Br J Anaesth. 2004 Oct 29 [Epub ahead of print] 

Gut permeability in paediatric cardiac surgery.

Malagon I, Onkenhout W, Klok G, van der Poel PF, Bovill JG, Hazekamp MG.

Department of Anaesthesia, Leiden University Medical Centre, 2300 RC Leiden, The
Netherlands.

BACKGROUND: Intestinal mucosal ischaemia can occur in infants and children
during and after cardiac surgery. Severe decreases in mucosal perfusion may
cause complications such as necrotizing enterocolitis and postoperative
mortality. We investigated gut permeability in paediatric patients undergoing
cardiac surgery using the dual sugar permeability test and absorption of two
other saccharides. METHODS: Thirty-four patients undergoing palliative or
corrective surgical procedures with and without cardiopulmonary bypass were
investigated. Intestinal permeability was measured using 3-O-methyl-D-glucose,
D-xylose, L-rhamnose and lactulose, given orally after induction of anaesthesia
and 12 and 24 h later. RESULTS: Lactulose/rhamnose ratios were raised from the
outset [median 0.39 (confidence interval 0.07-1.8 for patients undergoing
operations without cardiopulmonary bypass and 0.30 (0.02-2.6) with
cardiopulmonary bypass]. The highest lactulose/rhamnose ratios were recorded 12
h after surgery 0.32 (0.07-6.9), when cardiopulmonary bypass was used. This is
approximately seven times the value expected in healthy children. There was an
improvement in patients not undergoing cardiopulmonary bypass: 0.22 (0.03-0.85)
12 h and 0.11 (0-0.48) 24 h after induction of anaesthesia. Patients undergoing
repair of aortic coarctation showed the fastest recovery: 0.09 (0.03-0.31) 12 h
and 0.07 (0.04-0.35) 24 h after induction of anaesthesia. CONCLUSIONS: Patients
with congenital heart defects have abnormal gut permeability when compared with
healthy children of similar age. Cardiopulmonary bypass seems to affect the
intestinal barrier morphologically (lactulose and rhamnose absorption) and
functionally (3-O-methyl-D-glucose and D-xylose absorption).

Pediatr Pulmonol. 2004 Oct 28;38(6):470-476 [Epub ahead of print] 

Preoperative pulmonary hemodynamics determines changes in airway and tissue
mechanics following surgical repair of congenital heart diseases.

Habre W, Schutz N, Pellegrini M, Beghetti M, Sly PD, Hantos Z, Petak F.

Pediatric Anesthesia Unit, Geneva Children's Hospital, Geneva, Switzerland.

To characterize the effect of changes in pulmonary hemodynamics on airway and
tissue mechanics, forced oscillatory input impedance of the respiratory system
(Zrs) was measured between 0.4-12 Hz in two groups of children undergoing
surgical repair of congenital heart disease (CHD) immediately before sternotomy
and after chest closure during short apneic intervals. Children with lesions
associated with high pulmonary blood flow and/or pressure (septal defects; HP
group, n = 12) and children with hypoperfused lungs (tetralogy of Fallot; LP
group, n = 12) were included in the study. Airway resistance (Raw), and
coefficients of respiratory tissue damping (G) and elastance (H), were estimated
from Zrs by model-fitting. A postoperative reduction in pulmonary blood flow
and/or pressure in the HP group resulted in an immediate decrease in Raw of 29
+/- 9 (SE)% (P < 0.05), whereas children in the LP group had increases in Raw
(24 +/- 17%, no significance) after surgery. No significant change was observed
in G in either the HP (6.4 +/- 13%) or LP (27 +/- 23%) group, while H increased
in children of both the HP (23 +/- 8%, P < 0.05) and LP (36 +/- 7%, P < 0.01)
groups. These results suggest that the preoperative pulmonary hemodynamic
condition determines changes in airway mechanics: surgical repair of CHD leads
to an improvement in airway function only in children with congested lungs. The
adverse effects of surgery, mechanical ventilation, and/or cardiopulmonary
bypass may be responsible for the increased stiffness of the respiratory system
observed in both groups of children. Pediatr Pulmonol. 2004; 38:470-476. (c)
2004 Wiley-Liss, Inc.

N Engl J Med. 2004 Oct 14;351(16):1635-44. 

Fresh whole blood versus reconstituted blood for pump priming in heart surgery
in infants.

Mou SS, Giroir BP, Molitor-Kirsch EA, Leonard SR, Nikaidoh H, Nizzi F, Town DA,
Roy LC, Scott W, Stromberg D.

Department of Pediatrics, University of Texas Southwestern Medical Center and
Children's Medical Center, Dallas 75235, USA.

BACKGROUND: In an attempt to reduce the coagulopathic and inflammatory responses
seen after cardiopulmonary bypass, the use of fresh whole blood during heart
operations has become the standard of care for neonates and infants at many
institutions. We compared the use of fresh whole blood with the use of a
combination of packed red cells and fresh-frozen plasma (reconstituted blood)
for priming of the cardiopulmonary bypass circuit. METHODS: We conducted a
single-center, randomized, double-blind, controlled trial involving children
less than one year of age who underwent open-heart surgery. Patients were
assigned to receive either fresh whole blood that had been collected not more
than 48 hours previously (96 patients) or reconstituted blood (104 patients) for
bypass-circuit priming. Clinical outcomes and serologic measures of systemic
inflammation and myocardial injury were compared between the groups. RESULTS:
The group that received reconstituted blood had a shorter stay in the intensive
care unit than the group that received fresh whole blood (70.5 hours vs. 97.0
hours, P=0.04). The group that received reconstituted blood also had a smaller
cumulative fluid balance at 48 hours (-6.9 ml per kilogram of body weight vs.
28.8 ml per kilogram, P=0.003). Early postoperative chest-tube output,
blood-product transfusion requirements, and levels of serum mediators of
inflammation and cardiac troponin I were similar in the two groups. CONCLUSIONS:
The use of fresh whole blood for cardiopulmonary bypass priming has no advantage
over the use of a combination of packed red cells and fresh-frozen plasma during
surgery for congenital heart disease. Moreover, circuit priming with fresh whole
blood is associated with an increased length of stay in the intensive care unit
and increased perioperative fluid overload. Copyright 2004 Massachusetts Medical
Society.

Ann Thorac Surg. 2004 Oct;78(4):1389-96. 

An analysis of oxygen consumption and oxygen delivery in euthermic infants after
cardiopulmonary bypass with modified ultrafiltration.

Li J, Hoschtitzky A, Allen ML, Elliott MJ, Redington AN.

Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.

BACKGROUND: The balance between systemic oxygen consumption (VO2) and delivery
(DO2) is impaired after cardiopulmonary bypass (CPB) and is related to systemic
inflammatory response syndrome. We sought to assess VO2 and DO2 and their
relationship with proinflammatory cytokines after CPB with the use of modified
ultrafiltration (MUF) in infants. METHODS: Sixteen infants, aged 1-11.5 months
(median, 6.3 months), undergoing hypothermic CPB with MUF were studied during
the first 12 hours after arrival in the intensive care unit (ICU). The central
temperature was maintained at 36.8-37.1 degrees C using external cooling or
warming. VO2 was continuously measured using respiratory mass spectrometry.
Arterial blood samples for the tumor necrosis factor (TNF), interleukin-6
(IL-6), and interleukin-8 (IL-8) were taken and DO2 was calculated using the
Fick principle on arrival at the ICU, and 2, 4, 8, and 12 hours postoperatively.
Cytokines were additionally measured after induction of anesthesia and at the
end of MUF. RESULTS: VO2 significantly decreased by 18.8% during the study
period. DO2 was depressed throughout this period and reached a nadir at 8 hours
(357.1 +/- 136.2 ml x min(-1) x m(-2)). The decrease in cytokines was
accompanied with the decrease in VO2 despite varied relationships between the
levels of each of the cytokines and VO2 measurements. CONCLUSIONS: Our data
indicate an unusual continuous decrease in VO2 during the first 12 hours after
CPB in infants. Control of body temperature to maintain euthermia in addition to
the use of MUF may be beneficial to the balance between VO2 and DO2 in the early
postoperative period.

Ann Thorac Surg. 2004 Oct;78(4):1285-9; discussion 1285-9. 

Femoral cannulation is safe for type A dissection repair.

Fusco DS, Shaw RK, Tranquilli M, Kopf GS, Elefteriades JA.

Section of Cardiothoracic Surgery, Yale University School of Medicine, New
Haven, Connecticut, USA.

BACKGROUND: Recently, surgeons have embraced axillary artery cannulation for
type A aortic dissection repair out of concern for malperfusion phenomena with
traditional femoral artery cannulation. My colleagues and I sought to determine
whether these concerns are justified. METHODS: Records of 86 consecutive
patients (51 men and 35 women; age, 30 to 86 years; mean, 62 years) undergoing
surgical repair for acute type A dissection were reviewed. Cannulation site,
specific operative repair, and complications related to cannulation were noted.
RESULTS: Seventy-nine cannulations were performed in the femoral artery (47
left, 23 right, and 9 unspecified), 3 in the axillary artery (1 left and 2
right), and 4 in the ascending aorta or arch. Deep hypothermic arrest was used
in 64 operations. Seven involved re-sternotomy. Seventy patients had
supracoronary grafts (2 with valve replacement and 10 with valve resuspension),
and 16 underwent aortic root replacement. Fourteen patients were in shock from
cardiac tamponade. Eighty patients survived the operation, and 71 were hospital
survivors. Malperfusion on initiation of cardiopulmonary bypass was noted in 3
patients. In 1, the original cannulation site was the ascending aorta, and the
cannula was moved to the femoral artery for correction. In 2, the original
cannulation site was the femoral artery, and the cannula was moved to the
ascending aorta. Malperfusion on clamping of the aorta or on resumption of
aortic flow was noted in no patient. Postoperative ischemia of any vascular bed
was noted locally only in 3 (cannulated) lower extremities. CONCLUSIONS:
Straight femoral cannulation for all phases of type A dissection repair is
appropriate and yields excellent clinical results. The anticipated malperfusion
events are actually rare (2 of 79 with femoral artery cannulation, or 2.5%).

 J Am Coll Surg. 2004 Oct;199(4):607-14. 

Sildenafil citrate alleviates pulmonary hypertension after hypoxia and
reoxygenation with cardiopulmonary bypass.

Lyons JM, Duffy JY, Wagner CJ, Pearl JM.

Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical
Center, Cincinnati, OH 45229, USA.

BACKGROUND: Sudden reoxygenation of hypoxic neonates undergoing cardiac
operation exacerbates the systemic inflammatory response to cardiopulmonary
bypass secondary to reoxygenation injury, worsening cardiopulmonary dysfunction.
Reports suggest sildenafil decreases pulmonary hypertension and may affect
myocardial function. Sildenafil's efficacy for treating postbypass
cardiopulmonary dysfunction remains unknown. STUDY DESIGN: Fourteen neonatal
piglets (5 to 7 kg) underwent 90 minutes of hypoxia, 60 minutes of reoxygenation
with cardiopulmonary bypass, and 120 minutes of recovery. Six animals received
50 mg oral sildenafil and eight received saline at hypoxia. Data are presented
as mean +/- SD. RESULTS: Sildenafil prevented the high pulmonary vascular
resistance observed in controls (controls baseline 81 +/- 37 dynes. s/cm(5)
versus recovery 230 +/- 93 dynes. s/cm(5), p = 0.004; sildenafil baseline 38 +/-
17 dynes. s/cm(5) versus recovery 101 +/- 60 dynes. s/cm(5), p = 0.003). Despite
lower pulmonary vascular resistance after sildenafil, arterial endothelin-1
(ET-1) was increased in both groups (control baseline 1.3 +/- 0.5 pg/mL versus
recovery 4.5 +/- 3.7 pg/mL, p = 0.01; sildenafil baseline 1.3 +/- 0.3 pg/mL
versus recovery 9.8 +/- 4.9 pg/mL, p = 0.003). Intravenous nitric oxide (NO)
levels were preserved after sildenafil treatment (sildenafil baseline 340 +/- 77
nM versus recovery 394 +/- 85 nM). IV NO levels in controls were decreased when
compared with baseline (control baseline 364 +/- 83 nM versus recovery 257 +/-
97 nM, p = 0.028). Although levels of exhaled NO decreased in both groups, the
sildenafil-treated animals had higher levels of exhaled NO when compared with
controls at the end of recovery (0.6 +/- 0.4 parts per billion versus 1.8 +/-
0.9 parts per billion, respectively, p = 0.029). CONCLUSIONS: Sildenafil
alleviated pulmonary hypertension after reoxygenation with cardiopulmonary
bypass. Despite increased ET-1 levels, pulmonary vascular resistance was lower
with sildenafil treatment, suggesting sildenafil's effect on the pulmonary
vasculature is capable of countering vasoconstriction by ET-1. Further study
into the role of sildenafil in perioperative therapy and its interactions with
ET-1 are warranted.

Anesthesiology. 2004 Oct;101(4):862-71. 

Effects of cardiopulmonary bypass on sufentanil pharmacokinetics in patients
undergoing coronary artery bypass surgery.

Hudson RJ, Thomson IR, Jassal R.

Department of Anesthesia, St. Boniface General Hospital, University of Manitoba,
Winnipeg, Manitoba, Canada.

BACKGROUND: Complete pharmacokinetic modeling, including assessment of the
effect of cardiopulmonary bypass (CPB) on sufentanil disposition, has not been
reported. The aims of this investigation were to define a model that accurately
predicted sufentanil concentrations during and after cardiac surgery and to
determine if CPB had a clinically significant impact on sufentanil
pharmacokinetics. METHODS: Population pharmacokinetic modeling was applied to
data from 21 patients undergoing coronary artery bypass grafting. The predictive
ability of models was assessed by calculating bias, accuracy, and
measured:predicted concentration ratios versus time. A simple three-compartment
model, without covariates, was initially compared with models having weight or
gender as covariates and was subsequently used as the foundation for multiple
CPB-adjusted models (allowing step-changes of parameters at the start or end of
CPB). The primary criterion for choosing more complex models was a significant
improvement in log-likelihood; secondary criteria were significant improvement
in bias or accuracy. RESULTS: Neither covariate (weight or gender) models
improved bias or accuracy compared with the simple three-compartment model. A
final CPB-adjusted model with V2 and Cl3 changing at the start of CPB and V1,
Cl2, and Cl3 changing at the end of CPB had significantly greater log-likelihood
values when compared with the simple three-compartment model and with less
elaborate CPB-adjusted models. However, bias and accuracy for this final model
were not significantly different from the simple three-compartment model.
CONCLUSIONS: When sufentanil is infused at a constant rate, with initiation of
CPB, a pharmacokinetic model adjusted for CPB predicts that the sufentanil
concentration will decrease approximately 17% and that it will begin to return
to the prebypass concentration 12 min after initiation of CPB. At the end of
CPB, this model also predicts a brief spike of the sufentanil concentration.
These predictions reflect changes in the measured sufentanil concentrations.
However, compared with a simple, three-compartment model, incorporating
step-changes of pharmacokinetic parameters at the start or end of
cardiopulmonary bypass (or both) did not significantly improve overall
perioperative prediction of measured sufentanil concentrations. This suggests
that CPB has clinically insignificant effects on sufentanil kinetics in adults.

Transfusion. 2004 Oct;44(10):1453-62. 

The independent association of massive blood loss with mortality in cardiac
surgery.

Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA,
Ghannam M, Yeo E, Djaiani G, Karski J.

Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada.
keyvan.karkouti@uhn.on.ca

BACKGROUND: Although the association between massive perioperative blood loss
(MBL) and adverse outcomes is well recognized, it is unclear whether MBL is an
independent risk factor or, instead, simply a marker for other adverse events or
severity of illness. The objective of this cohort study was to quantify the
independent association of MBL in cardiac surgery with all-cause in-hospital
mortality. STUDY DESIGN AND METHODS: Data were prospectively collected on
consecutive patients who underwent cardiac surgery with cardiopulmonary bypass
at a quaternary-care academic center from 1999 to 2003. The number of red blood
cell (RBC) units transfused within 1 day of surgery was used as a surrogate
measure of perioperative blood loss. Receiver-operating characteristic curve
analyses were employed to identify the most appropriate cutoff for defining MBL.
The independent association of MBL with mortality was determined with
multivariable logistic regression analyses. Bootstrapping and sensitivity
analyses were used to confirm the validity of the results. RESULTS: MBL was
defined as receiving at least 5 units of RBCs within 1 day of surgery. Of 9215
patients analyzed, 1.8 percent (n = 169) died and 9.7 percent (n = 890) had MBL.
After adjusting for multiple potential confounders (including perioperative
adverse events), MBL was associated with an 8.1-fold (95% confidence interval,
3.9-17.0) increase in the odds of death. This risk estimate was stable across
different modeling conditions as well as in bootstrap sampling. CONCLUSION: MBL
after cardiac surgery has a strong, independent association with in-hospital
mortality.

Circulation. 2004 Oct 26;110(17):2597-600. Epub 2004 Jul 19. 

Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by
intravenous aprotinin during cardiothoracic surgery.

Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM.

British Heart Foundation Cardiac Surgery Unit, Eric Bywaters Centre, Imperial
College, London W12 0NN, UK. j.day@imperial.ac.uk

BACKGROUND: Protease-activated receptor-1 (PAR1) is the principal thrombin
receptor in the vasculature, and antagonists against this receptor are in
preclinical trials. Aprotinin, already approved for clinical use to reduce
transfusion requirements in cardiopulmonary bypass (CPB) surgery, has been shown
to inhibit PAR1 activation in vitro. Here, we exploit CPB as a model for
thrombin generation in humans to examine whether aprotinin can inhibit platelet
PAR1 activation clinically. METHODS AND RESULTS: PAR1 expression and function on
platelets was examined in coronary artery bypass grafting (CABG) patients
randomized into 2 groups: (1) those receiving saline infusion during CPB (n=17)
and (2) those receiving aprotinin (2x10(6) kallikrein inhibitor units [KIU] in
pump prime, 2x10(6) KIU loading dose, followed by 0.5x10(6) KIU/h [n=13]).
Platelets in the saline group showed loss of PAR1-specific function at 2 hours
after CPB, but this was preserved in the aprotinin group (P<0.001). These
effects were most likely targeted at PAR1 receptor cleavage, because (1) the
level of thrombin generated during CPB did not vary significantly between
groups, (2) expression of SPAN12, which detects only uncleaved PAR1 receptors,
was preserved in the aprotinin but not the placebo group (P<0.05), and (3)
supporting evidence in vitro showed reduced thrombin-induced PAR1 cleavage
(P<0.001) and platelet aggregation (P<0.001) in the presence of aprotinin.
CONCLUSIONS: This study demonstrates that platelet PAR1 activation by thrombin
can be inhibited by aprotinin. Our results extend the clinical mechanism of
action of aprotinin and provide the first proof of principle that PAR1 can be
inhibited clinically. This has implications beyond cardiac surgery for the
development of therapeutic PAR1 blockade.