Crit Care Med. 2004 Dec;32(12):2392-2397. 

Mesenteric injury after cardiopulmonary bypass: Role of poly(adenosine
5'-diphosphate-ribose) polymerase.

Szabo G, Soos P, Mandera S, Heger U, Flechtenmacher C, Seres L, Zsengeller Z,
Sack FU, Szabo C, Hagl S.

From the Department of Cardiac Surgery (GS, PS, SM, UH, F-US, SH) and Institute
of Pathology (CF), University of Heidelberg, Heidelberg, Germany; Department of
Cardiovascular Surgery (GS, PS, LS) and Department of Human Physiology and
Clinical Experimental Research (CZ), Semmelweis University, Budapest, Hungary;
and Inotek Pharmaceuticals Corporation (ZZ, CZ), Beverly, MA.

OBJECTIVES:: To investigate the effects of the ultrapotent poly(adenosine
5'-diphosphate-ribose) polymerase (PARP) inhibitor INO-1001 on cardiac and
mesenteric function during reperfusion in an experimental model of
cardiopulmonary bypass with cardioplegic arrest. 

DESIGN:: Prospective, randomized, and blinded experimental study. 

SETTING:: Research laboratory.

SUBJECTS:: Twelve anesthetized dogs underwent cardiopulmonary bypass with
hypothermic cardioplegic cardiac arrest. 
INTERVENTIONS:: After 60 mins of hypothermic cardiac arrest, either PARP inhibitor 
INO-1001 (1 mg/kg, n = 6) or vehicle (control, n = 6) was administered during reperfusion. 

MEASUREMENTS AND MAIN RESULTS:: Left ventricular hemodynamic variables 
were measured by combined pressure-volume-conductance catheters. 
Coronary and mesenteric blood flow and vasodilatory responses to acetylcholine and
 sodium nitroprusside as well as mesenteric lactate and creatinine phosphokinase 
 release were also determined. The administration of INO-1001 led to a significantly 
 improved recovery of left ventricular systolic function (p < .05) after 60 mins of reperfusion. 
 Coronary and mesenteric blood flow were also significantly higher in the INO-1001 group
(p < .05). Although the vasodilatory response to sodium nitroprusside was
similar in both groups before and after cardiopulmonary bypass and similar in
response to acetylcholine before cardiopulmonary bypass, PARP-inhibited dogs had
lower mesenteric vascular resistance after cardiopulmonary bypass (p < .05).
Mesenteric lactate and creatinine phosphokinase release was significantly lower
in the PARP inhibitor treated group (p < .05). 

CONCLUSION:: PARP inhibition with INO-1001 improves the recovery of myocardial 
function and prevents mesenteric vascular dysfunction and tissue injury after 
cardiopulmonary bypass with hypothermic cardiac arrest.

Anadolu Kardiyol Derg. 2004 Dec;4(4):296-300. 

Effects of enalaprilat infusion on hemodynamics and renal function in patients
undergoing cardiac surgery.

Turker H, Donmez A, Zeyneloglu P, Sezgin A, Ulucam M.

Department of Anesthesiology, University of Baskent, School of Medicine, Ankara,
Turkey.

OBJECTIVE: This study was undertaken to evaluate the effect of enalaprilat
infusion on hemodynamics and renal function during cardiopulmonary bypass (CPB).

METHODS: Thirty adults undergoing CPB were randomly allocated into 2 groups. All
patients received the same anesthetic protocol and same dopamine infusion
protocol (2 mg/kg(-1)/min(-1)) during the study. In addition to dopamine
infusion 15 patients received enalaprilat infusion (0.06 mg/kg(-1)/hr(-1))
during CPB. Blood creatinine, urea levels, and creatinine clearance (CLcr) were
measured and cardiac output (CO) was calculated by echocardiography
preoperatively and on the 6th postoperative day. Mean arterial pressure (MAP),
central venous pressure (CVP), systemic vascular resistance (SVR) measurements
were recorded during the operation and during postoperative 24 hours. 

RESULTS: In the control group postoperative blood creatinine and urea levels were
significantly higher and CLcr measurements were significantly lower than the
preoperative values (p<0.05). These values did not change in the enalaprilat
group. Mean arterial pressure was similar in both groups (p>0.05), but SVR was
lower (p<0.05) and CVP was higher (p<0.05) in the enalaprilat group than in the
control group. In the enalaprilat group postoperative CO measurements were
higher than the preoperative values (p<0.05). 

CONCLUSION: Our results demonstrate that enalaprilat infusion during CPB improves 
renal function and CO measurements in the early postoperative period.

Asian Cardiovasc Thorac Ann. 2004 Dec;12(4):312-5. 

Cardiac surgery in an Iranian teaching hospital: outcome and risk factors.

Hassantash SA, Mirpoor K, Afrakhteh M.

Department of Cardiovascular Surgery, Shahid Beheshti University of Medical
Sciences, Saadat-Abad, Tehran, Iran. sahassan@pol.net

Cardiac surgery in Iran has been associated with different facilities, equipment
and patient populations in comparison to countries from which most of the
academic papers used for identification of risk factors related to outcome and
subsequent establishment of risk stratification models originate from. During a
15-month period all patients admitted for adult cardiac surgery using
cardiopulmonary bypass (CBP) in a university affiliated teaching hospital were
enrolled in a prospective study. Appropriate statistical tests were used to
analyze data for mortality and morbidity. There were 730 adults (63% male, 37%
female), with age ranged from 16 to 82 (mean, 51.4 +/- 14.4). A mortality rate
of 5.3% and morbidity of 14.8% (major + minor) were observed in the whole group.
Factors correlated with mortality were: age (p = 0.019), emergency surgery (p <
0.0001), redo cardiac surgery (p = 0.01), left ventricular (LV) aneurysm (p <
0.001), presence of catastrophic states (p < 0.001), low ejection fraction (p =
0.04), history of hypertension (p = 0.05), the individual surgeon (p < 0.0001),
and CPB duration (p < 0.0001). Factors affecting morbidity included: female
gender (p = 0.04), age (p = 0.03), emergency surgery (p = 0.001), redo surgery
(p = 0.008), and catastrophic states (p < 0.001). The mortality in our study
group may be compared with reports presented in the literature. Factors such as
age, emergency surgery, redo cardiac surgery, and catastrophic states are
statistically related to both mortality and morbidity.

Can J Anaesth. 2004 Dec;51(10):1002-9. 

Aprotinin decreases the incidence of cognitive deficit following CABG and
cardiopulmonary bypass: a pilot randomized controlled study: [L'aprotinine
reduit l'incidence de deficit cognitif a la suite d'un PAC et de la circulation
extracorporelle : une etude pilote randomisee et controlee].

Harmon DC, Ghori KG, Eustace NP, O'callaghan SJ, O'donnell AP, Shorten GD.

Department of Anaesthesia and Intensive Care Medicine, Cork University Hospital,
Wilton Road, Cork, Ireland. dharmon@indigo.ie.

PURPOSE: Cognitive deficit after coronary artery bypass surgery (CABG) has a
high prevalence and is persistent. Meta-analysis of clinical trials demonstrates
a decreased incidence of stroke after CABG when aprotinin is administrated
perioperatively. We hypothesized that aprotinin administration would decrease
the incidence of cognitive deficit after CABG. 

METHODS: Thirty-six ASA III-IV patients undergoing elective CABG were included in 
a prospective, randomized, single-blinded pilot study. Eighteen patients received 
 aprotinin 2 x 10(6) KIU (loading dose), 2 x 10(6) KIU (added to circuit prime) and a 
 continuous infusion of 5 x 10(5) KIU*hr(-1). A battery of cognitive tests was administered to
patients and spouses (n = 18) the day before surgery, four days and six weeks
postoperatively. 

RESULTS: Four days postoperatively new cognitive deficit
(defined by a change in one or more cognitive domains using the Reliable Change
Index method) was present in ten (58%) patients in the aprotinin group compared
to 17 (94%) in the placebo group [95% confidence interval (CI) 0.10-0.62, P =
0.005); (P = 0.01)]. Six weeks postoperatively, four (23%) patients in the
aprotinin group had cognitive deficit compared to ten (55%) in the placebo group
(95% CI 0.80-0.16, P = 0.005); (P = 0.05). 

CONCLUSION: In this prospective pilot study, the incidence of cognitive deficit after 
CABG and cardiopulmonary bypass is decreased by the administration of high-dose
 aprotinin.

Anesth Analg. 2004 Dec;99(6):1598-603, table of contents. 

The response to activated protein C after cardiopulmonary bypass: impact of
factor V leiden.

Donahue BS.

Department of Anesthesiology, 504 Oxford House, Vanderbilt University,
Nashville, TN 37232, USA. brian.donahue@vanderbilt.edu

Activated protein C (aPC) resistance is a recognized hypercoagulable phenotype
that is associated with increased risk for thrombosis in multiple clinical
settings. Factor V Leiden (FVL) represents a specific inherited cause of aPC
resistance, but the perioperative thrombotic risk of FVL is unclear. In this
investigation, we sought to quantify whether cardiopulmonary bypass produces
alterations in aPC resistance in FVL carriers and noncarrier controls, testing
the hypothesis that FVL is associated with a relatively hypercoagulable
postoperative state. Two-hundred-five adult cardiac surgery patients were
prospectively enrolled into a genetic registry whose purpose was to study the
impact of genetic variables on clinical outcomes. For this study, 8 subjects
heterozygous for FVL were identified (group L), as well as 2 control groups:
group MC, matched controls, 18 matched subjects without FVL; and group UC,
unmatched controls, 11 consecutive subjects without FVL. Plasma was sampled at
the beginning of surgery, 10 min after protamine administration, and on
postoperative day 1, and assayed for resistance to aPC (normal aPC ratio is
>2.0). Both MC and UC groups exhibited normal aPC ratio at baseline (2.40 and
2.36, respectively), which increased significantly (to 2.76 and 2.75, P = 0.007
and 0.021, respectively) on postoperative day 1, indicating increased
postoperative sensitivity to aPC. Conversely, group L subjects exhibited aPC
resistance at baseline (aPC ratio 1.80), and did not change significantly
postoperatively (P = 0.867). Patients without FVL therefore show laboratory
evidence consistent with relative protection from postoperative thrombosis,
whereas FVL carriers do not. These findings provide mechanistic support for
previous speculations of increased postoperative thrombotic risk associated with
FVL.

Ann Thorac Surg. 2004 Dec;78(6):2131-8; discussion 2138. 

A closed perfusion system with heparin coating and centrifugal pump improves
cardiopulmonary bypass biocompatibility in elderly patients.

Lindholm L, Westerberg M, Bengtsson A, Ekroth R, Jensen E, Jeppsson A.

Department of Cardiothoracic Surgery, Sahlgrenska University Hospital,
Gothenburg, Sweden.

BACKGROUND: Cardiopulmonary bypass induces a systemic inflammatory and
hemostatic activation, which may contribute to postoperative complications. Our
aim was to compare the inflammatory response, coagulation, and fibrinolytic
activation between two different perfusion systems: one theoretically more
biocompatible with a closed-circuit, complete heparin coating, and a centrifugal
pump, and one conventional system with uncoated circuit, roller pump, and a
hard-shell venous reservoir. METHODS: Forty-one elderly patients (mean age, 73
+/- 1 years, 66% men) undergoing coronary artery bypass grafting or aortic valve
replacement were included in a prospective, randomized study. Plasma
concentrations of complement factors (C3a, C4d, Bb, and sC5b-9), proinflammatory
cytokines (tumor necrosis factor-alpha, interleukin-6, and interleukin-8),
granulocyte degradation products (polymorphonuclear elastase), and markers of
coagulation (thrombin-antithrombin) and fibrinolysis (D-dimer, tissue
plasminogen activator antigen and tissue plasminogen activator-plasminogen
activator inhibitor-1 complex) were measured preoperatively, at bypass during
rewarming (35 degrees C), 60 minutes after bypass, and on day 1 after surgery.
RESULTS: The mean concentrations of C3a (-39%; p = 0.008), Bb (-38%; p < 0.001),
sC5b-9 (-70%; p < 0.001), interleukin-8 (-60%; p = 0.009),
polymorphonuclear-elastase (-55%; p < 0.003), and tissue plasminogen activator
antigen (-51%; p = 0.012) were all significantly lower in the biocompatible
group during rewarming. Sixty minutes after bypass, the mean concentrations of
sC5b-9 (-39%; p = 0.006) and polymorphonuclear-elastase (-55%; p < 0.001) were
lower in the biocompatible group. CONCLUSIONS: The results suggest that a closed
perfusion system with a heparin-coated circuit and a centrifugal pump may
improve cardiopulmonary bypass biocompatibility in elderly cardiac surgery
patients in comparison with a conventional system.

Shock. 2004 Dec;22(6):533-7. 

Circulating levels of macrophage migration inhibitory factor are associated with
mild pulmonary dysfunction after cardiopulmonary bypass.

de Mendonca-Filho HT, Gomes RV, de Almeida Campos LA, Tura B, Nunes EM, Gomes R,
Bozza F, Bozza PT, Castro-Faria-Neto HC.

Laboratory of Immunopharmacology, Oswaldo Cruz Foundation, Rio de Janeiro, RJ,
Brazil. imunobiologia@procardiaco.com.br

Macrophage migration inhibitory factor (MIF) is a central mediator of
inflammatory response and acute lung injury that is secreted in response to
corticosteroids. A rise in systemic MIF levels was described after cardiac
surgery in steroid-treated patients. This study aimed to investigate the
circulating levels of MIF and the possible relationship of this cytokine to
pulmonary dysfunction after cardiopulmonary bypass (CPB). We included 74
patients without previous organ dysfunction undergoing elective coronary artery
bypass surgery (CABS). The same team performed all CABS via a standard technique
adding methylprednisolone (15 mg/kg) to the CPB priming solution (Group MP, n =
37). In the remaining patients (Group NS, n = 37), methylprednisolone was
withdrawn from the CPB priming. MIF, C-reactive protein (CRP), and total C3 were
assayed in peripheral blood sampled immediately before anesthesia induction and
3, 6, and 24 h post-CPB. Preoperative risk scores and peri- and postoperative
variables were documented. Postoperative kinetics of MIF and C3 were similar for
both groups. Levels of CRP 24 h post-CPB were higher in Group MP (P = 0.003).
Higher MIF levels were detected 6 h post-CPB, and returned to preoperative
levels 24 h after CPB. MIF levels 6 h post-CPB were inversely related to the
postoperative PaO2/FiO2 ratio (P = 0.0021) and were directly related to the
duration of mechanical ventilation (P = 0.014). Perioperative use of
methylprednisolone did not modify the MIF response to CPB, but it was related to
an enhanced acute phase response. Higher circulating MIF levels 6 h post-CPB
were associated with worse postoperative pulmonary short-course outcome.

Eur J Cardiothorac Surg. 2004 Dec;26(6):1161-8. 

beta2 adrenoceptor gene therapy ameliorates left ventricular dysfunction
following cardiac surgery.

Jones JM, Petrofski JA, Wilson KH, Steenbergen C, Koch WJ, Milano CA.

Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
mark.jones@royalhospitals.n-i.nhs.uk

OBJECTIVE: Heart surgery is associated with impairment of the myocardial
beta-adrenoceptor (betaAR) system. Effective therapies for post-operative
ventricular dysfunction are limited. Prolonged inotrope exposure is associated
with further betaAR down-regulation. Left ventricular (LV) dysfunction and
myocardial betaAR impairment were assessed following cardiopulmonary bypass
(CPB) and cardioplegic arrest in a pig model. Transfer of the human
beta2-adrenoceptor transgene (Adeno-beta2AR) during cardioplegic arrest was then
tested as a potential therapy. 

METHODS: Five groups of six neonatal piglets were
studied. One group did not undergo surgery (Group A). Adeno-beta2AR or phosphate
buffered saline (PBS) were delivered via the aortic root during cardioplegic
arrest. Groups B (PBS) and C (Adeno-beta2AR) were assessed at 2 days while
Groups D (PBS) and E (Adeno-beta2AR) were assessed at 2 weeks from the time of
surgery. An LV micromanometer was inserted under sedation to obtain pressure
recordings following surgery. betaAR density was measured subsequently. Results:
Following cardiac surgery LV betaAR density was reduced (104+/-5.7 vs 135+/-6.1
fmol/mg membrane protein; P=0.007), and, in response to beta agonist
stimulation, LV dP/dtmax was reduced (4337+/-405 vs 5328+/-194 mmHg/s; P<0.05)
compared to animals which did not undergo surgery. Adeno-beta2AR therapy during
cardiac surgery resulted in elevated LV betaAR density (520+/-250.9 fmol/mg) 2
days post-operatively compared to PBS (104+/-5.7 fmol/mg; P=0.002) and compared
to the no surgery group (135+/-6.1 fmol/mg; P=0.002). Elevated LV betaAR density
was also present at 2 weeks (315+/-74.1 vs 119+/-7.1 fmol/mg; P=0.002). In
addition, Adeno-beta2AR therapy enhanced beta agonist stimulated LV dP/dtmax
(5348+/-121 vs 4337+/-405 mmHg/s; P<0.05) and heart rate (209+/-6.9 vs
173+/-11.0 bpm; P<0.05), and reduced LVEDP (2.1+/-0.4 vs 6.4+/-1.8 mmHg; P<0.05)
compared to PBS treatment. Interestingly, gene delivery was cardiac-selective
and beneficial effects on function persisted for 2 weeks. Moreover, beta2AR gene
transfer ameliorated LV dysfunction following surgery such that there were no
significant differences between non-operated controls and animals treated with
Adeno-beta2AR during CPB and cardioplegic arrest. 

CONCLUSIONS: Reduced betaAR density and impaired LV function were present following 
CPB and cardioplegic arrest. Cardiac-selective beta2AR gene transfer during CPB resulted in
amelioration of LV dysfunction after cardiac surgery. Such a technique may offer
a new approach to post-operative ventricular support.

J Urol. 2004 Dec;172(6 Pt 1):2340-3. 

Surgical management of large adrenal masses with or without thrombus extending
into the inferior vena cava.

Ekici S, Ciancio G.

From the Department of Urology, Hacettepe University School of Medicine (SE),
Ankara, Turkey, and Departments of Surgery (Division of Transplantation) and
Urology, University of Miami School of Medicine (GC), Miami, Florida.

PURPOSE:: Surgical extirpation is the only curative treatment for large adrenal
masses with or without thrombus extending into the inferior vena cava. However,
occasionally complex surgical techniques are required, including venovenous
bypass or cardiopulmonary bypass (CPB). Additionally, applying techniques used
for organ transplantation can provide better exposure with less blood loss to
allow milking of the thrombus downward, limiting the need for bypass. 

MATERIALS AND METHODS:: Ten patients underwent surgery for large adrenal masses using
these techniques. Five patients had thrombi extending into the inferior vena
cava, causing Budd-Chiari syndrome in 1. A classification system was proposed
for adrenal masses associated with venous thrombus. 

RESULTS:: Median patient age was 51 years. Surgery was completed successfully in all patients. 
Only 1 patient with an adherent intra-atrial thrombus required CPB. Mean blood loss was 450 ml
(range 50 to 1,500) except in the patient who required CPB. Postoperative
complications occurred in 2 patients. One patient died on the postoperative day
7 of a presumed pulmonary emboli. Pneumothorax and empyema following traumatic
line placement developed in the other patient. Nine patients (90%) were free of
disease at a median followup of 18 months (range 10 to 84). 

CONCLUSIONS: Applying transplant techniques in the surgical extirpation of large adrenal
masses with or without tumor thrombus affords curative surgery enhanced access
and vascular control, and decreases the requirement for venovenous bypass and/or
CPB with less morbidity. It also provides acceptable midterm survival and
quality of life.