Jeffrey A. Alten

Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children

BACKGROUND Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. METHODS We conducted this trial of two targeted temperature interventions at 38 childrens hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. RESULTS A total of 295 patients underwent randomization. Among the 260 patients with data that could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. CONCLUSIONS In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644.).

Prophylactic Peritoneal Dialysis Following Cardiopulmonary Bypass in Children Is Associated with Decreased Inflammation and Improved Clinical Outcomes

OBJECTIVE To investigate impact of prophylactic peritoneal dialysis (PD) on clinical outcomes and inflammatory cytokines in children following cardiac surgery with cardiopulmonary bypass. DESIGN Prospective before-and-after nonrandomized cohort study. SETTING Pediatric cardiovascular intensive care unit in tertiary hospital. PATIENTS Fifty-two consecutive neonates and infants at high risk for postoperative fluid overload following cardiopulmonary bypass. All had PD catheters placed during primary cardiac surgery. INTERVENTION Initial 27 patients were managed with passive peritoneal drainage and diuretics (controls). Following 25 patients were started on prophylactic PD in immediate postoperative period and managed per PD protocol (+PD). OUTCOME MEASURES Cumulative fluid balance, indices of disease severity, and clinical outcomes were prospectively collected. Plasma interleukin-6 and interleukin-8 were measured immediately before-and-after cardiopulmonary bypass and at 24 and 48 hours post-cardiopulmonary bypass. RESULTS Demographics, diagnoses, and intraoperative variables were similar. Median net fluid balance was more negative in +PD at 24 hours, -24 mL/kg (interquartile range: -62, 11) vs. +18 mL/kg (interquartile range: -26, 11), P = .003, and 48 hours, -88 mL/kg (interquartile range: -132, -54) vs. -46 mL/kg (interquartile range: -84, -12), P = .004. +PD had median 55 mL/kg less fluid intake at 24 hours, P = .058. Peritoneal drain, urine, and chest tube output were comparable over first 24 hours. Mean inotrope score was lower in +PD at 24 hours. +PD had earlier sternal closure--24 hours (interquartile range: 20, 40) vs. 63 hours (interquartile range: 44, 72), P < .001--and a trend toward shorter duration of mechanical ventilation--71 hours (interquartile range: 49, 135) vs. 125 hours (interquartile range: 70, 195), P = .10. +PD experienced lower serum concentrations of interleukin-6 and interleukin-8 at 24 hours. CONCLUSIONS Prophylactic PD is associated with greater net negative fluid balance, decreased inotrope requirements, and lower serum concentrations of inflammatory cytokines in the early postoperative period.

Pediatric off-label use of recombinant factor VIIa.

OBJECTIVE. Our goal was to report our institutional experience with recombinant factor VIIa for the treatment and/or prevention of bleeding in nonhemophiliac children. METHODS. This was a retrospective case series in a tertiary pediatric referral hospital. RESULTS. During 1999–2006, 135 patients received recombinant factor VIIa for off-label use. The median number of doses was 2; the median dose was 88 μg/kg. The most common diagnoses among patients receiving recombinant factor VIIa were disseminated intravascular coagulation/sepsis (28), surgical bleeding (19), procedural prophylaxis (16), and trauma (15). The median volume of blood products administered 24 hours before recombinant factor VIIa treatment was 29.7 vs 11.7 mL/kg 24 hours after treatment. Only 1 high-risk patient had significant bleeding after receiving prophylactic recombinant factor VIIa before an invasive procedure. Nonsurvivors had significantly increased incidence of multiple organ dysfunction syndrome (75%) compared with survivors (23%). The largest group of patients (n = 28) received recombinant factor VIIa for bleeding and/or coagulopathy because of disseminated intravascular coagulation; the mortality in this group was 26 (93%) of 28. Eleven patients received multiple doses of recombinant factor VIIa to treat bleeding complications after hematopoietic stem cell transplant, without improvement in blood use. Mortality in medical patients was 58% vs 16% in surgical patients. Three patients had significant thrombotic adverse events after receiving recombinant factor VIIa, resulting in 2 deaths and 1 leg amputation. CONCLUSIONS. Off-label use of recombinant factor VIIa significantly decreases blood-product administration; surgical patients had control of life-threatening bleeding with low associated mortality. Prophylactic recombinant factor VIIa may be effective in preventing bleeding if given before invasive procedures in children at high risk. Prolonged use of recombinant factor VIIa for bleeding complications after hematopoietic stem cell transplant is not effective in preventing packed red blood cell transfusion. Presence of disseminated intravascular coagulation and mulitorgan dysfunction syndrome may help predict futility of recombinant factor VIIa treatment. Off-label use of recombinant factor VIIa is associated with thromboembolic events in children.

Early initiation of arginine vasopressin infusion in neonates after complex cardiac surgery.

Objective: To describe our experience with low-dose arginine vasopressin infusions (0.0003 U/kg/min) initiated in the operating room after the Norwood procedure or arterial switch operation. Design: Retrospective cohort study of 37 consecutive neonates. Setting: Pediatric cardiovascular intensive care unit in a tertiary hospital. Subjects: Nineteen patients that received low-dose arginine vasopressin infusion instituted in the operating room (arginine vasopressin+) were compared to 18 patients that did not receive early arginine vasopressin infusion (arginine vasopressin–). Interventions: None. Results: When comparing arginine vasopressin+ and arginine vasopressin− in the first 24 hrs after cardiovascular intensive care unit admission, there was no difference in demographic variables, heart rate, blood pressure, central venous pressure, maximum lactate, maximum arterial and central venous saturation difference, urine output, chest tube output, or peritoneal drain output. Mean fluid resuscitation in the first 24 hrs was significantly lower in the arginine vasopressin+ group compared to the arginine vasopressin− group (182 ± 61 mL/kg vs. 223 ± 53 mL/kg, p = .03). The arginine vasopressin+ group also reached median net negative cumulative fluid balance sooner (55 hrs: interquartile range 45, 74 vs. 76 hrs: interquartile range 69, 92; p = .02). Median maximum inotrope score in the first 24 hrs was significantly lower in arginine vasopressin+ (9: interquartile range 5, 12.5 vs. 16.5: interquartile range 10.3, 22.1; p = .02). There was a nonsignificant trend toward shorter duration of mechanical ventilation and cardiovascular intensive care unit length of stay in the arginine vasopressin+ group. The lowest serum sodium in the first 48 hrs was significantly lower in arginine vasopressin+ (132 vs. 137 mmol/L, p = .01). Conclusion: Low-dose arginine vasopressin infusion initiated in the operating room after complex neonatal cardiac surgery was associated with decreased fluid resuscitation and catecholamine requirements in the first 24 postoperative hours.

Severe invasive community-associated methicillin-resistant Staphylococcus aureus infections in previously healthy children.

Objective: An increase in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections has been reported in the literature. Most severe, life-threatening infections were previously thought to be associated with chronically ill or frail patients. Our pediatric intensive care unit (PICU) has seen a recent dramatic increase in primary, severe invasive CA-MRSA infections in healthy children. Design/Setting: A retrospective chart review of all previously healthy patients admitted to our 19-bed combined medical-surgical PICU with a primary diagnosis of severe invasive, culture-proven CA-MRSA disease during the past 6 years. Results: Eleven previously healthy patients were admitted to our PICU with severe, primary, invasive CA-MRSA infections from March 2006 through September 2007, in contrast to no patients meeting these criteria in the preceding 5 years. The mortality rate was 27%, compared with an overall PICU mortality rate during the study period of <7%. The mean PICU length of stay of these patients was 14.9 days, compared with an average PICU length of stay of 2.4 days. Despite initiation of treatment with vancomycin at admission to the PICU in all but one case, patients took a mean of 5.7 days to convert to negative blood cultures. Eight patients had bacteremia longer than 4 days. Six of the patients developed bilateral necrotizing pneumonia requiring prolonged mechanical ventilation. Conclusions: Severe CA-MRSA infections in healthy children are increasing at an alarming rate in our institution. This acute rise in incidence, coupled with an alarmingly high associated mortality rate, raises important questions about the initial empirical antibiotic therapy we use in caring for patients presenting with suspected life-threatening CA-MRSA disease. Vancomycin monotherapy may not be adequate treatment for severe CA-MRSA infections.

Postoperative Hydrocortisone Infusion Reduces the Prevalence of Low Cardiac Output Syndrome After Neonatal Cardiopulmonary Bypass.

Objective: Neonatal cardiac surgery with cardiopulmonary bypass is often complicated by morbidity associated with inflammation and low cardiac output syndrome. Hydrocortisone “stress dosing” is reported to provide hemodynamic benefits in some patients with refractory shock. Development of cardiopulmonary bypass-induced adrenal insufficiency may provide further rationale for postoperative hydrocortisone administration. We sought to determine whether prophylactic, postoperative hydrocortisone infusion could decrease prevalence of low cardiac output syndrome after neonatal cardiac surgery with cardiopulmonary bypass. Design: Double-blind, randomized control trial. Setting: Pediatric cardiac ICU and operating room in tertiary care center. Patients: Forty neonates undergoing cardiac surgery with cardiopulmonary bypass were randomized (19 hydrocortisone and 21 placebo). Demographics and known risk factors were similar between groups. Interventions: After cardiopulmonary bypass separation, bolus hydrocortisone (50 mg/m2) or placebo was administered, followed by continuous hydrocortisone infusion (50 mg/m2/d) or placebo tapered over 5 days. Adrenocorticotropic hormone stimulation testing (1 &mgr;g) was performed before and after cardiopulmonary bypass, prior to steroid administration. Blood was collected for cytokine analysis before and after cardiopulmonary bypass. Measurements and Main Results: Subjects receiving hydrocortisone were less likely to develop low cardiac output syndrome (5/19, 26% vs 12/21, 57%; p = 0.049). Hydrocortisone group had more negative net fluid balance at 48 hours (–114 vs –64 mL/kg; p = 0.01) and greater urine output at 0–24 hours (2.7 vs 1.2 mL/kg/hr; p = 0.03). Hydrocortisone group weaned off catecholamines and vasopressin sooner than placebo, with a difference in inotrope-free subjects apparent after 48 hours (p = 0.033). Five placebo subjects (24%) compared with no hydrocortisone subjects required rescue steroids (p = 0.02). Thirteen (32.5%) had adrenal insufficiency after cardiopulmonary bypass. Patients with adrenal insufficiency randomized to receive hydrocortisone had lower prevalence of low cardiac output syndrome compared with patients with adrenal insufficiency randomized to placebo (1/6 vs 6/7, respectively; p = 0.02). Hydrocortisone significantly reduced proinflammatory cytokines. Ventilator-free days, hospital length of stay, and kidney injury were similar. Conclusions: Prophylactic, postoperative hydrocortisone reduces low cardiac output syndrome, improves fluid balance and urine output, and attenuates inflammation after neonatal cardiopulmonary bypass surgery. Further studies are necessary to show if these benefits lead to improvements in more important clinical outcomes.

Clinical Epidemiology of Extubation Failure in the Pediatric Cardiac ICU: A Report From the Pediatric Cardiac Critical Care Consortium

Objective: To describe the clinical epidemiology of extubation failure in a multicenter cohort of patients treated in pediatric cardiac ICUs. Design: Retrospective cohort study using prospectively collected clinical registry data. Setting: Pediatric Cardiac Critical Care Consortium registry. Patients: All patients admitted to the CICU at Pediatric Cardiac Critical Care Consortium hospitals. Interventions: None. Measurements and Main Results: Analysis of all mechanical ventilation episodes in the registry from October 1, 2013, to July 31, 2014. The primary outcome of extubation failure was reintubation less than 48 hours after planned extubation. Repeated-measures analysis using generalized estimating equations to account for within patient and center correlation was performed to identify risk factors for extubation failure. Adjusted extubation failure rates for each hospital were calculated using logistic regression controlling for patient factors. Of 1,734 mechanical ventilation episodes (1,478 patients at eight hospitals) ending in a planned extubation, there were 100 extubation failures (5.8%). In multivariable analysis, only longer duration of mechanical ventilation was significantly associated with extubation failure (p = 0.01); the failure rate was 4% when ventilated less than 24 hours, 9% after 24 hours, and 13% after 7 days. For 503 patients intubated and extubated in the cardiac operating room, 15 patients (3%) failed extubation within 48 hours (12 within 24 hr). Case-mix-adjusted extubation failure rates ranged from 1.1% to 9.8% across hospitals. Patients failing extubation had greater median cardiac ICU length of stay (15 vs 3 d; p < 0.001) and in-hospital mortality (7.9 vs 1.2%; p < 0.001). Conclusions: Though extubation failure is uncommon overall, there may be opportunities to improve extubation readiness assessment in patients ventilated more than 24 hours. These data suggest that extubation in the operating room after cardiac surgery can be done with a low failure rate. We observed variation in extubation failure rates across hospitals, and future investigation must elucidate the optimal strategies of high-performing centers to reduce ventilation time while limiting extubation failures.

Prevention of hypovolemic circulatory collapse by IL-6 activated Stat3

Half of trauma deaths are attributable to hypovolemic circulatory collapse (HCC). We established a model of HCC in rats involving minor trauma plus severe hemorrhagic shock (HS). HCC in this model was accompanied by a 50% reduction in peak acceleration of aortic blood flow and cardiomyocyte apoptosis. HCC and apoptosis increased with increasing duration of hypotension. Apoptosis required resuscitation, which provided an opportunity to intervene therapeutically. Administration of IL-6 completely reversed HCC, prevented cardiac dysfunction and cardiomyocyte apoptosis, reduced mortality 5-fold and activated intracardiac signal transducer and activator of transcription (STAT) 3. Pre-treatment of rats with a selective inhibitor of Stat3, T40214, reduced the IL-6-mediated increase in cardiac Stat3 activity, blocked successful resuscitation by IL-6 and reversed IL-6-mediated protection from cardiac apoptosis. The hearts of mice deficient in the naturally occurring dominant negative isoform of Stat3, Stat3β, were completely resistant to HS-induced apoptosis. Microarray analysis of hearts focusing on apoptosis related genes revealed that expression of 29% of apoptosis related genes was altered in HS vs. sham rats. IL-6 treatment normalized the expression of these genes, while T40214 pretreatment prevented IL-6-mediated normalization. Thus, cardiac dysfunction, cardiomyocyte apoptosis and induction of apoptosis pathway genes are important components of HCC; IL-6 administration prevented HCC by blocking cardiomyocyte apoptosis and induction of apoptosis pathway genes via Stat3 and warrants further study as a resuscitation adjuvant for prevention of HCC and death in trauma patients.

Ultrasound-guided femoral vein catheterization in neonates with cardiac disease*.

Objective: To describe a novel technique for real-time, ultrasound-guided femoral vein catheterization in neonates with cardiac disease, and to compare it to a contemporaneous cohort of neonates undergoing femoral vein central venous line placement via landmark technique. Design: Retrospective cohort study of data extracted from a quality improvement database. Setting: Pediatric cardiac intensive care unit and cardiovascular operating room in pediatric tertiary hospital. Patients: One hundred fifteen neonates (mean weight, 3.07 ± 0.41 kg) with cardiac disease who underwent femoral central venous line attempts from January 2009 to September 2011. Measurements and Main Results: Study populations were similar in age, weight, and Risk Adjustment for Congenital Heart Surgery-1 category, but differed in intubation status (32% vs. 100%, ultrasound vs. landmark, p < .0001). Central venous line success rate was superior in the ultrasound group: 72 of the 76 (94.7%) vs. 31 of the 39 (79.5%), p = .02. Ultrasound group also had a superior first (75% vs. 30.8 %) and second attempt success rate (90.8% vs. 51.3%), p value for both < .0001. Inadvertent arterial puncture occurred less frequently in the ultrasound group: four of the 76 (5.3%) vs. nine of the 39 (23.1%), p = .01. There was a trend toward more venous thrombosis in the landmark group, 16 of the 39 (41%) vs. 18 of the 76 (23.7%), p = .08. Among all 115 subjects, there was a very strong association between greater than two central venous line attempts and the odds of being diagnosed with a deep venous thrombosis (odds ratio, 9.3; 95% confidence interval 3.5–24.8) and the odds of suffering an inadvertent femoral arterial puncture during the central venous line event (odds ratio, 8.8; 95% confidence interval 10.6–730). Conclusions: This novel long-axis real-time ultrasound technique facilitates placement of femoral vein central venous line in critically ill neonates with cardiac disease at a higher rate of success with fewer attempts and lower occurrence of complications when compared with the landmark technique.

Preoperative Trophic Feeds in Neonates with Hypoplastic Left Heart Syndrome

OBJECTIVE The aim of this is study is to determine if preoperative trophic feeds (TFs) can improve outcomes after Norwood palliation. DESIGN This is a retrospective cohort study. SETTING The setting is a pediatric cardiovascular intensive care unit in a tertiary hospital. PATIENTS The patients were 50 consecutive patients with hypoplastic left heart, excluding 5 patients with prematurity or other significant comorbidities. Thirty-one patients that received preoperative TFs (20-30 mL/kg) were compared with 14 that remained nothing by mouth. Decision to initiate feeds was based on attending preference. All patients had protocolized feeds postoperatively, with initiation via transpyloric tube when patient was on minimal inotropes. OUTCOME MEASURES Demographic, feeding, and other clinical outcome data were collected retrospectively from the patient medical record. RESULTS There were no differences in demographics or preoperative risk factors (mechanical ventilation and lowest pH) between the two groups. Overall survival to discharge was 78% (25/31 TF, 10/14 nothing by mouth, P = .7). Neonates receiving TFs had less fluid administration in the cardiovascular operating room (P = .002), a more negative 48-hour postoperative fluid balance (P = .03), and median 3 days shorter duration of mechanical ventilation (P = .006). Trophic feeds patients also had a nonsignificant trend toward lower peak lactic acid (P = .06), lower inotropic score (P = .15), shorter hospital length of stay (P = .19), and faster time to tolerance of full enteral and oral feeds by 3 and 8 days, respectively (P = .06 and .01). There were no episodes of necrotizing enterocolitis in either group. CONCLUSIONS Preoperative TFs before Norwood palliation appear safe and are associated with shorter duration of mechanical ventilation, a trend toward more stable postoperative hemodynamics, less fluid overload, and earlier postoperative feeding tolerance.