Excess birth prevalence of hypoplastic left heart syndrome in Wisconsin (1997-1999)

Christine E. Cronk, ScD, associate professor, Pediatrics (Neonatology), Medical College of Wisconsin; Andrew N. Pelech, MD, pediatric cardiologist, Children's Hospital of Wisconsin, associate professor, Pediatrics (Cardiology) Medical College; Marsha E. Malloy, RN, BSN, MBA, Rheumatology, Children's Hospital; D. Gail McCarver, MD, neonatologist, Children's Hospital, associate professor, Pediatrics (Neonatology), Medical College.

Hypopolastic Left Heart Syndrome (HLHS) is a continuum of cardiac malformations involving an underdeveloped left heart-aorta complex and inability of the left heart to support circulation. It is thought to arise from intracardiac blood flow abnormalities during early development. Up to a quarter of cases have other associated extra-cardiac abnormalities and the risk is elevated when other family members have congenital heart disease (CHD).

Cardiologists at Children's Hospital of Wisconsin had the clinical impression they were treating an unusually large number of infants with HLHS. Clinical impression often is the first indicator of a problem, however, documenting an increased incidence of a rare disease sometimes is very difficult. We set out to discover whether this impression could be corroborated by a careful evaluation of available records.

Methods
We looked for cases in the electronic medical records database at Children's Hospital and in the Pediatric Cardiology Database (PCDB). The PCDB records demographic information, the child's diagnosis and treatment. Infants whose diagnosis was confirmed by echocardiogram, catheterization, surgery or autopsy were included in the final sample. Three years (1997-1999) worth of data were evaluated. To calculate a rate of HLHS (in this case, birth prevalence), both a numerator (the number of cases) and a denominator (the number of births) are necessary. The numerator must include all of the cases (and only those cases) born in a given area. Parts of Wisconsin are served by centers in Minnesota and Chicago, so we excluded these areas. To evaluate possible regional concentrations we divided the state into four areas. Number of births was drawn from Wisconsin Bureau of Health Information vital records data. 

In order to decide if a particular condition is occurring more often than expected, a population risk has to be determined. This is not straightforward. While infants with HLHS usually are known to a medical system, keeping track of all the cases in a state usually is done by a central authority (for example a state birth defects surveillance system). Through the authority of a newly revised statute, Wisconsin is in the process of implementing such a system, however, no reliable statewide information is available for the years we evaluated.

Therefore, we estimated the population risk using rates reported in the United States and international birth defect surveillance systems. This information is available through two organizations, the National Birth Defects Prevention Network and Eurocat (European Registry of Congenital Anomalies and Twins). Rates for all or some years 1995-1999 were used. Rates reported in recent literature studies of HLHS, such as the Baltimore Washington Infant Study, also were included. These rates were weighted for quality and size of the surveillance system or study. The 75th percentile value from the compiled, weighted rates was statistically compared to HLHS rates from our data.  

To evaluate whether HLHS rates were mirrored by other CHD, we completed an analysis of cases, such as transposition of the great arteries (TGA) and tetralogy of fallot (TOF), using the methodology described above.

Results
Twenty-five U.S. and 47 international surveillance systems along with 20 published studies were used to determine an expected rate. Birth cohort sizes from these sources ranged from 5,045 to 2.6 million, and the number of HLHS cases identified ranged from 0 to 281. Their rate estimates included three-quarters fetal deaths and about half pregnancy terminations.

The weighted median HLHS rate was about two per 10,000 births, with 75 percent less than 2.5 per 10,000. Iowa had the highest rate in the United States (3.9 per 10,000 births) and two German surveillance systems reported rates above four per 10,000. Each of these systems ascertained fetal deaths and pregnancy terminations.
We confirmed 61 cases of HLHS born in the target areas of Wisconsin. There were more males and whites among these cases. Half had cardiac defects in addition to HLHS (for example, secundum atrial septal defect, double outlet right ventricle and unbalanced atrioventricular canal). Five cases had extra-cardiac defects.
HLHS rates for Wisconsin (3.69), the east central region (3.9 per 10,000) and southeast region (4.2 per 10,000) significantly were greater than 2.5 per 10,000 (weighted 75th percentile for population risk). In comparison, Wisconsin rates for TGA (3.4 per 10,000) and TOF (2.96 per 10,000) were not different from the weighted median population risk (TGA was 3.44 per 10,000; TOF was 3.14 per 10,000).

Discussion
This study indicates that rates of HLHS are elevated in eastern Wisconsin. The overall rate of about 3.7 per 10,000 births significantly is higher than 75 percent of reported rates. In contrast, Wisconsin birth prevalence for TGA or TOF are not elevated compared to the estimated population risk.

HLHS cases are concentrated in the southeast and east central regions, the two most populous and industrialized areas in the state. The majority of counties in the southeastern region had rates above three per 10,000. Suburban counties immediately contiguous to Milwaukee had a combined rate of nearly six per 10,000.

Causes for this elevated birth prevalence of HLHS are difficult to document. Loffredo (Epidemiology of cardiovascular malformations: Prevalence and risk factors. Am J Med Genet (Semin Med Genet) 97(4):319-25) reported a three-fold increase in HLHS in offspring of women exposed to solvents. Risk was increased in solvent-exposed families with a history of CHD. Because HLHS appears to have a genetic component, HLHS likely is the product of genetic susceptibility and solvent or other toxicant exposure.

The rates reported are probably underestimates of the true prevalence of HLHS. Fetal deaths and terminations were not ascertained (though they were included in the numbers of many of the sources we used to estimate population risk). Also, parents of infants who elected palliative care rather than treatment at birth would not have arrived for care at Children's Hospital.

There are at least two other possible explanations for our findings. First, we may have found more cases than the comparison surveillance systems and studies because our methods were more rigorous. Second, termination rates in Wisconsin are lower than elsewhere in this country and in Europe (Elam-Evans LD, Strauss LT, Herndon J, Parker WY, Whitehead S, Berg CJ. 2002. Abortion surveillance – United States, 1999. MMWR Surveillance Summaries. 51(9):1-14.). If this also reflects terminations for HLHS, our live birth rates would be inflated relative to live birth rates observed in places where terminations are more common.

We feel these limitations do not fully account for our findings. Our case ascertainment procedures were rigorous and the inclusion of false positive cases unlikely. We evaluated HLHS rates available in the literature and in surveillance system reports and used upper percentile rather than median values to test whether our rates were significantly different from the population risk.

In conclusion, this study demonstrated an elevated risk for HLHS in the eastern portion of Wisconsin, with regional concentration of cases in the most populous and industrialized areas. Elevated risks for other cardiac diagnoses were not apparent. We believe an environmental cause, probably interacting with genetic susceptibility, is the best explanation for these findings. Wisconsin's elevated rate is comparable to several others reported by international and U.S. systems and there may be similar interacting environmental and genetic factors shared across these sites.

Gastric tonometry and sublingual capnography

Alexis Sullivan, RN, BSN, Pediatric Intensive Care Unit,
Children's Hospital of Wisconsin.

Gastric tonometry (GT) is a new trend in tissue oxygenation assessment. It has been used to detect regional hypoperfusion. It is useful for early detection of hypoperfusion as the gut is one of the first organs to see redistribution of blood flow. Recent trends combine global measurements of oxygen delivery (DO2) (cardiac output) with regional measurement to maximize identification of early changes in oxygen balance and enhance patient outcomes.

Patients compensate to threats in oxygen balance first by increasing cardiac output and then redistributing blood flow by recruiting underperfused capillary beds, and lastly by increasing oxygen extraction by the cells. Cardiac output assessment and oxygen extraction assessment strategies have been available, and now with gastric tonometry, regional perfusion assessment is available.

Optimizing the balance of DO2 and VO2 (oxygen consumption) and increasing DO2 early may reduce mortality, morbidity and length of stay according to some researchers. Gastric tonometry measures regional gastric PCO2 by using a special nasogastric tube with a silicone balloon inserted into the stomach. CO2 diffuses from the mucosal wall and equilibriates with a medium inside the balloon and then a sample is withdrawn and CO2 is measured. Saline previously has been used as the medium, however, now an automated air tonometry type is available that uses caprography, eliminating the need to draw gastric samples. Saline tonometry can have technical problems including variability in the determination of saline PCO2.

PaCO2 is influenced by ventilation influences, so the gap between PgCO2 and arterial PCO2 is thought to be a more sensitive sign of gastric/splanchnic hypoperfusion. As an early warning sign, a change in PgCO2 may be noted up to four hours before a change in a global parameter (ic SVO2, base deficit, or lactate) reported by Pestel and Uhlig (Critical Care Medicine 2001).

According to Johan, Marc and Juoen (Critical Care Medicine Dec. 1998), an empty stomach at least two hours after a meal with a gastric PH>5 should be the standard method for testing (whether in air or fluid medium) or by using the duodenum for feeding.

For patients undergoing cardiac pulmonary bypass (CPB), elevation of PgCO2 during surgery was related to CPB and postop increase in Pg CO2 correlated with postop morbidity according to Imai, et al (Critical Care Medicine 2002).

Sublingual capnography uses a measurement device with a disposable PCO2 sensor connected to a fiberoptic cable and a blood gas instrument with software. The optical fiber ends with a silicone membrane that contains a fluorscent dye sensitive to CO2 concentrations. Sublingual capnography is being compared to gastric tonometry to assess if it is suitable for monitoring tissue hypoperfusion. Marik reported a good correlation in 76 patients comparing the correlation between the two methods (Chest 201-September). 

Current research studies in subjects with congenital heart disease

Kathy Mussatto, RN, BSN, research coordinator,
Herma Heart Center, Children's Hospital of Wisconsin.

Following is a list of current IRB-approved protocols involving cardiac patients. Contact the principle investigator or Kathy Mussatto, research coordinator, with questions.

Wisconsin Pediatric Cardiac Registry: Genetic and environmental study of etiologies of congenital heart defects. Principal investigators: Andrew Pelech, MD; Kathleen Hanson-Morris, MS, RN.

Outcomes in subjects supported with extracorporeal membrane oxygenation (ECMO) for heart disease. Principal investigator: Robert Jaquiss, MD.

Use of droperidol during cardiac anesthesia and its effects on the QT interval – A retrospective chart review. Principal investigator: Eckehard Stuth, MD.

A retrospective review of the use of coumadin in postop fontan patients. Principal investigator: Michelle Steltzer, RN, BSN, PNP.

Exercise tolerance in children following repair of hypoplastic left heart syndrome. Principal investigators: Michael Danduran, MS; Raymond Fedderly, MD.

Non-invasive near infrared spectroscopic oximetry to assess regional perfusion during surgical procedures with increased risk of impairment of regional perfusion. Principal investigators: Richard Berens, MD, Stuth.

Perioperative cardiovascular status in single ventricle patients undergoing staged palliation. Principal investigators: Stuth, Berens.

Predictive value of virtual crossmatching. Principal investigator: Steven Zangwill, MD.

A randomized, double-blind, placebo-controlled, dose-ranging study of sildenafil in the treatment of children age 1-16 who require chronic therapy for PHT. Principal investigator: Stuart Berger, MD.

Closure of multi-fenestrated or large atrial septal defects with the Amplatzer® septal occluder. Principal investigator: Pelech.

Morbidity associated with total anomalous venous connection repair in infancy. Principal investigator:  Peter Frommelt, MD.

A comparative, evaluator-masked, randomized, parallel, multi-center study to determine the safety and effectiveness of REPEL-CV for reducing postoperative adhesions following pediatric cardiothoracic surgery. Principal investigator: Jaquiss.

A randomized, double-blind study of regional vs. intravenous analgesia to promote early andotracheal extubation in children undergoing single ventricle palliation. Principal investigators: Stuth and Berens.

An exploratory study of the cognitive, academic and behavioral functioning of pediatric cardiothoracic transplant recipients. Principal investigator: Cheryl Brosig, PhD.

Pediatric cardiomyopathy registry. Principal investigator: Berger.

Post-market surveillance plan for the Amplatzer septal occluder. Principal Investigator: Pelech.

Infants with congenital heart disease: Family contexts. Principal investigator: Karen Pridham, PhD, RN.

Methadone: Weaning for opioid tolerance in Pediatric Intensive Care Unit patients. Principal investigator: Berens.

A multi-center, placebo-controlled, eight-month study of the effect of twice-daily Carvedilol in children with congestive heart failure due to systemic ventricular systolic dysfunction. Principal investigator: Berger.

Development of a pediatric quality of life inventory.  Principal investigators: Kathleen Mussatto, RN, and Nancy Ghanayem, MD.

Bioelectrical impedance analysis of intracellular and extracellular fluid volume in children undergoing open heart surgery. Principal investigator: Jaquiss.  

A pilot study to evaluate neurodevelopmental outcome, quality of life and impact on the family in survivors of complex congenital heart disease. Principal investigators: Mussatto and Brosig.  

Chronic hypoxia and resistance to myocardial ischemia. Principal investigator: John Baker, MD, PhD.  

Use of parenteral Phenoxybenzamine in infants and children during surgery for congenital heart disease.  Principal investigator: S. Bert Litwin, MD.  

Health-related quality of life and family impact in patients with complex congenital heart disease.  Principal investigator: Mussatto.

Surveillance of infants with hypoplastic left heart syndrome between stages I and II palliation. Principal investigator: Ghanayem.  

Postoperative fontan management

Following is the advanced practice nursing collaborative pracitce protocol used at Children's Hospital of Wisconsin.

The following protocol was developed to provide a consistent management plan for single ventricle patients undergoing the fontan procedure from admission to discharge.

Etiology
In review of the literature, the etiology of persistent pleural chest tube drainage is thought to be multi-factorial and not all clearly understood. Patients with elevated central venous pressures greater than 10 mm Hg is thought to be a risk factor for postoperative persistent chest tube drainage. Often children with right atrium pressures of 17 mm Hg or greater have persistent drainage. Children thought to have reasonable right atrium pressures of 12 to 15 mm Hg also have complications of persistent chest tube drainage.

Another variable is thought to be renin and angiotensin II. R. Mainwaring (Journal of Cardiac Surgery, 10 (2), 11-8) recognized persistently increased renin and angiotensin II in patients with prolonged chest tube drainage compared with those patients without prolonged chest tube drainage. The use of angiotensin-converting enzyme (ACE) inhibitors have been used in patients following fontan.

In addition, many surgical techniques and approaches (fenestration, non-fenestration, intracardiac or extracardiac) to the completion fontan have been utilized in the last several years.

Incidence
Persistent pleural drainage frequently is the cause of morbidity and prolonged hospitalizations following the fontan procedure. In the literature, persistent chest tube drainage greater than seven days is reported in 25 percent of patients. Persistent chest tube drainage greater than eight days is reported in 24 percent of patients, and greater than 14 days in 36 percent of patients.

The following information must be obtained prior to initiation of the practice protocol:
     History
     A. The patient must be a single ventricle post fontan surgery (regardless of hypoplastic left heart syndrome, hypoplastic right heart syndrome, fenestrated, non-fenestrated, extracardiac or intracardiac).
     B. Medication and diet history.

     Physical assessment/labs
     A. The patient must be hemodynamically stable as determined by the attending cardiologist, cardiothoracic surgeon and intensivist (typically after the first 24 hours postop).
     B. Normal renal function as evidenced normal creatinine for age and sex.
     C. The fontan procedure results in edematous bowel. Bowel sounds are a fair assessment of healthy bowel.
     D. Presence of bowel sounds is not necessary prior to initiation of captopril.
     E. Presence of bowel sounds and tolerating PO solids necessary for aldactazide initiation.
     F. Patient weight.

Plan
A daily physical assessment to be performed by a pediatric nurse practitioner under supervision of the attending cardiologist.
     A. Afterload reduction:
          1. Start home captopril dose or appropriate dose for weight.
          2. Begin to titrate dose to maximum of 1 mg/kg/dose TID (given Q8H) in the Pediatric Intensive Care Unit (PICU). Patient is transitioned to TID dosing once transferred to the 4th floor (dosing closest to tab form, for example 6.25 mg, 12.5 mg, 18.75 mg, or 25 mg.
          3. Reevaluation of afterload management by CPNP/MD if HR is 20 percent (when quiet and not agitated) above baseline and SBP less than 80 mmHg.
     B. Aggressive diuresis:
          1. To begin 24 hours postop and after initial fluid resuscitation.
          2. Lasix 1 mg/kg/dose IV Q8 hours to be started in the PICU.
          3. Aldactazide (spironolactone and hydrochlorothiazide) titrate dose of 2 mg/kg/day divided BID when taking PO (12.5-25 mg dosing or half to one tab BID).
          4. Follow daily weights.
          5. Transition to lasix PO one to two days prior to discharge.
          6. Diuretics will be continued at discharge and weaned by the primary cardiologist on an outpatient basis.

Note: When ordering afterload reduction and diuretics for these patients, the order frequency should be specified as TID or BID regardless of whether the patient is in the PICU. As per PICU standard of care, these medications still will be given Q8 or Q12 hours. When the child is transitioned to the 4th floor, the child's medication schedule can be maintained to an appropriate home schedule and eliminate late evening and early morning medications.
     C. Fluid restriction and diet:
          1. Eighty percent maintenance until chest tube drainage stops.
          2. Fluid restriction discontinued the last 24 hours of hospitalization.
          3. CT output not to be replaced with albumin unless specifically discussed with cardiology, cardiothoracic surgery and intensive care team.
          4. PO diet initiated stable from respiratory standpoint advanced as tolerated slowly from clear liquids to solids.
          5. Low-fat diet (Children's Hospital restricts fat to 30 percent of kcals).
          6. PO foods high in potassium are encouraged.
     D. Labs:
          1. Serum lytes, BUN and creatinine as needed in the PICU, upon transfer from the PICU and the QOD once transferred to the 4th floor.
          2. Serum creatinine at discharge.
     E. Respiratory:
          1. Respiratory protocol begins upon return from the OR in the PICU and throughout the hospitalization.
          2. Oxygen as needed for oxygen saturations less than 85 percent and weaned to minimum of half liter nasal cannula for Pox greater than or equal to 85 percent.
          3. Oxygen maintained at the lowest possible flow settings (minimum of half liter) until all chest tubes are discontinued.
     F. CT Drainage: Assess drainage and quantity
          1. If total CT drainage 10cc/kg/day on postop day (POD) eight, then NPO.
          2. If CT drainage on POD seven and eight (25 percent drop in drainage), then can delay NPO until POD 10.
          3. Once NPO, TPN and IL initiated via PICC line.
          4. PICC line initiated by Central Access Team per their standard of practice. (The Central Access Team inspects bilateral upper extremities for adequate vessel and child's anxiety for PICC line placement in the treatment room or radiology if indicated.
     G. Documentation in the medical record begins at initiation of the protocol, but not limited to vital signs, chest tube drainage (cc/kg/day), chest tube drainage site integrity, medications, dose, tolerance of drug, clinical response to drug, PO intake, daily weights and lab results.
     H. Education to parents:
          1. Dietary teaching of low-fat and/or no-fat diet by dietitian utilizing Children's Hospital teaching sheets and available resources (for example food selection and home preparation).
          2. How, when and side effects of medication are done by the nursing staff and CPNP using teaching sheets and pharmacy daily home medication record.
          3. Family is educated on signs and symptoms of respiratory distress and when to call cardiology/cardiothoracic surgery (for example increased work of breathing, decreased activity tolerance, retractions, nasal flaring and cyanosis).

Follow-up
     A. Prior to discharge, availability of all medications to be verified with patient's local pharmacy.
     B. Follow-up appointment with referring cardiolgoist within one week of discharge for CXR and follow-up labs if indicated.
     C. Referral for home nursing visits initiated by cardiology nurse practitioner, pediatric cardiologist or primary care physician when indicated.