TOP TEN SELECTED PAPERS - October 2008

1

Eur J Clin Pharmacol. 2008 Oct 30. [Epub ahead of print]

The pharmacokinetic profile of recombinant human erythropoietin is unchanged in
patients undergoing cardiac surgery.

McCluskey SA, Cheung WK, Katznelson R, Poonawala H, Fedorko L, Djaiani G, Mehta
B, Karkouti K.

Department of Anesthesia and Pain Management, Toronto General Hospital,
University Health Network, Eaton North 3-405, 200 Elizabeth Street, Toronto, ON, 
M5G 2C4, Canada, stuart.mccluskey@uhn.on.ca.

BACKGROUND: In anticipation of future studies, we examined the pharmacokinetics
profile of erythropoietin (EPO) in patients undergoing cardiac surgery. METHODS: 
Cardiac surgical patients were enrolled into one of six groups: four
cardiopulmonary bypass (CPB) groups [placebo (n = 6), 250 IU/kg EPO (n = 3), 500 
IU/kg EPO (n = 3), and 500 IU/kg EPO, two doses (n = 6)] and two off-pump
coronary artery bypass (OPCAB) groups [placebo (n = 3) and 500 IU/kg EPO (n =
3)]. The EPO was administered prior to anesthesia and 10 min after CPB (if
required). Blood samples for serum EPO were collected at baseline, 10 min after
dosing, 5 min after sternotomy, during CPB or the equivalent for OPCAB (5, 15,
45, 60 min), and post-CPB (5, 15, 45, and 60 min, 6, 12 and 24 h, and daily until
day 5). RESULTS: Endogenous EPO increased within 24 h of surgery in the placebo
group and remained elevated. There was approximately a 40% decrease in serum EPO 
concentration at the initiation of CPB due to an increase in circulatory blood
volume. There were no differences in apparent volume of distribution in the
plasma (Vc) (42.2 +/- 9.9, 39.8 +/- 6.3, 42.3 +/- 14.0 mL/kg), clearance (CL)
(4.63 +/- 1.14, 3.44 +/- 0.68, 4.27 +/- 0.52 mL h/kg), and t((1/2)) (16.4 +/- 8.0
16.9 +/- 10.6, 22.4 +/- 9.3 h) between the CPB treatment groups. The
pharmacokinetic profile of EPO in the OPCAB group was similar to that for the CPB
groups: Vc = 39.3 +/- 7.0 mL/kg, CL = 4.98 +/- 0.17 mL h/kg and t((1/2)) = 17.1
+/- 18.1 h. CONCLUSIONS: CPB had no apparent effect on the pharmacokinetics of
EPO.

Med Sci Monit. 2008 Nov;14(11):PI53-7.

Cerebroprotective effect of piracetam in patients undergoing coronary bypass
burgery.

Holinski S, Claus B, Alaaraj N, Dohmen PM, Kirilova K, Neumann K, Uebelhack R,
Konertz W.

Department of Cardiovascular Surgery, Charite Hospital, Medical University,
Berlin, Germany. sebastian.holinski@charite.de

BACKGROUND: Reduction of cognitive function is a possible side effect after
cardiac surgery using cardiopulmonary bypass. We investigated the
cerebroprotective effect of piracetam on cognitive performance in patients
undergoing coronary artery bypass surgery under cardiopulmonary bypass.
MATERIAL/METHODS: Patients scheduled for elective, primary and isolated coronary 
bypass surgery were randomised either to piracetam or placebo group. The study
was performed in a double blind fashion. Patients received either 12 g piracetam 
or placebo at the beginning of the operation. Six neuropsychological subtests
from the Syndrom Kurz Test and the Alzheimer's Disease Assessment Scale were
performed preoperatively and on the third postoperative day. To assess the
overall cognitive function and the degree of cognitive decline across all tests
after surgery we combined the six test-scores by principal component analysis.
RESULTS: A total number of 120 patients were enrolled into the study.
Preoperative overall cognitive function were not significantly different between 
the groups. The postoperative combined score of the neuropsychological tests
showed a deterioration of cognitive function in both groups (placebo-pre:
-0.06+/-0.99 vs placebo-post: -1.38+/-1.11; p<0.0005 and piracetam-pre:
0.06+/-1.02 vs piracetam-post: -0.65+/-0.93; p<0.0005). However, the piracetam
patients performed significantly better compared to the placebo patients after
the operation and had a less decline of overall cognitive function (p<0.0005).
CONCLUSIONS: Piracetam has a cerebroprotective effect in patients undergoing
coronary artery bypass surgery with the use of cardiopulmonary bypass. It reduces
an early postoperative substantial decline of neuropsychological abilities.

J Thorac Cardiovasc Surg. 2008 Oct;136(4):976-983.e3. Epub 2008 Jun 2.

Two-year survival, mental, and motor outcomes after cardiac extracorporeal life
support at less than five years of age.

Lequier L, Joffe AR, Robertson CM, Dinu IA, Wongswadiwat Y, Anton NR, Ross DB,
Rebeyka IM; Western Canadian Complex Pediatric Therapies Program Follow-up Group.

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

OBJECTIVE: Comprehensive outcome assessment of children receiving cardiac
extracorporeal life support. METHODS: From 2000 to 2004, 39 consecutive children 
(aged 1 day to 4.4 years) had cardiac extracorporeal life support.
Neurodevelopmental follow-up of all survivors was performed more than 6 months
after life support (aged 53 +/- 12 months). Developmental delay was defined as a 
score of less than 70 on the Bayley Scales of Infant Development II or Wechsler
Preschool and Primary Scale of Intelligence. Predictor variables for mortality
(at 2 years' follow-up) and delay were examined by univariate and multivariate
analyses. RESULTS: Indications for extracorporeal life support were progressive
low cardiac output in 14 (36%), failed weaning from cardiopulmonary bypass in 13 
(33%), cardiac arrest in 9 (23%), and hypoxia in 3 (8%). Cardiac anatomy was
single ventricle in 16 (41%), biventricular in 21 (54%), and myocarditis in 2
(5%). Survival was 18 (46%) at hospital discharge and 16 (41%) at 2 years. In
survivors, mental score was 73 +/- 16 (normal 100 +/- 15), and 8 (50%) had mental
delay. Initiating extracorporeal life support during cardiopulmonary
resuscitation and duration of this resuscitation were not associated with death
or mental delay. On multivariable Cox regression, lactate on admission to the
pediatric intensive care unit (hazard rate 1.13; 95% confidence intervals
1.08-1.27) and single ventricle anatomy (hazard rate 3.93; 95% confidence
intervals 1.62-9.49) were associated with death at 2 years. Stepwise multiple
regression found time for lactate to normalize on extracorporeal life support,
highest inotrope score during 120 hours of life support, and chromosomal
abnormality explained 76.7% of the variance in mental score. CONCLUSION: Cardiac 
extracorporeal life support had a 41% 2-year survival. Potentially modifiable
variables (time for lactate to normalize and highest inotrope score early during 
extracorporeal life support) explained 69% of mental score variance.

J Cardiothorac Vasc Anesth. 2008 Oct 21. [Epub ahead of print]

Cardiopulmonary Bypass Duration Is an Independent Predictor of Morbidity and
Mortality After Cardiac Surgery.

Salis S, Mazzanti VV, Merli G, Salvi L, Tedesco CC, Veglia F, Sisillo E.

Anesthesia and Intensive Care Unit, Centro Cardiologico Monzino IRCCS, Milan,
Italy;

OBJECTIVE: The aim of this study was to determine if there is a direct
relationship between the duration of cardiopulmonary bypass (CPB time [CPBT]) and
postoperative morbidity and mortality in patients undergoing cardiac surgery.
DESIGN: Retrospective study. SETTING: Cardiac surgery unit, university hospital. 
PARTICIPANTS: Five thousand six patients, New York Heart Association classes 1
through 4, who underwent cardiac surgery between January 2002 and March 2008.
INTERVENTIONS: All patients were subjected to CPB. MEASUREMENTS AND MAIN RESULTS:
The mean CPBT was 115 minutes (median 106). One hundred thirty-one patients
(2.6%) died during the same hospitalization. The postoperative median blood loss 
was 600 mL. Reoperations for bleeding occurred in 193 patients (3.9%), and 1,001 
patients received 3 or more units of red blood cells. There were 108 patients
(2.2%) with neurologic sequelae, 391 patients (7.8%) with renal complications, 37
patients (0.7%) with abdominal complications, and 184 patients (3.7%) with
respiratory complications. Seventy-two patients (1.4%) had an infective
complication, and 80 patients (1.6%) had a postoperative multiorgan failure. The 
multivariate analysis confirmed the role of CPBT, considered in 30-minute
increments, as an independent risk factor for postoperative death (odds ratio
[OR] = 1.57, p < 0.0001), pulmonary (OR = 1.17, p < 0.0001), renal (OR 1.31, p < 
0.0001), and neurologic complications (OR = 1.28, p < 0.0001), multiorgan failure
(OR = 1.21, p < 0.0001), reoperation for bleeding (OR = 1.1, p = 0.0165), and
multiple blood transfusions (OR = 1.58, p < 0.0001). CONCLUSIONS: Prolonged CPB
duration independently predicts postoperative morbidity and mortality after
cardiac surgery.

J Artif Organs. 2008;11(3):111-6. Epub 2008 Oct 5.

Poly-2-methoxyethylacrylate-coated bypass circuits reduce activation of
coagulation system and inflammatory response in congenital cardiac surgery.

Suzuki Y, Daitoku K, Minakawa M, Fukui K, Fukuda I.

Department of Thoracic and Cardiovascular Surgery, Hirosaki University School of 
Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan, ysuzuki@cc.hirosaki-u.ac.jp.

Surface-coated cardiopulmonary bypass (CPB) has been shown to have excellent
biocompatibility during cardiac surgery in adults, but there have been only a few
reports demonstrating the efficacy of this coating for congenital cardiac
surgery. We tested the efficacy of poly-2-methoxyethylacrylate (PMEA) coating for
CPB circuits in congenital cardiac surgery. Eleven operative cases of ventricular
septal defect were studied: group C (control: no coating, n = 5) and group P
(PMEA coating, n = 6). The platelet count and beta-thromboglobulin (betaTG),
fibrinogen (FBG), thrombin-antithrombin complex (TAT), and neutrophil elastase
levels were measured during the operation. Postoperative chest tube drainage was 
analyzed and the surface of the artificial lung was observed with an electron
microscope. Elevation of TAT and neutrophil elastase was suppressed in group P (P
< 0.05). Observation of the artificial lung surface using an electron microscope 
clearly revealed fewer blood cells were adherent to the surface in group P. The
FBG level and postoperative bleeding were relatively lower in group P, but there 
were no significant differences between groups. The platelet count and betaTG
level were the same in both groups. We concluded that the PMEA-coated circuit
reduces activation of the coagulation system and the inflammatory reaction in
pediatric cardiac surgery.

Eur J Cardiothorac Surg. 2008 Oct 1. [Epub ahead of print]

Logistic risk model predicting postoperative respiratory failure in patients
undergoing valve surgery.

Filsoufi F, Rahmanian PB, Castillo JG, Chikwe J, Adams DH.

Department of Cardiothoracic Surgery, Mount Sinai School of Medicine, 1190 Fifth 
Avenue, New York, NY 10029-1028, United States.

Background: Previous studies have been unable to identify independent
valve-related risk factors for postoperative respiratory failure (RF) in patients
undergoing valve surgery. This study was designed to determine the incidence and 
predictors of RF in these patients. We also aimed to create a model based on
these risk factors that could serve as a tool for the prediction of this
complication. Methods: We analyzed prospectively collected data of 2808 patients 
(mean age 63+/-15 years, 43% female) who underwent valve surgery from January
1998 to December 2006. Isolated valve surgery was performed in 2007 (72%)
patients whereas 801 (28%) received concomitant coronary artery bypass grafting
(CABG) procedures. The main outcome investigated was RF (ventilation >72h). Other
postoperative parameters included in the analysis were hospital mortality,
morbidity, length of hospital stay, discharge and late survival. Results:
Respiratory failure occurred in 12.2% (n=342) of patients. The incidence of RF
varied according to the procedures (single valve: 7.4-15.8%; multiple valves:
21.7-23.4%). The addition of CABG significantly increased the rate of RF
(isolated valves: 10.8%, combined valve/CABG 15.7%, p<0.001). Multivariate
analysis revealed preoperative renal failure, ejection fraction <30%, age >70
years, active endocarditis, emergent procedures, reoperation, diabetes,
congestive heart failure, previous myocardial infarction, female gender, double
aortic and mitral valve procedures, and cardiopulmonary bypass time >180min as
independent predictors of RF. Hospital mortality among patients with RF was 22.2%
(n=76) versus 2.7% (n=66) in the control group (p<0.001). A logistic equation
including the coefficients of the regression analysis was generated to calculate 
an individual patient's risk for the development of RF. Predictive accuracy of
the model and validation was measured (ROC area under the curve: 0.751).
Long-term survival of discharged patients with RF was significantly decreased
compared to those without RF. Conclusion: Respiratory failure is a common
complication particularly in patients undergoing complex valve operations such as
endocarditis or multiple valve procedures. The independent predictors of RF
including valve-related factors allowed us to create a predictive model with
great accuracy. The poor long-term survival of patients with RF underlines the
need to direct more resources towards prevention and treatment of this
complication.

Blood Coagul Fibrinolysis. 2008 Oct;19(7):725-6.

Practical approach to anticoagulation for cardiopulmonary bypass in the patient
with congenital prolonged activated partial thromboplastin time.

Cankovic L, Steenwyk BL, McGiffin DC, Nielsen VG.

Department of Anesthesiology, The University of Alabama at Birmingham, 901 19th
Street South, Birmingham, AL 35294, USA.

Patients with rare, congenital deficiencies of contact proteins (e.g., factor
XII, prekallikrein, high-molecular-weight kininogen) present an important
challenge with regard to safe anticoagulation during cardiopulmonary bypass.
Specifically, activated coagulation time values are obtained with devices that
utilize contact protein activators to generate thrombin and assess the efficacy
of heparin-mediated antithrombin activation, with an activated coagulation time
value of 480 s considered 'safe'. Patients with contact protein deficiencies will
routinely have activated coagulation time values that exceed normal baseline
values to an unpredictable extent, which, when coupled with heparin
administration may well exceed 480 s but still potentially not reflect adequate
antithrombin activation. We present the successful management of anticoagulation 
of a patient with either a prekallikrein or kininogen deficiency during
cardiopulmonary bypass for coronary artery bypass graft surgery with Hepcon-based
heparin concentration determinations. This approach, and the other alternatives
previously mentioned, can be utilized to safely care for these rare patients in
the setting of cardiac surgery.

Acta Anaesthesiol Scand. 2008 Oct;52(9):1204-12.

The inflammatory response to colloids and crystalloids used for pump priming
during cardiopulmonary bypass.

Tamayo E, Alvarez FJ, Alonso O, Castrodeza J, Bustamante R, Gómez-Herreras JI,
Florez S, Rodríguez R.

Department of Anaesthesiology and Reanimation, Valladolid University Hospital,
Valladolid, Spain. tamayo@med.uva.es

BACKGROUND: Systemic inflammatory response frequently occurs after coronary
artery bypass surgery and is strongly correlated with the risk of postoperative
morbidity and mortality. This study tests the hypothesis that the priming of the 
extracorporeal circuit with colloid solutions results in less inflammation in
patients undergoing cardiac surgery than priming with crystalloid solutions.
METHODS: A prospective, randomized study was designed. Forty-four patients
undergoing elective coronary artery bypass grafting were randomly allocated to
one of two groups: 22 patients primed with Ringer's lactate (RL) solution and 22 
patients primed with gelatin-containing solution during the surgery. Plasma
levels of interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-alpha, C-reactive
protein (CRP) and, complement 4 were measured during the surgical intervention
and over the following 48 postoperative hours. Cytokine levels were measured by
enzyme-linked assays from plasma samples obtained at specific time points pre-
and post-operatively. RESULTS: In both groups the serum levels of the
pro-inflammatory cytokines (IL-6, IL-8, TNF-alpha), CRP, complement 4, and
leukocytes increased significantly over the baseline, although no significant
differences were observed between the two groups. The operation time, blood loss,
need for inotropic support, extubation time, and length of intensive care unit
stay did not differ significantly between the two groups. CONCLUSION: Priming
with gelatin vs. RL produces no significant differences in the inflammatory
response in patients undergoing coronary artery bypass grafting with
cardiopulmonary bypass.

Pharmacotherapy. 2008 Nov;28(11):1413-20.

Successful use and dosing of bivalirudin after temporary total artificial heart
implantation: a case series.

Crouch MA, Kasirajan V, Cahoon W, Katlaps GJ, Gunnerson KJ.

1 Department of Pharmacy Practice, South University School of Pharmacy, Savannah,
Georgia.

Abstract The temporary total artificial heart (TAH-t) has emerged as an effective
bridge to transplantation for individuals with biventricular failure.
Implantation of a TAH-t creates a hypercoagulable state requiring a multidrug
approach that includes low-dose unfractionated heparin (UFH) in order to minimize
thromboembolism. A concern with UFH is the development of heparin-dependent
antibodies, which develop in up to 50% of patients receiving the drug as part of 
cardiopulmonary bypass. If UFH therapy continues postoperatively, the risk of
heparin-induced thrombocytopenia approaches 3%. Small investigations have
demonstrated that bivalirudin, given as a bolus of 0.75-1 mg/kg followed by an
infusion at 1.75-2.5 mg/kg/hour, is an effective alternative to UFH for
therapeutic anticoagulation during coronary artery bypass surgery, valve
replacement, or both. We describe a series of five adults (age range 24-58 yrs)
who received bivalirudin as an alternative to low-dose UFH after TAH-t
implantation. None of the patients had documented heparin-induced
thrombocytopenia. Treatment was started at the discretion of the treating
physician, and adjustments were based principally on the results of
thromboelastography. Additional general monitoring included activated partial
thromboplastin time, prothrombin time, international normalized ratio,
fibrinogen, D-dimer, platelet count, hemoglobin, hematocrit, and platelet
aggregation studies. Bivalirudin therapy was continued until successful warfarin 
implementation. All five patients received bivalirudin in addition to standard
antithrombotic therapy. Bivalirudin treatment started at a dosage of 0.005 or
0.01 mg/kg/hour with titration to maintain normocoagulability, which occurred
(without concomitant warfarin therapy) within the dosage range of 0.01-0.02
mg/kg/hour. Duration of TAH-t implantation was a mean of 38.8 days (range 25-60
days), and bivalirudin was continued for a mean of 15.2 days (range 7-24 days).
No major hemorrhagic events occurred during treatment, and all patients
successfully transitioned to warfarin therapy. Low-dose bivalirudin, as an
alternative to UFH, maintained normocoagulability after TAH-t implantation.
Further investigation is warranted to define the role and dosing of bivalirudin
in this situation.

J Perinatol. 2008 Sep 25. [Epub ahead of print]

Feeding abilities in neonates with congenital heart disease: a retrospective
study.

Jadcherla SR, Vijayapal AS, Leuthner S.

1Division of Neonatology, Pediatric Gastroenterology and Nutrition, Department of
Pediatrics, The Ohio State University College of Medicine, Nationwide Children's 
Hospital, Columbus, OH, USA.

Objective:An important area concerning morbidity among infants with congenital
heart defects (CHD) is related to feeding problems. Our objectives were to
characterize the evolution of feeding milestones related to transition to per
oral feeding among infants with CHD, and to identify associated variables
impacting the feeding abilities. Specifically, we differentiated the feeding
characteristics in neonates with acyanotic vs cyanotic CHD.Study Design:Feeding
progress was tracked during the first hospitalization in a retrospective chart
review study involving 76 infants (29 acyanotic, 47 cyanotic CHD). The ages at
which the following milestones attained were recorded: first feeds, maximum
gavage feeds, first nipple feeds and maximum nipple feeds, in addition to the
length of hospital stay. Effects of perinatal factors, duration of respiratory
support, vasopressor and narcotic use and use of cardiopulmonary bypass on the
feeding milestones were also evaluated. ANOVA, t-test, and stepwise linear
regression analysis were applied as appropriate. Data stated as mean+/-s.e.m., or
%; P<0.05 was considered significant.Result:Prenatal and birth characteristics
were similar (P=NS) between the neonates with acyanotic and cyanotic CHD.
Cyanotic CHD required three times prolonged use of ventilation, narcotics and
vasopressor use (all P<0.05, compared to the acyanotic group). In the acyanotic
group, prolonged respiratory support correlated linearly with time to attain
maximal gavage feeds and nippling (both, R(2)=0.8). In the cyanotic group,
delayed initiation of gavage feeds and prolonged respiratory support both
correlated linearly with time to attain maximal gavage feeds and nippling (both, 
R(2)=0.8). Age at first gavage feed correlated with maximum gavage feeds among
neonates with cyanotic CHD, and first nipple feed correlated with maximum nipple 
feeds among all groups (P<0.01). Use of cardiopulmonary bypass in cyanotic CHD
delayed the feeding milestones and prolonged the length of stay (both, P<0.05 vs 
non-bypass group); similar findings were not seen in the acyanotic
group.Conclusion:In contrast to neonates with acyanotic CHD, cyanotic CHD group
had significant delays with (a) feeding readiness, (b) successful gastric
feeding, (c) oromotor readiness and (d) successful oromotor skills. Co-morbid
factors that may directly influence the delay in feeding milestones include the
(a) duration of respiratory support and (b) use of cardiopulmonary bypass. Delays
in achieving maximum gavage and maximum nippling may suggest foregut dysmotility 
and oropharyngeal dysphagia.Journal of Perinatology advance online publication,