Biventricular Pacing in Children With Congenital Heart Disease
Condition: Congenital Heart Disease (CHD)
MeSH terms: Heart Diseases; Heart Defects, Congenital
Study type: Interventional

Summary: 
      Surgery with cardiopulmonary bypass (CPB) for congenital heart disease (CHD) causes low
      cardiac index (CI). With the increasing success of surgery for CHD, mortality has decreased
      and emphasis has shifted to post-operative morbidity and recovery. Children with CHD
      undergoing surgery with CPB can experience well-characterized post-operative cardiac
      dysfunction. When severe, patients can develop clinically important low cardiac output
      syndrome (LCOS) and hemodynamic instability. Management of LCOS and hemodynamic compromise is
      primarily accomplished via intravenous durgs like milrinone, dopamine or dobutamine, which
      affect the strength of the heart's muscular contractions. These are used to maintain adequate
      blood pressure (BP) and CI. However, inotropic agents are potentially detrimental to
      myocardial function and may increase risk for post-operative arrhythmia and impair
      post-operative recovery by increasing oxygen demand and myocardial oxygen consumption (VO2).
      In combination with the increased VO2 associated with CPB-induced systemic inflammatory
      response patients can develop a critical mismatch between oxygen supply and demand,
      essentially the definition of LCOS. Therefore, therapies that improve CI and hemodynamic
      stability without increased VO2 are beneficial. This study will test whether BiVp, a
      specialized yet simple pacing technique, can improve post-operative CI and recovery in
      infants with electro-mechanical dyssynchrony (EMD) after CHD surgery. This study hypothesizes
      that Continuous BiVp increases the mean change in CI from baseline to 48 hours in infants
      with EMD following CHD surgery compared to standard care alone.
    

Detailed description: 
      Research Design: Pilot-study for a large prospective, randomized, single-blinded, clinical
      trial.

      This study is a parallel-arm, randomized, single-blinded clinical trial based on a
      hemodynamic outcome that will inform a subsequent larger randomized trial based on clinical
      outcomes.

      Main research question: Does continuous BiVp for up to 48 hours in infants with EMD after CHD
      surgery increase CI as measured every 1-3 hours by the Fick method using an AMIS2000 mass
      spectrometer for VO2 measurement? Primary Hypothesis: Continuous BiVp increases the mean
      change in CI from baseline to 48 hours in infants with EMD following CHD surgery compared to
      standard care alone.

      Primary objective: The primary objective of this pilot study is to provide physiologic proof
      of principle data by testing the hypothesis that continuous BiVp increases the mean change in
      CI from baseline to 48 hours in infants with EMD following CHD surgery. Although this is
      suggested by our preliminary data, the number of infants with wide QRS was small and
      statistically underpowered. The current study will expand the target population and provide
      preliminary data for sample size calculation and outcome measures for a subsequent, larger,
      clinical trial based on clinical outcomes such as duration of mechanical ventilation, length
      of ICU stay and vasoactive-inotropic score.

      Secondary Hypotheses:

        1. BiVp reduces the maximum vasoactive-inotropic score over the 1st 48 hours after CHD
           surgery in infants with EMD compared to standard therapy.

        2. BiVp improves end-organ perfusion: cerebral NIRS, serum lactate, kidney (time to
           negative fluid balance, creatinine clearance and neutrophil gelatinase-associated
           lipocalin (NGAL)), liver function (AST, ALT) and brain natiuretic peptide (BNP) in the
           1st 48 hours in infants with EMD after CHD surgery compared to standard therapy.

        3. BiVp reduces duration of mechanical ventilation in infants with EMD after CHD surgery.

      Study population Screening: Potentially eligible patients will be screened by the study
      coordinator, Ms Rita Nobile, using the cardiovascular surgical schedule at SickKids.
      Consecutive patients will be enrolled to maximize representation of the target population.
      All screened patients will be registered in a screening log according to the CONSORT
      statement.60 Inclusion criteria-infants must meet all inclusion criteria to be enrolled: 1.
      Post-operative QRS duration ≥ 98th centile for age based on Davignon.61 2. 0-1 year of age
      undergoing biventricular repair of CHD under CPB. Based on a recent population undergoing CHD
      surgery over a 1-year period at SickKids, wthe investigators expect the following types of
      CHD to be included (Table 2, p.23): tetralogy of Fallot (40%), transposition of the great
      arteries (30%), complete atrioventricular septal defect (15%), interrupted aortic arch (4%),
      other (10%).

      Exclusion criteria- Exclusion criteria will be assessed before and after surgery by the study
      coordinator and investigators. The presence of any criterion will exclude an infant from the
      study:

      1. Extubation in operating room or expected extubation <12 hours after surgery. 2.
      Functionally univentricular heart disease (lack of septation into 2 ventricles each
      supporting pulmonary or systemic circulations). 3. Major extra-cardiac anomalies (expected to
      affect mechanical ventilation, ICU stay, 30-day mortality, expected to require intervention
      within 30-days, lethal genetic abn.(e.g. trisomy 13/18)). 4. Surgery without CPB or
      palliative surgery (e.g systemic-pulmonary shunt). 5. Weight <2.5 kg at time of surgery. 6.
      ECMO (at time of the ICU admission), infants expected to die or require ECMO within 12 hours
      after operation (judged by surgeon or ICU responsible physician); brain death within 12 hours
      after surgery (declared by ICU responsible physician). 7. Previous cardiac operation on CPB.
      8. Junctional, atrial ectopic or ventricular tachycardia.

      If BiVp (time zero in controls) has started and an arrhythmia precluding BiVp (listed above)
      or ECMO occurs ≤ 8 hrs after surgery, the patient will be excluded; if >8 hrs -analysis will
      be 'intention-to-treat'.

      Study Groups: Following these inclusion/ exclusion criteria there will be 3 study groups:

        1. Intervention group: Consented infants with wide QRS randomized to BiVp.

        2. Control group 1: Consented infants with wide QRS randomized to the control group.

        3. Control group 2 (observation group): Consented infants with narrow QRS will enter
           control group 2 without randomization. All study outcome measurements will be performed
           on this group. Enrolment, informed consent, randomization and definition of time zero:
           Informed signed consent will be obtained by the PIs and research coordinator from the
           infant's legal guardians prior to surgery. At surgery all consented patients will
           receive 3 temporary epicardial pacing leads: standard right atrial and RV leads, LV
           apical lead. On return to the intensive care unit, QRS width will be manually evaluated
           from an unpaced 12-lead ECG by Dr Stephenson, Friedberg or Schwartz. Children with
           prolonged QRS (≥98 centile61 by the longest QRS duration from any lead) (expected in
           ~48% of infants (Fig. 2, p.18) will be randomized in a 1:1 pacing: control ratio by
           computer-generated allocation (www.random.org) to receive either standard of care plus
           BiVp or to standard of care alone. Consented patients with QRS duration <98 centile will
           be allocated to the narrow QRS control group (control group 2). For the BiVp group time
           zero is defined by the start of pacing. For controls, time zero is 1 hour after arrival
           in the ICU (expected time BiVp will start in the intervention group).
    

Intervention name(s): Biventricular Pacing (BiVp)
Intervention type(s): Device
Intervention description(s): BiVp shortens QRS duration and synchronizes ventricular contraction; thereby decreasing wall stress and increasing CI and BP. In contrast to inotropes, BiVp does not increase myocardial VO2. Resynchronizing myocardial contraction normalizes glucose metabolism, myocardial perfusion and distribution of proteins essential to myocardial contraction and relaxation such as calcium-handling phospholamban. Overall, BiVp improves pump function, increases CI, improves myocardial perfusion and reduces VO2, improving hemodynamics.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Congenital Heart Disease (CHD); Cardiopulmonary Bypass (CPB); Cardiac Index; Hemodynamics; Pediatrics