ORIGINAL ARTICLES
Triiodothyronine in the Recovery of Stunned Myocardium in Dogs D. Novitzky, MD, FCS(SA), N. Matthews, DVM, D. Shawley, DVM, D. K. C. Cooper, MD, PhD, FRCS, a n d N . Zuhdi, MD Oklahoma Transplantation Institute, Baptist Medical Center, Oklahoma City, and School of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma
Two groups of dogs were subjected to a 15-minute period of regional myocardial ischemia by snaring the left anterior descending coronary artery proximal to its first diagonal branch. After release of the snare, the dogs were given either placebo (group 1: n = 7)or triiodothyronine (T,) therapy (group 2 n = 6).The dose of T3 given was 0.2 p g k g at 30-minute intervals to a total of six doses. Plasma free T3 level fell significantly during the ischemic period in both groups and continued to fall after reperfusion in group 1. In both groups, cardiac function deteriorated significantly during the period of
ischemia and rapidly returned to control level after reperfusion. After 90 minutes of reperfusion, however, deterioration of left ventricular function was observed in group 1and was significantly worse than in group 2, in which hemodynamic function was maintained and, in fact, improved to levels superior to control. It is suggested that T, therapy may be worthy of trial in patients in whom reperfusion of the myocardium takes place after a relatively short ischemic period (the "stunned myocardium"). (Ann Thoruc Surg 1991;51:10-7)
T
such as myocardial infarction and cardiogenic shock [lo], sepsis [ll], cardiopulmonary bypass [12, 131, and after brain death [14]. We have investigated the effects of triiodothyronine (T,) replacement therapy in a group of dogs after a period of myocardial ischemia (group 1: n = 7); the effect of T, on the global function of the left ventricle and on systemic and pulmonary hemodynamics has been documented and compared with the effects of placebo in a group of identically managed dogs (group 2: n = 6).
emporary myocardial ischemia for 15 minutes in dogs induces reversible myocyte injury-the so-called stunned myocardium [l].If blood supply to the area is reestablished, myocardial infarction will not occur. The temporary ischemia, however, leads to substantially prolonged regional left ventricular contractile dysfunction with akinesia or dyskinesia in the area at risk [Z]. Associated with this mechanical dysfunction is a significant biochemical abnormality characterized by a decrease in
For editorial comment, see page 5. myocardial adenosine triphosphate (ATP)and a reduction in the adenine nucleotide pool [3, 41. Associated with such a period of myocardial ischemia, there is a humoral and metabolic [5] response characterized by a significant increase in adrenergic activity [6] resulting in the release of endogenous and systemic catecholamines, activation of the angiotensin system, release of cortisol [7], and changes in the levels of the various thyroid hormones [7-91. The thyroid profile is characterized by the so-called acute euthyroid sick syndrome, consisting of low plasma free triiodothyronine (FT,), a variable level of free thyroxine, and a significant increase in reverse triiodothyronine. Levels of total triiodothyronine, total thyroxine, and thyroid-stimulating hormone remain unchanged. Similar thyroid hormonal observations have been made in other stress situations, Presented at the Twenty-fifth Anniversary Meeting of The Society of Thoracic Surgeons, Baltimore, MD, Sep 11-13, 1989. Address reprint requests to Lh Novitzky, Oklahoma Transplantation Institute, Baptist Medical Center, 3300 NW Expressway, Oklahoma City, OK 73112.
0
1991 by The Society of Thoracic Surgeons
Material and Methods Sixteen heartworm-free mongrel dogs of both sexes were used in these studies; all experimental procedures complied with the "Guiding principles in the use and care of animals" approved by the Council of the American Physiological Society.
Anesthesia After the insertion of a peripheral venous line, a loading dose of 30 mg/kg of phenobarbital was administered. A central venous line was inserted via the jugular vein, and a continuous infusion of phenobarbital, 5 mg kg-' * h-', was administered throughout the experiment. After endotracheal intubation, ventilation was sustained by an Ohio Metomatic veterinary ventilator on a volume mode. Throughout the experiment, the animal received 10 mL kg-' * h-' of normal saline solution. Arterial blood gases and electrolytes were measured at intervals and maintained within the normal ranges. At the end of the experiment, euthanasia was performed with a hypertonic KCl solution.
-
-
0003-4975/91/$3.50
Ann Thorac Surg 1991;51:1&7
Surgical Preparation A standard lead 2 was used for electrocardiographic monitoring. A Swan-Ganz catheter was floated through the right femoral vein into the pulmonary artery. A left thoracotomy was performed in the fifth intercostal space. The ribs were retracted, and the pericardium was incised parallel to the phrenic nerve, exposing the heart, the chest remaining open throughout the experiment. Pressure monitoring catheters were inserted into the left atrium and descending aorta. All pressures were measured by a Gould-Statham physiological pressure transducer interlinked with a Honeywell Simultrace-recorder model AR-6. The left anterior coronary artery (LAD) was identified proximal to its first diagonal branch. A No. 2 Dacron suture was passed around the LAD at this point, and the ends of the suture were introduced through a Silastic snare. A 14-gauge needle was introduced into the lumen of the left ventricle through the apex and directly connected to a pressure transducer.
Induction of Myocardial Ischemia (“Stunning“) Once the surgical preparation was completed, the animal’s condition was allowed to stabilize for 30 minutes, after which control hemodynamic status was measured. The LAD was then occluded by applying tension to the snare previously placed around the vessel. The anterolatera1 wall of the left ventricle rapidly became cyanotic and hypokinetic-dyskinetic. The animals tolerated the 15minute period of ischemic occlusion satisfactorily; however, at the time of reperfusion, ventricular fibrillation occurred in 8 of the 16 dogs, necessitating cardiac massage and attempted electrical defibrillation. In 5 animals, resuscitation was successfully accomplished; these dogs were included in the study (group 1, n = 2; group 2, n = 3). Resuscitation was unsuccessful in 3 dogs, which were excluded from the study.
Hernodynamic Monitoring The following variables were monitored: (1) cardiac output, (2) heart rate, (3) systemic arterial pressure (systolic, diastolic, and mean), (4) right atrial pressure (central venous pressure), (5) pulmonary artery pressure (systolic, diastolic, and mean), (6) left atrial pressure, (7) peak left ventricular pressure, (8)left ventricular end-diastolic pressure, and (9) positive and (10) negative time derivative of pressure (dP/dt). Stroke volume, systemic and pulmonary vascular resistances, and cardiac index were calculated. The mean cardiac output of three consecutive readings was obtained while ventilation was temporarily interrupted. Hemodynamic measurements were made before occlusion of the LAD, at the end of the 15-minute period of myocardial ischemia before release of the LAD snare, and at 10, 30, 60, 90, 120, and 180 minutes after reperfusion.
Measurement of Plasma Free T3 Plasma free T, was measured using a radioimmunoassay technique (Ciba Corning Diagnostics Corporation, Medfield, MA) at the following intervals: before LAD occlu-
NOVITZKY ET AL TRIIODOTHYRONINE AND STUNNED MYOCARDIUM
PPMOUML
r
0”
p.
C
‘
0 10
11
P < o.Ooo1
30
60
90
120
180
TIME IN MINUTES
Fig 1. Plasma free triiodothyronine (T,) levels in the placebo (solid line) and T,-treated (dotted line) dogs before, during, and after a 15-minute period of regional myocardial ischemia (C = control; time 0 indicates the time of myocardial reperfusion). Statistical differences are shown. The bars represent the standard error of the mean.
sion, at the end of the ischemic period before release of the LAD snare, and at 10, 60, 120, and 180 minutes after reperfusion.
T, Therapy (Group 2 Dogs Only) T, (or placebo in group 1) was administered as an initial loading dose of 0.2 Fg/kg 10 minutes after release of the LAD occlusion, followed by an intravenous bolus of the same dose at 30-minute intervals, for a total of six doses.
Statistical Analyses The animals were computer-randomized into group 1 (placebo: n = 7) or group 2 (T,: n = 6). The observer remained blinded throughout the experiment. The data were analyzed within each group by repeated measures analysis of variance and by t tests for unpaired data for group comparisons. A two-tail value of p less than 0.05 was considered significant.
Results Plasma FT, level decreased significantly by 40% (p < 0.04) in both groups during the ischemic period (Fig 1).In the placebo group (group l), a steady decline continued; by 180 minutes, FT, level had decreased a further 50%. From the time of the induction of ischemia (control) until the end of the experiment, the FT, level had decreased by 75% in this group (p < 0.0001). A similar pattern was observed in the T,-treated group (group 2) before the initiation of therapy, but thereafter, levels remained elevated (p < 0.0001) for the remainder of the experiment (see Fig 1).By 180 minutes after ischemia, the level of FT, was not significantly different from the control level. There were no significant changes in hematocrit in either group throughout the experiment, indicating that hemodilution did not play a role in the decrease in FT,. Function of the heart deteriorated significantly in both
12
NOVITZKY ET AL TRIIODOTHYRONINE AND STUNNED MYOCARDIUM
Ann Thorac Surg 1991;51:10-7
Table 1. Systemic Hemodynamics” Variable
Control
End of Ischemia
+10 min
+30 min
+60 min
+90 min
+120 min
+180 min
co PI T3
p value CI (mL/kg) PI T3
p value HR (beatdmin) PI T3
p value SV (mL) PI T3
p value BPS (mm Hg) PI T3
p value BPD (mm Hg) PI T3
p value BPM (mm Hg) PI T3
p value CVP (mm Hg) PI T3
p value SVR (Wood units) PI T3
p value
3.62(0.35) 2.73(0.27)d 3.44(0.45) 2.44(0.36)’
NS 176 (12.8) 175 (14.7)
NS 143 (4.2) 131 (10.1)
NS
NS 128 (12.5)d 130 (10.5)’
129 (7.9) 125 (10.0)
NS 107 (6.7) 98 (9.2)
168 (10.9) 188 (25.4)
151 (12.0)b 136 (9.0)d 203 (22.4) 204 (18.8)b
Triiodothyronine in the Recovery of Stunned Myocardium in Dogs D. Novitzky, MD, FCS(SA), N. Matthews, DVM, D. Shawley, DVM, D. K. C. Cooper, MD, PhD, FRCS, a n d N . Zuhdi, MD Oklahoma Transplantation Institute, Baptist Medical Center, Oklahoma City, and School of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma
Two groups of dogs were subjected to a 15-minute period of regional myocardial ischemia by snaring the left anterior descending coronary artery proximal to its first diagonal branch. After release of the snare, the dogs were given either placebo (group 1: n = 7)or triiodothyronine (T,) therapy (group 2 n = 6).The dose of T3 given was 0.2 p g k g at 30-minute intervals to a total of six doses. Plasma free T3 level fell significantly during the ischemic period in both groups and continued to fall after reperfusion in group 1. In both groups, cardiac function deteriorated significantly during the period of
ischemia and rapidly returned to control level after reperfusion. After 90 minutes of reperfusion, however, deterioration of left ventricular function was observed in group 1and was significantly worse than in group 2, in which hemodynamic function was maintained and, in fact, improved to levels superior to control. It is suggested that T, therapy may be worthy of trial in patients in whom reperfusion of the myocardium takes place after a relatively short ischemic period (the "stunned myocardium"). (Ann Thoruc Surg 1991;51:10-7)
T
such as myocardial infarction and cardiogenic shock [lo], sepsis [ll], cardiopulmonary bypass [12, 131, and after brain death [14]. We have investigated the effects of triiodothyronine (T,) replacement therapy in a group of dogs after a period of myocardial ischemia (group 1: n = 7); the effect of T, on the global function of the left ventricle and on systemic and pulmonary hemodynamics has been documented and compared with the effects of placebo in a group of identically managed dogs (group 2: n = 6).
emporary myocardial ischemia for 15 minutes in dogs induces reversible myocyte injury-the so-called stunned myocardium [l].If blood supply to the area is reestablished, myocardial infarction will not occur. The temporary ischemia, however, leads to substantially prolonged regional left ventricular contractile dysfunction with akinesia or dyskinesia in the area at risk [Z]. Associated with this mechanical dysfunction is a significant biochemical abnormality characterized by a decrease in
For editorial comment, see page 5. myocardial adenosine triphosphate (ATP)and a reduction in the adenine nucleotide pool [3, 41. Associated with such a period of myocardial ischemia, there is a humoral and metabolic [5] response characterized by a significant increase in adrenergic activity [6] resulting in the release of endogenous and systemic catecholamines, activation of the angiotensin system, release of cortisol [7], and changes in the levels of the various thyroid hormones [7-91. The thyroid profile is characterized by the so-called acute euthyroid sick syndrome, consisting of low plasma free triiodothyronine (FT,), a variable level of free thyroxine, and a significant increase in reverse triiodothyronine. Levels of total triiodothyronine, total thyroxine, and thyroid-stimulating hormone remain unchanged. Similar thyroid hormonal observations have been made in other stress situations, Presented at the Twenty-fifth Anniversary Meeting of The Society of Thoracic Surgeons, Baltimore, MD, Sep 11-13, 1989. Address reprint requests to Lh Novitzky, Oklahoma Transplantation Institute, Baptist Medical Center, 3300 NW Expressway, Oklahoma City, OK 73112.
0
1991 by The Society of Thoracic Surgeons
Material and Methods Sixteen heartworm-free mongrel dogs of both sexes were used in these studies; all experimental procedures complied with the "Guiding principles in the use and care of animals" approved by the Council of the American Physiological Society.
Anesthesia After the insertion of a peripheral venous line, a loading dose of 30 mg/kg of phenobarbital was administered. A central venous line was inserted via the jugular vein, and a continuous infusion of phenobarbital, 5 mg kg-' * h-', was administered throughout the experiment. After endotracheal intubation, ventilation was sustained by an Ohio Metomatic veterinary ventilator on a volume mode. Throughout the experiment, the animal received 10 mL kg-' * h-' of normal saline solution. Arterial blood gases and electrolytes were measured at intervals and maintained within the normal ranges. At the end of the experiment, euthanasia was performed with a hypertonic KCl solution.
-
-
0003-4975/91/$3.50
Ann Thorac Surg 1991;51:1&7
Surgical Preparation A standard lead 2 was used for electrocardiographic monitoring. A Swan-Ganz catheter was floated through the right femoral vein into the pulmonary artery. A left thoracotomy was performed in the fifth intercostal space. The ribs were retracted, and the pericardium was incised parallel to the phrenic nerve, exposing the heart, the chest remaining open throughout the experiment. Pressure monitoring catheters were inserted into the left atrium and descending aorta. All pressures were measured by a Gould-Statham physiological pressure transducer interlinked with a Honeywell Simultrace-recorder model AR-6. The left anterior coronary artery (LAD) was identified proximal to its first diagonal branch. A No. 2 Dacron suture was passed around the LAD at this point, and the ends of the suture were introduced through a Silastic snare. A 14-gauge needle was introduced into the lumen of the left ventricle through the apex and directly connected to a pressure transducer.
Induction of Myocardial Ischemia (“Stunning“) Once the surgical preparation was completed, the animal’s condition was allowed to stabilize for 30 minutes, after which control hemodynamic status was measured. The LAD was then occluded by applying tension to the snare previously placed around the vessel. The anterolatera1 wall of the left ventricle rapidly became cyanotic and hypokinetic-dyskinetic. The animals tolerated the 15minute period of ischemic occlusion satisfactorily; however, at the time of reperfusion, ventricular fibrillation occurred in 8 of the 16 dogs, necessitating cardiac massage and attempted electrical defibrillation. In 5 animals, resuscitation was successfully accomplished; these dogs were included in the study (group 1, n = 2; group 2, n = 3). Resuscitation was unsuccessful in 3 dogs, which were excluded from the study.
Hernodynamic Monitoring The following variables were monitored: (1) cardiac output, (2) heart rate, (3) systemic arterial pressure (systolic, diastolic, and mean), (4) right atrial pressure (central venous pressure), (5) pulmonary artery pressure (systolic, diastolic, and mean), (6) left atrial pressure, (7) peak left ventricular pressure, (8)left ventricular end-diastolic pressure, and (9) positive and (10) negative time derivative of pressure (dP/dt). Stroke volume, systemic and pulmonary vascular resistances, and cardiac index were calculated. The mean cardiac output of three consecutive readings was obtained while ventilation was temporarily interrupted. Hemodynamic measurements were made before occlusion of the LAD, at the end of the 15-minute period of myocardial ischemia before release of the LAD snare, and at 10, 30, 60, 90, 120, and 180 minutes after reperfusion.
Measurement of Plasma Free T3 Plasma free T, was measured using a radioimmunoassay technique (Ciba Corning Diagnostics Corporation, Medfield, MA) at the following intervals: before LAD occlu-
NOVITZKY ET AL TRIIODOTHYRONINE AND STUNNED MYOCARDIUM
PPMOUML
r
0”
p.
C
‘
0 10
11
P < o.Ooo1
30
60
90
120
180
TIME IN MINUTES
Fig 1. Plasma free triiodothyronine (T,) levels in the placebo (solid line) and T,-treated (dotted line) dogs before, during, and after a 15-minute period of regional myocardial ischemia (C = control; time 0 indicates the time of myocardial reperfusion). Statistical differences are shown. The bars represent the standard error of the mean.
sion, at the end of the ischemic period before release of the LAD snare, and at 10, 60, 120, and 180 minutes after reperfusion.
T, Therapy (Group 2 Dogs Only) T, (or placebo in group 1) was administered as an initial loading dose of 0.2 Fg/kg 10 minutes after release of the LAD occlusion, followed by an intravenous bolus of the same dose at 30-minute intervals, for a total of six doses.
Statistical Analyses The animals were computer-randomized into group 1 (placebo: n = 7) or group 2 (T,: n = 6). The observer remained blinded throughout the experiment. The data were analyzed within each group by repeated measures analysis of variance and by t tests for unpaired data for group comparisons. A two-tail value of p less than 0.05 was considered significant.
Results Plasma FT, level decreased significantly by 40% (p < 0.04) in both groups during the ischemic period (Fig 1).In the placebo group (group l), a steady decline continued; by 180 minutes, FT, level had decreased a further 50%. From the time of the induction of ischemia (control) until the end of the experiment, the FT, level had decreased by 75% in this group (p < 0.0001). A similar pattern was observed in the T,-treated group (group 2) before the initiation of therapy, but thereafter, levels remained elevated (p < 0.0001) for the remainder of the experiment (see Fig 1).By 180 minutes after ischemia, the level of FT, was not significantly different from the control level. There were no significant changes in hematocrit in either group throughout the experiment, indicating that hemodilution did not play a role in the decrease in FT,. Function of the heart deteriorated significantly in both
12
NOVITZKY ET AL TRIIODOTHYRONINE AND STUNNED MYOCARDIUM
Ann Thorac Surg 1991;51:10-7
Table 1. Systemic Hemodynamics” Variable
Control
End of Ischemia
+10 min
+30 min
+60 min
+90 min
+120 min
+180 min
co PI T3
p value CI (mL/kg) PI T3
p value HR (beatdmin) PI T3
p value SV (mL) PI T3
p value BPS (mm Hg) PI T3
p value BPD (mm Hg) PI T3
p value BPM (mm Hg) PI T3
p value CVP (mm Hg) PI T3
p value SVR (Wood units) PI T3
p value
3.62(0.35) 2.73(0.27)d 3.44(0.45) 2.44(0.36)’
NS 176 (12.8) 175 (14.7)
NS 143 (4.2) 131 (10.1)
NS
NS 128 (12.5)d 130 (10.5)’
129 (7.9) 125 (10.0)
NS 107 (6.7) 98 (9.2)
168 (10.9) 188 (25.4)
151 (12.0)b 136 (9.0)d 203 (22.4) 204 (18.8)b
