Bruce J. Leone

Cardiovascular and coronary physiology of acute isovolemic hemodilution : a review of nonoxygen-carrying and oxygen-carrying solutions

Acute isovolemic hemodilution is used increasingly to avoid the potentially serious side effects of homologous blood transfusions. Cardiovascular physiology during hemodilution is characterized by a marked increase in cardiac output and organ blood flow to compensate for the decrease in arterial oxygen-carrying capacity. During advanced hemodilution an increased oxygen extraction is also observed, such that oxygen consumption generally is maintained even during advanced hemodilution. The increase in cardiac output is related mainly to a decrease in blood viscosity and an enhanced sympathetic tone resulting in stimulation of the heart. The magnitude and the mechanisms involved in the increase depend upon species, state of awareness (awake versus anesthetized), type of anesthesia, type of exchange solution, and condition of the heart prior to hemodilution. Recent laboratory findings, as well as clinical practice in cardiac surgery, suggest that moderate hemodilution to hematocrit values of approximately 25% is well tolerated in single vessel coronary artery disease which should thus not be regarded as an absolute contraindication for moderate hemodilution. An integral concept to minimize homologous blood transfusions consists of preoperative autologous blood donation, preoperative isovolemic hemodilution, meticulous (asanguineous) surgical technique, and acceptance of minimum hemoglobin levels during the entire hospitalization. The incidence of homologous blood transfusions will be reduced using acute isovolemic hemodilution. This incidence will be further reduced once hemoglobin solutions become clinically available for specific indications. At present, research activities are concentrated on defining the critical level of hemodilution in various pathologic conditions and to investigate pharmacology and physiology of the new hemoglobin solutions. Finally, several chemically modified hemoglobin-based oxygen-carrying solutions devoid of renal toxicity will be available in the future. The cardiovascular physiology and pharmacology of these hemoglobin solutions have been studied. Cardiac output is generally constant and oxygen extraction is increased to maintain oxygen consumption during hemodilution with hemoglobin solutions. In most studies, some vasoconstriction was observed also, which might result from interaction of the hemoglobin molecule with the EDRF/NO system. However, with enhanced purification, chemical modification or microencapsulation of the hemoglobin molecule, vasoconstriction can be limited.

Jugular bulb saturation and cognitive dysfunction after cardiopulmonary bypass

Inadequate cerebral oxygenation during cardiopulmonary bypass may lead to postoperative cognitive dysfunction in patients undergoing cardiac operations. A psychological test battery was administered to 255 patients before cardiac operation and just before hospital discharge. Postoperative impairment was defined as a decline of more than one standard deviation in 20% of tests. Variables significantly (p < 0.05) associated with postoperative cognitive impairment are baseline psychometric scores, largest arterial-venous oxygen difference, and years of education. Jugular bulb hemoglobin saturation is significant if it replaces arterial-venous oxygen difference in the model. Factors correlated with jugular bulb saturation at normothermia were cerebral metabolic rate of oxygen consumption (r = -0.6; p < 0.0005), cerebral blood flow (r = 0.4; p < 0.0005), oxygen delivery (r = 0.4; p < 0.0005), and mean arterial pressure (r = 0.15; p < 0.05). Three measures were significantly related to desaturation at normothermia and at hypothermia as well: greater cerebral oxygen extraction, greater arterial-venous oxygen difference, and lower ratio of cerebral blood flow to arterial-venous oxygen difference. We conclude that cerebral venous desaturation occurs during cardiopulmonary bypass in 17% to 23% of people and is associated with impaired postoperative cognitive test performance.

Warming during cardiopulmonary bypass is associated with jugular bulb desaturation

The objective of this study was to characterize cerebral venous effluent during normothermic nonpulsatile cardiopulmonary bypass. Thirty-one (23%) of 133 patients met desaturation criteria (defined as jugular bulb venous oxygen saturation less than or equal to 50% or jugular bulb venous oxygen tension less than or equal to 25 mm Hg) during normothermic cardiopulmonary bypass (after hypothermic cardiopulmonary bypass at 27 degrees to 28 degrees C). Cerebral blood flow, calculated using xenon 133 clearance methodology, was significantly (p less than 0.005) higher in the saturated group (33.7 +/- 10.3 mL.100 g-1.min-1) than in the desaturated group (26.2 +/- 6.9 mL.100 g-1.min-1), whereas the cerebral metabolic rate for oxygen was significantly lower (p less than 0.005) in the saturated group (1.28 +/- 0.39 mL.100 g-.min-1) than in the desaturated group (1.52 +/- 0.36 mL.100 g-1.min-1) at normothermia. The arteriovenous oxygen difference at normothermia was lower in the saturated group (3.92 +/- 1.12 mL/dL) than in the desaturated group (5.97 +/- 1.05 mL/dL). Neuropsychological testing was performed in 74 of the 133 patients preoperatively and on day 7 postoperatively. There was a general decline in mean scores of all tests postoperatively in both groups with no significant difference between the groups. We conclude that cerebral venous desaturation represents a global imbalance in cerebral oxygen supply-demand that occurs during normothermic cardiopulmonary bypass and may represent transient cerebral ischemia. These episodes, however, are not associated with impared neuropsychological test performance as compared with the performance of patients with no evidence of desaturation.

Desensitization of myocardial beta-adrenergic receptors during cardiopulmonary bypass. Evidence for early uncoupling and late downregulation.

BackgroundCardiopulmonary bypass (CPB), a process routinely used during cardiac surgery, is a potent stimulant to the release of endogenous catecholamines. Hence, we tested the hypothesis that CPB results in myocardial β-adrenergic receptor (βAR) desensitization. Methods and ResultsWe obtained canine transmyocardial left ventricular biopsies before, during (155 minutes), and after CPB (pre-CPB, CPB, and post-CPB, respectively) and determined βAR density, proportion of β1AR to β2AR, and βAR coupling capacity to adenylyl cyclase. βAR density was stable at 112 ± 14 fmol/mg (pre-CPB) and 103 ± 9 fmol/mg (CPB) but decreased post-CPB to 84 % 7 fmol/mg. The ratio of β1AR to β2AR (determined by two-site fit for [1251]-iodocyanopindolol competition binding with the fI1AR selective antagonist 1C189.406) remained constant throughout (60 % 3:40 ± 3 pre-CPB, 55 ± 3:44 ± 3 CPB, and 61 ± 2:39 ± 2 post-CPB), revealing that both P1AR and β2AR subtypes were downregulated. A different pattern was noted in the functional properties of these receptors during CPB. Decreased maximal isoproterenol-stimulated adenylyl cyclase activity (252 ± 14 to 216 ± 12 pmol/30 min/mg), submaximal isoproterenol-stimulated adenylyl cyclase activity (183 ± 10 to 157 ± 11 pmol/30 min/mg), and zinterol-stimulated adenylyl cyclase activity (187 ± 11 to 159 ± 11 pmol/30 min/mg, a measure of βAR subtype activation) were noted during CPB, at the time when weaning from CPB takes place. However, this desensitized pattern was found to be completely reversed by 30 minutes post-CPB, with adenylyl cyclase activities returning to pre-CPB levels or slightly higher. Control dogs that did not receive CPB showed no change in βAR density or adenylyl cyclase activity. ConclusionsThese data suggest that myocardial βAR desensitization does occur during CPB in healthy, nonischemic canine myocardium and that this pattern is reversed 30 minutes after discontinuation of CPB. In addition, a slower process of βAR downregulation persists after discontinuation of CPB. Because successful weaning from CPB is a critical process during myocardial surgery, these findings have potentially important implications in the management of such patients.

The effects of mechanical cardiac stabilization on left ventricular performance

OBJECTIVEnMechanical cardiac stabilization is beneficial for precise coronary anastomoses on the beating heart. However, the effect of mechanical cardiac stabilization on hemodynamics, left ventricular performance, and the degree of injury to underlying tissue are uncertain.nnnMETHODSnTwelve swine (20-30 kg) underwent median sternotomy and a mechanical stabilizing device (United States Surgical, Norwalk, CT) was positioned astride a segment of left anterior descending coronary artery (LAD). Coronary blood flow was measured by Doppler. Sonomicrometry crystals were placed distal to the stabilizer in a region of myocardium subtended by the LAD, and a left ventricular micromanometer was inserted. Regional myocardial function was determined using the preload recruitable stroke work (PRSW) relationship. Data were acquired at three time points: 20 min before (PRE) and after placing the stabilizer (EXPT); and 20 min after removing the stabilizer (POST). Tissue subjacent to the stabilizer was then biopsied. Means +/- standard deviation are reported.nnnRESULTSnThe mechanical stabilizer caused a decrease in cardiac output from 4.2+/-1.5 to 3.6+/-1.3 l/min (P < 0.05), which returned to baseline values after its removal. Regional myocardial function (percent systolic shortening and MW and x-intercept of the PRSW relationship) was unchanged. Blood pressure, heart rate, and LAD blood flow remained constant. Histologic findings included a layer of myocyte necrosis less than 1 mm in depth immediately beneath the stabilizer.nnnCONCLUSIONSnThese data demonstrate that mechanical stabilization of the LAD may temporarily decrease cardiac output. This is not attributed to impaired contractility or ischemia, but is secondary to direct ventricular compression with reduced stroke volume. Injury to underlying tissue is negligible.

Anemia, hemodilution, and oxygen delivery.

he adequacy of oxygen delivery to all regions of the body is perhaps the best indicator of T sufficient red cell mass and cardiac output. In the present issue of Anesthesia & Analgesia, van Woerkens and colleagues (1) present the unfortunate case of a patient who succumbed to perioperative complications, refusing transfusion therapy because of religious beliefs despite severe anemia. These authors obtained informed consent from this patient to study his oxygen delivery and consumption during profound normovolemic hemodilution. We are thus given a glimpse of this patient’s physiologic responses to profound normovolemic hemodilution, with the conclusion that severe normovolemic hemodilution, to hemoglobin values as low as 4 g/dL, may be well tolerated in critically ill patients. In this era of acquired immunodeficiency syndrome, hepatitis, cytomegalovirus, and other potential complications of homologous blood transfusion, this case, considered in isolation, may suggest that more aggressive normovolemic hemodilution strategies be used (i.e., less homologous blood transfusion). Van Woerkens et al. suggest a new ”magic number,” an oxygen delivery rate of 184 mL.m-2. min-‘, as the critical value of oxygen delivery. Classically, a hematocrit of 30% has been recommended as optimal for the perioperative period (24 ) . These recommendations were based primarily on theoretical calculations of maximal oxygen delivery to peripheral organs. Because blood viscosity is related to hematocrit in a curvilinear manner, moderate hemodilution may increase blood fluidity by decreasing viscosity and result in greater tissue flow, which more than compensates for the decreased blood oxygen content. Oxygen delivery may actually be increased. Indeed, experimental data demonstrate that profound normovolemic hemodilution in otherwise healthy canines is well tolerated, with minimal complications and no evidence of impaired wound healing (5) . Clinical studies have also observed no in-

Hemodilution Induces Stable Changes in Global Cardiovascular and Regional Myocardial Function

The cardiovascular responses associated with isovolemic hemodilution have been described. However, the stability of these responses over time remains controversial. We hypothesized that the hemodynamic responses to isovolemic hemodilution are stable over time. Nine fentanyl-midazolam-anesthetized dogs were monitored to follow global cardiovascular and regional myocardial function. Isovolemic hemodilution was performed to a moderate (hemoglobin = 7.5 g%) target hemodilutional state that was maintained for 4 h. Data were obtained at each hemodilutional state and each hour during the 4-h period of sustained moderate hemodilution. During acute hemodilution, cardiac output increased from 2.6 ± 0.5 L/min to 3.0 ± 0.5 L/min (P < 0.05) and mean coronary flow increased from 20.8 ± 2.4 mL/min to 31.4 ± 5.5 mL/min (P < 0.05). Cardiac output and mean coronary flow remained elevated during the extended hemodilutional period. In addition, norepinephrine increased from 586 ± 152 pg/mL to 1135 ± 247 pg/mL (P < 0.05) during acute isovolemic hemodilution and remained at this increased level during extended hemodilution. Epinephrine levels did not change with hemodilution. Compensatory mechanisms such as increases in cardiac output and mean coronary flow observed during acute hemodilution persist during extended periods of hemodilution.

Regional differences in left ventricular wall motion in the anesthetized dog.

Data regarding left ventricular function suggest that the extent of shortening may differ between regions. This study was undertaken to determine the effects of negative inotropic drugs used during anesthesia on different areas of the left ventricle. Forty mongrel dogs were anesthetized and instrumented for measurement of global and regional function. Regional function in the short axis of the basal and apical territories of the left ventricle was assessed by subendocardial sonomicrometry. Three different interventions were performed: In the first group 67% N2O, replacing 67% N2, was added to opiate anesthesia; in the second group halothane was given by stepwise increases in inspired concentration to 2%; in the third group verapamil (60 micrograms.kg-1.h-1) was infused during isoflurane anesthesia. Apical and basal segmental shortening were compared. During baseline conditions and with agents in concentrations that caused minimal myocardial depression (67% N2O or 1.0% as opposed to 0.5% halothane) differences in systolic shortening between regions were statistically significant. Further myocardial depression affected the apex significantly more than the base: when substantial myocardial depression was induced by halothane (1.5 or 2%) or verapamil, differences in regional function were abolished. Thus, the apical region of the left ventricle is more dynamic and more sensitive to negative inotropic interventions than the basal region. This should be borne in mind when segmental myocardial function is evaluated.

Fat emboli in total knee arthroplasty. A prospective randomized study of computer-assisted navigation vs standard surgical technique

A prospective exploratory study of fat emboli in patients undergoing total knee arthroplasty was performed in patients randomly assigned to surgery with computer-assisted navigation or standard technique. Transesophageal echocardiography of the right atrium was recorded for 5 consecutive 1-minute intervals after tourniquet deflation. Emboli were graded on a scale of 0 to 3 based on embolism size, amount of atrium filled, and duration of embolic shower, creating an overall score of 0 to 9. The mean (SD, range) of the 5 overall scores for each total knee arthroplasty was 6.00 (0.76, 4.6-7.4) for computer-assisted navigation (22 patients) and 6.42 (0.97, 4.6-7.9) for standard technique (22 patients) (P=.14), with a 95% confidence interval for the difference of -0.11 to 0.95. We conclude that any difference in extent of emboli between the 2 surgical techniques is unlikely to be of clinical significance.

Esmolol Improves Left Ventricular Function via Enhanced β-Adrenergic Receptor Signaling in a Canine Model of Coronary Revascularization

Background Recent American Heart Association guidelines highlight the paucity of data on effectiveness and/or mechanisms underlying use of &bgr;-adrenergic receptor (&bgr;AR) antagonists after acute coronary syndromes in patients subsequently undergoing revascularization. It is important to assess whether &bgr;AR antagonists might protect the heart and improve ventricular function in this scenario. The authors therefore used esmolol (an ultra–short-acting &bgr;AR antagonist) to determine whether &bgr;AR antagonist treatment improves left ventricular function in a canine model of acute reversible coronary ischemia followed by coronary reperfusion during cardiopulmonary bypass (CPB). The authors also tested whether the mechanism includes preserved &bgr;AR signaling. Methods Dogs were randomized to either esmolol or saline infusions administered during CPB (n = 29). Pre-CPB and end-CPB transmyocardial left ventricular biopsies were obtained; plasma catecholamine concentrations, myocardial &bgr;AR density, and adenylyl cyclase activity were measured. In addition, left ventricular systolic shortening and postsystolic shortening were determined immediately prior to each biopsy. Results While &bgr;AR density remained unchanged in each group, isoproterenol-stimulated adenylyl cyclase activity decreased 26 ± 6% in the control group but increased 38 ± 10% in the esmolol group (pre-CPB to end-CPB, mean ± SD, P = 0.0001). Left ventricular systolic shortening improved in both groups after release of coronary (LAD) ligature; however, the esmolol group increased to 72 ± 23% of pre-CPB values compared to 48 ± 12% for the control group (P = 0.0008). Conclusions These data provide prospective evidence that esmolol administration results in improved myocardial function. Furthermore, the mechanism appears to involve enhanced myocardial &bgr;AR signaling.