. There is no improvement if minute ventilation is increased. Clinical use of inspired CO₂ may be limited by the accompanying fall in pH. Differentiation of cerebral from total-body effects of inspired CO₂ will require further study.     

Effects of diltiazem on renin-aldosterone and ACTH-adrenocortical function during upper abdominal surgery

Study Objective: To observe the effects of continuous intravenous infusion of diltiazem on the renin-aldosterone system and ACTH-adrenocortical axis responses during surgical stimulation.

Design: Randomized study of intravenous diltiazem.

Setting: Operating room at the Hyogo Medical College Hospital.

Patients: Twenty-three patients undergoing upper abdominal surgery were divided into two groups: the control group (n = 10) and the diltiazem group (n = 13). All the patients were without any complications and classified as ASA physical status I.

Interventions: Patients in the diltiazem group received an infusion of 10 μg/kg/ min for 90 to 120 minutes following skin incision.

Measurements and Main Results: Plasma adrenocorticotropic hormone, plasma aldosterone and cortisol concentrations, and plasma renin activity were determined with radioimmunoassay before the induction of anesthesia at 10, 30, 60, and 90 minutes after skin incision and at the end of anesthesia. Renin activity did not change significantly. Maximal increases in plasma adrenocorticotropic hormone, aldosterone, and cortisol observed 90 minutes after skin incision were 355 ± 95 pg/ml, 118 ± 30 pg/ml, and 14.2 ± 2.3 μg/dl in the control group versus 246 ± 41 pg/ml, 119 ± 25 pg/ml, and 15.0 ± 1.8 μg/dl in the diltiazem group, respectively, and there were no significant differences between these groups. Adrenocorticotropic hormone was significantly lower in the diltiazem group compared with that in the control group 60 minutes after the start of surgery (p < 0.05). There was marked natriuresis (40 ± 25 μEq/min vs 470 ± 147 μEq/min at the 90-minute mark) and diuresis (0.16 ± 0.13 ml/min vs. 2.53 ± 0.88 ml/min) in the diltiazen group.     

Bradykinin protects the rabbit heart after cardioplegic ischemia via NO-dependent pathways

Background. Depressed myocardial performance is an important clinical problem after open heart surgery. We hypothesized pretreating with bradykinin would pharmacologically precondition the heart and improve postischemic performance, and induce myocardial preconditioning by activating nitric oxide synthase.

Methods. Thirty-three rabbit hearts underwent retrograde perfusion with Krebs-Henseleit buffer (KHB) followed by 50 minutes of 37°C cardioplegic ischemia with St. Thomas’ cardioplegia solution (StTCP). Ten control hearts received no pretreatment. Ten bradykinin-pretreated hearts received a 10-minute infusion of 0.1 μMol/L bradykinin-enriched KHB and cardioplegic arrest with 0.1 μMol/L bradykinin-enriched StTCP. Six other hearts received 0.1 μMol/L HOE 140, a selective B2 receptor antagonist, added to both the 0.1 μMol/L bradykinin-enriched KHB and 0.1 μMol/L bradykinin-enriched StTCP solutions. Finally, six other hearts received 100 μMol/L of N-Ω-nitro- -arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, added to both the 0.1 μMol/L bradykinin-enriched KHB and 0.1 μMol/L bradykinin-enriched StTCP solutions.

Results. Bradykinin pretreatment significantly improved postischemic performance and coronary flow (CF) compared with control (LVDP: 53 ± 5* vs 27 ± 4 mm Hg; +dP/dt_max: 1,025 ± 93* vs 507 ± 85 mm Hg/s; CF: 31 ± 3* vs 22 ± 2 mL/min; *p < 0.05). Both HOE 140 and L-NAME abolished bradykinin-induced protection, resulting in recovery equivalent to untreated controls.

Conclusions. Bradykinin pretreatment improves recovery of ventricular and coronary vascular function via nitric oxide-dependent mechanisms. Pharmacologic preconditioning by bradykinin pretreatment may be an important new strategy for improving myocardial protection during heart surgery.     

Time to peak effect of neostigmine at antagonism of atracurium- or vecuronium-induced neuromuscular block

Study Objective: (1) To determine the time to peak effect of neostigmine (time to peak antagonism) during atracurium- or vecuronium-induced neuromuscular block; and (2) to determine the effect on time to peak effect of neostigmine during atracurium-induced neuromuscular block, when the dose of neostigmine is increased from 35 μg/kg to 70 μg/kg.

Design: Prospective, randomized clinical study.

Setting: Gynecologic operating room suite at a university hospital.

Patients: 45 ASA I and II women admitted for gynecologic laparotomy.

Interventions: Anesthesia was performed with thiopental sodium, fentanyl, halothane, nitrous oxide, and atracurium or vecuronium. Train-of-four (TOF) stimulation and mechanomyography were used to monitor neuromuscular transmission. Neostigmine was administered while a constant degree of neuromuscular block was maintained at a twitch height at a point between 4% and 11% of the control twitch height, using a continuous infusion of atracurium or vecuronium. The patients were randomized to three groups, with 15 patients in each group. Group 1 received atracurium block antagonized with neostigmine 35 μg/kg; group 2 received vecuronium block antagonized with neostigmine 35 μg/kg; and group 3 received atracurium block antagonized with neostigmine 70 μg/kg.

Measurements and Main Results: The degree of neuromuscular block at antagonism was similar in the three groups. Time to peak effect (mean ± SD) on TOF ratio was significantly longer in Group 1 (9.7 ± 3.0 minutes) versus Group 2 (6.6 ± 1.4 minutes; (p < 0.05). The time to peak effect on TOF ratio during atracurium-induced block was reduced from 9.7 ± 3.0 minutes to 6.3 ± 2.0 minutes when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg (p < 0.05). The peak effect on TOF ratio was significantly greater in Group 3 compared with Group 1 (p < 0.05), while it was similar in groups 1 and 2.

Conclusion: The time to peak effect of neostigmine 35 μg/kg is about 6 to 10 minutes when antagonizing a constant degree of atracurium- or vecuronium-induced neuromuscular block at a twitch height at a point between 4% and 11%. Even though the time to peak effect was longer with atracurium than with vecuronium, clinically significant differences between the antagonizing effect of atracurium versus vecuronium block were not demonstrated. The time to peak effect during atracurium-induced block decreased when the dose of neostigmine was increased from 35 μg/kg to 70 μg/kg.     

Pharmacodynamic effects of three doses of ORG 9426 used for endotracheal intubation in humans

Study Objective: To determine the pharmacodynamic characteristics of three incremental doses of ORG 9426 used for endotracheal intubation in patients.

Design: Double-blind, randomized administration of one of three doses of intravenous ORG 9426.

Setting: Inpatients requiring surgery at Georgetown University Medical Center.

Patients: Thirty-six patients, ages 18 to 65, ASA physical status I, II, and III, scheduled for general surgery.

Interventions: After Georgetown University Institutional Review Board approval and patient consent, patients were premeditated with midazolam or droperidol. Anesthesia was induced with thiopental sodium and fentanyl. Anesthesia was maintained with 60% nitrous oxide in oxygen. The ulnar nerve was stimulated supramaximally with a 2 Hz train-of four (TOF) every 20 seconds. Thumb contractions were measured with a force transducer. When TOF and anesthesia were stable, 2, 2.5, or 3 times the ED₉₅ of ORG 9426 (570 μg/kg 710 μg/kg or 850 μg/kg) was administered randomly. Tracheal intubation was attempted at maximal depression of the first TOF response (T₁).

Measurements and Main Results: The following parameters were measured: time interval from the injection of ORG 9426 to 90% depression of T₁ (T₁ 90% block), maximal T₁ depression (onset time), intubating conditions, clinical duration (time for return of T₁ to 25% of control), heart rate (HR), blood pressure (BP), and any adverse clinical experience. ORG 9426 provided adequate intubating conditions in all patients but two, independent of the dose used. Its onset time was rapid, but increasing the dose did not shorten the onset. T₁ 90% block was achieved rapidly (75 ± 25 seconds to 78 ± 18 seconds, means ± SD). The clinical duration of ORG 9426 was relatively short and lengthened with increasing doses (from 36 ± 18 minutes at 570 μg/kg to 42 ±10 minutes at 850 μg/kg. Spontaneous twitch recovery from 10% to 25% was similar in all dosage groups (5 ± 1 minutes to 6 ± 4 minutes). No clinically significant changes in HR and BP and no adverse clinical experiences were noted in any group.

Conclusion: These findings warrant further clinical evaluation of ORG 9426 for induction and maintenance of muscle relaxation in humans.     

Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries

Background. Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10⁻⁶ mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10⁻⁹ to 10⁻⁵ mol/L) after contraction by 3×10⁻⁸ mol/L of endothelin-1.

Results. Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% ± 10.2% and 65.9% ± 10.1% at 2 hours and 39.4% ± 4.7% and 68.4% ± 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% ± 8.2% and 45.0% ± 5.5% at 2 hours and 38.1% ± 8.2% and 56.5% ± 8.8% at 24 hours, respectively (NS).

Conclusions. In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.     

Patient-controlled drug administration during local anesthesia: A comparison of midazolam, propofol, and alfentanil

Study Objective: To evaluate the perioperative effects of alfentanil, midazolam, and propofol when administered using a patient-controlled analgesia (PCA) device during local anesthesia.

Design: Randomized, single-blind comparative study.

Setting: Outpatient surgery center at a university teaching hospital.

Patients: Ninety outpatients undergoing minor elective surgical procedures with local anesthetic infiltration were assigned to one of three treatment groups.

Interventions: After premedication with midazolam 1 mg intravenously (IV) and fentanyl 50 μg IV, patients were allowed to self-administer 2 ml bolus doses of either alfentanil 250 μg/ml, midazolam 0.4 mg/ml, or propofol 10 mg/ml at minimal intervals of 3 minutes to supplement a basal infusion rate of 5 ml/hr.

Measurements and Main Results: The total intraoperative dosages of alfentanil, midazolam, and propofol were 2.7 ± 1.1 mg, 4.7 ± 2.7 mg, and 114 ± 42 mg, respectively, for procedures lasting 48 ± 28 minutes to 51 ± 19 minutes (means ± SD). Propofol produced more pain on injection (39% vs. 4% and 6% in the alfentanil and midazolam groups, respectively). Episodes of arterial oxygen saturation less than 90% were more frequent with alfentanil (28%) than with midazolam (3%) or propofol (13%). Using the visual analog scale, patients reported comparable levels of discomfort, anxiety, and sedation during the operation in all three treatment groups. Postoperative picture recall was significantly decreased with midazolam versus alfentanil and propofol. Finally, postoperative nausea was reported more frequently in the alfentanil group (29%) than in the midazolam (10%) or propofol (18%) groups, contributing to a significant prolongation of the discharge time in the alfentanil-treated patients.

Conclusions: When self-administered as adjuvants during local anesthesia using a PCA delivery system, alfentanil, midazolam, and propofol were equally acceptable to patients. However, propofol and midazolam were associated with fewer perioperative complications than was alfentanil.     

Optimizing timing of early extubation in coronary artery bypass surgery patients

Background. This study was designed to assess the safety and efficacy of extubation performed within 4 hours of the patient’s arrival in the surgical intensive care unit after coronary artery bypass graft surgery.

Methods. A matched retrospective cohort study was performed including 412 consecutive patients undergoing isolated coronary artery bypass graft surgery between January 1996 and December 1997, constituting the experience of a single surgeon (J.H.L.). Early extubation (defined as extubation within 8 hours of arrival at the surgical intensive care unit) was achieved in 308 of 412 patients (75%). Patients extubated in fewer than 4 hours after arrival (n = 200) were compared with patients extubated within 4 to 8 hours (n = 108).

Results. Four deaths occurred in 412 patients, for an overall operative mortality rate of 1.0%. Patients extubated in fewer than 4 hours were younger than those extubated 4 or more hours after admission (62 versus 67 years old, respectively; p = 0.001), more likely to be male (74% versus 63%, p < 0.05), and had shorter aortic cross-clamp times (49.4 ± 15.0 versus 53.5 ± 14.0 minutes, p < 0.05) and cardiopulmonary bypass (CPB) times (65.2 ± 18.6 versus 72.1 ± 19.1 minutes, p < 0.05) compared to patients extubated later. Moreover, patients extubated in fewer than 4 hours had a shorter surgical intensive care unit length of stay (33.8 ± 25.7 versus 43.1 ± 43.0 hours, p < 0.05) and shorter postoperative length of stay (5.4 ± 2.4 versus 6.2 ± 2.6 days, p = 0.01) than those extubated later.

Conclusions. Extubation in fewer than 4 hours may offer a substantial advantage in terms of accelerated recovery compared with extubation within 4 to 8 hours. Very few differences in clinical parameters were noted between the two groups we studied, suggesting that efforts to reduce extubation times further might be worthwhile.     

Efficient naked plasmid cotransfection of lung grafts by extended lung/plasmid exposure time

Background. Multiple gene cotransfection may be an effective strategy to modulate concurrent pathologic events after lung transplantation. We investigated in vivo naked plasmid lung cotransfection during cold preservation and the role of lung parenchyma/naked plasmid exposure time.

Methods. F344 rats underwent left main bronchus instillation of pCF1-CAT (chloramphenicol acetyl transferase) (130 μg) ± pCF1-β-Gal (β-galactosidase) (130 μg) in saline. Part Ia: 4°C preservation versus cotransfection. Lung isografts (4 groups, N = 8) were stored after transfection for 1 (2 groups: one received only pCF1-CAT), 6, and 18 hours. Recipient sacrifice was after 48 hours. Part Ib: 4°C preservation versus transgene expression. Rats were sacrificed 48 hours after transfection in a nontransplant setting (2 groups, N = 8; one received only pCF1-CAT). In a third group (n = 8) lungs were harvested 24 hours after transfection, stored for 18 hours, and recipients were sacrificed after 24 hours. The CAT and β-Gal enzymatic-linked immunosorbent assays were performed. Part II: Lung/plasmid exposure time. In three groups (n = 6) after pCF1-CAT transfection the left main bronchus was not clamped, clamped for 10 minutes, or clamped for 1 hour. Sacrifice was after 48 hours.

Results. Part Ia: Lung CAT protein was (in picograms per 100 μg of total protein): median, 42 (range, 25 to 95) after 1 hour (only CAT); 67 (19 to 296) after 1 hour, 32 (6 to 157) after 6 hours; and 9 (5 to 243) after 18 hours. Lung β-Gal protein was (in picograms per 100 μg of total protein): median, 20 (range, 5 to 353) after 1 hour; 17 (6 to 157) after 6 hours; 4 (1 to 74) after 18 hours (1 hour versus 18 hours, p = 0.04 for both proteins). CAT and β-Gal production were significantly correlated (p = 0.0001, R = 0.924). Part Ib: Lung CAT protein was (in picograms per 100 μg of total protein): median, 2 (range, 0.6 to 10) no transplant, only CAT; 7 (0.3 to 13) no transplant; 3 (0.9 to 14) transplant. Part II: Left lung CAT protein was (in picograms per 100 μg of total protein): median, 31 (range, 6 to 83) no clamp; 74 (25 to 430) 10 minutes of clamp; 111 (30 to 263) 1 hour of clamp. Right lung CAT protein was (in picograms per 100 μg of total protein): median, 0.06 (range, 0 to 0.9) no clamp; 1 (0 to 6) 10 minutes of clamp; 1 (0 to 18) 1 hour of clamp.

Conclusions. Efficient lung isograft endobronchial cotransfection results from using naked plasmid. Cold preservation affects transfection efficiency but not transgene expression. Lung parenchyma/naked plasmid exposure time determines transfection efficiency.     

S100β after coronary artery surgery: release pattern, source of contamination, and relation to neuropsychological outcome

Background. S100β has been suggested as a marker of brain damage after cardiac operation. The aim of this study was to characterize the early S100β release in detail and relate it to neuropsychological outcome.

Methods. Three groups of patients were investigated. All patients underwent coronary artery bypass surgery (CABG) with extracorporeal circulation. In group A, 110 patients had sampling of S100β for the first 10 postoperative hours and also underwent neuropsychological testing. In group B, 14 patients were examined for the effect of autotransfusion on S100β levels. Eight patients in group C had their intraoperative bleeding processed with a cell-saving device.

Results. Group A had a heterogeneous release pattern with several rapid elevations in S100β concentration. In group B, high concentrations of S100β were found in the autotransfusion blood (range 0.2 to 210 μg/L) with a concurrent elevation of serum S100β levels after transfusion of shed blood. In group C, high levels of S100β were found in the blood from the surgical field (12.0 ± 6.0 μg/L) and decreased (1.1 ± 0.64 μg/L) after wash. Group C had significantly lower S100β values at the end of cardiopulmonary bypass compared to group A (0.53 ± 0.35 μg/L versus 2.40 ± 1.5 μg/L). S100β values were corrected for extracerebral contamination with a kinetic model. With this correction, an association was found between adverse neuropsychological outcome and S100β release in group A (r = 0.39, p < 0.02).

Conclusions. A significant amount of S100β is found both in the blood from the surgical field and in the shed mediastinal blood postoperatively. Infusion of this blood will result in infusion of S100β into the blood and interfere in the interpretation of early systemic S100β values.     

Effect of Low-Dose Positive Inotropic Drugs on Human Internal Mammary Artery Flow

Background. Dobutamine (a β-receptor agonist), enoximone (a type III selective phosphodiesterase inhibitor), and epinephrine (an - and β-mimetic) frequently are used in the perioperative management of patients undergoing coronary artery bypass grafting.

Methods. We performed a double-blind clinical study to compare the effects on internal mammary artery free flow of low doses of these three positive inotropic drugs. Thirty patients in whom the left internal mammary artery was used for coronary artery bypass grafting were randomized into three groups. Internal mammary artery free flow and hemodynamic measurements were evaluated before and 10 minutes after the intravenous infusion of dobutamine (3 μg · kg⁻¹ · min⁻¹), enoximone (200 μg/kg), or epinephrine (0.05 μg · kg⁻¹ · min⁻¹).

Results. A significant increase in free flow occurred only in the dobutamine group (33 ± 7.5 and 42.2 ± 7.9 mL/min before and after drug infusion, respectively; p = 0.013). Comparison of the increase in flow between the groups, however, showed no difference. These drugs, at doses designed to produce a positive inotropic effect, caused little increase in the free flow of the internal mammary artery.

Conclusions. The use of dobutamine, enoximone, and epinephrine as low-dose positive inotropic treatments in the perioperative and postoperative periods of coronary artery bypass grafting should depend on their positive inotropic effects rather than their vasodilative effects on the arterial grafts.     

Intravenous Phenylephrine Preconditioning of Cardiac Grafts From Non–Heart-Beating Donors

Background. Hypoxia and warm ischemia produce severe injury to cardiac grafts harvested from non-heart-beating donors. To potentially improve recovery of such grafts, we studied the effects of intravenous phenylephrine preconditioning.

Methods. Thirty-seven blood-perfused rabbit hearts were studied. Three groups of non-heart-beating donors underwent intravenous treatment with phenylephrine at 12.5 (n = 8), 25 (n = 7), or 50 μg/kg (n = 7) before initiation of apnea. Non-heart-beating controls (n = 8) received saline vehicle. Hypoxic cardiac arrest occurred after 6 to 12 minutes of apnea, followed by 20 minutes of warm in vivo ischemia. A 45-minute period of ex vivo reperfusion ensued. Nonischemic controls (n = 7) were perfused without antecedent hypoxia or ischemia.

Results. Phenylephrine 25 μg/kg significantly delayed the onset of hypoxic cardiac arrest compared with saline controls (9.6 ± 0.5 versus 7.7 ± 0.4 minutes; p = 0.00001), yet improved recovery of left ventricular developed pressure compared with saline controls (57.1 ± 5.3 versus 41.0 ± 3.4 mm Hg; p = 0.04). Phenylephrine 25 μg/kg also yielded a trend toward less myocardial edema than saline vehicle (p = 0.09).

Conclusions. Functional recovery of nonbeating cardiac grafts is improved by preconditioning. We provide evidence that the myocardium can be preconditioned with phenylephrine against hypoxic cardiac arrest.     

Myocardial metabolism and efficiency after warm continuous blood cardioplegia

Background. Warm continuous blood cardioplegia (WCBCP) has been recommended during prolonged cardiac arrest to minimize functional deterioration. Myocardial metabolism and efficiency after this cardioplegic modality are not well described.

Methods. Substrate oxidation, blood flow, and myocardial function were measured before, during, and after 3 hours of WCBCP in 7 pigs.

Results. Free fatty acid and glucose oxidation decreased by 60% ± 3.8% and 94% ± 1.2%, respectively, during cardioplegia (both p < 0.05) and increased to 62% ± 28% and 122% ± 62% of baseline during the early recovery phase (p < 0.05 for glucose). One hour after WCBCP oxidation rates were similar to baseline. The transient postcardioplegic increase in substrate oxidation was associated with a 43% ± 23% elevation of oxygen consumption (MVO₂) compared with baseline and a 62% ± 18% increase in myocardial blood flow. Cardiac output and mean arterial pressure did not change significantly after WCBCP, although myocardial function (stroke work, left ventricular end-systolic pressure, end-diastolic pressure, contractility, and efficiency) was depressed (p < 0.05). End-diastolic pressure and contractility improved from early to late phase of recovery, whereas the other indicators of ventricular function remained depressed.

Conclusions. Myocardial substrate oxidation was preserved after 3 hours of WCBCP, although ventricular function was moderately impaired. Thus, WCBCP with a seemingly normal substrate and oxygen supply was associated with a reduced cardiac efficiency.     

Calcitonin Gene-Related Peptide-Induced Preconditioning Improves Preservation With Cardioplegia

Background. Our recent work has shown that calcitonin gene-related peptide (CGRP) may play an important role in mediation of ischemic preconditioning. Therefore, we tested the hypothesis that CGRP-induced preconditioning protects against myocardial damage after prolonged cardioplegic arrest in isolated rat hearts.

Methods. Six groups were studied: the control, ischemic preconditioning, and CGRP-pretreated groups for both 4- and 8-hour hypothermic ischemia. All hearts were arrested using St. Thomas Hospital cardioplegia, and then reperfused with normothermic Krebs-Henseleit solution for 60 minutes after the 4- or 8-hour hypothermic ischemic period. Hearts were subjected to two cycles of 5-minute ischemia and 10-minute reperfusion in the ischemic preconditioning group. In the CGRP-pretreated group, Krebs-Henseleit solution containing CGRP (5 × 10⁻⁹ mol/L) was substituted for the ischemic period.

Results. At 30 minutes of reperfusion after 4-hour storage, left ventricular pressure (mm Hg) and its first derivative (dp/dt_max, mm Hg/s) in the control, ischemic preconditioning, and CGRP groups were 65.2 ± 5.93 and 1,170 ± 119, 94.13 ± 4.93 and 1,825 ± 145.83, and 85.47 ± 4.17 and 1,900 ± 123.13, respectively (p < 0.01). After 8-hour storage, left ventricular pressure (mm Hg) and dp/dt_max (mm Hg/s) in the same groups were 51.07 ± 5.83 and 815 ± 107.17, 83.47 ± 6.54 and 1,480 ± 120.91, and 84.8 ± 8.49 and 1,396 ± 126.16 (p < 0.01). Ischemic preconditioning and CGRP-induced preconditioning also significantly reduced the release of myocardial enzymes.

Conclusions. The present studies suggest that ischemic preconditioning protects against ischemia-reperfusion injury even after 8 hours of hypothermic preservation in isolated rat hearts, and that CGRP exerts preconditioning-like cardioprotection.     

Preconditioning: myocardial function and energetics during coronary hypoperfusion and reperfusion

Background. Ischemic preconditioning (IP) is gaining more acceptance as a protective method in beating heart surgery. Yet it remains controversial whether preconditioning can attenuate myocardial dysfunction during reperfusion after severe coronary hypoperfusion. We examined this issue and also the issue of whether this protection is mediated by adenosine A₁ receptors.

Methods. In isolated, blood-perfused rabbit hearts, the effects of IP (3 minutes of no flow ischemia and 8 minutes of reperfusion) during 30 minutes of coronary hypoperfusion and 60 minutes of reperfusion were investigated. In two groups (n = 8 each) with and without (control group) preconditioning, ventricular function was assessed by load-insensitive measures: slope of the end-systolic pressure–volume relation (E_max), slope of the stroke work/end-diastolic volume relation (M_w), and end-diastolic pressure–volume relation. External efficiency was calculated, and contractile efficiency was assessed using the reciprocal of the myocardial oxygen consumption–pressure–volume area relationship. To investigate the possible role of adenosine, the adenosine A₁ receptor antagonist DPCPX (2.5 μmol/L) was administered before preconditioning in a third group (n = 7).

Results. The effects of hypoperfusion on systolic function, diastolic function (dP/dt_min, end-diastolic pressure–volume relation), external efficiency, and contractile efficiency were similar in both the IP and control groups. Lactate efflux was significantly reduced after preconditioning (p = 0.02). During reperfusion, recovery of systolic function and coronary flow were significantly improved in the IP group compared with controls: aortic flow, 85% versus 63% (p = 0.01); dP/dt_max, 91% versus 67% (p = 0.001); pressure–volume area, 97% versus 68% (p = 0.01); E_max, 74% versus 62% (p = 0.03); and M_w, 94% versus 84% (p = 0.04). Release of creatine kinase was reduced in the IP group, 9.6 ± 1.3 U · 5 min⁻¹ · 100 g⁻¹ wet weight, versus controls, 12.7 ± 2.7 U · 5 min⁻¹ · 100 g⁻¹ wet weight (p = 0.04). During reperfusion, contractile efficiency (p = 0.03) and external efficiency (p = 0.02) recovered better in preconditioned than in untreated hearts. Recovery was less pronounced in the DPCPX group compared with the IP group (p, not significant).

Conclusions. The results, derived from load-insensitive measures, confirm that IP provides protection after episodes of severe hypoperfusion by attenuating systolic dysfunction without improving diastolic dysfunction and reduces the severity of anaerobic metabolism as well as ischemic injury. Contractile efficiency and external efficiency both indicate improved energetics after IP (oxygen utilization by the contractile apparatus). The protective effect, at least in part, is mediated by adenosine A₁ receptors.     

Brain Damage and Myocardial Dysfunction: Protective Effects of Magnesium in the Newborn Pig

Background. Brain damage is associated with myocardial dysfunction resulting from excessive release of endogenous catecholamines and Ca²⁺ overload. Magnesium ion, a natural Ca²⁺ blocker, has recently been recognized as a myoprotective agent.

Methods. Myocardial function was assessed in 3- to 7-day-old piglets from pressure–volume data (obtained by the conductance catheter/micromanometer technique) before and for 4 hours after ligation of the aortic arch vessels and was correlated with ultrastructural changes. Group a (n = 6) received MgSO₄ immediately after induction of brain damage for 4 hours, whereas group b (n = 6) did not receive MgSO₄ and served as control.

Results. In both groups after induction of brain damage, there was a significant (p < 0.05) increase in end-systolic elastance and preload-recruitable stroke work that persisted for 1 hour. However, after 2 and 4 hours, there was a significant (p < 0.05) reduction in both variables in group b (end-systolic elastance, 74% ± 5% and 59% ± 6%, respectively, and preload-recruitable stroke work, 77% ± 4% and 64% ± 3%, respectively, compared with baseline), and in group a, the values returned to baseline. The chamber stiffness index rose significantly (p < 0.05) in group b 15 minutes after induction of brain damage and remained significantly (p < 0.05) higher for 4 hours versus no significant change in group a. Plasma levels of epinephrine and norepinephrine were similar in the groups before and after brain damage. Electron microscopic study showed severe ultrastructural changes in group b and significantly milder changes in group a.

Conclusions. We conclude that MgSO₄ may protect the neonatal myocardium when administered immediately after brain damage.