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1.  Changes in arterial blood PO2, PCO2, and pH during deep hypothermic circulatory arrest in adults. 
Journal of Korean Medical Science  1997;12(3):199-203.
Safe limits of time and temperature during sleep hypothermic circulatory arrest (DHCA) still remain controversial. Furthermore, continuous changes of PaO2, PaCO2, and pH have never been measured during DHCA in humans. Continuous intraarterial blood gas (CIABG) monitoring is a new technology allowing us to study chronological changes occurring due to metabolism during DHCA. When the patients' temperature reached 18 approximately 20 degrees C following establishment of cardiopulmonary bypass (CPB), circulatory arrest was initiated. After a 20-minute period of DHCA, reperfusion commenced with 18 degree C blood. We continuously monitored PaO2, PaCO2, and pH immediately before, during and following DHCA. Data was analyzed by Student's t-test. PaO2, PaCO2, and pH of pre- and 5 minutes post DHCA were not significantly different from each other. However, during DHCA, the PaO2 was significantly decreased from 229 +/- 34 to 30 +/- 23 mmHg at 20-minute intervals. But the PaCO2 increased significantly after 20 minutes of circulatory arrest from 34 +/- 5 to 42 +/- 6 mmHg. However, the pH did not change significantly over the 20-minute period. The PaO2 level after 20 minutes is much lower than before DHCA, it would be well tolerated in normothermic adults. The PO2 level in the brain may be even lower given its high metabolic rate. So measuring arterial PO2 continuously during DHCA may provide a surrogate method for determining maximum safe time under DHCA for adults.
PMCID: PMC3054295  PMID: 9250914
2.  A meta-analysis of deep hypothermic circulatory arrest alone versus with adjunctive selective antegrade cerebral perfusion 
Annals of Cardiothoracic Surgery  2013;2(3):261-270.
Recognizing the importance of neuroprotection in aortic arch surgery, deep hypothermic circulatory arrest (DHCA) now underpins operative practice as it minimizes cerebral metabolic activity. When prolonged periods of circulatory arrest are required, selective antegrade cerebral perfusion (SACP) is supplemented as an adjunct. However, concerns exist over the risks of SACP in introducing embolism and hypo- and hyper-perfusing the brain. The present meta-analysis aims to compare postoperative outcomes in arch surgery using DHCA alone or DHCA + SACP as neuroprotection strategies.
Electronic searches were performed using six databases from their inception to January 2013. Two reviewers independently identified all relevant studies comparing DHCA alone with DHCA + SACP. Data were extracted and meta-analyzed according to pre-defined clinical endpoints.
Nine comparative studies were identified in the present meta-analysis, with 648 patients employing DHCA alone and 370 utilizing DHCA + SACP. No significant differences in temporary or permanent neurological outcomes were identified. DHCA + SACP was associated with significantly better survival outcomes (P=0.008, I2=0%), despite longer cardiopulmonary bypass time. Infrequent and inconsistent reporting of other clinical results precluded analysis of systemic outcomes.
The present meta-analysis indicate the superiority of DHCA + SACP in terms of mortality outcomes.
PMCID: PMC3741855  PMID: 23977593
Deep hypothermic circulatory arrest; antegrade cerebral perfusion; aortic arch surgery; meta-analysis
3.  Modified hypothermic circulatory arrest for emergent repair of acute aortic dissection type a: a single-center experience 
Deep hypothermic circulatory arrest (DHCA) with antegrade cerebral perfusion has been historically preferred for organ protection during surgical repair of the acute aortic dissection type A. However, in the past decades, different perfusion-specific strategies with a growing trend to increase the body temperature at circulatory arrest emerged. In this study, we retrospectively analyzed the clinical results of our modified protocol for cardiopulmonary bypass and hypothermia management.
Between February 2007 and September 2012, 54 consecutive patients suffering from acute aortic dissection type A underwent emergent surgery. All patients received hypothermic circulatory arrest in combination with antegrade cerebral perfusion. The patients were divided into two subsets according to the degree of hypothermia and perfusion strategies: namely the DHCA group and the group of modified hypothermic circulatory arrest (MHCA).
The overall 30-day mortality was 27.8% and was not significantly different between groups (DHCA, 33.3%, MHCA, 19%; p=0.253). The requirement for blood product transfusion in MHCA patients was significantly less as as compared with the patients in the DHCA group. No difference occurred in the incidence of temporary neurologic dysfunction, dialysis-dependent renal failure, or reexploration for bleeding between two groups of patients. The use of MHCA was identified as a protective factor against the postoperative composite complications (OR, 0.78; CI, 0.52 to 0.98; p=0.04) and the prolonged intensive care unit stay (OR, 0.8; 95% CI, 0.56 to 0.98; p=0.04).
Moderate hypothermia in combination with selective brain perfusion and systemic retrograde perfusion is associated with adequate cerebral and visceral protection, reduced postoperative complications and shortened intensive care unit stay in our series. This modified perfusion strategy may help in improving perioperative outcomes in this particular group of patients.
PMCID: PMC3658869  PMID: 23659191
Acute aortic dissection; Hypothermia; Circulatory arrest; Aortic surgery
4.  Outcomes after ascending aorta and proximal aortic arch repair using deep hypothermic circulatory arrest with retrograde cerebral perfusion: analysis of 207 patients 
Correction of ascending aorta and proximal aortic arch pathology with numerous surgical techniques having been proposed over the years remains a surgical challenge. This study was undertaken to identify risk factors influencing outcome after aortic arch operations, requiring deep hypothermic circulatory arrest (DHCA).
Between 1993 and 2010, 207 consecutive patients were operated for ascending aorta and proximal arch correction with the use of deep hypothermic circulatory arrest with retrograde cerebral perfusion. All patients were followed up with regular out-patient clinics, transthoracic echocardiography and, when required, chest computed tomography.
There were 102 (49.3%) emergencies (acute type A dissection) and 105 (50.7%) elective cases. Mean age: 63.5 ± 12 years. Mean circulatory arrest time was 25.4 ± 13 min. Unadjusted analysis of factors associated with 30-day mortality revealed emergency status, preoperative hemodynamic instability, acute dissection, reoperation, increased circulatory arrest time, postoperative bleeding, postoperative creatinine levels and presence of neurological dysfunction. Multi-adjusted analysis revealed duration of circulatory arrest as the only and main factor related to death. Thirty-day mortality was 2.4% for the elective and 7.2% for emergencies cases. Survival during long-term follow-up was 93, 82 and 53% at 1, 5 and 10 years, respectively.
Ascending aorta and proximal aortic arch replacement with brief duration of deep hypothermic circulatory arrest combined with retrograde cerebral perfusion is a safe method with acceptable short- and long-tem results.
PMCID: PMC3422955  PMID: 22687431
Aorta; Aortic arch; Thoracic aorta; Aneurysm; Cardiopulmonary bypass
5.  Selective antegrade cerebral perfusion reduces brain injury following deep hypothermic circulatory arrest in the piglets’ model by decreasing the levels of protein SUMO2/3-ylation 
Selective antegrade cerebral perfusion (SACP), which was adopted by many surgical groups for complex neonatal cardiac surgery, especially aortic arch repair, is a proven adjunct for neuroprotection during deep hypothermic circulatory arrest (DHCA). Several recent studies suggest that SUMO2/3 modification of proteins is markedly activated during deep hypothermia and believed to be an endogenous neuroprotective stress response. Here, we report that SACP reduces the increasing degree of SUMO2/3 conjugation following DHCA. Piglets were subjected to 1 h SACP and/or 1 h DHCA. DHCA was sufficient to markedly increase in protein SUMOylation by SUMO2/3 both in the hippocampus and cerebral cortex. SACP, especially at flow rate of 50 ml/kg/min, reduces the increasing degree of SUMO2/3 conjugation and also reduces levels of pro-apoptotic factors, Bax and Caspase 3, and increases levels of antiapoptotic factors, Bcl-2, following DHCA both in the hippocampus and cerebral cortex. This suggests that SACP at flow rate of 50 ml/kg/min is more appropriate for neuroprotection during DHCA in the pig model and level of protein SUMO2/3-ylation maybe an indicator of the degree of brain injury.
PMCID: PMC4276245  PMID: 25550987
Selective antegrade cerebral perfusion; SUMO2/3; deep hypothermic circulatory arrest; piglet; apoptosis; brain injury
6.  Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest? 
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest (DHCA)? Altogether, more than 62 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Four of the seven papers used thiopental alongside other neuroprotective methods and agents. The methods included the use of ice packs to the head and core systemic hypothermia. Agents used alongside thiopental included nicardipine and mannitol. Thiopental was found to have the ability to lower oxygen consumption, where oxygen consumption was measured using the phosphocreatinine and adenosine triphosphate ratio. The neuroprotective effect of thiopental was evaluated by assessing the electrical activity of the brain during circulatory arrest, by which it was shown to be advantageous. However, other trials suggested that adding thiopental during circulatory arrest did not provide any extra protection to the brain. The timing of thiopental administration is of importance in order to gain positive outcomes, as it's ability to lower the cerebral energy state may result in unfavourable results if added before hypothermic circulatory arrest, where this may lead to an ischaemic event. We conclude that the use of thiopental during deep hypothermic circulatory arrest is beneficial, but if administered too early, it may replete the cerebral energy state before arrest and prove to be detrimental.
PMCID: PMC3715186  PMID: 23644730
Thiopental; Barbiturate; Cerebral protection; Deep hypothermic circulatory arrest
7.  Results of Proximal Arch Replacement Using Deep Hypothermia for Circulatory Arrest: Is Moderate Hypothermia Really Justifiable? 
The American surgeon  2011;77(11):1438-1444.
The use of selective cerebral perfusion with warmer temperatures during circulatory arrest has been increasingly utilized for arch replacement over concerns regarding the safety of deep hypothermic circulatory arrest (DHCA). However, little data actually exists on outcomes following arch replacement and DHCA. This study examines modern results with DHCA for proximal arch replacement to provide a benchmark for comparison against outcomes with lesser degrees of hypothermia.
Between 7/2005–6/2010, 245 proximal arch replacements (“hemi-arch”) were performed using deep hypothermia; mean minimum core and nasopharyngeal temperatures were 18.0±2.1°C and 14.1±1.6°C, respectively. Adjunctive cerebral perfusion was used in all cases. Concomitant ascending aortic replacement was performed in 41%, ascending plus aortic valve replacement in 23%, and aortic root replacement in 32%.
Mean age was 58±14 years; 36% procedures were urgent/emergent. Mean duration of DHCA was 20.4±6.2 minutes. Thirty day/in-hospital mortality was 2.9%. Rates of stroke, renal failure, and respiratory failure were 4.1% (0.8% for elective cases), 1.2%, and 0.4%, respectively.
Deep hypothermia with adjunctive cerebral perfusion for circulatory arrest during proximal arch replacement affords excellent neurologic as well as non-neurologic outcomes. Centers utilizing lesser degrees of hypothermia for arch surgery, the safety of which remains unproven, should ensure comparable results.
PMCID: PMC3732664  PMID: 22196653
aortic surgery; hemi-arch; circulatory arrest; hypothermia; aortic arch
8.  Plasma proteomic changes during hypothermic and normothermic cardiopulmonary bypass in aortic surgeries 
Deep hypothermic circulatory arrest (DHCA) is a protective method against brain ischemia in aortic surgery. However, the possible effects of DHCA on the plasma proteins remain to be determined. In the present study, we used novel high-throughput technology to compare the plasma proteomes during DHCA (22°C) with selective cerebral perfusion (SCP, n=7) to those during normothermic cardiopulmonary bypass (CPB, n=7). Three plasma samples per patient were obtained during CPB: T1, prior to cooling; T2, during hypothermia; T3, after rewarming for the DHCA group and three corresponding points for the normothermic group. A proteomic analysis was performed using isobaric tag for relative and absolute quantification (iTRAQ) labeling tandem mass spectrometry to assess quantitative protein changes. In total, the analysis identified 262 proteins. The bioinformatics analysis revealed a significant upregulation of complement activation at T2 in normothermic CPB, which was suppressed in DHCA. These findings were confirmed by the changes of the terminal complement complex (SC5b-9) levels. At T3, however, the level of SC5b-9 showed a greater increase in DHCA compared to normothermic CPB, while 48 proteins were significantly downregulated in DHCA. The results demonstrated that DHCA and rewarming potentially exert a significant effect on the plasma proteome in patients undergoing aortic surgery.
PMCID: PMC4152143  PMID: 25050567
cardiopulmonary bypass; deep hypothermic circulatory arrest; proteomics; complement activation; biocompatibility
9.  Deep Hypothermic Circulatory Arrest Does Not Impair Neurodevelopmental Outcome in School-Age Children After Infant Cardiac Surgery 
The Annals of Thoracic Surgery  2010;90(6):1985-1995.
The purpose of this study was to assess deep hypothermic circulatory arrest (DHCA) as a modifier of neurodevelopmental (ND) outcomes in preschool children after cardiac surgery in infancy for repair of congenital heart defects (CHD).
This is a planned analysis of infants enrolled in a prospective study of apolipoprotein E polymorphisms and ND outcome after cardiac surgery. The effect of DHCA was assessed in patients with single or biventricular CHD without aortic arch obstruction. Neurodevelopmental assessment at 4 years of age included cognition, language, attention, impulsivity, executive function, social competence, and visual-motor and fine-motor skills. Patient and procedural variables were evaluated in univariate and multivariate models.
Neurodevelopmental testing was completed in 238 of 307 eligible patients (78%). Deep hypothermic circulatory arrest was used at the discretion of the surgeon at least once in 92 infants (38.6%) with a median cumulative duration of 36 minutes (range, 1 to 132 minutes). By univariate analysis, DHCA patients were more likely to have single-ventricle CHD (p = 0.013), lower socioeconomic status (p < 0.001), a higher incidence of preoperative ventilation (p < 0.001), and were younger and smaller at the first surgery (p < 0.001). By multivariate analysis, use of DHCA was not predictive of worse performance for any ND outcome.
In this cohort of children undergoing repair of CHD in infancy, patients who underwent DHCA had risk factors associated with worse ND outcomes. Despite these, use of DHCA for repair of single-ventricle and biventricular CHD without aortic arch obstruction was not predictive of worse performance for any ND domain tested at 4 years of age.
PMCID: PMC3297076  PMID: 21095350
10.  Current conduct of deep hypothermic circulatory arrest in China 
Deep hypothermic circulatory arrest for adult aortic arch repair is still associated with significant mortality and morbidity. Furthermore, there is still significant variation in the conduct of this complex perioperative technique. This variation in deep hypothermic circulatory arrest practice has not been adequately characterized and may offer multiple opportunities for outcome enhancement. The hypothesis of this study was that the current practice of adult deep hypothermic circulatory arrest in China has significant variations that might offer therapeutic opportunities for reduction of procedural risk.
An adult deep hypothermic circulatory arrest questionnaire was developed and then administered at a thoracic aortic session at the International Cardiothoracic and Vascular Anesthesia Congress convened in Beijing during 2010. The data was abstracted and analyzed.
The majority of the 56 respondents were anesthesiologists based in China at low-volume deep hypothermic circulatory arrest centers. The typical aortic arch repair had a prolonged deep hypothermic circulatory arrest time at profound hypothermia. The target temperature for deep hypothermic circulatory arrest was frequently measured distal to the brain. The most common perfusion adjunct was antegrade cerebral perfusion, typically monitored with radial arterial pressure and cerebral venous oximetry. The preferred neuroprotective agents were steroids and propofol.
The identified opportunities for outcome improvement in this delineated deep hypothermic circulatory arrest model include nasal/tympanic temperature measurement and routine cerebral perfusion, preferably with unilateral antegrade cerebral perfusion monitored with radial artery pressure and cerebral oximetry. Development and dissemination of an evidence-based consensus would enhance these practice-improvement opportunities.
PMCID: PMC3670723  PMID: 23734286
adult aortic arch repair; deep hypothermic circulatory arrest; China; temperature monitoring; retrograde cerebral perfusion; antegrade cerebral perfusion; steroids; propofol; neuroprotection; cerebral oximetry; questionnaire; practice variation; radial artery pressure; cardiopulmonary bypass
11.  Cerebral Tissue Hemoglobin Saturation in Children with Sickle Cell Disease 
Pediatric blood & cancer  2012;59(5):881-887.
Desaturation of hemoglobin (Hb) in cerebral tissue, a physiologic marker of brain vulnerable to ischemic injury, can be detected non-invasively by transcranial oximetry. Absolute cerebral oximetry has not been studied in sickle cell disease (SCD), a group at very high risk of cerebral infarction in whom prevention of brain injury is key.
We measured absolute Hb saturation in cerebral tissue (SCTO2) in children with SCD using near-infrared spectrophotometry and investigated the contributions of peripheral Hb saturation (SPO2), hematologic measures, cerebral arterial blood flow velocity, and cerebral arterial stenosis to SCTO2. We also assessed the effects of transfusion.
We studied 149 children with SCD (112 HbSS/Sβ0; 37 HbSC/Sβ+). SCTO2 was abnormally low in 75% of HbSS/Sβ0 and 35% of HbSC/Sβ+ patients. SCTO2 (mean±SD) was 53.2±14.2 in HbSS/Sβ0 and 66.1±9.2% in SC/Sβ+ patients. SCTO2 correlated with age, sex, Hb concentration, reticulocytes, Hb F, and SPO2, but not transcranial Doppler arterial blood flow velocities as continuous measures. In multivariable models, SPO2, Hb concentration, and age were significant independent determinants of SCTO2. Cerebral vasculopathy was associated with ipsilateral cerebral desaturation. Transfusion increased SCTO2 and minimized the inter-hemispheric differences in SCTO2 due to vasculopathy.
Cerebral desaturation, a physiologic marker of at-risk brain, is common in SCD, more severe in HbSS/Sβ0 patients, and associated with peripheral desaturation, more severe anemia, and increasing age. Cerebral oximetry has the potential to improve the identification of children with SCD at highest risk of neurologic injury and possibly serve as a physiologic guide for neuroprotective therapy.
PMCID: PMC3534844  PMID: 22678814
sickle cell disease; desaturation; hypoxemia; brain; risk factor; stroke
12.  Brain oxygen and metabolism during circulatory arrest with intermittent brief periods of low-flow cardiopulmonary bypass in newborn piglets 
We performed this study to determine whether brief intermittent periods of low-flow cardiopulmonary bypass during deep hypothermic circulatory arrest would improve cortical metabolic status and prolong the “safe” time of deep hypothermic circulatory arrest.
After a 2-hour baseline, newborn piglets were placed on cardiopulmonary bypass and cooled to 18°C. The animals were then subjected to 80 minutes of deep hypothermic circulatory arrest interrupted by 5-minute periods of low-flow cardio-pulmonary bypass at either 20 mL · kg−1 · min−1 (LF-20) or 80 mL · kg−1 · min−1 (LF-80) during 20, 40, 60, and 80 minutes of deep hypothermic circulatory arrest. All animals were rewarmed, separated from cardiopulmonary bypass, and maintained for 2 hours (recovery). The oxygen pressure in the cerebral cortex was measured by the quenching of phosphorescence. The extracellular dopamine level in the striatum was determined by microdialysis. Results are means ± SD.
Prebypass oxygen pressure in the cerebral cortex was 65 ± 7 mm Hg. During the first 20 minutes of deep hypothermic circulatory arrest, cortical oxygen pressure decreased to 1.3 ± 0.4 mm Hg. Four successive intermittent periods of LF-20 increased cortical oxygen pressure to 6.9 ± 1.2 mm Hg, 6.6 ± 1.9 mm Hg, 5.3 ± 1.6 mm Hg, and 3.1 ± 1.2 mm Hg. During the intermittent periods of LF-80, cortical oxygen pressure increased to 21.1 ± 5.3 mm Hg, 20.6 ± 3.7 mm Hg, 19.5 ± 3.95 mm Hg, and 20.8 ± 5.5 mm Hg. A significant increase in extracellular dopamine occurred after 45 minutes of deep hypothermic circulatory arrest alone, whereas in the groups of LF-20 and LF-80, the increase in dopamine did not occur until 52.5 and 60 minutes of deep hypothermic circulatory arrest, respectively.
The protective effect of intermittent periods of low-flow cardiopulmonary bypass during deep hypothermic circulatory arrest is dependent on the flow rate. We observed that a flow rate of 80 mL · kg−1 · min−1 improved brain oxygenation and prevented an increase in extracellular dopamine release.
PMCID: PMC2778579  PMID: 17000295
13.  Predictors of Massive Transfusion with Thoracic Aortic Procedures Utilizing Deep Hypothermic Circulatory Arrest 
Massive perioperative blood product transfusion may be required with thoracic aortic operations and is associated with poor outcomes. Our objective was to determine the independent predictors of massive transfusion in thoracic aortic surgery patients undergoing deep hypothermic circulatory arrest (DHCA).
The study consisted of 168 consecutive patients undergoing open thoracic aortic procedure utilizing DHCA between July 2005 and August 2008. We identified 26 preoperative and procedural variables as being potentially related to blood product usage. We tested the variables for association with total blood products transfused using a multivariate linear regression model and then constructed a logistic regression model for massive transfusion, defined as requiring 5 or more units of transfused packed red blood cells between incision and 48 hours postoperatively.
Multivariate linear regression determined six significant variables as accounting for 42% of the variation in total blood products transfused: age (P=0.008), preoperative hemoglobin (P=0.04), weight (P=0.02), cardiopulmonary bypass time (P<0.0001), emergent status (P<0.0001), and re-do median sternotomy (P<0.0001). A final predictive logistic regression model associated every 1 g/dL increase in preoperative hemoglobin OR=0.54 [0.43, 0.69], P<0.0001; every 10 minute increase in CPB time, OR=1.15 [1.05, 1.26], P=0.0026; and emergent status OR=4.02 [1.53, 10.55], P=0.0047 with massive transfusion.
Our model described CPB time, emergent status, and preoperative hemoglobin as independent predictors of massive transfusion. These variables, along with weight, age, and re-do median sternotomy are associated with total blood product usage in thoracic aortic operations involving DHCA.
PMCID: PMC3677722  PMID: 21167511
14.  Usefulness of Deep Hypothermic Circulatory Arrest and Regional Cerebral Perfusion in Children 
To compare the safety and usefulness of deep hypothermic circulatory arrest (DHCA) and regional cerebral perfusion (RCP) during pediatric open heart surgery. Between January 1, 2004 and September 30, 2012, 1250 children with congenital cardiac defect underwent corrective operation with the DHCA or RCP technique in the Shanghai Children's Medical Center. Of them, 947 cases underwent the operation with the aid of DHCA (DHCA group), and 303 cases with RCP (RCP group). The mean DHCA time was 30.64±15.81 (7–63) minutes and mean RCP time was 36.18±12.86 (10–82) minutes. The mortality rate was 7.18% (68/947) and 6.60% (20/30) in two groups, respectively. The postoperative incidences of temporary and permanent neurological dysfunction were 6.23% (59/947) in the DHCA group and 2.64% (8/303) in the RCP group (p<0.01). The incidence of other complications such as low cardiac output, renal dysfunction, and lung issues are similar in both groups. RCP is a reliable technique for cerebral protection and it facilitates time-consuming corrected procedures for complex congenital cardiac defect repair procedures.
PMCID: PMC3770196  PMID: 24066266
15.  Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery 
A 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.
Twelve neonates diagnosed with an aortic arch obstruction underwent cardiac surgery with cardiopulmonary bypass and approximately 30 minutes 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 24 hours 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).
Immediately 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.
In neonates, approximately 30 minutes 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 registration NCT01032876
PMCID: PMC3599234  PMID: 23390999
Cardiac surgery; Cerebral blood flow; Hypothermia; Inflammation; Neonatal ischemia; Randomized controlled trials
16.  Is it worth packing the head with ice in patients undergoing deep hypothermic circulatory arrest? 
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Is it worth packing the head with ice in patients undergoing deep hypothermic circulatory arrest (DHCA)? Altogether more than 34 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question, 5 of which were animal studies, 1 was a theoretical laboratory study and 1 study looked at the ability to cool using circulating water ‘jackets’ in humans. There were no available human studies looking at the neurological outcome with or without topical head cooling with ice without further adjunct methods of cerebral protection. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Four papers studied animals undergoing DHCA for 45 min–2 h depending on the study design, with or without packing the head with ice. The studies all demonstrated improved cerebral cooling when the head was packed with ice during DHCA. They also illustrated an improved neurological outcome, with better behavioural scores (P < 0.05), and in some, survival, when compared with animals whose heads were not packed in ice. One study examined selective head cooling with the use of packing the head with ice during rewarming after DHCA. However, they demonstrated worse neurological outcomes in these animals, possibly due to the loss of cerebral vasoregulation and cerebral oedema. One study involved a laboratory experiment showing improved cooling using circulating cool water in cryotherapy braces than by using packed ice. They extrapolated that newer devices to cool the head may improve cerebral cooling during DHCA. The final study discussed here demonstrated the use of circulating water to the head in humans undergoing pulmonary endarterectomy. They found that tympanic membrane temperatures could be maintained significantly lower than bladder or rectal temperatures when using circulating water to cool the head. We conclude that topical head cooling with ice is of use during DHCA but not during rewarming following DHCA and that it may be possible to advance topical head cooling techniques using circulating water rather than packed ice.
PMCID: PMC3445357  PMID: 22745303
Deep hypothermic circulatory arrest; Topical cooling; Head cooling; Topical hypothermia
17.  Increasing duration of deep hypothermic circulatory arrest is associated with an increased incidence of postoperative electroencephalographic seizures 
Electroencephalographic seizures have been shown to occur in 5% to 20% of neonates and infants after biventricular repair of a variety of cardiac defects. Occurrence of a seizure is a predictor of adverse long-term neurodevelopmental sequelae. The contemporary incidence of postoperative seizures after repair of cardiac defects such as hypoplastic left heart syndrome and other forms of single ventricle is not known.
A prospective study of 178 patients less than 6 months of age undergoing cardiopulmonary bypass with or without deep hypothermic circulatory arrest (DHCA) was conducted at a single institution from September 2001 through March 2003 to identify postoperative seizures assessed by 48-hour continuous video electroencephalographic monitoring.
Cardiac defects included transposition of the great arteries with or without a ventricular septal defect (n = 12), ventricular septal defect with or without coarctation (n = 28), tetralogy of Fallot (n = 24), hypoplastic left heart syndrome or variant (n = 60), other functional single ventricle (n = 14), and other defects suitable for biventricular repair (n = 40). Median age at the time of the operation was 7 days (range, 1–188 days) and was 30 days or less in 110 (62%) patients. DHCA was used in 117 (66%) patients, with multiple episodes in 9 patients. Median total duration of DHCA was 40 minutes (range, 1–90 minutes). Electroencephalographic seizures were identified in 20 (11.2%) patients. Seizures occurred in 15 (14%) of 110 neonates and 5 (7%) of 68 older infants. Seizures occurred in 1 (4%) of 24 patients with tetralogy of Fallot, 1 (8%) of 12 with transposition of the great arteries, and 11 (18%) of 60 with hypoplastic left heart syndrome or variant. By stepwise logistic regression analysis, once increasing duration of total DHCA (P = .001) was considered, no other variable improved prediction of occurrence of a seizure. Patients with DHCA duration of more than 40 minutes had an increased incidence of seizures (14/58 [24.1%]) compared with those with a DHCA duration of 40 minutes or less (4/59 [6.8%], P = .04). The incidence of seizures for patients with a DHCA duration of 40 minutes or less was not significantly different from those in whom DHCA was not used (2/61 [3.3%], P = .38).
In the current era, continuous electroencephalographic monitoring demonstrates early postoperative seizures in 11.2% of a heterogeneous cohort of neonates and infants with complex congenital heart defects. Increasing duration of DHCA was identified as a predictor of seizures. However, the incidence of seizures in children with limited duration of DHCA was similar to that in infants undergoing continuous cardiopulmonary bypass alone.
PMCID: PMC2840401  PMID: 16256779
18.  Inhaled Carbon Monoxide Provides Cerebral Cytoprotection in Pigs 
PLoS ONE  2012;7(8):e41982.
Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.
PMCID: PMC3413707  PMID: 22879904
19.  Antegrade versus retrograde cerebral perfusion for hemiarch replacement with deep hypothermic circulatory arrest: Does it matter? A propensity-matched analysis 
The choice of cerebral perfusion strategy for aortic arch surgery has been debated, and the superiority of antegrade (ACP) or retrograde (RCP) cerebral perfusion has not been shown. We examined the early and late outcomes for ACP versus RCP in proximal (hemi-) arch replacement using deep hypothermic circulatory arrest (DHCA).
A retrospective analysis of a prospectively maintained database was performed for all patients undergoing elective and nonelective hemiarch replacement at a single referral institution from June 2005 to February 2013. Total arch cases were excluded to limit the analysis to shorter DHCA times and a more uniform patient population for whom clinical equipoise regarding ACP versus RCP exists. A total of 440 procedures were identified, with 360 (82%) using ACP and 80 (18%) using RCP. The endpoints included 30-day/in-hospital and late outcomes. A propensity score with 1:1 matching of 40 pre- and intraoperative variables was used to adjust for differences between the 2 groups.
All 80 RCP patients were propensity matched to a cohort of 80 similar ACP patients. The pre- and intra-operative characteristics were not significantly different between the 2 groups after matching. No differences were found in 30-day/in-hospital mortality or morbidity outcomes. The only significant difference between the 2 groups was a shorter mean operative time in the RCP cohort (P = .01). No significant differences were noted in late survival (P = .90).
In proximal arch operations using DHCA, equivalent early and late outcomes can be achieved with RCP and ACP, although the mean operative time is significantly less with RCP, likely owing to avoidance of axillary cannulation. Questions remain regarding comparative outcomes with straight DHCA and lesser degrees of hypothermia.
PMCID: PMC4336168  PMID: 24908350
20.  Feasibility of absolute cerebral tissue oxygen saturation during cardiopulmonary resuscitation 
Critical Care  2013;17(2):R36.
Current monitoring during cardiopulmonary resuscitation (CPR) is limited to clinical observation of consciousness, breathing pattern and presence of a pulse. At the same time, the adequacy of cerebral oxygenation during CPR is critical for neurological outcome and thus survival. Cerebral oximetry, based on near-infrared spectroscopy (NIRS), provides a measure of brain oxygen saturation. Therefore, we examined the feasibility of using NIRS during CPR.
Recent technologies (FORE-SIGHT™ and EQUANOX™) enable the monitoring of absolute cerebral tissue oxygen saturation (SctO2) values without the need for pre-calibration. We tested both FORE-SIGHT™ (five patients) and EQUANOX Advance™ (nine patients) technologies in the in-hospital as well as the out-of-hospital CPR setting. In this observational study, values were not utilized in any treatment protocol or therapeutic decision. An independent t-test was used for statistical analysis.
Our data demonstrate the feasibility of both technologies to measure cerebral oxygen saturation during CPR. With the continuous, pulseless near-infrared wave analysis of both FORE-SIGHT™ and EQUANOX™ technology, we obtained SctO2 values in the absence of spontaneous circulation. Both technologies were able to assess the efficacy of CPR efforts: improved resuscitation efforts (improved quality of chest compressions with switch of caregivers) resulted in higher SctO2 values. Until now, the ability of CPR to provide adequate tissue oxygenation was difficult to quantify or to assess clinically due to a lack of specific technology. With both technologies, any change in hemodynamics (for example, ventricular fibrillation) results in a reciprocal change in SctO2. In some patients, a sudden drop in SctO2 was the first warning sign of reoccurring ventricular fibrillation.
Both the FORE-SIGHT™ and EQUANOX™ technology allow non-invasive monitoring of the cerebral oxygen saturation during CPR. Moreover, changes in SctO2 values might be used to monitor the efficacy of CPR efforts.
PMCID: PMC3672653  PMID: 23448653
21.  Response of Brain Oxygenation and Metabolism to Deep Hypothermic Circulatory Arrest in Newborn Piglets: Comparison of pH-Stat and Alpha-Stat Strategies 
The Annals of thoracic surgery  2007;84(1):170-176.
To determine the effect of pH-stat as compared with alpha-stat management on brain oxygenation, level of striatal extracellular dopamine, phosphorylation, and levels of protein kinase B (Akt) and cyclic adenosine 3’, 5’-monophosphate response element-binding protein (CREB), and levels of extracellular signal-regulated kinase (ERK)1/2, Bcl-2, and Bax in a piglet model of deep hypothermic circulatory arrest (DHCA).
The piglets were placed on cardiopulmonary bypass (CPB), cooled with pH-stat or alpha-stat to 18°C, subjected to 90 minutes of DHCA, rewarmed, weaned from CPB, and maintained for two hours recovery. The cortical oxygen was measured by: quenching of phosphorescence; dopamine by microdialysis; phosphorylation of CREB (p-CREB), ERK (p-ERK) 1/2, Akt (p-Akt), and level of Bcl-2, Bax by Western blots.
Oxygen pressure histograms for the microvasculature of the cortex show substantially higher oxygen levels during cooling and during the oxygen depletion period after cardiac arrest (up to 15 minutes) when using pH-stat compared with alpha-stat management. Significant increases in dopamine occurred at 45 minutes and 60 minutes of DHCA in the alpha-stat and pH-stat groups, respectively. The p-CREB and p-Akt in the pH-stat group were significantly higher than in the alpha-stat group (140 ± 9%, p < 0.05 and 125 < 6%, p < 0.05, respectively). There was no significant difference in p-ERK1/2 and Bax. The Bcl-2 increased in the pH-stat group to 121 ± 4% (p < 0.05) compared with the alpha-stat group. The ratio Bcl-2:Bax increased in the pH-stat group compared with the alpha-stat group.
The increase in p-CREB, p-Akt, Bcl-2, Bcl-2/Bax, and delay in increase of dopamine indicated that pH-stat, in the piglet model, prolongs “safe” time of DHCA and provides some brain protection against ischemic injury.
PMCID: PMC2782723  PMID: 17588406
22.  A meta-analysis of deep hypothermic circulatory arrest versus moderate hypothermic circulatory arrest with selective antegrade cerebral perfusion 
Annals of Cardiothoracic Surgery  2013;2(2):148-158.
A recent concern of deep hypothermic circulatory arrest (DHCA) in aortic arch surgery has been its potential association with increased risk of coagulopathy, elevated inflammatory response and end-organ dysfunction. Recently, moderate hypothermic circulatory arrest (MHCA) with selective antegrade circulatory arrest (SACP) seeks to negate potential hypothermia-related morbidities, while maintaining adequate neuroprotection. The present meta-analysis aims to compare postoperative outcomes in arch surgery using DHCA or MHCA+SACP as neuroprotective strategies.
Electronic searches were performed using six databases from their inception to January 2013. Two reviewers independently identified all relevant studies comparing DHCA with MHCA+SACP, as defined by a recent hypothermia temperature consensus. Data were extracted and meta-analyzed according to pre-defined clinical endpoints.
Nine comparative studies were identified for inclusion in the present meta-analysis. Stroke rates were significantly lower in patients undergoing MHCA+SACP (P=0.0007, I2=0%), while comparable results were observed with temporary neurological deficit, mortality, renal failure or bleeding. Infrequent and inconsistent reporting of systemic outcomes precluded analysis of other systemic outcomes.
The present meta-analysis indicated the superiority of MHCA+SACP in terms of stroke risk.
PMCID: PMC3741839  PMID: 23977575
Deep hypothermic circulatory arrest; moderate hypothermic circulatory arrest; antegrade cerebral perfusion; meta-analysis
23.  Total aortic arch replacement: current approach using the trifurcated graft technique 
Annals of Cardiothoracic Surgery  2013;2(3):347-352.
Since the pioneering work of DeBakey, Cooley, and colleagues more than 50 years ago, surgical treatment of aneurysms involving the transverse aortic arch has been associated with substantial morbidity and mortality. Over the past 15 years, techniques for replacing the diseased aortic arch have evolved substantially. Previously, our approach to these operations involved femoral cannulation, profound-to-deep hypothermic circulatory arrest and retrograde cerebral perfusion, and the island technique for reattaching the brachiocephalic vessels. In contrast, we currently use innominate artery cannulation, deep-to-moderate hypothermic circulatory arrest with antegrade cerebral perfusion, bilateral cerebral monitoring with near-infrared spectroscopy, and the trifurcated graft (Y-graft) technique for reattaching the arch branches. Cannulating the innominate artery to provide an inflow site for cardiopulmonary bypass has facilitated the use of antegrade cerebral perfusion as a cerebral protection strategy; the left common carotid artery is additionally perfused to provide bilateral cerebral perfusion. Despite having a systemic circulatory arrest time that often exceeds 60 minutes, these improved perfusion strategies make it possible to consistently avoid cerebral circulatory arrest all together. A moderate temperature target of between 18 and 23 °C is now used; this appears to reduce the risk of hypothermic coagulopathy and improve hemostasis. Y-graft techniques, such as the trifurcated graft approach, have the advantages of eliminating residual aortic arch tissue and being easily tailored to the needs of the individual patient. This report describes total aortic arch replacement in patients with aneurysms that are confined to the ascending aorta and transverse aortic arch.
PMCID: PMC3741858  PMID: 23977604
Aortic arch surgery; total arch replacement; trifurcated graft
24.  Principles of Antegrade Cerebral Perfusion During Arch Reconstruction in Newborns/Infants 
Antegrade cerebral perfusion (ACP) is a cardiopulmonary bypass technique that uses special cannulation procedures to perfuse only the brain during neonatal and infant aortic arch reconstruction. It is used in lieu of deep hypothermic circulatory arrest (DHCA), and thus has the theoretical advantage of protecting the brain from hypoxic ischemic injury. Despite this, recent comparative studies have demonstrated no difference in neurodevelopmental outcomes with ACP vs. DHCA for neonatal arch repair. This article presents animal and human data demonstrating that ACP flows less than 30 ml/kg/min are inadequate for many patients, and may be the explanation for lack of outcome difference vs. DHCA. A technique for ACP, its physiologic basis, and a neuromonitoring strategy are presented, and then the results of an outcome study are reviewed demonstrating that with ACP technique at higher flows of 50–80 ml/kg/min guided by neuromonitoring, periventricular leukomalacia (PVL) is eliminated on postoperative brain MRI after neonatal cardiac surgery.
PMCID: PMC2531241  PMID: 18396227
25.  Expression of CD11b (MAC-1) and CD162 (PSGL-1) on monocytes is decreased under conditions of deep hypothermic circulatory arrest 
Deep hypothermic circulatory arrest (DHCA) is a common technique used to protect vital organs during surgical interventions on the thoracic aorta or during surgery for complex congenital heart disease. Activated leukocytes are key mediators of inflammatory responses during ischemia. Intercellular crosstalk between leukocytes, platelets and endothelial cells is mediated by cell adhesion molecules. These molecules trigger complex cell-cell interaction mechanisms and initiate the release of proinflammatory molecules. One parameter that is known to have a significant impact on inflammatory cell activation and the production of proinflammatory markers is temperature. However, to the best of our knowledge, no data have yet been published on the effect of hypothermia on leukocyte surface markers during DHCA. Thus, the aim of the present study was to investigate the effect of hypothermia on the expression of cell adhesion molecules on monocytes under DHCA conditions in vitro. Blood samples collected from 11 healthy volunteers were incubated in a well-established model simulating circulatory arrest at 36°C and 18°C for 30 min. The expression of cluster of differentiation (CD) molecule 11B (CD11b), CD54 and CD162 on monocytes was measured as the mean fluorescence intensity (MFI) using flow cytometry. The expression level of CD11b on monocytes was significantly decreased following the incubation of the blood samples at 18°C compared with the level in blood samples incubated at 36°C (P<0.001). After 30 min of blood stasis in the circulatory arrest model, the expression level of CD162 on monocytes was significantly lower in the blood samples incubated at 18°C than in those incubated at 36°C (P<0.001). No association was identified between temperature and the surface expression of CD54 on monocytes following 30 min of stasis. These findings demonstrate that deep hypothermia decreases the expression of CD11b and CD162 on monocytes in an experimental setup simulating the conditions of DHCA. This may be the result of the inhibition of leukocyte-endothelial and leukocyte-platelet interactions, which may be a beneficial aspect of deep hypothermia that affects the inflammatory response and tissue damage during DHCA.
PMCID: PMC4079448  PMID: 25009606
CD11b; CD162; CD54; deep hypothermic circulatory arrest; leukocytes

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