Each year, more than 20,000 children undergo corrective heart repair in the United States, with many of these repairs performed with the use of cardiopulmonary bypass (Society of Thoracic Surgeons Data Quality Report, Fall 2009). Fortunately, using modern approaches, the surgical outcomes from corrective congenital heart surgery are quite good, with an estimated overall mortality of approximately 4%, although variability between centers exists.1,2 Preservation of myocardial function is a complex but important consideration during congenital heart surgical repair. Since the first attempts to correct congenital heart defects, much progress has been made. Most children undergoing surgery have good recoveries with short hospitalizations during the recovery period. However, both the corrective surgery and the use of cardiopulmonary bypass may affect the function of the myocardium,3–5 and low-output syndrome after surgery has an associated higher morbidity and mortality.6
With a goal of better understanding the in vivo energetic status of the cardiomyocyte during the stress of cardiac surgery, we have developed a novel optical method to assess intracellular oxygenation in the heart and have used this approach to measure intracellular oxygenation in the heart during surgical repair. This report describes the ability of our optical approach to noninvasively assess intracellular oxygenation and demonstrates that myocardial oxygenation may remain depressed during the transition from cardiopulmonary bypass support. This report is a descriptive initial study demonstrating the use of this noninvasive approach for measuring cellular oxygenation in the myocardium during surgery. Cellular oxygenation is distinct from the oxygenation of the blood and/or vasculature, and in this study, it is determined by measuring myoglobin oxygen binding. The novelty of this approach is that this measurement does not reflect the blood or vascular oxygenation but measures oxygen levels within the cells of the myocardium.
After informed consent was obtained from the patient's parents or guardian, seven children with congenital heart defects scheduled for surgical correction were enrolled in this study. Assent was also obtained from older children enrolled in this study. The study was approved by the Seattle Children's Hospital Institutional Review Board, which considered these measurements to be a nonsignificant risk to the subject. Surgical procedures for correction of the congenital defects were completed in the usual manner with the use of cardiopulmonary bypass for all patients. No changes to the procedures or surgical repair were made as a result of these measurements. Antegrade crystalloid cardioplegic solution was used in all cases. Diagnoses for these children and operations performed are listed in Table 1. Timing of bypass, aortic cross-clamp, and infusion of cardioplegic solution was recorded along with spectral acquisition for purposes of data comparison. After surgery, length of stay in the intensive care unit (ICU) was determined from the medical record.
After the heart was exposed for the surgical repair, periodic brief measurements of cellular oxygenation were made using a sterile optical probe designed for this study. Optical data were collected at multiple time points during the surgery including the prebypass period, during bypass, and after completion of the corrective repair, until just before chest closure.
The optical probe consists of a bifurcated set of optical fibers with one set bringing illuminating light to the heart surface. A quartz-tungsten-halogen white light source (Oriel Instruments Model No. 66184) with a filter and an electromechanical shutter (Oriel Instruments No. 76995) provided illumination, and the filter and shutter minimized any tissue heating. The second set of fibers returned remitted light from within the myocardium back to the detector. The working end of the optical probe was designed in a “bulls-eye” configuration, such that an illuminating ring of fibers surrounded a central detection set of fibers.7 The sets of fibers were separated by 1.25 mm to assure remitted light originated in the myocardium and did not simply reflect off the heart surface. Depth of sampling was estimated at approximately 0.4 mm based on the probe design.8 Optical spectra were acquired by a diffraction spectrograph (American Holographics No. 100S) with a 512 pixel photodiode array (Hamamatsu No. C4350), using a 400 msec exposure time. Spectral data were converted into digital form using a 16-bit analog to digital converter (National Instruments No. AT-MIO-16X), as described previously.9–11
Care was taken to place the optical probe on the free wall of the right ventricle in the same place for each measurement throughout the case. Multiple spectra (approximately 20) were acquired at each time point during surgery, and measurements were taken approximately every 5 minutes, as allowed by the surgical procedure. Optical spectra were obtained from 600 to 840 nm and were analyzed using the multiwavelength analysis method multivariate curve resolution (MCR).12
The optical analysis distinctly determines oxygen binding to the cellular protein myoglobin, which, similar to hemoglobin, has a characteristic spectral absorbance shift with oxygen binding. Similar to pulse oximetry, the optical signal can be analyzed to determine the percent oxygen bound, in this case to myoglobin, and this is representative of the average intracellular oxygen tension. We have previously demonstrated the utility of measuring myoglobin in the presence of hemoglobin in blood perfused tissue, for determining cellular oxygenation.7,13,14 Measurement of myoglobin oxygenation independent of hemoglobin oxygenation using multiwavelength spectral analysis has been validated in several laboratory studies, previously published.11,15–18 Measurements of cellular oxygenation at each time point were averaged and are expressed as mean ± SE.
Seven patients were enrolled in this study after informed consent was obtained from their parents. Figure 1 illustrates the change in cellular oxygenation in one of the subjects, patient 7 in the table. After a period of relatively stable oxygenation, cellular oxygenation decreased quickly with initiation of cardioplegic arrest and remained low during cardioplegic arrest. After release of the aortic cross-clamp, cellular oxygenation rapidly returned to a level similar to that of the initial baseline. A slight improvement after discontinuation of cardiopulmonary bypass can be seen as well.
In four of the seven cases, cellular oxygenation did not return as quickly to the original baseline as it did in the other three cases. Figure 2 illustrates a slower recovery after reperfusion after the aortic cross-clamp was released, in patient 3 in the table. As in Figure 1, a decrease in cellular oxygenation was seen with cardioplegic arrest, and oxygenation remained low until the aortic cross-clamp was released and the myocardium was reperfused. Before chest closure and the discontinuation of these measurements, oxygenation had returned to approximately the prebypass level.
Figure 3 shows cellular oxygenation from a patient receiving a second dose of cardioplegic solution because of a long aortic cross-clamp time. In this patient (patient 2 in the table), additional cardioplegic solution was infused approximately 30 minutes after initiation of the cross-clamp. The measured myoglobin saturation shows significant variability during the baseline measurements and during recovery. This may be due to variability in probe positioning and to changes in the myocardium. However, it can be seen that mean myoglobin saturation is generally highest during the period after initiation of cardiopulmonary bypass but before aortic cross-clamp. After the second dose of cardioplegic solution, the myocardium has its lowest oxygenation.
Figure 4 shows the mean cellular oxygenation for the seven patients studied at comparable points in time. Baseline cellular oxygenation, measured by myoglobin saturation, was approximately 50% just before initiation of aortic cross-clamp. There was a clear decrease in oxygenation during cardioplegic arrest, with an average value of approximately 20% at approximately 15 minutes after the first infusion of the cardioplegic solution. This corresponds with an intracellular pO2 of <1 mm Hg.18 Cellular oxygenation remained low throughout the period of cardioplegic arrest. There is a return to baseline after repair and discontinuation of bypass, shown at 30 minutes after release of aortic cross-clamp.
Although there are not enough patients to make generalizations about the relationship between cellular oxygenation during cardioplegic arrest and the functional outcome of the myocardium after surgery, a trend toward longer ICU stay for patients with slower cellular oxygen recovery is observed (Table 1). Among the four patients classified as demonstrating slow recovery, the average ICU length of stay was 2.25 days compared with an average stay of 1.33 days for those patients exhibiting rapid cellular oxygenation recovery (p = 0.06). Also, perhaps related to these findings is the duration of aortic cross-clamp. The slow recovery group had an average cross-clamp time of 40.1 ± 28.4 minutes, compared with an average cross-clamp time of 26.0 ± 8.5 minutes for the fast recovery group (p = 0.34). Duration of ICU length of stay was also undoubtedly related to the underlying diagnosis and complexity of the repair.
This study demonstrates for the first time that cardiac cellular oxygenation can be measured intraoperatively during cardiac surgery. Cellular oxygenation dropped fairly rapidly after initiation of cardioplegic arrest and remained low during the aortic cross-clamp period. Cellular oxygenation, as opposed to vascular oxygenation, represents the available oxygen at the cellular level necessary for metabolism and cell viability. It is logical to consider that cellular oxygenation during cardiopulmonary bypass may be directly related to the development or absence of cellular myocardial injury. Thus, direct measurement of cellular oxygenation may be useful in guiding future myocardial preservation techniques for operative repair.
The improvement in cellular oxygenation after initiation of cardiopulmonary bypass but before aortic cross-clamp, as shown in Figure 3, may be due to the improved oxygen delivery provided by the cardiopulmonary bypass circuit coupled with simultaneous unloading of the heart. After the second dose of crystalloid cardioplegic solution, oxygenation remains low. Room air-equilibrated crystalloid cardioplegic solution contains minimal oxygen and may wash out remaining blood in the coronary circulation.
The two subjects with atrial septal defects (patients 1 and 7 in the table) are interesting to review. These two children had the same defect and underwent the same type of repair. Both children had similarly short aortic cross-clamp times with the same surgical team and approach. It is unclear why their cellular oxygenation recovery patterns are different. This difference may represent individual patient responses to similar stressors or to other interpatient differences. Further investigation with larger numbers of patients with similar defects and repairs may shed light on this.
In this report, cellular oxygenation refers to a global measurement of myocyte oxygenation from the right ventricle. Cellular oxygenation from the right ventricular free wall was measured for practical considerations to avoid disruption of the surgical procedures. Improved optical probe designs are being investigated that would allow measurements to be made from the left ventricle and in infants.
Our laboratory has been investigating the utility of measurement of cellular oxygenation in both cardiac and skeletal muscle.7,9,10,15,19,20 Intracellular oxygenation may be an important marker for cellular, and thus tissue or organ well-being, and may become an important new monitoring modality. Cellular oxygenation represents the balance between oxygen delivery and consumption. Thus, a monitor of cellular oxygenation has the potential to provide more clinically relevant information than traditional markers used to assess tissue perfusion such as mixed venous blood oxygen saturation or serum lactate. Further development of this approach and additional clinical data are needed to establish a clinical benefit from monitoring cellular oxygenation.
Supported, in part, by the McMillen Foundation, the Children's Hospital Steering Committee, and the University of Washington Center for Commercialization.
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