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Ann Thorac Surg 2001;72:2088-2093
© 2001 The Society of Thoracic Surgeons

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Original article: cardiovascular

Hemodynamic effects of inspired carbon dioxide after the Norwood procedure

^a Division of Cardiac Surgery, Medical University of South Carolina, Charleston, North Carolina, USA
^b Division of Pediatric Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA

* Address reprint requests to Dr Bradley, Division of Cardiothoracic Surgery, Medical University of South Carolina, 96 Jonathan Lucas St, Charleston, SC 29425, USA
e-mail: bradlesm{at}musc.edu

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Mortality in the early postoperative period after the Norwood procedure remains substantial. Inspired carbon dioxide (CO₂) has been suggested to improve hemodynamic status in this setting. Inspired CO₂ can be delivered by one of two strategies, ie, with or without an accompanying increase in minute ventilation. The hemodynamic effects of these two strategies have not previously been studied in a controlled fashion.

Methods. Seventeen infants (median age, 9 days; range, 4 to 49 days) undergoing Norwood procedures were prospectively enrolled in this crossover study. Patients were studied while sedated, paralyzed, and mechanically ventilated 1 day to 6 days after operation. The inspired oxygen fraction was kept constant (mean value, 0.24 ± 0.01). Measurements were made at five time points: 1 = baseline; 2 = inspired CO₂ with increased ventilation; 3 = baseline; 4 = inspired CO₂ alone; and 5 = baseline. Mixed venous oxygen saturation was monitored using indwelling lines in the superior vena cava.

Results. Inspired CO₂ with increased ventilation produced a rise in mean airway pressure with no change in arterial CO₂ tension or pH. This strategy had no effect on hemodynamic status or oxygen delivery. Inspired CO₂ alone produced a rise in arterial CO₂ tension and a fall in arterial pH (respiratory acidosis). This strategy resulted in significant improvement in both variables of systemic oxygen delivery: mixed venous oxygen saturation increased from 48% ± 2% to 56% ± 2% (p < 0.05), and arteriovenous oxygen saturation difference decreased from 3% ± 2% to 26% ± 2% (p < 0.05).

Conclusions. Inspired CO₂ after the Norwood procedure can improve oxygen delivery. This improvement occurs only if minute ventilation is kept constant. There is no improvement if minute ventilation is increased. Clinical use of inspired CO₂ may be limited by the accompanying fall in pH. Differentiation of cerebral from total-body effects of inspired CO₂ will require further study.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
The Norwood procedure is widely used as palliation in neonates with hypoplastic left heart syndrome or other heart defects with a functional single ventricle and systemic outflow tract obstruction. Operative mortality continues to be substantial; even in recent large series (>100 patients) [1–4] from experienced centers, mortality rates ranged from 24% to 36%. Many operative deaths occur in the early postoperative period in the setting of low systemic cardiac output and oxygen delivery [3, 4]. Efforts to avoid such deaths have focused on limiting pulmonary blood flow and improving systemic blood flow. These measures have included the use of smaller systemic–pulmonary artery shunts, appropriate ventilator manipulations, and use of a variety of inotropic agents, vasopressors, and vasodilators [5–8]. Inspired carbon dioxide (CO₂) has been suggested to improve hemodynamic status after the Norwood procedure [9–11]. Some groups [9, 10, 12–14] have used inspired CO₂ routinely after the operation, whereas others [1, 3, 4, 6] have not.

Inspired CO₂ can be delivered by one of two strategies, ie, with or without an accompanying increase in minute ventilation. There are theoretical reasons why either strategy might improve hemodynamic status. Inspired CO₂ with increased minute ventilation would be expected to raise mean airway pressure with little change in arterial blood gases. In contrast, CO₂ alone would be expected to raise arterial CO₂ tension (PaCO₂) and lower arterial pH (respiratory acidosis). Either increased mean airway pressure [15] or respiratory acidosis [16] could increase pulmonary vascular resistance and decrease pulmonary blood flow. This decrease could result in a redistribution of cardiac output away from the lungs and to the body, thus improving systemic blood flow. Previous reports of inspired CO₂ use after Norwood procedures either described a strategy with increased ventilation [9–14] or did not provide exact details of the delivery strategy [17]. In none of these reports was the use of CO₂ studied in either a randomized or controlled fashion. Thus, the hemodynamic effects of CO₂ and the differing impacts of the two delivery strategies, are unknown.

The aims of the current study were twofold: to determine the hemodynamic effects of inspired CO₂ after a Norwood procedure and to compare the effects of inspired CO₂ with increased ventilation with those of inspired CO₂ alone. Superior vena cava (mixed venous) oxygen saturation was monitored to provide specific information on systemic oxygen delivery. This was a prospective, patient-controlled crossover study in which other respiratory and cardiac support variables were maintained constant so as not to confound the effects of the inspired CO₂.

	Material and methods

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This study was approved by the Institutional Review Board of the Medical University of South Carolina; informed consent was obtained from all parents. Seventeen patients undergoing a Norwood procedure between May 1998 and February 2000 were prospectively enrolled. During this period, 11 other patients underwent a Norwood procedure but were not enrolled in the study. Informed consent was not obtained from the parents of 5 of them. Three patients had bilateral superior venae cavae and were excluded because of concern over the safety and reliability of mixed venous oxygen saturation monitoring in this setting. One patient each was excluded because of early postoperative death, postoperative extracorporeal membrane oxygenator support and low systemic oxygen saturations.

Study protocol
Patients were studied in the intensive care unit after the Norwood procedure. During study, patients were sedated, paralyzed, and mechanically ventilated. All inotropic infusions were done at constant rates, and no blood transfusions were given. All patients were maintained at normothermia (37°C). Patients were mechanically ventilated with a Servo 300 ventilator (Siemens-Elema AB, Solna, Sweden) in pressure-regulated volume control mode (13 patients) or synchronized intermittent mandatory ventilation volume control mode (4 patients). Our general approach to ventilator management in these patients includes a tidal volume to give adequate chest excursion and a peak airway pressure of 20 to 25 cm H₂O, a rate to provide normal ventilation, and an inspired oxygen fraction (FIO₂) to give a systemic oxygen saturation of 75% to 80%. During the study, actual tidal volume was 16 to 27 mL/kg, FIO₂ was 0.21 to 0.30, inspiratory time was 0.65 to 0.85 second, and positive end-expiratory pressure was 2 to 5 cm H₂O; none of these settings were altered during the study. Increased ventilation was achieved by increasing the rate of the ventilator.

Patients were studied at five consecutive time points: 1 = baseline; 2 = inspired CO₂ with increased ventilation; 3 = baseline; 4 = inspired CO₂ alone; and 5 = baseline. Inspired CO₂ was delivered through the inspiratory limb of the ventilator circuit to produce an inspired CO₂ level of 21 mm Hg (3% at sea level). The ventilator inspiratory flow was unaffected by the use of inspired CO₂. The inspired CO₂ level was monitored using an end-tidal CO₂ monitor (UltraCap N-6000; Mallinckrodt Inc, Nellcor Perinatal Business, Pleasanton, CA) placed between the ventilator circuit and the patient’s endotracheal tube. Fourteen of the 17 patients were studied at all five time points and 3, at the first three times only. At least 15 minutes was allowed for stabilization at each time point before measurements were made.

Arterial blood gases and arterial pressures were determined from radial, femoral, or umbilical artery catheters. Systemic oxygen saturation was measured using arterial blood samples and by peripheral pulse oximetry. Common atrial pressure was measured using transthoracic lines placed in the operating room. Mixed venous oxygen saturation was determined by co-oximetry from samples drawn from transthoracic lines in the superior vena cava. These lines were placed in the operating room through the right atrial free wall into the superior vena cava; position was verified by postoperative chest roentgenogram. Arteriovenous oxygen saturation difference was derived by subtracting the mixed venous from the systemic oxygen saturation.

Statistical analysis
Results are shown as the mean ± the standard error of the mean. Comparison of the five time points of the study protocol was by repeated-measures analysis of variance. Multiple comparison studies were done with the Student-Newman-Keuls test. Significance was defined as a p value of less than 0.05.

	Results

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Patient demographics
The 17 patients had a median age of 9 days (range, 4 to 49 days) and a median weight of 3.0 kg (range, 2.2 to 3.8 kg). Thirteen were boys, and 4 were girls. Diagnoses included hypoplastic left heart syndrome (12 patients), double-inlet left ventricle (2 patients), tricuspid atresia with transposition (1 patient), unbalanced atrioventricular septal defect (1 patient), and interrupted aortic arch with subaortic stenosis (1 patient). Operation consisted of a standard Norwood procedure with pulmonary homograft reconstruction of the neoaorta in 14 patients and a modified Norwood procedure [18] in 3 patients. The systemic–pulmonary artery shunt size was 3.5 mm in 16 patients and 4.0 mm in 1 patient. All operations were performed through a median sternotomy and used cardiopulmonary bypass (mean time, 173 ± 20 minutes) and circulatory arrest (mean time, 50 ± 6 minutes).

Patients were studied in the intensive care unit a median of 2 days (range, 1 to 6 days) after the Norwood procedure. The sternum was open in 12 patients and closed in 5. During study, patients were sedated (infusion of fentanyl, 20 µg · kg^-1 · h^-1, or morphine sulfate, 0.1 mg · kg^-1 · h^-1), paralyzed (infusion of Norcuron [vecuronium bromide], 0.1 mg · kg^-1 · h^-1), and mechanically ventilated. No patient had spontaneous ventilation during the study. All patients were receiving dopamine hydrochloride, 2 to 12 µg · kg^-1 · min^-1. In addition, 7 patients were given milrinone lactate, 0.3 to 0.7 µg · kg^-1 · min^-1, 2 patients were receiving dobutamine hydrochloride, 5 µg · kg^-1 · min^-1, and 2 patients were given epinephrine, 0.03 µg · kg^-1 · min^-1. All infusions were maintained at constant rates, and no blood transfusions were given during the study. Mean hematocrit was 44% ± 4% (range, 37% to 50%). All patients were in sinus rhythm and were maintained at normothermia (37°C) throughout the study.

Inspired CO₂ with increased ventilation
Inspired CO₂ with increased ventilation was achieved by administering 3% CO₂ and increasing the ventilator rate from a mean of 14 to 28 breaths/min with no change in tidal volume or FiO₂ (Table 1). This strategy produced a rise in mean airway pressure to 8.0 cm H₂O but no change in PaCO₂, pH, or bicarbonate level (see Table 1). It also resulted in a small, but significant rise in both arterial oxygen tension (from 43 to 45 mm Hg) and systemic oxygen saturation (from 80% to 83%) (Table 2). However, inspired CO₂ with increased ventilation produced no change in either mixed venous oxygen saturation or arteriovenous oxygen saturation difference (Figs 1, 2). There were also no changes in heart rate, blood pressure, or common atrial pressure (Table 3).

View larger version (10K): [in this window] [in a new window]   Fig 1. Effect of inspired carbon dioxide on mixed venous (superior vena cava) oxygen saturation (SVO2) after Norwood procedure. Data are shown as the mean ± the standard error of the mean. (CO2 = inspired carbon dioxide alone; CO2 VENT = inspired carbon dioxide with increased ventilation; * = p < 0.05 versus times 1, 2, 3, and 5 by analysis of variance.)

View larger version (10K): [in this window] [in a new window]   Fig 2. Effect of inspired carbon dioxide on arteriovenous oxygen saturation difference (AVO2) after Norwood procedure. Data are shown as the mean ± the standard error of the mean. (CO2 = inspired carbon dioxide alone; CO2 VENT = inspired carbon dioxide with increased ventilation; * = p < 0.05 versus times 1, 2, 3, and 5 by analysis of variance.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
This study shows that inspired CO₂ can improve oxygen delivery in patients after a Norwood procedure. Inspired CO₂ resulted in a significant increase in mixed venous oxygen saturation and a significant decrease in arteriovenous oxygen saturation difference. However, these effects were dependent on the particular strategy used to deliver the inspired CO₂. They occurred if minute ventilation was held constant but not if it was increased.

In this study, the strategy of inspired CO₂ with increased ventilation produced no significant changes in hemodynamic variables, mixed venous oxygen saturation, or arteriovenous oxygen saturation difference. This strategy did produce an increase in mean airway pressure, and higher airway pressures can increase pulmonary vascular resistance [15]. However, the mean airway pressures in our patients were probably too low to affect pulmonary resistance. This is especially true in light of the resistance to pulmonary flow provided by the small systemic–pulmonary shunts (3.5 mm) in these patients. Thus, a strategy of inspired CO₂ with increased ventilation does not appear to offer clinically useful improvements in hemodynamic status and oxygen delivery.

Inspired CO₂ with increased ventilation did produce slight increases in both arterial oxygen tension and systemic oxygen saturation. These increases may have been due to increased pulmonary venous oxygen saturation. Although pulmonary venous saturations are often assumed to be normal after a Norwood operation (96% to 100%) [8, 19], this may not be the case. Pulmonary edema, atelectasis, and surfactant deficiency can occur as a result of preoperative pulmonary overcirculation, intraoperative lung deflation, and the side effects of cardiopulmonary bypass [5, 20]. The resulting intrapulmonary shunting and ventilation-perfusion mismatch will produce decreased pulmonary venous oxygen saturation. This is particularly true if FiO₂ is maintained at a low level, as in our study patients. Thus, it seems likely that increased airway pressure could have improved oxygenation through an effect on pulmonary venous saturation. However, this effect is relatively minor and could well be achieved by simply increasing FiO₂.

The alternative delivery strategy, ie, inspired CO₂ alone, produced respiratory acidosis, with a mean PaCO₂ of 56 mm Hg and pH of 7.35. This strategy resulted in significant improvement in mixed venous oxygen saturation and arteriovenous oxygen saturation difference, thereby implying increased systemic blood flow. One explanation for this effect is that respiratory acidosis is known to increase pulmonary vascular resistance [16]. Such an increase could redistribute cardiac output away from the lungs and to the body. Another explanation is that increased PaCO₂ is known to cause systemic vasodilation [21]. This could increase systemic blood flow either by improving total cardiac output or by redistributing cardiac output away from the lungs and to the body. Indeed, deliberate vasodilation with agents such as sodium nitroprusside and phenoxybenzamine has become increasingly popular after the Norwood procedure [8, 19].

The improvement in oxygen delivery produced by inspired CO₂ could potentially be clinically useful. In this study, we observed a mean improvement of 8% in mixed venous oxygen saturation and arteriovenous oxygen saturation difference. Our experience and results in previous studies [8, 19] have demonstrated that mixed venous oxygen saturation reaches a nadir 12 to 24 hours after a Norwood operation. Patients with a mixed venous saturation lower than 30% are at risk for anaerobic metabolism and metabolic acidosis [22]. Such patients could derive clinical benefit from even a relatively modest increase in oxygen delivery. Neonates with a low birth weight comprise a group who might particularly benefit from inspired CO₂. A small systemic–pulmonary artery shunt can effectively limit pulmonary blood flow in an average-sized neonate, but pulmonary overcirculation can be a major problem in small babies. Neonates weighing less than 2.5 kg remain a higher risk for a Norwood procedure, and this may be partially due to pulmonary overcirculation [1, 2]. Such patients might also derive clinical benefit from inspired CO₂.

In this study, inspired CO₂ alone also produced a slight increase in arterial oxygen tension with no change in systemic oxygen saturation (see Table 2). This apparent contradiction is likely explained by the fact that increased PaCO, and acidosis cause a rightward shift in the oxyhemoglobin dissociation curve (Bohr effect). Thus, for any given systemic saturation, arterial oxygen tension would be expected to be slightly higher than at baseline.

Several previous reports [9–14] have advocated the use of inspired CO₂ after a Norwood procedure. When details of the delivery strategy were provided, the policy usually involved inspired CO₂ with increased ventilation [9, 10, 12, 14], although in one report [13], inspired CO₂ was used to achieve a PaCO₂ of 45 to 55 mm Hg. These reports suggested that inspired CO₂ improves outcome. However, only one study [10] included comparison with historical controls in whom inspired CO₂ was not used. A more recent study [23] examined the use of inspired CO₂ preoperatively in 10 infants with hypoplastic left heart syndrome. Like our study, this one by Tabbutt and associates [23] was prospective and patient controlled. It found that a strategy of inspired CO₂ alone (with no increase in minute ventilation) produced a 6% to 8% improvement in mixed venous (superior vena cava) oxygen saturation and arteriovenous oxygen saturation difference. This effect of inspired CO₂ alone is essentially identical to that in our patients after a Norwood procedure. It is interesting that the effect of inspired CO₂ appears to be so similar preoperatively in patients whose pulmonary arteries are perfused at systemic blood pressure and postoperatively in patients whose pulmonary arteries are perfused by a shunt.

Inspired CO₂ has been studied in several animal models of single-ventricle heart defects [24–26]. All of these studies used a delivery strategy of inspired CO₂ alone; there was no increase in ventilation. Mora and coauthors [24] demonstrated that the respiratory acidosis resulting from 0% to 5% inspired CO₂ produced an increase in pulmonary vascular resistance in a neonatal piglet single-ventricle model. In a postnatal study of a single-ventricle model in fetal sheep, Reddy and associates [26] found that 5% inspired CO₂ (PaCO₂, 55 mm Hg and pH 7.25) produced an increase in pulmonary resistance, a decrease in systemic resistance, and a decrease in the ratio of pulmonary to systemic blood flow. These animal studies had the strength of direct measurement of pulmonary and systemic blood flows, which was not possible in our patients.

The current study has several strengths. It was prospectively conducted, and each patient served as his or her own control. Many respiratory and cardiac variables were controlled so as to isolate the effects of inspired CO₂. The patients were sedated and paralyzed to eliminate spontaneous respiration and to minimize responses to stimulation. Ventilatory variables, including FiO₂, tidal volume, positive end-expiratory pressure, and inspiratory time were kept constant during the study; only ventilator rate was deliberately changed to increase ventilation. Inotropic agents were kept constant to avoid changes in cardiac output and vascular resistance beyond those caused by inspired CO₂. The study protocol also allowed elimination of a "time effect." All of the changes seen during inspired CO₂ (time points 2 and 4) returned to baseline (time points 3 and 5). This return confirmed that the changes were due to inspired CO₂ and not simply to the passage of time during the protocol. Finally, sampling of blood from the superior vena cava gave data on mixed venous oxygen saturation and, by inference, systemic oxygen delivery. These data had not been available in previous studies of inspired CO₂ after Norwood procedures.

This study also has several limitations. Oxygen saturations in the superior vena cava reflect oxygen delivery to the upper body (primarily the cerebral bed), which may not be the same as that to the lower body. Increased CO₂ is known to decrease cerebral vascular resistance and increase cerebral blood flow [27], although cerebral blood flow may not be as responsive to hypercapnia after deep hypothermic circulatory arrest [28]. In our study, it is possible that inspired CO₂ improved oxygen delivery to the upper body (including the brain) but did not have the same effect on the lower body. Differentiating the cerebral and total-body effects of inspired CO₂ would require further study, including measurement of oxygen saturation in both vena cavae.

Another limitation of the current study is that the patients were studied while in hemodynamically stable condition. The lowest mixed venous oxygen saturation during the study was 37%, which is above the anaerobic threshold for neonates after a Norwood procedure [22]. The 1-month survival rate for our patients was 94%, and the hospital survival rate was 88%. It is possible that inspired CO₂ would have different or perhaps more pronounced effects in patients who were in hemodynamically unstable condition after a Norwood procedure. It should also be noted that 12 of the 17 patients had an open sternum at the time of the study. Like others [3, 7, 8], we have found it useful to electively delay sternal closure after Norwood procedures. However, there were no differences in the effects of inspired CO₂, either with or without increased ventilation, between patients with open and closed sternums.

In summary, this prospective, patient-controlled study found that inspired CO₂ can improve oxygen delivery after a Norwood procedure. This improvement occurs only if minute ventilation is kept constant, not if minute ventilation is increased. Inspired CO₂ is thus one of many interventions that may improve hemodynamic status in the early postoperative period. It may prove particularly useful in low-birth-weight neonates and in patients with low systemic oxygen delivery after a Norwood procedure. Differentiation of cerebral from total body effects of inspired CO₂ will require further study.

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