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Ann Thorac Surg 2000;70:751-755
© 2000 The Society of Thoracic Surgeons

Original articles: cardiovascular

Hyperoxia for management of acid-base status during deep hypothermia with circulatory arrest

Jeffrey M. Pearl, MDa, Donald W. Thomas, CCPa,b, Gary Grist, CCPb, Jodie Y. Duffy, PhDa, Peter B. Manning, MDa,b

a Children’s Hospital Medical Center, Cincinnati, Ohio, USA
b Children’s Mercy Hospital, Kansas City, Missouri, USA

Address reprint requests to Dr Pearl, Division of Pediatric Cardiothoracic Surgery, Children’s Hospital Medical Center, 3333 Burnet Ave, OSB-3 Cincinnati, OH 45229
e-mail: pearj0{at}chmcc.org


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Which blood gas strategy to use during deep hypothermic circulatory arrest has not been resolved because of conflicting data regarding the advantage of pH-stat versus {alpha}-stat. Oxygen pressure field theory suggests that hyperoxia just before deep hypothermic circulatory arrest takes advantage of increased oxygen solubility and reduced oxygen consumption to load tissues with excess oxygen. The objective of this study was to determine whether prevention of tissue hypoxia with this strategy could attenuate ischemic and reperfusion injury.

Methods. Infants who had deep hypothermic circulatory arrest (n = 37) were compared retrospectively. Treatments were {alpha}-stat and normoxia (group I), {alpha}-stat and hyperoxia (group II), pH-stat and normoxia (group III), and pH-stat and hyperoxia (group IV).

Results. Both hyperoxia groups had less acidosis after deep hypothermic circulatory arrest than normoxia groups. Group IV had less acid generation during circulatory arrest and less base excess after arrest than groups I, II, or III (p < 0.05). Group IV produced only 25% as much acid during deep hypothermic circulatory arrest as the next closest group (group II).

Conclusions. Hyperoxia before deep hypothermic circulatory arrest with {alpha}-stat or pH-stat strategy demonstrated advantages over normoxia. Furthermore, pH-stat strategy using hyperoxia provided superior venous blood gas values over any of the other groups after circulatory arrest.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
The type of blood gas strategy to use during deep hypothermic circulatory arrest (DHCA) is controversial with conflicting data regarding the advantage of pH-stat versus {alpha}-stat methods [1, 2]. The oxygen pressure field theory suggests that hyperoxia just before DHCA takes advantage of increased oxygen solubility and reduced oxygen consumption to load tissues with excess oxygen [3, 4]. Hypothetically by preventing tissue hypoxia in this manner, there would be less acid generated during DHCA, thus reducing ischemic and reperfusion injury.

The type of carbon dioxide (CO2) gas strategy applied during DHCA might affect oxygen loading. The pH-stat strategy adds CO2 to the system to keep the pH at 7.4 at the temperature at which the specimen is collected, which corrects the alkaline shift that normally occurs with cooling. The {alpha}-stat strategy allows the normal alkaline shift to occur. The pH is kept at 7.4 when the samples are corrected to 37°C. The pH-stat strategy has been associated with higher cerebral blood flow, with potential implications regarding the adequacy of cooling, oxygen delivery, and ultimately tissue oxygen tension. To test the hypothesis that tissue oxygen loading by using hyperoxia before DHCA reduces tissue hypoxia as measured by less acid generation, we conducted a retrospective analysis of infants who had DHCA using a combination of gas strategies.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
We reviewed the records of 37 infants who had DHCA for repair of congenital heart defects over a 24-month period. Patients were operated on at either Children’s Hospital Medial Center, Cincinnati, Ohio, or Children’s Mercy Hospital, Kansas City, Missouri. All patients had some degree of cyanosis preoperatively. Diagnoses included total anomalous pulmonary venous drainage, hypoplastic left heart syndrome, and interrupted aortic arch with ventricular septal defect. Diagnoses were evenly distributed among groups. Normoxia or hyperoxia management strategy was decided randomly by the perfusionist without regard to preoperative condition of the patient, with a trend toward normoxia in the early part of the study and hyperoxia later. Similar oxygenators, circuit designs, and anesthetic technique were used. The cardiopulmonary bypass (CPB) circuits were primed with blood, crystalloid cardioplegic solution, methylprednisolone, amicar, regitine, and furosemide. Minimum circuit volume was approximately 700 mL. During cooling, the hematocrit was maintained between 22% and 28% [5, 6] but was increased to 40% by ultrafiltration just before termination of CPB. Cooling and rewarming were done with a 10°C gradient between the tympanic temperature and arterial blood temperature.

Both perfusionists used {alpha}-stat CO2 strategy before September 1997 and pH-stat CO2 strategy thereafter. Pump flows were adjusted with a goal of 2.5 L · min-1 · m-2 as full support. Hypothermic 4:1 blood cardioplegia was used in all cases.

The initial fraction of inspired oxygen (FiO2) during CPB was set at 21% to limit the production of reactive oxygen species and to reduce potential reoxygenation injury [7, 8]. The FiO2 for the hyperoxia strategy was increased to 100% when the mixed venous oxygen saturation was above 80%, indicating adequate oxygen delivery on bypass and resolution of any significant oxygen debt. For the normoxia strategy, FiO2 was maintained at 21%. Cooling was done for a minimum of 20 minutes, and circulatory arrest was established at a tympanic membrane temperature of 18°C. The bypass volume was recirculated during circulatory arrest with the FiO2 at 21% and partial pressure of carbon dioxide (pCO2) maintained at a constant level based on the selected pH strategy. When bypass support was reinitiated, the FiO2 was maintained at 21% throughout rewarming to minimize the chance of reoxygenation injury.

In all normoxia patients the partial oxygen tension (pO2) value on a pump venous specimen at 18°C just before DHCA was less than 150 mm Hg. Tympanic, nasopharyngeal, and venous temperatures were monitored during cooling, with all patients at or below 18°C before circulatory arrest. For all hyperoxia patients the pump venous pO2 value at 18°C just before DHCA was greater than 300 mm Hg. The following four groups were compared: group I, {alpha}-stat and normoxia (n = 12); group II, {alpha}-stat and hyperoxia (n = 9); group III, pH-stat and normoxia (n = 8); and group IV, pH-stat and hyperoxia (n = 8).

Blood gases were analyzed on a Gem Premier monitor (Instrumentation Laboratories, Ann Arbor, MI). Blood gases were compared before and after DHCA to determine acid production during circulatory arrest, which reflected the degree of anaerobic metabolism. The pH measurements from just before circulatory arrest and just after reinitiating CPB were converted to [H+] by using a table, and the difference was calculated. Acid production during circulatory arrest was corrected for duration of arrest by dividing the amount of acid produced during arrest of individual patients by their duration of arrest and multiplying by 60, to yield a normalized amount of acid produced per hour of arrest. The CPB circuit volume was not altered during the arrest period to maintain a fixed system fluid volume that included the circuit volume and the patient’s blood volume. The system volume was reduced by ultrafiltration only during rewarming. There were no statistically significant differences in morbidity or mortality among groups. Overall early mortality in this complex group was 19%, with at least one death in each group.

Values were compared between groups by using Student’s t test or analysis of variance in the GraphPad Instat V2.02 statistical analysis program (GraphPad Software, San Diego, CA). Data are presented as the mean ± standard error. Probabilities of 0.05 or less were considered significant. Formal institutional review board approval was not required by our institution because of the retrospective nature of the study and the lack of true randomization.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
The average weight of all patients included in the study was 3.1 kg and did not differ between the groups. Circulatory arrest times were similar among groups, except for group II, in which the arrest time was significantly longer (72 minutes). There was a trend toward shorter average circulatory arrest time in group IV, but the difference was not significant. Cooling time was also similar between all four groups (Table 1).


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  		Table 1. Patient Characteristics and Resultsa

 
The pH values were lower after DHCA in patients managed with the normoxia strategy regardless of pH strategy. Only patients in group IV (hyperoxia and pH-stat) had normal pH levels after DHCA (Fig 1), and the base deficit was least depressed immediately after DHCA for group IV compared with all other groups (Figure 2).



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  		Fig 1. pH values of patients who had {alpha}-stat or pH-stat strategies. Only patients in group IV (pH stat and hyperoxia) had a normal pH after deep hypothermic circulatory arrest. Group IV had a greater pH after deep hypothermic circulatory arrest than any of the other three groups, indicating less acid generation. (*p < 0.05 compared with groups I through III.)

 


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  		Fig 2. Base excess values of patients who had {alpha}-stat or pH-stat strategies. The base excess, measured after deep hypothermic circulatory arrest, was lower in the pH-stat and hyperoxia patients (group IV) than in any other group. This correlated with a pH after deep hypothermic circulatory arrest within normal range. (*p < 0.05 compared with groups I through III.)

 
Among patients who had the pH-stat strategy, acid production per hour of circulatory arrest was lower in patients managed with hyperoxia (group IV compared with group III, p = 0.007). The same trend was detected in {alpha}-stat patients but did not reach statistical significance (group II compared with group I, p = 0.06). When all four groups were compared, group IV (pH-stat and hyperoxia) produced only 25% as much [H+] as the next closest group, group II ({alpha}-stat and hyperoxia, Fig 3).



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  		Fig 3. Acid production corrected for the time of circulatory arrest in normoxic and hyperoxic patients. Patients treated with hyperoxia before deep hypothermic circulatory arrest had less acid generation during deep hypothermic circulatory arrest than their respective normoxic cohorts. Patients in group IV (pH-stat and hyperoxia) had only 25% as much acid generation during 60 minutes of bypass than the next closest group. (*p < 0.05 compared with groups I through III.)

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
The unavoidable need to use DHCA during repair of certain congenital heart defects, combined with the potential for both short- and long-term neurologic sequelae, has resulted in abundant interest in techniques that limit the detrimental effects of DHCA [9, 10]. However, controversy exists regarding the technique for optimal management of CO2 levels during deep hypothermic CPB, especially when DHCA is used. Alpha-stat and pH-stat are the techniques commonly used, with some centers combining those techniques, eg, pH-stat for cooling and {alpha}-stat for rewarming [1, 2, 11]. Recent reports by Jonas [12, 13] provided the most persuasive arguments in favor of the pH-stat technique. Although hyperoxia was not manipulated as a variable, it was used during the cooling phase of bypass in their study.

In the oxygen pressure field theory, Grist [3, 4] suggested that hyperoxia just before DHCA can take advantage of increased oxygen solubility and reduced oxygen consumption to load tissues with excess oxygen. Hypothetically, by preventing tissue hypoxia in this manner, less acid would be generated from anaerobic metabolism during DHCA. The potential for hyperoxia to significantly reduce tissue hypoxia and the resulting acid generation during DHCA could be as significant a factor in limiting morbidity as the CO2 gas strategy.

Hypothermia has a profound impact on both oxygen utilization and solubility. The solubility of oxygen in saline increases from 0.03 mL · L-1 · mm Hg-1 at 37°C to about 0.05 mL · L-1 · mm Hg-1 at 18°C [14]. Therefore, if the pO2 at 18°C is 50 mm Hg, then 1 L of saline can contain about 2.5 mL of dissolved oxygen. At 18°C an infant’s oxygen consumption is reduced to one tenth of normal (0.6 mL · kg-1 · min-1). Under these hypothermic conditions, all of the oxygen dissolved in 1 kg of body tissue would be consumed in about 4 minutes rather than 15 seconds as during normothermia. Unfortunately, 4 minutes is still an inadequate amount of DHCA time for most repairs using that technique.

The average tissue pO2 can be estimated at approximately 1.5 times the venous O2 pressure (pvO2) [15]. High FiO2 during deep hypothermic CPB can increase the average tissue pO2. If the tissue pO2 is increased to 500 mm Hg at 18°C, then 1 L of saline can contain 25 mL (0.05 x 500) of dissolved oxygen. If oxygen consumption were 0.6 mL · kg-1 · min-1, then all of the oxygen dissolved in 1 kg of body tissue would be consumed in about 42 minutes. The degree of tissue hypoxia should be minimal and acid production from anaerobic metabolism would be negligible if the DHCA period terminated before all the oxygen was consumed.

The type of CO2 gas strategy applied during DHCA can also affect oxygen loading. The pH-stat strategy increases [H+] by increasing the dissolved CO2, causing vasodilatation and, therefore, might increase both systemic and cerebral blood flows. Conversely, the {alpha}-stat strategy might buffer any acid generation by removing dissolved CO2 from the system, thus shifting the CO2/HCO3 balance to the more alkaline side. The lower pCO2 results in decreased systemic and cerebral blood flow. Hence, the type of pH management strategy used could affect cerebral cooling and the ability to maximize cerebral and systemic tissue pO2 before DHCA.

One of the main advantages of the pH-stat technique is its ability to maximize cerebral oxygen loading before DHCA. Adding to the controversy surrounding {alpha}-stat and pH-stat is the fact that hyperoxia has been used in studies evaluating the pH-stat technique [16]. When hyperoxia is not used with either technique, the suggested superiority of pH-stat is less apparent [17]. In the present study, patients managed with a pH-stat strategy and hyperoxia had the lowest level of acid production during DHCA. The combination of these two strategies would theoretically maximize tissue oxygen loading before DHCA.

The group in which pH-stat and hyperoxia were used (group IV) had less acidosis than the other three groups, and only group IV had normal pH levels after DHCA. This finding suggests that the tissues in group IV patients had not converted to anaerobic metabolism and lactic acid generation during the arrest period. The decreased pH values after DHCA in groups I through III indicated the consumption of buffer base during the arrest period, which was confirmed by the greater changes in the base excess values of groups I through III.

Although the circulatory arrest time was shortest in group IV, this difference was not statistically significant. Although we do not believe that this slightly shorter circulatory arrest time accounted for the marked decrease in acid production in this group, this factor cannot be discounted completely. The addition of pCO2 in pH-stat patients theoretically provides a source of acid in addition to that from anaerobic metabolism. Therefore, the higher pCO2 after DHCA could artificially lower the pH. The fact that group IV patients had higher pH after DHCA is therefore even more significant in view of their higher pCO2. The suggested benefits of hyperoxia in group IV were supported by the data from the other hyperoxia group (group II, {alpha}-stat and hyperoxia), which had the second lowest acid production despite the longest circulatory arrest time. These data indicate that hyperoxia was a critical factor in decreasing acid production during circulatory arrest.

A pH-stat strategy has been shown to increase vasodilatation of the systemic vasculature resulting in better perfusion of the tissues. However pH-stat strategy without hyperoxia was not as effective in preventing acid production during DHCA as {alpha}-stat strategy with hyperoxia. This may be one source of inconsistency in reports of the application of the two CO2 gas strategies in other studies [17].

Our findings suggest that hyperoxia was at least as important, if not more important, than the choice of CO2 strategy, and they support the use of a pH-stat strategy, particularly with hyperoxia immediately before DHCA. This evidence supports the hypothesis that patients who have elevated pvO2 values just before DHCA have less acid generation during the arrest period than do patients with lower pvO2 values.

It is important to emphasize that the initial pO2 during CPB should be kept low (below 200 mm Hg) to prevent production of oxygen-derived free radicals and avoid reoxygenation injury, especially in cyanotic infants [7, 8]. Furthermore, a similar strategy of minimal pO2 should be used during reinstitution of bypass after circulatory arrest. It is possible that excessive oxygen during the circulatory arrest period could result in increased generation of injurious reactive oxygen species, so avoiding significant tissue hypoxia by oxygen loading before the ischemic period might negate that risk.

To ensure that all tissues have an adequate store of dissolved oxygen before DHCA, tissue oxygen saturation can be maximized by using a high FiO2, maintaining a blood flow of 2.5 L · min-1 · m-2 of body surface area, and cooling for at least 20 minutes. Patients who have DHCA with elevated pvO2 values should have less acid generation during the arrest period than those with lower pvO2 values. Less acid generation implies less tissue hypoxia during DHCA and might translate into decreased tissue damage and less postoperative morbidity. Further studies are needed to determine actual tissue damage and the effects of the various strategies on postoperative morbidity.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

  1. Burrows F.A. Con. J Cardiothorac Vasc Anesth 1995;9:219-221.[Medline]
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  5. Shinoka T., Shum-tim D., Jonas R.A., et al. Higher hematocrit improves cerebral outcome after deep hypothermic circulatory arrest. J Thorac Cardiovasc Surg 1996;112:1610-1621.[Abstract/Free Full Text]
  6. Shinoka T., Shum-tim D., Laussen P.C., et al. Effects of oncotic pressure and hematocrit on outcome after hypothermic circulatory arrest. Ann Thorac Surg 1998;65:155-164.[Abstract/Free Full Text]
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  8. Ihnken K., Morita K., Buckberg G.D., et al. Nitric oxide-induced reoxygenation injury in the cyanotic immature heart is prevented by controlling oxygen content during initial reoxygenation. Angiology 1997;48:189-202.
  9. Newburger J.W., Jonas R.A., Wernovsky G., et al. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993;329:1057-1064.[Abstract/Free Full Text]
  10. Bellinger D.C., Jonas R.A., Rappaport L.A., et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;332:549-555.[Abstract/Free Full Text]
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  17. Kirshbom P.M., Skaryak L.R., DiBernardo L.R., et al. pH-STAT cooling improves cerebral metabolic recovery after circulatory arrest in a piglet model of aortopulmonary collaterals. J Thorac Cardiovasc Surg 1996;111:147-157.[Abstract/Free Full Text]
Accepted for publication March 27, 2000.


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