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Ann Thorac Surg 2005;80:1401-1407
© 2005 The Society of Thoracic Surgeons
a Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina
b Department of Anesthesiology, Mayo Clinic, Jacksonville, Florida
c Neurologic Outcome Research Group (NORG) of the Duke Heart Center, Durham, North Carolina
Accepted for publication March 28, 2005.
* Address reprint requests to Dr Hill, Department of Anesthesiology, Box 3094, 3439 Hospital North, Duke University Medical Center, Durham, NC 27710 (Email: hill0012{at}mc.duke.edu).
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Abstract |
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METHODS: Thirty-six adult cardiac surgical patients were enrolled in a single-institution, randomized, controlled, single-blind dose escalation trial. Autologous whole blood was harvested from each patient to target an on-bypass hematocrit of 20% to 22%. Placebo, low dose (1.8 g/kg) or high dose (2.7 g/kg) AF0144 was administered. Transcranial Doppler ultrasonography was used to quantitate cerebral emboli and xenon-133 clearance was used to measure cerebral blood flow.
RESULTS: Cerebral blood flow was increased in both AF0144-treated groups compared with placebo (p = 0.006, low dose vs control; p = 0.036, high dose vs control). Numbers of cerebral emboli were greater in the high-dose AF0144-treated group versus control during the time periods from aortic cannulation through aortic cross-clamp placement (p = 0.026) and from aortic cross-clamp placement through cross-clamp removal (p = 0.008).
CONCLUSIONS: The perfluorocarbon emulsion, AF0144, increased cerebral blood flow during cardiopulmonary bypass. In addition, total cerebral emboli load during bypass was greater in patients receiving high-dose AF0144.
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Introduction |
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Acute normovolemic hemodilution is a blood-conservation technique used intraoperatively to reduce the need for allogeneic red blood cell transfusion. By replacing a portion of the patient's blood volume with colloid or crystalloid, harvested autologous blood may be reinfused after the surgical blood loss has abated. Although acute normovolemic hemodilution may reduce transfusion requirements during surgery, achievement of efficacy in transfusion avoidance requires that a significant amount of autologous blood be removed [6, 7]. With the removal of this autologous blood, oxygen carrying capacity (and potentially oxygen delivery) may be significantly impaired. In order to address these reductions in oxygen carrying capacity the addition of various oxygen carrying compounds in the setting of acute normovolemic hemodilution has been suggested. Three multicenter, randomized, controlled, single-blind phase 2 studies conducted in hemodiluted orthopedic [2], urologic [8], and cardiac surgical patients [9] have demonstrated the ability of AF0144 in doses as great as 2.7 g PFC/kg to reverse physiologic transfusion triggers. Physiologic triggers signaling the need for red blood cell transfusion include decreased partial pressure of oxygen in the venous blood, decreased mean arterial pressure, increased heart rate, and electrocardiographic changes suggestive of myocardial ischemia. The efficacy of AF0144 in reversing the physiologic triggers is believed to be due to increased partial pressure of oxygen in the tissue [2].
Despite the advanced level of clinical development of various oxygen-carrying solutions, including Perflubron (Alliance Pharmaceutical Corp), the impact on cerebral physiology has not been clearly ascertained in the setting of cardiac surgery. The purpose of this study was to determine the effects of AF0144 on cerebral blood flow (CBF) and cerebral emboli detected by transcranial Doppler ultrasonography during cardiopulmonary bypass (CPB).
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Material and Methods |
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Patients were initially randomized to either acute normovolemic hemodilution alone or acute normovolemic hemodilution combined with low-dose (1.8 gm PFC/kg) AF0144 therapy. After completion of safety evaluation for the initial 24 patients, 12 additional patients were enrolled in the dose-escalation phase of the study and treated with a higher dose of AF1044 (2.7 gm PFC/kg) according to the same protocol. Results of safety and preliminary efficacy evaluations for this patient group were previously reported [9].
Pulmonary and radial arterial catheters were inserted prior to induction of anesthesia. A retrograde internal jugular venous catheter was placed for sampling of blood from the jugular bulb. An intravenous anesthetic technique was used that consisted of induction with a fentanyl bolus (
50 mcg/kg) and a midazolam bolus ( 0.2 mg/kg) followed by continuous infusion of fentanyl ( 0.25 mcg/kg/min) and midazolam ( 1.0 mcg/kg/min). During CPB, maximum infusion rates were 0.05 mcg/kg/min for fentanyl and 0.5 mcg/kg/min for midazolam. Vecuronium or pancuronium were used for paralysis, guided by peripheral nerve stimulation. Continuous transcranial Doppler (Neuroguard [Medasonics Inc, Fremont, CA]) monitoring of the right middle cerebral artery was performed. A 2 MHz pulsed-wave transcranial Doppler probe with an 18-mm sample length gated at depths of 45 to 55 mm was utilized. Doppler signals were recorded from first placement of the probe immediately after induction of anesthesia until skin closure and emboli counts were determined using an automated counting system. To confirm the accuracy of emboli counts, the transcranial Doppler study was recorded on videotape, and the tape was postoperatively reviewed by an investigator (blinded to group assignment) who verified that every embolic signal counted was not an artifact.
After cannulation for CPB, heparinized autologous whole blood was collected into sterile collection bags from the venous return line upon initiation of CPB and stored in the operating suite (at room temperature with intermittent gentle agitation) until reinfused prior to completion of surgery. Hypothermic nonpulsatile CPB was performed using a Cobe CML membrane oxygenator and roller pump (Cobe Cardiovascular Inc, Aruada, CO) with an initial crystalloid prime volume of 1,800 mL. Initial bypass flow rates were 2.0 to 2.2 L/min/m2 with maximal oxygenation of the blood maintained by the oxygenator (FiO 2 1.0). Mean arterial pressures were maintained at 45 to 80 mm Hg using phenylephrine or sodium nitroprusside as necessary. After initiation of CPB and measurement of baseline CBF, but prior to cooling, the patient received the treatment (1.8 gm PFC/kg or 2.7 gm PFC/kg) or control solution (3 mL/kg balanced electrolyte solution) into the venous reservoir of the bypass machine. Subjects were then cooled to a nasopharyngeal temperature of 32°C, and after aortic cross clamping, crystalloid cardioplegia was used to arrest the heart.
During CPB the patients were monitored at 15-minute intervals for occurrence of a transfusion trigger including any one of the following: venous partial pressure of oxygen < 30 mm Hg, mixed venous oxygen saturation < 60%, or hematocrit < 15%. If a trigger was reached that was not reversible by adjustment in anesthesia or perfusion technique, patients received 1 unit (500 mL) of autologous whole blood, and the measurements were repeated 5 minutes after transfusion to reassess transfusion triggers. If all autologous blood had been returned to the patient, and additional transfusion triggers occurred, 1 unit of allogeneic packed red blood cells was administered and the triggers were reassessed. After cessation of CPB, all autologous whole blood was returned to the patient.
Cerebral blood flow was measured 5 minutes after the initiation of CPB before administration of the study treatment, 10 minutes after drug administration, 10 minutes after cooling to 32°C, and 5 minutes after the start of rewarming, using a previously-described xenon-133 clearance technique [10]. After injection of 3 millicuries of xenon-133 into the inflow limb of the CPB circuit, washout of xenon-133 from the brain was measured during a 3-minute time period using bilateral 16-mm cadmium detectors positioned over the temporoparietal region. Cerebral blood flow values from each side were averaged for subsequent analysis.
The statistical demographic characteristics of the treatment groups were compared with Fisher's exact test for categorical measures and with the Kruskal-Wallis test for numeric measures. Cerebral blood flow measurements were compared between groups using an overall repeated-measures analysis of variance model that accounted for dependence of repeated measures and tested treatment effect, time difference, and difference between treatments with time. If this overall model was significant, pairwise tests comparing each PFC group with the control group were performed using the same method. A follow-up analysis was also undertaken comparing groups only after treatment, because no difference was expected before treatment. Finally, if significant treatment differences were seen, an analysis of variance was used to compare groups at separate measurement times after checking for normality. Cerebral emboli count was analyzed in a similar fashion after a log transformation to achieve a normal distribution. An overall group difference was tested in a repeated measures of analysis of variance, followed by analysis of variance tests for difference among groups at specific periods during surgery. A p value < 0.05 was considered significant.
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Results |
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Comment |
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Several studies of PFC administration in the perioperative setting have been undertaken. Although the overall side-effect profile appears to be acceptable, the understanding of the effects of PFC on cerebral physiology is incomplete. One would expect that PFC-mediated increase in oxygen carrying capacity and delivery would lead to an autoregulatory-mediated decrease in CBF. However, pre-clinical data has demonstrated that in the setting of a complete PFC exchange transfusion in the rat [11] [12], significant increases in CBF occur. In these studies, the observed increase in CBF was attributed to a lower viscosity and overall decreased oxygen carrying capacity of the animal's circulation after exchange transfusion [11, 12]. In a study of cats undergoing complete PFC exchange, cerebral hyperemia was again observed that was found to be independent of nitric oxide-mediated vasorelaxation [13]. Infusion of PFC into monkeys breathing 100% oxygen after occlusion of the right middle cerebral artery resulted in elevated CBF, increased cortical oxygen delivery and recovery of electroencephalographic activity in the ischemic brain [14]. Later work using PFC as part of the priming solution for the CPB circuit in both goat [15] and pig [16] models of CPB revealed increases in CBF and oxygen delivery in the animals receiving PFC.
The effects of PFC on human cerebral physiology have been less studied. One PFC emulsion (Fluosol DA, 20% weight/volume PFC, [Green Cross Corp, Osaka, Japan]) was approved for human use in the United States as an adjunct for oxygen delivery during coronary angioplasty procedures. When administered to human volunteers with vasospasm, stenosis, or occlusion of a cerebral artery, Fluosol (Green Cross Corp) resulted in a 10% to 25% increase in CBF [17, 18], suggesting a potential beneficial cerebral effect. The study herein focused on the cerebral effects of the PFC emulsion, AF0144, in humans during cardiac surgery. Similar to prior animal studies, an increase in CBF occurred. This increase in CBF occurred without a change in mean arterial pressure compared with control patients. The mechanism for this is not entirely clear, but could potentially be a result of either a direct vasodilatory response of PFC on the cerebral vasculature or a decrease in blood viscosity at a pharmacologically stabilized mean arterial pressure on CPB.
Because of its ability to dissolve gases in the bloodstream, administration of PFC emulsion was investigated in a pig model of massive air embolism during CPB and was found to reduce neurologic injury [19]. As the ability of PFC to dissolve intravenous gas was presumed to be the mechanism for improving outcome in that study, we had anticipated that a decrease in the number of cerebral emboli might be seen in this study. However, we demonstrated an overall increase in emboli, likely as a consequence of the demonstrated increase in CBF. Although emboli counts were not increased during all time periods, the time periods in which AF0144 would most likely be circulating in highest concentration (from aortic cannulation to aortic cross clamp and from aortic cross clamp to aortic reperfusion) showed the largest increases. The potential clinical sequelae of this increased emboli delivery are significant. Transcranial Doppler is unable to distinguish between gaseous or particulate emboli. However, both stroke (due to macroembolization of thrombus, atherosclerotic, or other particulate debris [20]) and cognitive dysfunction (due to gaseous and particulate microembolization [21, 22] to the cerebral vasculature) are potential consequences of increased cerebral blood flow.
There were limitations in this present study. First, the relatively small sample size precluded determination of any relationship between increased CBF or emboli count with any potential adverse functional cerebral outcome. Neurocognitive outcome was examined, as previously reported [9], in patients from this present trial. Neurocognitive outcome was not significantly different among the groups, although the small study size precluded the ability to more thoroughly assess this parameter. The limited sample size of this phase 2 trial did not confer adequate power to examine cerebral outcomes such as stroke, which did not occur in this trial. More recently, a subsequent phase 3 trial in cardiac surgery was suspended by the sponsor, with approximately two-thirds of the target number (n = 600) of patients enrolled, due to concern over an imbalance in the incidence of stroke in the two groups [23]. Although the exact mechanism of this higher stroke rate was not determined, further clinical trials of AF0144 in cardiac surgical patients have not been re-started. Because of the unexpected increase in stroke rate for treated patients in the phase 3 trial, all data collected in the earlier phase 2 trial were reexamined. Although the sample size was small in this phase 2 study, the elevation in cerebral emboli in the high-dose treatment group combined with observed treatment-related elevation of cerebral blood flow offers a possible explanation for the clinical findings subsequently observed in the larger phase 3 study.
A further limitation was that the study design lacked a parallel control group for the high-dose treatment subjects. The control group and the low-dose treatment groups were randomized and parallel, but the high-dose treatment patients were studied consecutively after the initial safety evaluation. Although unlikely because of the relatively brief study duration of 17 months, the possibility exists that differences between the high-dose group and the control patients could have been the result of changing techniques over time related to surgical, anesthetic, perfusion, or hemodilution procedures. Another limitation was that the investigators were not blinded to the treatment, due to the opaque nature of the PFC emulsion. Although not significantly different between the groups, a trend toward a larger autologous blood harvest was present in the high-dose treatment group. The protocol was strictly followed and the high-dose group did not differ significantly from the other groups in patient size or hemoglobin. A theoretical concern exists that AF0144 emulsion particles might be detected as emboli by the transcranial Doppler, elevating emboli counts in the treated patients. However, because the median particle size (0.16 to 0.18 micrometers) is approximately 40 times smaller than that of a red blood cell [4], transcranial Doppler would be extremely unlikely to detect these particles.
Finally, the use of xenon-133 clearance measurements to measure CBF represents a potential limitation related to the known solubility of xenon in PFC emulsion. In a study measuring xenon elimination from dogs, the enhanced solubility of xenon in PFC-containing solutions increased the rate of xenon washout from canine skeletal muscle [24]. Although enhanced washout of xenon by PFC could artificially elevate CBF measurements, the significantly lower dose of AF0144 used in this trial compared with the canine study would be less likely to significantly impact the CBF measurements. Because the magnitude of CBF increase observed in the patients receiving AF0144 in this trial is consistent with the results of prior animal and human trials of perfluorocarbons and CBF [13–17, 19], the increased CBF observed after administration of AF0144 is likely a true finding.
Although these data suggest that PFCs may increase the risk of cerebral ischemia by embolic occlusion of cerebral vessels during CPB, circulating PFC may have some theoretical benefit during other types of major surgery. As previously discussed, PFC may decrease the size and number of gaseous emboli through absorption. Furthermore, even if PFC administration predisposes to cerebral embolization of atherosclerotic emboli after aortic manipulation, diffusion of oxygen into tissue due to increases in dissolved oxygen may actually enhance microvasculature oxygen delivery distal to a fixed atheromatous occlusion. Perfluorocarbon has been shown to be neuroprotective in animal models of focal cerebral ischemia [14, 19, 25, 26] and may prove helpful to humans as well.
Whether this effect on CBF and emboli that we demonstrated herein are unique to the PFC formulation (AF0144) itself or to all PFCs is unclear. Regardless, these potentially adverse effects suggest caution in pursuing further studies in this patient population. Although AF0144 may not be suited for use in cardiac surgery, the cerebral physiologic effect of increased CBF may be beneficial in a patient population not exposed to emboli-generating manipulations such as aortic manipulation and CPB.
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Appendix |
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Anesthesiology: Hilary P. Grocott, MD, Madan Kwatra, PhD, Joseph P. Mathew, MD, Mark F. Newman, MD, Debra A. Schwinn, MD, Mark Stafford-Smith, MD, Madhav Swaminathan, MD, David Warner, MD, Bonita L. Funk, RN, Chonna Campbell, BS, Glenn Davis, Eugenie Eaborn, RN, Roger L. Hall, AAS, Marcie Hanish, RN, Michael Hill, BS, Jerry L. Kirchner, BS, Lindsay Kuhn, BA, Satarah Latiker, BS, Erich Lauff, BA, Richard Morris, PhD, Charles R. Peters, MA, Meredith Prince, William Hansley, BS, Barbara Phillips-Bute, PhD, Andrew Slaughter, BS, Elizabeth Perez, RN, William D. White, MPH, and Sarah Woodring, BS
Behavioral Medicine: Michael A. Babyak, PhD and James A. Blumenthal, PhD
Cardiology: Daniel B. Mark, MD, MPH and Michael H. Sketch, Jr, MD
Neurology: Ellen R. Bennett, PhD, Carmelo Graffagnino, MD, Daniel T. Laskowitz, MD, John R. Lynch, MD, Warren J. Strittmatter, MD, and Kathleen A. Welsh-Bohmer, PhD
Perfusion Services: Greg Smigla, BS, CCP and Ian Shearer, BS, CCP
Surgery: Thomas A. D'Amico, MD, Robert Duane Davis, MD, Donald D. Glower, MD, David Harpole, MD, James Jaggers, MD, Andrew Lodge, MD, James E. Lowe, MD, Robert H. Messier, MD, Carmelo Milano, MD, Peter K. Smith, MD, Eric M. Toloza, MD, PhD, and Walter G. Wolfe, MD
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Acknowledgments |
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This article has been cited by other articles:
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  F. de Lange, K. Yoshitani, A. D. Proia, G. B. Mackensen, and H. P. Grocott Perfluorocarbon Administration During Cardiopulmonary Bypass in Rats: An Inflammatory Link to Adverse Outcome? Anesth. Analg., January 1, 2008; 106(1): 24 - 31. [Abstract] [Full Text] [PDF]
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 R. F. Mattrey Are Cerebral Emboli Real When Perfluorocarbon Emulsion (AF0144) is Used in Cardiac Surgery? Ann. Thorac. Surg., May 1, 2007; 83(5): 1922 - 1923. [Full Text] [PDF]
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S. E. Hill and H. P. Grocott Reply Ann. Thorac. Surg., May 1, 2007; 83(5): 1923 - 1923. [Full Text] [PDF]
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