Selma O. Algra

Neurological Injury After Neonatal Cardiac Surgery A Randomized, Controlled Trial of 2 Perfusion Techniques

Background— Complex neonatal cardiac surgery is associated with cerebral injury. In particular, aortic arch repair, requiring either deep hypothermic circulatory arrest (DHCA) or antegrade cerebral perfusion (ACP), entails a high risk of perioperative injury. It is unknown whether ACP results in less cerebral injury than DHCA. Methods and Results— Thirty-seven neonates with an aortic arch obstruction presenting for univentricular or biventricular repair were randomized to either DHCA or ACP. Preoperatively and 1 week after surgery, magnetic resonance imaging was performed in 36 patients (1 patient died during the hospital stay). The presence of new postoperative cerebral injury was scored, and results were entered into a sequential analysis, which allows for immediate data analysis. After the 36th patient, it was clear that there was no difference between DHCA and ACP in terms of new cerebral injury. Preoperatively, 50% of patients had evidence of cerebral injury. Postoperatively, 14 of 18 DHCA patients (78%) had new injury versus 13 of 18 ACP patients (72%) (P=0.66). White matter injury was the most common type of injury in both groups, but central infarctions occurred exclusively after ACP (0 vs 6/18 [33%]; P=0.02). Early motor and cognitive outcomes at 24 months were assessed and were similar between groups (P=0.28 and P=0.25, respectively). Additional analysis revealed lower postoperative arterial PCO2 as a risk factor for new white matter injury (P=0.04). Conclusions— In this group of neonates undergoing complex cardiac surgery, we were unable to demonstrate a difference in the incidence of perioperative cerebral injury after ACP compared with DHCA. Both techniques resulted in a high incidence of new white matter injury, with central infarctions occurring exclusively after ACP. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01032876.Background— Complex neonatal cardiac surgery is associated with cerebral injury. In particular, aortic arch repair, requiring either deep hypothermic circulatory arrest (DHCA) or antegrade cerebral perfusion (ACP), entails a high risk of perioperative injury. It is unknown whether ACP results in less cerebral injury than DHCA.nnMethods and Results— Thirty-seven neonates with an aortic arch obstruction presenting for univentricular or biventricular repair were randomized to either DHCA or ACP. Preoperatively and 1 week after surgery, magnetic resonance imaging was performed in 36 patients (1 patient died during the hospital stay). The presence of new postoperative cerebral injury was scored, and results were entered into a sequential analysis, which allows for immediate data analysis. After the 36th patient, it was clear that there was no difference between DHCA and ACP in terms of new cerebral injury. Preoperatively, 50% of patients had evidence of cerebral injury. Postoperatively, 14 of 18 DHCA patients (78%) had new injury versus 13 of 18 ACP patients (72%) ( P =0.66). White matter injury was the most common type of injury in both groups, but central infarctions occurred exclusively after ACP (0 vs 6/18 [33%]; P =0.02). Early motor and cognitive outcomes at 24 months were assessed and were similar between groups ( P =0.28 and P =0.25, respectively). Additional analysis revealed lower postoperative arterial Pco2 as a risk factor for new white matter injury ( P =0.04).nnConclusions— In this group of neonates undergoing complex cardiac surgery, we were unable to demonstrate a difference in the incidence of perioperative cerebral injury after ACP compared with DHCA. Both techniques resulted in a high incidence of new white matter injury, with central infarctions occurring exclusively after ACP.nnClinical Trial Registration— URL: . Unique identifier: [NCT01032876][1].nn# CLINICAL PERSPECTIVE {#article-title-31}nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01032876&atom=%2Fcirculationaha%2F129%2F2%2F224.atom

Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery

AbstractBackgroundA robust inflammatory response occurs in the hours and days following cerebral ischemia. However, little is known about the immediate innate immune response in the first minutes after an ischemic insult in humans. We utilized the use of circulatory arrest during cardiac surgery to assess this.MethodsTwelve neonates diagnosed with an aortic arch obstruction underwent cardiac surgery with cardiopulmonary bypass and approximately 30xa0minutes of deep hypothermic circulatory arrest (DHCA, representing cerebral ischemia). Blood samples were drawn from the vena cava superior immediately after DHCA and at various other time points from preoperatively to 24xa0hours after surgery. The innate immune response was assessed by neutrophil and monocyte count and phenotype using FACS, and concentrations of cytokines IL-1β, IL-6, IL-8, IL-10, TNFα, sVCAM-1 and MCP-1 were assessed using multiplex immunoassay. Results were compared to a simultaneously drawn sample from the arterial cannula. Twelve other neonates were randomly allocated to undergo the same procedure but with continuous antegrade cerebral perfusion (ACP).ResultsImmediately after cerebral ischemia (DHCA), neutrophil and monocyte counts were higher in venous blood than arterial (P = 0.03 and P = 0.02 respectively). The phenotypes of these cells showed an activated state (both P <0.01). Most striking was the increase in the ‘non-classical’ monocyte subpopulations (CD16intermediate; arterial 6.6% vs. venous 14%; CD16+ 13% vs. 22%, both P <0.01). Also, higher IL-6 and lower sVCAM-1 concentrations were found in venous blood (both P = 0.03). In contrast, in the ACP group, all inflammatory parameters remained stable.ConclusionsIn neonates, approximately 30xa0minutes of cerebral ischemia during deep hypothermia elicits an immediate innate immune response, especially of the monocyte compartment. This phenomenon may hold important clues for the understanding of the inflammatory response to stroke and its potentially detrimental consequences.Trial registrationClinicalTrial.gov: nNCT01032876

Bedside prediction rule for infections after pediatric cardiac surgery

PurposeInfections after pediatric cardiac surgery are a common complication, occurring in up to 30% of cases. The purpose of this study was to develop a bedside prediction rule to estimate the risk of a postoperative infection.MethodsAll consecutive pediatric cardiac surgery procedures between April 2006 and May 2009 were retrospectively analyzed. The primary outcome variable was any postoperative infection, as defined by the Center of Disease Control (2008). All variables known to the clinician at the bedside at 48xa0h post cardiac surgery were included in the primary analysis, and multivariable logistic regression was used to construct a prediction rule.ResultsA total of 412 procedures were included, of which 102 (25%) were followed by an infection. Most infections were surgical site infections (26% of all infections) and bloodstream infections (25%). Three variables proved to be most predictive of an infection: age less than 6xa0months, postoperative pediatric intensive care unit (PICU) stay longer than 48xa0h, and open sternum for longer than 48xa0h. Translation into prediction rule points yielded 1, 4, and 1 point for each variable, respectively. Patients with a score of 0 had 6.6% risk of an infection, whereas those with a maximal score of 6 had a risk of 57%. The area under the receiver operating characteristic curve was 0.78 (95% confidence interval 0.72–0.83).ConclusionsA simple bedside prediction rule designed for use at 48xa0h post cardiac surgery can discriminate between children at high and low risk for a subsequent infection.

Increasing duration of circulatory arrest, but not antegrade cerebral perfusion, prolongs postoperative recovery after neonatal cardiac surgery.

OBJECTIVEnDeep hypothermic circulatory arrest (DHCA) and antegrade cerebral perfusion (ACP) are 2 cardiopulmonary bypass techniques applied in aortic arch repair. In recent literature, cerebral effects of both techniques have received most attention, whereas the consequences for other organs have not been thoroughly investigated. Therefore, in this study, the impact of duration of DHCA and ACP on postoperative recovery was analyzed in a cohort of neonates undergoing aortic arch reconstruction.nnnMETHODSnAll consecutive neonates who underwent aortic arch reconstruction from 2004 to 2009 were included in this retrospective study. Length of stay on the intensive care unit (ICU-LOS), duration of mechanical ventilation, inotrope score, and areas under the curve (AUC) for lactate and creatinine were compared with respect to durations of DHCA and ACP, respectively. Correction for confounders was performed using multivariable linear regression.nnnRESULTSnEighty-three neonates were included, with a 30-day mortality of 4.8%. Longer duration of DHCA was associated with longer ICU-LOS both in univariable and multivariable analyses. Similarly, duration of mechanical ventilation and lactate and creatinine AUCs increased with duration of DHCA. Inotrope score was only associated with DHCA duration in univariable analysis. Duration of ACP did not affect any of the outcome parameters.nnnCONCLUSIONSnIncreasing duration of DHCA, but not ACP, during neonatal aortic arch reconstruction prolongs short-term postoperative recovery. This suggests all efforts should be made to reduce the duration of DHCA to the shortest period possible, which may be achieved by exclusive use of ACP or a combination of the 2 perfusion techniques.

Low-flow antegrade cerebral perfusion attenuates early renal and intestinal injury during neonatal aortic arch reconstruction

OBJECTIVEnDeep hypothermic circulatory arrest (DHCA) and antegrade cerebral perfusion (ACP) are 2 cardiopulmonary bypass strategies mainly used in aortic arch reconstructions. It has been suggested that during ACP, abdominal organs are better protected than during DHCA owing to partial perfusion via collaterals. We tested this hypothesis using intraoperative near-infrared spectroscopy (NIRS), lactate measurements, and biomarkers for early abdominal injury in neonates undergoing complex aortic arch repair.nnnMETHODSnNeonates scheduled for aortic arch reconstruction via median sternotomy between 2009 and 2011 were randomized to either DHCA or ACP. During surgery, regional oxygen saturations of the abdomen were monitored using NIRS. Immediately aafter DHCA or ACP, lactate concentrations from the inferior vena cava were compared with those from the arterial cannula. Postoperatively, biomarkers for early abdominal organ injury were measured in urine.nnnRESULTSnTwenty-five neonates were analyzed (DHCA, nxa0=xa012; ACP, nxa0=xa013). Procedures were performed at 18°C, and ACP flow was set at 35 to 50 mL · kg(-1) · min(-1). Median abdominal NIRS value during DHCA was 31% (IQR, 28%-41%) whereas during ACP it was 56% (IQR, 34%-64%; Pxa0<xa0.01 between groups). Immediately after DHCA, median lactate from the inferior vena cava was 4.2 mmol/L (IQR, 3.3-5.3 mmol/L) compared with 3.1 mmol/L (IQR, 2.9-4.4 mmol/L) after ACP (Pxa0=xa0.03). Postoperatively, biomarkers for renal and intestinal damage (gluthatione s-transferase and intestinal fatty acid binding protein, respectively) were higher in the DHCA group than for the ACP group (Pxa0=xa0.03, Pxa0=xa0.04, respectively).nnnCONCLUSIONSnThese results substantiate earlier suggestions that ACP provides more abdominal organ protection than DHCA in neonates undergoing aortic arch reconstruction.

Differential homeostatic dynamics of human regulatory T-cell subsets following neonatal thymectomy.

Disclosure of potential conflict of interest: R. P. Schleimer has consultant arrangementswith Interesect ENT, GlaxoSmithKline, Allakos, and Aurasense. L. C. Grammer has received grants and travel support for meetings or other purposes from the National Institutes of Health (NIH); has received grants from the Bazley Foundation; has consultant arrangements with Atellas Pharmaceuticals; is employed by Northwestern University and the Northwestern Medical Faculty Foundation; has grants/grants pending with the NIH, the Food Allergy Network, and SC has received payment for lectures, including service on speakers’ bureaus, from theAmericanAcademy ofAllergy, Asthma & Immunology and Mount Sinai; and receives royalties from Lippincott, UpToDate, BMJ, and Elsevier. B. K. Tan has received grants from the NIH and the Triological Society/American College of Surgeons; has consultant arrangements with Acclarent, Inc, and has received travel/accommodations/meeting expenses from the Foundation for Innovation, Education, and Research in Otorhinolaryngology. T. R. Torgerson has consultant arrangements with Baxter Biosciences and BDBiosciences; has grants/grants pending with Baxter Biosciences and CSL Behring; has received payment for lectures, including service on speakers’ bureaus, from Baxter Biosciences; receives royalties from New England Biolabs; and receives payment for the development of educational presentations from Baxter Biosciences. K. E. Harris has received grants from the NIH/ National Heart, Lung and Blood Institute (grant no. R37L068546 and grant no. R01HL078860), the NIH/National Institute for Allergy and Infectious Disease (grant no. T32A1083216), and the Ernest S. Bazley Trust. A. T. Peters has received payment for lectures, including service on speakers’ bureaus, from Baxter. A. Kato has received a grant from the NIH (grant no. R21HL113913). The rest of the authors declare that they have no relevant conflicts of interest.

Perioperative and bedside cerebral monitoring identifies cerebral injury after surgical correction of congenital aortic arch obstruction

Dear Editor, It is becoming increasingly clear that although life-saving, infant cardiac surgery encompasses a high risk of brain injury. Perioperatively performed MRI scans show the injury in most detail (in 40–70 % of complex cardiac cases), most commonly in the form of white matter injury [1]. In later childhood patients have an increased risk of delay in neurocognitive and motor development [2]. In our cohort of neonates undergoing aortic arch reconstruction while on cardiopulmonary bypass and cooling to deep hypothermia (n = 37), we assessed brain injury pre-, intraand postoperatively using multiple modalities: MRI scans acquired before and after surgery, and perioperative cerebral monitoring using near-infrared spectroscopy (NIRS), amplitude-integrated encephalography (aEEG) and serumbased biomarkers s100b and NSE (for details, see Electronic Supplemental Material). As recently published, we found new postoperative MRI injury in 55 % of patients, and at 2 years of age (n = 32), three patients had cerebral palsy, one had a mild motor delay (total motor delay of 13 %) and two had a cognitive delay (6 %) [3]. As MRI is not always feasible in critically ill patients, we sought to find a bedside marker of cerebral injury for direct use in the paediatric intensive care unit and found that the presence of aEEG seizure activity postoperatively correlated with new MRI injury; thus, 10 of 11 patients with aEEG seizures had a new injury, compared to 9 of 24 patients with a normal aEEG (p 0.01, see Fig. 1a). Also, when assessing the relationship with neurodevelopmental outcome, there was a significant relationship between these aEEG abnormalities and a worse motor outcome (median Psychomotor Developmental Index (PDI) 105 vs. 100, p = 0.03), but not cognitive outcome (median Mental Developmental Index (MDI) 100 vs. 100, p = 0.10; see Fig. 1b). When assessing NIRS measurements, we could not find any correlation to MRI or neurodevelopmental outcome. NSE and s100b did show a relationship with respectively worse motor and cognitive outcome when measured at 4 h after surgery (p 0.01 and p = 0.04; for details of statistical analyses, see Electronic Supplemental Material). The results are in line with those previously published by Clancy et al., who also saw a correlation between conventional EEG and MRI injury in a heterogeneous group of infants undergoing cardiac surgery [4]. In contrast, Gunn et al. did not find a

Minimizing the Risk of Preoperative Brain Injury in Neonates with Aortic Arch Obstruction

OBJECTIVEnTo determine whether prenatal diagnosis lowers the risk of preoperative brain injury by assessing differences in the incidence of preoperative brain injury across centers.nnnSTUDY DESIGNnFrom 2 prospective cohorts of newborns with complex congenital heart disease studied by preoperative cerebral magnetic resonance imaging, one cohort from the University Medical Center Utrecht (UMCU) and a combined cohort from the University of California San Francisco (UCSF) and University of British Columbia (UBC), patients with aortic arch obstruction were selected and their imaging and clinical course reviewed.nnnRESULTSnBirth characteristics were comparable between UMCU (n = 33) and UCSF/UBC (n = 54). Patients had a hypoplastic aortic arch with either coarctation/interruption or hypoplastic left heart syndrome. In subjects with prenatal diagnosis, there was a significant difference in the prevalence of white matter injury (WMI) between centers (11 of 22 [50%] at UMCU vs 4 of 30 [13%] at UCSF/UBC; P < .01). Prenatal diagnosis was protective for WMI at UCSF/UBC (13% prenatal diagnoses vs 50% postnatal diagnoses; P < .01), but not at UMCU (50% vs 46%, respectively; P > .99). Differences in clinical practice between prenatally diagnosed subjects at UMCU vs UCSF/UBC included older age at surgery, less time spent in the intensive care unit, greater use of diuretics, less use of total parenteral nutrition (P < .01), and a greater incidence of infections (P = .01). In patients diagnosed postnatally, the prevalence of WMI was similar in the 2 centers (46% at UMCU vs 50% at UCSF/UBC; P > .99). Stroke prevalence was similar in the 2 centers regardless of prenatal diagnosis (prenatal diagnosis: 4.5% at Utrecht vs 6.7% at UCSF/UBC, P = .75; postnatal diagnosis: 9.1% vs 13%, respectively, P > .99).nnnCONCLUSIONnPrenatal diagnosis can be protective for WMI, but this protection may be dependent on specific clinical management practices that differ across centers.

Perioperative neonatal brain injury is associated with worse school-age neurodevelopment in children with critical congenital heart disease

To assess the impact of perioperative neonatal brain injury and brain volumes on neurodevelopment throughout school‐age children with critical congenital heart disease (CHD).

Amplitude-Integrated Electroencephalography for Early Recognition of Brain Injury in Neonates with Critical Congenital Heart Disease

Objective To study perioperative amplitude‐integrated electroencephalography (aEEG) as an early marker for new brain injury in neonates requiring cardiac surgery for critical congenital heart disease (CHD). Study design This retrospective observational cohort study investigated 76 neonates with critical CHD who underwent neonatal surgery. Perioperative aEEG recordings were evaluated for background pattern (BGP), sleep‐wake cycling (SWC), and ictal discharges. Spontaneous activity transient (SAT) rate, inter‐SAT interval (ISI), and percentage of time with an amplitude <5 &mgr;V were calculated. Routinely obtained preoperative and postoperative magnetic resonance imaging of the brain were reviewed for brain injury (moderate‐severe white matter injury, stroke, intraparenchymal hemorrhage, or cerebral sinovenous thrombosis). Results Preoperatively, none of the neonates showed an abnormal BGP (burst suppression or worse) or ictal discharges. Postoperatively, abnormal BGP was seen in 18 neonates (24%; 95% CI, 14%‐33%) and ictal discharges was seen in 13 neonates (17%; 95% CI, 8%‐26%). Abnormal BGP and ictal discharges were more frequent in neonates with new postoperative brain injury (P = .08 and .01, respectively). Abnormal brain activity (ie, abnormal BGP or ictal discharges) was the single risk factor associated with new postoperative brain injury in multivariable logistic regression analysis (OR, 4.0; 95% CI, 1.3‐12.3; P = .02). Postoperative SAT rate, ISI, or time <5 &mgr;V were not associated with new brain injury. Conclusion Abnormal brain activity is an early, bedside marker of new brain injury in neonates undergoing cardiac surgery. Not only ictal discharges, but also abnormal BGP, should be considered a clear sign of underlying brain pathology.