Extracorporeal Membrane Oxygenation

Reversible Cardiopulmonary Disorders

The underlying principle of ECMO relies on the premise that the patient has a reversible disease process that can be corrected with either therapy (including the possibility of organ transplantation) or rest. Prolonged exposure to high-pressure mechanical ventilation with high concentrations of oxygen can have a traumatic effect on the newborn’s lungs and frequently leads to the development of bronchopulmonary dysplasia (BPD). It has been suggested that BPD can result from high levels of ventilatory support for as little as 4 days or less. The pulmonary dysfunction that follows barotrauma and oxygen toxicity associated with mechanical ventilation typically requires weeks to months to resolve. Therefore, patients who have been ventilated for a long time and in whom lung injury has developed require multidisciplinary decision-making.

Echocardiography should be performed on every patient being considered for ECMO to determine cardiac anatomy and function. Treatable conditions such as total anomalous pulmonary venous return and transposition of the great vessels, which may masquerade initially as pulmonary failure, can be surgically corrected but may require ECMO resuscitation initially. Infants with correctable cardiac disease should be considered on an individual basis. Indications for ECMO support in infants with cardiac pathology are based on clinical signs such as hypotension despite the administration of inotropes or volume resuscitation, oliguria (urine output < 0.5 mL/kg/h), and decreased peripheral perfusion. Also, ECMO is an excellent bridge to cardiac and lung transplantation.

Clinical Measurement Systems

Because of the invasive nature of ECMO, and the potentially life-threatening complications, investigators have worked to develop an objective set of criteria to predict which infants will have an 80% mortality without ECMO. Three clinical measurement systems have been developed and tested to assist in identifying patients who will benefit from ECMO support.

• 1.

  Oxygenation Index (OI) = (MAP × Fi O ₂ × 100)/ Pa O ₂

• where MAP = mean airway pressure. This index has been evaluated and found that an OI >40 in 3–5 postductal gases is predictive of a mortality risk ≥80%. Currently, most centers begin considering application of ECMO with an OI of 25 to reduce the barotrauma associated with high pressure mechanical ventilation.

• 2.

  Postductal Alveolar-Arterial Oxygen Gradient [( A-a ) D O ₂ ]

• An ( A-a ) D O ₂ of 610 Torr or greater despite 8 hours of maximal medical therapy predicted a mortality of 79%.

• 3.

  Ventilation Index = (Respiratory Rate × Pa CO ₂ × Peak Inspiratory Pressure)/1000

• Rivera et al. found that a ventilation index >40 and OI >40 were associated with a 77% mortality risk. They also found that the combination of peak inspiratory pressure ≥40 cmH ₂ O and an ( A-a ) D O ₂ >580 mmHg was associated with a mortality of 81%.

These clinical measurement systems are useful to quantitate the degree of cardiopulmonary derangement and subsequently categorize patients into candidates for ECMO or continued maximal medical therapy. However, the decision to initiate ECMO is often a clinical decision based on clinical judgment and the patient’s individual response to maximal medical therapy. Patients are commonly started on ECMO when they have failed maximal medical support, significant barotrauma is imminent, and are believed to have good potential for survivable organ recovery.

Classic Contraindications And Possible Treatment Expansion

The classic contraindications to ECMO are listed below. As ECMO treatment evolves and technology advances, many of these traditional contraindications to ECMO are being challenged.

• 1.

  Estimated gestational age <34 weeks: The higher incidence of intracranial bleeding in premature infants has historically precluded the use of ECMO in neonates <34 weeks estimated gestational age (EGA). However, recent data indicate that ECMO can potentially be used in infants with an EGA as low as 29 weeks with acceptable survival and rates of intracranial hemorrhage (ICH). Ideally, the development of nonthrombogenic coating of circuit components would obviate the need for systemic heparinization and decrease the risk of using ECMO in premature infants.

• 2.

  Birth weight <2 kg: Technical considerations and limitation of cannula size restrict ECMO candidates to infants weighing at least 2 kg. The smallest single-lumen ECMO cannula is 8 French, and flow through a tube is proportional to the fourth power of the radius. Small veins permit only small cannulas, resulting in flow that will be reduced by a power of four. Neonates who weigh <2 kg present technical challenges in cannulation and in maintaining adequate blood flow through the small catheters. However, as with EGA, this weight cut-off has been challenged, as survival of up to 40% can be achieved at birth weights as low as 1.6 kg.

• 3.

  ICH greater than grade II: Patients with small intraventricular hemorrhages (grade I) or small intraparenchymal hemorrhage can be successfully treated on ECMO by maintaining a lower than optimal activated clotting time in the range of 180–200 seconds. These patients should be closely observed for extension of the intracranial bleeding. Patients posing a particularly high risk for ICH are those with a previous ICH, a cerebral infarct, prematurity, coagulopathy, ischemic central nervous system injury, or sepsis. Consideration of these patients for ECMO should be individualized.

• Neonates with ICH of higher grades are at increased risk of extension of their hemorrhage with systemic heparinization. This remains true today, but the development of technologies that obviate the need for heparinization may allow the use of ECMO in neonates with preexisting ICH in the future. In addition, our experience has suggested that ECMO can be applied when expected mortality is higher in neonates with grade II ICH. In that setting, lower levels of anticoagulation are cautiously applied.

• 4.

  Bleeding complications: Infants with ongoing, uncontrollable bleeding or an uncorrectable bleeding diathesis pose a relative contraindication to ECMO. Any coagulopathy should be corrected before initiating ECMO because the need for continuous systemic heparinization adds an unacceptable risk of bleeding.

• 5.

  Mechanical ventilation for longer than 7–10 days: Classically, mechanical ventilation has been associated with a higher incidence of BPD and irreversible fibroproliferative lung disease. The duration of pre-ECMO mechanical ventilation is being challenged, as data from the ELSO registry demonstrate survival of 50–60% after pre-ECMO mechanical ventilation of up to 14 days.

• 6.

  Cardiac arrest that requires cardiopulmonary resuscitation (CPR): Many centers now consider patients who experience pre-ECMO cardiac arrest candidates for support. Survival rates up to 60% have been demonstrated in neonates who experience cardiac arrest prior to or during cannulation. Predictably, good outcomes are associated with effective CPR during the resuscitation.

• 7.

  Conditions incompatible with meaningful life after therapy—profound neurologic impairment, congenital anomalies, or other conditions: Every effort should be made to establish a clear diagnosis before the initiation of ECMO. Infants with anomalies incompatible with life do not benefit from ECMO (i.e., trisomy 13 or 18). ECMO is not a resource that is intended to delay an inevitable death. Many lethal pulmonary conditions, such as overwhelming pulmonary hypoplasia, congenital alveolar proteinosis, and alveolar capillary dysplasia, may present as reversible conditions but are considered lethal. However, with improvement in medical and surgical care, conditions once thought to be nonsurvivable require constant reassessment.

Persistent Pulmonary Hypertension of the Newborn

Pulmonary vascular resistance (PVR) is the hallmark and driving force of fetal circulation. Normal fetal circulation is characterized by PVR that exceeds systemic pressures, resulting in higher right-sided heart pressures and, therefore, preferential right-to-left blood flow through fetal shunts. The fetal umbilical vein carries oxygenated blood from the placenta to the inferior vena cava (IVC) via the ductus venosus. Because of the high PVR, the major portion of the blood that reaches the right atrium (RA) from the IVC is directed to the left atrium through the foramen ovale. The superior vena cava delivers deoxygenated blood to the RA that is preferentially directed to the right ventricle and pulmonary artery. This blood then takes the path of least resistance and shunts from the main pulmonary artery directly to the descending aorta via the ductus arteriosus, bypassing the pulmonary vascular bed and the left side of the heart. The lungs are therefore almost completely bypassed during fetal circulation.

At birth, with the infant’s initial breath, the alveoli distend and begin to fill with air. This is paralleled by relaxation of the muscular arterioles of the pulmonary circulation and the expansion of the pulmonary vascular bed. These effects lead to a rapid drop in PVR to below systemic levels that causes the left atrial pressure to become higher than the RA pressure. The result is closure of the foramen ovale, and all venous blood flows from the RA to the right ventricle and into the pulmonary artery. The ductus arteriosus also begins to close at this time. Therefore, all fetal right-to-left circulation ceases, completing separation of the pulmonary and systemic circulations. Anatomic closure of these structures takes several days to weeks. Thus, maintaining systemic pressure greater than the pulmonary circulation is vital to sustaining normal circulation.

Failure of the transition from fetal circulation to newborn circulation is described as PPHN or persistent fetal circulation (PFC). Clinically, PPHN is characterized by hypoxemia out of proportion to pulmonary parenchymal or anatomic disease. In hypoxic fetuses and infants, the proliferation of smooth muscle in the arterioles may extend far beyond the terminal bronchioles, resulting in thickened and more reactive vessels. In response to hypoxia, these vessels undergo significant self-perpetuating vasoconstriction. Although sometimes idiopathic, PPHN can occur secondary to a number of disease processes such as MAS, CDH, polycythemia, and sepsis.

Treatment for PPHN is directed at decreasing right-to-left shunting and increasing pulmonary blood flow. Previously, most newborns were treated with hyperventilation, induction of alkalosis, neuromuscular blockade, and sedation. Unfortunately, these therapies did not reduce morbidity, mortality, or the need for ECMO. ECMO allows for the interruption of the vicious cycle of pulmonary vasoconstriction and hypoxia. By providing richly oxygenated blood, ECMO promotes relaxation of the vasoreactive pulmonary vascular bed, allowing the pulmonary blood pressure to return to subsystemic values without the iatrogenic complications encumbered by overly aggressive conventional therapy.

Data recommending permissive hypercapnia and spontaneous respirations as principles of treatment for these children have been reported. Hyperventilation and neuromuscular blockade are not part of the treatment strategy. This strategy has decreased morbidity, mortality, and the need for ECMO in several centers.

Congenital Diaphragmatic Hernia

Of particular interest to pediatric surgeons are neonates with CDH. These patients are plagued with pulmonary hypertension and have pulmonary hypoplasia of both lungs. Often, pulmonary insufficiency ensues with a vicious cycle of hypoxia, hypercarbia, and acidosis. This process must be interrupted by medical management, which has vastly improved over the past two decades with the use of permissive hypercapnia/spontaneous respiration, pharmacologic therapy, and delayed elective repair.

Various other strategies have been tried to manage critically ill newborns with CDH. High-frequency oscillation may have its major role in forestalling respiratory failure when used as a front-line strategy rather than as a “rescue therapy.” Surfactant plays no more than an anecdotal role. Nitric oxide is frequently used as a vasodilator in the treatment of pulmonary hypertension in these patients, though evidence backing this practice is lacking. Other pulmonary vasodilators such as epoprostenol, sildenafil, and iloprost are starting to demonstrate some efficacy in babies with CDH. The primary indicator for ECMO in the CDH infant occurs when tissue oxygen requirements are not being met, as evidenced by progressive metabolic acidosis, mixed venous oxygen desaturation, and multiple organ failure. The other major indicator is increasing iatrogenic pulmonary injury.

The goal is to maintain preductal oxygen saturations >85%. Spontaneous breathing is preserved by avoiding muscle relaxants. Sedation is used as needed. Meticulous attention to maintaining a clear airway is obvious but critical. Permissive hypercapnia with spontaneous respiration is initiated with intermittent mandatory ventilation (IMV), 30–40 breaths per minute, equal I/E time, inspiratory gas flow of 5–7 L/min, peak inspiratory pressure (PIP) of 20–22 cmH ₂ O, and positive end-expiratory pressure (PEEP) of 5 cmH ₂ O. The Fi O ₂ is selected to maintain preductal Sa O ₂ >85%. If this method of ventilation is not effective, as demonstrated by severe paradoxical chest movement, severe retractions, tachypnea, inadequate or labile oxygenation (preductal O ₂ saturations <85%), or Pa CO ₂ >60 mmHg, then a new mode of ventilation is needed.

High-frequency ventilation would be the next option. It is delivered by setting the ventilator to IMV mode with a rate of 100, inspiratory time of 0.3 second, an inspiratory gas flow of 10–12 L, a PIP of 20, and a PEEP of 0 (due to auto-PEEP). The PIP is adjusted as needed based on chest excursion, trying to maintain the PIP at <25 mmHg. If high-frequency ventilation at the aforementioned parameters is unable to improve the hypoxia and hypercarbia, high-frequency jet ventilation (HFJV) or high-frequency oscillatory ventilation (HFOV) can be instituted. HFJV provide smaller volumes (1–3 mL/kg) more often at a much higher rate (240–660 breaths per minute), and expiration is passive. Oxygenation is proportional to mean airway pressure, and ventilation is proportional to amplitude (PIP vs PEEP). Jet pulsations produce high-velocity laminar flow that has the ability to bypass airway disruptions. HFOV differs in that it delivers smaller tidal volumes (1–2 mL/kg) at an even faster rate (8–15 Hz). The lung is inflated to a static volume and then oscillated around the mean airway pressure.

Of all the indications for ECMO in neonates, CDH has the worst prognosis, with survival of 50%. Therefore, patient selection for ECMO in neonates with CDH is of particular importance. There are several prenatal markers that can help risk stratify CDH severity and predict the need for ECMO postnatally. The lung-to-head ratio (LHR) is measured by prenatal ultrasonography (US). It is defined as the product of the orthogonal diameters of the contralateral lung divided by the head circumference. Severe pulmonary hypoplasia is considered when the LHR is <1.0 with liver herniation. The LHR is operator dependent and can be obtained only in a narrow gestational window. Therefore, O/E (observed/expected) LHR was developed that is accurate at any gestational age. Many centers are also relying on fetal magnetic resonance imaging (MRI) to measure total lung volume to predict mortality in fetuses with CDH. The total lung volume can be compared with the predicted lung volume based on gestational age. This O/E total fetal lung volume (TFLV) has been reported as a better predictor of mortality and the subsequent need for ECMO.

Whether a baby should first demonstrate some evidence of adequate lung parenchyma remains controversial. Some physicians believe the best method to evaluate pulmonary hypoplasia and predict outcome is to evaluate the patient clinically. This is assessed by having a recorded best Pa CO ₂ <50 mmHg and a preductal oxygen saturation >90% for at least 1 hour at any time in the clinical course. With these criteria, successful ECMO should yield an overall survival rate of 75% or better. If patients with lethal anomalies, overwhelming pulmonary hypoplasia, or neurologic complications are not included, survival approaches 85%. At the other extreme, Kays et al. have demonstrated 55% survival in infants who had a best pCO ₂ >100 and pH <7.0 during the initial resuscitation. He therefore suggests offering ECMO to all patients regardless of physiologic parameters. At the University of Michigan, we choose an intermediate approach. Infants with potentially lethal pulmonary hypoplasia are identified prenatally based on an LHR <0.8 with liver herniation, and a fetal MRI with O/E TFLV of <25%. These infants are resuscitated, and if the baby cannot demonstrate a pH >7, pCO ₂ <100, preductal Sa O ₂ >80%, and Pa O ₂ >40 (least important, as it will likely be potductl) on ventilatory support utilizing a PIP <25 on CMV or MAP <20 on HFOV, with appropriate sedation and optimization of blood pressure over the first 2 hours of life, we would not proceed to ECMO, but would move to comfort care. If the baby meets these criteria at any point prior to 2 hours, we proceed directly to ECMO. It should be noted that the most severe CDH patients who are offered ECMO will likely have significant long-term morbidity if they survive.

The proper ECMO modality in infants with CDH is also debatable. Most centers use venoarterial (VA) ECMO in CDH patients. However, 10- and 15-year reviews of the ELSO database have concluded that mortality is no different between venovenous (VV) and VA ECMO. Renal complications and inotrope use were more common with VV, but neurologic complications were more common with VA. Cannula size is the main limitation to VV ECMO use in infants with CDH, but our institutional practice is to use VV ECMO whenever double-lumen internal jugular vein (IJV) cannulation is possible. However, the choice between VA and VV should largely be based on the comfort of the surgeon and institution with each modality.

Extracorporeal Cardiopulmonary Resuscitation

Studies demonstrate that 1–4% of pediatric intensive care unit (PICU) admissions suffer a cardiac arrest. Survival to discharge for a patient who has an arrest in the PICU ranges from 14–42%. The ELSO data demonstrate that approximately 73% of extracorporeal cardiopulmonary resuscitation (ECPR) has been used for patients with primary cardiac disease. Overall survival to discharge in this population has more recently been reported as high as 49%. The American Heart Association recommends ECPR for in-hospital cardiac arrest refractory to initial resuscitation, secondary to a process that is reversible or amenable to heart transplantation. Conventional CPR must have failed, no more than several minutes should have elapsed, and ECMO must be readily available. Future research needs to analyze long-term neurologic status among survivors and which patients will benefit the most with as little morbidity as possible.

Second Course of Ecmo

Approximately 3% of patients who are treated with ECMO will require a second course. Survival after a second course of ECMO appear lower than after a single course in neonates, but in pediatric patients, the survival rates are comparable to those associated with the first course. Negative prognostic indicators for second-course ECMO patients include patients with renal impairment, higher number of first-course complications, age >3 years old, or a prolonged second course.