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Ann Thorac Surg 1997;64:1250-1255
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Complete Unloading Alone May Not Adequately Protect the Left Ventricle

Department of Cardiovascular and Thoracic Surgery and Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, Palo Alto Veterans Affairs Medical Center, and Department of Cardiovascular Physiology and Biophysics, Research Institute, Palo Alto Medical Foundation, Palo Alto, California

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. The benefit of left ventricular (LV) unloading for preserving LV function is commonly accepted, but its efficacy remains incompletely defined.

Methods. We studied the influence of complete LV unloading on LV systolic and diastolic mechanics using an in situ isovolumic preparation with two different coronary perfusion pressures (CPPs) in 12 dogs during prolonged normothermic cardiopulmonary bypass.

Results. Multivariate analysis of covariance with time as a covariate revealed that a high CPP (143 ± 36 mm Hg; n = 6) was associated with better preservation of systolic LV function over time as assessed by LV end-systolic elastance (p < 0.001) and the end-systolic pressure-volume relation physiologic intercept (p < 0.001) compared with a moderate CPP (107 ± 18 mm Hg; p < 0.005 versus a high CPP by t-test; n = 6). Dobutamine (2 µg • kg^-1 • min^-1) improved LV end-systolic elastance (p < 0.005) and LV physiologic intercept (p < 0.01) only in the high-CPP group. Conversely, impaired LV diastolic function (as measured by LV stiffness) was observed (p < 0.001) with a high CPP, but did not change with a moderate CPP.

Conclusions. These observations in canine hearts suggest that complete LV unloading may not preserve LV systolic function adequately over time when CPP is maintained in the accepted clinical range. A higher CPP is required to prevent deterioration over prolonged cardiopulmonary bypass times, but diastolic dysfunction still occurs.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Left ventricular (LV) unloading during cardiopulmonary bypass (CPB) or with the use of various assist devices generally is believed to diminish myocardial oxygen consumption, protect the ventricle [1–3], and decrease the extent of myocardial ischemic injury [4]. The following clinical examples using an empty, beating heart on CPB are based in part on this concept: coronary artery bypass grafting without cross-clamping, resuscitation of the heart after prolonged ischemic arrest, descending thoracic aortic operations (for patients with or without LV hypertrophy) using various CPB techniques, proximal coronary artery bypass graft anastomoses with a side-biting clamp, tricuspid or other procedures performed on an empty, beating heart, and combined procedures (eg, open heart operations and lung cancer resection or abdominal aortic aneurysm operations). On the other hand, using a canine model, Rabinov and colleagues [5] reported that hypertrophic ventricles can be damaged during 30 minutes of reperfusion on CPB when the coronary perfusion pressure (CPP) is less than 80 mm Hg, and that a normal ventricle can be injured when the CPP is less than 40 mm Hg [5].

One of the theoretic problems associated with LV unloading is that the cavity becomes small and the LV wall is relatively thick (even during diastole); intramyocardial pressure increases (especially in the subendocardial area), which disturbs diastolic coronary perfusion and results in subendocardial ischemia [6]. This potential problem could be more serious when the heart is unloaded completely (eg, an LV end-diastolic pressure near zero or even negative), when the CPP is low (particularly in the setting of coronary artery disease), or when the CPB time is prolonged. Little actually is known about the effects of complete LV unloading and CPP on LV function for in situ hearts, especially under conditions of prolonged CPB. Therefore, we studied the influence of LV unloading and CPP on LV systolic and diastolic mechanics over a protracted period using an isovolumic balloon method in a canine model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Surgical Preparation
Twelve healthy adult mongrel dogs (27.7 ± 2.7 kg) were premedicated with acepromazine (0.01 to 0.05 mg/kg intramuscularly) and atropine (0.05 mg/kg intravenously), anesthetized with sodium pentobarbital (20 to 25 mg/kg intravenously), intubated, and placed on artificial ventilation (Ohio Anesthesia Ventilator, Madison, WI). General anesthesia was maintained with inhalational isoflurane at 1.5% to 2.2%. A manometer-tipped catheter (Millar Instruments Inc, Houston, TX) was zeroed in a 37°C water bath. Systemic arterial pressure was monitored using a micromanometer through the side port of the left femoral introducer. The left chest was opened in the fifth intercostal space. The heart was exposed and suspended in a pericardial cradle.

A latex balloon the length of the LV long axis was tied onto a cannula that allowed passage of a micromanometer-tipped catheter into the balloon to measure intraballoon LV pressure directly (Fig 1). The balloon was connected to an autosyringe on a Harvard pump (model 55-1341; Harvard Apparatus, Natick, MA). The syringe, connecting circuit, and balloon were filled with warm saline solution and completely deaired.

View larger version (35K): [in this window] [in a new window]   Fig 1. . Multiple pump circuit, cannulation arrangement, and pressure monitoring sites. Aortic root pressure (= coronary perfusion pressure) was controlled by adjusting the tightness of the snare as well as by altering the pump flow rate in the second arterial cannula. (a. = artery; LA = left atrial; LV = left ventricular; PA = pulmonary artery.)

The left atrium was opened under electrically induced ventricular fibrillation and both mitral leaflets were excised. Cardioversion was performed immediately and arterial perfusion through the second cannula was started at 100 mL/min. The ascending aorta was snared gently, and the flow rate in the second arterial cannula was increased to 1 L/min to raise the aortic root pressure, which was monitored continuously and maintained constant (by adjusting the flow rate in the proximal arterial pump circuit) throughout the entire experiment. Aortic root pressure was used to measure CPP, and it was recorded every 30 minutes. Total flow in both arterial cannulas was kept constant by adjusting the flow rate in the first (femoral) pump circuit according to the flow in the second arterial cannula. For the first 6 dogs, the umbilical tape was snared moderately to increase the proximal aortic pressure to approximately 100 mm Hg; in the last 6 dogs, the tape was snared more tightly to increase the CPP even higher (ie, approximately 140 mm Hg).

Six 2-0 Ethibond (Ethicon, Somerville, NJ) sutures with pledgets were placed evenly around the mitral annulus. A customized plastic disk occluder the size of the mitral annulus at end-systole was chosen, and the six annular sutures were passed through the occluder. The balloon then was inserted into the ventricle through a notch in the occluder. The disk then was snuggled down tightly to the mitral annulus.

Experimental Protocol
The diastolic and systolic LV pressure-volume relations were measured by infusing saline into the balloon circuit at a constant rate of 72 mL/min until the balloon pressure reached 120 mm Hg; the fluid subsequently was withdrawn. During each measurement, the heart rate was maintained in a low-normal range (110 to 130 beats/min). One to two milligrams of ULFS-49 was given as needed. To obtain a stable preparation, the same infusion and withdrawal sequence was repeated three to five times, and the data obtained during the last balloon inflation were analyzed. Dobutamine infusion was started at 2 to 3 µg • kg^-1 • min^-1 approximately 2 hours after the initiation of CPB and was maintained at the same rate until the end of the experiment. In the interim, this preparation was used for other unrelated studies, which required LV loading by inflating the LV balloon periodically for a total of about 25 minutes in each group.

All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" presented by the National Academy of Sciences and published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985). The study was approved by the Stanford Medical Center Laboratory Research Animal Review Committee and conducted according to Stanford University policy.

Data Acquisition
The volume of the autosyringe was measured using a linear differential transformer sensor that detected the position of the plunger with respect to the cylinder of the syringe. All analog data (such as the electrocardiogram, instantaneous volume of the autosyringe, and pressure inside the LV balloon) were acquired and digitized at 240 Hz using a 486-based microcomputer (486-50 MHz; JDR Microdevices Inc, San Jose, CA) with a high-speed data acquisition card (DT3831-G; Data Translation Inc, Marlboro, MA) controlled by commercially available software (Labtech Control 3.2.0; Laboratory Technology Corp, Wilmington, MA).

Data Analysis
The definitions of the following three parameters are illustrated using data presented in a previous publication by our group that used this experimental preparation [7].

LEFT VENTRICULAR SYSTOLIC FUNCTION: PHYSIOLOGIC INTERCEPT.
The digitized data from beats with a systolic LV pressure in the range of 80 to 120 mm Hg were analyzed using commercially available software (Origin, version 3.0; MicroCalc Inc., Northampton, MA). Data from premature beats and the next two post-extrasystolic beats were excluded. A least-squares regression analysis was performed on the peak LV systolic pressure-volume points during balloon inflation and deflation. From this regression line, the LV volume at a developed LV pressure of 100 mm Hg (E_es100, in milliliters, where a smaller E_es100 reflects superior LV systolic function) was computed [7].

LEFT VENTRICULAR SYSTOLIC FUNCTION: END-SYSTOLIC ELASTANCE.
[Left ventricular end-systolic elastance (E_max, expressed as millimeters of mercury per milliliter) was defined as the slope of the LV systolic pressure-volume regression line described previously [8].

LEFT VENTRICULAR DIASTOLIC FUNCTION: DIASTOLIC CHAMBER STIFFNESS.
In a similar fashion, least-squares regression analysis was performed on the diastolic pressure-volume relation for the same beats as described previously; the slope (diastolic chamber stiffness [S_d], expressed as millimeters of mercury per milliliter, with a smaller value indicating better diastolic function or LV chamber compliance) was calculated [9].

Statistical Analysis
All data are reported as means ± one standard deviation. Because the two CPP groups (high and moderate) had data recorded at different times during CPB, analysis of covariance including the covariate of time was used to take CPB time into consideration in assessing the changes in LV mechanics between groups. Statistical significance was inferred when the (adjusted) p value was less than 0.05. For all statistical analyses, SYSTAT (version 5.02; SYSTAT Inc, Cary, NC) was used.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Aortic Root Pressure
The initial 6 dogs in the moderate-CPP group had an aortic root pressure less than 130 mm Hg (105 ± 15 mm Hg). The other 6 dogs (high-CPP group) had an aortic root pressure greater than 130 mm Hg (mean, 142 ± 36 mm Hg). The systemic arterial perfusion pressure ranged between 45 and 70 mm Hg.

Left Ventricular Systolic Function: E_es100
Table 1 shows the results for all animals with and without dobutamine infusion (2 to 3 µg • kg^-1 • min^-1) for both groups. Analysis of covariance with interaction revealed that the predictors of lower E_es100 (indicating better LV systolic function) were a high CPP (p < 0.005) and dobutamine infusion (p < 0.001) (Fig 2). In particular, animals with a CPP greater than 140 mm Hg had a low E_es100 throughout the long duration of CPB.

View larger version (40K): [in this window] [in a new window]   Fig 2. . Systolic and diastolic left ventricular function with complete left ventricular unloading on cardiopulmonary bypass (CPB) both with and without dobutamine infusion. The small schematic illustration in the upper left corner of each graph shows the trend of the variable under discussion in the high-CPP group (white arrow) and the moderate-CPP group (black arrow). (A) Left ventricular end-systolic elastance (Emax). The high-CPP group had a higher Emax and the expected response to dobutamine compared with the moderate-CPP group. (B) Left ventricular physiologic intercept (Ees100). The high-CPP group had a lower Ees100 (ie, better systolic left ventricular function) and more response (lower Ees100) to dobutamine infusion compared with the moderate-CPP group. (C) Left ventricular chamber stiffness (Sd). The high-CPP group had a higher Sd (ie, more stiff ventricular chamber) compared with the moderate-CPP group. (CPP = coronary perfusion pressure.)

LEFT VENTRICULAR DIASTOLIC FUNCTION: S_d.
Analysis of covariance with interaction revealed that a high CPP (P< 0.001) AND DOBUTAMINE INFUSION (P< 0.05) WERE PREDICTORS OF INCREASED LV S_d (see table 1; fig 2). diastolic lv chamber stiffness was higher, especially with a cpp greater than 140 mm hg. there was no significant interaction between cpp and dobutamine infusion with respect to lv diastolic mechanics.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Discrepancies exist in the literature regarding the putative benefit of LV unloading in terms of preserving either systolic or diastolic LV function. Those studies that reported a salutary effect of LV unloading [1–4] used LV assist devices, which usually do not unload the ventricle completely, partly because of limited drainage from the left atrium or ventricle. On the other hand, the studies that suggested the potential deleterious role of LV unloading used complete LV unloading, such as CPB [5] or a heterotopic transplant model [10]. In the current study, we used an isovolumic balloon method to unload the ventricle completely; the only time the ventricle was loaded at all was during the short periods of balloon inflation. Comparison of the above studies as well as the data in this current experiment suggest that complete LV unloading may be different from incomplete (or partial) LV unloading in terms of protection of LV functional properties.

In fact, previous experimental studies with isolated heart models using the isovolumic balloon technique (which assures complete LV unloading) showed enhanced LV systolic function with a higher CPP [11–15], which has been termed Gregg's phenomenon [16]. Conversely, no improvement in LV systolic function was seen with a high CPP in in situ heart models, where LV unloading is not complete [11, 17, 18], or when CPP was high [14]. The results of this study show that a higher CPP during complete LV unloading was associated with better preservation of systolic function (as measured by E_max and E_es100) during prolonged CPB. Our results also show that a higher CPP amplified the hemodynamic response to dobutamine infusion. Although this experiment does not elucidate the mechanisms responsible for the preservation of systolic function, given the relatively hypertrophied canine ventricle, it is possible that a higher CPP may minimize LV subendocardial ischemia [14].

On the other hand, our results suggest that a higher CPP was associated with progressively more impaired diastolic LV function, as indicated by increased LV S_d. This agrees with the results of some previous studies using isolated heart models [12, 19, 20], but other studies showed no diastolic dysfunction with a high CPP [13, 15]. Templeton and colleagues [15] examined LV diastolic function with a CPP ranging between 60 and 95 mm Hg; this lower CPP may explain why no deterioration in diastolic function was observed in their experiment. The mechanism of increase LV S_d might be myocardial edema [12] or vascular filling ("erectile effect") [19] caused by high-pressure perfusion or other factors. In the current experimental preparation, a "moderate" CPP was associated with preserved diastolic function for up to 4 hours, as shown in Figure 2. Because the optimal CPP during complete LV unloading is the one that has the least deleterious effect on both systolic and diastolic LV function, we speculate that such may be somewhere in between the two ranges of CPP studied in this experiment (ie, 142 and 105 mm Hg). This postulate is supported by the canine study of Nelson and colleagues [21], following hypothermic cardiac arrest with complete LV unloading on CPB with a mean CPP of 100 mm Hg, where systolic and diastolic LV function was maintained.

In terms of ways in which to improve the stability of experimental preparations, the method described here has several advantages. It produced a higher aortic root pressure and resulted in a stable in situ isovolumic preparation for an average of 3 hours. In this series of experiments, no heart failed completely during the study protocol. This method provides a higher CPP than do conventional CPB techniques without compromising systemic perfusion; this is clearly superior to other preparations that depend on clamping the descending aorta to maintain a high CPP (and thereby generate a major ischemic insult to the lower body that produces a catecholamine surge and other humoral responses [22]), and it elevates CPP more effectively than the conventional two-pump method (which perfuses the lower and upper halves of the body separately [23]). Because there is no cannula in the aortic root, this method does not interfere with other technical procedures. We believe that this preparation may be a useful tool for studies that demand a stable in situ isovolumic preparation for several hours.

This study has several limitations. First, we controlled the aortic root pressure by snaring the ascending aorta and adjusting the CPB perfusion rate in the second arterial cannula, but we did not measure directly coronary flow or myocardial oxygen consumption. Second, although these animals were used for an unrelated study, all experimental conditions were very similar between the two groups except for CPP. Third, the timing of each measurement was not exactly the same in the two groups; to adjust for this, the data were analyzed using analysis of covariance considering the covariate of CPB time, which turned out to be statistically indistinguishable between the groups. Fourth, we only compared a moderate CPP (105 ± 18.4 mm Hg) with a high CPP (142 ± 35.8 mm Hg) instead of adding a third group without additional root perfusion (which would have yielded a CPP of 45 to 70 mm Hg). Our preliminary data showed that with no augmentation of CPP, bradycardia and severe LV systolic dysfunction developed in the heart within 1 hour. Although we measured direct aortic root pressure (CPP), we simply categorized the animals into the two ranges of CPP, because it was difficult to keep the CPP at a preset constant level for several hours, but relatively easier to maintain it in a certain range, such as less than or greater than 130 mm Hg. Fifth, we used canine hearts, which are slightly more hypertrophic than human ventricles [24]; with less hypertrophy, good systolic function possibly may have been maintained with a lower CPP.

Because of these limitations and other characteristics of this canine model, the information obtained in this experiment cannot be extrapolated directly to the clinical setting; however, we believe that the results of this study do raise the following question: Is an empty, beating cardiac operation safe for all patients with currently accepted CPP? This obviously is more important for patients with coronary artery disease, incomplete revascularization, or left ventricular hypertrophy. Further investigation is necessary in the clinical setting to elucidate the safe threshold of CPP and LV unloading required to protect the ventricle more reproducibly through assisted extracorporeal circulation.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We gratefully acknowledge Cynthia E. Handen, BA, Geraldine C. Derby, RN, Erin M. Schultz, BS, and Mary K. Zasio, BA, in the performance of this work and Ms Phoebe E. Taboada for her assistance in the preparation of the manuscript.

Supported by grants HL-48837 and HL-29589 from the National Heart, Lung, and Blood Institute and the Veterans Affairs Medical Research Service.

Doctors Komeda, DeAnda, and Glasson are Carl and Leah McConnell Cardiovascular Surgical Research Fellows. Doctor DeAnda also was supported by Individual National Research Service Award HL-08928 from the National Heart, Lung, and Blood Institute and Dr Glasson also was supported by The Thoracic Surgery Foundation Research Fellowship Award.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Poster Session of the Thirty-third Annual Meeting of the Society of Thoracic Surgeons, San Diego, CA, Feb 3-5, 1997.

Address reprint requests to Dr Miller, Department of Cardiovascular and Thoracic Surgery, Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, CA 94305-5247 (e-mail: dcm{at}leland.stanford.edu).

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Masashi Komeda Abe DeAnda, Jr D. Craig Miller Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Komeda, M. Articles by Miller, D. C. Search for Related Content PubMed PubMed Citation Articles by Komeda, M. Articles by Miller, D. C.