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.     

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.     

Excimer versus carbon dioxide transmyocardial laser revascularization: effects on regional left ventricular function and perfusion

Background. Transmyocardial laser revascularization (TMR) has been established with the carbon dioxide (CO₂) laser. The largely unstudied excimer laser creates channels through chemical bond dissociation instead of thermal ablation, thereby avoiding thermal injury. We sought to compare the effects of CO₂ and excimer TMR in a porcine model of chronic ischemia.

Methods. Pigs underwent ameroid constrictor placement on the circumflex artery to create chronic ischemia. TMR was performed with CO₂ (n = 8) or excimer (n = 8) laser 6 weeks later; controls (n = 7) had ameroid placement only. Regional myocardial blood flow (RMBF), determined by radioactive microspheres, and regional myocardial function, determined by percent segmental shortening (%SS), were assessed 18 weeks after ameroid placement.

Results. Values are mean ± SD. In the ischemic zone, RMBF (mL/min/g) was improved in the CO₂ (0.73 ± 0.19) and excimer (0.78 ± 0.22) groups when compared with controls (0.55% ± 0.12%, p < 0.05). %SS was also improved in the CO₂ (15.2% ± 5.5%) and excimer (15.3% ± 5.1%) groups when compared with controls (8.0% ± 4.2%, p < 0.05).

Conclusions. Excimer and CO₂ TMR significantly improve RMBF and regional function in this porcine model of chronic myocardial ischemia despite fundamentally different tissue interactions.     

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.     

Heparin-Bonded Circuits Decrease Myocardial Ischemic Damage: An Experimental Study

Background. Heparin-bonded cardiopulmonary bypass circuits reduce complement activation, but their effect on myocardial function is unknown. This study was undertaken to determine whether heparin-bonded circuits reduce myocardial damage during acute surgical revascularization.

Methods. In 16 pigs, the second and third diagonal vessels were occluded with snares for 90 minutes followed by 45 minutes of cardioplegic arrest and 180 minutes of reperfusion with the snares released. During the period of coronary occlusion, all animals were placed on percutaneous bypass followed by standard cardiopulmonary bypass during the periods of cardioplegic arrest and reperfusion. In 8 pigs, heparin-bonded circuits were used, whereas 8 other pigs received nonbonded circuits.

Results. Animals treated with heparin-bonded circuits had the best preservation of wall motion scores (3.5 ± 0.3 versus 2.3 ± 0.2; 4 = normal to −1 = dyskinesis; p < 0.05), least tissue acidosis (change in pH = −0.31 ± 0.02 versus −0.64 ± 0.08; p < 0.05), smallest increase in lung H₂O (1.7% ± 0.7% versus 6.1% ± .5%; p < 0.05), and the lowest area of necrosis/area of risk (20.3% ± 2.2% versus 40.4% ± 1.6%; p < 0.05).

Conclusions. We conclude that heparin-bonded circuits significantly decrease myocardial ischemic damage during acute surgical revascularization.     

Depressed Function in Remote Myocardium After Myocardial Infarction: Influence of Orotic Acid

Background. We have previously shown that infarction impairs recovery of global function after subsequent cardioplegic arrest and that therapy with orotic acid improves recovery. The aim of this study was to measure the effect of infarction on regional and global left ventricular function and to determine whether orotic acid exerts a beneficial effect exclusive of the effects of cardioplegia.

Methods. Acute myocardial infarction was produced in dogs. They then received either orotic acid or placebo (control) orally (n = 12 per group). Fractional radial shortening and systolic wall thickening were measured by two-dimensional echocardiography before and 1 and 3 days after infarction with and without β-adrenergic blockade, and in 6 dogs up to 9 days after infarction. Global function was measured under anesthesia 4 days after infarction.

Results. In control animals, fractional radial shortening in the infarct decreased from 20.6% ± 5.1% before infarction to 3.0% ± 2.2% at day 1 and to 1.9% ± 1.9% at day 3 (p < 0.01). In the border zone radial shortening declined from 21.9% ± 3.7% to 11.0% ± 2.3% at day 1 and 9.3% ± 2.8% at day 3 (p < 0.05). In the noninfarcted myocardium radial shortening also declined from 27.1% ± 1.9% before infarction to 18.3% ± 2.3% on day 1 (p < 0.05) and to 16.0% ± 2.8% on day 3 after infarction (p < 0.05) with recovery to preinfarct levels by 9 days after infarction. These findings were confirmed by measurements of systolic thickening. Before infarction β-receptor blockade decreased fractional shortening in all regions of the left ventricle, but this effect was absent on day 3 after infarction, implying that the myocardium had become less responsive to β-adrenergic stimulation. Measurements of global function 4 days after infarction showed marked depression of stroke work. There was no effect of orotic acid treatment on regional or global function.

Conclusions. Myocardial infarction causes reversible depression of resting function and β-adrenergic responsiveness in the remote and border zone areas, which is not prevented by metabolic therapy with orotic acid. This finding may explain the adverse response of the infarcted heart to cardioplegic arrest.

(Ann Thorac Surg 1996;62:1765–72)     

Delayed impairment of cerebral oxygenation after deep hypothermic circulatory arrest in children

Background. Clinical studies of deep hypothermic circulatory arrest (DHCA) have focused only on the immediate postoperative period. However, experimental findings suggest impairment of cerebral oxygenation at 2 to 8 hours after reperfusion.

Methods. In 10 children who had DHCA for heart operations, transcerebral differences of hemoglobin oxygen saturation and plasma hypoxanthine, xanthine, and lactoferrin concentrations were measured in concurrently obtained cerebral venous, arterial, and mixed venous samples up to 10 hours postoperatively.

Results. Compared with preoperative levels (57% ± 7%), cerebral venous oxygen saturation was not significantly reduced until 2 hours (44% ± 6%) and 6 hours (42% ± 5%) after DHCA (p < 0.05). A statistically significant transcerebral (ie, cerebral vein versus artery) concentration difference of hypoxanthine was observed at 30 minutes (3.6 ± 0.9 μmol/L), 1 hour (3.4 ± 1.1 μmol/L), and 2 hours (3.1 ± 0.8 μmol/L) after DHCA but not preoperatively (0.4 ± 0.2 μmol/L). A transcerebral concentration difference of lactoferrin occurred 30 minutes after DHCA (196 ± 70 μg/mL) but not preoperatively (16 ± 20 μg/mL).

Conclusions. Cerebral venous oxygen saturation of hemoglobin decreased as late as 2 to 6 hours after DHCA, in association with impaired cerebral energy status. Neutrophil activation in the cerebral circulation occurred 30 minutes after reperfusion.     

Cytostatic Lung Perfusion by Use of an Endovascular Blood Flow Occlusion Technique

Background. Different modalities of cytostatic lung perfusion were compared regarding plasma and tissue drug concentrations to assess the efficacy of an endovascular blood flow occlusion technique.

Methods. A cytostatic lung perfusion study with doxorubicin hydrochloride was performed on large white pigs (n = 12). Plasma and tissue concentrations of doxorubicin were compared for isolated lung perfusion with open cannulation (ILP), blood flow occlusion perfusion with open cannulation of the pulmonary artery alone (BFO), and intravenous drug administration (IV). In a fourth group, thoracotomy-free BFO perfusion was performed by endovascular balloon catheterization of the pulmonary artery (endovascular BFO). The 3 animals in this group were used to compare the doxorubicin-perfused pulmonary tissue with the contralateral nonperfused lobes after 1 month.

Results. The mean lung tissue doxorubicin concentration at the end of perfusion was 19.8 ± 1.6 μg/g after ILP, 27.6 ± 2.2 μg/g after BFO (p = not significant), and 3.0 ± 0.8 μg/g after IV perfusion (p < 0.01). Whereas doxorubicin was not detectable in the plasma in the ILP group, concentrations ranged from not detectable to 0.44 μg/mL in the BFO group and from 0.31 to 0.84 μg/mL in the IV group (p < 0.05). Mean myocardial tissue concentration was not significantly different after BFO than IV perfusion (1.1 ± 0.5 μg/g and 1.8 ± 0.1 μg/g, respectively). In the endovascular BFO group, balloon-blocked pulmonary artery perfusion was successfully performed in all animals, and after 1 month, lung tissue showed no cytostatic-induced histologic changes.

Conclusions. Compared with ILP, BFO cytostatic lung perfusion produced an insignificantly higher lung-tissue concentration, corresponding to a sixfold to ninefold higher level than after IV perfusion. Plasma drug levels during BFO perfusion were lower than during IV perfusion. Endovascular BFO may be a promising technique for repeated cytostatic lung perfusion.     

Partial left ventriculectomy: which patients can be expected to benefit?

Background. Although some patients with end-stage heart disease will benefit from a partial left ventriculectomy, no criteria have been found for identifying this group preoperatively. Our experience with partial left ventriculectomy at two institutions—the Texas Heart Institute in Houston, TX, USA, and Dedinje Cardiovascular Institute in Belgrade, Yugoslavia—showed a higher survival rate and better postoperative myocardial function in the Yugoslavian patients.

Methods. We reviewed data from 42 patients (21 at each center) who had idiopathic cardiomyopathy, a left ventricular end-diastolic dimension of more than 70 mm, wall thickness of 1 cm or greater, and New York Heart Association class III or IV symptoms. The only significant difference in preoperative status between the two groups was duration of symptoms. Histologic specimens, blinded as to origin, were graded with regard to myocyte hypertrophy, cytoplasmic vacuolation, and fibrosis. Computer-assisted myocyte and nuclear morphometry was also performed.

Results. Immediately postoperatively, there were no significant intergroup differences in the reduction in cardiac dimension or in corrections of mitral regurgitation. During 6-month follow-up, however, the Texas Heart Institute patients had a lower cardiac index (1.8 versus 3.0 L·min⁻¹·m⁻²; p = 0.001) and left ventricular ejection fraction (24% versus 34%; p = 0.006) than the Dedinje Cardiovascular Institute patients. The Texas Heart Institute patients differed from the Dedinje Cardiovascular Institute patients in the degree of severe or moderate changes in myocyte hypertrophy (90% versus 29%; p = 0.0003) and fibrosis (71% versus 29%; p = 0.006), as well as in the measurements of median myocyte diameter (35 ± 7 μm versus 27 ± 4 μm; p = 0.0002) and median nuclear size (15 ± 4 μm versus 12 ± 2 μm; p = 0.0029).

Conclusions. In the Texas Heart Institute patients, the significant intergroup difference in clinical outcome may have been related to increased myocyte hypertrophy and fibrosis. Further studies should be performed to determine the usefulness of these criteria in selecting patients for partial left ventriculectomy.     

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.     

Leukocyte Depletion of Blood Cardioplegia Attenuates Reperfusion Injury

Background. Leukocytes are associated with myocardial injury during reperfusion after ischemia. Short periods of leukocyte depletion during reperfusion result in persistent attenuation of postischemic myocardial dysfunction.

Methods. Leukocyte depletion was examined in a canine model of regional myocardial ischemia and reperfusion. The extracorporeal circuit and cardioplegia circuits underwent leukocyte depletion by mechanical filtration. Animals were instrumented for baseline global function before 90-minute occlusion of the left anterior descending coronary artery. Global function during ischemia and at 5, 30, 60, and 90 minutes after a 60-minute cardioplegic arrest using continuous blood cardioplegia was assessed in leukocyte-depleted (n = 9) and control (n = 10) groups.

Results. No significant difference between groups was seen for systemic leukocyte counts, global function, or water content. Endothelial function was significantly protected as assessed by response to both calcium ionophore (endothelial-dependent, receptor-independent relaxation: leukocyte-depleted, 72% ± 19% of endothelin-induced constriction versus control, 46% ± 14%; p < 0.05) and acetylcholine (endothelial-dependent, receptor-dependent relaxation: leukocyte-depleted, 83% ± 11% versus control, 44% ± 15%; p < 0.05).

Conclusions. Leukocyte-mediated endothelial reperfusion injury can be attenuated by leukocyte depletion during reperfusion.     

Onset and recovery of neuromuscular blockade after two doses of rocuronium in children

Study Objective: To determine if 450 μg/kg (1.5 times the ED₉₅) of rocuronium would result in a comparable onset with a shorter duration of action when compared with 600 μg/kg (2 times the ED₉₅).

Design: Randomized, single-blind study.

Setting: Teaching hospital.

Patients: 85 ASA physical status I and II children ages 2 through 12, undergoing elective surgery with an inhalation induction using halothane.

Interventions: Group 1 received 600 μg/kg rocuronium, and Group 2 received 450 μg/kg rocuronium.

Measurements and Main Results: The two groups were compared using a Student’s t-test, with p < 0.05 significant. The time of onset, or time to 95% suppression of neuromuscular twitch with standard errors, was 140 ± 13 seconds (range 46 to 365 sec) in Group 1 and 148 ± 13 seconds (range 82 to 345 sec) in Group 2 (NS = not significant). The times to 25% return of twitch from baseline (T₂₅) in Groups 1 and 2 were 28 ± 1.5 minutes (range 14 to 45 min) and 26 ± 1.6 minutes (range 10 to 55 min), respectively (NS). The differences between these two doses in onset of, and recovery from, block were not found to be statistically significant. The results, however, excluded 5% of the higher dose group and 31% of the lower dose group who did not achieve 95% suppression of twitch. Time to maximal suppression of neuromuscular blockade, however, was not statistically significant for the 85 patients with a time of 270 ± 28 seconds (range 91 to 605 sec) with a mean maximal suppression of 98.7% in Group 1 and 313 ± 25 seconds (range 91 to 899 sec) with a mean maximal suppression of 93.1% in Group 2.

Conclusion: The two doses of rocuronium did not differ statistically in onset or duration. Rocuronium at 600 μg/kg offers more reliability than 450 μg/kg in achieving adequate muscle relaxation, and the lower dose may result in a significantly large number of patients who may have inadequate intubating conditions.     

Comparison of troponin-I and troponin-T after pediatric cardiovascular operation

Background. Although the diagnostic value of troponin-T in childhood is documented, little is known about the significance of troponin-I. It was the aim of this study to compare the diagnostic value of troponin-I and troponin-T in children and newborns to assess the perioperative potential myocardial damage.

Methods. Forty-eight children, mean, 51 ± 54 months (mean value ± 1 standard deviation) (range, 1 day to 204 months) undergoing cardiac operation were prospectively enrolled in the present study. Troponin-I, troponin-T, creatine kinase (CK), and the MB isoenzyme were measured before operation and postoperatively within 2 days.

Results. Postoperative values of troponin-I for children undergoing extracardiac operation were in the normal range. In children with interventions through the right atrium (n = 10) the mean value increase to 6.5 ± 6.1 μg/L (range, 1.8 to 24.3 μg/L) and even to a mean of 29.9 ± 21.1 μg/L (range, 7.5 to 90 μg/L) (p < 0.01) in children with atrial and additional ventricular surgical approach (n = 23). Troponin-I was of equal specificity and sensitivity compared to troponin-T, excepted in patients with postoperative renal failure in whom troponin-T raised to false pathological results.

Conclusions. For detection of perioperative myocardial damage troponin-I shows a higher specificity than CK-MB activity and CK-MB mass. The diagnostic value of troponin-I is similar to troponin-T, but compared with troponin-T, it has the advantage of not being influenced by renal failure.     

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.     

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.     

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.     

Superiority of magnesium cardioplegia in neonatal myocardial protection

Background. We have shown that magnesium can offset the detrimental effects of normocalcemic cardioplegia in hypoxic neonatal hearts. It is not known, however, whether magnesium offers any additional benefit when used in conjunction with hypocalcemic cardioplegia.

Methods. Twenty neonatal piglets underwent 60 minutes of ventilator hypoxia (FiO₂ 8% to 10%) followed by 20 minutes of normothermic ischemia on cardiopulmonary bypass (hypoxic-ischemic stress). They then underwent 70 minutes of multidose blood cardioplegic arrest. Five (Group 1), received a hypocalcemic (Ca⁺² 0.2 to 0.4 mM/L) cardiologic solution without magnesium, whereas in 10, magnesium was added at either a low dose (5 to 6 mEq/L, Group 2) or high dose (10 to 12 mEq/L, Group 3). In the last 5 (Group 4), magnesium (10 to 12 mEq/L) was added to a normocalcemic cardioplegic solution. Function was assessed using pressure volume loops and expressed as percentage of control.

Results. Compared to hypocalcemia cardioplegic solution without magnesium (Group 1), both high- and low-dose magnesium enrichment (Groups 2 and 3) improved myocardial protection resulting in complete return of systolic (40% vs 101% vs 102%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (39% vs 102% vs 101%) (p < 0.001 vs Groups 2 and 3), and reduced diastolic stiffness (267% vs 158% vs 154%) (p < 0.001 vs Groups 2 and 3). Conversely, even high-dose magnesium supplementation could not offset the detrimental effects of normocalcemic cardioplegia resulting in depressed systolic (End Systolic Elastance [EES] 41% ± 1%) (p < 0.001 vs Groups 2 and 3) and global myocardial function (40% ± 1%) (p < 0.001 vs Groups 2 and 3), and a marked rise in diastolic stiffness (258% ± 5%) (p < 0.001 vs Groups 2 and 3). Hypocalcemic magnesium cardioplegia has now been used successfully in 247 adult and pediatric patients.

Conclusions. Magnesium enrichment of hypocalcemic cardioplegic solutions improves myocardial protection resulting in complete functional preservation. However, magnesium cannot prevent the detrimental effects of normocalcemic cardioplegia when the heart is severely stressed. This study, therefore, strongly supports using both a hypocalcemic cardioplegic solution and magnesium supplementation as their benefits are additive.     

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.     

Effect of slow-release sodium fluoride on cancellous bone histology and connectivity in osteoporosis

We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 ± 0.176 g/cm² SD to 0.872 ± 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 ± 0.4μm/d to 1.1 ± 0.7, p = 0.0078) and adjusted apposition rate (0.4 ± 0.3 μm/d to 0.6 ± 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 ± 878 μm to 1052 ± 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm² of cancellous tissue area (0.22 ± 0.12 vs. 0.39 ± 0.27, p = 0.0077), the mean node to free-end ratio (0.23 ± 0.21 vs. 0.41 ± 0.46, p < 0.05), and in the mean node to node strut length per mm² of cancellous area (0.098 ± 0.101 vs. 0.212 ± 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length. When patients were divided into those with severe and mild-modest spinal bone loss (based upon initial lumbar bone density) the significant changes in connectivity occurred in patients with mild-moderate bone loss, but not in those with severe bone loss, suggesting that fluoride's effect is in part dependent on the presence of a certain critical amount of bone. This finding in combination with the previously reported increases in bone mass and bone material quality may explain the significant reduction in vertebral fracture rate observed with this particular fluoride regimen.     

Functional comparison of transmyocardial revascularization by mechanical and laser means

Background. As a result of the clinical benefit observed in angina patients treated by transmyocardial revascularization (TMR) with a laser, interest in mechanical TMR has been renewed. Although the injury induced by mechanical TMR is similar to laser TMR, the resultant impact on myocardial contractility is unknown. The purpose of this study was to determine whether mechanical TMR improves ventricular function as compared with laser TMR in chronically ischemic myocardium.

Methods. After establishing an area of chronic myocardial ischemia, 25 domestic pigs were randomized to treatment by: excimer laser (group I), a hot needle (50°C) (group II), a normothermic needle (group III), an ultrasonic needle (40 KHz) (group IV), or no treatment (group V). All devices create a transmural channel of the same diameter; 22 ± 1 transmural channels were created in each animal. Regional myocardial contractility was assessed by measuring ventricular wall thickening at rest and with dobutamine stress echocardiography. Six weeks after revascularization, the animals were restudied at rest and with stress. Postsacrifice and histologic analysis of angiogenesis and TMR effects was then assessed.

Results. Laser TMR provided significant recovery of ischemic myocardial function. This improvement in contractility after laser TMR was a 75% increase over the baseline function of the ischemic zone (p < 0.01). Mechanical TMR provided no significant improvement in function posttreatment. In fact, TMR achieved with an ultrasonic needle demonstrated a 40% worsening of the contractility versus the pretreatment baseline (p < 0.05). Histologic analysis demonstrated a significant increase in new blood vessels in the ischemic zone after laser TMR, which was not demonstrated for any of the other groups (p < 0.05). Additionally, evaluation of the mechanical TMR channels demonstrated significant scarring, which correlated with the functional results.

Conclusions. Using devices to create an injury analogous to the laser, mechanical TMR failed to improve the function of chronically ischemic myocardium. Only laser TMR significantly improved myocardial function.