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Ann Thorac Surg 1997;63:1725-1729
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

The Brain Uses Mostly Dissolved Oxygen During Profoundly Hypothermic Cardiopulmonary Bypass

Department of Anesthesia, University of Iowa, Iowa City, Iowa

Accepted for publication January 2, 1997.

	Abstract

Top Footnotes Abstract Introduction Methods Results Comment References

 
Background. During profoundly hypothermic cardiopulmonary bypass, cerebral venous oxygen saturation increases (eg, to 98% at 15°C). We reanalyzed results of clinical studies to learn why.

Methods. One hundred sixty-eight cerebral oxygen transport measurements were available from 96 infants and children undergoing profoundly hypothermic cardiopulmonary bypass during repair of congenital heart defects.

Results. Dissolved oxygen accounted for 2% to 17% of arterial oxygen content, depending on the arterial oxygen partial pressure and hemoglobin concentration. The fraction of the cerebral metabolic rate for oxygen obtained from dissolved oxygen depended on pump flow, temperature, hemoglobin concentration, and arterial oxygen partial pressure (all p < 10^-3). For "full-flow" cardiopulmonary bypass, temperatures less than 18°C, and arterial oxygen partial pressure measurements more than 180 mm Hg, the mean ± standard deviation of the fraction of cerebral metabolic rate for oxygen obtained from dissolved oxygen equaled 77% ± 19%.

Conclusions. Dissolved oxygen satisfies most of the brain's oxygen requirements during profound hypothermic cardiopulmonary bypass. This result reflects four properties of profound hypothermic cardiopulmonary bypass: (1) increases in hemoglobin's oxygen affinity due to profound hypothermia (which impairs oxygen transfer from hemoglobin to cerebral tissue), (2) use of hemodilution, (3) use of high arterial oxygen partial pressure, and (4) low cerebral metabolic rate of oxygen.

	Introduction

Top Footnotes Abstract Introduction Methods Results Comment References

 
See also page 1729.

Normally dissolved oxygen plays a trivial role in cerebral oxygen delivery and metabolism. For example, at a normal temperature (37°C), hemoglobin concentration (13 g/100 mL), and arterial oxygen partial pressure (P_aO₂ 80 to 100 mm Hg), dissolved oxygen makes up only 1% to 2% of the arterial oxygen content (C_aO₂). Accordingly, based on normal values of cerebral blood flow (CBF) and oxygen metabolism (CMRO₂), only 2% to 3% of CMRO₂ is obtained from dissolved oxygen. Dissociation from hemoglobin provides the rest of the oxygen. Therefore, at normothermia, hemoglobin supplies nearly all of the oxygen that the brain uses. However, cerebral oxygen transport may be altered dramatically in the setting of profound hypothermic cardiopulmonary bypass (CPB). The contribution of dissolved oxygen in maintaining cerebral oxygenation may increase in this setting.

The importance of dissolved oxygen in cerebral oxygenation may increase because of at least four properties of profound hypothermic CPB. First, hypothermia increases hemoglobin oxygen affinity. As temperature decreases during cooling, increasing hemoglobin oxygen affinity causes a progressive impairment of oxygen transfer from hemoglobin to plasma, with subsequent decreases in transfer to cerebral interstitium and cells [1]. This impairment of oxygen transport is minor at 27°C, but can be substantial at 17°C [1]. Second, during CPB, P_aO₂ can be maintained at very high levels (eg, >400 mm Hg), increasing the dissolved oxygen content of blood. Third, during hypothermic CPB, hemodilution decreases the hemoglobin-associated oxygen content of blood. Fourth, profound hypothermia greatly reduces CMRO₂. We hypothesized that, taken together, these four properties would increase the importance of dissolved oxygen in meeting brain oxygen requirements during profound hypothermic CPB.

To address this question, we analyzed the results of previously published clinical studies of CBF and CMRO₂ during moderate and profound hypothermic CPB in infants and children. We calculated the percentage of C_aO₂ that was present in the dissolved form (ie, the percentage of oxygen delivered to the brain that was dissolved). We also calculated the fraction of CMRO₂ obtained from dissolved oxygen (ie, the percentage of oxygen used by the brain that was dissolved). Our results show that dissolved oxygen satisfies most of the brain's oxygen requirements during profound hypothermic CPB.

	Methods

Top Footnotes Abstract Introduction Methods Results Comment References

 
We obtained cerebral oxygen transport data from previously published studies performed at the Boston Children's Hospital and at Duke University Medical Center [2–4]. Original CBF and CMRO₂ data from these studies were used in our analyses. Patients and methodologies were described in detail in the original reports [2–4]. We briefly summarize them here to put the data into a clinical context. After institutional review board approval and informed parental consent, infants and children undergoing repair of congenital heart defects were studied. During CPB, circulation was maintained using nonpulsatile pump flow and membrane oxygenation. -Stat blood gas management was used. Otherwise, neither CPB, anesthetic, nor surgical management was uniform among the patients. The studies [2–4] examined effects of pump flow rate and temperature on cerebral oxygenation (jugular venous oxygen partial pressure [P_jvO₂] and jugular venous oxygen hemoglobin saturation [S_jvO₂]). Jugular venous blood samples were obtained from catheters placed into the internal jugular vein, and advanced retrograde into the jugular venous bulb.

Collectively, these studies produced hundreds of cerebral oxygen transport measurements. We limited consideration to the 168 measurements (from 96 patients) obtained after cooling had been completed, but before circulatory arrest or rewarming had been started. Eight of the 168 measurements were from Boston Children's Hospital [3]. These eight measurements are special, because they were made while patients were receiving 100% oxygen through the oxygenator. For these, hemoglobin concentrations were taken as the mean of the study's values, the P_aO₂'s were taken as the mean of the study's reported range, and P_jvO₂'s were calculated from corresponding measured S_jvO₂'s.^*

To analyze the previously published clinical data, we used several algebraic relationships, which we present below. Statistical significance of relationships were tested using one-sided Pearson partial correlation coefficients [5]. We used one-sided tests because the directions of the relationships were known from basic physiology. The questions of interest were whether the relationships were strong enough to be detectable. Relationships were presented graphically, using the Lowess smoothing algorithm, with a tension of 1.0 [6]. Analysis was done after P_aO₂ and P_jvO₂ were temperature corrected [7]. T refers to nasopharyngeal temperature (°C). We limited consideration to steady-state CPB. Therefore, we assumed that T also equaled cerebral blood temperature. _bl refers to oxygen solubility in blood (milliliters of oxygen per 100 milliliters per millimeters of mercury). H refers to arterial hemoglobin concentration (g/100 mL). Therefore, the percentage of cerebral oxygen delivery in dissolved form equals

(1)

where [8]

(2)

The percentage of CMRO₂ obtained from dissolved oxygen equals

(3)

	Results

Top Footnotes Abstract Introduction Methods Results Comment References

 
Observational data are presented for the 168 measurements of cerebral oxygen transport that were available during steady-state hypothermic CPB in infants and children. Two to 17% of the C_aO₂ was in dissolved form, depending on P_aO₂ and hemoglobin concentration (Fig 1). Scatter in the data presented in Figure 1 is mostly from variation in the hemoglobin concentration within each frame. The outlier patient in the left-most frame had a hemoglobin concentration of 3.1 g/100 mL. At P_aO₂ less than 100 mm Hg or more than 400 mm Hg, dissolved oxygen accounted for less than 3% or more than 15% of the C_aO₂, respectively. Readers can use Figure 1 to determine the percentage of C_aO₂ that is in dissolved form.

View larger version (23K): [in this window] [in a new window]   Fig 1. . Percent of cerebral oxygen delivery in dissolved form (ie, percent of arterial oxygen content) versus arterial oxygen partial pressure (PaO2) and hemoglobin concentration. Hemoglobin concentration (along the top of the plot) has units of grams per 100 milliliters.

View larger version (27K): [in this window] [in a new window]   Fig 2. . Fraction of oxygen consumed by the brain obtained from dissolved oxygen versus percentage of oxygen delivered to the brain in dissolved form, nasopharyngeal temperature, and pump flow rate. Measurements represented by open and filled circles correspond to "full" (>70 mL • kg-1 • min-1) and "low" (70 mL • kg-1 • min-1) pump flow rates. The percentage of cerebral oxygen delivery (CMRO2) in dissolved form can be related to hemoglobin concentration and arterial oxygen partial pressure using Figure 1.

An important issue is the quantitative significance of dissolved oxygen in cerebral oxygenation during profound hypothermic CPB. This magnitude is given on the vertical axis of Figure 2. For "full-flow" CPB, temperatures less than 18°C, and P_aO₂ more than 180 mm Hg, the mean ± standard deviation of the fraction of oxygen used by the brain that was obtained from dissolved oxygen equaled 77% ± 19% (see Figs 1, 2).

	Comment

Top Footnotes Abstract Introduction Methods Results Comment References

 
Hypothermia greatly decreases CMRO₂. Accordingly, until recently, high S_jvO₂'s commonly observed during hypothermic CPB were considered to indicate solely that an excess of oxygen was available to the brain compared with consumption ("luxury perfusion"). However, hypothermia also greatly increases the oxygen affinity of hemoglobin. Our recent computer simulation studies showed that during profound hypothermic CPB high S_jvO₂ can be the result of impaired oxygen transfer from hemoglobin to plasma, and subsequently to the brain [1]. Consequently, our model predicted that during profound hypothermia reduced CBF could limit cerebral oxygenation, despite high levels of S_jvO₂. This prediction has since been verified clinically. Du Plessis and co-workers [9] used near-infrared spectroscopy to simultaneously measure the oxidized cerebral cytochrome oxidase levels and cerebral hemoglobin saturations in children undergoing profound hypothermic CPB. During cooling and initiation of low-flow CPB, cerebral hemoglobin saturation (S_jvO₂) increased. In contrast, during low-flow CPB, oxidized cerebral cytochrome oxidase levels decreased. Thus, oxygen availability at the tissue (ie, mitochondrial) level was diminished, despite high S_jvO₂. Thus, during profound hypothermia, increased S_jvO₂ can reflect an increase in the oxygen affinity of hemoglobin and impairment of oxygen transfer from blood to brain. Therefore, we hypothesized that at profound hypothermia oxygen available for diffusion to tissue might be derived almost entirely from that dissolved in blood, rather than from hemoglobin.

The fraction of C_aO₂ obtained from dissolved oxygen depends on the hemoglobin concentration and on P_aO₂. The percentage of total oxygen content present in the dissolved form is inversely related to the former and directly related to the latter. Indeed, our results show the expected effect of hemodilution and hyperoxia during CPB to increase the dissolved fraction of C_aO₂ from 2% to 17% (see Fig 1). Although this is a marked increase over normal values, the great bulk (83% to 98%) of C_aO₂ still remains hemoglobin associated.

What our analysis also shows is that as temperature decreases, the fraction of CMRO₂ obtained from dissolved oxygen increases far more than the proportion of dissolved oxygen in arterial blood (Fig 2). As temperature decreases, the brain satisfies an increasing proportion of CMRO₂ from dissolved, rather than hemoglobin-bound, oxygen. Thus, although most oxygen delivered to the brain remains hemoglobin associated (83% to 98% of C_aO₂), as temperature decreases, hemoglobin-associated oxygen becomes a progressively less important determinant of brain oxygenation. As shown in Figure 2, during profound hypothermic CPB with relatively high P_aO₂ (eg, >400 mm Hg), CMRO₂ can be met almost entirely by dissolved oxygen. Thus, during profound hypothermic CPB, at full-flow and high P_aO₂, hemoglobin contributes much less toward brain oxygenation than does dissolved oxygen. This result has important consequences. Most notably, neither (1) the degree of hemodilution, (2) the proportion of fetal hemoglobin present, (3) the effect of -stat or pH-stat blood gas management on hemoglobin oxygen affinity, (4) the pharmacologic alteration of hemoglobin oxygen affinity, (5) the Bohr effect, nor (6) the use of hemoglobin substitutes (eg, diaspirin cross-linked hemoglobin) is likely to have any substantive effect on cerebral oxygen transport.

The data shown in Figure 2 do not explain precisely why during profound hypothermic CPB, at full-flow and high P_aO₂, hemoglobin contributes much less toward brain oxygenation than does dissolved oxygen. It is unclear whether this result is attributable to a low CMRO₂ and high dissolved oxygen content or, instead, to a limitation of oxygen transfer from hemoglobin to plasma, and subsequently to brain. In other words, is hemoglobin oxygen affinity so great at profound hypothermia that it is functionally impossible for oxygen to be unloaded from hemoglobin to brain? If, in fact, it were functionally impossible for oxygen to be transferred from hemoglobin to brain during profound hypothermia, then a simplification of the Fick equation would describe brain oxygen transport:

(4)

In states where dissolved oxygen fully meets brain oxygen requirements, such as during full-flow CPB, one would expect that increasing P_aO₂ or cerebral blood flow would not increase CMRO₂. Instead, P_jvO₂ would increase and CMRO₂ would remain constant. This prediction holds for measurements made during full-flow (pump flow 70 mL • kg^-1 • min^-1, n = 128, CMRO₂ versus P_aO₂ r = 0.03, p = 0.73). In contrast, in states of low cerebral blood flow, where dissolved oxygen might not fully meet CMRO₂, equation 4 predicts that CMRO₂ would vary directly with P_aO₂. Therefore, during low-flow CPB, abnormally low CMRO₂ might be increased toward normal by simply increasing P_aO₂. We intended to test this prediction by analyzing the relationship between P_aO₂ and CMRO₂ during low-flow bypass. Unfortunately, there was insufficient variance in P_aO₂ values to study the effect of changing P_aO₂ on CMRO₂ (ie, P_aO₂ was relatively fixed). In particular, among the patients with measurements during low-flow CPB, lower and upper quartiles were 137 mm Hg and 187 mm Hg, respectively. All that we can conclude from the observational data is that in the setting of low-flow CPB with a relatively low P_aO₂, hemoglobin supplies most of the oxygen that is used by the brain (Fig 2).

Cardiopulmonary bypass could be conducted in such a way that dissolved oxygen alone can fully support cerebral oxygenation during profound hypothermia. Then, oxygen extraction from hemoglobin would not be needed to meet cerebral oxygen requirements. We have shown that to do so is clinically feasible during full-flow CPB at profound hypothermia (Fig 2). When dissolved oxygen is sufficient to fully meet CMRO₂, then it naturally follows that hemoglobin will remain nearly completely saturated. Hence, S_jvO₂ will be roughly 95% to 100%. Therefore, our results show that maintaining both P_aO₂ and CPB pump flow sufficiently high to maintain S_jvO₂ at 95% or greater [3] will ensure that cerebral oxygen delivery is adequate.

Recently, Newberger and colleagues [10], at The Boston Children's Hospital, reported the results of a clinical trial that compared neurologic outcomes in infants undergoing the arterial switch procedure using circulatory arrest versus low-flow CPB at 18°C. Infants who were randomized to low-flow CPB had less neurologic injury than those who were randomized to circulatory arrest. It is notable that the Boston Children's group routinely maintains the temperature-corrected P_aO₂ greater than 400 mm Hg during CPB [3, 9]. The high P_aO₂ used by the Boston Children's group substantially increased the amount of dissolved oxygen available to, and possibly used by, the brain during low-flow CPB. It is not known whether the superior neurologic outcome in their low-flow group would have been different had they used a lower P_aO₂. Thus, our results have implications for the appropriate interpretation of this important clinical study.

The oxygen partial pressure at which the oxyhemoglobin saturation equals 50% is called the P₅₀. The increased affinity of hemoglobin for oxygen caused by profound hypothermia is quantified by the decrease in the P₅₀. Infants undergoing CPB at 17°C with -stat blood gas management have P₅₀ = 5 mm Hg [11–13]. Adults have a P₅₀ = 7 mm Hg under the same conditions [11]. A class of drugs, allosteric inhibitors of hemoglobin, has been introduced that can increase hemoglobin P₅₀ [14]. Would pharmacologically increasing the P₅₀ of infants to that of adults significantly improve cerebral oxygenation (increase CMRO₂) during profound hypothermic CPB? Hypothetically an increase in P₅₀ would permit a greater ability to maintain CMRO₂. Yet, during full-flow profound hypothermic conditions, dissolved oxygen can fully support cerebral oxygenation (see Fig 2). Thus, under full-flow conditions, increases in P₅₀ would be expected to yield very small increases in CMRO₂.

In summary, our results show that hemoglobin-associated oxygen accounts for most of the C_aO₂ in infants and children during profound hypothermic CPB (see Fig 1). However, as temperature decreases, dissolved oxygen can satisfy an increasing proportion of the oxygen consumed by the brain see (Fig 2). Dissolved oxygen can fully meet brain oxygen requirements, when CBF is supported by full-flow profound hypothermic CPB (see Fig 2). Maintaining the P_aO₂ at high levels (ie, >400 mm Hg), to maximize dissolved C_aO₂, can support the brain's oxygen requirements.

	Footnotes

Top Footnotes Abstract Introduction Methods Results Comment References

 
Address reprint requests to Dr Dexter, Department of Anesthesia, University of Iowa, Iowa City, IA 52242.

^* To calculate P_jvO₂, we used the Hill equation, with P₅₀ appropriate for infants undergoing -stat blood gas management at the measured nasopharyngeal temperatures. Details of and justification for this use of the Hill equation are given in equations 2 through 5 of Reference [1]. Briefly, the Hill equation is accurate for S_jvO₂ more than 25%. The mean ± standard deviation of S_jvO₂ were 93% ± 2.4%. Furthermore, a highly accurate estimate of P_jvO₂ was not needed because P_jvO₂ only has an effect when it is large relative to P_aO₂ (Eq. 3). This condition was met, as the mean ± standard deviation of 100 x (1 - P_jvO₂/ P_aO₂) equaled 97% ± 0.7%.

Equation 3 assumes that the arterial and venous hemoglobin concentrations are equal. For 160 measurements, H was available from blood collected in both the arterial and jugular venous blood. The mean ± standard deviation of the arterial to venous gradient in hemoglobin concentration equaled 0.0 ± 1.0 g/100 mL.

We repeated the statistical analysis excluding the eight measurements from Boston Children's Hospital. The fraction of CMRO₂ obtained from dissolved oxygen still depended on pump flow rate, temperature, and percentage of C_aO₂ in dissolved form (p = 7 x 10^-4, 4 x 10^-5, and 5 x 10^-8, respectively).

	References

Top Footnotes Abstract Introduction Methods Results Comment References

 

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