Safety of prolonged ischemic arrest using hypothermic cardioplegia

J THoRAc CARDIOVASC SURG 79:705-712, 1980

Safety of prolonged ischemic arrest using hypothermic cardioplegia An evaluation was carried out of 200 consecutive patients undergoing elective cardiac operations. Hypothermic potassium (25 mEqlL) crystalloid cardioplegia was used for myocardial preservation during ischemic arrest. The purpose of this study was to determine if the length of cardioplegic arrest correlated with any parameter of myocardial injury. operative morbidity. or mortality. There were 154 patients undergoing coronary revascularization (CRG) and 46 valve replacement of repair (VRIR). The duration of cardioplegic arrest varied from 17 to 187 minutes. Eighteen patients (12%) in the CRG group and JJ (24%) in the VRIR group had arrest times of greater than 2 hours. In the CRG group. serum enzyme measurements, the incidence of inotropic support, perioperative myocardial infarction, and operative mortality rate did not correlate with the duration of ischemic arrest. In. the VRIR group, however. the CPK-MR level increased in proportion to the duration of ischemia; none of the other parameters changed significantly. Myocardial infarction was diagnosed in 3.7% of the coronary bypass (CRG) patients having cardioplegic arrest times of less than 120 minutes and in none of the 18 patients having longer arrest times. Three operative infarcts occurred in the VRIR group, two between 60 and 90 minutes of arrest and one between 120 and 150 minutes. The only clinical manifestation of prolonged cardioplegic arrest in the CRG patients was an increase in the incidence of postoperative arrhythmias. The results of this study support the safety of prolonged (3 hour) cardioplegic arrest under appropriate hypothermic conditions in the CRG group, but not necessarily in the VRIR group, where increased myocardial enzyme generation was noted. The proper reduction of myocardial temperature in the use of multidose cardioplegia is considered essential for optimal preservation.

Richard M. Engelman, M.D.,* John H. Rousou, M.D., Roger A. Vertrees, B.A., Charlene Rohrer, B.A., c.c.P., and Jackson Auvil, B.A., Springfield, Mass., and Farmington, Conn.

Potassium cardioplegia has been used with ever increasing frequency since initial clinical trials of the technique in 1974, through 1977. 1- 4 The ability of cardioplegia and hypothermia to provide complementary preservation has yielded results not achievable by either technique alone, and both together now represent an "optimal preservation technique". 5. 6 The best method of cardioplegic administration remains the From the Departments of Surgery, Baystate Medical Center, Springfield, Mass., and the University of Connecticut School of Medicine, Farmington, Conn. Presented at the World Congress of the International Cardiovascular Society, San Francisco, September, 1979. Supported in part by American Heart Association Grant-in-Aid 77606. *Chief of Cardiac Surgery, Baystate Medical Center. Received for publication Aug. 13, 1979. Accepted for publication Oct. 17, 1979. Address for reprints: Richard M. Engelman, M.D., Baystate Medical Center, 759 Chestnut SI., Springfield, Mass. 01107.

c.c.r.,

multidose approach, providing repeated cooling, acid washout, and renewal of electromechanical arrest. 5. 7 The upper limits of safety of cardioplegic arrest have never been clearly defined in a clinical setting, but experimentally 3 hours appears to be beyond the limit for satisfactory preservation.v 9 The present study was designed to evaluate prolonged cardioplegic arrest (2 to 3 hours) in a clinical setting. The goal of this review was to determine whether the duration of cardiop1egic arrest could be correlated with any parameter of myocardial injury, operative morbidity, or mortality.

Methods Two hundred consecutive patients operated upon electively for coronary and valvular disease at the Baystate Medical Center between February, 1978, and April, 1979, were reviewed retrospectively. For purposes of the study all patient data were entered into a computer and data retrieval was thereby expedited. The

0022-5223/801050705+08$00.8010 © 1980 The C. V. Mosby Co.

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706

Engelman et al.

patient categories were divided into two primary disease states, coronary heart disease and valvular disease. There were 154 patients undergoing coronary revascularization and 46, valve replacement or repair (nine with concomitant coronary bypass). The technique of hypothermic cardioplegic arrest was altered once during the duration of the study. The cardioplegic solution, made up in the pharmacy on the day of operation, consists of 700 cc Ringer's injection, 35 mEq sodium bicarbonate, 20 mEq potassium chloride, 12 cc 50% dextrose in water, 12.5 gm normal serum albumin, and q.s. 1 L with distilled water. This ultimate solution, while varying slightly with preparation, has 154 mEq/L sodium, 25 mEq/L potassium, 7 mgllOO ml calcium, 6 gm/L glucose, a pH of 7.5 to 7.6, and osmolality of 360 mOsm. The solution is cooled to near 4° C by immersion in crushed ice and is administered in a pressure-controlled manner at 50 to 75 torr into the aortic root immediately after aortic cross-clamping;'? During coronary revascularization a left ventricular vent was not employed, venting being carried out through the ascending aorta. 11 Routine left ventricular venting was performed in each valvular operation. Topical hypothermia with cold saline solution was employed and the myocardial temperature measured in the anterior and posterior portions of the left and right ventricles and septum. Sufficient cardioplegic solution was given to (1) arrest the heart and (2) bring the myocardial temperature to near 20° C in all areas of the heart. At the same time, perfusate temperature was maintained at 20° C or, if myocardial temperature was consistently elevated, 15° C. Initially, for the first 10 months of the study, 25° C was thought to be a satisfactory myocardial temperature. In the last 4 months of the study, the optimal desired temperature was lowered to 20° C. * The volume of cardioplegic solution initially administered to achieve this temperature was not predetermined and was occasionally greater than 1 L. Additional cardioplegic solution (usually 500 cc or more) and topical hypothermia were readministered every 15 to 30 minutes with the goal to maintain myocardial temperature at or below 20° C. No upper limit was set for the amount of cardioplegic solution to be administered, and more than 4 L. was occasionally given during prolonged arrest. The larger volumes of cardioplegic solutions have been used most recently since we have begun striving for a lower myocardial temperature. *The myocardial temperature was lowered to 20" C to avoid postoperative conduction disturbances. The incidence and significance of these disturbances are the subject of another report.

The Journal of Thoracic and Cardiovascular Surgery

Each patient was followed on an identical monitoring protocol to evaluate myocardial injury during and following operation. The electrocardiogram (ECG), technetium-99m pyrophosphate myocardial scan, levels of serum creatine phosphokinase (CPK) and creatine phosphokinase myocardial isoenzyme (CPK-MB), serum glutamic oxaloacetic transaminase (SGOT), and lactic dehydrogenase (LDH) were all assessed immediately prior to operation. Following operation, the ECG was monitored daily; a myocardial scan was carried out between 2 and 5 days; and all serum enzymes were measured at 4, 16, 40, and 64 hours during recovery. A record was kept of all inotropic and pressor agents administered and of all atrial and ventricular arrhythmias developing during the postoperative period. For purposes of providing comparative data, the upper limit of normal at our institution for CPK is 80 international units per liter (lUlL), for SGOT 45 lUlL, and for LDH 250 lUlL. The CPK-MB level is gauged on a basis of 0 to 4, as is the myocardial scan. Standard criteria are employed for evaluating the myocardial scan, with a positive finding of myocardial infarction being restricted to a 3 or 4+ uptake (meaning uptake equal to or greater than bone) with a focal or localized pattern. Because each patient had had a preoperative scan, a result was considered positive only in comparison with the control. A "definite" perioperative myocardial infarct was diagnosed when a patient had any three of the four following criteria: (I) ECG changes defined as the appearance and persistence of a new Q wave of at least 3 mm in depth and 30 msec in duration in patterns from two or more leads; (2) a postoperative myocardial scan of 3 or 4+; (3) a peak postoperative CPK-MB level of 3 or 4+; and (4) a composite peak postoperative serum enzyme elevation of CPK > 800, SGOT > 200, and LDH > 900. If one or more of these studies were lacking in any individual patient, fulfillment of the remaining criteria sufficed to diagnose a "definite" intraoperative or perioperative infarction. Atrial arrhythmias were defined as any supraventricular rhythm other than sinus in origin, regardless of rate. Ventricular arrhythmias were defined as frequent ventricular premature contractions, ventricular tachycardia, or fibrillation necessitating antiarrhythmic therapy. Only new postoperative arrhythmias (i.e., those not present immediately before operation) were recorded in this report. Operative death is recorded as any death within 30 days of operation or longer if the patient remained hospitalized because of a complication of the operation. All averaged numerical data are presented as the mean ± standard error of the mean

Volume 79 Number 5 May, 1980

Ischemic arrest with hypothermic cardioplegia

50

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Fig. 1. Incidence of ischemic arrest times in 154 patients having coronary revascularization (A) and 46 patients having valve replacement/ repair (B).

(SEM), and a statistical probability was measured by means of the Student's t test. Results The duration of cardioplegic arrest varied from 17 to 171 minutes in the coronary revascularization group (CBG) and from 22 to 187 minutes in the valve replacement/repair group (VR/R). The single patient with an arrest time at 187 minutes was considered for purposes of this study with the three other patients in the VR/R group having cardioplegic arrest for 150 to 180 minutes. For optimal data representation and com-

parison, each 30 minute interval of cardioplegic arrest from zero to 180 minutes was examined. The breakdown of the number of patients in each 30 minute arrest period, expressed as a percentage of the entire group, is illustrated in Fig. I. The duration of arrest in both the CBG and VR/R groups forms a bell-shaped curve with the usual length of arrest lasting between 60 and 120 minutes in both groups. Serum enzyme measurements. The peak postoperative CPK, CPK-MB, SGOT, and LDH (mean ± SEM) levels are listed for each arrest interval in Table I. There is no relationship apparent between the dura-

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Engelman et al.

Table I. Peak postoperative serum enzyme levels divided into 30 minute ischemic intervals Duration of arrest (min) 0-30

30-60

60-90

CPK (lUlL) CPK-MB (0-4) SOOT (lUlL) LDH (lUlL)

433 1.1 70 346

± 84 ±0.2 ± 7 ± 51

373 1.4 86 424

± ± ± ±

Coronary 48 0.2 18 35

CPK (IU/L) CPK-MB (0-4) SOOT (lUlL) LDH (lUlL)

605 2.7 143 675

± ± ± ±

350 2.5 102 654

± ± ± ±

Valve replacement/repair 182 614 ± 144 0.7 2.7 ± 0.4 142 ± 56 20 124 718 ± 124

31 0.4 22 70

revascularization 479 ± 39 1.8 ± 0.1 97 ± 12 469 ± 21

90-120

120-150

150-180

507 1.9 153 588

± ± ± ±

94 0.2 35 59

507 1.7 101 507

± ± ± ±

109 0.3 26 39

538 1.3 84 535

± ± ± ±

799 3.0 236 757

± ± ± ±

151 0.2 64 113

764 3.4 271 791

± ± ± ±

158 0.3 80 77

777 3.8 532 700

± 211 ± 0.4 ± 414 ± 128

140 0.7 15 108

Legend: CPK. Creatine phosphokinase. CPK-MB. Creatine phosphokinase myocardial isoenzyme. SaOT, Serum glutamic oxaloacetic transaminase. LDH, Lactic dehydrogenase.

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Fig. 2. The need for postoperative inotropic support is shown to be unassociated with prolongation of cardioplegic arrest beyond 120 minutes. There is a significant difference, however, between the needfor support following coronary bypass and valve replacement/repair. tion of ischemic arrest and any of the four serum enzyme levels in the CBG group, In the VR/R group, on the other hand, the CPK-MB and SGOT levels appear to rise with prolongation of arrest. The elevation in SGOT is not statistically significant, but there is a significant increase in the CPK-MB level with longer arrest intervals (correlation coefficient = 0,92, P < 0.05), This increase is clearly shown by a comparison of arrest times $120 minutes and> 120 minutes (Table II), Again, the apparent difference in mean SGOT levels in the VR/R group is not significant because of a large standard error, whereas the CPK-MB level is clearly elevated at the longer arrest periods. In each series of patients there was significantly less enzyme release during coronary revascularization (CBG) than during valve replacement/repair (VR/R), Inotropic support. A review of the incidence of inotropic and pressor postoperative support correlated

with the duration of cardioplegic arrest demonstrates in each group only a small, insignificant increase with prolongation of arrest (Fig, 2). However, there is a significant difference when CBG is compared with VR/R, The percent of patients requiring inotropic and/or pressor agents more than doubles in each time period from CBG to VR/R,

Intraoperative myocardial infarction and operative death (Table III). Results were available to evaluate all four diagnostic criteria of infarction in 148 of the 154 CBG patients (96%) and in 40 of the 46 VR/R patients (87%). Those patients not having all four criteria were generally missing a preoperative or postoperative myocardial scan or else the scan was uninterpretable. In each of these patients the diagnosis then was made when the remaining criteria were indicative of infarction, There were three deaths in the CBG group (1.9% overall mortality rate), Two patients in the 90 to 120 minute arrest group died of intraoperative infarction, and a third patient, an 81-year-old woman in the 120 to 150 minute group, died suddenly at home 1 week after discharge (16 days after operation). She had not had a perioperative infarction, An additional three surviving patients fulfilled the diagnostic criteria for perioperative infarction. Two were in the 60 to 90 minute group and the third, the 90 to 120 minute group, Thus 3,7% of the 136 patients having arrest times of 2 hours or less had an intraoperative infarction, whereas none of the 18 patients with longer arrest times had an infarction. In the VR/R group, as in the CBG patients, there was no significant correlation between either operative mortality or infarction and the duration of cardioplegic arrest. Two deaths occurred in the 90 to 120 minute category (one from neurologic injury and one from

Volume 79

Ischemic arrest with hypothermic cardioplegia

Number 5 May. 1980

Table II. Peak postoperative serum enzyme levels divided at

~

2 hours or > 2 hours of arrest

Coronary revascularization

I

'" 120 min No. of patients CPK (lUlL) CPK-MB (0-4) SGOT (lUlL) LDH (lUlL)

514 1.6 97 513

36 0.1 14 25

Valve replacement/repair

> 120 min

136 486 ::!: 1.7 ::!: 114::!: 500 ::!:

709

> 120 min

'" 120 min

18 ::!: 92 ::!: 0.3 ::!: 21 ::!: 37

684 2.9 194 740

35 ::!: 87 ::!: 0.2* ::!: 41 ::!: 93

768 3.5 366 758

II ::!: ::!: ::!: ::!:

114 0.2* 140 62

For legend see Table I. 'Difference significant. p < 0.05.

Table III. Incidence of infarction and operative death divided at


Coronary revascularization '" 120 min No. of patients Perioperative infarction (%) Operative mortality (%)

I

136 3.7 1.5

hemorrhage), and one death occurred in the 60 to 90 minute group from prolonged congestive heart failure 38 days after operation in a patient who had an intraoperative infarction. One death in a woman with a porcine mitral valve xenograft resulted from hypertensive ventricular rupture (120 to 150 minute arrest group). There was evidence of intraoperative infarction in only one of these four patients. In contrast, two patients, both surviving, had infarctions, one after 60 to 90 minutes of arrest and the other after a 120 to 150 minute arrest period. Thus, while the total operative mortality rate was 8.7%, the incidence of infarction was 6.5%. The comparison between patients with cardioplegic arrest < 120 and > 120 minutes (Table III) shows equal mortality rates but a slightly higher perioperative infarction rate at the longer ischemic period. This difference is not significant. Postoperative arrhythmias. The incidence of new atrial and/or ventricular arrhythmias was found to be very high in this study, 44% of CBG and 72% of VR/R patients. When examined in conjunction with the duration of cardioplegic arrest (Fig. 3), there is a good correlation (r = 0.92, P < 0.05) between the incidence of arrhythmia and the duration of ischemic arrest in the CBG patients, but there is no correlation in the VR/R patients. Discussion Some information regarding the safe duration of cardioplegic arrest in a clinical setting has been pub-

> 120 min 18

o 5.6

2 hours or > 2 hours of arrest Valve replacementlrepair '" 120 min 35 5.7 8.6

I

> 120 min II 9.1 9.1

lished, but much of this has been anecdotal and has not summarized recent data using "optimal" techniques. One of the earliest reports, by Roe and associates, t described survival after the use of single-dose potassium cardioplegia for more than 2 hours of arrest. Another review, by Tyers and associates, 2 discussed using continuous potassium cardioplegia and described 2 hours as the upper limit of safety. Conti and associates," using multidose cold potassium cardioplegia, indicated that on the basis of this experience 2 hours is an acceptable duration of ischemic arrest. The upper limit of acceptability was not specifically addressed. Our own technique is that of multidose cardioplegia. In our experimental work, as well as that of others, this approach has been found to be superior to either single-dose or continuous cardioplegia. 5-7 Using multidose hypothermic potassium cardioplegia, our laboratory has compared 2 and 3 hour arrest periods in the pig heart model. 8. 9. 12 Two hours of arrest followed by 30 minutes of normothermic reperfusion allow myocardial contractility and compliance to be equal to prearrest levels.P Myocardial adenosine triphosphate (ATP) falls II % (a statistically insignificant decrease), whereas creatine phosphate (CP) is actually increased by 24% above the control level. 9 This degree of myocardial preservation during 2 hours of arrest with hypothermic cardioplegia is considered to be "optimal. " However, extending the duration of arrest to 3 hours followed by a 30 minute reperfusion period results in a significant deterioration of function

7 10

The Journal of Thoracic and Cardiovascular Surgery

Engelman et al.

100 90

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Fig. 3. The incidence of postoperative arrhythmias is seen to increase with prolongation of cardioplegicarrest in the coronary revascularization group (A) while remaining unaffected by the duration of arrest in the valve replacement/repair group (B) .

(myocardial contractility depressed 51 %, compliance depressed 34%)8 and a significant decrease in ATP (24%) and CP (20%).9 Thus a 3 hour arrest is clearly beyond the limit of "optimal" preservation in the pig heart model. It is possible, albeit untested, that survival could be attained after 3 hours of arrest in this animal model, but there certainly would be a deterioration of function and possibly even infarction. In the clinical setting, as defined by the present study, there was no evidence of myocardial injury associated with arrest periods of up to 180 minutes in the

CBG patient. There was no increase in serum enzyme generation, no increased incidence of recognizable perioperative myocardial infarction, and only a minimal increase in the utilization of either inotropic or pressor agents. The only feature of the patient's course which in any way correlated with prolongation of arrest was the incidence of arrhythmia development. In the VR/R patient, prolongation of arrest was associated with more CPK-MB generation (significant) and a slightly higher incidence of perioperative myocardial infarction (not significant). It may be that, particularly

Volume 79 Number 5

Ischemic arrest with hypothermic cardioplegia

7I 1

May, 1980

in the patient with hypertrophic valvular disease, prolonged (3 hour) cardioplegic arrest at hypothermic levels is not commensurate with optimal preservation. The results of this study would support, but not prove, this contention. The frequency with which arrhythmias developed in our patients (44% in CBO and 72% VR/R) is consistent with other published reports. 13 - 15 Smith and associates'" documented arrhythmias in 74% of valve replacements, and Johnson and associates" presented data demonstrating a 47% to 60% incidence of arrhythmias in coronary revascularization depending upon the use of prophylactic digitalization. More recently, Boudoulas and associates" were able to reduce the incidence of supraventricular arrhythmias from 30% to 5% in patients undergoing coronary revascularization by simply not discontinuing propranolol following operation. The most likely explanation for the frequency of arrhythmias after cardiac operations is related to the stress of the operation. It has been shown that the plasma catecholamine level is increased dramatically during major surgical procedures!" (e.g., cardiac"). In addition, in the patient undergoing coronary revascularization, there is the added feature of chronic beta receptor blockade with propranolol, which neary all patients are receiving. Abrupt discontinuation of this medication leads to (1) a hypersensitivity of beta adrenergic receptors'? and (2) increased levels of triiodothyronine " (T 3 ) . Both of these responses can predispose to tachyarrhythmias. Indeed, in most cardiac surgical centers at present, including our own, propranolol is discontinued abruptly at the time of operation. It has been recommended that this practice be abandoned, 15 but, largely because after operation there is no longer a fear of acute myocardial infarction with propranolol withdrawal, most surgeons are reluctant to continue to employ a negative inotropic agent. This review also provided an opportunity to compare the effects of operative intervention on a sequential group of patients having coronary revascularization and valve replacement or repair. The data, particularly serum enzyme generation (CPK, CPK-MB, SOOT, and LDH), and the need for inotropic or pressor support (Tables II and III), show a significant difference between the two groups of patients. Specifically, there is less enzyme generation in the postoperative CBO patient than in the VR/R patient, a finding in agreement with that of Tyers and associates"; the need for inotropic or pressor agents is significantly lower; and the incidence of infarction is less. The explanation for these findings probably lies in the fact that there is

greater preoperative intrinsic myocardial dysfunction in patients with valvular disease than in the CBO group, and the myocardial hypertrophy of valvular disease is prone to subendocardial ischemic injury. Finally, the necessity to perform intracardiac operations in patients with valvular disease may simply be associated with more enzyme generation than is manipulation of the nonvented heart receiving a coronary bypass graft. REFERENCES Roe BB, Hutchinson NH, Ullyot OJ, Smith DL: Myocardial protection with cold, ischemic, potassium-induced cardioplegia. J THoRAc CARDIOVASC SURG 73:366-374, 1977 2 Tyers GFO, Manley NJ, Williams EH, Wine CR, Williams DR, Kurusz M: Preliminary clinical experience with isotonic hypothermic potassium arrest. J THoRAc CARDIOVASC SURG 74:674-681, 1977 3 Molina JE, Feiber W, Sisk A, Polen T, Collins B: Cardioplegia without fibrillation or defibrillation in cardiac surgery. Surgery 81:619-626, 1977 4 Conti VR, Bertranou EG, Blackstone EH, Kirklin JW, Digerness SB: Cold cardioplegia versus hypothermia for myocardial protection. J THORAC CARDIOVASC SURG 76:577-589, 1978 5 Engelman RM, Levitsky S, O'Donoghue MJ, Auvil J: Cardioplegia and myocardial preservation during cardiopulmonary bypass. Circulation 58:Suppl 1: 107-113, 1978 6 Engelman RM, O'Donoghue MJ, Auvil J: Techniques for myocardial preservation during ischemic arrest. Surg Forum 28:229-231, 1977 7 Nelson RL, Fey KH, Follette DM, Livesay 11, DeLand EC, Maloney JU Jr, Buckberg GD: Intermittent infusion of cardioplegic solution during aortic cross-clamping. Surg Forum 27:241-243, 1976 8 O'Donoghue MJ, Engelman RM, Auvil J: Multidose cardioplegia for myocardial preservation during prolonged ischemic arrest. Surg Forum 29:274-276, 1978 9 Engelman RM, Rousou JH, Longo F, Auvil J, Vertrees R: The time course of myocardial high energy phosphate degradation during cardioplegic arrest. Surgery 86: 138147, 1979 10 Vertrees RA, Auvil J, Rousou JH, Engelman RM: A technique of myocardial preservation perfusion. Ann Thorac Surg 28:601-602, 1980 II Engelman RM, Rousou JH: Left ventricular venting during cardioplegic arrest. Ann Thorac Surg 2 8:603, 1980 12 Engelman RM, Auvil J, O'Donoghue MJ, Levitsky S: The significance of multidose cardioplegia in myocardial preservation during ischemic arrest. J THORAC CARDIOVASC SURG 75:555-563, 1978 13 Smith R, Grossman W, Johnson L, Segal H, Collins J, Dalen J: Arrhythmias following cardiac valve replacement. Circulation 45: 1018-1023, 1972

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14 Johnson LW, Dickstein RA, Fruehan CT, Kane P, Potts JL, Smulyan H, Webb WR, Eich RH: Prophylactic digitalization for coronary artery bypass surgery. Circulation 53:819-822, 1976 15 Boudoulas H, Snyder GL, Lewis RP, Kates RE, Karayannacos PE, Vasko JS: Safety and rationale for con-' tinuation of propranolol therapy during coronary bypass operation. Ann Thorac Surg 26:222-227, 1978 16 Halter lB, Pflug AE, Porte D Jr: Mechanism of plasma catecholamine increases during surgical stress in man. J Clin Endocrinol Metab 45:936-944, 1977

The Journal of Thoracic and Cardiovascular Surgery

17 Boudoulas H, Lewis RP, Kates RE, Dalamangas G: Hypersensitivity to adrenergic stimulation after propranolol withdrawal in normal subjects, Ann Intern Med 87:433436, 1977 18 Kristensen BD, Steiness E, Weeke JW: Propranolol withdrawal and thyroid hormones in patients with essential hypertension. Clin Pharmacol Therap 23:624-629, 1978

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