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Ann Thorac Surg 2003;75:1542-1548
© 2003 The Society of Thoracic Surgeons

Original article: cardiovascular

Contrast echocardiography: potential for the in-vivo study of pediatric myocardial preservation

Meredith L.K. Sheil, MBBS, FRACPa,b*, Timothy B. Cartmill, MBBS, FRACSa,b, Graham R. Nunn, MBBS, FRACSa, Gary F. Sholler, MBBS, FRACPa, Olli T. Raitakari, MD, PhDd, David S. Celermajer, PhD, FRACPa,c,d

a Adolph Basser Cardiac Institute, The Children’s Hospital, Westmead, NSW, Australia
b department of Paediatrics and Child Health, University of Sydney, Sydney, Australia,
c department of Medicine, University of Sydney, Sydney, Australia
d Royal Prince Alfred Hospital, Sydney, Australia

Accepted for publication November 22, 2002.

* Address reprint requests to Dr Sheil, Adolph Basser Cardiac Institute, The Children’s Hospital Westmead, Locked Bag 4001, Westmead, NSW, Australia 2145
e-mail: meredits{at}chw.edu.au


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Myocardial contrast echocardiography (MCE) has been used successfully during adult cardiac surgery to image myocardial perfusion. Recently it has been suggested this technique is capable of detecting microvascular injury and inflammation because sonicated albumin microbubbles adhere to activated neutrophils and, in the presence of denuded or inflamed endothelium, they persist within the microvasculature rather than passing unimpeded, which results in profound slowing of their transit rates. The technique has not previously been used during congenital heart surgery; however significant potential is suggested in this setting in which myocardial inflammation may contribute to postoperative myocardial dysfunction, a leading cause of morbidity and mortality. We have performed a preliminary study to assess the safety and feasibility of MCE in the pediatric intraoperative environment and to examine myocardial transit rates.

METHODS: Sonicated albumin microbubbles were injected with cardioplegia during bypass in 16 children (aged 3 weeks to 8.5 years). Images were collected using transesophageal echocardiography. Complications, postbypass electrocardiographic, echocardiographic, and outcome data were recorded. Myocardial transit rates were calculated using videointensity analysis, assessed for reproducibility and correlated with demographic and intraoperative variables and postoperative outcome.

RESULTS: The technique was performed safely, with good reproducibility. Myocardial persistence of microbubbles, which occurred in 6 patients, was associated with crystalloid cardioplegia, prolonged preischemic bypass (r = 0.72, p = 0.004), or ischemic time (r = 0.69, p = 0.002).

CONCLUSIONS: Intraoperative MCE shows potential as an in vivo technique for the study of pediatric myocardial preservation.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Postoperative myocardial dysfunction is a leading cause of morbidity and mortality in children undergoing repair of congenital heart disease (CHD) [1]. Inflammatory mechanisms due to interaction between blood and the cardiopulmonary bypass (CPB) circuit and to ischemia/reperfusion of the heart are believed to play a significant role in the development of this condition [2–4]. The relative contribution of inflammatory mechanisms in vivo in individual pediatric cases is difficult to assess, however, owing to the heterogeneity of CHD, the lack of a real time method of assessment, and the constraints of interfering with surgical procedures.

Recently it has been shown that sonicated albumin microbubbles attach to activated neutrophils and in the presence of injured or inflamed endothelium they persist within the microvasculature rather than passing unimpeded [5]. Therefore myocardial transit rates of such microbubbles, measured using myocardial contrast echocardiography (MCE), may serve as an in vivo marker of coronary neutrophil-endothelial cell interaction—a significant component of the inflammatory response. The technique of intraoperative MCE [6] although previously used in adults has not been utilized in children [7]. We have adapted this technique to minimize interference with the surgical procedure and measured myocardial transit rates in children undergoing CPB to assess the feasibility, safety, and reproducibility of this technique and to investigate whether myocardial persistence of microbubbles occurs in this setting. We have examined factors associated with microbubble persistence in order to direct further studies.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
This protocol underwent review and conformed to the guidelines of the Children’s Hospital Ethics and Drug Committees. Written informed consent was obtained from parents of all patients entered in the study.

Patient protocol
The initial subject group comprised 7 consecutive patients referred for repair of CHD considered to be at "low" surgical mortality risk. After the safe performance of the technique in this group, a further 9 consecutive patients undergoing higher risk surgery were included (Table 1). Enrolled patients underwent the usual anesthetic induction and transesophageal echocardiographic (TEE) probe placement. Cardiopulmonary bypass was established after heparin administration (300 U/kg) with bicaval and ascending aortic cannulation. The extracorporeal circuit comprised a Stokert SIII (System 1 or 2) heart lung machine. A standard one-quarter or three-eighths inch circuit was used with a Cobe UPCML/Polystan Safe Micro membrane oxygenator with an open venous reservoir and Bentley AF54OD/Capiox CXA502 arterial filter. Nonpulsatile flow rates were used to maintain mean systemic pressures of 30 to 60 mm Hg. Systemic temperatures were maintained between 24°C to 33°C although lowered to 18°C in 2 patients who underwent a period of circulatory arrest.


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  		Table 1. Preoperative, Intraoperative, and Cardioplegia Variables and Myocardial Transit Rates ({alpha} Values) During First, Second, and Third Doses of Cardioplegia

 
Cardioplegia solution was chosen at the surgeon’s discretion. Crystalloid cardioplegia was used in 2 children (Table 1) and consisted of a base solution (Delta West, Bentley, Western Australia) containing sodium (81 mmol/L), potassium (30 mmol/L), calcium (0.7 mmol/L), chloride (78 mmol/L), glucose (28 mmol/L), and mannitol (28 mmol/L) with added buffer solution containing sodium bicarbonate and carbonate to achieve a pH of 7.6, and albumin (100 mL) to achieve a final concentration of 4 g/100 mL. Blood cardioplegia was used in 14 patients and consisted of 4 parts oxygenated blood to 1 part cardioplegic base solution. Base solution contained sodium (48.6 mmol/L), potassium (82 mmol/L), calcium (0.74 mmol/L), chloride (132 mmol/L), and mannitol (26 mmol/L; Baxter Healthcare; Old Toongabbie, NSW, Australia). Sodium bicarbonate 8.4% was added to achieve a pH of 7.6

Cardioplegia (15 mL/kg) was delivered antegrade through a DLP catheter into the cross-clamped aortic root. Infusions were repeated at regular 20-minute intervals during cross clamping. Myocardial contrast echocardiography was performed during the second half of cardioplegia delivery in as many as three cardioplegia infusions encompassing an ischemic time of 0 to 40 minutes.

Myocardial contrast echocardiography
Myocardial contrast echocardiography was performed with an Acuson 128XP/10c (Seimens, Mountview, CA) with pediatric transesophageal biplane probe using the transgastric midpapillary short axis view of the left and right ventricles. Using 7.5 MHz scanning, power and gain settings were adjusted to achieve optimum imaging and then held constant for the period of the study. Microbubble delivery was achieved using a power injector (MedRad Mark IV [Medrad, Indianola, PA]), connected through tubing to the cardioplegia delivery system by a three-way tap inserted on the anesthetic side of the point of entry of the cardioplegia recirculation line. This allowed the microbubble delivery system to be deaired, flushed, and loaded during cardioplegia recirculation before cardioplegia delivery. Sonicated albumin microbubbles (0.25 to 0.5 mL; Albunex; Molecular Biosystems, San Diego, CA) were loaded into the tubing through a three-way tap at the power injector end and delivered as a bolus over a constant duration of 1 second after cardiac arrest had been achieved. A second bolus was given during the first dose when time permitted (n = 9 patients). Cardioplegia settings and microbubble dose (optimized to avoid too great or too little intensity of myocardial contrast effect) were documented and repeated precisely for all subsequent MCE evaluations in each patient. Videotape images (Sony SVO-9500 MDP [Sony Corporation, Tokyo, Japan]) were collected onto super VHS tape.

Analysis of myocardial transit rates of microbubbles
Echocardiographic images were analyzed off-line using a videodensitometric analysis software package (National Institutes of Health-Image PC, Scion Corp, Frederick, MD) and previously described algorithms for the derivation of myocardial transit rate [6]. Videotape images encompassing the period of contrast appearance and disappearance from the myocardium were captured on a computer (Compaq Prolinea 5133 [Hewlett Packard, Palo Alto, CA]) in an 8 bit format at 15 frames/s. A region of interest was defined over the interventricular septum, transferred for frame by frame analysis and average videointensity over time was plotted. These time-intensity data were background subtracted and fitted to a gamma variate function y = Ate-{alpha}t, where y = videointensity, t = time, A = a scaling factor, and {alpha} is proportional to mean myocardial transit rate. Curve fitting was performed using SPSS statistical software package (SPSS, Chicago, IL).

Images from 11 randomly selected patients were analyzed twice by blinded observers to assess both intraobserver and between observer variability in myocardial transit rate assessment.

Demographic, intraoperative, and postoperative variables
Age, weight, and body surface area were recorded as well as cardiac lesion and preoperative arterial saturation. After induction of anesthesia and insertion of an arterial line, blood samples were drawn for preoperative hematocrit and biochemical analysis. Cardioplegia was sampled through a side port at the time of delivery for similar analysis. Cardioplegia flow, pressure, and temperature were recorded and repeated as closely as possible during all subsequent doses in each patient. Myocardial temperature was monitored using a 15-mm disposable right-angle thermocouple myocardial temperature probe (Shiley, Irvine, CA) inserted into the right ventricular myocardium in 9 cases. Cross-clamp time, perfusion records, and inotrope requirements for separation from bypass were documented. Cardiac rhythm and six-lead ECG were documented after reperfusion and echocardiographic assessment was performed in the immediate period after separation from bypass. Postoperative outcome was documented by noting days ventilated, days in intensive care, days on inotropic support, and the number of inotropic drugs utilized. Postoperative management was performed by staff unaware of the results of myocardial transit rate assessments.

Statistical analysis
Data are expressed as mean ± standard deviation. Comparisons among preoperative variables, perfusate variables, and myocardial transit rates were performed using univariate and multiple linear regression. Group comparisons were made using the Student two-tailed independent t test or the nonparametric Mann-Whitney U test as appropriate. Differences were considered significant at p = 0.05 or less.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Sixteen children (8 male, 8 female) were enrolled. Cardiac lesions are documented in Table 1. The age range was 3 weeks to 8.5 years (mean 33 ± 33 months), the weight range was 3.2 to 35.2 kg (mean 12.8 ± 9.4 kg), and the body surface area range was 0.2 to 1.2 m2 (mean 0.5 ± 0.3 m2).

Safety issues
Complications
There were no overt physical complications associated with the use of this technique. Microbubble delivery was controlled remote from the surgical field and readily incorporated with minimal to no disruption to the surgical procedure. Air from the open heart trapped in the aortic root caused myocardial opacification at the onset of cardioplegia delivery before microbubble delivery and unrelated to it in 2 cases and precluded MCE assessment (microbubbles were not injected in these cases). These events required a change in surgical protocol to improve deairing of the aortic root before cardioplegia delivery. Inadvertent air embolization due to MCE was avoided by checking and flushing all lines before microbubble delivery and was confirmed during echocardiographic imaging.

Postoperative outcome in the low surgical mortality risk group
Children with no preoperative cyanosis or significant heart failure, aged more than 6 months, and with a short cross-clamp time (patients 1 to 7, Table 1) were considered to have low surgical mortality risk (n = 7). Postoperative myocardial dysfunction was not expected in this group based on usual outcomes within the unit. Safety was assessed in these patients before enrolling higher risk cases. All children demonstrated prompt resumption of sinus rhythm after release of the cross clamp, except 1 patient in whom ventricular fibrillation occurred briefly after atrial septal defect repair and readily reverted to sinus rhythm after direct current shock. All patients demonstrated absence of significant ST-segment changes on electrocardiographic recordings and no evidence of segmental or global ventricular dysfunction on postbypass TEE. Dopamine (5 µg/kg) was used routinely for separation from bypass. No child required additional inotropic support. All were extubated on or soon after their return to the ward. One child required reintubation for acute laryngeal edema, the rest were discharged from the intensive care unit within 24 hours.

Myocardial image quality
The transgastric short axis view provided adequate myocardial images in all patients, with good contrast effect throughout the interventricular septum and left ventricular myocardium during the first dose of cardioplegia. Contrast effect in the right ventricular free wall was less consistently seen because of attenuation from microbubbles in the interventricular septum and echocardiographic interference from air over the surface of the right ventricle. Interference with image quality precluded MCE evaluation during 4 of 16 subsequent doses of cardioplegia owing to inadvertent air embolization with cardioplegia or to aortic regurgitation of cardioplegia (Table 1).

Myocardial transit rate assessment
Repeatability
The mean myocardial transit rates ({alpha} values) for all patients during the first dose was 1.56 ± 0.58 s-1 (range 0.52 s-1 to the fastest rate of 2.7 s-1). The mean of differences between two separate transit rate assessments during the first dose of cardioplegia was 0.13 s-1, measurement error (ME) 0.16 s-1 with 95% confidence interval (95%CI) 0.31 s-1, and intraclass correlation coefficient (ICC) 0.93 (1 indicates perfect repeatability and < 0.8 indicates poor repeatability). The mean difference in measurements of the same observer (analyzed blindly on a different day) was 0.04 s-1 with ME 0.07 s-1, 95%CI 0.13 s-1, and ICC 0.98. The mean difference between two independent observers was 0.11 s-1 with ME 0.15 s-1, 95%CI 0.3 s-1, and ICC 0.93.

Myocardial opacification and myocardial persistence of microbubbles
Two distinctly different patterns of myocardial opacification were visible to the naked eye during microbubble delivery. In one the microbubbles appeared and disappeared briskly; in the other microbubbles appeared and then persisted within the myocardium, producing a prolonged opacification effect. This second pattern translated to a marked prolongation of the washout phase of the time intensity curve and profound slowing (< 1.0 s-1) of myocardial transit rate.

Both patients receiving crystalloid cardioplegia displayed myocardial persistence of microbubbles during the first and all subsequent doses of cardioplegia and consequently demonstrated transit rates that were more than 2 standard deviations slower than patients receiving blood cardioplegia (0.52 and 0.56 versus 1.7 ± 0.4 s-1, p = 0.03). (This phenomenon has been previously described as associated with crystalloid cardioplegia delivery [6]). Figure 1 illustrates time intensity curves from 2 representative neonates. The pattern of myocardial persistence of microbubbles with delayed washout and marked widening of the curve (corresponding to significant slowing of transit rate) can be seen in the neonate receiving crystalloid cardioplegia. In this study however this phenomenon was not confined to children receiving crystalloid cardioplegia.



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  		Fig 1. Videointensity curves from 2 neonates receiving blood (triangles, with dashed line) or crystalloid (circles, with solid line) cardioplegia, showing markedly delayed washout of sonicated albumin microbubbles in the patient receiving crystalloid cardioplegia (see methods for details). (pxl = pixels; te = time multiplied by exponential.)

 
Myocardial transit rates during blood cardioplegia
Mean myocardial transit rate during the first dose of blood cardioplegia was 1.7 ± 0.4 s-1 (range, 0.9 s-1 to 2.7 s-1). Myocardial persistence of microbubbles was noted during the first dose of blood cardioplegia in a child with pulmonary atresia and ventricular septal defect who underwent a prolonged period of CPB for repairing pulmonary artery stenoses before aortic root cross clamping. It also appeared to be developing in a second child who underwent a similarly prolonged preischemic bypass time. There was a strong correlation between preischemic bypass time and initial myocardial transit rate (r = 0.72, p = 0.004). The pattern of myocardial persistence of microbubbles also developed in 3 children during doses subsequent to the first dose of cardioplegia (Table 1). In these children microbubble transit was brisk during the first dose but the washout phase was dramatically prolonged during the second (n = 2) or third (n = 1) dose of cardioplegia. Correspondingly transit rates during the second or third doses of cardioplegia were significantly slower than during the first dose (1.7 ± 0.1 versus 1.1 ± 0.2 s-1, p = 0.02). There was significant correlation between elapsed ischemic time (0, 20, or 40 minutes) and transit rate, (r = 0.69, p = 0.002). (Patients with prolonged preischemic bypass were excluded from this analysis).

There were no significant differences between cardioplegia variables (pH, PO2, PCO2, Na+, K+, hematocrit, temperature, or flow) or myocardial temperatures between first and subsequent MCE assessments that might account for this profound alteration in myocardial transit in these cases and none of these variables correlated with myocardial transit rates (Tables 1 and 2).


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  		Table 2. Correlation Among Preoperative, Intraoperative, and Cardioplegia Variables and Myocardial Transit Rates in Children Receiving Blood Cardioplegia

 
Postoperative outcomes
Postoperative outcomes in the low surgical mortality risk group are outlined above. In addition to those outcomes 9 children (including 4 neonates) with significant preoperative congestive cardiac failure (n = 4) or cyanosis (n = 5) underwent more complex surgery requiring longer ischemic times (patients 8 to 16, Table 1). These children were considered to be at higher risk of postoperative myocardial dysfunction and mortality based on usual outcomes within the unit and demonstrated evidence of this with the need for escalating or prolonged inotropic support (mean days on inotropic support, 5; range, 1 to 10), prolonged respiratory support (mean days ventilated, 4; range, 1 to 10), and intensive care unit stay (mean, 5 days; range, 2 to 10). There was 1 postoperative death, which occurred because of technical problems with coronary reimplantation in a child with transposition of the great arteries and complex coronary artery anatomy, and postoperative pulmonary hypertension occurred in 1 child with atrioventricular septal defect.

Correlation between transit rates and postoperative outcome
Postoperative outcome is known to be related to the length of hypothermic ischemia in congenital heart surgery [8]. Consistent with this we found a correlation between cross-clamp time and postoperative outcome (r = 0.7, p = 0.01). As we also found a correlation between myocardial transit rates and cross clamp time, final myocardial transit rate also appeared predictive of postoperative outcome, including days in intensive care (r = -0.69, p = 0.006), days on inotropic support (r = -0.77, p = 0.001; Fig 2), days ventilated (r = -0.6, p = 0.01), and number of inotropic drugs required (r = -0.7, p = 0.007).



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  		Fig 2. Correlation between the final myocardial transit rate recorded for each patient and postoperative support requirements in the 14 children receiving blood cardioplegia. (A) Number of days on inotropic support (r = -0.77, p = 0.001). (B) Number of days in intensive care (r = -0.69, p = 0.006).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In this study, we report our experience with intraoperative MCE for pediatric patients with regard to feasibility, safety, repeatability, and potential to provide novel insights into myocardial preservation.

There are inherent limitations to the technique of MCE. The principle limitation is the inability to standardize input function (aortic root volume, dose and volume of distribution of microbubbles etc) to make reliable between-patient assessments of myocardial transit rates. In addition beating heart assessments require different techniques, algorithms, and methods of analysis than arrested heart assessments. For the purposes of this initial study we addressed these issues by confining ourselves to examining myocardial transit rates during cardioplegia delivery and investigating changes over time within individual patients (in whom the input function can be standardized). We present results from between-patient analyses only where marked differences were observed (notably due to the phenomenon of microbubble persistence). In that event we have documented that MCE can be performed safely with minimal interference with surgical technique for a wide range of pediatric patients undergoing CPB. Transit rates assessments are reproducible and changes to patterns of microbubbles flow over time can be detected within individual patients. Myocardial persistence of microbubbles occurs in some cases and that, coupled with results from recent intravital studies, suggests MCE may provide a means of detecting acute inflammatory events at the microvascular level in real time, in vivo during cardiac surgery.

Safety
Previous investigators have demonstrated the safety of injecting sonicated albumin microbubbles through direct coronary or aortic root injection both in adults [7] and children [9]. The microbubbles are smaller than red blood cells and pass through the microcirculation without obstruction or interference with coronary hemodynamics before rapidly dissolving [10]. In the setting of surgery for CHD it is difficult to document biochemical evidence of injury potentially related to microbubble delivery in a meaningful fashion because patients undergo varying cardiac incisions and periods of myocardial ischemia. Such a study would require patient numbers beyond the scope of this initial study but the rapid and uncomplicated recovery of all children undergoing short ischemic times is in keeping with previous studies attesting to the safety of this technique.

Image quality and repeatability
Sonicated albumin microbubbles are fragile and readily destroyed by exposure to high pressure, ultrasound, and sheer forces. Despite this our modified technique proved capable of producing high-quality images of left ventricular and interventricular septal perfusion, allowing for reproducible assessment of myocardial transit rates in the majority of cases. In the open heart deairing of the aortic root before cardioplegia delivery is required to maximize image acquisition. Alternative techniques such as direct epicardial echocardiography may be more optimal for imaging perfusion of the right ventricular free wall.

Changes to microbubble flow patterns
In the beating heart, microbubbles pass through the microcirculation with a rheology similar to red blood cells. They therefore act as free flowing tracers and their transit rates correspond to myocardial blood flow [10]. In the arrested heart, when input factors are controlled microbubble transit rates should reflect cardioplegia flow rates; however, that is not always so. A distinctly different pattern is known to occur during crystalloid cardioplegia delivery [6]. When microbubbles are delivered with crystalloid cardioplegia a fraction persists within the myocardium until dissolved. That causes a dramatic prolongation of myocardial opacification effect seen using echocardiography. The marked delay in microbubble washout results in a significant prolongation of the transit time measured using videointensity analysis [6, 11].

An initial study investigating this phenomenon demonstrated that adhesion of microbubbles within the microvasculature was associated with disruption of the endothelial glycocalx due to the low hematocrit of the crystalloid cardioplegia [12]. Although the exact mechanism of adhesion was not elucidated in this setting, the finding prompted further investigation into the relationship between microvascular persistence of microbubbles and microvascular pathology. That led to the discovery that albumin shell microbubbles bind to activated neutrophils and, in the setting of ischemia/reperfusion or cytokine-induced inflammation, microvascular persistence of microbubbles occurs and correlates directly with adhesion of activated neutrophils to postcapillary venules [5]. Several subsequent studies have confirmed that microvascular persistence of microbubbles can be used as a means of detecting tissue inflammation [13].

We found that a pattern of persistence of sonicated albumin microbubbles, consistent with adhesion of microbubbles within the myocardial microvasculature, occurred in some pediatric patients during cardioplegia delivery and it was not confined to those receiving crystalloid cardioplegia. It also occurred in patients receiving blood cardioplegia in whom it was unrelated to hematocrit and appeared instead to be related to the length of time the patient had been on CPB or the ischemic time or both at the time of assessment.

Cytokine-induced inflammation occurs throughout CPB [2] and neutrophil-endothelial cell interaction related to ischemia/reperfusion, although most characteristically thought of as occurring at the time of removal of the cross clamp, has the potential to occur whenever ischemic myocardium is flushed with blood containing activated neutrophils such as during blood cardioplegia delivery. In cyanotic children similar inflammatory events may occur owing to abrupt reoxygenation at the onset of CPB [14]. It is therefore possible that the neutrophil-endothelial interaction begins within the coronary microvasculature well before release of the cross clamp in this setting. Our results coupled with those of previous studies suggest that adherence of activated neutrophils to postcapillary venules may occur during prolonged preischemic bypass and during prolonged hypothemic myocardial ischemia in pediatric patients.

The activation and binding of neutrophils with subsequent migration and release of damaging oxygen radicals is believed to play a pivotal role in the development of post-CPB myocardial dysfunction [3, 15]. Our finding that microbubble persistence appeared predictive of the development of postoperative myocardial dysfunction is consistent with a role of neutrophil-endothelial interaction in this condition. We have not attempted to confirm these associations at a structural or biochemical level in this initial study; however, we believe that these findings attest to the potential of this in vivo technique and suggest that more detailed studies of the relationship between myocardial persistence of albumin shell microbubbles and microvascular pathology during CPB are indicated.

Our current findings demonstrate that intraoperative transesophageal MCE can be performed safely during surgery for CHD. High-quality images allow reproducible assessment of myocardial transit rates of microbubbles and the detection of changes to patterns of flow over time in individual patients. Microvascular persistence of microbubbles is known to occur in response to inflammatory events at the microvascular level. Our data demonstrate that this phenomenon occurs during cardioplegia delivery in some cases. As microvascular inflammatory events are believed to impact upon postoperative myocardial performance, MCE may provide exciting new opportunities for the real time, in vivo study of pediatric myocardial preservation.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Doctor Sheil is supported by the Children’s Hospital Fund and the National Heart Foundation, Australia; Dr Raitakari is supported by the Academy of Finland and Turku University Hospital; and Dr Celermajer is suported by The Medical Foundation, University of Sydney. The authors thank Dr Jennifer Peat, PhD, statistician, The Children’s Hospital Westmead, for her assistance.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  6. Keller M.W., Spotnitz W.D., Matthew T.L., Glasheen W.P., Watson D.D., Kaul S. Intraoperative assessment of regional myocardial perfusion using quantitative myocardial contrast echocardiography: an experimental evaluation. J Am Coll Cardiol 1990;16:1267-1279.[Abstract]
  7. Sheil M., Kaul S., Spotnitz W. Myocardial contrast echocardiography; development, applications and future directions. Am J Invest Radiol 1996;3:260-275.
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  11. Keller M.W., Geddes L., Spotnitz W., Kaul S., Duling B.R. Microcirculatory dysfunction following perfusion with hyperkalemic, hypothermic cardioplegic solutions and blood reperfusion. Effects of adenosine. Circulation 1991;84:2485-2494.[Abstract/Free Full Text]
  12. Lindner J.R., Ismail S., Spotnitz W.D., Skyba D.M., Jayaweera A.R., Kaul S. Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalx damage. Circulation 1998;98:2187-2194.[Abstract/Free Full Text]
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