Helen Holtby

Beneficial Effect of Oral Sildenafil Therapy on Childhood Pulmonary Arterial Hypertension Twelve-Month Clinical Trial of a Single-Drug, Open-Label, Pilot Study

Background—Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sildenafil is a type 5 phosphodiesterase inhibitor and pulmonary vasodilator. Therefore, we hypothesized that sildenafil would improve distance walked in 6 minutes and hemodynamics in children with PAH. Methods and Results—After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, we administered oral sildenafil at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3 to 18). Diagnoses were primary (n=4) and secondary (n=10) PAH. We repeated the 6-minute walk test at 6 weeks and at 3, 6, and 12 months (n=14) and cardiac catheterization (n=9) after a median follow-up of 10.8 months (range, 6 to 15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278±114 to 443±107 m over 6 months (P=0.02), and at 12 months, the distance walked was 432±156 m (P=0.005). A plateau was reached between 6 and 12 months (P=0.48). Mean pulmonary artery pressure decreased from a median of 60 mm Hg (range, 50 to 105) to 50 mm Hg (range, 38 to 84) mm Hg (P=0.014). Median pulmonary vascular resistance decreased from 15 Wood units m2 (range, 9 to 42) to 12 Wood Units m2 (range, 5 to 29) (P=0.024). Conclusions—Oral sildenafil has the potential to improve hemodynamics and exercise capacity for up to 12 months in children with PAH. Confirmation of these results in a randomized, controlled trial is essential.

Risk, Clinical Features, and Outcomes of Thrombosis Associated With Pediatric Cardiac Surgery

Background— Thrombosis, usually considered a serious but rare complication of pediatric cardiac surgery, has not been a major clinical and/or research focus in the past. Methods and Results— We noted 444 thrombi (66% occlusive, 60% symptomatic) in 171 of 1542 surgeries (11%). Factors associated with increased odds of thrombosis were age <31 days (odds ratio [OR], 2.0; P=0.002), baseline oxygen saturation <85% (OR, 2.0; P=0.001), previous thrombosis (OR, 2.6; P=0.001), heart transplantation (OR, 4.1; P<0.001), use of deep hypothermic circulatory arrest (OR, 1.9 P=0.01), longer cumulative time with central lines (OR, 1.2 per 5-day equivalent; P<0.001), and postoperative use of extracorporeal support (OR, 5.2; P<0.001). Serious complications of thrombosis occurred with 64 of 444 thrombi (14%) in 47 of 171 patients (28%), and were associated with thrombus location (intrathoracic, 45%; extrathoracic arterial, 19%; extrathoracic venous, 8%; P<0.001), symptomatic thrombi (OR, 8.0; P=0.02), and partially/fully occluding thrombi (OR, 14.3; P=0.001); indwelling access line in vessel (versus no access line) was associated with lower risk of serious complications (OR, 0.4; P=0.05). Thrombosis was associated with longer intensive care unit (+10.0 days; P<0.001) and hospital stay (+15.2 days; P<0.001); higher odds of cardiac arrest (OR, 4.9; P<0.001), catheter reintervention (OR, 3.3; P=0.002), and reoperation (OR, 2.5; P=0.003); and increased mortality (OR, 5.1; P<0.001). Long-term outcome assessment was possible for 316 thrombi in 129 patients. Of those, 197 (62%) had resolved at the last follow-up. Factors associated with increased odds of thrombus resolution were location (intrathoracic, 75%; extrathoracic arterial, 89%; extrathoracic venous, 60%; P<0.001), nonocclusive thrombi (OR, 2.2; P=0.01), older age at surgery (OR, 1.2 per year; P=0.04), higher white blood cell count (OR, 1.1/109 cells per 1 mL; P=0.002), and lower fibrinogen (OR, 1.4/g/L; P=0.02) after surgery. Conclusions— Thrombosis affects a high proportion of children undergoing cardiac surgery and is associated with suboptimal outcomes. Increased awareness and effective prevention and detection strategies are needed.

Decreased Exhaled Nitric Oxide May Be a Marker of Cardiopulmonary Bypass-Induced Injury

BACKGROUND Nitric oxide is an endothelium-derived vasodilator. Cardiopulmonary bypass may induce transient pulmonary endothelial dysfunction with decreased nitric oxide release that contributes to postoperative pulmonary hypertension and lung injury. Exhaled nitric oxide levels may reflect, in part, endogenous production from the pulmonary vascular endothelium. METHODS We measured exhaled nitric oxide levels before and 30 minutes after cardiopulmonary bypass in 30 children with acyanotic congenital heart disease and left-to-right intracardiac shunts undergoing repair. RESULTS Exhaled nitric oxide levels decreased by 27.6%+/-5.6% from 7+/-0.8 to 4.4+/-0.5 ppb (p < 0.05) 30 minutes after cardiopulmonary bypass despite a reduction in hemoglobin concentration. CONCLUSIONS The decrease in exhaled nitric oxide levels suggests reduced nitric oxide synthesis as a result of pulmonary vascular endothelial or lung epithelial injury. This may explain the efficacy of inhaled nitric oxide in the treatment of postoperative pulmonary hypertension. Furthermore, strategies aimed at minimizing endothelial dysfunction and augmenting nitric oxide production during cardiopulmonary bypass may decrease the incidence of postoperative pulmonary hypertension. Exhaled nitric oxide levels may be useful to monitor both cardiopulmonary bypass-induced endothelial injury and the effect of strategies aimed at minimizing such injury.

Prevention of Early Sudden Circulatory Collapse After the Norwood Operation

Background—After modifications in our perioperative management protocol, we have observed a decrease in sudden circulatory collapse after the Norwood operation. The current study examines early outcomes after the Norwood operation in our unit in an attempt to identify variables that may have altered the risk of unexpected circulatory collapse. Methods and Results—We studied 105 consecutive neonates who underwent a Norwood operation in our institution. Our treatment protocol has changed in the past 3 years to include the use of alpha-blockade with phenoxybenzamine (POB) for systemic afterload reduction and selective cerebral perfusion. Forty-eight infants had selective cerebral perfusion. Forty-two infants received POB. Sixty patients had hypoplastic left heart syndrome. There was no difference in age, diagnosis, number of neonates with weight <2.5 kg, aortic size diameter <2 mm, highest preoperative lactate level, and shunt size indexed to body weight among patients with or without use of POB. Twenty-five infants had circulatory collapse during the first 72 hours. Twelve of them could be explained by technical issues. Thirteen others who appeared clinically stable had early sudden circulatory collapse without an apparent cause. Sixteen out of 25 neonates died. Of those with technical problems, 8 out of 12 died. Based on the hazard function, 3 incremental risk factors for early circulatory collapse were technical issue at operation (P<0.001), longer cross-clamp time (P<0.007), and no use of POB (P<0.002). For a technically successful operation, freedom from circulatory collapse at 72 hours is 95% with the use of POB versus 69% without (P<0.002). Diagnosis, aortic size, atrioventricular valve function, birth weight, age at operation, and total circulatory arrest time and were not predictive of early sudden circulatory collapse. Conclusion—Recent changes in our treatment protocol have resulted in a decrease incidence of sudden circulatory collapse after the Norwood operation. Optimal surgical technique is the most important predictor of early survival. The use of aggressive afterload reduction with POB reduced the risk of early sudden arrest.

Early extubation after pediatric cardiac surgery: systematic review, meta-analysis, and evidence-based recommendations

Abstract  Objective: To derive evidence‐based recommendations regarding early extubation strategy after congenital cardiac surgery. Outcomes: Incidence of total mortality, morbidity, reintubation, length, and costs of intensive care unit and hospital stay. Evidence: Medline, Embase, and the Cochrane‐controlled trial register on the Cochrane library were searched from the earliest achievable date of each database to present. No language restrictions were applied. Retrieved reprints were evaluated according to a priori inclusion criteria, and those included were critically appraised using established internal validity criteria. Benefits and Harms: Early extubation (in the operating room or ≤6 hours after surgery) was associated with a lower early mortality. There was a trend toward lower ICU and hospital length of stays, lower hospital costs, and less respiratory morbidity. There was no difference in the rate of reintubation in those extubated early versus late. Conclusion: Early extubation appears safe and is associated with reduction in length of ICU and hospital stay without adverse effects on mortality or morbidity. However, studies to date are poor, heterogeneous, and not suitable to determine a causal effect. Therefore, there is need for a well‐designed randomized clinical trial to demonstrate the potential significant benefits of early extubation. (J Card Surg 2010;25:586‐595)

Reconstituted fresh whole blood improves clinical outcomes compared with stored component blood therapy for neonates undergoing cardiopulmonary bypass for cardiac surgery: A randomized controlled trial

Objective This study compared the effects of reconstituted fresh whole blood against standard blood component therapy in neonates undergoing cardiac surgery. Methods Patients less than 1 month of age were randomized to receive either reconstituted fresh whole blood (n = 31) or standard blood component therapy (n = 33) to prime the bypass circuit and for transfusion during the 24 hours after cardiopulmonary bypass. Primary outcome was chest tube drainage; secondary outcomes included transfusion needs, inotrope score, ventilation time, and hospital length of stay. Results Patients who received reconstituted fresh whole blood had significantly less postoperative chest tube volume loss per kilogram of body weight (7.7 mL/kg vs 11.8 mL/kg; P = .03). Standard blood component therapy was associated with higher inotropic score (6.6 vs 3.3; P = .002), longer ventilation times (164 hours vs 119 hours; P = .04), as well as longer hospital stays (18 days vs 12 days; P = .006) than patients receiving reconstituted fresh whole blood. Of the different factors associated with the use of reconstituted fresh whole blood, lower platelet counts at 10 minutes and at the end of cardiopulmonary bypass, older age of cells used in the prime and throughout bypass, and exposures to higher number of allogeneic donors were found to be independent predictors of poor clinical outcomes. Conclusions Reconstituted fresh whole blood used for the prime, throughout cardiopulmonary bypass, and for all transfusion requirements within the first 24 hours postoperatively results in reduced chest tube volume loss and improved clinical outcomes in neonatal patients undergoing cardiac surgery.

Energy expenditure and caloric and protein intake in infants following the Norwood procedure.

Objectives: Cardiopulmonary bypass in infants results in a hypermetabolic response. Energy requirements of these patients have not been well studied. We assessed energy expenditure and caloric and protein intake during the first 3 days following the Norwood procedure. Design: Clinical investigation. Setting: Children’s hospital. Patients: Seventeen infants (15 boys, age 4–92 days, median 7 days). Interventions: &OV0312;o2 and &OV0312;co2 were continuously measured using respiratory mass spectrometry in 17 infants for the first 72 hrs following the Norwood procedure. The respiratory quotient was determined as &OV0312;co2/&OV0312;o2. Energy expenditure was calculated using the modified Weir equation. Measurements were collected at 2- to 4-hr intervals. The mean values in the first 8 hrs, hours 8–32, hours 32–56, and the last 16 hrs were used as representative values for postoperative days 0, 1, 2, and 3. Total caloric and protein intakes were recorded for each day. Measurements and Main Results: Energy expenditure, &OV0312;o2, and &OV0312;co2 were initially high; declined rapidly during the first 8 hrs; and were maintained relatively stable in the following hours (p < .0001). Respiratory quotient showed a significant linear increase over the 72 hrs (p = .002). Energy expenditure on days 0, 1, 2, and 3 was 43 ± 11, 39 ± 8, 39 ± 8, and 41 ± 6 kcal/kg/day, respectively. Total caloric intake was 3 ± 1, 14 ± 5, 31 ± 16, and 51 ± 16 kcal/kg/day. Protein intake was 0, 0.2 ± 0.2, 0.6 ± 0.5, and 0.9 ± 0.5 g/kg/day on days 0, 1, 2, and 3, respectively. Conclusions: Infants exhibit a hypermetabolic response immediately following the Norwood procedure. Caloric and protein intake was inadequate to meet energy expenditure during the first 2 days after surgery. Further studies are warranted to examine the effects of caloric and protein supplementation on postoperative outcomes in infants after cardiopulmonary bypass.

Assessment of the relationship between cerebral and splanchnic oxygen saturations measured by near-infrared spectroscopy and direct measurements of systemic haemodynamic variables and oxygen transport after the Norwood procedure

Objectives: To evaluate the clinical utility of near-infrared spectroscopic (NIRS) monitoring of cerebral (Sco2) and splanchnic (Sso2) oxygen saturations for estimation of systemic oxygen transport after the Norwood procedure. Methods: Sco2 and Sso2 were measured with NIRS cerebral and thoracolumbar probes (in humans). Respiratory mass spectrometry was used to measure systemic oxygen consumption (V̇o2). Arterial (Sao2), superior vena caval (Svo2) and pulmonary venous oxygen saturations were measured at 2 to 4 h intervals to derive pulmonary (Qp) and systemic blood flow (Qs), systemic oxygen delivery (Do2) and oxygen extraction ratio (ERo2). Mixed linear regression was used to test correlations. A study of 7 pigs after cardiopulmonary bypass (study 1) was followed by a study of 11 children after the Norwood procedure (study 2). Results:Study 1. Sco2 moderately correlated with Svo2, mean arterial pressure, Qs, Do2 and ERo2 (slope 0.30, 0.64. 2.30, 0.017 and −32.5, p < 0.0001) but not with Sao2, arterial oxygen pressure (Pao2), haemoglobin and V̇o2. Study 2. Sco2 correlated well with Svo2, Sao2, Pao2 and mean arterial pressure (slope 0.43, 0.61, 0.99 and 0.52, p < 0.0001) but not with haemoglobin (slope 0.24, p > 0.05). Sco2 correlated weakly with V̇o2 (slope −0.07, p  =  0.05) and moderately with Qs, Do2 and ERo2 (slope 3.2, 0.03, −33.2, p < 0.0001). Sso2 showed similar but weaker correlations. Conclusions: Sco2 and Sso2 may reflect the influence of haemodynamic variables and oxygen transport after the Norwood procedure. However, the interpretation of NIRS data, in terms of both absolute values and trends, is difficult to rely on clinically.

Comparison of the Profiles of Postoperative Systemic Hemodynamics and Oxygen Transport in Neonates After the Hybrid or the Norwood Procedure A Pilot Study

Background— After the Norwood procedure, early postoperative neonatal physiology is characterized by hemodynamic instability and imbalance of oxygen transport that is commonly attributed to surgical myocardial injury and a systemic inflammatory response to cardiopulmonary bypass (CPB). Because the Hybrid procedure (arterial duct stenting and bilateral pulmonary artery banding) avoids CPB, cardioplegic arrest, and circulatory arrest, we hypothesized that the Hybrid procedure is associated with superior postoperative hemodynamics and oxygen transport. Methods and Results— Oxygen consumption (VO2) was continuously measured using respiratory mass spectrometry for 72 hours after Hybrid (n=6) and Norwood (n=13) procedures. Arterial, superior vena cava, and pulmonary venous blood gases and pressures were measured at 2- to 4-hour intervals to calculate systemic and pulmonary blood flows (Qs, Qp), and systemic vascular resistance (SVR), total pulmonary vascular resistance including pulmonary arterial band or B-T shunt (tPVR), cardiac output (CO), oxygen delivery (DO2), and oxygen extraction ratio (ERO2). Rate-pressure product was calculated as heart rate×systolic arterial pressure. When compared with the Norwood procedure, the early postoperative Hybrid patients had lower CO, higher SVR, and higher Qp:Qs ratios. In addition, the DO2 and VO2 were both lower in the Hybrids with higher ERO2 and lactate levels. This early postoperative pattern reversed after 48 hours. Conclusions— Although Hybrid procedure avoids CPB and cardioplegic arrest, the early hemodynamic profile is not superior to the Norwood in terms of cardiac output and control of pulmonary blood flow. These data strongly suggest that a “hands off” approach to postoperative care in Hybrid patients may not be appropriate in patients with preoperative diminished myocardial function; and in such patients a Norwood-derived management strategy (afterload reduction and inotropic support) should be considered.

Clinical Outcomes, Program Evolution, and Pulmonary Artery Growth in Single Ventricle Palliation Using Hybrid and Norwood Palliative Strategies

BACKGROUND Hybrid strategies for single ventricle palliation may differ from Norwood strategies in terms of anatomic and physiologic growth stimuli to the pulmonary arteries (PA), hemodynamics, resource utilization, and survival. Few studies have directly compared these strategies. METHODS In all, 58 patients underwent Norwood (Blalock-Taussig shunt; n = 39) or hybrid (n = 19) single ventricle palliation (2004 to 2007). Hemodynamics, PA morphology, hemodynamics, resource utilization, and survival were reviewed. RESULTS At pre-stage 2 evaluation, there were nonsignificant trends toward lower ventricular end-diastolic pressure, higher mixed venous saturation, and larger Nakata and lower lobe indices in the hybrids. Mean PA pressures were not different between groups. Four Norwood patients (10%) underwent transplantation before stage 2 palliation. Forty-two patients underwent stage 2 palliation (bidirectional cavopulmonary shunt or stage 2 hybrid (aortic arch reconstruction and bidirectional cavopulmonary shunt). Requirement for PA plasty, postoperative CVP, stage 2 survival, and 1-year survival were similar between groups. Combined (stage 1 plus stage 2) intubation time, intensive care unit time, and hospital length of stay was shorter for hybrids in comparison with Norwood survivors (p < 0.05). Comparison of resource utilization at the time of arch reconstruction (Norwood procedure or stage 2 hybrid), demonstrated a time-related trend toward improvement (weak negative correlation: intubation, rho = -0.386, p = 0.172; intensive care unit stay, rho = -0.487, p = 0.077; hospital stay, rho = -0.429, p = 0.126) in the hybrid group, but not in the Norwood group. CONCLUSIONS Hybrid palliation does not have a significant adverse impact on PA development, with comparable PA growth and hemodynamics. The demonstration of equivalent survival, diminished hospital utilization, and trends indicating ongoing refinement of the hybrid strategy warrants a prospective randomized trial.