J Cereb Blood Flow Metab  2002 Jan;22(1):105-17

Antioxidant tempol enhances hypothermic cerebral preservation during prolonged
cardiac arrest in dogs.

Behringer W, Safar P, Kentner R, Wu X, Kagan VE, Radovsky A, Clark RS, Kochanek
PM, Subramanian M, Tyurin VA, Tyurina YY, Tisherman SA.

Safar Center for Resuscitation Research, and the Departments of
Anesthesiology/Critical Care Medicine, Surgery, Environmental and Occupational
Health, and Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania,
U.S.A.

SUMMARY: The authors are systematically exploring pharmacologic preservation for
temporarily unresuscitable exsanguination cardiac arrest in dogs. They
hypothesized that the antioxidant Tempol improves cerebral outcome when added to
aortic saline flush at the start of cardiac arrest. In study A, no drug (n = 8),
Tempol 150 mg/kg (n = 4), or Tempol 300 mg/kg (n = 4) was added to 25 mL/kg
saline flush at 24 degrees C (achieving mild cerebral hypothermia) at the start
of 20-minute cardiac arrest. In study B, no drug (n = 8) or Tempol 300 mg/kg (n
= 7) was added to 50 mL/kg saline flush at 2 degrees C (achieving moderate
cerebral hypothermia) at the start of 40-minute cardiac arrest. Cardiac arrest
was reversed with cardiopulmonary bypass. Mild hypothermia lasted for 12 hours,
controlled ventilation was sustained to 24 hours, and intensive care was
provided for up to 72 hours. In study A, overall performance category 1 or 2
(good outcome) was achieved in all eight dogs treated with Tempol compared with
three of eight dogs in the control group ( P = 0.03). In study B, good outcome
was achieved in all seven dogs treated with Tempol versus only two of 8 dogs in
the control group ( P = 0.007). In both studies, neurologic deficit scores were
significantly better in the Tempol group, but not total histologic damage
scores. At 72 hours, electron paramagnetic resonance spectroscopy of Tempol
revealed direct evidence for its presence in the brain. Single- and
double-strand DNA damage, nitrotyrosine immunostaining, total antioxidant
reserve, and ascorbate acid levels were similar between groups, and thiol levels
were decreased after Tempol in study B. The authors conclude that when added to
aortic saline flush at the start of prolonged cardiac arrest, the antioxidant
Tempol can enhance mild or moderate hypothermic cerebral preservation in terms
of improved functional outcome. The mechanisms involved in this beneficial
effect need further clarification.

Pediatr Surg Int  2002;18(1):54-9

Plasma vascular endothelial growth factor level is a predictor of the severity
of postoperative capillary leak syndrome in neonates undergoing cardiopulmonary
bypass.

Abrahamov D, Erez E, Tamariz M, Dagan O, Pearl E, Abrahamov Y, Gendel B, Desai
N, Kats J, Vidne B, Barak V.

Department of Cardiothoracic Surgery, Rabin Medical Center, Tel-Aviv University,
Petah-Tikva, Israel; 13 Shai Agnon St., P.O.B. 4241, Jerusalem, Israel.

Capillary leak syndrome (CLS), characterized by extravascular fluid accumulation
and significant organ dysfunction, is a serious complication in children
undergoing cardiopulmonary bypass (CPB). We examined the relationship between
plasma vascular endothelial growth factor (VEGF) levels and severity of CLS. The
kinetics of VEGF in the plasma of 11 neonates and 7 older children undergoing
CPB were investigated, correlating plasma VEGF levels and CLS clinical
presentation. The degree of postoperative CLS was quantified by measuring
parameters of extracellular volume and end-organ dysfunction. A chest-wall
soft-tissue-width index (CSTWI) was designed in order to standardize the
extracellular fluid accumulation. Most CLS parameters were significantly more
prominent in the neonatal patients. Low plasma VEFG levels (>35 pg/ml) were
found in 3 neonatal control patients and all but, sample from the older group
patient. The neonates had significantly higher preoperative VEGF plasma levels
(684.4 +/- 559.1 pg/ml, P = 0.02), which decreased during the operation to
levels below 35 pg/ml and increased again 24 h postoperatively to levels
significantly higher than in the older patients (484 +/- 270.3 pg/ml, P =
0.001). Multilinear regression analysis found preoperative VEGF levels to
independently correlate with CLS as represented by CSTWI (P < 0.01, r = 0.726).
Both the occurrence of post-CPB CLS and plasma VEGF levels pre- and
postoperatively were thus higher in neonates than in children. Plasma VEGF level
is a predictor of the severity of postoperative CLS.

J Thorac Cardiovasc Surg  2002 Jan;123(1):137-44

Soluble Fas may be a proinflammatory marker after cardiopulmonary bypass in
children.

Joashi U, Tibby SM, Turner C, Mayer A, Austin C, Anderson D, Durward A, Murdoch
IA.

Departments of Pediatric Intensive Care and Pediatric Cardiothoracic Surgery,
Guy's Hospital, London, United Kingdom.

OBJECTIVES: Ischemia-reperfusion injury after cardiopulmonary bypass is known to
provoke an inflammatory response, which can be attenuated with steroid
pretreatment. Cardiopulmonary bypass is also known to stimulate apoptosis.
Induction of the cellular apoptotic cascade occurs via interaction between two
membrane receptors: Fas and Fas ligand. Both molecules also exist in soluble
forms, whose significance remains undetermined; however, both may have a
proinflammatory role. We aimed to document the temporal profile of soluble Fas
and soluble Fas ligand after cardiopulmonary bypass and to investigate whether
steroid pretreatment alters this response. METHODS: The study was of a
nonrandomized, nonblinded, prospective nature. Twenty-seven infants were
monitored prospectively, of whom 13 received dexamethasone at induction of
anesthesia. Soluble Fas, soluble Fas ligand, and interleukin 6 were measured
from induction of anesthesia until 24 hours after admission to the intensive
care unit. Data on clinical and laboratory variables were also collected at the
same time intervals. RESULTS: As expected, dexamethasone pretreatment attenuated
interleukin 6 release and the clinical systemic inflammatory response after
bypass. Soluble Fas showed a remarkably similar profile to interleukin 6, in
terms of temporal release and attenuation with steroids. There was also a
correlation between maximum soluble Fas and markers of capillary leak (colloid
requirement and drain loss). Conversely, soluble Fas ligand release was
unchanged by cardiopulmonary bypass and steroid administration. However,
patients with higher soluble Fas ligand levels exhibited a more dramatic drop
and delayed recovery in monocyte count, consistent with the role of this
molecule in apoptosis. CONCLUSIONS: Release of soluble Fas and soluble Fas
ligand follows a markedly different temporal profile after cardiopulmonary
bypass. The similarity between soluble Fas and interleukin 6, together with the
attenuation of both with steroids, may suggest a role for soluble Fas as a
proinflammatory marker.

J Thorac Cardiovasc Surg  2002 Jan;123(1):119-129

Delivery of a nonpotassium modified maintenance solution to enhance myocardial
protection in stressed neonatal hearts: A new approach.

Kronon MT, Allen BS, Halldorsson A, Rahman S, Barth MJ, Ilbawi M.

Division of Cardiovascular Surgery, The Heart Institute for Children, Hope
Children's Hospital, Oak Lawn, Ill, and The Division of Cardiothoracic Surgery,
The University of Illinois of Chicago, Chicago, Ill.

OBJECTIVES: This study was undertaken to compare conventional cardioplegic
strategies with a new approach that uses a modified nonpotassium maintenance
solution between cardioplegia doses in stressed neonatal hearts. METHODS:
Thirty-five neonatal piglets underwent 60 minutes of ventilator hypoxia
(inspired oxygen fraction 8%-10%) followed by 20 minutes of ischemia on
cardiopulmonary bypass. In 10 animals bypass was discontinued without further
ischemia (stress control group). The other 25 received a warm blood cardioplegic
induction and were separated into 5 groups. In 5 animals cardiopulmonary bypass
was discontinued without further ischemia (cardioplegia control group); the
remaining 20 underwent an additional 70 minutes of cold blood cardioplegic
arrest. Five received only intermittent cardioplegia every 20 minutes, whereas
15 also received cold blood maintenance infusions between cardioplegic doses
(integrated strategy). In 5 of these animals the blood was unmodified, whereas
in 10 a modified nonpotassium "cardioplegia-like" solution was delivered either
antegradely (n = 5) or retrogradely (n = 5). Myocardial function was assessed by
pressure-volume loops (expressed as percentage of control); vascular function
was assessed by coronary vascular resistance. RESULTS: All piglets that
underwent hypoxic ischemic stress alone (controls) died. Warm induction alone
(cardioplegic controls) partially repaired the stress injury. Intermittent
cardioplegia preserved the depressed systolic function (end-systolic elastance
40% vs 39%), increased diastolic stiffness (255% vs 239%), reduced adenosine
triphosphate (10.6 vs 12.2 &mgr;g/g tissue), and elevated coronary vascular
resistance at levels identical to warm induction alone; infusing unmodified
blood between cardioplegia doses (standard integrated) improved results
slightly. In contrast, infusion of a cold modified solution (antegrade or
retrograde) between cardioplegia doses (modified integrated) completely restored
systolic function (end-systolic elastance 100% and 97%, P <.001 vs intermittent
and standard integrated), only minimally increased diastolic stiffness (159% and
156%, P <.001 vs intermittent and standard integrated), restored adenosine
triphosphate (18.8 and 16.6 &mgr;g/g, P <.001 vs intermittent and standard
integrated), and normalized coronary vascular resistance (P <.001 vs
intermittent and standard integrated). This strategy was used in 72 consecutive
hypoxic patients (21 arterial switch operations, retrograde; 51 Fontan
procedures, antegrade) with a 2.8% mortality. CONCLUSIONS: Infusion of a cold
modified solution between cardioplegic doses (modified integrated protection)
significantly improved myocardial protection in the stressed neonatal heart, was
effective delivered either antegradely or retrogradely, and was used
successfully for hypoxic (stressed) pediatric patients.

Am Heart J  2002 Jan;143(1):15-21

Prophylactic intravenous use of milrinone after cardiac operation in pediatrics
(PRIMACORP) study. Prophylactic Intravenous Use of Milrinone After Cardiac
Operation in Pediatrics.

Hoffman TM, Wernovsky G, Atz AM, Bailey JM, Akbary A, Kocsis JF, Nelson DP,
Chang AC, Kulik TJ, Spray TL, Wessel DL.

Children's Hospital of Philadelphia, Philadelphia, Pa 19104, USA

BACKGROUND: Many pediatric patients undergoing cardiac surgery involving
cardiopulmonary bypass have a predictable fall in the cardiac index 6 to 18
hours after surgery, the so-called low cardiac output syndrome (LCOS). Because
patients who have LCOS require more monitoring and support and have a prolonged
stay in the intensive care unit, the syndrome is associated with a costly
morbidity. Milrinone, a phosphodiesterase III inhibitor, improves cardiac muscle
contractile force and vascular muscle relaxation through positive inotropic and
vasodilatory effects. The purpose of the Prophylactic Intravenous Use of
Milrinone After Cardiac Operation in Pediatrics (PRIMACORP) study is to evaluate
the safety and efficacy of the prophylactic use of milrinone in pediatric
patients at high risk for development of LCOS after undergoing cardiac surgery.
METHODS: Patients in the multicenter, randomized, double-blind,
placebo-controlled, parallel treatment study will be randomized to 1 of 3
treatment arms: (1) low-dose milrinone (25 microg/kg intravenous bolus over 60
minutes followed by a 0.25 microg/kg/min infusion for 35 hours), (2) high-dose
milrinone (75 microg/kg intravenous bolus over 60 minutes followed by a 0.75
microg/kg/min infusion for 35 hours), or (3) placebo. RESULTS: The primary end
point for efficacy evaluation will be based on a composite variable consisting
of death or development of LCOS requiring additional mechanical or pharmacologic
support, up to 36 hours after randomization. A 2-sided test with a 0.025 type I
error will be used for the primary end point analysis. The PRIMACORP study will
enroll a total of 240 patients. Six additional secondary end points will be
analyzed. CONCLUSIONS: The PRIMACORP study will address several questions
regarding the safety and efficacy of prophylactic milrinone use in pediatric
patients at high risk for development of LCOS after cardiac surgery.

Pediatrics  2002 Jan;109(1):1-7

Infant heart transplantation at stanford: growth and neurodevelopmental outcome.

Fleisher BE, Baum D, Brudos G, Burge M, Carson E, Constantinou J, Duckworth J,
Gamberg P, Klein P, Luikart H, Miller J, Stach B, Bernstein D.

Department of Pediatrics. Department of Cardiothoracic Surgery, Stanford
University School of Medicine, Stanford, California. Central Institute for the
Deaf, Washington University, St Louis, Missouri.

OBJECTIVE: To evaluate the growth and neurodevelopmental outcome of 18 surviving
Stanford patients who received heart transplantations before their second
birthday. METHODS: We compared the growth and neurodevelopmental outcome of
these 18 patients with a second group of age-matched comparison patients who
underwent other heart surgery requiring cardiopulmonary bypass. RESULTS:
Difficulties with growth and development were more common in the transplant
group as were neurologic abnormalities. Speech and language delays as well as
hearing problems were also more common in the transplant group. CONCLUSION:
Multicenter prospective longitudinal neurodevelopmental outcome studies of
infant heart transplant patients should be conducted to provide a more efficient
basis for evaluating management protocols and assessment of long-term outcomes
and of the need for early intervention services.

Anesth Analg  2002 Jan;94(1):44-9, table of contents

The pharmacokinetics of epsilon-aminocaproic acid in children undergoing
surgical repair of congenital heart defects.

Ririe DG, James RL, O'Brien JJ, Lin YA, Bennett J, Barclay D, Hines MH,
Butterworth JF.

Department of Anesthesiology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina 27157-1009, USA. dririe@wfubmc.edu

epsilon-Aminocaproic acid (epsilonACA) is often administered to children
undergoing cardiac surgery by using empiric dosing techniques. We hypothesized
that children would have different pharmacokinetic variables and require a
dosing scheme different from adults to maintain stable and effective serum
epsilonACA concentrations. Eight patients were enrolled in our study. epsilonACA
50 mg/kg was administered three times IV: before, during, and after
cardiopulmonary bypass (CPB). Nine serum samples were obtained. epsilonACA
plasma concentrations were measured by using high-performance liquid
chromatography, and pharmacokinetic modeling was done by using NONMEM. The best
fit was seen with a two-compartment model with volume of distribution (V(1))
adjusted for weight and CPB. Compared with published results in adults, modeling
suggests that weight-adjusted V(1) is larger in children than in adults before,
during, and after CPB. Clearance from the central compartment (k(10)) was also
greater in children than adults, and declined during CPB. Redistribution rates
from the central compartment, k(12) and k(21), were greater in children and not
affected by CPB. We modeled several different dosing regimens for epsilonACA
based on the larger V(1), and higher redistribution and clearance variables. We
conclude that, because of the developmental differences in pharmacokinetic
variables of epsilonACA, when compared with adult patients, a larger initial
dose and faster infusion rate as well as an addi-tional dose on CPB are needed
to maintain similar concentrations. IMPLICATIONS: Pharmacokinetic modeling of
epsilon-aminocaproic acid in children undergoing cardiac surgery suggests that
there are developmental differences in pharmacokinetic variables. Based on these
data, a dosing modification in children is suggested which may better maintain
serum concentrations in children when compared with adults.

J Am Coll Cardiol  2002 Jan 2;39(1):102-8

The effects of hypothermia on human left ventricular contractile function during
cardiac surgery.

Lewis ME, Al-Khalidi AH, Townend JN, Coote J, Bonser RS.

Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Birmingham,
United Kingdom.

OBJECTIVES: We investigated the interaction of heart rate (HR), temperature and
contractility using a validated load independent method. BACKGROUND: Temperature
manipulation is an integral part of cardiac surgery, and postoperative
hypothermia is extremely common. Myocardial contraction is a series of enzymatic
and physico-chemical reactions that may be differentially affected by
temperature. METHODS: Ten patients undergoing coronary artery bypass grafting
were studied during moderately hypothermic cardiopulmonary bypass. After conduit
procurement and heparinization but before grafting, the patient was placed on
cardiopulmonary bypass and rewarmed to 37 degrees C, and the left ventricle (LV)
was instrumented with a conductance catheter allowing continuous pressure and
volume measurement. The LV pressure volume relationship was examined to assess
the contractility at 37, 35, 33 and 31 degrees C, with fixed atrial pacing (100
beats/min) in five patients and at 80 and 120 beats/min, at 33 and 37 degrees C
in five patients. RESULTS: At a HR of 100 beats/min, lower temperature resulted
in a highly significant decrease in maximal elastance (100% at 37 degrees C, 29
+/- 3.5% at 31 degrees C, p < 0.0001). At 37 degrees C, increasing HR increased
contractility (80 beats/min 100%, 120 beats/min 205.9%, p = 0.0021); however, at
33 degrees C contractility fell with increasing HR (80 beats/min 100%, 120
beats/min, 53.7%, p = 0.0014). CONCLUSIONS: At normothermia LV contractility has
a direct relationship with HR. In hypothermic conditions this relationship
inverses. Clinical strategies maintaining higher HRs at colder temperatures
result in reduced contractility. These factors are important in the management
of cardiac surgical patients.

Anesthesiology  2002 Jan;96(1):80-7

Systemic free radical activation is a major event involved in myocardial
oxidative stress related to cardiopulmonary bypass.

Clermont G, Vergely C, Jazayeri S, Lahet JJ, Goudeau JJ, Lecour S, David M,
Rochette L, Girard C.

Submitted for publication February 7, 2001.

BACKGROUND: Cardiopulmonary bypass (CPB) can induce deleterious effects that
could be triggered in part by radical oxygen species; however, their involvement
in the course of surgery has been elusive. The aim of this study was to evaluate
the time course and origin of radical oxygen species release, myocardial or not,
in patients undergoing coronary artery surgery involving CPB. METHODS: Blood
samples were taken from periphery and coronary sinus of patients during CPB, and
oxidative stress was evaluated by direct and indirect approaches. Direct
detection of alkyl and alkoxyl radicals was assessed by electron spin resonance
spectroscopy associated with the spin-trapping technique using
alpha-phenyl-N-tert-butylnitrone. RESULTS: The authors showed that the spin
adduct concentration was not influenced by anesthesia and pre-CPB surgery. A
rapid systemic increase of plasma spin adduct concentration occurred after
starting CPB, and it stayed at a high concentration until the end of CPB. At the
beginning of reperfusion period, radical oxygen species release was accelerated
in the coronary sinus; however, it was not significant. A positive correlation
was found between alpha-phenyl-N-tert-butylnitrone adduct concentrations and (1)
the duration of CPB and (2) concentration of postoperative creatine
phosphokinase of muscle band (CPK MB). Plasma vitamin E and C, ascorbyl radical,
uric acid, thiol, plasma antioxidant status, and thiobarbituric acid reacting
substances were also measured but did not give relevant indications, except for
uric acid, which seemed to be consumed by the heart during reperfusion.
CONCLUSION: The results indicate that a systemic production of free radicals
occurs during CPB that may overwhelm the production related to reperfusion of
the ischemic heart. This systemic oxidative stress is likely to participate in
secondary myocardial damage.