Persistent fetal circulation

Abstract

Persistent fetal circulation (PFC), also known as persistent pulmonary hypertension of the newborn, is defined as postnatal persistence of right-to-left ductal or atrial shunting, or both in the presence of elevated right ventricular pressure. It is a relatively rare condition that is usually seen in newborns with respiratory distress syndrome, overwhelming sepsis, meconium and other aspiration syndromes, intrauterine hypoxia and ischemia, and/or neonatal hypoxia and ischemia. This condition causes severe hypoxemia, and, as a result, has significant morbidity and mortality. Improved antenatal and neonatal care; the use of surfactant; continuous monitoring of oxygenation, blood pressure and other vital functions; and early recognition and intervention have made this condition even more rare. In modern neonatal intensive care units, anticipation and early treatment of PFC and its complications in sick newborns are commonplace. Thus, severe forms of PFC are only seen on isolated occasions. Consequently, it is even more imperative to revisit PFC compared with the time when there were occasional cases of PFC seen in neonatal intensive care units, and to discuss evolving treatment and management issues that pertain to this syndrome.

Persistent fetal circulation (PFC), also known as persistent pulmonary hypertension of the newborn, was first described as “unripe births of mankind” by William Harvey in 1628 in his book Exercitatio Anatomica De Motu Cordis et Sanguinis in Animalibus (1). However, the syndrome went unnoticed for a long time – until the latter half of the 19th century. In the 1950s, several investigators independently rediscovered this syndrome. Novelo et al (2) presented a paper that described postnatal persistence of fetal circulatory patterns. Lind and Wegelius (3) demonstrated that “the foramen ovale has either failed to close or reopened” in asphyxiated infants. They also noted two cases in which “the ductus arteriosus was found to be open with a direction of the foetal flow from the pulmonary artery to the aorta” (3). Burchell et al (4) showed that right to left ductal shunting was exacerbated by hypoxia. Berglund (5) observed that right to left atrial shunting occurred in an infant with respiratory distress syndrome. Several publications that discussed various aspects of this condition followed. In 1969, Gersony et al (6) published case reports of two newborns with pulmonary hypertension and described this condition as ‘persistent fetal circulation’.

FETAL AND POSTNATAL CIRCULATION

To appreciate the mechanism of PFC, one has to be familiar with fetal circulation and perinatal circulatory adaptation. In utero, the fetus derives its oxygenated blood and nutrients from the placenta through the umbilical vein. Most of this blood bypasses the liver through the ductus venosus and enters the inferior vena cava, which ends in the right atrium. Once again, the flow of blood is such that most of it passes through the foramen ovale into the left atrium and then into the left ventricle. This blood, rich in oxygen and nutrients, is pumped out from the left ventricle to the brain and the upper part of the body. Some of this blood in the right atrium from the inferior vena cava, mixed with superior venacaval blood, goes into the right ventricle, enters the pulmonary arterial trunk and then bypasses the lungs through the ductus arteriosus to the descending aorta. This mixed blood is used to nourish the lower half of the body and to return to the placenta for reoxygenation via the umbilical arteries. Thus, portions of the aorta proximal to the point where the ductus joins the aorta (preductal aorta) carry blood that is relatively richer in oxygen than those portions distal to the ductus and aorta junction (postductal aorta). As a result, the head, neck and right upper extremity (supplied by branches from the preductal aorta) receive more oxygen than the trunk, the left upper extremity and both lower extremities (7).

After birth, the infant takes its first breath and is exposed to myriads of stimuli. The pulmonary vessels dilate, and pulmonary vascular resistance (PVR) decreases remarkably while the systemic vascular pressure rises above the PVR. This allows blood from the right ventricle to enter the lungs for oxygenation. In most cases, this increased oxygenation, along with other factors, causes the ductal wall to constrict and the ductus arteriosus to close functionally. Within days, anatomical occlusion occurs, with extensive neointimal thickening and loss of smooth muscle cells, and the ductus becomes a strand-like structure with no lumen (8).

Furthermore, as left-sided pressures rise higher than right-sided pressures, the foramen ovale functionally closes (9). With the clamping of the umbilical cord and the cessation of blood flow, pressures in the portal sinus decrease. This causes the muscle in the sinus wall near the ductus venosus to contract (10). The lumen of the duct becomes filled with connective tissue, and, in two months, the ductus venosus becomes a fibrous strand embedded in the wall of the liver (11), thus establishing adult circulation.

If, for any reason, right-sided pressures remain high relative to those on the left side, fetal circulation will most likely persist through one or both of the fetal channels mentioned above. Therefore, PFC is defined as postnatal persistence of right to left ductal or atrial shunting, or both in the presence of elevated right ventricular pressure.

FACTORS AFFECTING PVR

Because a lower PVR generally promotes functional closure of the ductus and foramen ovale while a high PVR encourages PFC, it is useful to know which substances increase and which substances decrease PVR. Factors known to lower PVR include oxygen, nitric oxide, prostacyclin, prostaglandins E₂ and D₂, adenosin, magnesium, bradykinins, atrial natriuretic factor, alkalosis, histamine, acetylcholine, beta-adrenergic stimulation and potassium channel activation. Factors that increase PVR are hypoxia, acidosis, endothelin-1, leukotrienes, thromboxanes, platelet activating factors, prostaglandin F₂-alpha, alpha-adrenergic stimulation and calcium channel activation (12). Thus, it is important to recognize clinical conditions that affect PVR and to treat them appropriately.

EPIDEMIOLOGY AND COURSE

PFC was seen in one/1500 live births in the 1980s (13). It occurs more commonly in males, and appears to occur more frequently at higher altitudes (14). Most cases of PFC result in either complete recovery or death. Occasionally, there may be long term sequelae such as chronic lung disease (15), cerebral infarction (16) resulting in specific motor and/or cognitive deficits (17), and sensorineural hearing loss (18). An association with sudden infant death syndrome has also been suggested (19). The underlying cause determines the prognosis (20).

ETIOLOGY

PFC can be primary or secondary to other factors. The majority of cases are secondary to insults that cause hypoxia and ischemia in utero. In primary PFC, there is hypertrophy and increased muscularization of the walls of the pulmonary vessels. Thus, after birth, these vessels have a greater tendency to continue to stay constricted. As such, these vessels do not dilate as expected, resulting in high right-sided pressures. Cases in which vessels fail to dilate with time and treatment prove to be fatal. Diagnosis is usually made by autopsy (21).

Idiopathic PFC seemingly has no predisposing factors. Any number of problems or situations can result in idiopathic PFC, including hypoxia, acidosis, hypothermia, hypoglycemia, etc, and some of them may not have been documented. Investigative and interventive efforts in the future are most likely to make this subset of PFC occur in fewer patients (22).

Secondary PFC is most commonly seen in infants with lung diseases, the most common cause being meconium aspiration (23). The resulting hypoxia and acidosis cause pulmonary vasoconstriction and increased right-sided pressures. Other common causes are diaphragmatic hernia (24), hyaline membrane disease (25), sepsis syndrome (22) and pulmonary thromboembolism (26).

Several congenital heart defects can produce pulmonary hypertension in the newborn (27). Paediatric cardiologists are frequently consulted to differentiate between PFC, which implies a structurally normal heart, and a congenital heart defect, which is responsible for pulmonary hypertension. A discussion of pulmonary hypertension in the newborn secondary to a cardiac cause is beyond the scope of the present paper. Consequently, this paper only describes PFC in the neonate with a structurally normal heart.

PFC has also been noted in cases of sepsis syndromes caused by group B streptococcus (28), Listeria monocytogenes, Escherichia coli and Haemophilus influenzae type b (29). It is believed that the increased release of the pulmonary vasoconstrictor thromboxane is responsible for PFC.

Several perinatal factors trigger PFC. Because hypoxia and acidosis are known pulmonary vasoconstrictors, any condition that disrupts utero-placental circulation, such as placental abruption or placental insufficiency, causes ‘priming’ of fetal pulmonary vasculature, with hypertrophy and thickening of the muscular layer of pulmonary vessels. This priming makes the neonate more susceptible to PFC, and more sensitive to secondary triggers of PFC such as neonatal hypoxia and cold stress (30). Late clamping of the umbilical cord allows a larger placental transfusion, thereby, increasing the hematocrit. This rise in hematocrit may result in increased viscosity and sludging of pulmonary circulation, which in turn cause hypoxia and ventilation profusion mismatch, thereby increasing PVR and resulting in higher pressures on the right side relative to the left side (31). Maternal ingestion of cyclooxygenase inhibitors, such as acetylsalicylic acid, indomethacin, salicylates and naproxen, can induce constriction of the fetal arterial duct in utero (32). Arterial constriction leads to excessive pulmonary blood flow in the fetus and subsequent hypertrophy of the pulmonary vessels, resulting in pulmonary hypertension and severe PFC postnatally.

DIAGNOSIS

When the right arm and head remain pink, while the left arm and lower body are cyanotic, a clinical condition with differential cyanosis occurs. This condition is due to the difference in oxygen content in preductal and postductal blood, and is relatively specific for PFC. However, not all cases of PFC present with this picture.

Thus, the above condition lacks sensitivity (22). When pulmonary hypertension is present, closure of the pulmonic valve is more forceful, resulting in a loud second heart sound (P2). However, loud P2s are also heard in patients with aortic atresia, pulmonary atresia, transposition of the great vessels and truncus arteriosus, etc (22); thus, this sign lacks specificity.

A positive partial pressure of arterial oxygen (PaO₂) gradient greater than 15 mmHg between the right radial artery and the descending aorta blood suggests PFC, but it is not present in every case (33). The hyperoxia test involves the inhalation of 100% oxygen. Blood gases before and after inhalation are recorded. A change of less than 20 mmHg in PaO₂ can indicate either PFC or congenital cyanotic heart disease (34), particularly when these conditions cannot be corrected by improved ventilation, whereas a change in PaO₂ of 20 mmHg or greater implies a respiratory disorder. This blood gas test is not specific. Modified versions include the hyperoxia-continuous positive airway pressure test (applying 6 to 10 cmH₂O of continuous positive airway pressure) and the hyperoxiahyperventilation test (the infant is hyperventilated mechanically to achieve a partial pressure of carbon dioxide in the low 20s and a pH greater than 7.55). These tests are not very reliable. Furthermore, they are very aggressive, with the potential for permanent injury to the patient (35); as a result, they have been abandoned.

Electrocardiogram can be normal or abnormal and, thus, cannot distinguish PFC from congenital heart disease (22). At one time, cardiac catheterization and dye demonstration of the right to left shunt was the most conclusive diagnostic test. The hazards involved with this procedure have limited its use (34). Currently, echocardiography with a pulse Doppler probe has become the diagnostic test. It is a noninvasive method that can rule out the presence of congenital heart disease. It accurately determines both the pressure and velocity of blood flow in major vessels of fetuses and newborns, including the direction of blood flow through the ductus and the foramen ovale (36). A depth-gated pulse Doppler probe can estimate right to left shunts. It can also help to assess biventricular function and to provide an estimation of pulmonary artery pressures (37), thus making the diagnosis relatively easy in the absence of congenital heart disease.

MANAGEMENT

Upon the birth of any infant, reversible events, such as hypothermia, hypoxia, acidosis and hypoglycemia, should be sought, and corrected as quickly and as early as possible. Any obvious underlying cause of cardio-respiratory distress should be treated, and the infant should be watched carefully for signs of improvement and/or deterioration. The vital functions of such infants must be monitored continuously. Despite the measures mentioned above, if the fraction of inspired oxygen (FiO₂) rises, to maintain oxygen saturation above 95%, PFC should be a part of the differential diagnosis and a tertiary care centre should be notified.

Infants with PFC are very sensitive to their environment and tend to be extremely unstable. They are, in general, mechanically ventilated, sedated and often paralyzed with muscle relaxants. Therefore, procedures such as suctioning, changing endotracheal tubes, bathing and repositioning should be kept to a minimum. If cyanosis is present, congenital heart defects have to be ruled out before the cyanosis is attributed to PFC. Vital functions have to be monitored continuously. Stable infants with PFC and with initially acceptable oxygen saturations have been known to suddenly drop their saturations to very low levels when saturations drop below a critical level, usually below 95% (the flip-flop phenomenon). Therefore, it is important to recognize this crisis, and oxygen saturations should be kept above 95% until FiO₂ levels are in an acceptable range (below 50%). Aggressive treatment should be reserved only for patients who are unresponsive to conservative management, as described above (38).

Tolazaline is believed to cause the release of histamine (38), a pulmonary vasodilator, thereby, decreasing PVR. Complications with its use include systemic hypotension, gastrointestinal bleeding, increased gastrointestinal secretions and acute tubular necrosis (39,40). Because of myriad untoward effects, its use has been abandoned. Corticosteroids transiently improve lung function. They also help to increase systemic blood pressure over the pulmonary pressure, thereby creating a gradient that helps to increase pulmonary blood flow, thereby improving oxygenation.

Surfactant, besides its use in premature babies with hyaline membrane disease, is believed to improve lung function in term babies with congenital diaphragmatic hernia (41), meconium aspiration syndrome (42) and bacterial pneumonia (43). Thus, early treatment with surfactant prevents the development of PFC. Modified natural surfactants have demonstrated superior ability in improving oxygenation, decreasing mortality, and lowering the frequency of retinopathy and bronchopulmonary dysplasia in neonates (44,45) compared with artificial surfactants. The above abilities may be due to the retention of the hydrophobic surfactant-associated proteins. Early or prophylactic treatment of respiratory distress syndrome (RDS) with surfactant appears to be more effective than treatment once RDS has developed. This may be related to the avoidance of ventilator-induced lung injury and/or more uniform distribution of surfactant when it is given before lung injury occurs. Most protocols include doses, scheduled 6 to 12 h apart, beginning either in the delivery room or at the first clinical sign of respiratory distress (46). Direct bolus instillation of surfactant down the endotracheal tube has proved to have both decreased mortality and morbidity in neonatal RDS (47), whereas aerolized surfactants have proved to be ineffective (48). Adverse effects of surfactant therapy include changes in cerebral perfusion in premature infants (49) and transient airway obstruction from bolus administration. The latter can be avoided by slower administration of surfactant (50). Although surfactant therapy may not cure the underlying cause, it decreases mortality from acute lung injury (50) and PFC.

Controlled hyperventilation has been used to decrease PVR by making the blood more alkalotic (40). This method has to be employed with extreme caution because decreased partial pressure of carbon dioxide levels may result in cerebral ischemia (51) and susequent neurodevelopmental deficits. Other complications include pneumothorax, bronchopulmonary dysplasia and chronic lung disease (51); in some cases, an increased rate of hearing loss has also been noted (18). Another way to treat acidosis is to administer sodium bicarbonate and/or tromethamine. Adverse effects include fluid and sodium overload, especially in renally compromise infants (52).

Eicosanoids may be used as adjuncts in the management of PFC. Prostacyclin is a potent vasodilator that may have some specificity for pulmonary vasculature (53). Prostaglandin E₁ is a nonspecific pulmonary vasodilator. Prostaglandin D₂ is a vasodilator specific to pulmonary circulation (54).

The administration of cardiotonic drugs should be reserved for infants in whom myocardial dysfunction and/or persistent hypotension is documented. The ideal pressors would increase myocardial contractility and cardiac output without increasing oxygen consumption, thereby increasing systemic blood pressure above the pulmonary pressure and forcing blood flow to lungs and high risk organs such as the brain, liver, heart, kidneys and intestine. Dopamine at low doses combined with high doses of dobutamine is commonly used. At high doses, dopamine acts as an alpha-adrenergic stimulator, which increases PVR (55) and results in a negative outcome.

Several vasoactive substances are made endogenously. Endothelin type 1, made by vascular endothelium, is a pulmonary vasoconstrictor. The vascular endothelium produces an endothelium-derived relaxing factor, which was later identified as nitric oxide (12). Nitric oxide stimulates a guanylate cyclase, which in turn produces cyclic-guanosinemonophosphate. Cyclic-guanosinemonophosphate activates a protein kinase, which subsequently removes calcium ions from inside the cells, thereby causing the smooth muscle to relax (56).

Exogenous, inhaled nitric oxide at low doses causes potent, sustained and selective pulmonary vasodilation (57). High doses of nitric oxide improve oxygenation only for brief periods (58) and may cause side effects (59). The effects of nitric oxide may be suboptimal when lung volumes are decreased, as seen in patients with conditions such as pneumonia, atelectasis and pulmonary edema (60). Interactions of nitric oxide with high frequency oscillatory ventilation have been shown to be therapeutically successful (61). Other methods of alveolar recruitment, such as prone positioning and the use of surfactant, may also enhance the effects of nitric oxide. Nitric oxide has demonstrated effectiveness in infants with RDS while other vasodilators, such as nitroglycerin and sodium nitroprusside, have failed (62). One reason for the failure is that nitric oxide is inactivated after binding to hemoglobin and, thus, does not decrease systemic pressures. Another reason is that blood flow is redirected from poorly aerated regions to better aerated areas at low doses of nitric oxide, an event not seen in other modes of vasodilator therapy (63). The loss of this selective effect at high doses of nitric oxide is most likely due to the ability of nitric oxide to reach poorly ventilated lung regions, a response not seen at low doses. Potential toxicities of nitric oxide therapy include methemoglobinemia (12), exposure to nitrogen dioxide and the generation of peroxynitrite. Peroxynitrite can directly cause oxidation, peroxidation and nitration of critical proteins and enzyme systems, inhibit surfactant function, and induce cell apoptosis and lung inflammation (64). However, these effects have been noted at doses higher than those recommended for clinical use. Furthermore, numerous studies have demonstrated protective effects of nitric oxide, including decreased oxidant injury (65) and decreased neutrophil accumulation (66). Neurotoxicity, possibly resulting from DNA at high doses, strand breakage and inhibition of DNA repair systems, has been observed (12,67). However, nitric oxide - may also have tumoricidal effects (68). Other adverse effects of nitric oxide include dependency (69) and prolonged bleeding times (nitric oxide inhibits platelet adhesion (12,70). Nitric oxide is the treatment of choice for PFC and can be potentially life-saving. The dose varies from 1 to 80 ppm, and is introduced through the inhalation limb of the ventilator with a continuous nitric oxide monitor. The usual starting dose in infants is 20 ppm. This dose can be increased or decreased quickly every 15 to 30 min until a steady state dose is reached, which can be as low as 1 ppm or as high as 80 ppm.

Extracorporeal membrane oxygenator (ECMO) therapy is used in cases of severe PFC where all other modes of therapy have failed. It is a modified form of cardiopulmonary bypass and is used in situations such as congenital diaphragmatic hernia and meconium aspiration syndrome in which the lungs need a ‘rest’ for recovery. Venous blood from the right atrium is drained by a cannula, oxygenated by a membrane lung and returned to the patient through either the right common carotid artery (venoarterial [VA] ECMO) or through the femoral vein (venovenal [VV] ECMO). The membrane lung has two compartments, one with flowing blood and the other with flowing gas, that are separated by a silicon rubber membrane through which gas exchange occurs. Patients continue to be intubated and on ventilators, but at low pressure, rate and fraction of inspired oxygen settings. The purpose of this strategy is to prevent their lungs from collapsing (71).

Major disadvantages of VA ECMO include the requirement of artery ligation after ECMO and embolization of air, clots or debris returning from the ECMO circuit into the arterial circulation (72). As a result, it is less commonly used. Some centres repair arterial vessels during decannulation (73). The preferred route in many centres is VV ECMO because it limits the risk of embolization to the central nervous system (74). However, because the portion of cardiac output that is drained into the ECMO circuit is less with VV ECMO than that with VA ECMO, the arterial saturation in VV ECMO is usually lower. In most patients, arterial saturations of 80% to 85% are adequate to maintain tissue needs and are obtainable with VV ECMO. Patients who do not receive sufficient oxygen may require a switch to VA ECMO (75). A double-lumen single cannula also exists for use in VV ECMO. The advantage is that only a single surgical site is required. This technique avoids the risk of cerebral emboli seen in VA ECMO and reduces recirculation problems noted in VV ECMO (76). For ECMO therapy to be successful, it is imperative to avoid complications that may result in early discontinuation of ECMO before adequate lung function has been restored (77). Heparanization is required to prevent clotting of the ECMO circuit. To limit the risk of bleeding, the platelet count must be kept above 100,000/mm³. Low levels of platelets and/or fibrinogen may necessitate the administration of platelets, fresh frozen plasma, cryoprecipitate and blood transfusions (71,78). Positive end-expiratory pressure must be maintained to prevent atelectasis (79). Patients generally require parenteral nutrition; however, enteral feeding is encouraged to retain the integrity of the gut mucosa. If enteral feeding cannot be tolerated by the patient, supplementation of hyperalimentation with low levels of feeding can be an alternative (80).

Many patients are volume overloaded from treatment for hemodynamic instability before ECMO (81). Furthermore, the nonpulsatile flow of blood during ECMO may alter renal blood flow and result in increased levels of renin, aldosterone or antidiuretic hormone. Decreased atrial filling pressures in VA ECMO may give rise to increased amounts of atrial natriuretic factor. The combined effects of these events may result in fluid retention. Diuretics, low dose dopamine or hemofiltration can all be used to maintain fluid balance (82). Sedation and analgesia are required for infants on ECMO. Tolerance to medications often develops, necessitating higher doses. Alterations in drug clearance and volume of distibution during ECMO may require modification of standard dosing regimens (83). Only patients who have not responded to less stressful modes of therapy should receive ECMO because it is quite aggressive and can have serious complications. Complications include thromboembolism, air embolism, bleeding, stroke, seizures, systemic hypertension, atelectasis and hemolysis. A typical duration of ECMO is 3.5 days (71).

CONCLUSIONS

Even though PFC is seen less often than in previous years, it is a serious condition that requires early diagnosis and prompt treatment. Treatment can be gentle or aggressive, depending on the response. Hypothermia, hypoxia, acidosis and hypoglycemia should be corrected quickly and efficiently. Vital functions of infants must be monitored continuously, with particular attention given to maintain oxygen saturation above 95%. Underlying causes of PFC should be sought and treated. If there is no improvement, a tertiary care centre should be consulted. Supportive treatments, such as sedation, paralysis, mechanical ventilation and blood pressure support, should be introduced as necessary.

Administration of nitric oxide through the ventilator should be introduced as soon as the diagnosis of PVC is confirmed. ECMO is used as a last resort. With improving technology, early diagnosis and early treatment with nitric oxide, the use of ECMO has become very minimal. It would be wonderful to see PFC as a disease of the past.