J Thorac Cardiovasc Surg. 2003 Jul;126(1):133-42.  

Protection of the human heart with ischemic preconditioning during cardiac
surgery: Role of cardiopulmonary bypass.

Ghosh S, Galinanes M.

OBJECTIVE: Studies on the effects of ischemic preconditioning in the human heart
have yielded conflicting results and therefore remain controversial. This study
investigated whether ischemic preconditioning was able to protect against
myocardial tissue damage in patients undergoing coronary artery surgery with
cardiopulmonary bypass and on the beating heart. METHODS: A total of 120
patients were studied and divided into 3 groups: group I: cardiopulmonary bypass
with intermittent crossclamp fibrillation; group II: cardiopulmonary bypass with
cardioplegic arrest using cold blood cardioplegia; group III: surgery on the
beating heart. In each group (n = 40), patients were randomly subdivided (n =
20/subgroup) into control and preconditioning groups (1 cycle of 5 minutes of
ischemia/5 minutes reperfusion before intervention). Ischemic preconditioning
was induced by clamping the ascending aorta in groups I and II or by clamping
the coronary artery in group III. Serial venous blood levels of troponin T were
analyzed before surgery and at 1, 4, 8, 24, and 48 hours after termination of
ischemia. In addition, in vitro studies using right atrial specimens obtained
before the institution of cardiopulmonary bypass, and then again 10 minutes
after initiation of bypass, were performed. The specimens were equilibrated for
30 minutes before being allocated to 1 of the following 2 groups (n = 6 per
group): (1) ischemia alone (90 minutes of ischemia followed by 120 minutes of
reoxygenation) or (2) preconditioning with 5 minutes of ischemia and 5 minutes
of reoxygenation before the long ischemic insult. Creatine kinase leakage (U/g
wet weight) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
reduction (mmol/l per gram wet weight), an index of cell viability, were
assessed at the end of the experiment. RESULTS: There were no perioperative
myocardial infarctions or deaths in any of the groups studied. The total release
of troponin T was similar in groups I and II (patients undergoing surgery with
cardiopulmonary bypass) and in the release profile; they were unaffected by
ischemic preconditioning. In contrast, the total troponin T release for the
first 48 hours was significantly reduced by ischemic preconditioning in group
III (patients undergoing surgery without cardiopulmonary bypass) from 3.1 +/-
0.1 to 2.1 +/- 0.2 ng. h. mL. Furthermore, the release profile that peaked at 8
hours in the control group shifted to the left at 1 hour. In the in vitro
studies, the atrial muscles obtained before cardiopulmonary bypass were
protected by ischemic preconditioning (creatine kinase = 2.6 +/- 0.2 and
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction = 152 +/-
24 vs creatine kinase = 5.4 +/- 0.6 and
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide reduction = 87 +/-
16 in controls; P <.05); however, the muscles obtained 10 minutes after
initiation of cardiopulmonary bypass were already protected (creatine kinase =
0.8 +/- 0.1 and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
reduction = 316 +/- 38), and ischemic preconditioning did not result in further
improvements. CONCLUSIONS: Ischemic preconditioning is protective in patients
undergoing coronary artery surgery on the beating heart without the use of
cardiopulmonary bypass, but it offers no additional benefit when associated with
bypass regardless of the mode of cardioprotection used, because cardiopulmonary
bypass per se induces preconditioning.

Circulation. 2003 Jul 21 [Epub ahead of print].  

Effect of Two Different Bypass Techniques on the Serum Troponin-T Levels in
Newborns and Children. Does pH-Stat Provide Better Protection?

Nagy ZL, Collins M, Sharpe; T, Mirsadraee S, Guerrero RR, Gibbs J, Watterson KG.

Yorkshire Heart Centre and Department of Chemical Pathology, Leeds Teaching
Hospitals, Leeds, UK, and Department of Cardiac Surgery, University of Debrecen,
Hungary.

BACKGROUND: Cardiac troponin-T is a sensitive marker of myocardial damage. In a
prospective study, the effect of 2 different pH strategies during
cardiopulmonary bypass on ischemic myocardial injury and clinical outcome was
measured in a pediatric population. METHODS AND RESULTS: One hundred one
patients (31 neonates 13.2+/-8.3 days and 70 children 34.5+/-44.1 months of age)
undergoing open-heart surgery were selected to either alpha-stat (n=51) or
pH-stat (n=50) acid-based management protocol. Serum troponin-T levels were
measured before and 30 minutes after bypass and then 4 and 24 hours
postoperatively. Surgical procedure, bypass details, inotropic support
requirement, and postoperative recovery were recorded. Baseline troponin-T level
was higher in neonates than in children (0.18+/-0.22 versus 0.04+/-0.05 micro
g/L, P=0.02). Also, a higher baseline level was found in patients with pulmonary
hypertension (0.13+/-0.21 versus 0.04+/-0.05 micro g/L, P=0.04). Cyanotic
children showed a higher peak troponin-T level (3.76+/-3.11 versus 1.67+/-1.33
micro g/L, P=0.04). Peak troponin levels showed a correlation with the length of
circulatory arrest and aortic cross-clamp time. Postoperative levels remained
high at 24 hours in patients requiring inotropic support. Peak troponin-T levels
were significantly lower in the pH-stat group in patients with pulmonary
hypertension (P=0.03) and in cases where circulatory arrest (P=0.01) or
inotropic support (P=0.01) was necessary during operation than in those with
alpha-stat technique. Postoperative ventilation time and length of intensive
care unit stay were also significantly longer with alpha-stat than with pH-stat
technique (P=0.005 and P=0.006, respectively). CONCLUSIONS: Cardiac troponin-T
sensitively reflects myocardial damage in children. Our results suggest that
pH-stat acid-based management protocol may provide better protection against
ischemic myocardial damage than alpha-stat technique.

Eur J Cardiothorac Surg. 2003 Jul;24(1):125-32.  

Timing of steroid treatment is important for cerebral protection during
cardiopulmonary bypass and circulatory arrest: minimal protection of pump prime
methylprednisolone.

Shum-Tim D, Tchervenkov CI, Laliberte E, Jamal AM, Nimeh T, Luo CY, Bittira B,
Philip A.

Division of Cardiovascular Surgery, The Montreal Children's Hospital, McGill
University Health Center, Montreal, Quebec, Canada

OBJECTIVES: The contact of cardiopulmonary bypass surface and patient's blood
activates systemic inflammatory response which aggravates ischemia-reperfusion
injury. This study evaluates the effects of cardiopulmonary bypass (CPB) and
deep hypothermic circulatory arrest (DHCA) on cerebral protection using
different steroid administration protocols. METHODS: Eighteen (n=6/group) 4
week-old piglets were divided in three groups. Methylprednisolone (30 mg/kg) was
administered intravenously 4 h prior to CPB in Group I, or added in pump prime
in group II. Group III received no steroid. All animals were cooled to 15
degrees C followed by 100 min of DHCA, then rewarmed over 40 min and sacrificed
6 h after CPB. Post-operative weight gain, bioelectrical impedance, colloid
oncotic pressure (COP) and interleukin-6 (IL-6) were evaluated. Determination of
cerebral trypan blue and immunohistochemical assays of transforming growth
factor (TGF)-beta(1) and caspase-3 activities were performed. RESULTS:
Post-operative % weight gain (13.0+/-3.8 (I) versus 26.4+/-9.9 (II) versus
22.6+/-6.4 (III), P=0.02); % bioimpedance reduction (14.5+/-8.0 (I) versus
38.3+/-13.3 (II) versus 30.5+/-8.0 (III), P=0.003); mean COP (mmHg) (14.9+/-1.8
(I) versus 10.9+/-2.0 (II) versus 6.5+/-1.8 (III), P=0.0001) and systemic IL-6
levels (pg/ml) (208.2+/-353.0 (I) versus 1562.1+/-1111.4 (II) versus
1712.3+/-533.2 (III), P=0.01) were significantly different between the groups.
Spectrophotometric analysis of cerebral trypan blue (ng/g dry weight) was
significantly different between the groups (0.0053+/-0.0010 (I) versus
0.0096+/-0.0026 (II) versus 0.0090+/-0.0019 (III), P=0.004). TGF-beta(1) scores
were 3.3+/-0.8 (I) versus 1.5+/-0.8 (II) versus 1.5+/-0.5 (III), P<0.05, groups
I versus II and I versus III. Remarkable perivascular caspase-3 activity was
observed in groups II and III. CONCLUSION: Different timing of steroid
administration results in different inflammatory mediator response. Steroid in
CPB prime is not significantly better than no steroid treatment, while systemic
steroid pre-treatment significantly decreases systemic manifestation of
inflammatory response and brain damage.

Intensive Care Med. 2003 Jul 5 [Epub ahead of print].  

Effect of cardiopulmonary bypass on lactate metabolism.

Mustafa I, Roth H, Hanafiah A, Hakim T, Anwar M, Siregar E, Leverve XM.

Intensive Care Unit, Harapan Kita National Cardiovascular Center, Jakarta,
Indonesia.

OBJECTIVE. We have investigated the role of cardiopulmonary bypass on lactate
metabolism in patients undergoing uncomplicated surgery for elective coronary
artery bypass grafting (CABG). DESIGN. Prospective non-randomized observational
study. SETTINGS. National Cardiovascular Center. PATIENTS. Three independent
groups were studied: preoperative ( n=20), postoperative with bypass (CPB, n=20)
and postoperative without bypass (NO-CPB, n=20). INTERVENTIONS. Lactate
metabolism was investigated with the use of an exogenous lactate challenge test
(2.5 mmol Na-lactate/kg body weight in 15 min). Blood lactate was sequentially
determined after the end of infusion. Lactate clearance and endogenous
production were estimated from the area under the curve, and a bi-exponential
fitting permitted modeling the lactate-decay into two compartments. MEASUREMENTS
AND MAIN RESULTS. Lactate metabolism parameters (basal lactate, clearance,
endogenous production and half-lives [HL] I and II) were not different between
the NO-CPB and preoperative groups. In the CPB group, as compared to the other
two groups, basal lactate and endogenous production were not significantly
affected while lactate clearance (CPB: 6.02+/-0.97 versus preoperative:
9.41+/-0.93 and NO-CPB: 9.6+/-0.8 ml/kg per min) and HL-I (CPB: 10.6+/-1.4
versus preoperative: 17.2+/-2.3 and NO-CPB: 18.8+/-2.5 min) were decreased (
p<0.001) and HL-II was increased (CPB: 171+/-41versus preoperative: 73+/-12 and
NO-CPB: 48+/-2.9 min, p<0.01). CONCLUSION. While surgery and anesthesia per se
do not seem to alter lactate metabolism, CPB significantly decreased lactate
clearance, this effect being possibly related to a mild liver dysfunction even
in uncomplicated elective surgery.

Ann Thorac Surg. 2003 Jul;76(1):136-40.  

Continuous ultrafiltration attenuates the pulmonary injury that follows open
heart surgery with cardiopulmonary bypass.

Huang H, Yao T, Wang W, Zhu D, Zhang W, Chen H, Fu W.

Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, Xinhua
Hospital, Shanghai Second Medical University, Shanghai, China.
wenfeik@online.sh.cn

BACKGROUND: Pulmonary injury after cardiac surgery is one of the complications
of cardiopulmonary bypass. We evaluated the ultrafiltration technique in
preventing and relieving the pulmonary injury that can follow open heart surgery
with cardiopulmonary bypass (CPB). METHODS: Thirty patients with congenital
heart defects were divided into two groups. In the control group conventional
cardiopulmonary bypass was used without ultrafiltration. In the treated group,
in addition to the same cardiopulmonary bypass procedure, balanced
ultrafiltration plus modified ultrafiltration was used throughout
cardiopulmonary bypass. Pulmonary function, hematocrit, serum albumin, and some
inflammatory mediators were measured. RESULTS: Compared with measurements before
anesthesia the pulmonary static compliance at 15 minutes and 6 hours post bypass
had decreased by 27.8% and 34.0% in the control group versus 12.6% and 15.4% in
the treated group, the airway resistance had increased by 38.0% and 45.2% in the
control group versus 9.5% and 4.7% in the treated group, and the
alveolar-arterial oxygen difference increased by 73.4% and 62.0% in the control
group versus 52.1% and 35.9% in the treated group. Hemodilution from
cardiopulmonary bypass caused the hematocrit and serum albumin to decrease by
35.8% and 32.8% in the control group versus 36.1% and 34.5% in the treated group
at the termination of CPB. After 10 to 15 minutes modified ultrafiltration the
hematocrit and serum albumin increased by 40.0% and 47.6%. At the termination of
CPB the serum concentrations of interleukin-6, thromboxane B2, and endothelin-1
were increased by 160%, 265%, and 890% in the control group versus 103%, 208%,
and 838% in the treated group compared with those before anesthesia.
CONCLUSIONS: The combined use of balanced ultrafiltration and modified
ultrafiltration can effectively concentrate the blood, modify the increase of
some harmful inflammatory mediators, attenuate the lung edema and inflammatory
pulmonary injury, and mitigate the impairment of pulmonary function.

Pediatr Crit Care Med. 2003 Jul;4(3):299-304.  

Bradykinin and histamine generation with generalized enhancement of
microvascular permeability in neonates, infants, and children undergoing
cardiopulmonary bypass surgery.

Neuhof C, Walter O, Dapper F, Bauer J, Zickmann B, Fink E, Tillmanns H, Neuhof
H.

Department of Internal Medicine/Cardiology (CN, HT), Department of Internal
Medicine/Division of Clinical Pathophysiology and Experimental Medicine,
Department of Thoracic and Cardiovascular Surgery, Department of Pediatric
Cardiology, Department of Anesthesiology, and Department of Internal
Medicine/Clinical Pathophysiology and Experimental Medicine,
Justus-Liebig-University of Giessen, Germany; and the Department of Clinical
Chemistry and Biochemistry, Ludwig-Maximilians University of Munich, Germany.
E-mail: heinz.neuhof@innere.med.uni-giessen.de

OBJECTIVE: To investigate whether generation and liberation of bradykinin and
histamine contribute to generalized edema formation in pediatric cardiopulmonary
bypass surgery. DESIGN: Prospective observational study. SETTING: Pediatric
heart surgery of a university hospital. PATIENTS: Forty-one neonates, infants,
and children undergoing cardiopulmonary bypass to correct congenital cardiac
anomalies. INTERVENTIONS: Plasma concentrations of bradykinin and histamine were
determined before, during, and after cardiopulmonary bypass. Fluid balance was
evaluated by control of fluid intake and output. MEASUREMENTS AND MAIN RESULTS:
The susceptibility to generalized edema formation increased significantly (r =
-.457; p <.005) with decreasing age. Approximately three times higher plasma
concentrations of bradykinin (p <.001) were found at the onset of anesthesia and
during the total observation period in patients with a fluid retention of >6% of
body weight compared with patients with a lower retention rate. Plasma
bradykinin reached significantly (p <.01) higher peak concentrations of 237.9
+/- 58.6 fmol/mL during cardiopulmonary bypass and of 227.5 +/- 90.7 fmol/mL
during the early postoperative period in patients with severe edema formation in
contrast to only 86.6 +/- 10.9 and 65.5 +/- 26.8 fmol/mL in patients with minor
fluid retention. A tendency (p =.06) to slightly increasing histamine
concentrations from 2.07 +/- 0.13 nmol/L at baseline to 3.32 +/- 1.41 nmol/L
during 90 mins of cardiopulmonary bypass was only observed in patients with high
fluid retention. CONCLUSIONS: Bradykinin seems to be essentially involved in the
enhancement of microvascular permeability in pediatric cardiopulmonary bypass
surgery, although a dominant causal role cannot be claimed by this study.
Histamine, however, doesn't appear to play a major role and may only contribute
as a cofactor. To what extent an increased expression of bradykinin-1 and
bradykinin-2 receptors or a reduced potential of bradykinin-degrading enzymes is
involved is the object of a further clinical study.

Cytometry. 2003 Jul;54B(1):54-7.  

Immune consequences of pediatric and adult cardiovascular surgery: Report of the
7th Leipzig workshop.

Tarnok A, Emmrich F.

Pediatric Cardiology, Cardiac Center Leipzig, University of Leipzig, Germany.

Cardiovascular surgery in children and adults is among the most common types of
interventions in the western hemisphere for innate and acquired defects. In the
recent decades, the risk of cardiovascular surgery has been reduced
substantially. Nevertheless, open heart surgery is risky for the patient and can
lead to postoperative complications such as postpericardiotomy syndrome,
capillary leak syndrome, or multiple organ failure. To gain further
understanding into the response to cardiovascular surgery, it is necessary to
join forces from several disciplines of medicine and natural sciences.
Interdisciplinarity is the basic concept of the Leipzig Workshop. The consensus
of the workshop was that cardiovascular surgery with cardiopulmonary bypass
induces a systemic antiinflammatory response due to (a) elimination of activated
cells, (b) compensatory reaction to a local proinflammatory responses, (c)
interleukin-10 release, (d) anesthetics and medication, and (e) leukocyte
extravasation. The subsequent proinflammatory reaction is the response to
surgical trauma modulating the antiinflammatory reaction. Novel therapeutic
approaches include the introduction of autologous endothelial progenitor cells
from the peripheral blood into the sites of injury. The analysis of immune
response and outcome prediction require novel analytical tools that allow fast,
accurate, and quantitative determination of the desired parameters in a
multiplexed manner (i.e., cytomics), such as flow cytometric microbead array
assays and slide-based cytometry. The major goal is predictive medicine by
cytomics, i.e., the individualized risk assessment by analyzing the cytome in
combination with sophisticated data pattern recognition. These developments may
lead to individualized therapy for the benefit of the patient and cost
reduction. Cytometry Part B (Clin. Cytometry) 54B:54-57, 2003. Copyright 2003
Wiley-Liss, Inc.

Anesthesiology. 2003 Jul;99(1):54-9.  

Evaluation of a new point-of-care celite-activated clotting time analyzer in
different clinical settings. The i-STAT celite-activated clotting time test.

Paniccia R, Fedi S, Carbonetto F, Noferi D, Conti P, Bandinelli B, Giusti B,
Evangelisti L, Pretelli P, Palmarini MF, Abbate R, Prisco D.

Dipartimento di Area Critica Medico-Chirurgica, Sezione di Clinica Medica
Generale e Cliniche Specialistiche, Centro di Riferimento Regionale per la
Trombosi, Florence, Italy. r.paniccia@dac.unifi.it

BACKGROUND: Activated clotting time (ACT) is used to monitor heparin therapy
during cardiopulmonary bypass, interventional cardiology, and hemodialysis.
Traditionally, ACT is performed by use of the Hemochron system. Recently, a new
device, the i-STAT system, has been introduced to measure ACT. The aim of this
study was to correlate the performances of these two systems and to compare ACT
values with heparin levels. METHODS: One hundred sixty-five samples from 29
patients undergoing cardiopulmonary bypass or hemodialysis were assayed in
duplicate with two Hemochron and two i-STAT devices. Heparin levels were
determined by anti-factor Xa assay. RESULTS: The Hemochron ACT ranged from 88 to
1,028 s, and the i-STAT ACT ranged from 80 to 786 s. Heparin plasma levels
ranged from 0.01 to 10.8 U/mL. Bland-Altman analysis showed a mean difference
between the two methods of 24 +/- 101 s. Strong relationships between
anti-factor Xa activity and Hemochron ACTs (r2 = 0.69, P < 0.001) and i-STAT
ACTs (r2 = 0.79, P < 0.001) were observed. During cardiac surgery, significant
correlations were found: Hemochron, r2 = 0.61, P < 0.001 and i-STAT, r2 = 0.74,
P < 0.001. During hemodialysis, relationships between anti-factor Xa activity
and ACTs were found: Hemochron, r2 = 0.62, P < 0.001 and i-STAT, r2 = 0.55, P <
0.001. CONCLUSIONS: During cardiopulmonary bypass procedure and hemodialysis,
i-STAT provides measurements of clotting time quite similar to Hemochron ACT,
which were significantly correlated with heparin levels.

Anesthesiology. 2003 Jul;99(1):48-53.  

Relationship between aortic-to-radial arterial pressure gradient after
cardiopulmonary bypass and changes in arterial elasticity.

Kanazawa M, Fukuyama H, Kinefuchi Y, Takiguchi M, Suzuki T.

Department of Anesthesiology, Tokai University School of Medicine, Bohseidai,
Isehara, Kanagawa, Japan. masa@webscopy.com

BACKGROUND: An aortic-to-radial arterial pressure gradient may develop during
and after cardiopulmonary bypass (CPB). The mechanisms of this pressure gradient
remain controversial. To clarify the cause of the pressure gradient after CPB,
the authors investigated the relationship between the pressure gradient and
changes in the pulse wave velocity (PWV) before and after CPB. METHODS: The
pressure gradient from the aorta to the radial artery and a change in PWV were
measured with a wire (0.37 mm in diameter) tipped with a miniature pressure
transducer in 12 patients undergoing cardiac surgery. The pressure distributions
and waveforms were measured and recorded with electrocardiograph. The PWV was
calculated by measuring the propagation time between the R wave of the
electrocardiograph and the rising point of the arterial pressure waveform at
10-cm intervals. RESULTS: After CPB, 7 of 12 patients demonstrated a marked
pressure gradient. In these patients, the pressure distribution showed a gradual
decrease toward the periphery without a precipitous step-down in pressure at any
one specific anatomic location. The PWV decreased as the intraarterial pressure
decreased from the aorta to the radial artery, and the relative arterial
elasticity decreased linearly toward the periphery. CONCLUSIONS: The results
showed that the decrease in PWV implies a decrease in arterial elasticity, and
the decrease in the arterial elasticity correlated with the decrease in
intraarterial pressure. These findings demonstrated that a radial artery
pressure lower than the aortic pressure after CPB may be due to the decrease in
arterial elasticity.