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J Thorac Cardiovasc Surg 2004;127:738-745
© 2004 The American Association for Thoracic Surgery

Surgery for congenital heart disease

Alteration of the critical arteriovenous oxygen saturation relationship by sustained afterload reduction after the norwood procedure

^a Department of Anesthesiology, Milwaukee, Wis USA
^b Pediatric Critical Care Medicine, Milwaukee, Wis USA
^c Cardiothoracic Surgery, Milwaukee, Wis USA
^d Pediatric Cardiology, Milwaukee, Wis USA
^e Children's Hospital of Wisconsin, Milwaukee, WI, USA
^f Medical College of Wisconsin, Milwaukee, Wis, USA

Presented in part at the annual meeting of the American Society of Anesthesiologists, New Orleans, La, October 2001.

Received for publication March 18, 2003; revisions received April 22, 2003; revisions received May 19, 2003; accepted for publication June 18, 2003.

^* Address for reprints: George Hoffman, MD, Pediatric Anesthesiology and Critical Care Medicine, Children's Hospital of Wisconsin, #735, 9000 West Wisconsin Ave, Milwaukee, WI 53226, USA
ghoffman{at}mcw.edu

	Abstract

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OBJECTIVES: Hemodynamic vulnerability after the Norwood procedure for hypoplastic left heart syndrome results from impaired myocardial function, and critical inefficiency of parallel circulation. Traditional management strategies have attempted to optimize circulatory efficiency by using arterial oxygen saturation (SaO₂) as an index of pulmonary/systemic flow balance, attempting to maintain SaO₂ within a theoretically optimal critical range of 75% to 80%. This optimal range of SaO₂ has not been verified clinically, and strategies targeting SaO₂ may be limited by the fact that SaO₂ is a poor predictor of systemic oxygen delivery. We have previously reported higher venous saturation (SvO₂), lower arteriovenous oxygen content difference, lower systemic vascular resistance, lower pulmonary/systemic flow ratio, and improved survival with the perioperative use of phenoxybenzamine and continuous monitoring of SvO₂. In this investigation, we tested the hypothesis that intense afterload reduction with phenoxybenzamine would modify the SvO₂-SaO₂ relationship by preventing deterioration of systemic oxygen delivery at high SaO₂.

METHODS: Seventy-one consecutive neonates undergoing the Norwood procedure with and without phenoxybenzamine were studied. Perioperative hemodynamic management targeted SvO₂ greater than 50%. Hemodynamic data were prospectively acquired for 48 hours postoperatively and analyzed to assess the effect of phenoxybenzamine on the relationship between SaO₂ and SvO₂ and other hemodynamic indices. Sixty-two patients received phenoxybenzamine 0.25 mg/kg on cardiopulmonary bypass; 9 who did not served as controls.

RESULTS: In control patients, SvO₂ peaked at an SaO₂ of 77%, with reduced SvO₂ at SaO₂ > 85% and SaO₂ < 70% (P < .01), while arteriovenous oxygen content difference increased with SaO₂ greater than 80% (P < .001). In patients receiving phenoxybenzamine, the SvO₂ increased linearly with SaO₂ greater than 65% (P < .001), and arteriovenous oxygen content difference was constant at all SaO₂ (P = ns). The SvO₂ was higher, and the arteriovenous oxygen content difference lower, across the whole SaO₂ range with phenoxybenzamine (P < .0001).

CONCLUSIONS: A critical range of SaO₂ for optimizing systemic oxygen delivery was confirmed in control patients, and was effectively eliminated by phenoxybenzamine, specifically by eliminating the systemic hypoperfusion associated with high SaO₂. This effect allows higher SaO₂ to be included in a rational hemodynamic strategy to improve systemic oxygen delivery in the early postoperative management of patients receiving intense afterload reduction with phenoxybenzamine. The predictability of SvO₂ from SaO₂ is low in both groups, emphasizing the importance of SvO₂ measurement in these patients.

Several models with differing assumptions about complex univentricular circulation have been developed to guide management when clinical data are incomplete. Norwood and colleagues^1,2,5 have argued that maintenance of arterial saturation (SaO₂) in the 75% to 80% range would optimize circulatory efficiency with a resulting SvO₂ of 50% to 60% and pulmonary/systemic flow ratio (Qp/Qs) near 1.0. This management strategy is based largely on circulatory modeling with a constant arteriovenous oxygen content difference, but highly variable Qp/Qs and therefore SaO₂.^1,2,5,6 Alternatively, the SaO₂-SvO₂ relationship has been modeled at constant total cardiac output, with variable Qp/Qs and systemic flow, also resulting in a narrow optimum range of SaO₂ to maximize SvO₂ or systemic oxygen delivery.⁶ In either case, the circulatory models predict a critical range of SaO₂ for optimal circulatory efficiency, but the exact target SaO₂ remains dependent on other parameters such as oxygen consumption (VO₂), cardiac output, and hemoglobin, as well as knowledge of Qp/Qs to fully resolve the resulting SvO₂.⁶ Strategies to balance the circulation have typically relied on manipulation of medical gases to raise pulmonary vascular resistance (PVR) and restrict SaO₂ to the target range of 75% to 80%.^1,2,5,7-10

In a less restrictive model assuming complete systemic and pulmonary mixing, and permitting variability in both Qp/Qs and total cardiac output, we demonstrated a wide range of SvO₂ at any SaO₂, and the essential lack of predictability of SvO₂ from SaO₂.¹¹ This theoretical inadequacy of SaO₂ as a predictor of SvO₂, the intrinsic contradictions and complexities of management strategies which rely on SaO₂ limitation as a means of maximizing oxygen delivery, and less than optimal outcomes using approaches based on prediction of SvO₂ from SaO₂, motivated us to search for a better management method. Direct, continuous measurement of SvO₂ allowed the detection of critical reductions in systemic oxygen delivery and provided additional data to more closely estimate Qp/Qs and guide subsequent intervention.^3,12 We observed wide variability in SvO₂ despite maintenance of SaO₂ in the traditional target range,^12,13 emphasizing the dynamic relationships between reduction in systemic oxygen delivery, reflex elevation in systemic vascular resistance (SVR), systemic-pulmonary flow tradeoff, and further reductions in systemic perfusion with systemic vasoconstriction, which, if unchecked, would lead to overt failure of systemic perfusion.

We hypothesized that the relevance of increases in SVR as a cause of instability after the Norwood procedure could be confirmed by examination of the relationship between SaO₂ and SvO₂ for evidence of deterioration of systemic oxygenation at higher SaO₂. In this investigation, we analyzed our prospectively collected physiologic database to attempt to confirm the existence of a critical SaO₂ range to maximize SvO₂, and to test the hypothesis that this relationship would be altered by intense afterload reduction with phenoxybenzamine.

	Materials and methods

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Patient population and management strategy
All patients undergoing the Norwood procedure for hypoplastic left heart syndrome from July 1996 to July 2000 were included in this study. After appropriate preoperative stabilization, all patients underwent surgical palliation consisting of anastomosis of the pulmonary artery to the ascending aorta combined with augmentation of the ascending aorta, transverse arch, and proximal descending aorta with pulmonary homograft, placement of a systemic–pulmonary artery shunt (3.0-4.5 mm), and creation of a nonrestrictive atrial septal defect.¹² This procedure was performed with synthetic opioid-based perioperative anesthesia,¹⁴ hypothermic CPB with pH-stat blood gas management to facilitate cooling to a temperature of 26°C, -stat management before and after circulatory arrest at 16°C to 18°C, and modified ultrafiltration. On initiation of CPB, phenoxybenzamine 0.25 mg/kg was administered to 62 of 71 infants according to a prospective nonrandomized surgeon-directed protocol with Food and Drug Administration and institutional review board approval and parental informed consent. During rewarming, all patients received milrinone 50 µ · kg^-1 followed by infusions of milrinone at 0.5 µ · kg^-1 · min^-1 and dopamine at 3 µ · kg^-1 · min^-1. Oximetric catheters (4F OxyCath, Abbott Laboratories, N Chicago, Ill) were surgically placed in the superior vena cava (SVC) to allow continuous monitoring of SvO₂. Before separation from CPB, infusions of nitroprusside or norepinephrine were titrated to achieve an approximate SVR index of 12 Wood units (mean arterial pressure of 40 mm Hg at CPB flow index of 3.2 L/m²/min), and epinephrine was added for additional inotropic support if necessary. Patients were transported to the pediatric intensive care unit (ICU) after hemostasis for postoperative management, which included routine delayed sternal closure.

Postoperative management targets included mean arterial blood pressure (MAP) greater than 45 mm Hg, SvO₂ greater than 50%, SaO₂ 70% to 85%, and clinical evidence of end-organ function (urine output of at least 1 mL · kg^-1 · h^-1, biochemical evidence of adequate gluconeogenesis, and behavioral responses after withdrawal of neuromuscular blockade). Systemic diastolic pressure was not specifically targeted unless electrophysiologic evidence of ischemia was present with continuous ST analysis (Solar 3000, Marquette Electronics Inc, Milwaukee, Wis). All patients received continuous fentanyl infusions at 5 to 10 µg · kg^-1 · h^-1, and neuromuscular blockade was maintained by vecuronium infusion until postoperative day 1. A normothermic environment was maintained with servo controlled warmers (Ohio Infant Warmer System, Ohmeda Inc, Columbia, Md). Ventilator settings were adjusted to maintain arterial normocapnia (PaCO₂ 35 to 45 mm Hg) with inflating pressures of 24 to 28 cm H₂O, positive end-expiratory pressure of 4 to 5 cm H₂O, and an FIO₂ of 0.3 to 1.0 to assure fully saturated pulmonary capillary blood.¹⁵ Specifically, room air was not used as a ventilating gas, and FIO₂ was adjusted to maximize SvO₂. Low SvO₂ (40% or less) with Qp/Qs near 2.0 or greater was addressed by attempts to lower SVR with additional analgesia or sedation, nitroprusside, or, in patients who had received phenoxybenzamine on CPB, initiation of a phenoxybenzamine infusion (0.25 mg/kg per day or 10 µg · kg^-1 · h^-1). A low SvO₂ with Qp/Qs near 1.0 was addressed by transfusion of red cells to achieve a hematocrit value in the 45% to 50% range, and additional inotropic support when necessary.

Monitoring and data collection
A prospective perioperative database for all patients undergoing the Norwood repair for hypoplastic left heart syndrome since July 1996 was maintained for demographic, surgical, and 48-hour postoperative hemodynamic and laboratory data. Physiologic parameters included invasive arterial (MAP) and atrial pressures (RAP), arterial saturation (N-200, Nellcor, Haywood, Calif), inspired oxygen and end-tidal carbon dioxide tension, and oximetric SvO₂ from the SVC as an approximation of mixed venous saturation.^1,16 These parameters were continuously displayed, digitally acquired, and averaged using either a dedicated personal computer–based monitoring cart (DAP-102; Microstar Labs, Belleview, Wash; DasyLab, DasyTec GmBH, Concord, NH) or a multichannel clinical information system (Marquette Solar). Arterial and venous blood gases and co-oximetry (ABL, Radiometer, Copenhagen, Denmark) were obtained at clinically appropriate intervals. The physiologic parameters, laboratory data, ventilator parameters, and medication infusion rates were recorded hourly for the first 48 postoperative hours with a standardized, prospective data record.

From measurements of SaO₂, SvO₂, MAP, RAP, and hemoglobin concentration, hemodynamic and oxygen transport indices were derived according to standard formulas. These derived parameters included arteriovenous O₂ difference in saturation (Sa-vO₂) and content (Ca-vO₂), as well as oxygen extraction ratio (O₂ER, [Sa-vO₂]/SaO₂), and oxygen excess factor ( SaO₂/[Sa-vO₂]), both flow-independent indices of systemic oxygen status. Pulmonary/systemic flow ratio (Qp/Qs) was calculated from SaO₂ and SvO₂ using an assumed pulmonary capillary saturation of 97%.^3,4,12,15 Additional parameters derived from an assumed oxygen consumption of 160 mL · min^-1 · m^{-2 13,17-19} included pulmonary blood flow (Qp), systemic blood flow (Qs), systemic oxygen delivery (DO₂), systemic vascular resistance index (SVRI), and total pulmonary vascular resistance index (PVRI).

Statistical analysis
Data were summarized as mean ± standard deviation (SD) when continuous, or number and percent when discrete. Oximetric data were excluded during extracorporeal membrane oxygenator (ECMO) support and when the SaO₂-SvO₂ difference was less than 8%.¹³ Exploratory analysis of the SvO₂-SaO₂ relationship was performed by locally weighted regression,²⁰ and fractional polynomial regression models were fit for each group. The data were subsequently partitioned into 6 equal-width strata of SaO₂ values from 65% to 90% for quantitative analysis. A 2-way repeated-measures analysis of variance (ANOVA) model was used to test for differences in hemodynamic parameters across intervals of SaO₂, to test for the effect of phenoxybenzamine, and for the interaction of phenoxybenzamine on the SaO₂ effect. Potential confounding differences in other vasoactive drug doses, FIO₂, and shunt size, were addressed by entry of these parameters into the model as noninteracting covariates. Post-hoc tests of differences at high SaO₂ were performed with Tukey’s wholly significant difference (WSD) correction for multiple comparisons, with significance cutoff at P < .05 after correction. All analysis was performed with Stata statistical software (StataCorp, College Station, Tex).

	Results

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Data from 71 patients comprising 2820 patient-hours (mean 40, median 47, range 6 to 48 hours/patient) were analyzed. There were no significant demographic differences between patients managed with phenoxybenzamine (n = 62) or without (n = 9; Table 1). Two patients were placed on ECMO support within the first 48 hours for SvO₂ below 25%, metabolic acidosis, and impending cardiovascular collapse, one of whom survived; the overall hospital survival for patients in this study was 68 of 71 or 95.7%.

View larger version (53K): [in this window] [in a new window]   Figure 1. The distribution of arterial and venous saturation values found over first 48 hours in all patients is shown. SaO2 (mean 77.9, SD 5.5) was more tightly controlled than SvO2 (mean 54.9, SD 10.7). Approximately 26% of the measured values for SvO2 were less than the target of 50%, and 1.8% were less than the anaerobic threshold of 30% (shaded area).

In control patients, the SvO₂-SaO₂ relationship showed reduction of SvO₂ at both high and low SaO₂, with a peak at SaO₂ of 77%, in an inverse-square pattern. In patients receiving phenoxybenzamine, the relationship between SvO₂ and SaO₂ was continuously and linearly positive over the range of SaO₂ from 60% to 90%. The mean predictive error was greater in control than phenoxybenzamine groups (±11.5% vs ±8.3%, P < .001). The actual data and fitted equations are shown in Figure 2.

View larger version (46K): [in this window] [in a new window]   Figure 2. The relationship between SvO2 and SaO2 over the first 48 hours is shown for patients managed with and without phenoxybenzamine. Hourly data and fitted fractional polynomial regression lines with 95% prediction intervals are shown for the control (left panel, n = 307) and phenoxybenzamine (right panel, n = 2513) groups; the SvO2-SaO2 relationship was distinctly different between groups, as shown by fitted fractional polynomial equations. The SvO2 peaked at SaO2 of 77% in control patients, but continuously increased as SaO2 increased in phenoxybenzamine patients.

View larger version (16K): [in this window] [in a new window]   Figure 3. The means and 95% confidence intervals (CI) of SvO2 and Ca-vO2 at intervals of SaO2 is shown for control and phenoxybenzamine groups. The SvO2 was higher with phenoxybenzamine across the whole range (P < .02); the SaO2 effect was highly significant (P < .0001). The Ca-vO2 was lower with phenoxybenzamine across the whole range (P < .001); the SaO2 effect was highly significant (P < .0001). With phenoxybenzamine, the Ca-vO2 did not vary with SaO2 (P = not significant). Significance was assessed by 2-way repeated measures analysis of variance with adjustment for differences in hemoglobin, FIO2, PaCO2, shunt size, and doses of dopamine, milrinone, epinephrine, norepinephrine, and nitroprusside as covariates. Significant differences between groups by Tukey WSD post-tests at each SaO2 interval are signified by *.

View larger version (14K): [in this window] [in a new window]   Figure 4. The means and 95% confidence intervals of MAP, Qp/Qs, and SVRI at intervals of SaO2 in control and phenoxybenzamine groups. The MAP, Qp/Qs, and SVRI were lower with phenoxybenzamine across the whole range (P < .001); the SaO2 effect was highly significant (P < .0001). Significant differences between groups by Tukey WSD after 2-way repeated measures analysis of variance at each SaO2 interval are indicated by *.

	Discussion

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In contrast, patients receiving afterload reduction with phenoxybenzamine did not demonstrate this hemodynamic deterioration at high SaO₂, instead demonstrating a relatively constant arterial pressure, low SVR, and less variability in Qp/Qs. The hemodynamics in patients receiving phenoxybenzamine tended to behave as predicted by models with constant Qp/Qs and a variable total cardiac output, with both SaO₂ and SvO₂ increasing with cardiac output. The clinical effect was that SaO₂ as high as 90% was not associated with deterioration in SvO₂. Thus, high SaO₂ resulted, not from high Qp/Qs but from higher cardiac output, in the phenoxybenzamine group. The increasing difference between groups at increasing SaO₂ provides strong evidence for a fundamental alteration in the circulatory determinants of SaO₂ and SvO₂.

Errors in derived indices such as Qp/Qs and SVRI may result from the limitations imposed by assumptions of pulmonary vein saturation¹⁵ and oxygen consumption.^17,18 We specifically did not wean FIO₂ to limit SaO₂ and would attempt to reduce work of breathing in unparalyzed patients with low SvO₂ by sedation and ventilator adjustment. No further benefit of pharmacologic paralysis on oxygen consumption has been demonstrated,¹⁹ and no systematic deviations in this clinical approach were evident between groups. Neither of these factors would change the primary finding of the alteration SaO₂-SvO₂ relationship by phenoxybenzamine.

Although the analysis of clinical data in this study is unique, the early patients in this study have been the subjects of prior investigation.^12,13 Differential expansion of the size of the treatment group has occurred because we have since administered phenoxybenzamine for all Norwood procedures, except for 2 patients without parental consent for phenoxybenzamine; the resulting imbalance in group size would only reduce the power to detect a statistically significant pharmacologic effect. Because phenoxybenzamine was administered without randomization, the differences between treatment groups could result from existing differences in integrated cardiovascular reflex responses or in treatment variables between patients. However, the groups were highly similar in all factors except for the use of phenoxybenzamine, and the different patterns of response persisted after controlling for differences in other treatment variables.

With continuous recordings of oximetric SvO₂ in the acute postoperative period, we have demonstrated rapid deterioration in SvO₂ associated with systemic vasoconstriction in patients not receiving phenoxybenzamine.¹² Since norepinephrine is the postganglionic sympathetic neurotransmitter, -adrenergic blockade would be expected to blunt the profound sympathetic vasomotor responses observed in high-risk neonates undergoing complex cardiovascular procedures.¹⁴ Although other drugs may be as effective as phenoxybenzamine in reducing SVR under resting conditions, we did not achieve similar results in the control group with routine use of milrinone and sodium nitroprusside.

The perioperative medical management of these patients requires synthesis of information from multiple sources to derive management decisions, which may involve compromise between competing goals. Our vasoactive drug strategy used milrinone for post-ß receptor amplification of inotropy and vasodilation, and dopamine for dopaminergic effects only. A fixed dose of phenoxybenzamine was administered on CPB to all patients in the phenoxybenzamine group to block -adrenergic vasoconstriction, and titration of short-acting drugs to modify SVR was necessary. We used epinephrine and norepinephrine liberally to modify SVR and to provide potent inotropy, and occasionally added low-dose nitroprusside for additional vasodilation. We added an infusion of phenoxybenzamine in 46 of 62 patients in the phenoxybenzamine group if the postoperative hemodynamic pattern showed a need for more consistent SVR reduction. Through multiple stepwise manipulations, the medication mixture could become complex in some patients, and this study did not specifically address strategies to simplify vasoactive drug use. However, our data suggest that -adrenergic blockade is a more effective approach to modify the intense sympathetically mediated vasomotor responses in these infants, and the use of a very long-acting drug like phenoxybenzamine commits the patient to a treatment strategy based on sustained SVR reduction. Optimization of hemodynamics by control of SVR, as predicted in a mathematical model of post-Norwood circulation,²² was confirmed by our data.

The data also provide direct evidence of the poor predictive value of SaO₂ for systemic oxygen delivery, as predicted from theoretical models,^11,21-23 and emphasizing the importance of continuous SvO₂ monitoring^11-13 to indicate systemic oxygen status. A priori, we did not anticipate any predictable relationship between SaO₂ and SvO₂; instead, we relied on continuous SvO₂ measurement to guide management aimed at provision of adequate oxygen delivery. Even in the phenoxybenzamine group, only 32% of the SvO₂ variance could be explained by SaO₂; therefore, we do not advocate acute postoperative management of these patients without SvO₂ monitoring.

The findings of the current study support management strategies based on the measurement and maximization of SvO₂, given the poor predictive value of SaO₂ for SvO₂. The data provide support both for management strategies such as intentional hypercapnia²⁴ to raise PVR when SVR is relatively uncontrolled, and for pharmacologic control of SVR with phenoxybenzamine. With the latter strategy, higher SaO₂ is not deleterious, and is typically associated with improved systemic oxygen delivery.

	References

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