AAMJ, VOL (12), NO (4), OCT 2014 SUPLL

AL-AZHAR ASSIUT MEDICAL JOURNAL

PROPHYLACTIC VASOPRESSIN VERSUS NOREPINEPHRINE

IN PATIENTS RECEIVING THE ANGIOTENSIN-
CONVERTING ENZYME INHIBITOR UNDERGOING
CORONARY ARTERY BYPASS GRAFT SURGERY
Mahmoud Ismail Allam Eissa
Department of Anesthesia and ICU, Faculty of medicine, Al-Azhar University,
Egypt.

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ABSTRACT
Preoperative medication by angiotensin-converting enzyme (ACE)
inhibitors in coronary artery patients predisposes to vasoplegic shock early
after coronary artery bypass grafting which is a life-threatening condition,
intractable to the usual management with fluid administration, inotropes, and
even vasopressor catecholamines. Aim: In this study we compare the effects of
intraoperative infusion of low-dose of vasopressin ( 0.03 units per minute)
versus low dose of norepinephrine (0.03-0.05 mic/kg/min) on the patients’
hemodynamic status, the incidence of post-cardiopulmonary bypass (CPB)
vasodilatory shock, vasoactive drug requirement and blood or blood products
requirements in patients undergoing coronary artery bypass graft (CABG)
surgery. Materials: In our study 60 patients undergoing coronary artery bypass
grafting were included in a blind randomized basis. The patients were randomly
divided to three groups, group A who were not receiving norepinephrine or
vasopressin, group B who were infused with norepinephrine 0.03-0.05
mic/kg/min., group C who were infused with 0.03 IU/min vasopressin. Pre-
operative demographic, biochemical, echocardiographic, and angiographic
data were collected. Measurements of MAP, CVP, SVR, HR, MPAP, and CI
were performed during, and after the operation. The transfusion of blood and
blood products, and requirement for catecholamine support were included in
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the data collected. Results: In group C: The incidence of vasodilatory shock

was significantly lower, higher significant values of MAP, and SVR were
recorded in the patients of group C. Also the need for blood and blood product
transfusion and vasoactive support were significantly lower. In conclusion,
infused of prophylactic intra-operative low-dose vasopressin is beneficial for its
hemodynamic profile, reduces the doses of requirements of catecholamines and
blood or blood product transfusion and contributes to prevention of the
postcardiotomy vasoplegia.
INTRODUCTION
Coronary artery bypass grafting by using cardiopulmonary bypass (CPB)
may be complicated by persistent hypotension due to low systemic vascular
resistance in 5-22% of patients [1, 2]. Different causes have been associated,
like preoperative treatment with Angiotensin- converting enzyme inhibitors,
reduced left ventricular function, hypothermia, duration of CPB, total
cardioplegic volume infused and systemic inflammatory response syndrome
(SIRS), or inappropriate low arginine-vasopressin secretion [3, 4].
An advanced form of this post-cardiotomy hypotension is the so-called
vasodilatory or vasoplegic shock which is a life-threatening condition,
intractable to the usual management with fluid administration, inotropes, and
even vasopressor catecholamines [4-7].
Vasoplegic shock is relatively common complication of cardiopulmonary
bypass (CPB). It is characterized by an adequate or elevated cardiac output, low
mean arterial pressure, and evidence of organ dysfunction. Such physiologic
changes in association with a low blood pressure suggest organ dysfunction
secondary to insufficient perfusion pressure in turn secondary to vasodilatation.
They lead to the initiation of vasopressor therapy with the aim of restoring
vessel tone toward the normal and improving the perfusion of vital organs [8].

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The infusion of catecholamines often complicates the cardiovascular

stabilization by producing arrhythmias and entering into a vicious circle.
Vasopressin has been introduced as adjunctive to catecholamines in cardiac
arrest and in advanced vasodilatory shock, and the results have shown that it is
more effective than vasopressor catecholamines [9-11].
Angiotensin-converting enzyme (ACE) inhibitors have been shown to
decrease mortality and adverse cardiovascular events and improve the quality of
life in such patients [12].
The discontinuation of ACE inhibitors before cardiac surgery is a matter
subject to debate. Some authors advocate the discontinuation of ACE inhibitors
before cardiac surgery, whereas others do not [13, 14]. The continuation of ACE
inhibitors has the following potential beneficial effects during cardiac surgery:
attenuation of sympathetic responses to intubation and skin incision, prevention
of hypertension, improved renal function, and protection of the heart against
ischemia and reperfusion injury. [15].The sudden withdrawal of ACE inhibitors
after chronic use may cause rebound hypertension and increase ischemia-related
events [16].
On the contrary, there are several reports of adverse events in the
perioperative period in patients receiving preoperative ACE inhibitors,
including hypotension upon induction of anesthesia and weaning from CPB and
an increased requirement for vasoconstrictors during and after separation from
CPB in patients undergoing cardiac surgery [17, 18].
Preoperative treatment with ACE inhibitors also blunts the vasoactive
response in anesthetized patients by modulating other vasoconstrictive
neurohormones such as arginine vasopressin (AVP). AVP deficiency has been
purported to be one of the mechanisms of post-CPB vasodilatory shock, thus
rendering patients receiving ACE inhibitors at risk for developing this
syndrome. [19].

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Moreover, low-dose exogenous vasopressin has little vasoconstrictor effect

in normotensive subjects but dramatically improves hemodynamics in post-CPB
vasodilatory shock. Therefore, it was hypothesized that the correction of AVP
deficiency with low-dose vasopressin “replacement” therapy would be the ideal
prophylaxis for preventing post-CPB vasodilatory syndrome in patients
receiving preoperative ACE inhibitors [20].
Norepinephrine is a potent and commonly used α-adrenergic agent. α-
adrenergic effects increase vascular tone, but may decrease cardiac output,
oxygen delivery, and regional blood flow, especially in cutaneous, splanchnic,
and renal beds despite adequate perfusion pressure [21].
AVP is a peptide hormone formed in the hypothalamus, which is then
transported through axons to the posterior pituitary. AVP is a potent
vasoconstrictor which has been used to restore vascular tone in hypotensive
states including cardiac arrest, septic, postcardiotomy and hemorrhagic shock
and intraoperative hypotension [22- 24].
AVP stimulates V1-receptors of vascular smooth muscle leading to
vasoconstriction. AVP can also induce vasoconstriction by blocking activated
ATP/potassium channels within the muscle cell membrane. AVP is a potent
vasoconstrictor of skin, skeletal muscle, fat, pancreas and thyroid gland. The
effect is less potent in coronary, mesenteric and renal circulation. AVP has little
effect on blood pressure under normal conditions. Impaired liver function and
50% mortality has been reported despite improved cardio circulatory function in
advanced vasodilatory shock in patients of which almost 50% were cardiac
surgical [25, 26].
AIM OF THE WORK
Our study was to compare the effects of intraoperative infusion of low-
dose of vasopressin ( 0.03 units per minute) versus low dose of norepinephrine
(0.03-0.05 mic/kg/min) on the patients’ hemodynamic status, on the incidence

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of post-CPB vasodilatory shock, and vasoactive drug requirement in patients

undergoing coronary artery bypass graft (CABG) surgery and to assess whether
low-dose vasopressin or norepinephrine can alter post-CPB hemodynamics and
vasoactive drug requirement in patients receiving the ACE inhibitors
MATERIAL AND METHODS
This study was conducted following approval from the Ethics Committee
and our hospital’s Scientific Committee and written informed consent was
obtained from each patient. Sixty patients undergoing elective CABG surgery
on CPB between April 2012 and October 2013 were included in this
prospective, randomized, double-blinded study. Only patients receiving the
ACE inhibitor lisinopril for at least the past 4 weeks preoperatively were
included. All the patients underwent selective coronary artery bypass grafting
by the same anesthetic and surgical team.
The inclusion criteria for the patients were the following:
1. Patients were on ACE inhibitors (lisinopril) for at least 4 weeks prior to
surgical procedure
2. Patients had normal or mild impaired left ventricular function
From the study patients were excluded, according to the following criteria:
1. Patients with concomitant valvular disease or congestive heart failure
2. Moderate or severe left ventricular dysfunction
3. Patient in shock or severe hemodynamic instability
4. Severe lung disease or documented pulmonary hypertension, expressed by
systolic pulmonary pressure >30-35 mm Hg
5. Hepatic dysfunction (serum bilirubin ≥3.0 mg/dL)
6. Renal dysfunction (serum Creatinine ≥2.0 mg/dL)
7. Significant carotid stenosis or history of stroke
8. Significant peripheral vascular disease
9. Hypersensitivity to vasopressin

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10. Those undergoing emergency surgery or re-operation

Patients were randomly allocated to 1 of 3 groups:
Group A: Patients who continued ACE inhibitor until the morning of
surgery, and not receiving intra-operative vasopressin or norepinephrine
Group B: patients who continued ACE inhibitor until the morning of
surgery and received norepinephrine infusion intraoperatively.
Group C: patients who continued ACE inhibitor until the morning of
surgery and received vasopressin infusion intraoperatively
Full laboratory investigations, chest x-ray, electrocardiography,
transthoracic echocardiography, and coronary angiography were performed
preoperatively. With the exception of diuretics, all other cardiac medications
were continued until the day of surgery. Anti-platelet drugs were stopped 5-7
days before surgery except aspirin. ACE inhibitor was continued till the day of
surgery. Patients were fasted overnight. They were premedicated with
lorazepam 2 mg and ranitidine 150 mg orally the night before surgery and one
hour before shifting patient to the operating room.
In the operating room, Peripheral venous cannula and radial artery cannula
were inserted under local anesthesia .Monitoring with 5-lead
electrocardiography, invasive and non-invasive blood pressure, and pulse
oximetry was established. End-tidal carbon dioxide, central venous pressure
(CVP), temperature, urine output, intermittent arterial blood gas, serum
electrolytes, blood sugar, activated coagulation time, cardiac output and its
related parameters, and trans-esophageal echocardiography monitoring were
performed intraoperatively for all patients
A pulmonary artery catheter was then inserted via the right internal jugular
vein. Cardiac output (CO) was measured by thermo dilution technique. Cardiac
index (CI), Mean pulmonary artery pressure (MPAP) and systemic vascular
resistance (SVR) were calculated.

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A standard anesthetic technique was used for all patients in the 3 groups.
General anesthesia was induced with fentanyl (3-5 mic/kg), midazolam (0.05
mg/kg), etomidate (0.2-0.3 mg/kg), and cisatracurium (0.2-0.3 mg/kg)
intravenously. Patients were intubated and mechanically ventilated to maintain
normoxia and normocarbia (mode SIMV, tidal volume 6-10 ml/kg, rate 12/min,
inspiratory: expiratory ratio 1:2, fractional inspired oxygen concentration 0.6).
Anesthesia was maintained during operation by propofol infusion 1-2 mg/kg/h.,
fentanyl infusion 2-3 mic/kg/h.and cisatracurium infusion 1-2 mic/kg/min. plus
2% Sevoflurane in oxygen-air mixture. Hypotension upon the induction of
anesthesia (systolic arterial pressures [SAP] ≤ 90 mmHg) was treated with
intravenous fluids or vasopressor (phenylephrine). SAP ≥140 mmHg was
controlled initially with bolus dose of fentanyl or propofol and then
nitroglycerin infusion.
CABG surgery was performed under standard CPB techniques following
protocol, which consisted of median sternotomy, systemic anticoagulation with
3-5 mg/kg of heparin, activated coagulation time 480 seconds, ascending aorta
and right atrial appendage cannulation, and non-pulsatile flow of 2.5 L/min/m2.
CPB circuit prime included lactated Ringer’s solution, mannitol and blood, or
hydroxyethyl starch may be added to obtain a hematocrit of 25% to 27%.
Antegrade cold cardioplegia solution at was administered after aortic cross-
clamping at a dose of 20 ml/kg and repeated at a dose of 10 ml/kg every 20
minutes. Systemic hypothermia of 31°C to 33°C was used during distal
anastomoses. α-stat method of arterial blood gas was used, and the pH was
maintained at 7.4. The mean arterial pressure (MAP) was maintained between
50 and 75 mmHg during CPB by the administration of nitroglycerin or
phenylephrine. Rewarming was started at the time of anastomosing the last
distal graft. The aortic cross-clamp was removed after anastomosis of the last
distal graft. Ventricular fibrillation was managed with defibrillation, additional

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lidocaine and magnesium sulphate, and repeat defibrillation as required. Atrial

fibrillation was managed with cardioversion and overdrive pacing. A slow sinus
rhythm (heart rate < 60/min) was managed with atrial pacing. All proximal
anastomoses were performed with partial clamping of the aorta and low tidal
volume ventilation. Patients were weaned from CPB at a nasopharyngeal
temperature of 35°C to 36°C after resuming ventilation with 6 to 10 ml/kg tidal
volume. Hemodynamic parameters were stabilized. Anticoagulation was
reversed with protamine (1.3 times heparin dose) intravenously. A persistently
elevated activated coagulation time was managed with an additional dose of
protamine (1-2 mg/kg). The transfusion of blood and blood components was
used to maintain the post-CPB hematocrit more than 25% and/or to correct
coagulopathy. Patients in (group A) received normal saline, Patients in (group
B) received norepinephrine infusion, and patients in (group C) received
vasopressin infusion for the duration of the study. The study drug was started at
the 20 min before beginning CPB and was continued until the patients were
stable without vasopressor support. Doctors, clinical staff, and patients were
blinded to the identity of the study drug.

Postoperatively, all patients were shifted to the intensive care unit (ICU).
The same team of doctors cared for all patients and followed standard practices
with regard to patient care. The whole blood was given if hematocrit decreased
<25%. Platelet concentrates and fresh frozen plasma were transfused if
excessive chest drainage guided by coagulation profile and thromboelastogram.
For analgesia, morphine 5 mg was administered after shifting patient to
intensive care unit, 3 mg if there is pain before extubation and morphine PCA
(patient control analgesia) after extubation. The requirement and duration of
vasoactive drugs were recorded. Hemodynamic measurements were made
before and after intubation, after sternotomy, 5 minutes after termination of
CPB, before shifting, on admission to ICU, 2 hours postoperatively and on 1, 2

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and 3 postoperative days. Hemodynamic parameters that were recorded

included heart rate (HR), Mean arterial pressure (MAP), central venous
pressure(CVP), mean pulmonary artery pressure (MPAP), pulmonary capillary
wedge pressure (PCWP), Cardiac index (CI), and systemic vascular resistance
(SVR). Of these, MPAP, PCWP, CI, and SVR were recorded only in the
operating room. Anesthesia time, CPB time, aortic cross clamp time, and
number of grafts were recorded. The duration of mechanical ventilation, ICU
stay, hospital stay, mediastinal drainage, blood and blood products requirement,
and vasoactive requirement were recorded.
Statistical analysis of data: collected data organized, tabulated and
statistically analyzed using statistical package for social science (SPSS), version
16 (SPSS Inc., USA), running on IBM compatible computer. Numerical data
were represented as mean and standard deviation; for parametric data, one-way
ANOVA was used to compare between the three groups. Tukey’s post-hoc test
was used for pair-wise comparisons when ANOVA test is significant.
Qualitative data were presented as frequencies (n) and percentages (%). Chi-
square (x2) test was used to compare between the three groups. P value <0.05
was considered statistically significant.

RESULTS
Sixty patients were randomized to group A (n =20), group B (n = 20), and
group C (n = 20). There was no significant deference between the three groups
as regard to age, gender, height, and weight (Table 1). The 3 groups were
similar with respect to the incidence of hypertension; diabetes, smoking,
obesity, previous myocardial infarction, physical status, functional class,
hematologic, biochemical, echocardiographic, angiographic data, and
preoperative medications (Table 2).

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Table(1) Demographic Data

Group A Group B Group C

Variables P- value
n=20 n=20 n=20
Age (y) 56.95±10.64 59.65±9.07 54.45 ±8.54 0.32
Sex (n) (male/female) 18/2 19/1 16/4 0.23
Height(cm) 161.50± 5.92 164.4 ± 5.98 163.3 ± 8.01 0.39
Weight(kg) 67.5 ± 5.92 69.5 ± 5.92 65.1 ± 6.83 0.09

Table (2) Preoperative Variables

Group
Group A Group B P-
Variables C
n=20 n=20 value
n=20
Hypertension (n) (%) 10 (50%) 13(65%) 7(35%) 0.165
Diabetes (n) (%) 8(40%) 5(25%) 3(15%) 0.198
Smoker (n) (%) 7(35%) 5(25%) 8(40%) 0.592
Obesity (n) (%) 6(30%) 5(25%) 4(20%) 0.766
Previous myocardial infarction (n)
4(20%) 8(40%) 7(35%) 0.367
(%)
ASA (n) (II/III/IV) 2/13/5 2/10/8 1/14/5 0.717
NYHA (n) (II/III/IV) 10/8/2 11/8/1 11/9/0 0.71
1.90±0.7 1.95±0.8
EURO score 1.85±0.81 0.93
9 9
12.33±1.1 11.9± 12.8±1.1
Hemoglobin (g/dL) 0.07
0 1.15 2
1.06±0.3 0.86±0.3
Creatinine (mg/dL) 0.90±0.34 0.162
4 5
N of vessels diseased (1/2/3) 2/8/10 1/3/16 0/8/12 0.191
Left main (n) (%) 4(20%) 3(15%) 4(20%) 0.895
45.50± 49.30± 47.95±
Ejection fraction (%) 0.52
5.92 5.53 5.41
Lt. V. dysfunction (n) (absent/mild) 8/12 7/13 6/14 0.47
RWMA (n) (%) 10(50%) 12(60%) 8(40%) 0.45
4.35 4.80 5.40±0.1
Lisinopril dose (mg/d) 0.13
±0.49 ±0.89 2
Medications (n) (%)
Ɓ blocker 18(90%) 17(85%) 19(95%) 0.574
Calcium channel blocker 5(25%) 3(15%) 6(30%) 0.521
Nitrate 14(70%) 16(80%) 15(75%) 0.766

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The duration of anesthesia, CPB and aortic cross-clamp times, and the
number of grafts were similar in the 3 groups with no significant difference.
(Table3).
Table (3) Intraoperative Variables

Group A Group B Group C

Variables (mean± SD) P- value
n=20 n=20 n=20
duration of anesthesia (hr) 4.34±0.82 3.95±0.95 4.68±1.07 0.06
CPB time (min) 82 ±11.83 76 ±11.83 78.5 ±11.24 0.27
Aortic cross-clamp time (min) 44.5 ±5.92 42.50±5.92 43.5 ±5.92 0.57
Number of grafts 3.15±0.75 3.35±0.67 2.8 ±0.83 0.07
Abbreviation: SD, standard deviation.

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Table (4): Hemodynamic Parameters Observed at Various Stages in the 3

Groups
Gro Base post- post- post- Before arrival to 1st h. in 2 h in 1st 2nd 3rd
up line intubation sternotomy CPB shifting ICU ICU ICU POD POD POD
71.90 74.10 75.70 91.40* 98 * 107.2* 105.6* 104.4* 106.3 106.9* 110.8*
A ± ± ± ± ± ± ± ± *± ± ±
HR (beats/min) 8.43 10.67 9.28 8.00 10.42 8.52 3.62 7.43 4.88 6.89 1.28
76.2 76.3 79.5 90 * 91.2* 96.20* 100.4* 103.1 100.8* 101.9*
B 101.1 ±
± ± ± ± ± ± ± *± ± ±
8.87 9.58 8.69 6.41 4.56 7.52 9.03 10.73 4.97 6.01 7.77
74.9 78.3 76.60 82.3* 88.2* 92.3* 95.1 * 92.7* 95.5* 94.3*
C _
± ± ± ± ± ± ± ± ± ±
6.13 6.70 10.85 6.65 10.67 9.27 9.79 7.18 8.69 9.90
94.3 72.4* 78.3* 74.2* 80.4* 85.4* 84.4* 95.6 95.8 95.6 97.3
A
± ± ± ± ± ± ± ± ± ± ±
MAP (mmHg) 11.24 7.34 6.13 6.49 4.40 8.22 7.34 6.38 5.85 7.00 3.43
93.2 74.9* 81.6* 80.5* 83.8* 86* 85.1* 93.9 95 95.1 100.8
B
± ± ± ± ± ± ± ± ± ± ±
12.30 8.40 6.67 4.60 8.47 5.79 6.74 5.28 7.97 6.05 1.62
100.1 77.2* 84* 91.5 93.4 97.6 97.2 100.4 101.2 100.4 _
C
± ± ± ± ± ± ± ± ± ±
13.57 8.72 7.24 6.65 6.36 9.20 7.90 7.09 6.58 5.91 _
7.40 7.80 7.20 8.90 7.30 7.10 8.40 7.00 8.30 7.80 8.80
A ± ± ± ± ± ± ± ± ± ± ±
CVP (mmHg) 2.63 2.74 2.86 3.51 2.95 1.97 2.32 4.06 3.56 1.87 1.87
6.40 6.60 5.50 5.90 6.40 4.50 6.00 6.40 5.20 7.60 7.60
B ± ± ± ± ± ± ± ± ± ± ±
2.01 2.37 2.27 1.97 1.84 1.78 1.56 2.01 2.86 1.43 1.43
7.00 8.30 8.80 8.10 9.00 5.60 5.20 5.40 4.60 6.60
C _
± ± ± ± ± ± ± ± ± ±
2.98 2.75 2.20 1.66 2.11 1.78 1.55 2.76 1.65 1.90
18.50 16.10 20.20 14.80 15.50
A ± ± ± ± ±
Mean PAP
3.03 5.90 7.77 8.11 6.69
(mmHg)
21.40 20.70 24.0 20.10 21.0
B ± ± ± ± ±
5.34 7.70 8.37 5.41 3.43
16.8 15.70 14.50 13.40 16.70
C ± ± ± ± ±
4.05 5.89 5.19 6.22 3.74
9.10 8.90 7.40 6.40 6.70
A ± ± ± ± ±
PCWP (mmHg) 2.33 2.77 2.07 1.43 1.64
12.00 14.60 18.80 10.80 14.80
B ± ± ± ± ±
7.15 8.58 4.29 4.29 4.29
8.90 7.20 7.00 9.30 6.70
C ± ± ± ± ±
3.45 3.94 1.49 2.75 1.83
2.10 1.78 2.17 2.37 2.38
A ± ± ± ± ±
CI (L/min/m2) 0.37 0.19 0.32 0.41 0.27
2.02 1.54 1.92 2.40 2.32
B ± ± ± ± ±
0.29 0.20 0.29 0.34 0.29
2.32 1.87 2.56 2.65 2.65
C ± ± ± ± ±
0.57 0.44 0.32 0.54 0.40

1238 746* 775* 749* 854*

SVR (dyne · s · A ± ± ± ± ±
cm5) 189.49 161.74 219.6 247.6 187.98
1247 812* 836* 863* 895*
B ± ± ± ± ±
218.12 256.76 223.06 195.50 237.3
1276 768* 784* 1241 1250
C ± ± ± ± ±
216.24 245.75 255.30 114.35 263.52

*p < 0.05 for mean change from baseline within the group

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All patients were in normal sinus rhythm preoperatively. The baseline

hemodynamic parameters were similar in the 3 groups. The HR increased after
the termination of CPB and remained so for the duration of the study in the 3
groups. Patients who not received norepinephrine or vasopressin
intraoperatively (Group A), the MAP and SVR decreased from 94.3 ± 11.24
mmHg and 1238 ± 189.49 dynes · s · cm5 to m72 ± 7.34 mmHg and 746 ±
161.74 dynes · s · cm5 (p 0<.05) after the induction of anesthesia and 78.3 ±
6.13 mmHg and 775 ± 219.6 dynes · s · cm5 (p < 0.05) after sternotomy. In
patients who received norepinephrine intraoperatively (group B), the MAP and
SVR decreased from 93.2 ± 12.3 mmHg and 1247 ±218.12 dynes · s · cm5 to
74.9± 8.4 mmHg and 812 ± 256.76 dynes · s · cm5 (p < 0.05) after the induction
of anesthesia and 81.6 ± 6.67 mmHg and 836 ± 223.06 dynes · s · cm5 (p
0<.05) after sternotomy. In patients who received vasopressin (group C), MAP
and SVR decreased from 100.1 ± 13.57 mmHg and 1276 ± 216.24 dynes · s ·
cm5 to 77.2 ± 8.72 mmHg and 768 ± 245.75 dynes · s · cm5 (p <0.05) after the
induction of anesthesia but normalized to m 91.5± 6.65 mmHg and 1241 ±
114.35 dynes · cm5 after CPB. CVP, MPAP, PCWP, and CI were stable and
comparable throughout the study period in the 3 groups (Table 4).
The mean norepinephrine infusion-time was 2.00± 0.6 days and the mean
vasopressin infusion-time was 1.70± 0.25 days. (Table5).
Vasodilatory shock is considered the unstable hemodynamic state
characterized by a systolic arterial pressure of less than 80 mmHg (or mean
arterial pressure < 50 mm Hg), despite of a cardiac output more than 5 L/min (or
a cardiac index > 2.5 L/min/m2) (9, 10). According to this definition, three (3)
patient of group A (15%), and two (2) patients of group B (10%) developed
Vasodilatory shock, during the first 24 hours of Postoperative observation but
no cases in group C (table 6).

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Table (5): Frequency and Duration of Vasoactive Drug Use

Group A Group B Group C
Variables P- value
n=20 n=20 n=20
n(%) 15(75%) 13(65%) 4(20%)* 0.001*
Dopamine
Duration 2.20± 0.78 2.00± 0.81 1.13± 0.54* 0.045*
n(%) 6(30%) 5(25%) 1(5%)* 0.035*
Epinephrine
Duration(d) 2.50± 0.37 2.30± 0.59 1.96± 0.51* 0.021*
n(%) - 20(100%)* - < 0.001*
Norepinephrine
Duration(d) - 2.00± 0.6* - < 0.001*
n(%) - - 20(100%)* < 0.001*
Vasopressin
Duration(d) - - 1.70± 0.25* < 0.001*
*p < 0.05
Table (6) Postoperative Variables
Group A Group B Group C P-
Variables
n=20 n=20 n=20 value
858.5 749 502.00
mediastinal bleeding in 1st 48 (ml) 0.015*
±287.57 ±268.42 ±220.29*
Re-exploration due to excessive bleeding (n)
4(20%) 0(00%) 0(00%) 0.014*
(%)
Vasodilatory shock n(%) 3(15%) 2(10%) 0(00%) 0.013*
10.02
duration of MV (h) 10.45 ±2.38 5.95 ± 2.16* 0.001*
±3.08
ICU stay(days) 2.5 ± 0.94 2.65 ±0.66 1.49 ± 0.66* 0.004*
hospital stay (days) 5.94 ±1.74 5.98 ±1.50 5.44 ± 0.75 0.635
packed RBCs(units) 3.10 ±1.79 2.10±1.28 0.80 ±0.78* 0.003*
FFP(units) 4.10 ±1.52 2.9 ±1.37 1.70 ± 0.82* 0.001*
platelets(units) 10.30 ±3.05 9.0 ±1.49 6.10 ± 2.02* 0.001*
*p < 0.05.

Fig. (1):The HR at various stages in the 3 groups; *p < 0.05 for intergroup
differences between group A and group B; #p < 0.05 for intergroup
differences between group A and group C

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Fig.(2): The MAP at various stages in the 3 groups; *p < 0.05 for
intergroup differences between group A and group B; #p < 0.05 for
intergroup differences between group A and group C.

As regard to the requirement for different vasoactive drugs, In group A,

75% of patients required dopamine and 30% required epinephrine more
frequently than patients in group B where 65% of patients required dopamine
and 20% required epinephrine, This difference was present but not significant in
comparison to patients in group C where 20% of patient required dopamine and
5% required epinephrine, (significant difference) (Table 5).
The requirement of blood and blood products, mediastinal drainage,
duration of mechanical ventilation, and ICU stay were less in group B than
group A (non-significant) but in group C, there were significant decrease (Table
6).
Various transient arrhythmias were observed on aortic cross clamp
removal. One patient in group C manifested atrial fibrillation, 1 patient in group
B developed ventricular fibrillation, and 2 patients each in groups A and B
developed ventricular extra-systoles.

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DISCUSSION
Perioperative hemodynamic control is principally determined by the
interplay between the sympathetic nervous system, renin-angiotensin system
(RAS), hypothalamic release of AVP, and end-organ responsiveness within the
cardiovascular system. In patients with a limited cardiovascular reserve such as
after myocardial infarction and under the effect of anesthesia, pharmacologic
RAS blockade with ACE inhibitors is thought to precipitate unstable
hemodynamics. [27].
The vasodilatory shock is a state of abrupt hemodynamic deterioration
following open heart surgery. It is mainly characterized by a vasodilatory
hypotension (SBP < 0 mmHg, COP >5 L/min, SVR < 800dynes · s · cm5, CI
≥2.5 L/min/m2, and norepinephrine dependence)) associated with lactic
acidosis, tachycardia, and low filling pressures [27, 28].
The hypotension is characteristically unresponsive either to catecholamine
administration, or to preload increase by excessive fluid infusion [29]. This
situation is attributed to a loss of vascular tone, due to either the inflammatory
mediators produced by the cardiopulmonary bypass, hypothermia or the
administered vasodilators such as phosphodiesterase inhibitors, nitrates, etc
[28]. Some factors such as congestive heart failure (with EF < 35%),
preoperative use of angiotensin-converting enzyme inhibitors and/or B-blockers
and/or amiodarone and phosphodiesterase inhibitors, seem to be associated with
increased postoperative incidence of the vasodilatory shock [29 - 31].
In patients receiving preoperative ACE inhibitors, attenuation of the effects
of angiotensin II may reduce circulating norepinephrine levels and decrease
vascular responsiveness to norepinephrine after CPB. [32]. ACE inhibitors also
blunt the vasoactive response in anesthetized patients by modulating other
vasoconstrictive neurohormones such as AVP [34]. These effects may be
compounded by downregulation of the baroreceptor reflex as well as

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downregulation and desensitization of adrenergic receptors after cardiac

surgery.
Increased levels of atrial natriuretic peptide during rewarming and after the
discontinuation of CPB also decrease vasomotor tone in the presence of ACE
inhibitors [33]. Preoperative treatment with ACE inhibitors has been associated
with hypotension upon the induction of anesthesia and separation from CPB and
an increased requirement for vasoconstrictors after separation from CPB. [34].
Three main mechanisms of low SVR syndrome have been identified:
activation of K adenosine phosphate channels on vascular smooth muscle
[35,36]; pathologic activation of vasodilator mechanisms as suggested by
increased levels of tumor necrosis factor, nitric oxide, and atrial natriuretic
peptide[37].; and impaired baroreflex-mediated AVP secretion/deficiency.
Patients with post-CPB low SVR syndrome have AVP levels in the range of 5 -
15 pg/ml, whereas normally AVP levels during and after CPB are in the range
of 100 to 200 pg/ml [38].
In this study of 60 patients with good or mildly impaired left ventricular
function undergoing CABG surgery, all patients continued lisinopril until the
morning of surgery. In patients not receiving vasopressin or norepinephrine
(group A), MAP and SVR decreased after the induction of anesthesia (p < 0.05)
and further after CPB (p <0.05) and continue intraoperatively till shifting patient
to intensive care. In patients receiving norepinephrine (group B), MAP and SVR
decreased after the induction of anesthesia (p <0.05), and continue
intraoperatively till shifting patient to intensive care, the decrease in MAP and
SVR in group B less is than in group A but not significant difference between
the two groups. In patients receiving vasopressin (group c), MAP and SVR
decreased after the induction of anesthesia and after sternotomy (p <0.05), till
start low dose of vasopressin before CPB, and after starting vasopressin MAP
and SVR improved. This is because of preoperative ACE inhibitor use blunt the

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vascular compensatory mechanisms, so after induction of anesthesia and due to

loss of compensatory mechanisms, MAP and SVR will decrease [37].
Therefore because AVP mediates vasoconstriction by inhibiting the effectors
that cause post-CPB vasodilation, low-dose vasopressin appeared to be the ideal
prophylaxis for its prevention in patients taking ACE inhibitors. Initial reports
of AVP use were primarily case reports. Many cases have been described
wherein AVP was used for hypotension refractory to catecholamine
vasopressors in patients on CPB [39, 40]. The first randomized trial comparing
vasopressin (0.1 U/min) with saline placebo was performed in patients after left
ventricular–assist device placement and orthotopic heart transplantation [32,
41]. Vasopressin resulted in significant improvement in MAP by nearly 40%
and reduction in norepinephrine requirement by almost 30% without any
complications.
Several studies in the past have shown that the perioperative administration
of vasopressin restores the vascular tone in patients following cardiopulmonary
bypass, especially in cases that are refractory to norepinephrine [42, 43]. This
result could be warranted by the known action of vasopressin: in low doses it
has little or no influence on blood pressure of the normotensive patients, while
the same doses in patients in vasodilatory shock produce an effective
constrictive vessel action [44]. The increased cardiac index is attributed not only
to the preload and after load changes, but also to the increased myocardial
Contractility [45, 46].
In 2003, Morales and colleagues conducted a randomized, double-blind
placebo-controlled study (level 2) to assess the effect of vasopressin (1.8 IU/hr)
infusion starting 20 minutes before CPB in 27 patients undergoing cardiac
surgery while on ACE inhibitors. The 13 patients allocated to vasopressin
infusion had significantly decrease in the duration of catecholamine use
(vasopressin at 5 ± 6 hours vs. placebo at 11 ± 7 hours; p < 0.03) and a number

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of hypotensive episodes (vasopressin at 1 ± 1 Vs. placebo at 4 ± 2; p <0.01)

[47].
In another study, Morales and colleagues found that vasopressin (0.03
IU/min) infusion starting 20 minutes before CPB was associated with a shorter
intubation time (vasopressin at 1.0 ± _ 0.4 days; placebo at 1.4 ± 0.5 days;( p <
0.02), and length of intensive care unit stay (vasopressin at 1.2 ± 0.4 days;
placebo at 2.1 ± 1.4 days;( p <0.03) [44].
In 2002, Dunser and colleagues in a separate study found that vasopressin
(4 ± 6 IU/hr) infusion to postoperative CPB patients with catecholamine-
resistant shock increase MAP by 27 mm Hg (49.1%) and decrease
norepinephrine requirement by0.49 mcg/min/kg (30.2%) with no change in
cardiac index and a significant increase in the left ventricular stroke work index
[48].
In another study by the same group, vasopressin (4 ± 6 IU/hr) infusion to
patients with catecholamine resistant septic (58.3%) or postoperative CPB shock
(41.6%) increased MAP by 24 mmHg (40.7%) and heart rate by 6 beats per
minute (5.2%) with no change in stroke volume, but a significant decrease in
cardiac index [49].
The mean infusion rate of vasopressin in group C, was 0.03 mic/kg/min,
this low dose was appropriate for maintaining hemodynamics, decreasing
requirement for dopamine and epinephrine, less need to blood and blood
products transfusion and less incidence of post-CPB vasodilatory shock.
Mutlu G and Factor P, consider as appropriate the dose of <0.04 U/min and
showed that it is safe and effective, even for the treatment of the septic
vasodilatory shock. Higher dosages of vasopressin may be associated with
several complications such as decreased coronary blood flow and cardiac
output, ventricular arrhythmias and gut ischemia [50, 51].

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Torqersen C, et al in their randomized and controlled trial by comparing

two doses of 0.033 and 0.067 IU/min of arginine vasopressin infusion in
patients with advanced vasodilatory shock, they showed that the patients
receiving dose of 0.067 IU/min required significantly less norepinephrine,
developed lower metabolic acidosis, without significant differences in MAP-
levels, rate of adverse events and ICU-mortality, even for the 48 hours after the
operation [56].
There were no cases reported with post-CPB vasodilatory shock (0%) in
group C compared with three cases (15%) in group A and two cases (10%) in
group B.
According to Argengiano et al, both low ejection fraction and use of ACE
inhibitors were independent risk factors for the development of postoperative
vasodilatory shock. In fact, while the incidence of vasodilatory shock in patients
with a normal EF was 3.3%, in patients with a low ejection fraction or receiving
ACE inhibitors, it was 26.9% and 26.7%, respectively [52].
Papadopoulos et al., found that the incidence of vasodilatory shock was
significantly lower in the group of vasopressin 8% versus 20% in the control
group when he compared the effect of low dose of vasopressin infusion in
patient underwent CABG [53].
Blood and blood products requirement was less in group B than in group A
(non-significant difference).In group C, there is significant decrease in blood
and blood products requirement, this can be explained by hemodynamic
stability, so need less volume replacement, less incidence of vasoplegic
syndrome which cause oozing that requires blood and blood products
transfusion, vasopressin enhances blood coagulation due to increase the plasma
concentrations of factors VIII and von Willebrand. Vasopressin also causes
vasoconstriction and probably the increase adhesion of platelets (there are
receptors V1 on them) [54, 55].

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Concerning the postoperative needs of dopamine, our data showed that in

the vasopressin group (group C) the percentage of patients requiring
administration of dopamine was significantly lower in comparison with group A
or B (4 pts or 20% versus 15 pts or 75% versus 13 pts or 65%). Similarly, a
significant difference was observed in the number of patients requiring additive
infusion of epinephrine in group C in comparison with group A or B (1 pt or 5%
versus 6 pts or 30% versus 5 pts or 25%).
Papadopoulos et al., found that the need for catecholamines was
significantly low in vasopressin group when he compared the effect of low dose
of vasopressin infusion in patient underwent CABG [53].
The post-operative duration of mechanical ventilation, and the length of
ICU stay was significantly low in group C in comparison with group A or B,
this explained by hemodynamic stability, less blood and blood product
requirement and less catecholamines requirement(Table6).
CONCLUSIONS
In summary, infusion of low dose vasopressin (0.03 U/min) 20 minutes
before cardiopulmonary bypass and continued after CABG till stabilization of
patients in whom with preoperative medication with ACE inhibitors, is more
Beneficial than use of low dose of norepinephrine(0.03-0.05 mic/kg/min). It
significantly obtained a better hemodynamic profile, and lower blood loss. The
use of low” dose vasopressin seems to be preventive for the incidence of
observed post-cardiotomy vasodilatory shock. Finally, it decreases both
dopamine and epinephrine requirement, it is considered as a useful agent for
decreasing all their side-effects and so decrease the duration of post-operative
MV, and length of ICU stay.

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