Real-Time Myocardial Contrast Echocardiography in Rat: Infusion Versus Bolus Administration

To compare the feasibility of real-time myocardial contrast echocardiography (MCE) in rats with infusion and bolus administration of a second-generation ultrasound contrast agent BR1. B-mode real-time MCE was performed in 12 Sprague Dawley rats following the BR1 infusion or bolus injection. The myocardium signal intensity (SI) was plotted against time and was fitted to exponential functions. The plateau SI (A) and rate of SI increase (β) for the infusion study and peak signal intensity (PSI) for the bolus study were obtained. ^99mTc-Sestamibi and Evans blue were used to assess myocardial blood perfusion and to calculate the myocardium perfusion defect area ex vivo. High-quality real-time MCE images were successfully obtained using each method. At baseline, all LV segments showed even contrast distribution. Following left anterior descending coronary artery (LAD) ligation, significant perfusion defect was observed in LAD beds with a significantly decreased A* β and PSI values compared with LCx beds (Infusion: A*β _LAD: 5.42 ± 1.57dB, A*β _LCx: 46.52 ± 5.32dB, p < 0.05; Bolus: PSI _LAD: 2.11 ± 0.67dB, PSI _LCx: 20.68 ± 0.72 dB, p < 0.05), which was consistent with ^99mTc-Sestamibi distribution findings. Myocardial perfusion defect areas, assessed by both methods, showed no differences and showed good correlation with Evans blue staining. ED frames were more favorable for imaging analysis. Both infusion and bolus administration of the contrast agent combined with real-time MCE technique can provide a reliable and noninvasive approach for myocardial perfusion assessment in rats and the infusion method was more suitable for quantitative analysis of myocardial blood flow. (E-mail: suhaili@fmmu.edu.cn)     

Real-time myocardial blood flow imaging in normal human beings with the use of myocardial contrast echocardiography.

Triggered myocardial contrast echocardiography (MCE) has been used successfully to quantify myocardial blood flow and assess coronary stenosis in animal models, but practical considerations have limited its broad clinical use. Real-time MCE may have practical advantages to assess perfusion and real time myocardial blood flow in human beings. We compared real-time MCE with triggered imaging in 23 normal human volunteers by using an investigational ultrasound contrast agent (DMP-115) and a commercially available ultrasound platform (Acuson Sequoia). Peak myocardial opacification (reflecting myocardial blood volume) after contrast infusion was quantified digitally in gray scale units (GU). In 13 subjects, myocardial blood flow reserve was assessed during dipyridamole infusion with the use of intermittent destruction-replenishment techniques. Real-time MCE resulted in a 30- to 45-GU increase from baseline compared with a 20- to 70-GU increase with triggered imaging. Real-time MCE showed no statistical difference in opacification (P = .131 by analysis of variance) among any of the myocardial regions of interest. Triggered imaging resulted in heterogeneous opacification among the regions of interest (P < .05 by analysis of variance). Dipyridamole did not significantly change peak myocardial opacification (myocardial blood volume) for either technique. Quantification of flow reserve revealed that myocardial blood flow reserve for the dipyridamole group was 3.6 +/- 0.4 (mean +/- 1 standard error of the mean). Real-time MCE is feasible in normal human volunteers and provides homogenous opacification of the myocardium. Furthermore, quantification of myocardial blood flow with real-time MCE in normal human beings produces results that are consistent with the known physiology of the coronary microcirculation.     

Intermittent harmonic imaging and videodensitometry significantly enhance ability of intravenous air-filled ultrasonographic contrast agent to produce ventricular and myocardial opacification.

We used visual and videodensitometric evaluation to investigate the influence of intermittent harmonic imaging (IHI) compared with intermittent fundamental imaging on cavity and myocardial signal intensity after administration of the air-filled transpulmonary contrast agent BY963. Twelve patients were studied with intermittent fundamental imaging and IHI after administration of 5 mL and 10 mL of contrast agent. Contrast effect was graded in the parasternal short-axis view. Visually, IHI improved opacification of both the right and left ventricular cavities, especially the left. Densitometrically, right ventricular opacification did not differ significantly between imaging modalities, whereas left ventricular cavity opacification was significantly higher when using IHI. Myocardial opacification was observed in a small minority of segments when assessed by visual estimation, whereas videodensitometry revealed opacification in 42 of 48 anterior, 39 of 48 posterior, and 42 of 48 septal segments. Differences were not significant between doses. We conclude that with IHI and densitometry, air-filled contrast agents like BY963 show significantly improved performance in producing cavity and myocardial contrast effects.     

Optimal thrombolytic strategies for acute myocardial infarction--bolus administration

Optimal strategies for thrombolysis in myocardial infarction (TIMI) are still being sought because the TIMI 3 flow rates achievable using standard regimens average approximately 60%. Double bolus administration of recombinant tissue plasminogen activator (tPA) is a novel approach with potential for earlier patency combined with ease of administration. We reviewed total patency rates, TIMI 3 patency rates, mortality, stroke and intracranial haemorrhage rates in the major trials of accelerated infusion tPA/bolus tPA/reteplase in acute myocardial infarction. A direct comparison was performed with results of two recent trials of double bolus (two 50 mg boli, 30 min apart) vs. accelerated infusion tPA: the Double Bolus Lytic Efficacy Trial (DBLE), an angiographic study, and the COBALT Trial, a mortality study. The DBLE trial showed equivalent patency rates for accelerated infusion and double bolus administration of tPA. Reviewing other angiographic trials, total patency and TIMI 3 patency rates achievable with double bolus tPA were comparable to those with accelerated infusion tPA or bolus reteplase administration. The COBALT study demonstrated a 30-day mortality of 7.53% in patients treated with accelerated infusion tPA compared with 7.98% for double bolus tPA treated patients. The small excess in mortality with double bolus treatment was confined to the elderly; in those < or = 75 years, mortality rates were 5.6% and 5.7%, for double bolus and accelerated infusion, respectively, and rates for death or non-fatal stroke were 6.35% and 6.3%, respectively. Comparison with other trials demonstrated mortality, stroke and intracranial haemorrhage rates with double bolus treatment similar to those associated with either accelerated infusion tPA or bolus reteplase treatment. Double bolus administration of tPA to patients with acute myocardial infarction is associated with total patency, TIMI 3 patency, mortality, stroke and intracranial haemorrhage rates similar to those associated with either accelerated infusion of tPA or bolus reteplase.     

Persistent opacification of the left ventricle and myocardium with a new echo contrast agent.

Echo contrast agents with long survival times open up new fields of application in the investigation of tissue perfusion and cardiovascular function. The purpose of this study was to characterize the time-course of the opacification of the heart cavities and myocardium with a new long-lasting second-generation, phospholipid-based echo contrast agent containing perfluoropentane (BY963-C5F12), and to compare its contrast potency with that of air-filled phospholipid monolayer (BY963-air). Doses of 0.03 mL/kg, 0.08 mL/kg and 0.16 mL/kg of BY963-air and BY963-C5F12 were administered intravenously to six conscious dogs weighing 25-36 kg. A transthoracic echocardiography was performed to evaluate peak intensity and area under the curve (AUC) from regions-of-interest placed in the right ventricle, left ventricle and left ventricular (LV) myocardium using acoustic densitometry. All injections were well tolerated, without wall-motion abnormalities or ECG changes. The LV cavity and myocardium were uniformly and well opacified for both echo contrast agents. However, at all administered doses, the contrast efficacy and duration were much more pronounced using BY963-C5F12 than with BY963-air. For the myocardium, the average peak intensity increased from 11.9+/-2.8 to 15.0+/-2.7 (not significant) following injection of BY963-air and from 12.8+/-3.2 to 18.7+/-2.8 (p < 0.01) following IV administration of BY963-C5F12; the latter corresponding to an increase in myocardial opacification of 46%. In conclusion, these results show the high myocardial opacification of BY963-C5F12 as compared to BY963-air. The simple incorporation of a perfluorocarbon gas into the phopholipid monolayer BY963 instead of air alters the acoustic properties of this contrast agent, resulting in qualitatively different application potentials for tissue opacification.     

Determinants of myocardial hypoperfusion analyzed for the interventricular septum using power Doppler harmonic imaging with contrast echocardiography in humans: a methodologic approach for clinical practice.

BACKGROUND: To evaluate determinants of myocardial hypoperfusion using power Doppler harmonic imaging (PDHI) with myocardial contrast echocardiography (MCE) in clinical practice, a retrospective clinical study was performed comparing echocardiographic and angiographic data. Angiographic data of patients with a normal coronary angiogram (non-CAD) and symptomatic patients with low flow conditions caused by a stenosis of the left anterior descending coronary artery (LAD) or occlusion, or TIMI-II-flow in the LAD were compared with the PDHI data. METHODS AND RESULTS: In 32 patients, MCE was performed with a System Five Performance ultrasound system (GE Vingmed Ultrasound, Horten, Norway). Myocardial perfusion was semiquantitatively analyzed with the EchoPac 6.2b.134 software, bolus injection with Optison (0.35 mL with 5 mL saline flush), and continuous infusion with Levovist (400 mg/mL(-1); 3.5-5 mL/min(-1)) were performed (8 non-CAD patients, 8 CAD patients, respectively). After bolus injection, Doppler intensity (DI) kinetics showed a significant decrease of maximum DI wash-in rate (eg, apical septum [AS]: 4.9 +/- 3.3 vs 2.4 +/- 1.9 dB/s(-1)), of peak maximum DI (eg, AS: 25.3 +/- 6.3 vs 16.4 +/- 5.7 dB), and of DI determined 10 and 20 seconds after peak maximum DI (eg, AS: 22.1 +/- 4.9 vs 10.8 +/- 4.6 dB; AS: 20.4 +/- 5.3 vs 8.0 +/- 3.8 dB, respectively) using a trigger interval once every 3 cardiac cycles when normal perfused areas were compared with hypoperfused areas. During infusion coronary transit time (3.3 +/- 0.9 vs 7.0 +/- 3.6 seconds), maximum DI wash-in rate (eg, AS: 3.2 +/- 1.3 vs 1.3 +/- 0.8 dB/s(-1)) and DI-maximum plateau (eg, AS: 28.6 +/- 4.7 vs 18.3 +/- 6.4 dB) significantly decreased, respectively. CONCLUSION: Regional myocardial hypoperfusion at rest can be detected by using PDHI with MCE in clinical practice, according to a standardized methodologic protocol.     

Cyclic variation of myocardial signal intensity in real-time myocardial perfusion imaging

BACKGROUND: The presence of cyclic intensity variation during real-time myocardial perfusion imaging (RTPI) has been controversially discussed. We investigated whether cyclic intensity variation is systematically found during RTPI and whether such variations are related to regional functional parameters. METHODS: Intraoperative RTPI were obtained in 12 pigs before, during, and after left descending coronary artery occlusion with 60 mL/h SonoVue infusion. Furthermore, RTPI was performed in 14 patients after slow bolus injection of 0.7 mL of Optison. Instantaneous regional systolic to diastolic (S/D) myocardial intensity ratios were calculated after high mechanical index bubble destruction. S/D ratios were correlated with A- and beta-values, and fractional area shortening. RESULTS: Systematic cyclic S/D changes were present in both experimental settings showing significantly higher systolic values (animals, S/D 1.28 +/- 0.44; patients, S/D 1.25 +/- 0.7). Cyclic S/D variation was not related to fractional area shortening, or A- or beta-values (all r < 0.3, not significant). CONCLUSION: Consistent cyclic changes in myocardial contrast intensity can be measured both in intraoperative animals and in patients, showing higher systolic values. S/D ratios are not related to regional functional parameters.     

Lanreotide effect on splanchnic blood flow in healthy subjects: effect of the rate of infusion

BACKGROUND: Somatostatin is a naturally occurring peptide advocated for the management of hemodynamic complications of chronic liver diseases. The route of administration (bolus application or constant infusion) has been a question of debate. AIM: Our aim was to explore the effects of the somatostatin analog lanreotide, given as a bolus injection or continuous infusion, on food-stimulated hemodynamics in humans. METHODS: Twelve healthy subjects (6 men and 6 women) were studied in a double-blind, double-dummy, randomized, crossover study. After a baseline period of 60 minutes, each subject received either a placebo bolus injection and an intravenous infusion of 100 microg/h lanreotide over a period of 8 hours or a placebo infusion over a period of 8 hours and an 800-microg lanreotide bolus injection. Simultaneously, a liquid test meal (Ensure Plus, 6.3 kJ/mL; Abbott Laboratories, Abbott Park, Ill) was perfused intraduodenally at 3 mL/min over a period of 8 hours. Diastolic blood pressure, heart rate, and superior mesenteric arterial and portal venous volume flows were measured at regular intervals by use of echo-Doppler technology. Plasma lanreotide levels were determined at defined intervals. RESULTS: Lanreotide as a 100-microg/h infusion for 8 hours was bioequivalent with lanreotide as an 800-microg bolus injection (mean area under the plasma concentration-time curve [AUC] extrapolated to infinity [AUC( infinity )], 1844.3 ng.min/L versus 1971.0 ng.min/L; AUC(infinity) ratios, 0.99; confidence interval, 0.95-1.02), and clearance was identical (479.2 mL/min versus 413.4 mL/min, P >.05). As expected, significant differences were observed in maximum plasma concentrations (75.58 ng/mL versus 4.85 ng/mL, P <.001) after infusion and bolus injections, respectively. Lanreotide at 100 microg/h over a period of 8 hours was well tolerated and abolished food-stimulated splanchnic hyperemia in both the superior mesenteric artery and the portal vein (mean AUC above baseline values [AUC(ab)], 37.25 L/min.min and 0.51 L/min.min, respectively). In contrast, the same dose of lanreotide given as a bolus injection only temporarily blunted postprandial hyperemia (mean AUC(ab) for superior mesenteric artery, 251.4 L/min.min, P <.001; mean AUC(ab) for portal vein, 194.95 L/min.min, P <.001), and subjects had significantly more side effects. CONCLUSION: On the basis of tolerability and hemodynamic effects, an intravenous infusion of lanreotide seems superior to a bolus injection of the same dose.     

Benefit of slow infusion of hypertonic saline/dextran in swine with uncontrolled aortotomy hemorrhage

In laboratory models of uncontrolled hemorrhage, immediate resuscitation from hemorrhage is associated with high mortality. However, in clinical practice, resuscitation is often delayed and the rate of fluid administration is limited. We hypothesized that a slow rate of infusion after delayed resuscitation, reflecting the clinical environment, might improve survival in the presence of uncontrolled hemorrhage. To investigate the rate of administration in the presence of delayed resuscitation, we subjected anesthetized swine weighing 35 to 45 kg to wire suture abdominal aortotomy that resulted in an uncontrolled hemorrhage. After a 30-min delay, hemorrhaged swine were infused i.v. with 4 mL/kg hypertonic saline/Dextran solution (7.5% saline in 6% Dextran 70) administered as a bolus over 1 min or as a slow infusion over 12 min (the time period to administer a similar volume to a human with a gravity feed i.v. and an 18-gauge needle) and were then monitored for another 90 min. Survival increased to 78% (seven of nine) in the slow infusion group compared with a survival rate of 56% (five of nine) in the bolus group and 50% (7/14) in the untreated controls. Blood loss was significantly higher in the bolus group (926 +/- 77 mL) compared with the slow infusion (714 +/- 83 mL) and control groups (604 +/- 46 mL). Hypertonic saline/Dextran administered slowly significantly increased cardiac output and blood pressure. Taken together, these results are consistent with the hypothesis that resuscitation solutions can be effective for treatment of uncontrolled hemorrhage when administered at a slow infusion rate 30 min after the insult.     

Comparison of the tolerability of recombinant human hyaluronidase + normal saline and recombinant human hyaluronidase + lactated ringer's solution administered subcutaneously: A phase IV, double-blind, randomized pilot study in healthy volunteers

Background: Recombinant human hyaluronidase (rHuPH20) (150 U) is approved by the US Food and Drug Administration to facilitate subcutaneous fluid administration in adults and children.Objective: This Phase IV, double-blind, randomized pilot study was designed to compare the tolerability, flow rate, and safety profile of subcutaneous infusions of normal saline (NS) and lactated Ringer's (LR) solutions following subcutaneous administration of rHuPH20.Methods: Healthy volunteers received 1 mL rHuPH20 (150 U) in each thigh, followed by simultaneous gravity-driven subcutaneous infusions of 500 mL of LR solution into 1 thigh and NS solution into the contralateral thigh. Subjects rated infusion-site discomfort in each thigh using a 100-mm (0 = no pain to 100 = most severe pain) visual analog scale (VAS) at baseline (ie, after catheter placement/ rHuPH20 injection and just prior to the start of the infusions) and at the following times: after infusion of 250 mL, after infusion of 500 mL (end of infusion), and when thigh circumference returned to within 5% of baseline. Adverse events (AEs) were recorded throughout the study. The primary tolerability end point was the maximal increase from baseline in infusion-site discomfort on the VAS. Secondary end points included infusion flow rate, change in thigh circumference, subject preference for leftversus right-thigh infusion, and safety profile measures.Results: Fifteen subjects (14 women, 1 man; mean age, 41 years [range, 20–60 years]) were included in the study. Mean (SD) maximal increase from baseline VAS pain score was significantly greater with NS solution than with LR solution (20.0 [19.4] vs 9.4 [18.3] mm, respectively; P = 0.005). Mean infusion flow rate was not significantly different between the NS and LR solutions (384.1 [118.1] vs 395.8 [132.8] mL/h). No significant differences between solutions were observed in mean maximal change in thigh circumference (5.2% [1.6%] vs 5.3% [1.5%]). All subjects expressed global preference for LR infusion over NS infusion. All subjects experienced ≥1 AE; the majority of AEs were mild, localized infusion-site reactions. Of all AEs (regardless of their relationship to study drug or procedure), 81% were mild injectionsite reactions that were similar in nature for the NS and LR solutions. Although the types of mild local AEs were similar for the 2 infusions, they were numerically more common with NS infusions (15 subjects [100%]) than with LR infusions (9 subjects [60%]). For the NS and LR solutions, the most frequent infusion-site AEs were pain (67% vs 40%, respectively), erythema (47% vs 13%), and irritation (27% vs 20%).Conclusions: This small pilot study found that the mean maximal increase from baseline in self-assessed pain VAS scores was statistically significantly higher with NS solution than LR solution. In addition, all subjects preferred LR solution to NS solution, and the incidence of some infusion-site AEs was numerically greater with NS solution. Although the VAS score indicated a statistically significant difference in tolerability favoring LR, the modest changes from baseline suggest both solutions were generally well tolerated and support the use of both NS and LR, as appropriate, for rHuPH20-facilitated subcutaneous isotonic fluid infusion in healthy adults. These results need to be confirmed in larger, controlled clinical studies.     

Cerebrospinal fluid and plasma pharmacokinetics of morphine infusions in pediatrie cancer patients and rhesus monkeys

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of morphine administered as a continuous infusion were studied in pediatric cancer patients and in monkeys with implanted Ommaya reservoirs.

In monkeys administered a constant infusion of 0.15 mg morphine sulfate/kg/h, morphine steady-state plasma and CSF concentrations were 84.4 ±20.0 ng/ml and 25.3 ± 4.9 ng/ml, respectively, for a CSF : plasma ratio of 0.30 ± 0.05. For comparison, the monkeys also received morphine as an intravenous bolus at a dose of 0.45 mg morphine sulfate/kg. The CSF:plasma area under the concentration-time curve (AUC) ratio was 0.40 ± 0.07, similar to that seen with continuous infusion.

Morphine pharmacokinetics were also studied in cancer patients administered long-term infusions of morphine sulfate over a wide dosage range (0.04–31 mg/kg/h). The steady-state plasma concentration of morphine was linearly related to the infusion rate although variability was noted. The average clearance value was 23 ml/min/kg which is at the upper end of the estimates reported for morphine clearance using bolus administration. No evidence for morphine accumulation using long-term administration was observed. A limited number of CSF samples obtained by lumbar puncture showed comparable CSF and plasma concentrations of unbound morphine assuming morphine is approximately 30% bound in human plasma.     

Assessment of no-reflow phenomenon after acute myocardial infarction with harmonic angiography and intravenous pump infusion with Levovist: comparison with intracoronary contrast injection.

Myocardial contrast echocardiography (intracoronary application) has emerged as an accurate method to detect the "no-reflow phenomenon." To investigate the diagnostic value of harmonic angiography after intravenous infusion of Levovist in assessing "no-reflow," both intracoronary and intravenous contrast injections were performed in a group of patients with acute myocardial infarction. Seventeen consecutive patients with a successfully reperfused acute myocardial infarction within 6 hours of symptom onset were selected for this study. All patients underwent contrast echocardiography with harmonic angiography with Levovist (400 mg/mL, intravenous pump infusion, trigger intervals 1:4 to 1:8) and sonicated albumin (0.5 to 1 mL, intracoronary bolus) on day 1 after the achievement of a sustained coronary reflow. Myocardial perfusion was qualitatively assessed with a 12-segment model. The endocardial length of the residual contrast defect after reflow was also calculated. Forty-four of 204 segments were not analyzed after intravenous contrast echocardiography and 37 after intracoronary contrast echocardiography because of artifacts. Intracoronary and intravenous injections showed a perfusion defect in 31 (19%) segments, with a concordance of 89% (kappa coefficient, 0.72). Concordance in anteroseptal, anterolateral, and inferolateral segments was 95% (kappa = 0.92), 88% (kappa = 0.66), and 83% (kappa = 0.57), respectively. With intracoronary injection used as the reference method, intravenous injection had a sensitivity of 74% and a specificity of 93% for diagnosing contrast defects. The endocardial extent of no-reflow was 18 +/- 19 after intravenous and 21 +/- 17 after intracoronary contrast echocardiography (P = not significant). Intravenous contrast echocardiography with Levovist reliably identifies the no-reflow phenomenon after successful reperfusion, especially in acute anteroseptal myocardial infarction.     

Differing susceptibility of echocardiographic contrast agents to adverse effects of biologic factors: multicenter, videodensitometric comparison of octafluoropropane-filled microspheres with air-filled microspheres for left ventricular opacification.

BACKGROUND: Echocardiographic contrast enhancement of the left ventricle has diagnostic value in the assessment of regional and global left ventricular (LV) function. The efficacy of both octafluoropropane-filled human albumin microbubbles (OCTA) and of air-filled human albumin microbubbles (AIR) for LV endocardial delineation and qualitative LV opacification has previously been reported. However, pulmonary disease, obesity, impaired LV function, and decreased echogenicity may diminish the efficacy of contrast agents for LV opacification. The purpose of this study was to compare the susceptibility of 2 contrast agents currently approved by the Food and Drug Administration to these biologic factors. METHODS: To compare quantitative LV opacification with OCTA (0.2, 0. 5, 3.0, 5.0 mL) versus AIR (0.08 mL/kg, 0.22 mL/kg), we performed videodensitometry in 199 patients (average age 59.2 +/- 13.3 years, 79% men) studied in 2 identical, prospective, multicenter, blinded trials, of whom 74 had impaired LV function, pulmonary disease, or both, 70 were obese (body mass index >30 kg/m(2)), and 45 were nonechogenic (>/=4 of 6 endocardial segments were not seen in the apical 4-chamber view). Changes in videodensity from noncontrast to contrast agent with the same gain settings were determined at end diastole and end systole (gray scale 0 to 255 U) for 2 regions of interest: left ventricle apex-to-mid-cavity and mid-cavity-to-base. The relative influence of clinically evident pulmonary disease, impaired LV function on echocardiography, and echogenicity on LV opacification produced by both contrast agents was determined by multivariate analysis. RESULTS: Significant videodensity increases ranging from 67% to 143% were observed with both agents. At the recommended initial doses (0.5 mL for OCTA, 0.22 mL/kg for AIR), OCTA produced greater opacification than AIR in both regions of interest and at both phases of the cardiac cycle. Poor LV function was associated with decreased LV opacification for AIR but not for OCTA. Diminished echogenicity was more strongly associated with impaired opacification for AIR than for OCTA. Obesity and clinically evident pulmonary disease were associated with diminished chamber opacification with both OCTA and AIR. CONCLUSIONS: In addition to the superiority of octafluoropropane-filled microspheres to air-filled microspheres for LV opacification, the efficacy of OCTA is relatively unaffected by impaired LV function and is less susceptible to the effects of poor echogenicity than AIR.     

Ringer's lactate with or without 3% dextran-60 as volume expanders during abdominal aortic surgery.

OBJECTIVE: To compare a solution of 3% dextran-60 (D60) in Ringer's lactate (RL) with RL alone as maintenance fluids for abdominal aortic surgery. DESIGN: Randomized control trial of 20 consecutive patients undergoing elective aortic reconstructive surgery. SETTING: A surgical ICU in a university hospital. PATIENTS: Consecutive patients, mean age 64 yr. Five patients had abdominal aneurysm, 12 had aortic obstruction disease, and three had aortic renal bypass surgery. These patients were followed for 1 month. INTERVENTIONS: Pulmonary artery occlusion pressure of at least 10 mm Hg and a urine output greater than 30 mL/h were used to guide the intraoperative fluid infusion rates, which were 36 and 104 mL/kg of D60 and RL, respectively (ratio 1:2.9). MEASUREMENTS AND MAIN RESULTS: Body weight at 24 hr had increased more with RL (7.8 kg) than with D60 (3.2 kg) infusion (p less than .01), despite intraoperative urine volumes of 151 and 92 mg/kg with RL and D60, respectively. Total intravascular albumin decreased from 0.7 g/kg (1.4 to 0.7 g/kg) in both groups, corresponding to a plasma volume (PV) loss of 13 mg/kg without fluid infusions. A total intravascular dextran of 0.5 g/kg resulted in a PV expansion at 1 hr of 4.4 mL/kg above preoperative level, in sharp contrast to 7.0 mL/kg decrease in PV with RL. Of the intraoperative 3% D60 and RL infused, an estimated 51% D60 and 6% RL remained as PV expansion at 1 hr. CONCLUSIONS: A diluted colloid solution in Ringer's lactate is of significant value in maintaining intravascular volumes and hemodynamics during and after major operative procedures.     

Potential causes of insufficient bladder contrast opacification and premature microbubble destruction during contrast-enhanced voiding urosonography in children

Contrast-enhanced voiding urosonography (ceVUS) has been recognized as a child-friendly examination with high diagnostic accuracy for vesicoureteric reflux detection. A single bolus and the infusion techniques of ceVUS are described. Insufficient bladder contrast opacification during the filling phase and premature destruction of SonoVue microbubbles might occur. Data regarding SonoVue's features, doses, bladder contrast opacification, US bladder parameters, urine catheter, antibiotic prophylaxis, and childrens behaviors were collected to discover the possible causes of the contrast vanishing observed during bladder filling in 10% of examinations and in the later phase of ceVUS in 5% of examinations. An updated ceVUS examination protocol is suggested.     

Assessment of myocardial viability in prior myocardial infarction by intravenous bolus microbubble injection: a new time domain index to estimate regional relative myocardial blood volume.

We tested whether the duration of myocardial opacification by harmonic power Doppler imaging after intravenous bolus microbubble injection (with a definition of "the end of opacification") would reflect the remaining vascular bed in infarcted segments. In 28 patients with previous myocardial infarction and 20 control patients, we performed harmonic power Doppler imaging after intravenous bolus injection of 1.5 g of Levovist. Using multiframe trigger mode in which 4 consecutive frames were imaged at every sixth end systole, which formed 1 "burst," we recorded anterior/septal and inferior/posterior walls separately on the center of each apical view with individual boluses. The duration of segmental opacification was measured as the number of "bursts" in which color signals persisted until the fourth frame. The duration was similar between the anterior/septal and inferior/posterior walls (13 +/- 3 vs 13 +/- 3 bursts, not significant) in the control group. In myocardial infarction patients, the duration was significantly shorter in the infarcted than in the control segments (6 +/- 6 vs 14 +/- 3 bursts, P < .001) and their ratio and difference exhibited significant correlations (r = 0.82, P < .001 and r = 0.91, P < .001, respectively) with the activity ratio on thallium Tl 201 single-photon emission computed tomography at rest. Thus, the duration of opacification by harmonic power Doppler imaging after intravenous bolus microbubble injection, the measurement of which was standardized by using multiframe trigger mode, may be useful in assessing regional myocardial viability in patients with previous myocardial infarction.     

Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1-40). Evidence for intermittent somatostatin secretion.

Growth hormone (GH) secretory patterns were studied in a patient with ectopic growth hormone releasing factor (GRF) secretion and in normal men given continuous infusions of human growth hormone releasing factor (1-40)-OH (hGRF-40). In the patient with ectopic GRF secretion, GH secretion was pulsatile despite continuously elevated immunoreactive GRF levels. To determine if pulsatile GH secretion is maintained in normal subjects, we administered to six healthy young men vehicle or hGRF-40, 2 ng/kg per min, for 24 h and gave a supramaximal intravenous bolus dose of hGRF-40, 3.3 micrograms/kg, after 23.5 h of infusion. hGRF-40 infusion resulted in greater GH secretion than did vehicle infusion and pulsatile GH secretion was maintained throughout hGRF-40 infusion. During the 23.5 h of vehicle infusion, total GH secretion (microgram; mean +/- SEM) was 634 +/- 151 compared with 1,576 +/- 284 during hGRF-40 infusion (P = 0.042). The GH response to the intravenous bolus of hGRF-40 was greater after vehicle infusion than after hGRF-40 infusion; 877 +/- 170 and 386 +/- 125 micrograms of GH was secreted after the bolus on vehicle and hGRF-40 days, respectively (P = 0.015). The total amount of GH secreted during the 25.5 h of the two study days was not different; 1,504 +/- 260 and 1,952 +/- 383 micrograms were secreted during vehicle and hGRF-40 days, respectively (P = 0.36). Not only was pulsatile GH secretion maintained during hGRF-40 infusion, but there was augmentation of naturally occurring GH pulses, which is in contrast to the effect of gonadotropin-releasing hormone on gonadotropin secretion. We suggest that GH pulses are a result of GRF secretion that is associated with a diminution or withdrawal of somatostatin secretion.     

Setting up ultrasonic equipment for myocardial contrast echocardiography with venous injection of optison (FS-69): An experimental study

Background Although Optison (FS-69) is commercially available in the United States, the optimal setup of ultrasonic equipment for myocardial contrast echocardiography has yet to be elucidated. Here we examine the optimal setting for adequate opacification of the myocardium. Method Optison (0.1 ml) was administered intravenously during recording of the short axis view of the left ventricle using the Toshiba prototype echocardiographic system in 11 open-chest beagledogs. Myocardial opacification was evaluated by calculating the baseline-subtracted peak video intensity (256 gray scale) at four regions of the left ventricular wall: the anterior, lateral, posterior, and septal walls. We examined the fundamental (3.75 MHz) and second harmonic (2.5/5.0 MHz) imaging during both continuous and intermittent (one pulse per cardiac cycle) mode. Acoustic power (AP) decreased in steps of 1.5 dB from maximal mechanical index (1.4). We also examined the effect of the distance between and the heart by placing an ultrasonic spacer with a width of 1 cm or 3 cm. Results Myocardial opacification was hardly, recognized by the continuous mode; however, the intermittent mode provided sufficient opacification in either the fundamental or harmonic mode. Excessive acoustic power did not improve myocardial opacification. The influence of high acoustic power was significant in the field near the transducer. Conclusion The left ventricular myocardium is clearly opacified by venous administration, of Optison when the mechanical settings of the ultrasonic equipment are appropriate.     

The pharmacokinetics, safety, and tolerance of cefepime administered as an intravenous bolus or as a rapid infusion

OBJECTIVE: To evaluate the pharmacokinetics, safety, and tolerability of cefepime administered as an intravenous bolus and short infusion. METHODS: A single-dose, pharmacokinetic study was conducted on 16 healthy men. Fifty milliliters of a 40 mg/mL solution of cefepime was administered by continuous infusion in intervals of three, five, 10, or 15 minutes. Blood was sampled three minutes through 12 hours after the end of the infusion. Analysis of cefepime was performed by reverse-phase HPLC with ultraviolet detection. Cefepime plasma concentrations versus time were evaluated by noncompartmental methods. History and physical examinations were conducted within two weeks of the start of the study, 24 hours before dosing, and at the end of the study. Assessments for adverse events were made throughout the study. RESULTS: Maximum concentration (Cmax) increased with decreasing time of infusion and was similar to reference values of Cmax. Pharmacokinetic characteristics of cefepime were not affected by the time of infusion and were on average: mean residence time was 2.3 hours, half-life 1.9 hours, the AUC extrapolated to infinity 239 microg x h/mL, total body clearance 142 mL/min, and steady-state volume of distribution 19 L. No serious adverse events, local tolerance at injection site, or significant laboratory abnormalities were noted. CONCLUSIONS: Cefepime 2 g was safely administered to healthy subjects as a rapid, single bolus, and its key pharmacokinetic parameters were consistent with those from longer infusions and other studies.     

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.