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Ann Thorac Surg 2000;69:491-497
© 2000 The Society of Thoracic Surgeons

Original Articles

Biologically variable pulsation improves jugular venous oxygen saturation during rewarming

W. Alan C. Mutch, MDc, R. Keith Warrian, MDb, Gerald M. Eschun, MDa, Linda G. Girling, BSca, Leonard Doiron, CPCb, Mary S. Cheang, MMathc, Gerald R. Lefevre, MDa

a Department of Anesthesia, University of Manitoba, Winnipeg, Manitoba, Canada
b Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada
c Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

Address reprint requests to Dr Mutch, Department of Anesthesia, St. Boniface General Hospital, 409 Taché Ave, Winnipeg, MB, Canada R2H 2A6
e-mail: amutch{at}ms.umanitoba.ca


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Conventional pulsatile (CP) roller pump cardiopulmonary bypass (CPB) was compared to computer controlled biologically variable pulsatile (BVP) bypass designed to return beat-to-beat variability in rate and pressure with superimposed respiratory rhythms. Jugular venous O2 saturation (SjvO2) below 50% during rewarming from hypothermia was compared for the two bypass techniques. A SjvO2 less than 50% during rewarming is correlated with cognitive dysfunction in humans.

Methods. Pigs were placed on CPB for 3 hours using a membrane oxygenator with {alpha}-stat acid base management and arterial filtration. After apulsatile normothermic CPB was initiated, animals were randomized to CP (n = 8) or BVP (roller pump speed adjusted by an average of 2.9 voltage output modulations/second; n = 8), then cooled to a nasopharyngeal temperature of 28°C. During rewarming to stable normothermia, SjvO2 was measured at 5 minute intervals. The mean and cumulative area for SjvO2 less than 50% was determined.

Results. No between group difference in temperature existed during hypothermic CPB or during rewarming. Mean arterial pressure, arterial partial pressure O2, and arterial partial pressure CO2 did not differ between groups. The hemoglobin concentration was within 0.4 g/dL between groups at all time periods. The range of systolic pressure was greater with BVP (41 ± 18 mm Hg) than with CP (12 ± 4 mm Hg). A greater mean and cumulative area under the curve for SjvO2 less than 50% was seen with CP (82 ± 96 versus 3.6% ± 7.3% · min, p = 0.004; and 983 ± 1158 versus 42% ± 87% · min; p = 0.004, Wilcoxon 2-sample test).

Conclusions. Computer-controlled BVP resulted in significantly greater SjvO2 during rewarming from hypothermic CPB. Both mean and cumulative area under the curve for SjvO2 less than 50% exceeded a ratio of 20 to 1 for CP versus BVP. Cerebral oxygenation is better preserved during rewarming from moderate hypothermia with bypass that returns biological variability to the flow pattern.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Cerebral injury with cardiopulmonary bypass (CPB) remains a serious concern. Increasing attention has been focused on cognitive dysfunction, which follows CPB. Carefully conducted prospective studies indicate that psychomotor deterioration occurs in up to 70% of patients [1–5]. Cognitive dysfunction following cardiac operation is correlated to low jugular venous O2 saturation (SjvO2) during rewarming from hypothermic CPB [6]. Low SjvO2 can also occur with normothermic CPB [7]. When SjvO2 is less than 50%, a marked increase in cognitive impairment occurs. Jugular venous desaturation has recently been shown to continue into the postoperative period [8]. Effective prophylaxis of cerebral hypoxia in the perioperative period would benefit patients undergoing open heart operations.

We have previously shown that biologically variable pulsatile (BVP) bypass that attempts to recreate spontaneous biological rhythms during CPB can markedly de-crease, by greater than 75-fold, the incidence and severity of SjvO2 less than 50% seen with apulsatile bypass [9]. In this study we have examined if the significant improvement in cerebral oxygenation is also evident when BVP was compared to conventional pulsatile (CP) bypass.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
The Committee for Animal Experimentation at the University of Manitoba approved the experimental protocol. Animals were handled according to the standards of the Canadian Council on Animal Care.

Surgical preparation
Following premedication (atropine 0.6 mg and ketamine 10 mg/kg IM), 16 pigs (30 to 40 kg) were anesthetized with 2.0% end-tidal isoflurane in O2. Muscle relaxation was with pancuronium bromide iv (20 mg as a bolus then 10 mg/kg/hr throughout the experiment). Sternotomy was performed to permit ascending aortic (6.5-mm Jostra; Hirrlingen, Germany) and right atrial (28F Polystar; Vaerlose, Denmark) cannulation. The left internal jugular vein was cannulated in a retrograde manner (after ligation of all extracranial branches) for cerebral venous blood sampling and hemodynamic measurements. The femoral artery and vein were cannulated for hemodynamic and blood gas measurements. Temperature was recorded from calibrated nasopharyngeal and jugular venous probes. On bypass, pump arterial inflow and venous outflow temperatures were also recorded.

Following operation, a 30-minute stabilization period ensued. Before commencing CPB, 100 mg of sodium hydrocortisol succinate was administered iv. The bypass circuit was primed with pentaspan, lactated Ringer’s, and mannitol (20%) to a total volume of 1.5 liters. After intravenous heparin (12 to 15,000 IU iv and 1,000 IU per hour as circumstances may require to maintain activated clotting time (ACT) >500 seconds), apulsatile CPB was begun. Animals received 10 mL/kg/h lactated Ringer’s during bypass. We used a Cobe Stöckert roller pump, a hollow fiber membrane oxygenator, and open system reservoir (Cobe Optima; Cobe, Arvada, CO) and arterial filtration (Bentley Duraflo II 1040D, 40-µ mesh; Bentley, Irvine, CA) with {alpha}-stat acid-base management. With initiation of CPB, isoflurane (1.0% inspired) was administered with O2 flow into the oxygenator. In addition, propofol was infused throughout the bypass period at 3 mg/kg/h. Normothermic apulsatile bypass was maintained for approximately 30 minutes to ensure stable hemodynamics and hemoglobin. Following these measurements, active cooling to 28°C by heat exchanger began. If ventricular fibrillation did not occur, the heart was arrested with 40 mEq of KCl. The aorta was subsequently cross-clamped. Animals were randomized to either CP bypass using a Cobe Stöckert pulse module (1 to 1 pulsation with the start and stop sliders adjusted to give a pulse pressure of approximately 25 mm Hg), or BVP bypass as previously described [9]. Hypothermic CPB was continued for 75 to 90 minutes. During this period, isoflurane concentration was decreased to 0.5% inspired. Rewarming to baseline temperature occurred over a 30 to 45 minute period, with a maximal 8°C temperature gradient between arterial and jugular venous blood. During rewarming, the isoflurane concentration was again increased to 1.0% inspired. When baseline temperature was reached, the temperature remained unchanged for a further 30 minutes.

Blood gas data were obtained at stable normothermic CPB (Normo-CPB), at 30-minute intervals during hypothermic CPB and at end hypothermia (Hypo-CPB). During rewarming, blood gases were obtained every 5 min-utes until return to baseline temperature (Rew1-CPB), then every 5 minutes over the next 30 minutes (Rew2-CPB) at stable temperature. Blood gases were measured using a Radiometer ABL3 (Radiometer, Copenhagen, Denmark), and arterial and jugular venous O2 content (CaO2 and CjvO2 respectively) and hemoglobin levels measured using a Radiometer OSM3 set for porcine blood. Total bypass time was constant at 3 hours. At the end of each experiment, the animal was injected with a lethal dose of sodium thiopental and the roller pump stopped.

Computer-controlled pulsation
The computer-controller and software for the roller pump are patented (U.S. patent #5,647,350). BVP bypass recreated the systolic arterial pressure (SAP) variations as downloaded from a previously saved data file of invasive arterial pressure recorded from a lightly anesthetized, spontaneously breathing pig [9].

Statistical analyses
Time-related changes for temperature, hemodynamics, and blood gas data were evaluated by analysis of variance (ANOVA) for repeated measures. When ANOVA was significant, comparisons were made with the least-squares means test. Bonferroni’s correction was applied when multiple comparisons were made (p < 0.05/n; where n = number of comparisons). The corrected p value was considered statistically significant. The area under the curve for SjvO2 less than 50% was an index of cerebral hypoxia during the time from end hypothermia to Rew2-CPB. For each experiment, the cumulative product when SjvO2 was less than 50% was {Sigma}([50 - SjvO2 < 50]% x 5 minutes). The mean value, {Sigma}([50 - SjvO2 < 50%]% x 5 minutes)/number of observations over the entire measuring period, was also determined for each group. If SjvO2 at any time period was less than or equal to 50%, then saturation multiplied by time product was set to 0. Measurement of the area where saturation was less than 50% was calculated by computer using the trapezoid rule. Cerebral perfusion pressure (CPP) was calculated as MAP minus jugular venous pressure (JVP). Data are presented as mean ± standard deviation (SD) unless noted.

The two pulsation techniques were compared in the following manner: mean systolic arterial pressure (SAP) was determined, then instantaneous SAP was subtracted from mean SAP, this value was squared, then log transformed. These data were partitioned into incremental bins of equal size to determine their frequency distribution. The probability of each frequency was determined by Ni/N where Ni = number of observations in a given frequency bin, and N = total number of observations. A log transform of the probability distribution was derived. The log probability distribution versus log SAP variation was plotted. The confidence interval and correlation coefficient were derived by regression analysis.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
The pigs were moderately heavier in the BVP group (37 ± 3 versus 34 ± 7 kg; p = 0.005). Mean pulse pressure was not different (group x time interaction; p = 0.776). At Rew-2 CPB mean pulse pressure was 28 ± 5 mm Hg with BVP (a mean of means; because of the variability with BVP we determined pulse pressure [up to 120 peak and valley determinations], then took the mean of this difference) and 26 ± 6 mm Hg with CP. The systolic arterial pressure range was much larger with BVP (41 ± 18 mm Hg) than with CP (12 ± 4 mm Hg).

Temperature and hemodynamic data
At the 4 measurement sites, temperature was very stable between groups at all time periods (Table 1). Per design, significant decreases in temperature were seen during the period of hypothermic CPB. The mean temperature difference between groups at Rew1-CPB did not exceed 0.4°C at any measurement site. At Rew2-CPB, mean temperature did not differ by more than 0.2°C between groups. Despite similar temperatures at specific times, the cerebral rewarming rate was faster with BVP than with CP (0.17 ± 0.4°C/min versus 0.13 ± 0.02°C/min, respectively). There were no differences in MAP, CVP, JVP, or CPP, between groups. The pump flow rate was significantly greater with initiation of CPB in the CP group. At other time periods, during hypothermia and with rewarming, pump flow rates did not differ. The SVR was similar between groups with initiation of CPB. In the CP group, with hypothermia and during rewarming, SVR was greater than at normo-CPB. The SVR was greater in the CP group during hypothermia and at Rew1-CPB, but there was no significant difference between groups at the final measurement period.


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  		Table 1. Temperature and Hemodynamic Data

 
Blood gas data
Mean arterial partial pressure O2 (PaO2) was greater than 275 mm Hg at all time periods and not different between groups (Table 2). The expected decrease in arterial partial pressure CO2 (PaCO2) with hypothermia and {alpha}-stat acid-base management was seen. There was no difference in PaCO2 between groups. A small but significant difference in arterial pH (0.05 units) was seen between groups at Rew2-CPB. Hemoglobin decreased significantly in both groups with onset of CPB, but was similar between groups. The SjvO2 was not different during initial normothermic CPB. With CP, 8 of 8 pigs had a SjvO2 less than 50% at Rew2-CPB compared to 3 of 8 pigs with BVP (p = 0.013 by Fisher exact test).


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  		Table 2. Blood Gas Data

 
The relationship between SjvO2 during the period of rewarming is shown in Figure 1. For both mean and mean cumulative areas for SjvO2 less than 50% the ratio was 23 to 1 with the larger area associated with CP. The values for these ratios were (82 ± 96 versus 3.6% ± 7.3% · min for mean area, p = 0.004; and 983 ± 1158 versus 42% ± 87% · min for mean cumulative area, p = 0.004, Wilcoxon 2-sample test).



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  		Fig 1. Internal jugular venous O2 saturation (SjvO2) percent versus time. Blood was sampled every 5 minutes from the end of hypothermic cardiopulmonary bypass (CPB) until rewarmed to baseline temperature then maintained at this temperature for 30 minutes. There are 8 experiments in each group. The thick dashed horizontal line shows where SjvO2 equals 50%. The mean area and cumulative mean area for SjvO2 less than 50% is markedly greater with conventional pulsatile (CP) bypass.

 
Figure 2 shows the relationship between arterial-jugular venous O2 content difference (CaO2 - CjvO2) over time. Significantly greater CaO2-CjvO2 was seen with CP bypass during rewarming. Croughwell and associates showed O2 content difference is strongly correlated to cognitive dysfunction after CPB [6].



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  		Fig 2. The arterial-jugular venous O2 content difference for both groups (mean ± standard error of the mean). CaO2-CjvO2 was significantly greater with conventional pulsatile (CP) bypass (group x time interaction; p = 0.0014; *significant differences between groups at time period shown).

 
Figure 3 shows the log probability versus log SAP variation for BVP and CP. With both types of pulsation, the relationship followed an inverse power law distribution (l/fa) with a = 2.41 ± 0.25 and 1.98 ± 0.26, for BVP and CP bypass, respectively. The variation in SAP was much greater in the BVP group [maximal variation 605 (mm Hg)2 versus 32 (mm Hg)2].



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  		Fig 3. Log-log plot of probability distribution versus systolic arterial pressure (SAP) variability used to program the computer-controlled biologically variable roller pump. A l/fd plot is obtained. (a = 2.41 ± 0.25). A similar plot for conventional pulsatile bypass (CP) is shown. (a = 1.98 ± 0.26). The probability of a given SAP variation is much greater with biologically variable pulsatile bypass (BVP).

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
These experiments demonstrate that cerebral hypoxia (defined as SjvO2 < 50%) is reduced with BVP compared to CP bypass in a porcine model. These differences occurred during the period of rewarming to a stable normothermic nasopharyngeal temperature from moderate hypothermia (28°C). The advantage of BVP was confirmed in this experimental model. Previously, we showed that cerebral hypoxia (assessed in the same manner) was greater with apulsatile bypass [9]. Based on our experiments we would rank the risk of cerebral hypoxia with bypass as apulsatile is greater than conventional pulsatile, which is greater than biologically variable pulsatile perfusion.

In this study, 8 of 8 animals managed with CP had SjvO2 less than 50% at steady state normothermic nasopharyngeal temperature following hypothermic CPB (Fig 1). In contrast, only 3 of 8 animals with BVP had venous saturation less than 50% at this time period (p = 0.013; Fisher exact test). The mean and cumulative area under the less than 50% saturation curve was markedly greater with CP (mean ratios of at least 20 to 1). Significantly greater desaturation with CP bypass indicates greater parenchymal hypoxia in this group, placing the brain at a greater risk of injury. Other causes for possible differences in SjvO2 between the 2 groups have been carefully controlled. For instance, temperatures between groups were similar at measured time periods. Additionally, depth of anesthesia, CPP, PaO2, PaCO2, and hemoglobin were not different between groups. We have previously shown a correlation between SjvO2 and cerebral oxygenation as assessed by magnetic resonance imaging (MRI) [10]. Using the same porcine model, cerebral parenchymal oxygenation decreased (as measured by T2*-weighted imaging) following rewarming to normothermic temperatures. McDaniel and associates reported similar findings [11]. Croughwell and colleagues showed that cognitive decline following CPB was strongly correlated to maximal CaO2-CjvO2 difference (p = 0.0013; logistic regression model) [6]. Over a range of oxygen content difference from less than 3 to greater than 6% volume there was a 2.6 fold increase in cognitive dysfunction. If the changes in CaO2-CjvO2 seen in this experiment with pigs were also seen in humans, BVP would result in a 2.0-fold reduction in cognitive dysfunction compared to CP bypass (Fig 2).

There are 3 plausible explanations for the differences in SjvO2 and CaO2-CjvO2 seen between groups: (1) differences in CPP with altered autoregulation contributing to cerebral ischemia; (2) differences in microembolic load to the brain; or (3) differences in critical closure of collapsible vessels with tone. We have shown that autoregulation is altered during both hypothermic and normothermic CPB [12]. No significant differences in CPP were seen between groups. We did not find a correlation between SjvO2 and CPP during hypothermia and over the rewarming period (r = 0.066; not significant with 46 degrees of freedom). Thus differences in autoregulation between groups seems unlikely. The microembolic load to the brain should have been minimal; nonatheromatous aorta, {alpha}-stat acid-base management, membrane oxygenation, arterial filtration, no aortic unclamping, and no cardiac ejection on rewarming [13–17]. Reperfusion of poorly oxygenated parenchyma must occur with rewarming, because SjvO2 is significantly lower than in the initial normothermic CPB period. Microemboli would need to be washed out of the vascular bed during rewarming for venous desaturation to occur, an unlikely situation once impacted in the microcirculation. The remaining plausible explanation for the differences in SjvO2 is an alteration in critical closure of collapsible vessels with tone [18]. The cerebral circulation has been successfully modeled using these concepts [19]. Small increases in critical closing pressure of parenchymal arterioles during CPB would decrease driving pressure across cerebral vessels while they remain continuously perfused (until critical closing pressure equals or exceeds inflow pressure) [18]. With hypothermia, cerebral vascular tone is already increased and the left shift of the oxyhemoglobin dissociation curve predisposes to inadequate O2 delivery [20]. Upon rewarming, cerebral vascular tone decreases, as CBF increases to meet metabolic requirements. This decrease in tone would decrease closing pressure and increase driving pressure across the vascular bed. The accrued O2 debt could now be repaid, presenting as decreased SjvO2.

Pulsatile perfusion compared to apulsatile perfusion is associated with enhanced capillary bed patency and increased release of endothelial derived relaxing factor (nitric oxide) from blood vessel walls [21] limiting any pathological increase in vascular tone. In this experiment, differing modes of pulsation resulted in differing cerebral oxygenation.

Figure 4 explains how increased SAP variation could influence collapse of vessels with tone. A model based on the work by Suki and colleagues [22] is adapted to the cerebral circulation instead of the lung. Increasing critical closing pressure, until this pressure equals or exceeds regional perfusion pressure, will result in less regional flow. Once collapsed, greater CPP is required to open this circulatory bed again. The greater SAP variation (by 3.5-fold), shown as SD with BVP, represents a noisier signal than the variation seen with CP. Greater noise at peak systole or maximal instantaneous roller pump RPM rate could better recruit collapsed microvasculature seen with increased critical closing pressure. With hypothermia, there is a propensity to increase critical closing pressure as vascular tone increases. With rewarming the noisier pulse pressure with BVP more readily recruits closed vessels. The addition of noise to an input signal (SAP variation) to enhance an output signal (increased SjvO2) in a nonlinear system is an example of stochastic resonance [22].



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  		Fig 4. A model of how increased systolic arterial pressure (SAP) variation could influence collapse of vessels with tone.

 
With BVP, the systolic pressure range was 3.5-fold greater than with CP. Such an enhanced pressure envelope may help to prevent vessel closure from occurring, or if it does, allow collapsed vessels to be recruited earlier and more easily during rewarming. Recruitment clearly occurs in both groups, but the O2 debt is more marked in the CP group. Using MRI techniques sensitive to tissue oxygenation [10] we showed that greater than 30% of the cerebral parenchyma was at risk of hypoxia during CPB. Such brain hypoxia, with possible neuronal damage, may contribute to postoperative neuropsychological dysfunction seen following CPB [6]. Parenchymal hypoxia is compatible with the finding that cerebral edema, as assessed by MRI [23] was seen in all patients, 1 hour after cardiac operation.

Examination of Figure 3 reveals that both CP and BVP demonstrated inverse power law frequency distributions (l/fa). Such variation in physiological signals is ubiquitous in nature [24]. Inverse power law behavior with CP, an example of monotonous pulsation, suggests that the variation that remains is a consequence of dynamic vascular tone. The probability of a given SAP variation is much greater with BVP. The natural variation in heart rate, blood pressure, and respiration are severely diminished with bypass. This natural variation is noticeably damped with CP but has been deliberately reintroduced with BVP.

In conclusion, biologically variable pulsatile bypass was associated with better cerebral oxygenation on rewarming from hypothermic bypass compared to conventional pulsatile CPB in this porcine model. These results suggest that BVP may aid in prophylaxis from the cerebral hypoxia seen with CPB. The computer-controlled pulsatile bypass pump could be used clinically. Whether cerebral oxygenation during bypass would be improved, and result in better preserved cognitive function in humans, must await further study.


   Acknowledgments
 
The authors thank Barb Robson for excellent technical assistance.


   Footnotes
 
The Crocus Investment Fund and the Industrial Research Assistance Program provided funding for this study. Some of the concepts discussed are protected by U.S. Patent #5,647,350; "Control of Life Support Systems," owned by Biovar Life Support Inc, jointly held by Drs Mutch, Lefevre, the University of Manitoba, and the Crocus Investment Fund.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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Accepted for publication July 14, 1999.




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