Antithrombin activity and heparin response in neonates and infants undergoing congenital cardiac surgery: a retrospective cohort study.

PURPOSE: The immature coagulation system during infancy has age-related physiological differences in proteins that contribute to significant variation in heparin responsiveness through alterations in heparin-enhanced thrombin inhibition. The primary aim of this study was to evaluate the relationship between preoperative antithrombin (AT) activity and heparin responsiveness in neonates and infants undergoing congenital cardiac surgery. METHODS: In this retrospective cohort study, neonates (aged 0-28 days) and infants (aged 29-365 days) undergoing congenital cardiac surgery in the 12-month period from October 2013 to 2014 were studied. The two age groups were compared for the primary endpoint of heparin response measured by the heparin sensitivity index (HSI), with heparin loading doses and heparin resistance being secondary endpoints. Multivariable linear regression analyses were used to explore the relationship between AT activity and heparin response measured by HSI. RESULTS: There were 122 infants and 19 neonates included in the study. After adjusting for low-molecular-weight heparin, unfractionated heparin, and platelet count, there was a significant relationship between AT activity and HSI (r = 0.44; P = 0.009). The median [interquartile range] HSI did not differ between neonates and infants (0.76 [0.69- 0.98] vs 0.89 [0.70-1.10] sec·unit(-1)·kg(-1), respectively; median difference, 0.08; 95% confidence interval [CI], -0.01 to 0.17; P = 0.182), despite the mean (standard deviation) AT activity differing between age groups [60 (16)% vs 84 (18)%, respectively; mean difference, 24; 95% CI, 15 to 32; P < 0.001]. CONCLUSIONS: There was a moderate relationship between AT activity and heparin response measured by HSI. Comparing neonates and infants, there was similar heparin responsiveness measured by HSI despite differing AT activity levels. These findings should help guide the perioperative administration of exogenous AT to neonates and infants and suggest that, outside the neonatal period, preoperative AT activity may be used to identify children at risk of decreased heparin responsiveness.

Challenges with heparin-based anticoagulation during cardiopulmonary bypass in children: Impact of low antithrombin activity.

BACKGROUND: Antithrombin is one of the main natural coagulation system inhibitors. It is potentiated by heparin, and may be a key component of heparin response, particularly in infants aged <1 year. We sought to determine the impact of baseline antithrombin activity on response to heparin and thrombin generation during cardiopulmonary bypass (CPB). METHODS: Secondary analysis was performed using linear regression analyses, which combined patients from a trial of individualized versus weight-based heparin management for 90 infants aged <1 year undergoing cardiac surgery. RESULTS: Mean baseline antithrombin activity was 0.69 ± 0.16 U/mL, and it was lower in neonates than in older infants (0.57 ± 0.15 vs 0.77 ± 0.12 U/mL; P < .001). Lower baseline antithrombin activity was associated with lower postheparin anti-Xa activity (EST [SE]: +0.47 (0.19) U/mL per 100 U/kg heparin; P = .01) and higher heparin doses during surgery (EST [SE]: +51 (17) U/kg per hour; P = .003). The administration of fresh frozen plasma attenuated the effect of low baseline antithrombin activity (interaction P value = .009). Patients with lower anti-Xa activity recorded during CPB had higher levels of thrombin-antithrombin complex (EST [SE]: +12.8 (4.7) ng/mL per -1 U/mL anti-Xa; P = .006); prothrombin activation fragment 1.2 (EST [SE]: +0.13 (0.07) log pg/mL per -1 U/mL anti-Xa; P = .06); and D-dimer (EST [SE]: -0.25 (0.09) log ng/mL per -1 U/mL anti-Xa; P = .009) in the postoperative period after adjustment for baseline antithrombin activity, duration of CPB, amount of fresh frozen plasma and heparin used throughout surgery in multivariable models. CONCLUSIONS: Low circulating antithrombin activity is associated with lower heparin efficacy, which ultimately leads to a lower ability to suppress thrombin generation during CPB. Determination of risk factors for heparin resistance, and potentially, antithrombin replacement therapy, may individualize and improve anticoagulation treatment.

Remote ischemic preconditioning in children undergoing cardiac surgery with cardiopulmonary bypass: a single-center double-blinded randomized trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) harnesses an innate defensive mechanism that protects against inflammatory activation and ischemia-reperfusion injury, known sequelae of cardiac surgery with cardiopulmonary bypass. We sought to determine the impact of RIPC on clinical outcomes and physiological markers related to ischemia-reperfusion injury and inflammatory activation after cardiac surgery in children. METHODS AND RESULTS: Overall, 299 children (aged neonate to 17 years) were randomized to receive an RIPC stimulus (inflation of a blood pressure cuff on the left thigh to 15 mm Hg above systolic for four 5-minute intervals) versus a blinded sham stimulus during induction with a standardized anesthesia protocol. Primary outcome was duration of postoperative hospital stay, with serial clinical and laboratory measurements for the first 48 postoperative hours and clinical follow-up to discharge. There were no significant baseline differences between RIPC (n=148) and sham (n=151). There were no in-hospital deaths. No significant difference in length of postoperative hospital stay was noted (sham 5.4 versus RIPC 5.6 days; difference +0.2; adjusted P=0.91), with the 95% confidence interval (-0.7 to +0.9) excluding a prespecified minimal clinically significant differences of 1 or 1.5 days. There were few significant differences in other clinical outcomes or values at time points or trends in physiological markers. Benefit was not observed in specific subgroups when explored through interactions with categories of age, sex, surgery type, Aristotle score, or first versus second half of recruitment. Adverse events were similar (sham 5%, RIPC 6%; P=0.68). CONCLUSIONS: RIPC is not associated with important improvements in clinical outcomes and physiological markers after cardiac surgery in children. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov. Unique identifier: NCT00650507.

Anesthetic considerations for neonates undergoing modified Blalock-Taussig shunt and variations.

The first Blalock-Taussig (BT) shunt was reported in 1944, and during the last 70 years, the procedure has evolved with the development of new materials and devices, and surgical approaches. It has, however, remained central to the palliation of neonates with complex congenital heart disease. The indications have expanded from the original aim of alleviating cyanosis and the pathophysiological results of chronic hypoxemia. They now include lesions with single ventricles, and rehabilitation of small pulmonary arteries. The physiology and hemodynamics of BT shunt circulations are very complex, and adverse hemodynamic events can be difficult to recognize. The consequences of shunt failure can be fatal, and the mortality (3-15%) and morbidity remain distressingly high even in the current era. Neonates undergoing BT shunt procedures or undergoing noncardiac surgery with this anatomy are challenging for the anesthesiologists to manage. There is a significant incidence of periprocedural cardiac arrest, often related to myocardial ischemia. A clear understanding of the anatomy and physiology is important. Any discussion of BT shunt in the current era has to include consideration of hypoplastic left heart syndrome and 'single ventricle' physiology.

Neurological injury and anesthetic neurotoxicity following neonatal cardiac surgery: does the head rule the heart or the heart rule the head?

The improvements in care of children with heart disease have resulted in a major decrease in mortality and increased attention to adverse events and quality of survival. There is important neurological morbidity in children with congenital heart disease. Some problems such as stroke or seizure may be immediately apparent, but others, such as learning disability and motor delay emerge over time. The etiology is multifactorial and includes genetic, procedural and social causes. Only some factors are modifiable. Over the last decade, evidence has been presented that anesthetic drugs may be a potential cause of CNS morbidity. Neonates and infants may be particularly vulnerable to this. The purpose of this article is to describe the multiple known causes of neurodevelopmental impairment in children with heart disease, including anesthetic agents, and to explore the relationship between congenital heart disease and its treatment in this regard.

Heparin brand is associated with postsurgical outcomes in children undergoing cardiac surgery.

BACKGROUND: We sought to determine whether the use of specific unfractionated heparin brands during cardiopulmonary bypass for pediatric cardiac surgery was associated with differences in postoperative outcomes, especially regarding the incidence of bleeding and thromboembolic complications. METHODS: We compared postoperative outcomes for pediatric cardiac surgeries performed with Hepalean (Organon Teknika) to those performed with PPC heparin (Pharmaceutical Partners of Canada). Differences in clinical outcomes were determined in multivariable logistic and linear regression models adjusted for patients and surgery characteristics. RESULTS: In all, 903 operations were reviewed, 289 (32%) using Hepalean and 614 (68%) using PPC heparin. Patient demographics and surgical variables were comparable between groups. In multivariable regression models, adjusted for patients' characteristics, heparin use and choice of antifibrinolytic agents, the use of PPC heparin was associated with greater use of red blood cell transfusions in the first 48 postoperative hours (estimates +1.6 mL/kg, p<0.001), increased odds of bleeding complications (odds ratio 3.8, p=0.04), thromboembolic complications (odds ratio 4.7, p=0.01), early unplanned reoperation (odds ratio 6.9, p=0.03), longer postoperative intensive care unit stay (estimate +3.2 days, p<0.001), and longer hospital stay (estimate +3.6 days, p<0.001). CONCLUSIONS: Brand of unfractionated heparin used during cardiopulmonary bypass for pediatric cardiac surgery was associated with bleeding complications and clinical outcomes. Different brands of unfractionated heparin should not be considered equivalent without proper validation in formal trials.

Longer blood storage is associated with suboptimal outcomes in high-risk pediatric cardiac surgery.

BACKGROUND: The negative effects of long-term storage of allogeneic red blood cells (RBCs) on outcomes in adult cardiac surgery have been established, but evidence of a similar effect in pediatric cardiac surgery is limited. METHODS: The weighted average duration of storage for RBC units used in 1,225 pediatric cardiac operations was determined. Operations were divided into high RBC use (more than 4 units or more than 150 mL/kg) or low RBC use. For both categories, associations between storage duration and surgical outcomes, adjusted for relevant patient characteristics, were evaluated. RESULTS: High RBC use was associated with higher surgical complexity. Storage duration for patients who received low RBC volumes was not associated with surgical outcomes. For patients with high RBC transfusion volumes, longer storage duration (per day) was associated with higher odds of bleeding complications (odds ratio 1.029, p=0.07), renal insufficiency (odds ratio 1.085, p=0.001), higher inotrope score after surgery (12 to 24 hours +0.08, p=0.002; 24 to 48 hours +0.07, p<0.001), greater chest tube drainage (24 hours +1.5 mL/kg, p<0.001), longer postoperative hospitalization (+0.3 days p=0.02), and increased in-hospital mortality (odds ratio 1.054, p=0.03). Effects of RBC transfusions on postoperative bleeding were greatest for storage duration longer than 14 days. CONCLUSIONS: The freshest RBC units available should be used for pediatric cardiac operations expected to require more than 4 units or more than 150 mL/kg of allogeneic RBC transfusions, with no units more than 14 days old being transfused whenever possible.

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, 1.1/10(9) 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.

Improved outcomes associated with intraoperative steroid use in high-risk pediatric cardiac surgery.

BACKGROUND: Corticosteroids are commonly administered perioperatively in pediatric cardiac surgery to reduce cardiopulmonary bypass induced inflammation. However, their effects on outcomes and potential for adverse events are not well defined. METHODS: A review was undertaken of cardiac operations between September 2004 and December 2007 carrying a comprehensive Aristotle score 10 or greater. A nonrandomized comparison was undertaken comparing those patients having received intraoperative methylprednisolone at anesthesia induction or in the bypass circuit prime with those who did not. To account for nonrandom assignment of steroid use, a propensity model was created to establish each patient's probability of having received steroids (∼150 variables evaluated, 17 in final model, c-stat 0.94, p < 0.001). Associations between postoperative outcomes and intraoperative steroid use were modeled in multivariable linear regression models adjusted for propensity score and relevant surgical characteristics. RESULTS: In 221 identified cases, 134 (61%) patients received intraoperative steroids; of these, 44 (33%) also received preoperative doses. In propensity-adjusted regression models, intraoperative steroid use was associated with lower chest tube volume loss in the first 24 postoperative hours (-5.3 mL/kg, p < 0.001), and shorter durations of stay in intensive care (-2.3 days, p < 0.001) and hospital (-4.1 days, p < 0.001). Use of an additional preoperative dose resulted in further improvements, especially a reduction in duration of mechanical ventilation (-1.7 days versus no steroids, -1.2 days versus intraoperative steroids only, p = 0.002). Steroids were not associated with increased postoperative lactate, creatinine, or glucose levels, or odds of infection. CONCLUSIONS: Intraoperative steroid use is associated with improved postoperative outcomes for children undergoing high-risk cardiac surgery, with further benefits associated with a preoperative dose.

Randomized, controlled trial of individualized heparin and protamine management in infants undergoing cardiac surgery with cardiopulmonary bypass.

OBJECTIVES: We sought to determine whether infants (younger than 1 year old) had similar clinical benefits with individualized anticoagulation management as older children and adult undergoing cardiopulmonary bypass (CPB). BACKGROUND: Individualized heparin and protamine management in older children and adults undergoing CPB has been associated with improved clinical outcomes. METHODS: Ninety infants younger than 1 year of age undergoing CPB were enrolled in a randomized, controlled trial comparing weight-based anticoagulation management using activated clotting time (ACT) to individualized management with Hemostasis Management System Plus. Manufacturer's guidelines were followed for the first 33 patients. A modified protocol was used for the last 57 patients with adjustments for coagulation system immaturity and hemodilution on CPB. RESULTS: The hemostasis management system (HMS) device consistently underestimated plasma anti-Xa levels, leading to an overestimated required heparin dose. After a blinded interim analysis revealed poor outcomes in the experimental HMS group using manufacturer guidelines, the safety committee suspended the study pending protocol modifications. The use of the HMS device following the modified protocol resulted in more stable anti-Xa levels during CPB with improved post-operative outcomes including reduced need for transfusions (71 ml/kg vs. 80 ml/kg; p = 0.003), ventilation time (33 h vs. 49 h; p = 0.04), intensive care (88 h vs. 99 h; p = 0.003), and hospital length of stay (192 h vs. 216 h; p < 0.001), compared with the weight-based protocol. CONCLUSIONS: This study supports the use of the HMS device, with a modified protocol for infants younger than 1 year of age, for anticoagulation management during CPB. Clinical guidelines for the use of the HMS device should be modified for infants younger than 1 year of age.

Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans.

OBJECTIVES: We conducted a randomized controlled trial of the effects of remote ischemic preconditioning (RIPC) in children undergoing repair of congenital heart defects. BACKGROUND: Remote ischemic preconditioning reduces injury caused by ischemia-reperfusion in distant organs. Cardiopulmonary bypass (CPB) is associated with multi-system injury. We hypothesized that RIPC would modulate injury induced by CPB. METHODS: Children undergoing repair of congenital heart defects were randomized to RIPC or control treatment. Remote ischemic preconditioning was induced by four 5-min cycles of lower limb ischemia and reperfusion using a blood pressure cuff. Measurements of lung mechanics, cytokines, and troponin I were made pre- and postoperatively. RESULTS: Thirty-seven patients were studied. There were 20 control patients and 17 patients in the RIPC group. The mean age and weight of the RIPC and control patients were not different (0.9 +/- 0.9 years vs. 2.2 +/- 3.4 years, p = 0.4; and 6.9 +/- 2.9 kg vs. 11.5 +/- 10 kg, p = 0.06). Bypass and cross-clamp times were not different (80 +/- 24 min vs. 88 +/- 25 min, p = 0.3; and 55 +/- 13 min vs. 59 +/- 13 min, p = 0.4). Levels of troponin I postoperatively were greater in the control patients compared with the RIPC group (p = 0.04), indicating greater myocardial injury in control patients. Postoperative inotropic requirement was greater in the control patients compared with RIPC patients at both 3 and 6 h (7.9 +/- 4.7 vs. 10.9 +/- 3.2, p = 0.04; and 7.3 +/- 4.9 vs. 10.8 +/- 3.9, p = 0.03, respectively). The RIPC group had significantly lower airway resistance at 6 h postoperatively (p = 0.009). CONCLUSIONS: This study demonstrates the myocardial protective effects of RIPC using a simple noninvasive technique of four 5-min cycles of lower limb ischemia and reperfusion. These novel data support the need for a larger study of RIPC in patients undergoing cardiac surgery.

Inclusion of oxygen consumption improves the accuracy of arterial and venous oxygen saturation interpretation after the Norwood procedure.

OBJECTIVE: Management strategy for the postoperative Norwood neonate has been formulated from models that have estimated oxygen consumption (VO2). Superior vena caval oxygen saturation (SVO2), systemic arterial and superior vena caval oxygen saturation difference (Sa-VO2), and oxygen excess factor (Omega = arterial oxygen saturation/Sa-VO2) have been used as indirect indicators to estimate systemic blood flow (Qs) and oxygen delivery (DO2). We sought to examine the correlation of the indirect indicators to VO2-derived measures of oxygen transport. METHODS: Respiratory mass spectrometry was used to continuously measure VO2 after the Norwood procedure (n = 13). Measured saturations and the direct Fick equation were used to obtain pulmonary blood flow, Qs, DO2, and oxygen extraction ratio (ERO2) values. Correlations to SVO2, Sa-VO2, and Omega were sought. RESULTS: There was a close correlation of SVO2, Sa-VO2, and Omega to ERO2 (r = 0.92, 0.96, and 0.97, respectively; P < .0001). Correlation to Qs and DO2 was variable (r = 0.39 to 0.78, respectively; P < .0001). Correlation to VO2 was poor but significant (r = 0.24 to 0.40, P < .0001). Inclusion of VO2 improved the correlation to Qs and DO2 (r = 0.66 to 0.97, P < .0001). CONCLUSIONS: The close correlation of SVO2, Sa-VO2, and Omega to ERO2 indicates that each is a measure of the balance of DO2 and extraction. The significant but less reliable correlation to DO2 and VO2 indicates the values for SVO2, Sa-VO2, and Omega do not discriminate between the contribution of DO2 and VO2. Measured VO2 and hemodynamics may improve the optimization of postoperative management strategy in the individual neonate.

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. CONCLUSIONS: 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.

Levels of exhaled nitric oxide before and after surgical and transcatheter device closure of atrial septal defects in children.

OBJECTIVES: We have shown that exhaled nitric oxide levels decrease after surgical closure of congenital left-to-right cardiac shunts. It remains unclear whether the change in exhaled nitric oxide levels reflects endothelial injury caused by the use of cardiopulmonary bypass or the decrease in pulmonary blood flow attendant on shunt closure. Transcatheter atrial septal defect closure permits shunt closure without the use of cardiopulmonary bypass. Therefore we compared changes in exhaled nitric oxide levels after surgical and transcatheter device closure of atrial septal defects. METHODS: We enrolled sequentially 30 children undergoing atrial septal defect closure. Fifteen patients (age range, 0.4-16 years; median age, 6.5 years) underwent surgical atrial septal defect closure with cardiopulmonary bypass, and 15 patients (age range, 4-17 years; median age, 8.4 years) had device closure of the atrial septal defect in the catheterization laboratory. We measured nitric oxide levels in end-tidal expiratory gas with a rapid-response chemiluminescent analyzer before and after atrial septal defect closure. RESULTS: After surgical repair of the atrial septal defect, exhaled nitric oxide decreased by 21%, from 10.9 +/- 4.4 to 8.4 +/- 3.3 ppb (P <.005), whereas after transcatheter defect closure, exhaled nitric oxide increased by 23%, from 7.6 +/- 2.6 to 9.3 +/- 3.7 ppb (P <.005). Hemoglobin levels in patients undergoing surgical intervention were significantly lower (P =.0001) postoperatively. CONCLUSIONS: We confirmed that exhaled nitric oxide, despite a fall in hemoglobin, decreases after surgical closure of atrial septal defects. In contrast, exhaled nitric oxide levels increase after transcatheter closure. Exhaled nitric oxide levels may reflect bypass-induced endothelial cell injury and are independent of changes in pulmonary blood flow.