Case January 2026

Cardio-Respiratory Interactions

Case prepared by Dr Gabriel Altit - Neonatologist - NH-TNE Specialist; Montreal Children's Hospital

January 2026

Case presentation

Targeted neonatal echocardiography was requested to guide the management of an extremely preterm infant with profound hypoxemia and marked differential cyanosis at 10 days of life. At the time of evaluation, preductal oxygen saturation ranged from 67% to 75%, while postductal saturation was markedly lower, around 40%. Blood pressure was within the expected range for postmenstrual age (24 weeks), measuring 58/47 mmHg (mean 51 mmHg) via an umbilical arterial catheter positioned in the postductal aorta. The infant was receiving inhaled nitric oxide at 20 ppm because of a prior diagnosis of pulmonary hypertension and inability to wean, in the setting of severe rebound hypoxemia. Respiratory support consisted of high-frequency jet ventilation with an FiO₂ of 100%, a mean airway pressure of 15 cmH₂O, and a rate of 420 breaths per minute.

Targeted neonatal echocardiography demonstrated right-to-left shunting at both the patent ductus arteriosus and the patent foramen ovale, with preserved right and left ventricular systolic function. Right-to-left ductal shunting directed deoxygenated blood from the pulmonary artery into the descending aorta, explaining the severe postductal desaturation, while interatrial shunting through the foramen ovale contributed to systemic hypoxemia and low preductal saturations. Pulse-wave Doppler interrogation of the right and left pulmonary arteries revealed very low flow velocities with characteristic mid-systolic notching, consistent with markedly elevated pulmonary vascular resistance.

The respiratory status was notable for significant hypercapnia, with a PaCO₂ of 65 mmHg, in the context of ventilation using a high mean airway pressure. Chest radiography showed marked lung hyperinflation with flattened diaphragms and a small cardiac silhouette. The key therapeutic intervention was prompt optimization of respiratory mechanics. The clinical team was advised to rapidly reduce the mean airway pressure, perform airway suctioning, and improve lung aeration. These interventions resulted in an immediate reversal of both ductal and interatrial shunting. As intra-alveolar pressure decreased and pulmonary perfusion improved, the shunt direction changed: the ductus arteriosus became fully left-to-right due to relief of extravascular vascular compression, and the foramen ovale shifted to predominantly left-to-right flow as right ventricular afterload decreased and left atrial preload improved through increased pulmonary venous return. This hemodynamic transition was accompanied by a striking bedside clinical response, with rapid normalization of oxygen saturations to 100%, resolution of the preductal–postductal gradient, and successful reduction of inspired oxygen from 100% to 45%. Over the subsequent 24 hours, the infant continued to improve, allowing complete discontinuation of inhaled nitric oxide, with FiO₂ requirements decreasing to approximately 25–30% by 48 hours off iNO.

Discussion and Physiology:

This case illustrates the profound and immediate impact of ventilatory strategy on neonatal cardiopulmonary physiology, highlighting how targeted respiratory optimization can rapidly reverse maladaptive shunt physiology and restore effective systemic oxygenation. The striking clinical improvement in this case can be explained by core principles governing the interaction between lung mechanics and pulmonary vascular physiology. The direction of flow across transitional shunts is governed by different but related mechanisms. Flow across the patent ductus arteriosus is primarily determined by the balance between pulmonary and systemic vascular resistance accross the various timepoints of the cardiac cycle, which establishes the pressure gradient between the pulmonary artery and the aorta. In contrast, shunting across the patent foramen ovale is largely determined by atrial pressure relationships, which are strongly influenced by ventricular compliance, filling and atrio-ventricular valve integrity (insufficiency and/or stenosis) rather than vascular resistance per se.

In the setting of normal atrioventricular and ventriculoarterial concordance, low pre-ductal oxygen saturation is most commonly attributable to impaired pulmonary oxygenation, typically due to ventilation–perfusion mismatch at the alveolar level, resulting in reduced oxygen content of pulmonary venous return. Pre-ductal desaturation may also arise from intracardiac mixing, particularly when a significant fraction of right atrial blood crosses into the left atrium, introducing deoxygenated blood directly into the systemic circulation at the pre-ductal level. Right to left shunting at the atrial level is dependent on the relationship in compliance between the downstream right and left ventricles, as well as integrity of corresponding atrio-ventricular valves and atrial filling. Additional sources of mixing that can further lower pre-ductal saturation include right-to-left shunting at the ventricular level in the presence of a ventricular septal defect, as well as retrograde delivery of desaturated blood into the ascending aorta via the ductus arteriosus. The latter is typically observed in conditions associated with left ventricular outflow tract obstruction or markedly reduced systemic ventricular output, whether due to functional impairment or structural disease of the systemic ventricle.

In this infant, severe hypoxia, hypercapnia, and acidosis created a potent milieu for pulmonary vasoconstriction. Elevated PaCO₂ and low pH are among the strongest stimuli for increasing pulmonary vascular resistance (PVR). In parallel, the use of a high mean airway pressure (MAP) during mechanical ventilation further exacerbated pulmonary hypertension by mechanically compressing alveolar and extra-alveolar capillaries, thereby increasing resistance to pulmonary blood flow and elevating pulmonary artery pressure. Together, these chemical and mechanical factors drove right ventricular afterload to suprasystemic levels, sustaining right-to-left shunting at the ductal level. The decreased pulmonary blood flow reduces left atrial preload, and de facto reduces left ventricular preload. This leads to increase right to left shunting at the atrial level due to underfilling of the left atrium, as well as a component of decreased right ventricular compliance. It can also further promote the right to left shunting at the ductal level due to decrease aortic filling. The therapeutic strategy directly targeted these determinants of elevated PVR. Reducing the MAP relieved mechanical compression of the pulmonary microvasculature, immediately lowering the mechanical component of PVR. This allows for more pulmonary blood flow and a decreased fraction of right to left ductal shunting, as well as increased left atrial preload and left ventricular filling, improving systemic flow. Improved left atrial filling also decreases the magnitude of right to left shunting at atrial level. The intrathoracic pressure by the increased mean airway pressure can also affect the right atrial pressure by extra-cardiac compression. Dropping the MAP can decrease the extra-cardiac pressure and the magnitude of right to left inter-atrial shunting. Concurrent airway suctioning and improved lung aeration enhanced alveolar ventilation, promoting more effective CO₂ elimination. As hypercapnia resolved and pH normalized, the powerful chemical stimulus for pulmonary vasoconstriction was rapidly removed, resulting in pulmonary vasodilation. With increased pulmonary blood flow, the fraction of dexoygenated blood shunting accross the inter-atrial shunt reduced and the left atrium was better preloaded, leading to improve aortic filling as well. This reversal of the afterload gradient led to immediate shunt reversal: the PDA transitioned to fully left-to-right flow, and atrial shunting across the PFO also became left-to-right. With elimination of right-to-left shunting, deoxygenated blood was no longer delivered to the systemic circulation. Instead, the full cardiac output traversed a now low-resistance pulmonary vascular bed, allowing efficient oxygenation and resulting in rapid, sustained normalization of systemic oxygen saturation.

This illustrative case highlights the tight coupling between respiratory mechanics and cardiovascular physiology in extremely preterm infants, in whom ventilatory management often becomes the dominant determinant of hemodynamic status. Very immature newborns are exquisitely sensitive to increases in mean airway pressure, which raise intra-alveolar and intrathoracic pressures and mechanically compress the pulmonary vasculature. This acute increase in pulmonary vascular resistance imposes a sudden afterload on the immature right ventricle, which has limited capacity to tolerate even modest elevations in afterload, leading to reduced pulmonary blood flow and impaired pulmonary venous return. In this context, reflex escalation of cardiovascular medications may worsen toxicity without addressing the primary pathophysiology. Instead, the initial and most effective intervention is reduction of excessive mean airway pressure to relieve pulmonary vascular compression, restore pulmonary blood flow, and re-establish left atrial and left ventricular filling, thereby improving cardiac output. Hypercapnia and respiratory acidosis further amplify this maladaptive physiology by acting as potent pulmonary vasoconstrictors, often in the setting of lung hyperinflation and auto-PEEP due to insufficient expiratory time. Sustained exposure to high airway pressures may lead to progressive right ventricular dilation, severe tricuspid regurgitation, elevated right atrial pressure, and right-to-left atrial shunting with systemic desaturation. In extreme cases, critically reduced right ventricular output results in severe underfilling of the pulmonary artery, creating a physiology that mimics functional pulmonary valve stenosis or atresia, with minimal or absent antegrade RV outflow and pulmonary blood flow becoming effectively ductal-dependent. This case underscores how targeted correction of lung mechanics, rather than escalation of cardiovascular support, is often the key to reversing profound cardiopulmonary instability in the most immature infants.

Key Messages:

Lung overdistension and high mean airway pressure markedly increase pulmonary vascular resistance, reduce pulmonary blood flow, and drive right-to-left shunting at both the atrial and ductal levels, resulting in hypoxemia and systemic hypoperfusion.
Reduced pulmonary blood flow leads to left atrial and left ventricular underfilling, decreased left ventricular cardiac output, while hypercapnia and acidosis further worsen pulmonary vasoconstriction and right ventricular afterload.
Targeted reduction of mean airway pressure and correction of hyperinflation can rapidly restore pulmonary blood flow, normalize shunt direction, improve oxygenation, and reestablish effective systemic cardiac output.
Cardiac disturbances in the most immature extremely premature infants may be secondary to adverse cardio-respiratory interactions. The first priority is to reassess respiratory status and ventilatory strategy, with close attention to mean airway pressure (MAP) and any degree of hyperinflation, as these infants are extremely sensitive to even modest increases in MAP. Hyperinflation can occur at MAPs as low as 8–9 cmH₂O and significantly affect both pulmonary vascular resistance and systemic venous return. Similarly, ventilatory settings that drive PaCO₂ into the normal range may exacerbate left-to-right ductal shunting, and in such cases mild permissive hypercapnia (PaCO₂ 50–60 mmHg) may be preferable. Once these cardio-respiratory contributors are addressed, it is essential to avoid polypharmacy and to target a single physiologic pathway rather than layering multiple drugs without a clear mechanistic rationale.
An Echo/TnECHO assessment can help define the predominant mechanism and guide more precise therapy to avoid multiple agents being introduced, but only once the respiratory care has been optimized. Finally, after optimizing respiratory status, if a patient is still considered to have cardiovascular instability requiring pharmacologic support, it is important to avoid piling on multiple agents. An ineffective drug should be discontinued before introducing another, rather than adding therapies without evidence of benefit.

Cardiorespiratory interactions:

The fundamental distinction between spontaneous breathing and positive pressure ventilation (PPV) lies in intrathoracic pressure: spontaneous breaths generate negative pressure that augments venous return, whereas PPV increases intrathoracic pressure and tends to impair preload.
Cardiac output depends on stroke volume and heart rate; PPV primarily influences cardiac output by altering preload and afterload, rather than heart rate or intrinsic contractility.
PPV reduces systemic venous return by increasing right atrial pressure and diminishing the pressure gradient driving venous drainage into the thorax, potentially lowering right ventricular preload and cardiac output.
PPV can improve right ventricular afterload by optimizing lung volume and restoring functional residual capacity, thereby reducing pulmonary vascular resistance—provided overdistension is avoided. If there is overdistension - it will increase pulmonary vascular resistance and right ventricular afterload which is poorly tolerated, especially by immature premature infants.
Right ventricular output determines left ventricular preload; impaired right-sided filling or output translates directly into reduced left atrial filling and systemic cardiac output.
A major benefit of PPV is left ventricular afterload reduction: increased intrathoracic pressure lowers left ventricular wall stress, functioning as a form of mechanical left ventricular assistance.
Abrupt withdrawal of PPV in patients with left ventricular dysfunction may precipitate acute cardiac failure due to sudden restoration of high afterload.
Right and left ventricular function are interdependent; excessive negative intrathoracic pressure increases right ventricular filling and septal shift, impairing left ventricular filling and output (e.g., pulsus paradoxus).
Negative pressure ventilation augments venous return and right ventricular preload but increases left ventricular afterload, making it beneficial in preload-dependent states and potentially harmful in left ventricular dysfunction.

Relationship between functional residual capacity, lung inflation, mean airway pressure, and their impact on pulmonary vascular resistance and right ventricular afterload

Figure. Relationship between lung volume, functional residual capacity (FRC), mean airway pressure, pulmonary vascular resistance (PVR), and right ventricular (RV) afterload. Pulmonary vascular resistance follows a U-shaped relationship with lung volume. At low lung volumes (near residual volume, RV), alveolar collapse and reduced lung inflation lead to narrowing and derecruitment of extra-alveolar vessels, resulting in elevated PVR. As lung volume increases toward FRC, recruitment and distension of extra-alveolar vessels (e.g., corner vessels) predominate, leading to a reduction in total PVR and optimal RV afterload conditions. With further lung inflation toward total lung capacity (TLC), increasing alveolar pressure compresses alveolar (septal) vessels, causing a rise in PVR despite continued extra-alveolar vessel distension. The net effect is a U-shaped total newborn PVR curve, highlighting FRC as the zone of minimal PVR and most favorable RV loading conditions. The schematic illustrates the balance between pulmonary vascular recruitment and compression across low and high lung volumes, emphasizing how excessive atelectasis or overdistension—often influenced by mean airway pressure—can increase RV afterload.

Positive pressure ventilation - Heart-Lung Interactions

RV Preload
- Reduction in Venous Return: Positive pressure ventilation increases intrathoracic pressure, which decreases the pressure gradient between the systemic veins and the right atrium. This reduction in the pressure gradient leads to decreased venous return to the heart. This results in reduced RV preload, which means less filling of the right ventricle during diastole. Hypovolemic Patients**: Patients with low blood volume are more susceptible to significant decreases in RV preload, potentially leading to reduced cardiac output and hypotension.

RV Afterload
- Increase in Pulmonary Vascular Resistance (PVR): Positive pressure ventilation can increase alveolar pressure, leading to compression of pulmonary capillaries and an increase in PVR.
- However, under-insufluation and alveolar collapse may also contribute negatively to PVR. As such, there is a inverse U-shape relationship where there is a tight zone where alveolar recruitment may optimize PVR.
- In patients with preexisting right heart failure or pulmonary hypertension, increased RV afterload can exacerbate right ventricular dysfunction and lead to worsening of heart failure symptoms.
LV Preload
- Reduction in Pulmonary Venous Return: The reduction in RV preload due to decreased venous return results in less blood being pumped into the pulmonary circulation and subsequently to the left atrium. This results in decreased LV preload, which means less filling of the left ventricle during diastole. Reduced LV preload can lead to decreased stroke volume and cardiac output. This effect is more pronounced in patients with compromised LV function.
LV Afterload
- Reduction in LV Afterload: Positive pressure ventilation increases intrathoracic pressure, which is transmitted to the aorta and other large arteries. This results in a reduction of transmural pressure (the difference between intrathoracic pressure and blood pressure within the aorta), effectively reducing LV afterload. This results in decreased resistance against which the left ventricle must pump blood, potentially improving LV ejection. For patients with LV dysfunction or heart failure, reduced afterload can enhance stroke volume and cardiac output.

Targeted Neonatal Echocardiography

Pulsed Wave (PW) Doppler envelope of the Right Pulmonary Artery. The waveform shows a sharp systolic peak with a Peak Systolic Velocity (PSV). The envelope has a relatively "clean" appearance with a well-defined spectral window, suggesting laminar flow without significant turbulence. The acceleration time appears brisk. There is mid-systolic notching, elevating the suspicion for increased pulmonary vascular resistance in the right pulmonary vasculature.

Pulsed Wave Doppler interrogation of the Left Pulmonary Artery. The waveform here is similar in morphology to the RPA. The acceleration time appears brisk. There is mid-systolic notching, elevating the suspicion for increased pulmonary vascular resistance in the left pulmonary vasculature.

Apical four-chamber view. There is intracavitary flow acceleration in both ventricles, a pattern that may be observed in the presence of significant ventricular hypertrophy and/or reduced ventricular preload with increased wall apposition. In this case, right ventricular preload is reduced, with a small right atrium and only trace tricuspid regurgitation. Right ventricular systolic function is preserved, as assessed by TAPSE and fractional area change (not shown). Left ventricular preload is also reduced, consistent with diminished pulmonary blood flow.

B-mode apical four-chamber view. This view demonstrates preserved right and left ventricular systolic function. Left ventricular ejection fraction was calculated at 64%.

Apical sweep to the left ventricular apical five-chamber view. Anterior angulation from the apical window demonstrates the inflow–outflow tract relationship of the left ventricle. Color Doppler reveals intracavitary flow acceleration/aliasing at a Nyquist limit of 104 cm/s, consistent with left ventricular underfilling, with a possible contribution from ventricular hypertrophy (difficult to assess in the setting of reduced preload). There is normal inflow across the mitral valve without mitral regurgitation, and unobstructed systolic flow from the left ventricular cavity through the left ventricular outflow tract and aortic valve, excluding subvalvular or valvular obstruction.

Modified subcostal view. The right atrium is seen underfilled. The right ventricle has intra-cavitary acceleration and some degree of underfilling with apposition of ventricular walls during systole. There is a strict right to left inter-atrial shunt.

PW-Doppler at the level of the inter-atrial shunt (here a PFO). We can appreciate that the velocities are all negative, confirming that the inter-atrial shunt in completely right to left. In this context, one must rule out structural causes of this finding. The first one to rule-out is total anomalous pulmonary venous return. Then, one must rule out anything that would obstruct the flow from the right atrium to the right ventricle, and obstruction from the right ventricle to the pulmonary artery. Other reasons of a strict right to left inter-atrial shunt are outlined here.

Subcostal view demonstrating a dilated inferior vena cava and subhepatic veins. This finding may reflect appropriate right-sided filling and adequate systemic venous return. However, it can also represent excessive transmission of intrathoracic pressure to the right atrium, resulting in elevated right atrial pressure due to extracardiac compression. In this setting, venous dilatation reflects impaired venous drainage rather than true intravascular volume loading. One may appreciate the Umbilical Venous catheter arriving at the IVC-RA junction through the ductus venosus.

Colour outlining that there is some degree of retrograde flow (red) in the subhepatic vein where the cursor is placed.

The patent ductus arteriosus is large and unrestrictive, near completely right to left ("blue" blood coming from the MPA to the descending aorta). The PDA is larger than the left pulmonary artery in this tripod view.