The respiratory and cardiac systems are integrally related both anatomically and functionally and as a result there are significant interactions, particularly in the newborn period.
Inappropriately high airway pressure during mechanical ventilation leads to adverse hemodynamic effects, including a reduction in left and right ventricular output, a decrease in venous return, and an increase in pulmonary vascular resistance. Inappropriately low airway pressure can also have detrimental effects by decreasing lung volume and consequently increasing pulmonary vascular resistance.
Positive end-expiratory pressure and mean arterial pressure in the range commonly used in clinical practice in settings of lung diseases with low compliance and in the absence of low lung volume or hyper-expansion have mild effects on hemodynamics.
In addition to the direct effects of ventilator settings on the cardiovascular system, the chosen treatment strategy and aims, such as a particular blood gas goal, can have a significant effect on the cardiovascular system. Although the impact of acidosis on the cardiovascular system is not well studied, there is accumulating evidence that excessive hypercapnia, especially in the first few postnatal days, attenuates cerebral blood flow autoregulation and likely contributes to reperfusion injury in preterm infants.
The cardiorespiratory system consists of two organ systems—the heart and cardiovascular system and the lungs and pulmonary vasculature—that are designed to work together to deliver an adequate supply of oxygen to the tissues to meet the demands of oxygen consumption. There are complex anatomic and physiologic relationships between these two organ systems. An understanding as to how they interact both normally and in the presence of pathologic conditions or interventions, such as the provision of positive pressure, is essential for any clinician working with sick children and infants. Changes in intrathoracic pressure affect both organ systems and within the cardiovascular system there are different effects on the left- and right-sided structures. A delicate balance needs to be maintained between the distending airway pressure needed to optimize lung volume—and thus oxygenation—while also avoiding excessive pressure that would compromise global cardiac function that is necessary for adequate systemic blood flow, which is essential for normal oxygen delivery. Both optimal oxygenation and normal cardiac output are required to deliver adequate oxygen to the tissues. Reduced tissue oxygenation often has a multifactorial causation; however, many of the issues are related to what is happening at the level of the cardiorespiratory interaction.
The initial cardiorespiratory interaction is during birth at the time of the circulatory transition and umbilical cord clamping. A normal relationship between the spontaneously breathing infant with normal lungs and cardiovascular system should ensue, in which case there is a balance between the closely associated lungs and heart. If there is a pathologic condition, particularly respiratory distress, then the interventions required to support the respiratory system such as positive-pressure ventilation may adversely affect the function of the heart. Similarly, abnormalities of cardiac function such as ventricular failure can result in lung congestion and the need for respiratory support. Finally, changes in the pulmonary vasculature, particularly in the neonatal transition where failure of the normal fall in pulmonary vascular resistance (PVR) can impair cardiac function. The predominant influence on the cardiorespiratory interaction is mean airway pressure (MAP), which most directly affects the intrathoracic pressure. The effect of inspiration/expiration in addition to MAP is minimal. Adjunctive respiratory therapies such as inhaled nitric oxide may also rapidly change the balance between cardiac and respiratory systems.
Cardiorespiratory Interactions at Birth
In utero the fetus has fluid-filled lungs with a very low pulmonary blood flow (PBF; about 10% of postnatal flow ) and minimal tidal volume changes, such that any pressure exerted on the heart physically and via venous return is steady and unchanging. The interposition of the placenta and the unique fetal shunts—the ductus venosus, foramen ovale (FO), and patent ductus arteriosus (PDA)—into the fetoplacental circulation results in a fetal circulation quite different from that of the postnatal infant just minutes after birth. Instead of being two parallel circulations, there is admixture of blood at several levels. Oxygenated blood returning from the placenta via the umbilical vein passes through the ductus venosus and into the inferior vena cava (IVC). Blood then streams into the right atrium, where owing to the anatomy of the right atrium and FO, the oxygenated blood is directed preferentially across the FO into the left atrium, thus improving the oxygenation level of blood passing from the left atrium into the left ventricle and subsequently toward the systemic circulation. The presence of the PDA and fetal conditions (hypoxemia, vasoconstricting factors) that cause increased PVR result in preferential blood flow from the right ventricle via the right-to-left shunting PDA into the systemic circulation. The significantly reduced blood flow to the pulmonary circulation means that the normal main source of preload to the left atrium (when there is no placental flow)—the pulmonary venous return—is significantly limited in utero. Blood passing from the right ventricle via the PDA and from the left ventricle into the aorta travels down the descending aorta and deoxygenated blood is then sent to the placenta via iliac and eventually umbilical arteries to complete the fetoplacental circulation. The main flow to the left atrium is provided by the placental return and some flow from lower body via the IVC; this is an important consideration when the timing of umbilical cord clamping in the newborn transition is considered. Interruption of the placental blood flow return before establishment of the PBF through the lungs puts the transitioning newborn at risk of a loss of preload to the systemic ventricle with a subsequent fall in systemic cardiac output.
The events of the perinatal cardiopulmonary transition constitute the first, and possibly most crucial, cardiorespiratory interaction and there is potential for significant complications. Such complications range from premature interruption of the placental blood flow, resulting in an acute drop in cardiac output, to failure to properly transition, leading to the syndrome of persistent pulmonary hypertension of the newborn (PPHN; Table 17.1 ). Keeping the cardiorespiratory events of the transition in sequence has become an important aspect of management at birth. The key initial event is inflation of the lungs (usually by crying but also by use of positive-pressure devices), resulting in a rapid increase in PBF and reversal of the ductal shunt to become left to right. Additionally, the lung liquid must be rapidly absorbed; the most recent animal imaging data suggest that this occurs via transepithelial gradients developed during inspiration. With the increased PBF, adequate left atrial filling is established and the umbilical cord can now be cut without acutely reducing the left atrial return. In this sequence, oxygenation is provided by the lungs before the placental “lung” is removed by cord clamping. Failure to allow the natural sequence of events to unfold may result in significant hemodynamic instability, at least in animal models. The first response to clamping the umbilical cord and separating from the low-resistance placenta before lung aeration is a rapid increase in arterial pressure and blood flow and a rapid reduction in cardiac output from lack of LA filling, followed by a surge in blood pressure and blood flow as PBF is established. These hemodynamic changes are much less marked if the PBF is established by lung aeration before cord clamping (termed physiologically based cord clamping). Delaying cord clamping increases the likelihood that the newborn will establish breathing/lung inflation before the umbilical cord is clamped. The benefits of a delay in cord clamp time have generally been ascribed to the receipt of a placental transfusion. The magnitude of the transfusion is dependent on a number of factors, including gravity, time, flow/patency of the umbilical vessels, and spontaneous breathing efforts. Respiratory efforts result in significant fluctuations in umbilical cord blood flow and can potentially enhance the placental transfusion received as well as stabilize the hemodynamics of the transition as discussed previously. The consequences of an increased understanding of the cardiorespiratory interactions at birth are that there may be physiologic advantages to providing positive pressure and initial resuscitative measures while the infant is still attached to the umbilical cord. Equipment and techniques to allow this to happen are currently in development.
|Inspiration||Stimulation or PPV||Fluid absorption |
↑ Pulmonary blood flow
Reversal of PDA shunt
|Lung aeration before cord clamping||Stimulation, CPAP/PPV a||Placental transfusion|
|Establishing FRC||CPAP/PPV||Improved oxygenation, |
↓ Risk of PPHN
|Avoidance of hyperoxia||Avoidance of hyperoxia||Improved response to iNO in case of PPHN|
Umbilical cord milking is another alternative for provision of a placental transfusion to the newborn. Less is known about the physiology of this technique and the cardiorespiratory effects on placental transfusion. Because transfusion occurs over a shorter period, there is less opportunity for the effect of the respiratory system on the volume of transfusion and subsequent cardiac flow on effects. The cardiovascular benefits still seem to be present, including higher mean blood pressure and less inotrope use.
After inflation of the lungs and the commencement of spontaneous negative-pressure breathing, there are further cardiorespiratory interactions with venous blood return to the heart enhanced by the negative-pressure generated during normal inspiration. This can be seen on blood flow traces showing a respiratory pattern, more so in adults. If an infant requires positive-pressure support—either by continuous positive airway pressure (CPAP) or mechanical ventilation—some degree of impact on the cardiovascular system is inevitable. Mechanical ventilation raises intrathoracic pressure and reduces venous return and preload to the right heart, thus also impairing right ventricular (RV) performance, especially if the distending pressure is excessive relative to the compliance of the lungs. Mechanical ventilation also significantly affects PVR and RV afterload. The left ventricle, in contrast, receives venous return from within the thorax so it is less affected by changes in intrathoracic pressure. Cardiac output from the left ventricle is dependent on blood flow from the right ventricle, so changes in RV output will also affect left ventricular (LV) output. Increased pressure in the right ventricle can cause a conformational change in the heart with displacement of the interventricular septum that decreases LV preload and compliance. Although LV contractility is not affected by positive-pressure ventilation, the LV output can be significantly affected by changes in the LV myocardial wall tension (the difference between LV systolic pressure and mean intrathoracic pressure). There is also a potentially positive effect of mechanical ventilation and raised intrathoracic pressure on the LV with lower LV afterload owing to a decreased transmyocardial pressure gradient in the setting of higher intrathoracic pressure ( Fig. 17.1 ).
After birth the neonate is exposed to higher oxygen tension compared with fetal life. Routine use of oxygen supplement can deleteriously affect the cardiovascular transition. Indeed, animal models have shown a reduction in response to inhaled nitric oxide in sheep with PPHN exposed to a high fraction of inspired oxygen.
Each of the elements of cardiovascular function can be affected by the respiratory system—the preload via changes in intrathoracic pressure and PBF, the contractility by direct impingement on ventricles within a confined space, and the afterload by changes in the PVR (both overinflation and underinflation increase PVR) —that also translates to inadequate filling of the left atrium in the setting of reduced PBF.
The Physiology of Cardiovascular and Respiratory Interaction
During normal phasic spontaneous breathing with negative intrathoracic pressure, the passive systemic venous return can easily fill the right atrium, which is at low pressure, with the additional augmenting effect of inspiration. The end-diastolic volumes of both ventricles change in different directions: enhanced venous return into the RV from outside the thorax increases RV filling, which makes the LV stiffer and harder to fill. When positive pressure is applied, the opposite happens: impaired RV filling and easier LV filling. The end result of these changes is fluctuations in the systemic arterial pressure. In a ventilated adult, ventilator-induced changes in preload can result in a variable stroke volume and subsequently variation in the pulse pressure. The rise in arterial pressure during a positive-pressure breath is counterintuitive as the expectation would be reduction in venous return and subsequently the pulse pressure should decrease. Factors that may account for this include an increase in pulmonary venous return from squeezing of capillaries, decreased LV afterload, mechanical assistance of LV contraction by compression, and adrenergic stimulation with increased inotropy. The degree of pulse pressure variation can be used to predict responsiveness to a volume bolus during supportive hemodynamic management. Interestingly, the effect of mechanical ventilation on the right ventricle is opposite: impaired venous return and cardiac output, which in turn reduces the venous return to the left atrium that will result in a fall in LV output as well. Pulse pressure variation is also seen in neonates in association with cardiopulmonary interactions, but it is probably not as variable and thus not likely to be as predictive of fluid responsiveness. This may be due to the greater compliance of the newborn chest wall compared with that of the adult, which may decrease the transmission of positive pressure to the pleural space and mediastinum.
Preload is an important driver of adequate cardiac contractility and subsequently cardiac output and the newborn heart are particularly sensitive to changes in preload. Worsening respiratory disease can affect both right and left sides of the heart ( Table 17.2 ). Higher MAP impairs systemic venous return to the right atrium, necessitating higher central venous pressure (CVP) to counteract the increased intrathoracic pressure, particularly in the setting of positive-pressure ventilation. If the reduced systemic venous return is not balanced by increased CVP, the preload to the right ventricle is reduced and thus right ventricular output (RVO) will fall. A reduction in RVO results in reduced PBF, which apart from the effect on oxygenation, will also have an impact on the preload and filling to the left atrium and, subsequently, the systemic cardiac output. The reduction in PBF can be exacerbated by the state of recruitment of the lungs. Underrecruited lungs result in collapse in the supporting tissues around blood vessels in the lung, thus increasing PVR. If the lungs are overinflated, the increased pressure from the air-filled structures in the lung causes compression of pulmonary vasculature and results in impaired PBF and reduced return to the left atrium ( Fig. 17.2 ). If there is increased pulmonary vasoconstriction (such as in PPHN), this will also impair blood flow through the lungs. An index of severity of raised PVR can be obtained by assessing the pulmonary venous return, in which case the pulmonary venous velocity is reduced. Direct impingement of the heart, either by excessive MAP with overdistended lungs or by dilation of either ventricle, can cause septal bowing and reduction of ventricular cavity, typically of the LV by the RV with PPHN.
|Component||Respiratory Alteration||Resultant Effect|
|Preload||High mean airway pressure |
High pulmonary vascular resistance
|↓ RV preload |
↓ LV preload
|Contractility||High pulmonary vascular resistance |
Acidosis secondary to permissive hypercapnia
|↓ RV contractility |
↓ Contractility a
|Afterload||High pulmonary vascular resistance |
Positive intrathoracic pressure
|↑ RV afterload |
↓ LV afterload
At low MAPs, the negative influence on cardiac output is mediated primarily through reduced systemic venous return, whereas at higher MAPs direct effects on PVR and myocardial function become important. In the sickest infants, all of these factors are likely to be important. MAP is often very high, hypoxia and acidosis are common, and pulmonary artery pressure is high as suggested by the commonly observed low ductal blood flow velocity. Both ventricles also show the ability to substantially increase output when the preload is increased by a ductal or atrial shunt, confirming a degree of myocardial reserve. The effect of positive-pressure ventilation in reducing systemic venous return and cardiac output may be as important in preterm infants as it has been recognized to be in adults. There are few studies on the effect of ventilation on cardiac output in the preterm infant. Hausdorf and Hellwege demonstrated a 25% to 30% reduction in ventricular stroke and cardiac output, with no effect on blood pressure, by increasing positive end-expiratory pressure (PEEP) from 0 to 8 cm H 2 O in a group of preterm infants. This is clinically important because an aggressive effort to improve arterial oxygenation may reduce perfusion and thus compromise tissue oxygen delivery. Trang et al. suggested that this occurs at PEEP levels above 6 cm H 2 O in preterm infants. However, the absolute level of PEEP or MAP is not as important as the appropriateness of those pressures for the compliance of the lungs; the more compliant the lungs are, the greater the transmission of distending airway pressure to the mediastinum and thus the greater the impairment of cardiac output.
Interventions to counteract the deleterious effects of respiratory diseases and ventilator support on the preload primarily involve judicious use of ventilation settings to avoid excessive MAP and addressing the underlying pathophysiology of the lung disease—for example, reducing PVR. However, there is some evidence from adults and one study in the preterm newborn to suggest that volume expansion can correct some of the preload deficit that results from positive-pressure ventilation and improve cardiac output in the short term.
Mechanical ventilation does not appear to directly affect myocardial contractility. However, through a decrease in LV afterload it may enhance LV contractility. On the other hand, as discussed earlier, inappropriately high or low lung volume can increase PVR and therefore through an increase in RV afterload can impair RV contractility. In addition, ventilator strategies aimed at permissive hypercapnia with resulting acidosis can decrease myocardial contractility, at least in adults (see the “Effect of Acidosis and Permissive Hypercapnia” section). In the term infant, poor cardiac output is most often the result of an asphyxial insult or sepsis. Poor cardiac output in the preterm infant has been seen primarily as a consequence of an immature myocardium, especially in the first few postnatal days of the very premature infant. LV ejection fraction, admittedly a broad measure of myocardial function in the preterm infant, was not significantly associated with either ventricular output. The predominantly left-to-right pattern of ductal shunting reduces RV output, and atrial shunting reduces LV output (LVO) by shunting blood from the systemic back to the pulmonary circulation. This effect is apparent even in the first postnatal days.
Afterload also potentially has a large effect on cardiac output in the transitioning newborn. The afterload to which the right ventricle is exposed is determined primarily by what is happening in the lungs, both in terms of aeration and in terms of the pulmonary vascular pressure. Optimization of lung recruitment and addressing raised PVR are both important strategies to improve RV function. Judicious management of the shunting through the PDA may also be important with strategies to allow the PDA to remain open and promote a right-to-left shunt, sometimes reducing afterload on the RV and allowing improved forward flow out of the ventricle. Although as discussed earlier, positive-pressure ventilation can enhance LV contractility by reducing the LV afterload (wall stress), systemic vascular resistance (SVR) plays a more important role in changes in LV afterload than mechanical ventilation.
The newborn myocardium and cardiac function are more vulnerable to both preload and afterload changes than in older infants and adults and this is even more so in preterm infants. They have a simpler structure with fewer mitochondria, and differences in the myofibrils themselves result in less reserve and ability to compensate for changes in blood volume and peripheral resistance.
Effect of the Respiratory System on the Cardiovascular System
In a normal spontaneously breathing infant during inspiration, the negative intrathoracic pressure increases the transmural pressure in the right atrium (RA) and RV, thereby increasing the venous return. During expiration the opposite effects occur; however, owing to the presence of valves in the venous system, these effects are relatively small. On the other hand, when a patient is receiving positive-pressure respiratory support, during inspiration the pleural pressure increases and therefore venous return to the RA is impeded while the improvement in venous return occurs during the expiratory phase.
The effect of phases of respiration during mechanical ventilation on the left and RV filling is different. During expiration, both phases of ventricular filling (early passive and atrial) increase on the right side and decrease on the left side. The increase in LV filling during inspiration may be related to the increase in intraalveolar/interalveolar pressure improving drainage to the left atrium (LA) and improved LV distensibility owing to lower RV volume.
Effects of PEEP, CPAP, and MAP
The effects of PEEP, CPAP and MAP on venous return, PVR, and cardiac function for the most part depend on the lung compliance and lung volume. Both extremes of lung volume can increase PVR (see Fig. 17.2 ). This increase in RV afterload can impair RV function and through ventricular interdependence also adversely affect LV function.
In an experiment on premature lambs with normal lungs ventilated with a tidal volume of 5 mL/kg and receiving PEEP of 4 cm H 2 O, PEEP was changed randomly to 0, 8, and 12 cm H 2 O. Increasing PEEP from 4 to 8 H 2 O and from 4 to 12 H 2 O decreased PBF by 20.5% and 41%, respectively, and caused corresponding changes in PVR; reducing PEEP from 4 to 0 H 2 O did not affect PBF. Interestingly, despite decreasing PBF, increasing PEEP from 4 to 8 H 2 O and then 12 cm H 2 O improved oxygenation, presumably as the result of improvement in lung recruitment and ventilation-perfusion matching. Higher PVR and lower PBF with an increase in PEEP have also been shown in a swine model with normal pulmonary function test results. Again, it needs to be emphasized that these animals had normal lung compliance and therefore any PEEP above 4 cm H 2 O would be excessive.
Although the effects of increase in PEEP/MAP in human neonates are similar to those of animal models, they are less prominent. When the PEEP increased from 0 to 4 cm H 2 O and 8 cm H 2 O in preterm infants after the acute phase of respiratory distress syndrome (RDS), both left and right cardiac output decreased. In a more recent and larger study, preterm and term infants supported by mechanical ventilation with a baseline PEEP of 5 cm H 2 O were exposed to a brief period of higher PEEP of 8 cm H 2 O. The researchers found a statistically nonsignificant 5% decrease in RVO and no effect on systemic circulation as evidenced by unchanged superior vena cava (SVC) flow for the infants as a group. However, the effect on SVC flow was variable; a third of the subjects showed a significant (about 25%) increase and another third demonstrated a significant decrease in SVC flow. These divergent effects are probably explained by differences in the underlying lung pathology; those with more compliant lungs had a decrease in flow with higher PEEP, while those with more atelectatic lungs showed improved flow with higher PEEP. In this study, no change in ductal diameter or in percentage of right-to-left shunt was noted. Another study assessed the effect of change in PEEP from a baseline of 5 cm H 2 O to 2 and 8 cm H 2 O on ductal shunting and systemic flow in ventilated extremely preterm infants with a PDA. Reduction of PEEP to 2 cm H 2 O had no significant effect. There was no change in SVC flow or cerebral regional oxygen saturation, but there was a mild reduction in LVO with a resultant decrease in the LVO-to-SVC ratio when PEEP was increased to 8 cm H 2 O. This is suggestive of a mild reduction in left-to-right ductal shunting. However, the low LVO could also reflect a reduction in venous return. Interestingly, a recent study found no difference in LVO, RVO, or SVC flow with CPAP of 4, 6, and 8 cm H 2 O in stable preterm infants with minimal lung disease. This lack of any hemodynamic effect may be attributed to ineffective pressure transmission via a noninvasive nasal interface. Studies of preterm infants being weaned from CPAP have shown variable results; some reported no effect, whereas others demonstrated lower RVO and SVC flow during CPAP treatment.
A study of the impact of lung recruitment with high-frequency oscillation on pulmonary, systemic, and ductal blood flow in preterm infants with RDS demonstrates interesting findings. Before giving surfactant, the MAP was increased stepwise until the fraction of inspired oxygen (F io 2 ) was less than 0.25 or no further improvement in oxygenation was noted; this was termed the opening pressure. Then the MAP was decreased until deterioration in oxygenation was noted; this was termed the closing pressure. Then lungs were recruited again and MAP was kept at 2 cm H 2 O above the closing pressure; this was termed the optimal pressure. Despite very high MAP at the optimal pressure (20 cm H 2 O), the hemodynamic effects were small. The RVO decreased by 17%, but no changes in SVC flow, ductal diameter, or flow pattern were noted.
Based on the available literature, the impact of PEEP or CPAP of up to 8 cm H 2 O on ductal diameter and flow, systemic flow and PBF in preterm infants appear to be negligible or minimal. This is in contrast to animal studies, which have demonstrated a significant reduction in venous return and PBF and an increase in PVR. Although this may be the result of interspecies differences, the main reason for the discrepancy is likely the difference in lung compliance. Animal studies in general evaluated the impact of PEEP in models with normal lung compliance, whereas in human studies subjects had lung disease with presumably variable decrease in compliance. Indeed, as noted earlier, even a very high MAP appears to have little effect on the hemodynamics in subjects with poor lung compliance. Therefore the positive airway pressure more readily affects intrapleural pressure and overdistends the alveoli if it is inappropriately high for the degree of reduced compliance. As such, inappropriately high PEEP and MAP can result in increased PVR and reduction in PBF, leading to hypoxemia and decreased systemic blood flow.
Effect of Tidal Volume
Little is known about the effect of different tidal volumes on hemodynamics. In a pediatric swine model with normal lung function, increasing tidal volume (up to 25 mL/kg) resulted in progressive and exponential increase in PVR and reduction in RVO and these effects were more pronounced with higher PEEP. These deleterious effects appear to be the result of decreased preload (impaired venous return) and lung overdistention with physical compression of the microvasculature. Clearly, a grossly excessive tidal volume of this degree has deleterious effects. In addition, as discussed earlier, normal lung compliance in these animal models limits the applicability of the findings to human subjects with lung disease.
Effect of Acidosis and Permissive Hypercapnia
Permissive hypercapnia is a common lung-protective strategy used in the care of neonates with lung disease. Acceptance of higher carbon dioxide (CO 2 ) levels than normal allows for use of lower ventilator settings and smaller tidal volumes with a resultant decrease in volutrauma and lung injury. Because the renal compensatory metabolic alkalosis takes several days to take hold and may be further delayed in extremely premature infants owing to renal tubular immaturity, permissive hypercapnia leads to acidosis, especially in the first few postnatal days. Little is known about the impact of acidosis on cardiovascular function and cerebral hemodynamics in neonates.
The ionic channels in the myocyte are pH sensitive. Some promote and others reduce the influx of calcium, with the net effect of an increase in intracellular calcium with an acidic pH. However, owing to the inhibition of myofibrillar responsiveness in acidic pH, myocardial contractility decreases despite an increase in intracellular calcium. In adult humans, acidosis and permissive hypercapnia affect the heart and vascular system, leading to a decrease in myocardial contractility and a drop in SVR. Despite the decrease in contractility, cardiac output increases, most likely secondary to low afterload. Most of the effects of hypercapnia on the cardiovascular system appear to be mediated via altering pH as the above-mentioned effects tend to attenuate or completely disappear with administration of a base or with passage of time as compensatory metabolic alkalosis sets in. Interestingly, animal studies suggest that the myocardial and vascular responses to acidosis are developmentally regulated and differ in newborn versus adult subjects. Newborn animals exhibit a more tolerant myocardium but greater vasodilation in response to acidosis. Little is known about the effects of acidosis in human neonates. A recent prospective cross-sectional study evaluated the effect of pH and CO 2 on cardiovascular function in hemodynamically stable preterm infants. The pH ranged from 7.02 to 7.46 and CO 2 from 28 to 76 mm Hg and base excess from −13 to +6 mEq/L. They found no relationship between various indices of myocardial contractility and pH in the first 2 weeks after birth. There was no relationship between either LVO or SVR with pH (or CO 2 ) during the transitional period (first 3 days). However, a weak but significant negative correlation between LVO and pH and positive correlation between SVR and pH were noted after the transitional period (postnatal day 4–14). CO 2 had a positive and negative correlation with LVO and SVR, respectively, during the post-transitional period. The observed association remained significant even after adjusting for the effect of base deficit. This lack of reduction in contractility in contrast to the findings in adults may be due to higher intracellular buffer in neonates compared to that of the mature myocardium. As for the effect of pH and CO 2 on cardiac output and SVR, there appears to be a postnatal maturational process in the cardiovascular response with the pattern becoming similar to that seen in adults only after the first 3 postnatal days. Attempts at normalizing pH in the case of metabolic acidosis by giving sodium bicarbonate yields minimal hemodynamic effects. When sodium bicarbonate was given to ventilated preterm infants with metabolic acidosis, despite an increase in pH from mean 7.24 to 7.30, the increase in cardiac output was transient and likely was reflective of volume administration. Similarly, correction of metabolic acidosis with sodium bicarbonate had no effect on cerebral, renal, and splanchnic regional tissue oxygenation in very low-birth-weight neonates.