Met-Hemoglobin Is a Biomarker for Poor Oxygen Delivery in Infants Following Surgical Palliation.

BACKGROUND: Infants with cyanotic congenital heart disease demonstrate wide fluctuations in hemoglobin (Hb), oxygen saturation, and cardiac output following palliation. Methemoglobin (Met-Hb), the product of Hb oxidation, may represent a compensatory mechanism during hypoxia and may be utilized as a biomarker. METHODS: Arterial and venous Met-Hb levels were obtained from infants requiring palliation. The primary outcome was to describe the relationship between Met-Hb and other indices of tissue oxygenation (venous saturation, estimated arteriovenous oxygen difference [Est AV-Diff], and lactate). Secondary outcomes were to determine the impact of elevated Met-Hb levels ≥1.0% and the effect of red blood cell (RBC) transfusion on Met-Hb levels. RESULTS: Fifty infants and 465 Met-Hb values were studied. Venous Met-Hb levels were significantly higher than arterial levels (venous: 0.84% ± 0.36% vs arterial: 0.45% ± 0.18%; P < .001). Venous Met-Hb demonstrated a significant inverse relationship with venous oxygen saturation (R = -0.6; P < .001) and Hb (R = -0.3, P < .001) and a direct relationship with the Est AV-Diff (R = 0.3, P < .001). A total of 129 (29.6%) venous Met-Hb values were elevated (≥1.0%) and were associated with significantly lower Hb and venous saturation levels and higher Est AV-Diff and lactate levels. Methemoglobin levels decreased significantly following 65 RBC transfusions (0.94 ± 0.40 vs 0.77 ± 0.34; P < .001). Linear mixed models demonstrated that higher venous Met-Hb levels were associated with lower measures of tissue oxygenation and not related to any preoperative clinical differences. CONCLUSION: Methemoglobin may be a clinically useful marker of tissue oxygenation in infants following surgical palliation.

Elevated free hemoglobin and decreased haptoglobin levels are associated with adverse clinical outcomes, unfavorable physiologic measures, and altered inflammatory markers in pediatric cardiac surgery patients.

BACKGROUND: There are data suggesting that free hemoglobin (Hb), heme, and iron contribute to infection, thrombosis, multiorgan failure, and death in critically ill patients. These outcomes may be mitigated by haptoglobin. STUDY DESIGN AND METHODS: 164 consecutively treated children undergoing surgery for congenital heart disease were evaluated for associations between free Hb and haptoglobin and clinical outcomes, physiologic metrics, and biomarkers of inflammation RESULTS: Higher perioperative free Hb levels (and lower haptoglobin levels) were associated with mortality, nosocomial infection, thrombosis, hours of intubation and inotropes, increased interleukin-6, peak serum lactate levels, and lower nadir mean arterial pressures. The median free Hb in patients without infection (30 mg/dL; 29 interquartile range [IQR], 24-52 mg/dL) was lower than in those who became infected (39 mg/dL; IQR, 33-88 mg/ 31 dL; p = 0.0046). The median mechanical ventilation requirements were 19 (IQR, 7-72) hours in patients with higher levels of haptoglobin versus 48 (IQR, 18-144) hours in patients with lower levels (p = 0.0047). Transfusion dose, bypass duration, and complexity of surgery were all significantly correlated with Hb levels and haptoglobin levels. Multivariate analyses demonstrated that these variables were independently and significantly associated with outcomes. CONCLUSIONS: Elevated pre- and postoperative levels of free Hb and decreased levels of haptoglobin were associated with adverse clinical outcomes, inflammation, and unfavorable physiologic metrics. Transfusion, RACHS score, and duration of bypass were associated with increased free Hb and decreased haptoglobin. Further investigation of the role of hemolysis and haptoglobin as potential mediators or markers of outcomes is warranted.

Outcomes Using a Conservative Versus Liberal Red Blood Cell Transfusion Strategy in Infants Requiring Cardiac Operation.

BACKGROUND: The optimal hemoglobin for infants after cardiac operation is unknown. Red blood cells (RBCs) are commonly transfused to maintain high hemoglobin concentrations in the absence of a clinical indication. We hypothesized that infants can be managed with a postoperative conservative RBC transfusion strategy, resulting in lower daily hemoglobin concentrations, without evidence of impaired oxygen delivery (ie, lactate, arteriovenous oxygen difference [avO2diff]), or adverse clinical outcomes. METHODS: Infants weighing 10 kg or less undergoing biventricular repair or palliative (nonseptated) operation were randomly assigned to either a postoperative conservative or liberal transfusion strategy. Conservative group strategy was RBC transfusion for a hemoglobin less than 7.0 g/dL for biventricular repairs or less than 9.0 g/dL for palliative procedures plus a clinical indication. Liberal group strategy was RBC transfusion for hemoglobin less than 9.5 g/dL for biventricular repairs or less than 12 g/dL for palliative procedures regardless of clinical indication. RESULTS: After the operation of 162 infants (82 conservative [53 biventricular, 29 palliative], 80 liberal [52 biventricular, 28 palliative]), including 12 Norwood procedures (6 conservative, 6 liberal), daily hemoglobin concentrations were significantly lower within the conservative group than the liberal group by postoperative day 1 and remained lower for more than 10 days. The percentage of patients requiring a RBC transfusion, number of transfusions, and volume of transfusions were all significantly lower within the conservative group. Despite lower hemoglobin concentrations within the conservative group, lactate, avO2diff, and clinical outcomes were similar. CONCLUSIONS: Infants undergoing cardiac operation can be managed with a conservative RBC transfusion strategy. Clinical indications should help guide the decision for RBC transfusion even in this uniquely vulnerable population. Larger multicenter trials are needed to confirm these results, and focus on the highest risk patients would be of great interest.

Cuffed endotracheal tubes in neonates and infants undergoing cardiac surgery are not associated with airway complications.

STUDY OBJECTIVE: To determine the incidence of postoperative airway complications in infants <5kg in weight undergoing cardiac surgery intubated with Microcuff (Kimberley-Clark, Roswell, GA) endotracheal tubes (ETTs). DESIGN: Retrospective review of infants weighing <5.0 kg with congenital heart disease (CHD) presenting for cardiac surgery. SETTING: Single-center, tertiary pediatric cardiac critical care unit at a university hospital. PATIENTS: A total of 208 infants weighing <5 kg underwent cardiac surgery for CHD from 2008 to 2013. INTERVENTION: Intubation with Microcuff (Kimberley-Clark) ETTs. STUDY DESIGN: Retrospective review of infants weighing <5.0 kg with CHD presenting for cardiac surgery to a single-center tertiary care university hospital. MEASUREMENTS: Perioperative data were collected. Primary outcome was development of tracheal stenosis and/or reintubation for stridor. Stridor was defined as mild (≤2 doses of racemic epinephrine), moderate (>2 doses of racemic epinephrine), or severe (requiring reintubation). Secondary outcomes were variables possibly contributing to postextubation stridor. Infants with a tracheostomy, airway anomalies, and death prior to initial extubation were excluded. Logistic regression analysis was performed to evaluate the association between clinical risk factors and the incidence of postextubation stridor. RESULTS: A total of 208 infants weighing <5 kg underwent cardiac surgery for CHD from 2008 to 2013; 12 subjects were excluded for death prior to initial extubation. No infant developed tracheal stenosis. The incidence of any stridor was 20.9% (95% confidence interval, 15.8%-27.1%) with severe stridor in 2 cases (1%). Age at surgery, weight, duration of intubation, dexamethasone use, and ETT size were not significantly associated with postextubation stridor. Presence of a comorbidity was significantly associated with stridor (P=.01). CONCLUSIONS: Microcuff ETTs in infants <5.0 kg in weight undergoing cardiac surgery are associated with a low incidence of severe postextubation stridor. Because cuffed ETTs allow for improved control of ventilation/oxygenation and decreased risk of aspiration, they should be considered for use in this high-risk population. Larger studies are needed to confirm these results.

Longer RBC storage duration is associated with increased postoperative infections in pediatric cardiac surgery.

OBJECTIVES: Infants and children undergoing open heart surgery routinely require multiple RBC transfusions. Children receiving greater numbers of RBC transfusions have increased postoperative complications and mortality. Longer RBC storage age is also associated with increased morbidity and mortality in critically ill children. Whether the association of increased transfusions and worse outcomes can be ameliorated by use of fresh RBCs in pediatric cardiac surgery for congenital heart disease is unknown. INTERVENTIONS: One hundred and twenty-eight consecutively transfused children undergoing repair or palliation of congenital heart disease with cardiopulmonary bypass who were participating in a randomized trial of washed versus standard RBC transfusions were evaluated for an association of RBC storage age and clinical outcomes. To avoid confounding with dose of transfusions and timing of infection versus timing of transfusion, a subgroup analysis of patients only transfused 1-2 units on the day of surgery was performed. MEASUREMENTS AND MAIN RESULTS: Mortality was low (4.9%) with no association between RBC storage duration and survival. The postoperative infection rate was significantly higher in children receiving the oldest blood (25-38 d) compared with those receiving the freshest RBCs (7-15 d) (34% vs 7%; p = 0.004). Subgroup analysis of subjects receiving only 1-2 RBC transfusions on the day of surgery (n = 74) also demonstrates a greater prevalence of infections in subjects receiving the oldest RBC units (0/33 [0%] with 7- to 15-day storage; 1/21 [5%] with 16- to 24-day storage; and 4/20 [20%] with 25- to 38-day storage; p = 0.01). In multivariate analysis, RBC storage age and corticosteroid administration were the only predictors of postoperative infection. Washing the oldest RBCs (> 27 d) was associated with a higher infection rate and increased morbidity compared with unwashed RBCs. DISCUSSION: Longer RBC storage duration was associated with increased postoperative nosocomial infections. This association may be secondary in part, to the large doses of stored RBCs transfused, from single-donor units. Washing the oldest RBCs was associated with increased morbidity, possibly from increased destruction of older, more fragile erythrocytes incurred by washing procedures. Additional studies examining the effect of RBC storage age on postoperative infection rate in pediatric cardiac surgery are warranted.

Transfusion of cell saver salvaged blood in neonates and infants undergoing open heart surgery significantly reduces RBC and coagulant product transfusions and donor exposures: results of a prospective, randomized, clinical trial.

OBJECTIVE: To evaluate whether transfusion of cell saver salvaged, stored at the bedside for up to 24 hrs, would decrease the number of postoperative allogeneic RBC transfusions and donor exposures, and possibly improve clinical outcomes. DESIGN: Prospective, randomized, controlled, clinical trial. SETTING: Pediatric cardiac intensive care unit. PATIENTS: Infants weighing less than 20 kg (n = 106) presenting for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Subjects were randomized to a cell saver transfusion group where cell saver blood was available for transfusion up to 24 hrs after collection, or to a control group. Cell saver subjects received cell saver blood for volume replacement and/or RBC transfusions. Control subjects received crystalloid or albumin for volume replacement and RBCs for anemia. Blood product transfusions, donor exposures, and clinical outcomes were compared between groups. MEASUREMENTS AND MAIN RESULTS: Children randomized to the cell saver group had significantly fewer RBC transfusions (cell saver: 0.19 ± 0.44 vs. control: 0.75 ± 1.2; p = 0.003) and coagulant product transfusions in the first 48 hrs post-op (cell saver: 0.09 ± 0.45 vs. control: 0.62 ± 1.4; p = 0.013), and significantly fewer donor exposures (cell saver: 0.60 ± 1.4 vs. control: 2.3 ± 4.8; p = 0.019). This difference persisted over the first week post-op, but did not reach statistical significance (cell saver: 0.64 ± 1.24 vs. control: 1.1 ± 1.4; p = 0.07). There were no significant clinical outcome differences. CONCLUSION: Cell saver blood can be safely stored at the bedside for immediate transfusion for 24 hrs after collection. Administration of cell saver blood significantly reduces the number of RBC and coagulant product transfusions and donor exposures in the immediate postoperative period. Reduction of blood product transfusions has the potential to reduce transfusion-associated complications and decrease postoperative morbidity. Larger studies are needed to determine whether this transfusion strategy will improve clinical outcomes.

Washing red blood cells and platelets transfused in cardiac surgery reduces postoperative inflammation and number of transfusions: results of a prospective, randomized, controlled clinical trial.

OBJECTIVES: Children undergoing cardiac surgery with cardiopulmonary bypass are susceptible to additional inflammatory and immunogenic insults from blood transfusions. We hypothesize that washing red blood cells and platelets transfused to these patients will reduce postoperative transfusion-related immune modulation and inflammation. DESIGN: Prospective, randomized, controlled clinical trial. SETTING: University hospital pediatric cardiac intensive care unit. PATIENTS: Children from birth to 17 yrs undergoing cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Children were randomized to an unwashed or washed red blood cells and platelet transfusion protocol for their surgery and postoperative care. All blood was leuko-reduced, irradiated, and ABO identical. Plasma was obtained for laboratory analysis preoperatively, immediately, and 6 and 12 hrs after cardiopulmonary bypass. Primary outcome was the 12-hr postcardiopulmonary bypass interleukin-6-to-interleukin-10 ratio. Secondary measures were interleukin levels, C-reactive protein, and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: One hundred sixty-two subjects were studied, 81 per group. Thirty-four subjects (17 per group) did not receive any blood transfusions. Storage duration of blood products was similar between groups. Among transfused subjects, the 12-hr interleukin ratio was significantly lower in the washed group (3.8 vs. 4.8; p = .04) secondary to lower interleukin-6 levels (after cardiopulmonary bypass: 65 vs.100 pg/mL, p = .06; 6 hrs: 89 vs.152 pg/mL, p = .02; 12 hrs: 84 vs.122 pg/mL, p = .09). Postoperative C-reactive protein was lower in subjects receiving washed blood (38 vs. 43 mg/L; p = .03). There was a numerical, but not statistically significant, decrease in total blood product transfusions (203 vs. 260) and mortality (2 vs. 6 deaths) in the washed group compared to the unwashed group. CONCLUSIONS: Washed blood transfusions in cardiac surgery reduced inflammatory biomarkers, number of transfusions, donor exposures, and were associated with a nonsignificant trend toward reduced mortality. A larger study powered to test for clinical outcomes is needed to determine whether these laboratory findings are clinically significant.

Children with single-ventricle physiology do not benefit from higher hemoglobin levels post cavopulmonary connection: results of a prospective, randomized, controlled trial of a restrictive versus liberal red-cell transfusion strategy.

OBJECTIVE: To examine the impact of a restrictive vs. liberal transfusion strategy on arterial lactate and oxygen content differences in children with single-ventricle physiology post cavopulmonary connection. Children with single-ventricle physiology are routinely transfused postoperatively to increase systemic oxygen delivery, and transfusion thresholds in this population have not been studied. DESIGN: Prospective, randomized, controlled, clinical trial. SETTING: Pediatric cardiac intensive care unit in a teaching hospital. PATIENTS: Infants and children (n = 60) with variations of single-ventricle physiology presenting for cavopulmonary connection. INTERVENTIONS: Subjects were randomized to a restrictive (hemoglobin of < 9.0 g/dL), or liberal (hemoglobin of ≥ 13.0 g/dL) transfusion strategy for 48 hrs post operation. Primary outcome measures were mean and peak arterial lactate. Secondary end points were arteriovenous (C(a-v)o2) and arteriocerebral oxygen content (C(a-c)o2) differences and clinical outcomes. MEASUREMENTS AND MAIN RESULTS: A total of 30 children were in each group. There were no significant preoperative differences. Mean hemoglobin in the restrictive and liberal groups were 11 ± 1.3 g/dL and 13.9 ± 0.5 g/dL, respectively (p < .01). No differences in mean (1.4 ± 0.5 mmol/L [Restrictive] vs. 1.4 ± 0.4 mmol/L [Liberal]) or peak (3.1 ± 1.5 mmol/L [Restrictive] vs. 3.2 ± 1.3 mmol/L [Liberal]) lactate between groups were found. Mean number of red blood cell transfusions were 0.43 ± 0.6 and 2.1 ± 1.2 (p < .01), and donor exposure was 1.2 ± 0.7 and 2.4 ± 1.1 to (p < .01), for each group, respectively. No differences were found in C(a-v)o2, C(a-c)o2, or clinical outcome measures. CONCLUSION: Children with single-ventricle physiology do not benefit from a liberal transfusion strategy after cavopulmonary connection. A restrictive red blood cell transfusion strategy decreases the number of transfusions, donor exposures, and potential risks in these children. Larger studies with clinical outcome measures are needed to determine the transfusion threshold for children post cardiac repair or palliation for congenital heart disease.

Bispectral index as a guide for titration of propofol during procedural sedation among children.

OBJECTIVE: To determine whether the bispectral index (BIS) monitor could be used to guide physicians in titrating propofol to an effective safe level of deep sedation for children undergoing painful medical procedures. DESIGN: Multiphase clinical trial. SETTING: Outpatient treatment center of a university children's hospital. PATIENTS: Pediatric outpatients undergoing painful medical procedures. INTERVENTIONS: Patients were sedated with propofol for the procedures. Patients were monitored with a BIS monitor, and the BIS score was correlated with the patient's clinical level of sedation. The BIS score was then used as a guide to titrate propofol in the last phase of the study. MEASUREMENTS AND MAIN RESULTS: The study consisted of 3 phases. In a chart review of data for 154 children who underwent 212 procedures, propofol was found to be safe and effective, with consistent dosing among the intensivists administering the medication. The children received a mean bolus dose of propofol of 1.56 mg/kg, with a mean total dose of propofol of 0.33 mg/kg per minute for the duration of the procedure. In the second phase, 21 patients ranging in age from 27 weeks to 18 years, with normal neurologic function, were sedated with propofol. An observer who was blinded to the BIS scores recorded clinical levels of sedation and reactivity (with a modified Ramsay scale and reactivity score) every 1 to 3 minutes. Another observer recorded the BIS scores at the same times. A total of 275 data points were collected and evaluated. All data points from the times at which patients were considered to be sedated adequately were used to construct a normal distribution of BIS scores. The mean BIS score was 62. This distribution was used to predict that a maximal BIS score of 47 was needed to ensure adequate sedation for 90% of the population. In the third phase of the study, an algorithm was devised to determine the target BIS score necessary for adequate sedation of 95% of the patients. We chose an initial BIS score of 50 (at which 85% of the patients in phase 2 were sedated) because of the possibility of data from phase 2 being skewed toward oversedation. Propofol was administered by an intensivist in an attempt to maintain the target BIS score. A blinded observer noted the patient's clinical level of sedation. In this group, there were 2 failures, ie, patients were clinically uncomfortable despite a BIS score of < or =50, representing only 90% success. Therefore, with the algorithm, propofol was titrated to sedate the next patients to a BIS score of 45. These patients required a mean bolus dose of 1.47 mg/kg and a mean total dose of 0.51 mg/kg per minute to maintain a BIS score of 45. They awakened in 12.75 minutes. All patients were sedated adequately, all procedures were successful, and no patients experienced complications from the sedation. To eliminate variability in the way propofol was dosed, the next 10 patients were given propofol according to a standardized protocol. These 10 children received an initial bolus of 1 mg/kg, with incremental bolus doses of 0.5 mg/kg per dose (maximum: 20 mg) to achieve and to maintain a BIS score of 45. With this protocol, all patients were sedated adequately and none experienced complications from the sedation. The patients required a mean bolus dose of 2.23 mg/kg and a mean dose of 0.52 mg/kg per minute to maintain a BIS score of 45. The mean time until awakening was 14.9 minutes. Regarding the total dose over time and the time until awakening, there was no statistical significance between this group and the group sedated to a BIS score of 45 without the dosing protocol. CONCLUSION: The BIS monitor can be a useful monitoring guide for the titration of propofol by physicians who are competent in airway and hemodynamic management, to achieve deep sedation for children undergoing painful procedures.

Duration of mechanical ventilation in life-threatening pediatric asthma: description of an acute asphyxial subgroup.

OBJECTIVE: Acute asphyxial asthma (AAA) is well described in adult patients and is characterized by a sudden onset that may rapidly progress to a near-arrest state. Despite the initial severity of AAA, mechanical ventilation often restores gas exchange promptly, resulting in shorter durations of ventilation. We believe that AAA can occur in children and can lead to respiratory failure that requires mechanical ventilation. Furthermore, children with rapid-onset respiratory failure that requires intubation in the emergency department (ED) are more likely to have AAA and a shorter duration of mechanical ventilation than those intubated in the pediatric intensive care unit (PICU). METHODS: An 11-year retrospective chart review (1991-2002) was conducted of all children who were aged 2 through 18 years and had the primary diagnosis of status asthmaticus and required mechanical ventilation. RESULTS: During the study period, 33 (11.4%) of 290 PICU admissions for status asthmaticus required mechanical ventilation. Thirteen children presented with rapid respiratory failure en route, on arrival, or within 30 minutes of arrival to the ED versus 20 children who progressed to respiratory failure later in their ED course or in the PICU. Mean duration of mechanical ventilation was significantly shorter in the children who presented with rapid respiratory failure versus those with progressive respiratory failure (29 +/- 43 hours vs 88 +/- 72 hours). Children with rapid respiratory failure had greater improvements in ventilation and oxygenation than those with progressive respiratory failure as measured by pre- and postintubation changes in arterial carbon dioxide pressure, arterial oxygen pressure/fraction of inspired oxygen ratio, and alveolar-arterial gradient. According to site of intubation, 23 children required intubation in the ED, whereas 10 were intubated later in the PICU. Mean duration of mechanical ventilation was significantly shorter in the ED group versus the PICU group (42 +/- 63 hours vs 118 +/- 46 hours). There were significantly greater improvements in ventilation and oxygenation in the ED group versus the PICU group as measured by pre- and postintubation changes in arterial carbon dioxide pressure and arterial oxygen pressure/fraction of inspired oxygen ratio. CONCLUSIONS: AAA occurs in children and shares characteristics seen in adult counterparts. Need for early intubation is a marker for AAA and may not represent a failure to maximize preintubation therapies. AAA represents a distinct form of life-threatening asthma and requires additional study in children.