December 2011 Hypoplastic Left Heart Syndrome in in THIS ISSUE the Neonate by Srilatha Alapati, MD and P

NEONATOLOGY TODAY News and Information for BC/BE Neonatologists and Perinatologists

Volume 6 / Issue 12 December 2011 Hypoplastic Left Heart Syndrome in IN THIS ISSUE the Neonate By Srilatha Alapati, MD and P. Syamasundar other complex forms of congenital heart disease Hypoplastic Left Heart Syndrome Rao, MD in whom a two-ventricle repair is not possible. in the Neonate by Srilatha Alapati, MD and P. Syamasundar Rao, MD In this review, we will discuss anatomic, physiol- Page 1 Introduction ogic, and clinical features, noninvasive and invasive evaluation, management, and prognosis of A Brief History of Xenon and In the past, we discussed several general topics HLHS. Neuroprotection about Congenital Heart Disease (CHD) in the by Meredith Holmes, BA and Jerold F. neonate,1-5 but recently we began addressing Pathological Anatomy Lucey, MD, FAAP individual cardiac lesions such as transposition of Page 10 the great arteries6 and Tetralogy of Fallot.7 In this The left ventricle is usually a thick-walled, slit-like issue of Neonatology Today we will discuss Hy- cavity, especially when mitral atresia is present. DEPARTMENTS poplastic Left Heart Syndrome. Usually the aortic valve is severely stenosed or Medical Meeting Focus atretic and its annulus hypoplastic. Similarly, the Page 9 Hypoplastic Left Heart Syndrome mitral valve may be hypoplastic, severely stenotic or atretic. When the mitral valve is open, the left Medical News, Products and The term, Hypoplastic Left Heart Syndrome ventricular cavity is very small. Endocardial fi- Information (HLHS), initially proposed by Noonan and broelastosis is usually present. The ascending Page 11 Nadas,8 describes a diminutive left ventricle with aorta is hypoplastic; its diameter may be 2 to 3 underdevelopment of mitral and aortic valves. A mm or less. While it is very small, it is sufficient to NEONATOLOGY TODAY patent foramen ovale or an atrial septal defect is supply adequate coronary blood flow in a retro- Editorial and Subscription Offices usually present. The ventricular septum is usually grade fashion. The left atrium is also small, re- 16 Cove Rd, Ste. 200 intact. A large patent ductus arteriosus supplies flecting the limited blood flow in utero. The atrial Westerly, RI 02891 USA www.NeonatologyToday.net blood to the systemic circulation. Coarctation of septum is usually thickened; the foramen ovale the aorta is also commonly present. may be small and, occasionally, it may be closed. Neonatology Today (NT) is a monthly A patent ductus arteriosus is usually present and newsletter for Neonatologists and Peri- Hypoplastic Left Heart Syndrome is a uniformly is required for survival. natologists that provides timely news and information regarding the care of lethal cardiac abnormality unless it is surgically newborns and the diagnosis and treat- addressed. Since the description of surgical pal- A severely hypoplastic left ventricle may also be ment of premature and/or sick infants. liation by Norwood in the early 1980s9,10 and the present in hearts with double-outlet right ventricle report of allograft cardiac transplantation by Bai- with mitral atresia, unbalanced complete atrio- © 2011 by Neonatology Today ISSN: 11 1932-7129 (print); 1932-7137 (online). ley in the mid 1980s for treatment of HLHS, the ventricular canal and other complex heart de- Published monthly. All rights reserved. interest in this lesion has remarkably increased. fects; in some studies, these variants constitute The Norwood surgical approach consists of a as many as 25% of Hypoplastic Left Heart Syn- Statements or opinions expressed in Neo- series of three operations: Norwood procedure dromes patients.12 natology Today reflect the views of the authors and sponsors, and are not neces- (Stage I), hemi-Fontan or bidirectional Glenn sarily the views of Neonatology Today. procedure (Stage II), and Fontan conversion Pathophysiology (Stage III). Orthotopic heart transplantation provides an alternative therapy, with results similar to Prenatal Circulation Upcoming Medical Meetings those of the staged surgical palliation. Currently, (See website for additional meetings) the survival rate of infants treated with these sur- In utero, the oxygenated blood from the pla- NeoPREP: An Intensive Review gical approaches is similar to that of infants with centa is returned to the inferior vena cava, and Update of Neonatal- Perinatal Medicine Jan. 21-27, 2012; New Orleans, LA USA NEONATOLOGY TODAY eweb.aap.org/NeoPREP CALL FOR PAPERS, CASE STUDIES NEO: The Conference for AND RESEARCH RESULT Neonatology Feb. 23-26, 2012; Orlando, FL USA www.neoconference.com Do you have interesting research results, observations, human in- SR2.0: Speciallty Review in terest stories, Neontology and Perinatology 2.0 reports of meetings, etc. to share? Feb. 23-27, 2012; Orlando, FL USA www.specialityreview.com Submit your manuscript to: [email protected] Recruitment Ads: Pages 2 and 8 which instead of shunting across the patent saturation, systemic blood flow is decreased. was responsible for 25% of cardiac deaths in foramen ovale into the left atrium mixes with When the systemic blood flow decreases be- the neonatal period.15 There is a higher inci- the superior vena caval blood in the right low a critical level, the perfusion becomes poor, dence of HLHS in patients with Turner Syn- atrium. The pulmonary venous blood return- and metabolic acidosis and oliguria may de- drome, Noonan Syndrome, Smith-Lemli-Opitz ing into the left atrium is shunted across the velop. There is also decreased flow to the Syndrome, and Holt-Oram Syndrome than in atrial septum because of mitral valve obstruc- coronary arteries and brain, with a risk of myo- normal children. Certain chromosomal duplica- tion. This mixed right atrial blood then crosses cardial or cerebral ischemia respectively. Alter- tions, translocations, and deletions are also the tricuspid valve into the right ventricle and natively, if pulmonary vascular resistance is associated with HLHS. into the pulmonary artery.13 Complete admix- significantly higher than systemic vascular ture of all venous return (that from the pla- resistance, there will be hypoxemia. Gender centa as well as the fetus) results in blood flow with identical oxygen saturation to all parts of In summary, the postnatal circulation in HLHS The HLHS is more common in males than in the fetal heart. Because of widely patent duc- depends on three major factors: females, with a 55-70% male preponderance. tus arteriosus and high pulmonary vascular • Adequacy of inter-atrial communication resistance in the fetus, most of the blood is • Patency of the ductus arteriosus Age directed into the aorta via the ductus with only • Level of pulmonary vascular resistance a small portion of the blood from the main pul- Babies with HLHS typically present within the monary artery entering the branch pulmonary Epidemiology first 24-48 hours of life. Presentation occurs arteries and lungs. Once in the aorta, the blood as soon as the ductus arteriosus begins to gets distributed into the aortic arch, brachio- Prevalence constrict, thereby decreasing systemic blood cephalic vessels and ascending aorta on the flow, producing shock, and, without interven- one hand and descending aorta on the other. Recently reported prevalence of HLHS varies tion, causing death. Infants with pulmonary The quantitative distribution into these different between 0.21 and 0.28 per 1000 live births.14 It venous obstruction (absent or restrictive pat- vascular beds depends on their relative vascu- comprises 1.2-1.5% of all congenital heart ent foramen ovale) may present even sooner. lar resistances. The aortic arch and ascending defects.15 Hypoplastic Left Heart Syndrome Very rarely, an infant with persistence of high aortic blood flows in a reverse direction and accounts for 7-9% of all congenital heart dis- pulmonary vascular resistance and widely supplies the coronary arteries. ease diagnosed in the first year of life.14,15 Be- open ductus arteriosus may present later before surgical treatment was available, HLHS cause of balanced pulmonary and systemic Postnatal circulation circulations.

The newborn infant with HLHS has a complex Mortality/Morbidity cardiovascular physiology. Fully saturated pulmonary venous blood returning to the left Without surgery, HLHS is uniformly fatal usu- atrium cannot flow into the left ventricle be- ally within the first 2 weeks of life. As alluded to cause of atresia, hypoplasia, or stenosis of the above, survival for a longer period occurs mitral valve. Therefore, pulmonary venous rarely and is related to persistence of the duc- blood must cross the atrial septum (Figure 1). tus arteriosus along with balanced systemic This blood mixes with desaturated systemic and pulmonary circulations. venous blood in the right atrium and from there is transmitted into the right ventricle and the Following the Norwood procedure,16 overall pulmonary artery. The right ventricle then must success (survival to hospital discharge) is ap- pump this mixed blood to both the pulmonary proximately 75%. Success rates are higher and the systemic circulations that are con- (85%) in patients with no or a low number of nected in parallel, rather than in series, by the preoperative risk factors and lower (45%) in ductus arteriosus. Blood exiting the right ven- patients with important and/or multiple risk tricle may flow into the lungs via the branch Figure 1. Box diagram of Hypoplastic Left factors. The risk factors for poor result include pulmonary arteries or into the aorta via the Heart Syndrome. The pulmonary venous re- prematurity and major non-cardiac malforma- ductus arteriosus (Figure 1). The blood flow turn cannot exit into the left ventricle and its tions. Other identified risk factors include sur- into the aortic arch and ascending aorta is in a egress has to be into the right atrium via the gery in older infants, significant tricuspid regur- retrograde direction (Figure 1). patent foramen ovale (PFO). Because there is gitation, and pulmonary venous hypertension. no forward flow from the left heart into the hy- High Aristotle Scores are also associated with The relative flows to the pulmonary and sys- poplastic aorta, the systemic perfusion is de- poor prognosis. temic circuits depend on the relative resis- pendent upon the patent ductus arteriosus tances of the two vascular beds. Following (PDA). Retrograde flow into the brachio- Orthotopic heart transplantation results in early birth, pulmonary vascular resistance de- cephalic vessels and coronary arteries is also and long-term success similar to that of staged creases. This allows a higher percentage of shown. If the ductus constricts, the systemic reconstruction. Among low-risk patients who the right ventricular output to go to the lungs perfusion is compromised. If the foramen ovale undergo staged reconstruction or transplanta- instead of the body. Although increased pul- is obstructive the infant will develop signs of tion, actuarial survival at 5 years is approxi- monary blood flow results in higher oxygen pulmonary venous obstruction. mately 70%.

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NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 3 Most studies report neurodevelopmental dis- border, indicating tricuspid regurgitation and abilities in a significant number of patients who diastolic flow rumble over the precordium, indi- survive either staged surgical reconstruction or cating increased right ventricular diastolic filling cardiac transplantation. may be heard.

Clinical Features Non-invasive Evaluation

History Chest X-ray

In the current era, most HLHS cases are diag- The findings on chest X-ray are generally nosed prenatally with an abnormal four- non-diagnostic but reflect the degree of atrial chamber view in the screening obstetric ultra- level shunting. With restrictive atrial shunt there sound. Prenatal diagnosis of the disease al- will be evidence of pulmonary edema and with lows adequate time for parental counseling non-restrictive atrial level shunt there will be and as well as delivery planning at a tertiary cardiomegaly and an increase in pulmonary Figure 3. Electrocardiogram of an infant with care hospital, which also avoids transport- vascular markings (Figure 2). Hypoplastic Left Heart Syndrome showing right related morbidities. Following delivery, patient axis deviation and right atrial and right ventricular hypertrophy and decreased R waves in should be started on prostaglandin E1 (PGE1) to maintain ductal patency and should have an leads V6 and V7. echocardiogram to confirm the diagnosis of HLHS and to assess the adequacy of the atrial septum.

In neonates with no prenatal diagnosis of HLHS, the time of presentation depends on the degree of atrial level restriction, ductal patency and the level of pulmonary vascular resistance. Most neonates are born at term and initially appear normal. As the ductus arteriosus begins to close (normally over the first 24-48 hours of life), symptoms of cyanosis, tachypnea, respiratory distress, pallor, lethargy, metabolic acidosis, and oliguria develop. Without intervention to reopen the ductus arteriosus, death rapidly ensues. Similar symptomatology may be expected if a precipi- Figure 2. Chest roentgenogram in an infant Figure 4. Two-dimensional echocardiographic tous drop in pulmonary vascular resistance with Hypoplastic Left Heart Syndrome dem- occurs. apical 4-chamber view of the heart in a patient onstrating cardiomegaly and increased with Hypoplastic Left Heart Syndrome showing pulmonary vascular markings. Patients with restrictive atrial level shunting the hypoplastic left ventricle (LV), an enlarged (about 2-5%) can present with respiratory and hypertrophied right ventricle (RV) and en- symptoms and profound cyanosis because of larged right atrium (RA). LA, left atrium. obstruction to pulmonary venous return. Electrocardiogram

Physical Examination The electrocardiogram may not be diagnostic in neonates. Right axis deviation and right ven- Before the initiation of PGE1 infusion to rees- tricular hypertrophy are common, but not dis- tablish patency of the ductus arteriosus, infants tinctly different from the electrocardiogram of may exhibit signs of cardiogenic shock, includ- the normal neonate. Decreased left ventricular ing the following: hypothermia, tachycardia, forces are noted in the left precordial leads respiratory distress, central cyanosis and pal- (Figure 3). lor, poor peripheral perfusion with weak pulses in all extremities and in the neck and Echocardiogram hepatosplenomegaly. After reestablishment of systemic blood flow via the ductus arteriosus, Echocardiography is the test of choice for di- signs of shock resolve, leaving the stable agnosing HLHS. Two dimensional imaging infant with tachycardia, tachypnea, and mild readily shows the hypoplastic left ventricle (Figures 4 and 5) and aorta (Figure 6) and central cyanosis. If a coarctation of the aorta Figure 5. Two dimensional echocardiographic enlarged right atrium, right ventricle (Figure 4 is present, arterial pulses in the legs may be precordial short axis view of the heart in a pa- and 5) and main pulmonary artery. Evalua- more prominent than those in the arms, par- tient with Hypoplastic Left Heart Syndrome tion of the aortic arch and thoracic aorta for ticularly the right arm. demonstrating the hypoplastic left ventricle evidence of coarctation and interruption of (LV) and a large right ventricle (RV). Findings on physical examination include aortic arch is important. prominent right ventricular impulse, normal first heart sound and a loud single second Doppler and color flow Doppler are important transverse arch shows retrograde systolic heart sound. Usually no murmur is noted; in assessing the hemodynamics. High Dop- flow (Figure 8); this finding indicates ductal- however, a nonspecific, soft, systolic ejection pler velocity across the atrial septum indi- dependent systemic circulation and supports murmur at the left sternal border; high-pitched cates restrictive inter-atrial communication left ventricular inadequacy for biventricular holosystolic murmur at the lower left sternal (Figure 7). Doppler interrogation of the repair.

4 NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 cuspid regurgitation and also to assess the branch pulmonary artery anatomy (Figures 9 and 10), and to rule out recurrent aortic coarctation and aorto-pulmonary collateral vessels. If significant collateral vessels are found, they may be occluded with coils at the same time.

Cardiac catheterization is also a standard procedure before the Fontan conversion operation. Hemodynamic data to calculate pulmonary vascular resistance and trans pulmonary gradients are obtained to assess the suitability for next stage procedure. Angiograms are obtained in similar fashion to pre-Glenn catheteri- Figure 6. Two dimensional echocardiographic, Figure 8. Doppler interrogation of the trans- zation. The pulmonary artery angiograms are supra-sternal notch, long-axis view of the aortic verse arch shows retrograde systolic flow performed via superior vena cava (Figure 11). arch in a patient with Hypoplastic Left Heart (white arrow); this finding indicates ductal- Coil embolization of collateral vessels is usu- Syndrome. This still frame shows markedly dependent systemic circulation. ally done at this time. hypoplastic ascending aorta (AAO), serving only to deliver blood in a retrograde fashion to Catheter Interventions the coronary arteries. The descending aorta (DAO) is tortuous and the appearance is In the neonate, obstruction at the level of pat- suggestive of aortic coarctation. ent foramen ovale is relieved by blade/balloon atrial septostomy. In cases where the blade/ balloon atrial septostomy is not possible because of hypoplastic left atrium; static dilation of the atrial septum with a balloon angioplasty catheter can be done to relieve the obstruction.17, 19

In patients with hypoxemia due to clotted Blalock-Taussig (BT) shunts after Stage I palliation and if the patient is not ready for next stage procedure, balloon dilation or stent Figure 9. Selected cineangiographic frame in a placement in BT shunt can be done to improve left-axial oblique view of an infant with the oxygenation.20,21 Similar interventional pro- Hypoplastic Left Heart Syndrome following cedures may also become necessary in cases Norwood procedure with Blalock-Taussig (BT) with obstruction of Sano shunts. shunt demonstrating good-sized right (RPA) Figure 7. Subcostal views of the atrial septum and left (LPA) pulmonary arteries. Note mod- If there is recurrent aortic coarctation, balloon in a patient with Hypoplastic Left Heart Syn- erate narrowing of the proximal RPA. angioplasty may help relieve the obstruction drome demonstrating patent foramen ovale and may help achieve reduced right ventricular (blue arrow) in the left-hand panel and high newborn period; it may be performed in cases afterload.22 velocity turbulent flow (yellow arrow) across the with significantly restrictive inter-atrial commu- patent foramen ovale (PFO) in the right-hand nication. In these cases, transcatheter opening If significant branch pulmonary artery stenosis panel. LA, left atrium; RA, right atrium; SVC, of the atrial septum17,18 is undertaken to create or main pulmonary artery stenosis is noted be- superior vena cava. an atrial septal defect to relieve left atrial hyper- fore a bidirectional Glenn or Fontan conversion tension and pulmonary edema before the or after Fontan repair, pulmonary artery rehabili- tation is done either by balloon angioplasty or by Two-dimensional and Doppler echocardio- Stage I surgical procedure. placement of intravascular stents.23 graphic features are sufficiently characteristic of HLHS so that cardiac catheterization and Routine catheterization at age 6 months before the bidirectional Glenn or hemi-Fontan op- If aortopulmonary collaterals are noted, they can angiography are no longer necessary for be occluded in the catheterization lab by coil diagnosis of this anomaly. erations, is performed to obtain hemodynamic data and calculate pulmonary vascu- embolization.24

Cardiac Catheterization and Angiography lar resistance, to evaluate the size and pressures in the pulmonary arteries and to In patients with fenestrated Fontan, the fenes- assess the suitability of the patient for next tration can be closed by transcatheter As indicated above cardiac catheterization is methods.25,26 rarely necessary for diagnostic purposes in the stage procedure. Angiograms are obtained to assess the right ventricular function, tri-

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NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 5 ventional methods to open atrial septum, these may not be feasible because of hypoplastic left atrium. Static dilatation of the atrial septum17,19 with a balloon angioplasty catheter may be used which may not only relieve the obstruction, but also keep some restriction such that there is no rapid fall in the pulmonary vascular resistance. Rarely stent implantation17 may become necessary.

Infants should remain in room air with acceptable oxygen saturation (by pulse oximetry) in the low 70s. An exceptional circumstance is the infant with severe hypoxemia caused by pulmonary venous hypertension. Figure 10. Selected cineangiographic frame in Figure 11. Selected frame from superior vena a right-axial oblique view of an infant with caval (SVC) cineangiogram in an infant with Inotropic support is indicated only in severely ill Hypoplastic Left Heart Syndrome following hypoplastic left heart syndrome following neonates with concurrent sepsis or profound Norwood procedure with Sano (SANO) shunt Norwood procedure with subsequent bidirec- cardiogenic shock and acidosis. The administra- demonstrating right (RPA) and left (LPA) tional Glenn procedure demonstrating right tion of inotropes can adversely affect the bal- pulmonary arteries. (RPA) and left (LPA) pulmonary arteries and no ance between pulmonary and systemic vascular obstruction at the superior vena cava- resistance and should be weaned off as soon pulmonary artery junction. Management as the baby is stabilized. Diuretics can be used to manage pulmonary over circulation before A thorough explanation of different treatment severe, this results in systemic hypo-perfusion, surgery. approaches – supportive care, multistage surgi- metabolic acidosis and shock. cal palliation, cardiac transplantation, including It is important to recognize that the status of their advantages and disadvantages, should be After establishing ductal patency, maneuvers pulmonary vascular resistance can change provided to the parents. should be used to minimize systemic vascular rapidly, and calls for close monitoring of the resistance and maximize pulmonary vascular patients until Norwood procedure; interventions Preoperative Medical Care resistance. Importantly, maneuvers to increase several times a day may become necessary. PVR have been more efficacious. Intubation Successful preoperative management depends and mechanical ventilation with sedation and Surgical Care mainly on 3 factors: paralysis permits hypoventilation to elevate the • Providing adequate systemic flow. PaCO2, in the range of 45-50 mmHg. Metabolic The goal of surgical reconstruction of Hypoplas- • Limiting pulmonary over-circulation. acidosis should be corrected with sodium bicar- tic Left Heart Syndrome is to eventually sepa- • Providing adequate egress of pulmonary bonate. The hematocrit should be maintained rate the pulmonary and systemic circulations by venous return from the left atrium between 40–45% to provide adequate oxygen achieving a Fontan circulation. The right ventri- carrying capacity and to increase the blood vis- cle remains the systemic ventricle while blood In HLHS, the blood flow to systemic circulation cosity, the latter may also serve to elevate PVR. passively flows to the lungs. This ultimate re- (coronary arteries, brain, liver and kidneys) Supplemental oxygen to increase the oxygen construction is accomplished in the following 3 mainly depends on the patency of ductus arte- saturations should be avoided. stages: riosus. Treatment with PGE1 should be initiated immediately when HLHS is diagnosed or sus- Sub-ambient oxygen (FIO2 of 15-19%) with Norwood Procedure (Stage I). This procedure pected to establish ductal patency and ensure supplemental Nitrogen or Carbon Dioxide can is usually performed during the first week of life, adequate systemic perfusion. The patient's be used to elevate PVR; although this is an after the infant has been stabilized in the Neo- physiologic state often directs initial PGE1 dos- attractive concept, it should not be pursued for natal Intensive Care Unit. The goals of the pro- ing. For patients who present in shock with sus- long periods because severe pulmonary hyper- cedure are (1) to establish reliable systemic pected ductal closure or a restrictive duct, initial tension may complicate the postoperative circulation without the ductus arteriosus and (2) dose will range from 0.05 to 0.1 mcg/kg/minute. course. However, this does not seem to ad- to provide enough pulmonary blood flow for Once ductal patency is ensured, the infusion versely affect the pulmonary vasculature on adequate oxygenation, while simultaneously rate can be gradually decreased to an effective long-term follow-up.27 protecting the pulmonary vascular bed in prepa- dose of 0.02 mcg/kg/minute. Maintaining ductal ration for Stages II and III. patency with the lowest effective PGE1 dose to Because of obstruction at the mitral valve, pul- 9,10 minimize the dose-dependent side effects of monary venous blood must cross the atrial sep- The Norwood procedure includes (1) per- PGE1 such as hypotension, prompting volume tum via a PFO and mix with desaturated sys- forming an atrial septectomy to provide unre- resuscitation and respiratory depression, requir- temic venous blood in the right atrium. In some stricted blood flow across the atrial septum, (2) ing mechanical ventilatory support is the rec- patients the PFO may be restrictive. Mild restric- ligating the ductus arteriosus, (3) creating an ommended course of action. tion is acceptable and may be beneficial in that anastamosis between the main pulmonary it may maintain high pulmonary vascular resis- artery and the aorta to provide systemic blood The pulmonary vascular resistance of a new- tance and encourage good systemic flow. Se- flow, (4) eliminating coarctation of the aorta born is slightly less than the systemic vascular vere restriction may cause severe hypoxemia and (5) placing an aorta–to–pulmonary artery resistance and begins to fall soon after birth. In and pulmonary edema. Periodic monitoring by shunt (usually a modified Blalock-Taussig the patient with HLHS, decreased pulmonary echo-Doppler studies is recommended. When shunt) to provide pulmonary circulation. More vascular resistance (PVR) causes progressive severe restriction develops, transcatheter inter- recently, connecting a Gore-Tex graft from the increase in pulmonary blood flow with a con- ventions to enlarge the atrial septal defect may right ventricular outflow tract to the pulmonary comitant decrease in systemic blood flow. When be performed. While Rashkind’s balloon sep- artery (i.e., Sano operation) has been advocat- tostomy and Park blade septostomy are con- ed28,29 instead of conventional modified Blalock-Taussig shunt. The major theoretical

6 NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 advantage of this arrangement is the avoid- odic endomyocardial biopsy is performed for Summary and Conclusions ance of aorto-pulmonary runoff, which results more precise monitoring. in higher coronary and systemic perfusion Hypoplastic Left Heart Syndrome is a con- pressures and may potentially lessen the inci- Emerging Therapies stellation of left heart anomalies including dence of ventricular ischemia. Early studies of diminutive left ventricle with under devel- hemodynamics documented higher diastolic Hybrid Approach to Hypoplastic Left Heart opment of mitral and aortic valves and a coronary perfusion pressures.29,30 However, Syndrome: Bilateral banding of the branch small and hypoplastic aorta. A patent fora- studies comparing the two techniques among pulmonary arteries via median sternotomy and men ovale and a patent ductus arteriosus contemporary patient groups have identified no implanting stent in the ductus arteriosus is per- are usually present and are required for advantage of one technique over the other.31 formed initially.35 At the time of the second survival. Coarctation of the aorta may also stage, aortic arch reconstruction, atrial septec- be present. Pulmonary venous blood Follow-up. Upon hospital discharge, most tomy, and bidirectional Glenn shunt are per- crosses the atrial septum and mixes with infants remain on digoxin to augment cardiac formed. This is followed by Fontan conversion. systemic venous blood in the right atrium function, on diuretics to help manage right Although reduction of early mortality is theoreti- and from there is transmitted into the right ventricular volume overload, and on aspirin to cally feasible, larger experience with this ap- ventricle and the pulmonary artery. The prevent thrombosis of the shunt. If tricuspid proach than is currently available is necessary pulmonary and the systemic circulations are regurgitation is present, afterload reduction prior to general adaptation of this method of connected in parallel by the ductus arterio- with Ccaptopril10 should be used, Caution is management of all HLHS patients. sus and the blood exiting the right ventricle taken in patients receiving diuretic therapy to is distributed into the lungs via the branch avoid intravascular volume depletion that Prevention by Fetal Intervention: Fetal pulmonary arteries and into body via the might reduce total cardiac output as well as echocardiography studies have shown de- ductus arteriosus. HLHS comprises increase the risk of shunt thrombosis owing to velopment of HLHS in fetuses initially found 1.2-1.5% of all congenital heart defects and hyperviscosisty. Oxygen saturation is typically to have severe/critical aortic stenosis. Some is uniformly lethal unless it is promptly iden- 70-80% in room air. data suggest that fetal intervention to re- tified, treated with PGE1 and surgically pal- lieve aortic valve stenosis (by balloon aortic liated. Patients who are clinically-identified The incidence of inter-stage mortality is ap- valvuloplasty) may promote normal devel- HLHS either by prenatal ultrasound or by- proximately 5% to 15.32 The presence of a opment of the left ventricle.36 Further re- presention with symptoms as the ductus restrictive atrial communication, arch obstruc- search into this type of approach is needed. begins to close. The time of presentation tion, obstructed shunt flow, pulmonary artery depends on degree of atrial level obstruc- distortion, and atrio-ventricular valve insuffi- Catheter-assisted Fontan: Konert et al. tion, ductal patency and the level of pulmo- ciency have also been associated with inter- proposed a staged surgical-catheter ap- nary vascular resistance. The diagnosis can stage mortality.33 Commonly acquired child- proach;37 they performed a modified hemi- usually be made with echo-Doppler studies. hood gastrointestinal or respiratory diseases Fontan procedure, instead of bidirectional The initial management of HLHS is by that result in hypovolemia and/or acute hy- Glenn shunt that is later completed by tran- prompt infusion of PGE1 to keep the ductus poxemia have also been implicated as causes scatheter methodology. This reduces the open. Balancing the pulmonary and sys- for inter-stage death.33 After successful total number of operations required. temic circulation to maintain adequate sys- Stage 1 palliation, any of the above-mentioned temic perfusion and ensuring adequacy of pathologic processes can lead to increased Prognosis patent foramen ovale for easy egress of left metabolic demands and an unfavorable oxy- atrial blood while waiting for surgery are the gen supply/demand relationship, placing the The survival rate of infants treated with surgi- next tasks. Surgical management is either infant with minimal myocardial reserve at even cal approaches (multi-stage surgical correc- by multi-stage surgical procedures, consist- greater risk for mortality until progression to tion or cardiac transplant) is similar to that of ing of Norwood procedure (Stage I) in the cavopulmonary anastamosis. Therefore, transi- infants with other complex forms of congenital neonatal period, hemi-Fontan or bidirec- tioning infants to home after Stage 1 palliation heart disease in which a two-ventricle repair is tional Glenn procedure (Stage II) at about warrants ongoing vigilance well beyond the not possible. The major mortality is at the time six months of age, and Fontan conversion initial early postoperative period. of Norwood, Stage I. Overall survival at hospi- (Stage III) one year later or orthotopic heart tal discharge after the Norwood procedure is transplantation. Currently, the actuarial sur- Additional Surgery. Bidirectional Glenn pro- nearly 75%.38 Success rates are higher in vival rate of infants treated with these surgi- cedure (Stage II), usually performed approxi- uncomplicated cases and lower in cases in cal approaches is 70% at 5 years and is mately 6 months after the Norwood procedure which important preoperative risk factors are similar to that of infants with other complex and Fontan procedure (Stage III), performed present, such as: age greater than 1 month, forms of congenital heart disease in whom a approximately 12 months after the bidirec- significant preoperative tricuspid insufficiency, two-ventricle repair is not possible. tional Glenn procedure will not be discussed pulmonary venous hypertension, associated since the current paper is focusing on neo- major chromosomal or non-cardiac abnor- References nates. Interested readers are referred to dis- malities, prematurity and high Aristotle cussions presented elsewhere.34 Scores (>20).39 Survival after the bidirec- 1. Rao PS. Perinatal circulatory physiology: tional Glenn/hemi-Fontan and Fontan opera- It’s influence on clinical manifestations of Cardiac Transplantation. Heart transplanta- tions is nearly 90-95%. The actuarial survival neonatal heart disease – Part I. Neonatol- tion is another surgical option.11 The infant rate after staged reconstruction is 70% at 5 ogy Today 2008; 3(2):6-12. must remain on PGE1 infusion to keep the years. Neurodevelopmental prognosis is not 2. Rao PS. Perinatal circulatory physiology: ductus arteriosus patent while waiting for a known; however, abnormalities are reported. It’s influence on clinical manifestations of donor heart to become available. Approxi- Approximately 20% of infants listed for car- neonatal heart disease – Part II. Neonatol- mately 20% of infants listed for heart transplan- diac transplantation die while waiting for a ogy Today 2008; 3(3):1-10. tation die while waiting for a suitable donor donor heart. After successful transplantation, 3. Rao PS. An approach to the diagnosis of organ. After successful cardiac transplantation, the survival rate at 5 years is approximately cyanotic neonate for the primary care pro- infants require multiple medications for modu- 80%. When the preoperative mortality is vider. Neonatology Today 2007; 2 (6):1-7. lation of the immune system and prevention of considered, the overall survival rate after 4. Rao PS. Principles of management of the graft rejection and frequent outpatient surveil- cardiac transplantation is approximately neonate with congenital heart disease lance to identify rejection early and prevent 70%, or similar to the results for staged re- Neonatology Today 2007; 2(8):1-10. lasting damage to the transplanted heart. Peri- construction.

NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 7 5. Rao PS. Neonatal cardiac emergencies: Management strategies, Neonatology Today 2008; 3(12):1-5. 6. Rao PS. Transposition of the great arteries in the neonate. Neonatology Today 2010; 5(8):1-5. 7. Alapati S, Rao PS. Tetralogy of Fallot in the neonate. Neonatology Today 2011; 6(5):1-10. 8. Noonan JA, Nadas AS. The hypoplastic left heart syndrome. Pediat Clinics N Amer. Opportunities available in neonatology 1958;5:1029. 9. Norwood WI, Kirklin JK, Sanders SP. Hy- poplastic left heart syndrome: experience HCA, the largest healthcare company in the US, owns with palliative surgery. Am J Cardiol. Jan and/or manages over 160 hospitals in 20 states. Listed 1980;45:87-91. below are our current opportunities in Neonatology. 10. Norwood WI, Lang P, Hansen DD. Physi- Whether you are looking for your first position post fellow- ologic repair of aortic atresia-hypoplastic ship or somewhere to complete your career, chances are left heart syndrome. N Engl J Med. Jan 6 we have something (or will in the future) that will fit your 1983;308:23-6. needs. Call or email today for more information! 11. Bailey L, Concepcion W, Shattuck H, Huang L. Method of heart transplantation Trident Medical Center, Charleston, South Carolina for treatment of hypoplastic left heart syn- We are searching for an additional Neonatologist to join drome. J Thorac Cardiovasc Surg. Jul our Level II NICU. The candidate should be proficient in: 1986;92:1-5. UAC, UVC, peripheral venous and arterial access (includ- 12. Rao PS, Striepe V, Merrill WH. Hypoplastic ing PCCL placement), ET intubation, chest tubes, lumbar left heart syndrome. In: Kambam J (ed.). puncture, paracentesis and thoracentesis. The successful Cardiac Anesthesia for Infants and Chil- candidate will be BE/BC and licensable in the state of dren. St. Louis, MO: Mosby-Year Book,; South Carolina. Our health system has been serving the 1994:296-309 beautiful Charleston community for three decades, and 13. Rudolph AM. Congenital Diseases of the between our Trident and Summerville Medical Centers, Heart. Chicago: Year Book Medical; 1974. we deliver more babies than anywhere else in the city! 14. Botto LD, Correa A, Erickson JD: Racial Boasting a comfortable climate, great location, historical and temporal variations in the prevalence charm and a variety of resources, the Charleston area is of heart defects. Pediatr 2001; 107:1. one of the best places to live in the nation. 15. Fyler DC. Prevalence trends. In: Fyler DC, ed. Nadas' Pediatric Cardiology Hanley & Terre Haute Regional Hospital, Terre Haute, Indiana Belfus. Philadelphia: 1992 Neonatologist Needed To Expand NICU - Medical Direc- 16. Norwood WI Jr. Hypoplastic left heart syn- torship Opportunity! Currently we have a 3-bed Level II drome. Ann Thorac Surg. Sep NICU. We are seeking a Neonatologist to expand our 1991;52:688-95. services to a 9-12 bed Level III unit. We are initially seek- 17. Rao PS. Role of Interventional Cardiology ing one physician with plans to add additional in the future. In Neonates: Part I. Non-Surgical Atrial Pediatricians will provide back up support. We offer a Septostomy. Congenital Cardiol Today. competitive compensation and benefits package including 2007;5(12):1-12 paid malpractice, PTO, CME and more! 18. Park SC, Neches WH, Zuberbuhler JR, Lenox CC, Mathews RA, Fricker FJ. Clini- Sunrise Children’s Hospital, Las Vegas, Nevada cal use of blade atrial septostomy. Circula- Largest NICU in the state of Nevada (72 beds) seeks 2 more Neonatologists to join our group tion 1978;58:600-6. of 8. We handle 450 deliveries per month, 200 heart surgeries annually and 10,000 patient 19. Rao PS. Static balloon dilatation of the days per year. Sunrise also has the state’s only high risk OB unit and offers a full complement atrial septum. Am Heart J. of Pediatric Specialists, clinical trial research, device development and teaching opportunities. 1993;125:1826-8. We offer competitive salary, bonus and incentive program in a very busy practice. BC/BE in 20. Rao PS, Levy JM, Chopra PS. Balloon Neonatology and licensure or the ability to be licensed in Nevada are required. angioplasty of stenosed Blalock-Taussig anastomosis: role of balloon-on-a-wire in Please send a letter and current CV to: Kathy Kyer dilating occluded shunts. Am Heart J. Nov Pediatric Subspecialty Recruitment Manager 1990;120:1173-8. [email protected] 21. Tsounias E, Rao PS. Stent therapy for clotted Blalock–Taussig shunts. Congenital 937.235.5890 Cardiol Today. 2010;8(7)1-9.

SPECIALTY REVIEW - IN NEONATOLOGY AND PERINATOLOGY 2.0 SR2.0: February 23-27, 2012; Walt Disney World Dolphin Resort, Orlando, FL USA Continuous Quality Improvement Pre-Conference A comprehensive review of February 22, 2012; Walt Disney World Dolphin Resort, Orlando, FL USA neonatal-perinatal medicine www.specialtyreview.com

8 NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 22. Siblini G, Rao PS, Nouri S, Ferdman B, wood procedure: A study of 122 postmor- Jureidini SB, Wilson AD. Long-term follow- tem cases. Ann Thorac Surg JANUARY MEDICAL MEETING up results of balloon angioplasty of postop- 1997;64:1795–1802. FOCUS erative aortic recoarctation. Am J Cardiol 34. Rao PS, Turner DR, Forbes TJ. 1998;81:61-7. Hypoplastic Left Heart Syndrome. eMedi- NeoPREP®: An Intensive Review and 23. Rao PS, Balfour IC, Singh GK, Jureidini cine from WebMD. Updated September Update of Neonatal-Perinatal Medicine SB, Chen S. Bridge stents in the manage- 22, 2009. Available at: Jan. 21-27, 2011; New Orleans, LA USA ment of obstructive vascular lesions in chil- http://emedicine.medscape.com/article/890 http://eweb.aap.org/NeoPREP dren. Am J Cardiol 2001;88(:699-702. 196-overview 24. Siblini G, Rao PS. Coil Embolization in the 35. Galantowicz M, Cheatham JP. Lessons An intensive review of neonatal-perinatal management of cardiac problems in chil- learned from the development of a new medicine emphasizing the process of dren. J Invasive Cardiol. Sep hybrid strategy for the management of evidence-based clinical decision making and 1996;8(7):332-340. hypoplastic left heart syndrome. Pediatr focusing on the scientific basis for the clinical 25. Rao PS, Chandar JS, Sideris EB. Role of Cardiol 2005;26:190-9 practice of neonatology. It is also prepara- inverted buttoned device in transcatheter 36. Tworetzky W, Wilkins-Haug L, Jennings tory education program based on the content occlusion of atrial septal defect or patent RW, et al. Balloon dilation of severe aortic specifications outline developed by the foramen ovale with right-to-left shunting stenosis in the fetus: potential for prevention American Board of Pediatrics (ABP) for the associated with previously operated com- of hypoplastic left heart syndrome: candi- neonatal-perinatal subspecialty. plex congenital cardiac anomalies. Am J date selection, technique, and results of Cardiol 1997;80:914-21. successful intervention. Circulation The course emphasizes a learner-centered 26. Rao PS. Catheter-based device closure of 2004;110:2125-31. educational approach featuring: lectures, Fontan fenestration (Letter). Cathet Car- 37. Konertz W, Schneider M, Herwig V, interactive mini-lectures, Q&A sessions, diovasc Intervent 2001;52:407. Kampmann C, Waldenberger F, Hausdorf group case-based discussions, and mock 27. Day RW, Barton AJ, Pysher TJ, Shaddy G. Modified hemi-Fontan operation and review question sessions. A comprehensive RE. Pulmonary vascular resistance of chil- subsequent nonsurgical Fontan comple- syllabus will be provided to attendees. dren treated with nitrogen during early in- tion. J Thorac Cardiovasc Surg fancy. Ann Thorac Surg 1998;65:1400-4. 1995;110:865-7. Planning Committee: Camilia Martin, MD, 28. Sano S, Ishino K, Kawada M et al. Right 38. Bove EL. Current status of staged recon- FAAP, Chair; Eric Eichenwald, MD, FAAP, ventricle-to-pulmonary artery shunt in first- struction for hypoplastic left Co-Chair; Marilyn Escobedo, MD, FAAP; Jay stage palliation of hypoplastic left heart heart syndrome. Pediatr P. Goldsmith, MD, FAAP; Lu-Ann Papile, syndrome. J Thorac Cardiovasc Surg. Cardiol 1998;19:308-15. MD, FAAP; Brenda Poindexter, MD, FAAP; 2003;126:504-10 39. Sinzobahamvya N, Photiadis J, Kumpikaite Renate D. Savich, MD, FAAP; Michele 29. Sano S, Ishino K, Kado H, Shiokawa Y, D, et al: Comprehensive Aristotle score: Catherine Walsh, MD, FAAP. Sakamoto K, Yokota M. Outcome of right implications for the Norwood procedure. ventricle-to-pulmonary artery shunt in first- Ann Thorac Surg. 2006;81:1794-800. Topics Include: stage palliation of hypoplastic left heart • Analysis/Interpretation of Evidence syndrome: a multi-institutional study. Ann NT • Asphyxia & Resuscitation Thorac Surg. Dec 2004;78:1951-7; discus- • Fetal & Neonatal Development sion 1957-8. Corresponding Author • Bilirubin Metabolism 30. Pizarro C, Malec E, Maher KO, et al. Right • Cardiology, Dermatology, Endocrinology, ventricle to pulmonary artery conduit im- Nephrology, Neurology, Hematology, proves outcome after stage I Norwood for P. Syamasundar Rao, MD, Professor and Oncology, Pulmonology, Gastroenterology hypoplastic left heart syndrome. Circula- Emeritus Chief of Pediatric Cardiology & Nutrition tion. Sep 9 2003;108(10 Suppl Director, Pediatric Cardiology Fellowship • Fluid & Electrolyte Metabolism 1):II155-II160. Programs • Genetics & Dysmorphology 31. Ghanayem NS, Jaquiss RDB, Cava JR, et University of Texas-Houston Medical • Infection & Immunology al. Early postoperative hemodynamic com- School • Ethics parison of the right ventricle to pulmonary 6410 Fannin, UTPB Suite #425 • Pharmacology artery conduit and the innominate artery to Houston, TX 77030 USA • Pregnancy, Prenatal Care, Labor & Delivery pulmonary artery shunt for hypoplastic left Phone: 713-500-5738 • Perinatology heart syndrome: Results of a single institu- Fax: 713-500-5751 • Resuscitation tion randomized prospective study. Ann [email protected] • Surgical Emergencies Thorac Surg 2006;82:1603–9. 32. Tweddell JS, Hoffman GM, Mussatto KA, et Faculty includes over 40 well-known physi- Srilatha Alapati, MD al. Improved survival of patients undergoing cians in the field. See website for details. Interventional Pediatric Cardiology Fellow palliation of hypoplastic left heart syndrome: University of Texas-Houston Medical Lessons learned from 115 consecutive pa- Sponsored by the AAP Section on School tients. Circulation 2002;106:82–89. Perinatal Pediatrics and the American Children’s Memorial Hermann Hospital 33. Bartram U, Grunenfelder J, Van Praagh R. Academy of Pediatrics (AAP) Houston, TX USA Causes of death after the modified Nor-

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NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 9 A Brief History of Xenon and Neuroprotection

By Meredith Holmes, BA and Jerold F. Lucey, haemodynamic and neurohumoral effects cade resulting in neuronal death.9 10 Block- MD, FAAP with nitrous oxide. In a study of Lachmann ing the NMDA receptor and thereby excito- et al.7 forty patients were randomized to toxicity may, therefore, help to decrease receive either 70% nitrous oxide or 70% brain damage and dysfunctions in central Xenon and krypton were discovered by xenon in oxygen. While all the patients nervous system disorders. William Ramsay and his student Morris were paralyzed during surgery the xenon Travers in 1898.1 Ramsey was awarded the group had lower opiate requirements, less Possible neuroprotection by and therapeutic Nobel Prize in chemistry in 1904 for his tendency to desaturation following induction action of xenon was first addressed by Wil- work on a new family of elements, the inert and reported ‘nice feelings and pleasant helm et al.11 in a study which demonstrated or noble gases.1 Xenon is by far the least dreams.’ Boomsma et al.2 used an almost that xenon reduces neuronal degeneration abundant of all the noble gases in the at- identical anaesthetic protocol and found induced by intraperitoneal administration of mosphere, only a couple of milliliters are in less alteration of stress hormones during N-methyl-DL-aspartate (NMDLA) and pre- an average room.1 It is also very expensive; xenon anaesthesia than during nitrous ox- vents excitotoxic neuronal death in cultured to fill a small balloon with xenon would cur- ide anesthesia. Both studies concluded that neurons. Studies showed that xenon re- rently cost about 140 dollars.2 xenon was a slightly better anaesthetic duces cerebral infarct volume induced by agent. The cost of xenon was a major im- middle cerebral artery occlusion (MCAO), Medical interest in xenon first began be- pediment to its widespread acceptance as a as well as NMDA - induced Ca 2 + influxes cause of studies being done on the effect of replacement for nitrous oxide. in cortical cultured neurons, a major critical pressure on mentation, particularly in rela- event involved in excitotoxic neuronal tion to deep sea diving. Studies by Benke3 death.12 Other anesthetics with known observed the effects of air on mentation at NMDA receptor antagonist action like keta- 4 atm and noted that the effects were abol- mine and nitrous oxide exhibit neurorotec- ished by breathing 100% Oxygen gas. The “Medical interest in xenon tive properties, but xenon uniquely has not conclusion drawn was that the ‘narcotic’ first began because of shown any co-existing neurotoxicity.10 Xe- effects of air were due to the helium, nitro- non exerts its neuroprotective effect at sub gen and argon. Lawrence et al.4 postulated studies being done on the anesthetic concentrations. This is clinically that 80% krypton at atmospheric pressure effect of pressure on important because other anesthetics with should be as potent as air at 6 atm and xe- known neuroprotective properties need to non should be equivalent in anaesthestic mentation, particularly in be administered at far higher concentrations potency to air at 25 atm.4 The hypothesis to protect against ischemic brain injury in was tested on mice at atmospheric pressure relation to deep sea animal models.11 and found that in mice exposed to 60-80% diving.” xenon, rapid onset of Central Nervous Sys- Xenon attenuates on-going neuronal injury tem (CNS) effects, such as ataxia, convulsive on both in vitro and in vivo models of movements, and limb weakness was ob- hypoxic-ischaemic injury when administered served. The effects of the gas were seen during and after the insult.11 The neuropro- within two minutes and reversed within 15 The mechanism underlying the chemical tective efficacy of xenon could be observed minutes after the xenon was removed. The activity of xenon was first discovered in when administered before an insult, referred study found that krypton was significantly less 1998 by Franks et al.8 The study found that to as preconditioning.12 Xenon has been potent as an anaesthetic agent than xenon. although most general anaesthetics en- shown to enhance hypothermic neuropro- hance the activity of inhibitory GABA tection. Moderate therapeutic hypothermia Interested in finding the action of anesthet- (y-aminobutyric acid type-A) receptors, the reduces brain injury and decreases death ics, Cullen and Gross5 experimented with effect of xenon on these receptors was neg- and/ or disability with improved intact neu- inert gases on rats, rabbits, and mice and ligible. The group proposed and conclu- rology following experimental and clinical found the effects of xenon to be the most sively found evidence that xenon powerfully perinatal asphyxia. The frequency of death pronounced. In 1951 the same team re- inhibits the excitatory NMDA (N-methyl-D- and disability still remain high in cooled in- ported the first use of xenon for surgical asparate) receptor channels believed to be fants necessitating the development of addi- anesthesia in humans.5 The first patient the target of ketamine and nitrous oxide.8 tional neuroprotective therapies.13,14 Ex- was an 81-year-old male undergoing an This subtype of glutamate-activated iono- periments with rats and pigs showed the orchidectomy, the second patient was a 38 tropic channels is implicated in synaptic combination of xenon and hypothermia ad- year old female having a tubal ligation. The mechanisms underlying learning, memory, ministered 4 hours after hypoxic-ischemic authors concluded that xenon was capable and the perception of pain. injury provided synergistic neuroprotection of producing complete anesthesia. In 1953 in studies up to 30 days after the injury as Pittinger et al.6 used xenon as a primary Finding the mechanism for xenon as an did a study on cultured neurons injured by anaesthetic in five patients all undergoing anesthetic led directly to the finding of the oxygen-glucose deprivation.15 The mecha- the same surgery to determine the clinico- neuroprotective properties of xenon. Al- nism for the combination of both hypother- pathological effects of xenon. All patients though glutamate is essential for normal mia and xenon was proposed to be an anti- received at least one hour of 80% xenon. brain function, the presence of excessive apoptotic action.15 A study by Thoresen et There were no reported problems and they amounts of glutamate leads to cell death. al.16 combining hypothermia and 50% xe- were unable to detect any changes in the The term excitotoxicity denotes the process non as post hypoxic-ischemic therapy found patients’ blood or urine biochemistry. whereby activation of glutamate receptors, the rats’ functional improvement to last especially those of the NMDA subtype, long-term, and was accompanied by greater In 1990 two papers examined xenon’s leads to excess calcium entry into cells improved histopathology than either of the safety and efficiency and compared its which, in turn, triggers a biochemical cas- therapies alone. Thoresen’s studies have

10 NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 References neuroprotection from neonatal asphyxia. Ann Neurol 2005;58:182-193. “We are about to enter a 1. Kennedy RR, Stokes JW, Downing P. 16. Hobbs C, Thoresen M, Tucker A, et al. Anaesthesia and the ‘inert’ gases with Xenon and hypothermia combine addi- new era of brain cooling special reference to xenon. Anaesth tively, offering long-term functional and plus what? Neonatologist Intens Care 1992;20(1):66-70. histopathologic neuroprotection after 2. Boomsma F, Rupreht J, Man In’t Veld neonatal hypoxia/ischemia. Stroke will have many choices, AJ, De Jong FH, et al. Haemodynamic 2008;39:1307-1313. perhaps too many! The and neurohumoral effects of xenon 17. Thoresen M, 2011, Physiology and and anaesthesia. AAGBI 1990;273- neuroprotection of the newborn, average time required to 278. www.bristol.ac.uk/neuroscience/people 3. Benke AR. Respiratory resistence, oil- /person/14619 (March 2011). plan, organize, find a water solubility, and mental effects 18. Zanelli S, Buck M, Fairchild K. Pysiol- sponsor and get FDA of argon, compared with helium and ogic and pharmacologic considera- nitrogen. Am J Physiol tions for hypothermia therapy in neo- approval to carry out a 1939;126(2):409-415. nates. Journal Perinatology large randomized control 4. Lawrence JH, Loomis WF, Tobias CA, 2011;31:377-386. Turpin FH. Preliminary observations 19. First baby given xenon gas to prevent trial is over 10 years.” on the narcotic effect of xenon with a brain injury, BBC World News, review of values for solubilities of http://news.bbc.co.uk/2/hi/uk_news/en gases in water and oils. J Physiol gland/bristol/somerset/8611130.stm 1946;105:197-204. (March 2001). found that adding xenon inhalation to hy- 5. Cullen SC, Gross EG. The anesthetic 20. Thoresen M. Hypothermia and xenon. pothermia doubles neuroprotection in both properties of xenon in animals and Hot Topics in Neonatology 2010: 165- small and large newborn brain injury 17 human beings with additional observa- 175. Unpublished. models. These studies concluded that if tions on krypton. Science applied to humans, sub-anesthetic concen- 1951;113:580-582. NT trations of xenon in combination with mild 6. Pittinger CB, Moyers J, et al. Clinico- hypothermia could provide a safe and effec- pathologic studies associated with tive therapy for perinatal asphyxia. For an xenon anesthesia. Anesth organ system-based assessment of physi- 1953;14(1):10-17. Corresponding Author ologic changes associated with hypother- 7. Lachmann B, Armbruster S et al. mia, as well as the effects of hypothermia Safety and efficacy of xenon in routine on drug metabolism and clearance, see 18 use as an inhalational anaesthetic. Zanelli S et al. Lancet 1990;335(8073):1413-5. 8. Franks NP, Dickinson R, et al. How The first baby to receive xenon gas to pre- does xenon produce anaesthesia. Na- vent brain injury was Riley Joyce in April of ture 1998;396:324. 2010 as a part of Marianne Thoresen’s fea- 9. Ma D, Wilhelm S, Maze M, Franks NP. sibility study “CoolXenon” at the University of 19 Neuroprotective and neurotoxic prop- Bristol. By June 2010 nine infants were erties of the inert gas xenon. Br J An- treated with whole body hypothermia and 20 aesth 2002; 89:739-46. 50% xenon for up to 18 hours. Thoresen 10. Ma D, Hossain M, Rajakumaraswamy Meredith Holmes, BA believes that further work is needed in order N, et al. Combination of xenon and 303 Wellington Dr. to define an effective time window to start isoflurane produces a synergistic pro- Charlottesville VA 22903 USA xenon with hypothermia treatment. Xenon is tective effect against oxygen-glucose Tel: 434.989.6497 expensive and requires special ventilators. deprivation injury in a neuronal-glial There are limited data on the window of op- co-culture model. Anesth 2003; 99: [email protected] portunity for delayed treatment. Further clini- 748-51. cal trials are in progress in England. 11. Wilhelm S, Ma D, Maze M, Franks NP. Effects of xenon on in vitro and in vivo Comment models of neuronal injury. Anesthesi- ology 2002;96(6):1485-91. We are about to enter a new era of brain 12. Ma D, Hossain M, Pettet G, Luo Y, Lim cooling plus what? Neonatologist will have T, et al. Xenon preconditioning re- many choices, perhaps too many! The aver- duces brain damage from neonatal age time required to plan, organize, find a asphyxia in rats. J Cereb Blood Flow sponsor and get FDA approval to carry out a Metab 2006;26:199-208. large randomized control trial is over 10 13. David HN, Leveille F, Chazalviel L, years. MacKenzie ET, et al. Reduction of ischemic brain damage by nitrous ox- We should be very careful in selecting “what” ide and xenon. J Cereb Blood Flow should be added to cooling for future large Metab 2003;23:1168-1173. Jerold F. Lucey, MD, FAAP trials. Xenon would by my choice at this time. 14. Bona E, Hagberg H, Loberg EM, Ba- Editor Emeritus, Pediatrics The leaders in Xenon research are in Eng- genholm R, Thoresen M. Ped Re- Distinguished Professor of Pediatrics, land and Norway. They will soon be ready to search 1998;43(6):738-745. 2011-14 start organizing large trials. We should con- 15. Ma D, Hossain M, Chow A, Arshad M, University of Vermont sider joining them to carry out the large in- Battson R, Sanders R, et al. Xenon Burlington, VT 05401 USA ternational trials. and hypothermia combine to provide

NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 11 Medical News Products and Information

A Fetus Can Sense Mom's Psychological that way for the well-being of the infant. "A involved and printable scripts and supple- State more reasonable approach would be, to mental resources. The free training is pro- treat women who present with prenatal vided as a courtesy of the CARES Institute As a fetus grows, it's constantly getting depression. Sandman says. "We know how and its partners in the project, the Medical messages from its mother. It's not just to deal with depression." The problem is, University of South Carolina, Allegheny hearing her heartbeat and whatever music women are rarely screened for depression General Hospital and the National Child she might play to her belly; it also gets before birth. Traumatic Stress Network. chemical signals through the placenta. A new study, which will be published in Psy- In the long term, having a depressed “Although we originally developed TF-CBT chological Science, a journal of the Asso- mother could lead to neurological problems to help children recover from sexual abuse, ciation for Psychological Science, finds and psychiatric disorders, Sandman says. we learned it could be adapted to effectively that this includes signals about the In another study, his team found that older treat stress disorders caused by a range of mother's mental state. If the mother is de- children whose mothers were anxious dur- traumas,” Deblinger said. “We created TF- pressed, that affects how the baby devel- ing pregnancy, which often is co morbid with CBTWeb to make this evidenced-based ops after it's born. depression, have differences in certain program available on a scale that we brain structures. It will take studies lasting couldn’t possibly match through in-person In recent decades, researchers have found decades to figure out exactly what having a training. The website enables us to extend that the environment a fetus is growing up depressed mother means to a child's long- our help to children around the world who in—the mother's womb—is very important. term health. have endured traumas or tragic circum- Some effects are obvious. Smoking and stances.” drinking, for example, can be devastating. "We believe that the human fetus is an ac- But others are subtler; studies have found tive participant in its own development and TF-CBTWeb has most recently become that people who were born during the is collecting information for life after birth," part of the regular staff training for the Vic- Dutch famine of 1944, most of whom had Sandman says. "It's preparing for life based tim Support Unit of the Ministry of Justice starving mothers, were likely to have on messages the mom is providing." in Jamaica and is being used in similar health problems like obesity and diabetes fashion by agencies across the United later. States. Web-Based Training Helps Mental Health Curt A. Sandman, Elysia P. Davis, and Professionals Worldwide “Researchers in the Congo are using TF- Laura M. Glynn of the University of CBT to work with that nation’s former child California-Irvine study how the mother's Over the past six years, more than 100,000 soldiers,” Deblinger said. “There is also psychological state affects a developing mental health professionals – an average of ongoing NIMH-funded research in Zambia fetus. For this study, they recruited pregnant nearly 1,400 per month – have registered and an international TF-CBT group is form- women and checked them for depression for a free online training program that ing that will include researchers and clini- before and after they gave birth. They also teaches an innovative therapy to help chil- cians from the Netherlands, Norway, Swe- gave their babies tests after they were born dren recover from post-traumatic stress den, Germany and Japan.” to see how well they were developing. caused by abuse, violence or natural disas- ter. TF-CBTWeb (www.tfcbt.musc.edu) was The CARES Institute and its partners They found something interesting: what created by the Medical University of South have developed two other websites that mattered to the babies was if the environ- Carolina in collaboration with the CARES supplement the TF-CBTWeb training ment was consistent before and after birth. (Child Abuse Research, Education and program. TF-CBT Consult That is, the babies who did best were those Services) Institute at the UMDNJ-School of (http://etl2.library.musc.edu/tf-cbt-consult/in who either had mothers who were healthy Osteopathic Medicine. This web-based dex.php) provides a searchable resource both before and after birth, and those training allows mental health professionals that mental health professionals can ac- whose mothers were depressed before birth to self-direct their training in trauma-focused cess for questions about implementing TF- and stayed depressed afterward. What cognitive based therapy (TF-CBT), a treat- CBT in everyday practice situations. slowed the babies' development was chang- ment approach developed by Esther CTGWeb (http://ctg.musc.edu/) expands ing conditions—a mother who went from Deblinger, PhD, Co-Director of the CARES the core program to address the unique depressed before birth to healthy after or Institute, in collaboration with Drs. Judith concerns of children who experience trau- healthy before birth to depressed after. "We Cohen and Anthony Mannarino. matic grief. must admit, the strength of this finding sur- prised us," Sandman says. TF-CBTWeb training can usually be com- The CARES Institute provides an array of pleted in about 10 hours. The program in- medical and mental health services devel- Now, the cynical interpretation of our re- cludes specific step-by-step instructions for oped to meet the diagnostic and therapeu- sults would be that if a mother is de- each component of the therapy, streaming tic needs of children through an individual- pressed before birth, you should leave her video demonstrations of the procedures ized plan for the specific circumstances of

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12 NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 each child and family. The CARES Institute health care professionals, states a study cases, families received apologies for is a nationally recognized model of excel- published in CMAJ (Canadian Medical As- these incidents. lence in healing children and families who sociation Journal). have experienced abuse, neglect and vio- "The initiation of [the] family-based patient lence. Hospitals in Canada have instituted sys- safety reporting system provided new op- tems to encourage reporting of adverse portunities to learn and improve the safety The University of Medicine and Dentistry of events — things that may negatively affect of health care provision without an addi- New Jersey (UMDNJ) is the nation's largest the recovery or health of a patient — in tional reporting burden for health care pro- free-standing public health sciences univer- patient care. In pediatrics, it is estimated viders," write the authors. "Giving families sity with more than 6,000 students on five that 1% of children in hospitals experience the opportunity to report patient safety campuses attending the state's three median adverse event and 60% of these are events did not remove the barriers to re- cal schools, its only dental school, a gradu- preventable. However, there is lower reporting by providers (time pressure, culture ate school of biomedical sciences, a school porting of these events by health care pro- of blame, fear of reprisal and lack of belief of health related professions, a school of fessionals compared with those docu- in the value of reporting) but served to nursing and New Jersey’s only school of mented on charts. complement such reporting." public health. UMDNJ operates University Hospital, a Level I Trauma Center in New- Researchers from British Columbia con- The authors conclude that "further re- ark, and University Behavioral HealthCare, ducted a study to determine whether an search is needed to delineate how best to which provides a continuum of healthcare adverse event system involving families harness the potential of families to im- services with multiple locations throughout would result in a change in events report- prove the safety of the health care sys- the state. ing by health care providers. The re- tem." searchers expected that reporting rates would increase and that families would In a related commentary CDC’s New Congenital Heart Defect provide useful information on patient www.cmaj.ca/site/embargo/cmaj111311.pdf, Website safety. Drs. Charles Vincent and Rachel Davis, Imperial Centre for Patient Safety & Serv- The Center for Disease Control (CDC) has The study included 544 families whose ice Quality, Imperial College, London, UK, a new Congenital Heart Defects website children were on an inpatient ward that state that "paying close attention to pa- www.cdc.gov/ncbddd/heartdefects/index.html, provided general medical, general surgical, tients' and families' experience of care and that is research-based and user-friendly. neurologic or neurosurgical care in British their reports of safety issues may be the Columbia's Children's Hospital to babies, best early warning system we have for Some of the new features of the site in- children and adolescents. Each family detecting the point at which poor care de- clude: submitted a report and of these 544 par- teriorates into care that is clearly danger- • Easy-to-read information on prevention, ticipants, 201 (37%) noted at least one ous." risk factors, diagnosis, and living with a adverse event or near miss during hospi- congenital heart defect. talization, for a total of 321 adverse events. Imperial Centre of Patient Safety and Serv- • Information about specific congenital Adverse events included medication prob- ice Quality www.cpssq.org heart defects. lems such as a reaction or incorrect dos- • A compilation of important data and age, treatment complications, equipment scientific publications. problems and miscommunication. Most of Nearly Half of Physician Practices Do • An overview of the work CDC and its these events — 313 out of 321 — were not Not Meet National Standards for partners are doing in the area of reported by the hospital. "Medical Homes" congenital heart defects. However, "the results of this study showed Many Americans do not have access to a The site also includes free patient materials. that the introduction of a family-initiated "medical home"-a physician practice that is adverse event reporting system adminis- able to manage ongoing care for patients You may also follow CDC’s posting mes- tered at the time of discharge from a pe- and coordinate care among specialists and sages about congenital heart defects diatric inpatient surgical ward was not other health care facilities, according to a on CDC’s Facebook page associated with a change in the rate of University of Michigan Health System-led (www.facebook.com/#!/CDC) reporting of adverse events by health care study. providers," writes Dr. Jeremy Daniels, University of British Columbia, with co- The study revealed that nearly half (46%) Families Report Adverse Events in authors. of physician practices do not meet national Hospitalized Children Not Tracked by standards to qualify as a medical home. Health-care Providers Only 2.5% of the events noted by families were documented by health care providers, "Our study findings are particularly worri- Families of hospitalized children can pro- although "almost half of the adverse events some because the medical home model of vide valuable information about adverse reported by families represented valid care is seen as providing higher quality, events relating to their children's care that safety concerns, not merely reports of dis- more cost-efficient care" said John complements information documented by satisfaction," states the authors. In 139 Hollingsworth, MD, MS, the lead author

NEONATOLOGY TODAY ! www.NeonatologyToday.net ! December 2011 13 who conducted the study as a Robert Hollingsworth and his coauthors urge Wood Johnson Foundation Clinical policy-makers "to address the challenges NEONATOLOGY TODAY Scholar at the University of Michigan. facing smaller practices" in order to "make "Ideally, medical homes will help keep the benefits of medical homes more equi- © 2011 by Neonatology Today patients with chronic diseases from get- table and widely accessible." They sug- ISSN: 1932-7129 (print); 1932-7137 (online). ting lost in the shuffle of our complex, gest legislative incentives to help solo or Published monthly. All rights reserved. fragmented health care system, yet a small practices to affiliate with larger phy- growing number of patients do not have sician organizations, practice team-based Publishing Management access to them." care, and adopt health information tech- Tony Carlson, Founder & Senior Editor nology. They also recommend initiatives Richard Koulbanis, Publisher & Editor-in-Chief The study authors mapped physician that would enable regional centers to fa- John W. Moore, MD, MPH, Medical Editor practice data from the National Ambula- cilitate medical home reforms in less tory Medical Care Survey to the National populated areas. Editorial Board: Dilip R. Bhatt, MD; Barry D. Committee on Quality Assurance's stan- Chandler, MD; Anthony C. Chang, MD; K. K. dards for medical homes. They found that The study, "Adoption of Medical Home In- Diwakar, MD; Willa H. Drummond, MD, MS larger, multi-specialty groups have a frastructure Among Physician Practices: (Informatics); Philippe S. Friedlich, MD; Lucky greater potential for meeting medical Policy, Pitfalls, and Possibilities," was pub- Jain, MD; Patrick McNamara, MD; David A. home standards, but nine out of 10 Ameri- lished online on October 18 in the journal Munson, MD; Michael A. Posencheg, MD; cans receive health care from physicians Health Services Research. It is part of a DeWayne Pursley, MD, MPH; Joseph who practice in smaller, single-specialty special issue on "Bridging the Gap Be- Schulman, MD, MS; Alan R. Spitzer, MD; groups. tween Research and Health Policy" featur- Dharmapuri Vidysagar, MD; Leonard E. ing research articles from current and for- Weisman, MD; Stephen Welty, MD; Robert The 2010 Health Care Reform Law pro- mer Robert Wood Johnson Foundation White, MD; T.F. Yeh, MD vides incentives to build medical home Clinical Scholars that will be released in capacity with the goal of improving care print in February 2012. FREE Subscription - Qualified Professionals and controlling costs. Federal support for Neonatology Today is available free to qualified electronic health records and higher reim- Additional Authors: Sanjay Saint, MD, medical professionals worldwide in neonatology bursement rates for medical homes are MPH; Rodney A. Hayward, MD; of U-M and and perinatology. International editions avail- intended to gradually increase the number the VA Ann Arbor Healthcare System. able in electronic PDF file only; North American of medical homes. Yet, Hollingsworth says David C. Miller, MD, MPH.; Joseph W. edition available in print. Send an email to: that current market forces could push Sakshaug, MS; of U-M. Lingling Zhang, [email protected]. Include your name, ti- health care practices that do not have the MA; of Harvard Business School. tle(s), organization, address, phone, fax and infrastructure to be medical homes in the email. opposite direction and cautions that the For more than three decades, the Robert push toward medical homes could inad- Wood Johnson Foundation Clinical Schol- Manuscript Submissions vertently cause some practices to close ars® program has fostered the develop- Send your manuscript to: and further restrict access to care, espe- ment of physicians who are leading the [email protected] cially in rural areas. transformation of health care in the United States through positions in academic Sponsorships and Recruitment Advertising The researchers' findings also suggest that medicine, public health, and other leader- For information on sponsorships or recruitment health care disparities could be exacer- ship roles. Through the program, future advertising call Tony Carlson at 301.279.2005 bated because vulnerable populations, leaders learn to conduct innovative re- or send an email to [email protected] such as patients living below the poverty search and work with communities, or- level, often see doctors in practices that do ganizations, practitioners, and policy- 824 Elmcroft Blvd., Ste. M not meet standards for becoming a medical makers on issues important to the health Rockville, MD 20850 USA home. and well-being of all Americans. This pro- Tel: +1.301.279.2005; Fax: +1.240.465.0692 gram is supported in part through a col- www.NeonatologyToday.net "Patients from the poorest neighborhoods laboration with the US Department of Vet- visit practices that do not meet medical erans Affairs. For more information, visit home standards at higher rates than those http://rwjcsp.unc.edu. in the more affluent neighborhoods," says Hollingsworth, an assistant professor of urology at the U-M Medical School. "These NEONATOLOGY TODAY people are already economically disadvan- taged and, on top of that, they wouldn't CALL FOR PAPERS, CASE STUDIES AND RESEARCH RESULTS have access to the potentially higher quality of care offered by this delivery system Do you have interesting research results, observations, human interest stories, reform." reports of meetings, etc. to share? Submit your manuscript to: [email protected]

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