Clin Pharmacol Ther. 2005 Nov;78(5):477-85. 

A pilot study indicating that bradykinin B(2) receptor antagonism attenuates
protamine-related hypotension after cardiopulmonary bypass.

Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown NJ.

Veterans Affairs Medical Center and Department of Anesthesiology, Department of
Cardiothoracic Surgery, and Division of Clinical Pharmacology, Departments of
Medicine and Pharmacology, Vanderbilt University School of Medicine.

BACKGROUND: The administration of protamine to patients who received heparin
during cardiopulmonary bypass (CPB) induces hypotension. Protamine inhibits the
carboxypeptidase N-mediated degradation of bradykinin, a peptide that causes
vasodilation and tissue-type plasminogen activator (t-PA) release. This study
tests the primary hypothesis that blocking the bradykinin B(2) receptor would
attenuate protamine-related hypotension. METHODS: We conducted a prospective,
double-blind, randomized study in 16 adult male patients undergoing elective
cardiac surgery requiring CPB and taking an angiotensin-converting enzyme (ACE)
inhibitor preoperatively, because ACE inhibition increases bradykinin
concentrations during CPB. Subjects were randomized to receive either saline
solution (N = 8) or the bradykinin B(2) receptor antagonist HOE 140 (100 mug/kg,
N = 8) before the administration of protamine. Mean arterial pressure (MAP) and
t-PA activity were measured intraoperatively and before and after protamine
administration. RESULTS: Protamine administration caused a significant increase
in bradykinin concentrations in the saline solution group (from 6.0 +/- 1.3 to
10.0 +/- 1.6 fmol/mL, P = .043), as well as the HOE 140 group (from 6.5 +/- 1.8
to 14.3 +/- 4.6 fmol/mL, P = .042). Protamine significantly decreased MAP in the
saline solution group (from 69.8 +/- 4.4 mm Hg to a mean individual nadir of
56.1 +/- 2.6 mm Hg, P = .031), but bradykinin receptor antagonism blunted this
effect (from 74.3 +/- 3.7 mm Hg to a mean individual nadir of 69.6 +/- 1.2 mm Hg
in the HOE 140 group, P = .545). Hence, during protamine infusion, MAP was
significantly lower in the saline solution group compared with the HOE 140 group
(P = .002). t-PA activity decreased significantly during administration of HOE
140 (from 3.59 +/- 0.31 to 1.67 +/- 0.42 IU/mL, P = .001) but not during saline
solution (from 2.12 +/- 0.48 to 1.44 +/- 0.36 IU/mL, P = .214). Similarly, t-PA
activity decreased significantly during protamine administration in the HOE 140
group (from 1.67 +/- 0.42 to 0.77 +/- 0.26 IU/mL, P = .038) but not in the
saline solution group (from 1.44 +/- 0.36 to 0.99 +/- 0.26 IU/mL, P = .132).
CONCLUSION: Increased bradykinin contributes to protamine-related hypotension
through its B(2) receptor in ACE inhibitor-treated patients.

Chest. 2005 Nov;128(5):3447-53. 

Effect of modified ultrafiltration on pulmonary function after cardiopulmonary
bypass.

Mahmoud AB, Burhani MS, Hannef AA, Jamjoom AA, Al-Githmi IS, Baslaim GM.

Division of Cardiothoracic Surgery, King Faisal Specialist Hospital and Research
Center, Jeddah, Saudi Arabia.

BACKGROUND: Pulmonary dysfunction is one of the most common manifestations of
inflammatory response after cardiopulmonary bypass (CPB). OBJECTIVE: This
prospective randomized study was conducted to evaluate the effect of a modified
ultrafiltration (MUF) technique on pulmonary function after CPB in children.
METHODS: Forty patients weighing from 5 to 10 kg with congenital heart disease
who required CPB for primary biventricular operative repair were prospectively
randomized into two groups. The control group received conventional
ultrafiltration (CUF) during CPB, and the study group received CUF and MUF.
Pulmonary compliance (static and dynamic) and gas exchange capacity of the lung
expressed as oxygen index, respiratory index, ventilation index, and
alveolar-arterial oxygen pressure difference were measured after intubation
(baseline), at the termination of CPB, at the end of MUF, on admission to the
ICU, and 6 h postoperatively. RESULTS: There was no significant difference in
lung compliance and gas exchange between the two groups before CPB. CPB produced
a significant decrease in static and dynamic lung compliance in both groups. In
the control group, static and dynamic lung compliance decreased from 1.0 +/- 0.3
to 0.90 +/- 0.3 mL/cm/kg and 0.87 +/- 0.2 to 0.71 +/- 0.1 mL/cm/kg (+/- SE) [p =
0.0002 and p = 0.002, respectively]. In the study group, static and dynamic lung
compliance decreased from 1.0 +/- 0.2 to 0.89 +/- 0.03 mL/cm/kg and 0.94 +/- 0.2
to 0.77 +/- 0.1 mL/cm/kg (p = 0.002 and p = 0.002, respectively). There was no
significant difference in the decrease in static (p = 0.9) or dynamic lung
compliance (p = 0.3) between the two groups. MUF produced a significant
immediate improvement in both static lung compliance (0.89 +/- 0.2 to 0.98 +/-
0.2 mL/cm/kg, p = 0.03) and dynamic lung compliance (0.77 +/- 0.1 to 0.93 +/-
0.2 mL/cm/kg, p = 0.007). The same was observed regarding the gas exchange
capacity. CPB produced a significant decrease in lung gas exchange capacity, and
MUF produced a significant immediate improvement in lung gas exchange capacity.
The effect of MUF on lung compliance and gas exchange capacity was not sustained
after admission to the ICU nor 6 h later postoperatively. There was no
significant difference in the time of extubation between the two groups (12 +/-
3 h and 13 +/- 2 h, p = 0.4), the length of ICU stay, or the total hospital stay
postoperatively. CONCLUSIONS: The use of MUF after CPB can produce an immediate
improvement in lung compliance and gas exchange capacity, which may effectively
minimize pulmonary dysfunction postbiventricular repair of congenital heart
disease. However, these improvements are not sustained for the first 6 h
postoperatively and do not reduce the duration of postoperative intubation, ICU
stay, or total hospital stay.

J Heart Lung Transplant. 2005 Nov;24(11):1814-20. Epub 2005 Jul 27. 

High donor age, low donor oxygenation, and high recipient inotrope requirements
predict early graft dysfunction in lung transplant recipients.

Pilcher DV, Snell GI, Scheinkestel CD, Bailey MJ, Williams TJ.

Department of Intensive Care Medicine, The Alfred Hospital, Prahran, Victoria,
Australia. dvpilcher@doctors.org.uk

BACKGROUND: Early dysfunction in lung transplants is characterized by poor
oxygenation, which may then lead to prolonged mechanical ventilation. This may
be due to a combination of donor, recipient, and management factors. Our aim was
to determine the incidence and severity of hypoxia and graft dysfunction and
which factors were directly associated with poor oxygenation within the first 24
hours after lung transplantation. METHODS: A retrospective study of all 128 lung
transplants between 1999 and 2002 was undertaken. Multiple linear regression
analysis was performed to determine which donor, recipient, operative, and
intensive care unit (ICU) parameters were associated with the worst recorded
arterial blood gas partial pressure of oxygen (PAO2)/fraction of inspired oxygen
(FIO2) ratio in the initial 24 hours after operation. RESULTS: Eighty-three
percent of the patients (104 of 128) had a PAO2/FIO2 ratio below 300 within the
first 24 hours post-transplantation, and 60% (77 of 128) had a PAO2/FIO2 ratio
below 200. A high donor age (p = 0.004), low donor PAO2 (p = 0.007), and high
post-operative inotrope requirements (p = 0.02) were correlated with a low
PAO2/FIO2 ratio. Recipient diagnosis, ischemic time, use of cardiopulmonary
bypass, fluid balance in the ICU, and cardiac index were not related. There was
no difference in the long-term outcomes of patients with high or low PAO2/FIO2
ratios. CONCLUSIONS: A low PAO2/FIO2 ratio is a common finding in the first 24
hours after lung transplantation. Donor factors such as age and PAO2, and the
need for increasing inotrope requirements in ICU predict early graft dysfunction
and hypoxia.

J Thorac Cardiovasc Surg. 2005 Nov;130(5):1319. 

Attempted control of hyperglycemia during cardiopulmonary bypass fails to
improve neurologic or neurobehavioral outcomes in patients without diabetes
mellitus undergoing coronary artery bypass grafting.

Butterworth J, Wagenknecht LE, Legault C, Zaccaro DJ, Kon ND, Hammon JW Jr,
Rogers AT, Troost BT, Stump DA, Furberg CD, Coker LH.

Department of Anesthesiology, Wake Forest University School of Medicine,
Winston-Salem, NC 27157-1009, USA. jfbivjbutter@yahoo.com

OBJECTIVE: Hyperglycemia worsens outcomes in critical illness. This randomized,
double-blind, placebo-controlled clinical trial tested whether insulin treatment
of hyperglycemia during cardiopulmonary bypass would reduce neurologic,
neuro-ophthalmologic, and neurobehavioral outcomes after coronary artery bypass
grafting. METHODS: Three hundred eighty-one nondiabetic patients undergoing
isolated coronary artery bypass grafting were given infusions of insulin or
placebo when their blood glucose concentration exceeded 100 mg/dL during
cardiopulmonary bypass. The primary outcome measure was the combined incidence
of new neurologic, neuro-ophthalmologic, or neurobehavioral deficits or
neurologic death observed at 4 to 8 days postoperatively. This same measure was
assessed secondarily at 6 weeks and 6 months. Length of hospital stay was also
compared as a secondary assessment. RESULTS: The 2 groups were well matched at
baseline. The insulin-treated group had significantly lower blood glucose
concentrations during bypass. Sixty-six percent of subjects in the
insulin-treated group and 67% of subjects in the control group demonstrated a
new or worsening neurologic, neuro-ophthalmologic, or neurobehavioral deficit or
neurologic death at the 4- to 8-day assessment. Outcomes were also similar in
the 2 groups at 6 weeks (37% and 39% incidence, respectively) and 6 months (30%
and 25%, respectively). Median lengths of stay were 7 and 6 days, respectively,
in the treatment and control groups. None of these outcome differences was
statistically significant. CONCLUSION: Attempted control of hyperglycemia during
cardiopulmonary bypass had no significant effect on the combined incidence of
neurologic, neuro-ophthalmologic, or neurobehavioral deficits or neurologic
death and failed to shorten the length of hospital stay. These results do not
contradict those of other studies showing that aggressive control of
hyperglycemia in the postoperative period will improve outcome.

Ann Thorac Surg. 2005 Nov;80(5):1672-8; discusison 1678. 

Steroid supplementation: a legitimate pharmacotherapy after neonatal open heart
surgery.

Ando M, Park IS, Wada N, Takahashi Y.

Department of Pediatric Cardiac Surgery, Sakakibara Heart Institute, Tokyo,
Japan. maando@shi.heart.or.jp

BACKGROUND: An inflammatory response together with multiple organ failure
subsequent to cardiopulmonary bypass is especially prominent in neonates. The
behavior of glucocorticoids during this period in these patients is not known.
If adrenal insufficiency should exist, it could considerably compromise
postoperative recovery. METHODS: Twenty neonates undergoing biventricular repair
were enrolled. Ten patients were assigned to receive hydrocortisone treatment
and the other 10 to receive placebo. The treatment group received stress-dose
hydrocortisone sodium succinate after discontinuation of cardiopulmonary bypass:
0.18 mg.kg(-1).hr(-1) for 3 days, 0.09 mg.kg(-1).hr(-1) for 2 days, and 0.045
mg.kg(-1).hr(-1) for 2 days. The placebo was 5% glucose solution. RESULTS:
Patients had adrenal insufficiency (cortisol < 5 microg/dL) from 24 to 72 hours
in the placebo group. This was associated with a simultaneous reduction of left
ventricular shortening fraction (p < 0.0001, analysis of variance; p = 0.0203,
Student's t test), the necessity to increase inotropic agents (p = 0.043,
analysis of variance), and an increase in serum lactate level (p = 0.049,
Student's t test). During this period, serum cortisol level was maintained above
the normal level (> 23 microg/dL) in the hydrocortisone group. The placebo group
had a greater positive fluid balance (p = 0.027, Student's t test) and greater
total body edema in the immediate postoperative period (p = 0.065, Student's t
test). Blood oxygenation constantly improved, and the duration on mechanical
ventilation was shorter (83.5 +/- 42.1 versus 138.2 +/- 89.7 hours; p = 0.098)
in the hydrocortisone group. CONCLUSIONS: Adrenal insufficiency may occur after
neonatal open heart surgery. Stress-dose hydrocortisone supplementation blunts
other organ dysfunction and can be considered a legitimate pharmacotherapy in
this cohort.

J Thromb Haemost. 2005 Nov;3(11):2428-36. 

Lepirudin in patients with heparin-induced thrombocytopenia - results of the
third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and
HAT-3.

Lubenow N, Eichler P, Lietz T, Greinacher A; Hit Investigators Group.

Department of Immunology and Transfusion Medicine, Ernst-Moritz-Arndt University
Greifswald, Greifswald, Germany.

OBJECTIVES: To assess efficacy and safety of lepirudin in patients with
heparin-induced thrombocytopenia (HIT) in a prospective study (HAT-3) as well as
in a combined analysis of all HAT study data. PATIENTS/METHODS: Patients with
laboratory-confirmed HIT were treated with lepirudin in three different
aPTT-adjusted dose regimen and during cardiopulmonary bypass (CPB). Endpoints
were new thromboembolic complications (TEC), limb amputations, and death and
major bleeding. A historical control group (n = 120) was used for comparison.
RESULTS: After start of lepirudin in 205 patients treated in HAT-3, the combined
endpoint occurred in 43 (21.0%). Thirty (14.6%) patients died, 10 (4.9%)
underwent limb amputation, and 11 (5.4%) new TECs occurred. Major bleeding
occurred in 40 patients (19.5%) (seven during CPB surgery). Combining all
prospective HAT trials (n = 403), after start of lepirudin treatment, the
combined endpoint occurred in 82 patients (20.3%), with 47 deaths (11.7%), 22
limb amputations (5.5%), 30 new TECs (7.4%), and 71 (17.6%) major bleedings.
Compared with the historical control group (log-rank test), the combined
endpoint after start of treatment was reduced (29.7% vs. 52.1%, P = 0.0473),
primarily because of reduction in new thromboses (11.9% vs. 32.1%, P = 0.0008).
Mean lepirudin maintenance doses ranged from 0.07 to 0.11 mg kg(-1) h(-1). Major
bleeding was more frequent in the lepirudin-treated patients (29.4% vs. 9.1%, P
= 0.0148). CONCLUSIONS: The rate of new TECs in HIT patients is low after start
of lepirudin treatment. The rate of major bleeding of 17.6% might be reduced by
reducing the starting dose to 0.1 mg kg(-1) h(-1).

Eur J Cardiothorac Surg. 2005 Nov;28(5):705-10. Epub 2005 Sep 6. 

Vasoplegic syndrome--the role of methylene blue.

Shanmugam G.

Department of Cardiac Surgery, Royal Hospital for Sick Children, Glasgow G3 8SJ,
UK. sgunpat@hotmail.com

Vasoplegic syndrome is a recognized complication following cardiac surgery using
cardiopulmonary bypass and is associated with increased morbidity and mortality.
In several patients profound post-operative vasodilatation does not respond to
conventional vasoconstrictor therapy. Methylene blue has been advocated as an
adjunct to conventional vasoconstrictors in such situations. There is limited
data pertaining to the use of methylene blue and a number of reports have been
anecdotal observations. This article reviews the incidence and problems
associated with the vasoplegic syndrome, the mechanism of action of methylene
blue, its effects and adverse reactions and the literature supporting its
intra-operative and post-operative use. In cases where first-line therapy fails,
the use of methylene blue seems to be a potent approach to refractory
vasoplegia. The early use of methylene blue may halt the progression of low
systemic vascular resistance even in patients responsive to norepinephrine and
mitigate the need for prolonged vasoconstrictor use. However, dosing regimens
and protocols need to be clearly defined before widespread routine use. Whether
methylene blue should be the first line of therapy in patients with vasoplegia
is a matter of debate, and there is inadequate evidence to support its use as a
first line drug. More scientific evidence is needed to define the role of MB in
the treatment of catecholamine refractory vasoplegia.

Circ J. 2005 Nov;69(11):1302-7. 

Early defibrillation and circulatory support can provide better long-term
outcomes through favorable neurological recovery in patients with
out-of-hospital cardiac arrest of cardiac origin.

Hase M, Tsuchihashi K, Fujii N, Nishizato K, Kokubu N, Nara S, Kurimoto Y,
Hashimoto A, Uno K, Miura T, Ura N, Asai Y, Shimamoto K.

Division of Traumatology and Critical Care Medicine, Sapporo Medical University
School of Medicine, Sapporo, Japan. hase@sapmed.ac.jp

BACKGROUND: Early defibrillation and cardiopulmonary bypass have been postulated
to be a promising intervention against out-of-hospital cardiac arrest (OHCA);
however, little is known about the long-term prognosis. The effects of early
recovery of circulation (ROC) on neurological recovery and the long-term outcome
in patients with OHCA were examined. METHODS AND RESULTS: Functional recovery
and long-term (22.0+/-15.3 months) outcome were examined in 100 patients with
definite diagnosis of OHCA. Spontaneous circulation recovered in 79% of the
patients (using on-site counter shock in 20% of the patients). Cardiopulmonary
bypass was performed in 38 of the OHCA patients. The total survival and
favorable neurological recovery rates were 40% and 25%, respectively. The
patients with favorable recovery obtained early ROC (28.2+/-16.0 min).
Receiver-operating characteristic analysis showed that a period of less than 35
min for ROC was the optimal period for achieving a favorable recovery, with
sensitivity of 68% and specificity of 73%. The patients with a prior history of
heart failure or reduced left ventricular ejection fraction exhibited more
frequent, exacerbated heart failure and ventricular arrhythmias. CONCLUSIONS:
Early ROC using on-site counter shock or cardiopulmonary bypass might result in
better long-term outcome in patients with OHCA of cardiac origin.

Br J Anaesth. 2005 Nov;95(5):596-602. Epub 2005 Sep 23. 

Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic
transfusion in complex non-coronary cardiac surgery: randomized double-blind
placebo-controlled pilot study.

Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS.

Department of Anaesthesia, Southampton University Hospitals, Tremona Road,
Southampton SO16 6YD, UK. ravi.gill@suht.swest.nhs.uk

BACKGROUND: Receiving an allogeneic transfusion may be an independent predictor
of mortality for patients undergoing cardiac surgery. Furthermore, these
patients utilize 15% of all donated blood in the UK. In our unit, 80% of
patients undergoing complex non-coronary cardiac surgery requiring
cardiopulmonary bypass (CPB) receive an allogeneic transfusion. Activated
recombinant FVII (rFVIIa) may be effective in reducing this need for
transfusion. METHODS: Twenty patients undergoing complex cardiac surgery were
randomized to receive rFVIIa or placebo after CPB and reversal of heparin.
RESULTS: Two patients in the rFVIIa group received 13 units of allogeneic red
cells and coagulation products compared with eight patients receiving 105 units
of allogeneic red cells and coagulation products in the placebo group (relative
risk of any transfusion 0.26; confidence interval 0.07-0.9; P=0.037). The groups
did not differ for adverse events. CONCLUSION: Despite major limitations
(underpowered study and prone to type I error), we have shown that rFVIIa
significantly reduces the need for allogeneic transfusion in complex
non-coronary cardiac surgery without causing adverse events.

Vascul Pharmacol. 2005 Dec;43(6):434-40. Epub 2005 Nov 8. 

Correlation between pulmonary gas exchange and basal and nitroglycerin
(GTN)-induced exhaled nitric oxide (eNO) in patients undergoing cardiac surgery.

Kovesi T, Szabo A, Royston D, Marczin N.

Department of Anaesthetics, Royal Brompton and Harefield NHS Trust, Heart
Science Centre, Harefield Hospital, Harefield, United Kingdom.

The relationship between eNO and events in the alveolar-capillary unit in acute
lung injury remains to be established. Since endogenous eNO largely originates
from the airway epithelium, but nitroglycerin (GTN)-induced eNO is due to
microvascular/alveolar metabolism, we have proposed to use basal and GTN-induced
eNO as metabolic markers of the airway- and microvascular/alveolar function,
respectively. The current work investigates the relationship between basal and
GTN-induced eNO and oxygenation parameters (PaO(2)/FiO(2) ratio) in patients
undergoing cardiac surgery utilising cardiopulmonary bypass (CPB). Breath by
breath eNO measurements were made in 10 patients before, and 1 and 3 h after CPB
either under basal conditions or following intravenous administration of GTN (1,
2 and 3 mug/kg). Basal eNO remained unchanged, whereas GTN-induced eNO was
reduced following CPB. Also, there was a transient reduction in PaO(2)/FiO(2)
ratio 1 h after CPB (32+/-4 vs. 44+/-3 kPa). A negative correlation was found
between oxygenation and basal eNO by Pearson's correlation test and linear
regression analysis suggesting that decreased oxygenation was associated with
increased basal eNO. In contrast, a decrease in GTN-induced eNO positively
correlated with reduced oxygenation index (R=0.533, p=0.002). These data suggest
that differential relationships exist between basal and nitrovasodilator-induced
eNO and oxygenation indices during subclinical lung injury in patients following
CPB and that GTN-induced eNO evolution may reflect better microvascular events
and injury.