Eur J Cardiothorac Surg. 2005 Aug 29; [Epub ahead of print] 

Pro-inflammatory cytokines after different kinds of cardio-thoracic surgical
procedures: is what we see what we know?

Franke A, Lante W, Fackeldey V, Becker HP, Kurig E, Zoller LG, Weinhold C,
Markewitz A.

Department of Cardiovascular Surgery, Bundeswehr Central Hospital, Rubenacher
Str.170, D 56072 Koblenz, Germany.

Objective: Due to the combination of local trauma, extracorporeal circulation
(ECC), and pulmonary and myocardial reperfusion, cardiac surgery leads to
substantial changes in the immune system and possibly to post-operative
complications. Procedures without ECC, however, have failed to demonstrate clear
advantages. We hypothesized that ECC is far less important in this context than
the reperfusion/reventilation of the lung parenchyma and the surgical trauma. We
therefore conducted a prospective observational study to compare immune
reactions after cardiac operations with those after thoracic surgery. Methods:
Serum levels of pro-inflammatory interleukin (IL)-6, IL-8, tumor necrosis factor
(TNF)-alpha as well as C-reactive protein (CRP), lipoprotein-binding protein
(LBP) and procalcitonin (PCT) were measured pre-operatively (d0), at the end of
the operation (dx), 6h after the operation (dx+), on the 1st (d1), 3rd (d3), and
5th (d5) post-operative days in 108 patients (pts) undergoing elective coronary
artery bypass grafting (CAB) with ECC (n=42, CPB CAB), off-pump coronary artery
bypass surgery (n=24, OP CAB) without ECC or thoracic surgery (n=42, TS).
Results: After cardiac surgery (CS), IL-6 and IL-8 increased and reached a
maximum on dx+. IL-6 returned to baseline values at d3, whereas IL-8 remained
elevated until d5. No difference was found between OP CAB and CPB CAB patients.
In the TS patients, IL-6 increased later (dx+) and absolute levels were lower
than in the CS patients. No increase in IL-8 was noted in the TS patients. Due
to the high variation in the results obtained in all three groups, there was no
significant change in TNF-alpha. A comparison of TS, OP CAB, and CPB CAB
revealed that the CS patients had higher levels on d0, dx, d3, and d5. Serum
levels of CRP, LBP, and IL-2R increased from dx+ to d5 in all groups and reached
maximum values on d3. Whereas we found no difference in CRP and IL-2R between
the groups, LBP levels were significantly higher from dx+ to d3 after OP CAB.
PCT was elevated from dx+ to d3 in all pts. Similar levels were noted for the TS
and OP CAB patients. The CPB CAB patients showed the highest levels.
Conclusions: Surgical trauma and reperfusion injury appear to represent the
predominant factors resulting in immunologic changes after cardiac surgery.
Cardiopulmonary bypass (CPB) may be less important for immune response and
acute-phase reactions than previously suspected. In addition, our data indicate
a relationship between IL-6 synthesis and the degree of surgical trauma. IL-8
appears to be elevated only after cardiac surgery whereas PCT liberation
depended on the use of ECC.

Intensive Care Med. 2005 Aug 17; [Epub ahead of print] 

Mechanical ventilation strategies and inflammatory responses to cardiac surgery:
a prospective randomized clinical trial.

Wrigge H, Uhlig U, Baumgarten G, Menzenbach J, Zinserling J, Ernst M, Dromann D,
Welz A, Uhlig S, Putensen C.

Department of Anesthesiology and Intensive Care Medicine, University of Bonn,
Sigmund-Freud-Strasse 25, 53105, Bonn, Germany, hermann.wrigge@ukb.uni-bonn.de.

OBJECTIVE: To examine whether postoperative mechanical ventilation with lower
tidal volumes (V(T)) has protective effects on inflammatory responses induced by
cardiopulmonary bypass (CPB) surgery in smokers and nonsmokers.DESIGN AND
SETTING: Prospective, randomized, controlled clinical trial in the intensive
care unit of a university hospital.PATIENTS AND PARTICIPANTS: We examined 44
patients (22 smokers, 22 nonsmokers) immediately after uncomplicated CPB
surgery.INTERVENTIONS: Ventilation was applied for 6 h with either V(T) of
either 6 or 12 ml/kg ideal body weight.MEASUREMENTS AND RESULTS: The time course
of serum tumor necrosis factor (TNF) alpha, interleukin (IL) 6, and IL-8
determined 0, 2, 4, and 6 h after randomization did not differ significantly
between the ventilatory strategies. By contrast, in bronchoalveolar lavage
fluids sampled after 6 h only TNF-alpha levels were significantly higher in the
high V(T) group than the low V(T) group (50+/-111 pg/ml vs. 1+/-7 pg/ml). IL-6
and IL-8 concentrations did not differ between groups. Subgroup analysis of
patients with serum TNF-alpha level higher than 0 pg/ml after surgery revealed
lower TNF-alpha serum levels during lower V(T) ventilation. All observed effects
were small, independent of patients' history of smoking, and were not correlated
with duration of ventilation and ICU stay.CONCLUSIONS: Ventilation with lower
V(T) had no or only minor effect on systemic and pulmonary inflammatory
responses in patients with healthy lungs after uncomplicated CPB surgery. Our
data do not suggest a clinical benefit of using low V(T) ventilation in these
selected patients.

Anaesth Intensive Care. 2005 Aug;33(4):457-61. 

The relationship between oxygenator exhaust P(CO2) and arterial P(CO2) during
hypothermic cardiopulmonary bypass.

Graham JM, Gibbs NM, Weightman WM, Sheminant MR.

Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands, Perth,
Western Australia.

During cardiopulmonary bypass the partial pressure of carbon dioxide in
oxygenator arterial blood (P(a)CO2) can be estimated from the partial pressure
of gas exhausting from the oxygenator (P(E)CO2). Our hypothesis is that P(E)CO2
may be used to estimate P(a)CO2 with limits of agreement within 7 mmHg above and
below the bias. (This is the reported relationship between arterial and
end-tidal carbon dioxide during positive pressure ventilation in supine
patients.) During hypothermic (28-32 degrees C) cardiopulmonary bypass using a
Terumo Capiox SX membrane oxygenator, 80 oxygenator arterial blood samples were
collected from 32 patients during cooling, stable hypothermia, and rewarming as
per our usual clinical care. The P(a)CO2 of oxygenator arterial blood at actual
patient blood temperature was estimated by temperature correction of the
oxygenator arterial blood sample measured in the laboratory at 37 degrees C.
P(E)CO2 was measured by connecting a capnograph end-to-side to the oxygenator
exhaust outlet. We used an alpha-stat approach to cardiopulmonary bypass
management. The mean difference between P(E)CO2 and P(a)CO2 was 0.6 mmHg, with
limits of agreement (+/-2 SD) between -5 to +6 mmHg. P(E)CO2 tended to
underestimate P(a)CO2 at low arterial temperatures, and overestimate at high
arterial temperatures. We have demonstrated that P(E)CO2 can be used to estimate
P(a)CO2 during hypothermic cardiopulmonary bypass using a Terumo Capiox SX
oxygenator with a degree of accuracy similar to that associated with the use of
end-tidal carbon dioxide measurement during positive pressure ventilation in
anaesthetized, supine patients.

Neurology. 2005 Aug 17; [Epub ahead of print] 

Is there cognitive decline 1 year after CABG? Comparison with surgical and
nonsurgical controls.

McKhann GM, Grega MA, Borowicz LM Jr, Bailey MM, Barry SJ, Zeger SL, Baumgartner
WA, Selnes OA.

From the Departments of Neurology (Drs. McKhann and Selnes) and Surgery (Dr.
Baumgartner and M.A. Grega), School of Medicine; the Zanvyl Krieger Mind/Brain
Institute (Dr. McKhann, L.M. Borowicz, and M.M. Bailey); and the Department of
Biostatistics (Dr. Zeger and S.J.E. Barry), Bloomberg School of Public Health,
Johns Hopkins University, Baltimore, MD.

Abstract-- BACKGROUND: It is widely assumed that decline in cognition after
coronary artery bypass grafting (CABG) is related to use of the cardiopulmonary
bypass pump. Because most studies have not included comparable control groups,
it remains unclear whether postoperative cognitive changes are specific to
cardiopulmonary bypass, general aspects of surgery, or vascular pathologies of
the aging brain. METHODS: This nonrandomized study included four groups: CABG
patients (n = 140); off-pump coronary surgery (n = 72); nonsurgical cardiac
controls (NSCC) with diagnosed coronary artery disease but no surgery (n = 99);
and heart healthy controls (HHC) with no cardiac risk factors (n = 69). Subjects
were evaluated at baseline (preoperatively), 3 months, and 12 months. Eight
cognitive domains and a global cognitive score, as well as depressive and
subjective symptoms were analyzed. RESULTS: At baseline, patients with coronary
artery disease (CABG, off-pump, and NSCC) had lower performance than the HHC
group in several cognitive domains. By 3 months, all groups had improved. From 3
to 12 months, there were minimal intrasubject changes for all groups. No
consistent differences between the CABG and off-pump patients were observed.
CONCLUSIONS: Compared with heart healthy controls (HHC), the groups with
coronary artery disease had lower cognitive test scores at baseline. There was
no evidence that the cognitive test performance of coronary artery bypass
grafting (CABG) patients differed from that of control groups with coronary
artery disease over a 1-year period. This study emphasizes the need for
appropriate control groups for interpreting longitudinal changes in cognitive
performance after CABG.

Br J Anaesth. 2005 Aug 12; [Epub ahead of print] 

Glucose, insulin and potassium applied as perioperative hyperinsulinaemic
normoglycaemic clamp: effects on inflammatory response during coronary artery
surgery.

Visser L, Zuurbier CJ, Hoek FJ, Opmeer BC, de Jonge E, de Mol BA, van Wezel HB.

Department of Anaesthesia, University of Amsterdam, Meibergdreef 9, 1105 AZ,
Amsterdam, The Netherlands.

BACKGROUND: /B>. The clinical benefits of glucose-insulin-potassium (GIK) and
tight glycaemic control in patients undergoing coronary artery bypass grafting
(CABG) may be partly explained by an anti-inflammatory effect. We applied GIK as
a hyperinsulinaemic normoglycaemic clamp for >25 h and quantified its effect on
systemic inflammation in patients undergoing CABG. METHODS: /B>. Data obtained
in 21 non-diabetic patients with normal left ventricular function scheduled for
elective coronary artery surgery, who were randomly allocated to a control or
GIK group, were analysed. In GIK patients, regular insulin was infused at a
fixed rate of 0.1 IU kg(-1) h(-1). The infusion rate of glucose (30%) was
adjusted to maintain blood glucose levels within a target range of 4.0-5.5 mmol
litre(-1). Plasma concentrations of interleukins 6, 8 and 10, C-reactive protein
(CRP) and serum amyloid A (SAA) were measured on the day of surgery and on the
first and second postoperative days (POD1 and POD2). RESULTS: In the GIK group
hypoglycaemia (glucose <2.2 mmol litre(-1)) did not occur, whereas hyperglycemia
(glucose >6.1 mmol litre(-1)) developed in 15% of all measurements. In control
patients, hyperglycaemia developed in >80% of all measurements in the presence
of low endogenous insulin levels. CRP and SAA levels increased in both groups,
with maximum levels measured on POD2. GIK treatment significantly reduced CRP
and SAA levels. Interleukin levels increased significantly in both groups
following cardiopulmonary bypass, but no differences were found between the
groups. CONCLUSION: /B>. Hyperinsulinaemic normoglycaemic clamp is an effective
method of maintaining tight glycaemic control in patients undergoing CABG and it
attenuates the systemic inflammatory response in these patients. This effect may
partly contribute to the reported beneficial effect of glycaemic control in
patients undergoing CABG.

Chest. 2005 Aug;128(2):838-47. 

Cardioprotective effects of acute normovolemic hemodilution in patients
undergoing coronary artery bypass surgery.

Licker M, Ellenberger C, Sierra J, Kalangos A, Diaper J, Morel D.

Department of Anesthesiology, Pharmacology, and Surgical Intensive Care,
University Hospital of Geneva, Geneva, Switzerland. marc-joseph.licker@hcuge.ch

STUDY OBJECTIVES: We hypothesized that lowering blood viscosity with acute
normovolemic hemodilution (ANH) would confer additional cardioprotection in
patients undergoing coronary artery bypass surgery (CABG) with aortic
cross-clamping. DESIGN: In a prospective, randomized controlled trial, we
studied the efficacy of ANH in anesthetized patients prior to cardiopulmonary
bypass for the prevention of myocardial injuries. SETTING: Cardiac surgical
center in a university hospital. PATIENTS AND METHODS: Patients scheduled to
undergo elective CABG entered the study protocol and were randomly allocated to
one of two groups: ANH (n = 43 patients) or standard care management (n = 41
patients). In the ANH group, the whole-blood/colloid exchange was aimed to
achieve a hematocrit value of 28%. All patients were managed with standard
myocardial preservation techniques including cold-blood cardioplegia and
anesthetic preconditioning. The outcome measures included the release of
myocardial enzymes (plasma troponin I and creatinine phosphokinase),
perioperative hemodynamic changes, need for pharmacologic cardiovascular
support, and cardiac complications. RESULTS: In the hemodilution group, the
postoperative release of troponin I (mean peak plasma concentration, 1.4 ng/mL;
95% confidence interval, 1.0 to 1.8) and myocardial fraction of creatine kinase
(mean, 29 U/L; 95% confidence interval, 23 to 35) were significantly lower than
in the control group (mean, 3.8 ng/mL; 95% confidence interval, 3.2 to 4.5; and
71 U/L; 95% confidence interval, 53 to 89). Requirement for inotropic support
was significantly lower in the protocol patients (7 of 41 patients vs 15 of 39
patients), and fewer patients presented with either atrial fibrillation,
atrioventricular conduction blockade, or combined disorders (12 of 41 patients
vs 26 of 39 patients, p < 0.05). CONCLUSIONS: In addition to conventional
myocardial preservation techniques, preoperative ANH achieved further cardiac
protection in patients undergoing on-pump myocardial revascularization.

Lancet. 2005 Aug 13-19;366(9485):556-62. 

Capillary leak syndrome in children with C4A-deficiency undergoing cardiac
surgery with cardiopulmonary bypass: a double-blind, randomised controlled
study.

Zhang S, Wang S, Li Q, Yao S, Zeng B, Ziegelstein RC, Hu Q.

Department of Anaesthesiology, Union Hospital, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, People's Republic of China.

BACKGROUND: Capillary leak syndrome is a life-threatening complication after
cardiopulmonary bypass (CPB), with an incidence of about 4-37% in children
worldwide. On the basis of previous results, we undertook a randomised
controlled study to investigate the priming with plasma rich in the C4A isotype
of complement component 4 on the incidence of capillary leak syndrome in
children with C4A deficiency. METHODS: In a hospital in Wuhan, China, we
randomly assigned 116 neonates, infants, and children lacking complement
component C4A to receive C4A-free or C4A-rich plasma priming (n=58 each, 20
mL/kg). The primary outcome was capillary leak syndrome, identified as an
increased transvascular escape rate of Evans blue dye from plasma.
Concentrations of activated complement components C4 and C3, inflammatory
mediators interleukin 6, interleukin 8, tumour necrosis factor (TNF) alpha,
plasma protein, and PaO2/F(I)O2 ratios (ratio of the partial arterial pressure
of oxygen to the fractional concentration of oxygen in inspired air) were
measured before and 4 h after CPB. Analysis was by intention to treat. FINDINGS:
Three (5%) patients given C4A-rich plasma priming had capillary leak syndrome
compared with 56 (97%) given C4A-free plasma (p<0.0001). At 4 h after CPB,
activated C4, interleukin 6, interleukin 8, and TNFalpha concentrations were
higher, whereas PaO2/F(I)O2 ratios and plasma protein concentrations were
significantly lower in the C4A-free group than changes in the C4A-rich group.
Activated C3 rose equally in both groups. Activated C4 significantly correlated
with interleukin 6, interleukin 8, and TNFalpha concentrations; PaO2/F(I)O2
ratios; and the escape rate of Evans blue dye at 4 h after CPB. Two patients in
the C4A-free group died of respiratory and renal failure on day 3 after CPB.
INTERPRETATION: In paediatric patients with C4A deficiency, C4A-rich plasma
priming reduces the incidence of CPB-related capillary leak syndrome by blocking
the activated C4 increase and attenuating the systemic inflammatory response
after CPB.

J Am Coll Cardiol. 2005 Aug 16;46(4):707-13. 

Plasma tissue factor plus activated peripheral mononuclear cells activate
factors VII and X in cardiac surgical wounds.

Hattori T, Khan MM, Colman RW, Edmunds LH Jr.

Harrison Department of Surgical Research, School of Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania, USA.

OBJECTIVES: The purpose of this study was to test the hypothesis that activated
monocytes with soluble plasma tissue factor (pTF) activate factors VII and X to
generate thrombin. BACKGROUND: Despite heparin, thrombin is progressively
generated during cardiac surgery with cardiopulmonary bypass (CPB), produces
intravascular fibrin and fibrinolysis, and causes serious thromboembolic and
nonsurgical bleeding complications. Thrombin is primarily produced in the
surgical wound, but mechanisms are unclear. METHODS: In 13 patients,
interactions of mononuclear cells, platelets, pTF, and pTF fractions to activate
factors VII and X were evaluated in pre-bypass, perfusate, and pericardial wound
blood before and during CPB. RESULTS: Monocytes are activated in wound, but not
in pre-bypass or perfusate plasma (monocyte chemotactic protein-1 = 29.5 +/- 2.1
pmoles/l vs. 2.8 +/- 1.2 pmoles/l and 3.3 +/-1.4 pmoles/l, respectively). Wound
pTF is substantially elevated compared to other locations (3.64 +/- 0.45
pmoles/l vs. 0.71 +/- 0.65 pmoles/l and 1.31 +/- 1.4 pmoles/l). Supernatant
wound pTF contains 81.7% of TF antigen; wound microparticle pTF contains 18.3%.
Wound monocytes and all C5a-stimulated monocytes (but not activated platelets)
completely convert factor VII to factor VIIa with wound pTF. Activated monocytes
more efficiently activate factor X with wound supernatant TF/factor VII(VIIa)
complex than with wound microparticle TF/factor VII(fVIIa). The correlation
coefficient (r) between wound thrombin generation (F1.2) and wound pTF
concentration is 0.944 (p = 0.0004). CONCLUSIONS: During cardiac surgery with
CPB, wound monocytes plus wound pTF or wound microparticle-free supernatant pTF
preferentially accelerate activation of factor VII and factor X. This system
represents a novel mechanism for thrombin generation via the TF coagulation
pathway.

Crit Care Med. 2005 Aug;33(8):1749-56. 

Role of hemodilutional anemia and transfusion during cardiopulmonary bypass in
renal injury after coronary revascularization: implications on operative
outcome.

Habib RH, Zacharias A, Schwann TA, Riordan CJ, Engoren M, Durham SJ, Shah A.

Department of Cardiovascular Surgery, St. Vincent Mercy Medical Center, Toledo,
OH, USA.

OBJECTIVE: Acute renal injury and failure (ARF) after cardiopulmonary bypass
(CPB) has been linked to low on-pump hematocrit (hematocrit). We aimed to 1)
elucidate if and how this relation is modulated by the duration of CPB (TCPB)
and on-pump packed red blood cell transfusions and 2) to quantify the impact of
post-CPB renal injury on operational outcome and resource utilization. DESIGN:
Retrospective review. SETTING: A Northwest Ohio community hospital. PATIENTS:
Adult coronary artery bypass surgery patients with CPB but no preoperative renal
failure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We quantified
post-CPB renal injury via 1) the peak postoperative change in serum creatinine
(Cr) level relative to pre-CPB values (%DeltaCr) and 2) ARF, defined as the
coincidence of post-CPB Cr > or =2.1 mg/dL and >2 times pre-CPB Cr. The separate
effects of lowest hematocrit, intraoperative packed RBC transfusions, and TCPB
on %DeltaCr and ARF were derived via multivariate regression, overlapping
quintile subgroup analyses, and propensity matching. Lowest hematocrit (22.0%
+/- 4.6% sd), TCPB (94 +/- 35 mins), and pre-CPB Cr (1.01 +/- 0.23 mg/dL) varied
widely. %DeltaCr varied substantially (24 +/- 57%), and ARF was documented in 89
patients (5.1%). Both %DeltaCr (p < .001) and ARF (p < .001) exhibited sigmoidal
dose-dependent associations to lowest hematocrit that were 1) modulated by TCPB
such that the renal injury was exacerbated as TCPB increased, 2) worse in
patients with relatively elevated pre-CPB Cr (> or =1.2 mg/dL), and 3) worse
with intraoperative packed red blood cell transfusions (n = 385; 21.9%), in
comparison with patients at similar lowest hematocrit. Operative mortality (p <
.01) and hospital stays (p < .001) were increased systematically and
significantly as a function of increased post-CPB renal injury. CONCLUSIONS: CPB
hemodilution to hematocrit <24% is associated with a systematically increased
likelihood of renal injury (including ARF) and consequently worse operative
outcomes. This effect is exacerbated when CPB is prolonged with intraoperative
packed red blood cell transfusions and in patients with borderline renal
function. Our data add to the concerns regarding the safety of currently
accepted CPB practice guidelines.

Effects of hemodilution, blood loss, and consumption on hemostatic factor levels
during cardiopulmonary bypass.

Chandler WL.

Department of Laboratory Medicine, University of Washington, Seattle, WA.

Objectives: The purpose of this study was to determine quantitatively the
effects of consumption, hemodilution, and blood loss on coagulation and
fibrinolytic factor levels during cardiopulmonary bypass. Design: A combination
of measured levels of prothrombin, antithrombin, fibrinogen, plasminogen, and
antiplasmin along with their activation markers F1.2, thrombin-antithrombin
complex, fibrinopeptide A, plasmin-antiplasmin complex, and D-dimer were used
with a computer model of each patient's vascular and hemostatic systems to
estimate the cardiopulmonary bypass-associated loss of each factor because of
hemodilution, blood loss, and consumption. Setting: University hospital.
Participants: Nine patients undergoing coronary artery bypass graft surgery.
Interventions: None. Measurements and Main Results: At baseline, it was
estimated that on average 2%, 3%, and 25%, respectively, of the baseline liver
secretion of plasminogen, prothrombin,and fibrinogen were consumed by activation
of these proteins. During cardiopulmonary bypass, thrombin and plasmin
generation were increased, whereas fibrin generation was decreased because of
heparin. Compared with baseline, hemodilution during cardiopulmonary bypass
resulted in an average 35% +/- 7% decrease in the concentration of coagulation
and fibrinolytic proteins, whereas blood loss was responsible for an average 6%
+/- 5% decrease in these proteins. Blood loss varied substantially among
patients, resulting in <1% to 14% decreases in hemostatic protein levels. On
average, consumption because of activation resulted in less than a 1% drop in
the concentration of coagulation and fibrinolytic factors during cardiopulmonary
bypass. Conclusions: Hemodilution is the primary cause of the drop in
coagulation and fibrinolytic proteins during routine cardiopulmonary bypass,
followed by blood loss, whereas consumption accounts for less than a 1% drop in
most patients.