[CANCER RESEARCH 49, 4423-4426, August 15, 1989] Inotropic and Vasoactive Drug Treatment of Interleukin2 InducedHypotension in Sheep Stuart Zeilender, Donald Davis, R. Paul Fairman, and Frederick L. Glauser1
Pulmonary Division, Medical College of VirginiajMcGuire Veterans Administration Hospitals, Richmond, Virginia 23298-0050
ABSTRACT 7-12), is unclear. Treatment of the hypotension remains em piric and consists of administering inotropic and vasoactive The side effects associated with recombinant interleukin 2 administra drugs such as dopamine and/or phenylephrine with i.v. fluids tion, including systemic hypotension and a vascular leak syndrome, may and/or decreasing or discontinuing rIL-2 administration (3, 7- limit therapy before reaching maximum doses of this innovative and 12). promising treatment for cancer. In an attempt to reverse this hypotension We have previously shown that in a sheep model (16-18) in without decreasing cardiac output and systemic oxygen delivery (/><>.). which 9 x IO6 units/kg total dose of rIL-2 (without other we studied several inotropic agents, dobutamine, dopaminc, amrinone, CaCl2, and a pure a-adrenergic vasoconstrictor, methoxamine. These concomitant medication) is administered continuously over 3 were administered singly or in combination to sheep with chronically days, there is a predictable fall in SVR, increase in cardiac implanted arterial and pulmonary artery catheters following 24 h of 3 x output, and decrease in SBP beginning at 24 h which parallels 10s units/kg recombinant interleukin 2. Compared to baseline values, 24 the findings in humans. The present study was designed to h of recombinant interleukin 2 infusion caused a significant increase in identify a drug regimen that could be administered to reverse cardiac output from 4.4 ±0.9 (SD) to 5.0 ±0.6 liters/min, a significant these changes without adversely affecting cardiac output, oxy fall in systemic vascular resistance (SVR) from 21 ±7tol5±5 units, gen delivery (D0 ), oxygen consumption (Pb2), oxygen extrac a decrease in mean systemic blood pressure (SBP) from 88 ±9 to 78 ± tion, or LVSW.2 6 mm Hg, and a decrease in left ventricular stroke work from 51.5 ±8 to 49 ±6gram meters (/' < 0.05) without any change in /)<>,.Dopamine, dobutamine, and CaCl2 returned SBP to baseline values by increasing MATERIALS AND METHODS cardiac output without increasing SVR. Methoxamine increased SBP by increasing SVR, but cardiac output decreased significantly. A combina Pilot Studies tion of 12 /¿g/kg/minofdopamine and 2 to 3 mg of methoxamine infused The dose of each inotropic and/or vasoactive medication (see below) over 15 min resulted in an increase in SBP, cardiac output, and SVR to baseline values while maintaining £>,,,andoxygen consumption ((•'<>,).was determined in normal sheep by performing dose-response curves beginning with the lowest dose recommended for humans (19, 20). The We suggest that this latter combination would be appropriate for clinical final dose chosen for the inotropic agents and methoxamine was that use since it returns physiological parameters to normal. which increased cardiac output and SVR at least 15%, respectively, over baseline values. Amrinone in dosages varying from 10 to 40 Mg/ INTRODUCTION kg/min had no effect on baseline cardiac output. An arbitrary dose of 20 Mg/kg/min was chosen to determine if amrinone was effective during Administration i.v. of rIL-22 with or without so called lym- rIL-2 infusion. phokine activated killer cells is a new treatment for patients To determine if the sequence of administration of various inotropic/ with far advanced cancer (1-8). Early results have been encour vasoactive agents and combinations (see below) affected hemodynamic aging. Some series report up to a 50% partial or complete responses (see below), the following sequence of drugs was administered remission rate (1-9). However, rIL-2 infusion is associated with over a 3-day period in one sheep: Day 1 (see below for dosage), dopamine and methoxamine, methoxamine, CaCl2, amrinone, dobuta multiple side effects, including systemic hypotension and a mine, and dopamine. Between the administration of each drug all vascular leak syndrome (1-15), which often necessitate decreas parameters were allowed to return to baseline values before the next ing or discontinuing therapy. Originally, the systemic hypoten drug was administered. Day 2, amrinone, CaCl2, dopamine, methox sion was thought to be due to intravascular volume depletion amine, dobutamine, and dopamine plus methoxamine. On Day 3 the from the vascular leak syndrome. However, in recent clinical order of drugs given on Day 1 was reversed. Evaluation of these data reports, a decrease in SVR, SBP, and LVSW and an increase revealed no more than a 7% variation between sequences for SBP, in cardiac output have been found within 2 h to 5 days in PAP, RAP, PWP, cardiac output, SVR, LVSW, RVSW, arterial blood patients receiving bolus infusions of rIL-2 with or without gases, and arterial oxygen saturation. However, the Day 1 sequence concomitant administration of lymphokine activated killer cells took 6.5 h to complete; Day 2, 5.5 h; and Day 3, 4.5 h. We thus used (12-15). Whether these changes are due to rIL-2 directly, the Day 3 sequence since these experiments were the shortest to release of vasoactive cytokines by rIL-2, or cofactors such as complete. administration of such drugs as acetaminophen or indometha- Experimental Design cin for fever and chills, ranitidine for prophylaxis against gas Ten sheep (Sheep 1-10) weighing 30-35 kg were lightly anesthetized trointestinal bleeding, hydroxyzine for pruritus, and parenteral meperidine for shaking chills, which most patients receive (3, with 30 mg/kg Surital i.v. A balloon tipped flow directed catheter was inserted into the pulmonary artery under pressure monitoring. A carotid Received 11/9/88; revised 4/17/89; accepted 5/18/89. artery catheter was inserted percutaneously. The animal was returned The costs of publication of this article were defrayed in part by the payment to its cage and allowed to awaken. The next day the animal was placed of page charges. This article must therefore be hereby marked advertisement in in a body sling in a special cage and allowed free access to food and accordance with 18 U.S.C. Section 1734 solely to indicate this fact. water. Baseline measurements (termed "baseline control") of SBP, ' To whom requests for reprints should be addressed, at Medical College of Virginia, Pulmonary Division. 1200 E. Broad St., Box 50, Richmond, VA 23298- PAP, RAP, PWP, cardiac output (in triplicate), HR, arterial blood 0050. gases, and arterial O2 saturation were obtained twice 1 h apart and the 2The abbreviations used are: rIL-2, recombinant interleukin 2; SVR, systemic values were averaged. From these data SVR, LVSW, RVSW, and Z>02 vascular resistance; SBP, mean systemic blood pressure; LVSW, left ventricular were determined (see below). rIL-2 (3 x IO5 units/kg) was infused stroke work; PAP, mean pulmonary artery pressure; RAP, right atrial pressure; PWP, pulmonary wedge pressure; RVSW, right ventricular stroke work; HR, through the proximal port of the Swan Ganz catheter over 24 h. The heart rate; g.m., gram meters. above parameters were then remeasured twice 1 h apart. The average 4423
Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1989 American Association for Cancer Research. INOTROPIC AND VASOACT1VE DRUG TREATMENT OF IL-2 INDUCED HYPOTENSION of these two is reported as "baseline rIL-2." The rIL-2 infusion was dobutamine increased PAP significantly (P < 0.05). Dopamine continued and the following drugs were administered i.v. in the follow and dobutamine increased HR significantly compared to base ing dosage and sequence. line control and baseline rIL-2 values. Methoxamine increased Inotropic Agent, (a) Ten ml of 10% CaCl2 were infused over 15 min SBP and SVR significantly and caused a significant fall in followed by measurement of the above parameters. CaCl2 was chosen cardiac output compared to baseline control and baseline rlL- because raising extracellular levels may cause an influx of calcium into cells. Intracellular calcium is important in modulating myocardial 2 values. In contrast, cardiac output was maintained at baseline rIL-2 levels, and SVR, SBP, and LVSW were increased signif contractility and peripheral arterial vasoconstriction; (¿>)dopamine,12 Mfi/kg/min over IS min, /3-adrenergic and dopaminergic agent; (c) icantly when dopamine and methoxamine were administered attirinone, 20 /¿g/kg/minover IS min, phosphodiesterase inhibitor; (d) together. dobutamine, 15 ¿ig/kg/minover 15 min, /3-adrenergic agent. Arterial Blood Gases and D
DISCUSSION SBP - RAP SVR = — = Units In this sheep model, i.v. administration of rIL-2 is associated Do2 = CO x CaO2 = mi/min with a fall in SVR, SBP, and LVSW and a concomitant increase in cardiac output. Although the sequence of these physiological CaO2 = (Hb x % arterial O2 saturation) + 0.003 PaO2 changes is not known, we postulate that the decreased SVR is Fo2 = CO x (CaO2 - CvO2) a primary event. The reduction of afterload permits an increase CvO2 = (Hb x % mixed venous O2 saturation) + 0.003 PO2 in cardiac output. However, this increase is not enough to maintain SBP and systemic hypotension results. These findings O2 extraction = K02/A>2= % are similar to those reported in patients receiving rIL-2 and in LVSW = CO/HR x systolic BP - PWP x 0.0136 = g.m septic patients (9-13, 15). Even though the cardiac output is RVSW = CO/HR x systolic PAP - RAP x 0.0136 = g.m high in septic patients, myocardial depression is present since the left ventricular ejection fraction falls, and heart rate and in which CO is cardiac output, CaO2 is content of oxygen in the arterial left ventricular end diastolic volumes increase. We feel that our blood, Hb is hemoglobin, CvO2 is content of oxygen in mixed venous model also displays some degree of myocardial depression since blood, BP is blood pressure, and HR is heart rate. the heart rate increases as the cardiac output rises and LVSW Vascular pressures were recorded on a Hewlett Packard physiological falls significantly (Table 1) after 24 h of rIL-2 infusion. recorder. Thermodilution cardiac output was performed using a Lyons Whether rIL-2 itself or some mediator(s) causes the periph cardiac output machine. Arterial blood gases and saturation were determined on an IL blood gas analyzer. eral vasodilation and myocardial depression is not known. rlL 2 increases the developed isometric tension of the isolated rat Statistics right atria after coincubation with either arachidonic acid or calcium ionophore 23187 (21). In contrast, in the isolated Analysis of variance using a Stat Pack program on an Apple desk top computer was used. When a significant difference was found a perfused working rat heart there was no change in cardiac paired t test was used. Values are reported as means ±SD. Baseline output, coronary flow, or cellular morphology at the end of a rIL-2 values were compared to baseline control values. All treatment 1-h infusion of 1,100, or 1000 units/ml of IL-2 (22). Addition values are compared to baseline rIL-2 values. P < 0.05 was considered ally, rIL-2 does not directly alter endothelial function as evi significant. denced by the application of rIL-2 to endothelial cell mono- layers. Albumin flux as a reflection of increased permeability does not increase (23). RESULTS It is possible that the myocardial depression and peripheral Induced and Derived Hemodynamics (Sheep 1-10) (Table 1). vasodilation may be due to rIL-2 induced release of vasoactive After 24 h of rIL-2 infusion, there was a significant fall in SVR cytokines such as tumor necrosis factor and/or interleukin 1. It and SBP and a significant increase in cardiac output and HR is known that endotoxin administration is associated with in compared to baseline control values (P < 0.05). There was a creased blood levels of tumor necrosis factor which could me significant fall in LVSW, but not RVSW, after 24 h of rIL-2 diate the cardiac output increase and SBP and SVR decrease infusion compared to baseline control values. (24-28). Additionally, tumor necrosis factor infusion leads to CaCl?, dopamine, and dobutamine all increased SBP and many of the hemodynamic changes found with sepsis, endotox- cardiac output to baseline control values. Amrinone had no emia, and rIL-2 infusion (24,25). The "final" common pathway effect. SVR was unaffected by any of these agents and only for the depressed myocardial function and peripheral vasodila- 4424
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Table 1 rIL-2 induced and derived hemodynamic changes (Sheep 1-10): response to inotropic and vasoactive agents output Hg)88 (liters/min)4.4 Hg)14.416.617.024.016.41817.619.62.51.565.2"3.13.62.22.1PWP(mmHg)7.6 BaselinecontrolBaseline +9°78 ±0.95.0 ±715 ±.88.4 1.110.9 rIL-2DopaminerDobutamineAmrinoneCaCl2MethoxamineMethoxamine+6*91 ±0.6*6.0 ±5*15 ±.87.4 29.8 ±4"92 +27.0 +514 ±.811.2 3.518.3 ±13''77 ±Ia5.0 ±616 ±6.07.8 3.6"9.6 +1187 ±I6.1 ±614 ±.38.8 1.513.7 +IS"104+ ±0.83.0 ±530+ ±.313.6 48.1 \1a100+ +0.5"5.0 13"25 ±4.1*9.8 +113.6+ + dopamineSBP(mm 10"Cardiac ±2SVR(units)21 ±5"PAP(mm ±1.3HR(beats/min)1041251562861411331061152018*2246"7.4182313"LVSW51.549553643.462.446.26586'67"91277"RVSW(g-ni)9.81.7 °Mean ±SD. * P < 0.05 compared to baseline control. c Dopamine, 12 jig/kg/min for 15 min; dobutamine, 15 ^g/kg/min for 15 min; amrinone, 20 ng/kg/min for 15 min; methoxamine, 5 mg over 15 min; dopamine, 12 iig/kg/min, plus methoxamine, 2-3 mg over 15 min. d P < 0.05 compared to baseline IL-2.
Table 2 rIL-2 induced changes in PaO? and oxygen delivery (D0¡)(Sheep 1-10): drug (methoxamine) alone. At the dose used (3 to 5 mg infused response to inotropic and vasoactive agents over 15 min) this drug significantly increased SVR. However, this increase in afterload was associated with a marked fall in CO and a decrease in DQl (Table 2), both clinically undesirable BaselinecontrolBaseline ±3°105 rIL-2DopamineDobutamineAmrinoneCaCl2MethoxamineMethoxamine±4105 events. ±5102 A more "physiological" approach to reverse the rIL-2 induced ±3104±5101 hypotension might be to combine an inotropic drug, such as ±6101 dopamine, with low doses of an a-adrenergic vasoconstrictor ±7103 thus maintaining A,, while simultaneously increasing SVR and + dopaminePa02(torr)103 + 5Oo2(ml/min)610697868980728615420700128139167250*16714071*140 °Mean ±SD. SBP. This proved true when using the combination of dopamine * P< 0.05 compared to baseline IL-2. and methoxamine. In one additional study (data not shown) this combination of drugs given over 3 days was not associated Table 3 rIL-2 induced changes in D0¡,V0„andoxygen extraction (O2 Ext): with tachyphylaxis. In additional studies this combination of Sheep 11-15 methoxamine and dopamine had no adverse effects on V0l Ext(%)16.3 (Table 3). O2 extraction did fall from baseline values with rlL- (ml/min)771 (ml/min)126+ 2 and dopamine/methoxamine administration, but since the Baseline control ±86" 18 + 2.2 Z>o2tended to increase, overall Vai remained stable. Thus, we Baseline rIL-2 883 + 118 116 ±24 12.4 ±0.5* Methoxamine + dopamineOo2 925 ±210Voi 113 ±30O2 12.2 ±2.5 could not find any deleterious effects of the dopamine and °Mean ±SD. methoxamine combination on A>2or Vo2. * P < 0.05 compared to baseline control. Although the combination of methoxamine and dopamine did not have an adverse effect on O0¡or KO!,it is possible that tion may be a fall in intracellular calcium mediated by either this drug combination could be associated with altered or de increases in cyclic GMP and/or decreases in cyclic AMP (29, creased peripheral tissue perfusion. One sign of inadequate 30). perfusion would be the development of an anióngap metabolic Regardless of the etiology of the hemodynamics changes, the acidosis from lactic acidosis. Calculation of the anióngap in all clinician is faced with the problem of maintaining SBP, cardiac our groups revealed no increase. In addition, the combination output, Fo2, and A>2in patients receiving rIL-2. For this reason of methoxamine and dopamine at the doses we used could lead we administered a variety of inotropic and vasoactive substances to selective decreases in renal perfusion. We did not evaluate singly and in combination ("Results," tables). As our results this possibility directly, but if this combination is used in indicate, all of the inotropic agents, except for amrinone, in patients, total intake and outputs, urine electrolytes, and urine creased SBP to baseline control levels (Table 1). However, at osmolality should be checked at least daily to be sure that renal least in sheep, dobutamine is associated with a marked increase perfusion is adequate. in heart rate, 286 ±46 beats/min. This degree of tachycardia One would expect PWP to fall if a vascular leak were present, [not found in a dog study in which this drug was used to reverse but in our study PWP remained stable during rIL-2 infusion. the hemodynamic findings associated with endotoxemia (31)] However, our animals received 1 liter of i.v. fluids/day in could be associated with decreased diastolic filling which may addition to ad libitum p.o. intake and this may have maintained translate into less blood flow to an already dysfunctional heart. intravascular volume. Even if intravascular volume had de Thus, if this degree of tachycardia occurs in humans receiving creased, some degree of myocardial dysfunction may have ele rIL-2 it would constitute a contraindication to the use of vated PWP to the normal range. There is a dearth of data dobutamine. Although dopamine causes an approximate 20% regarding PWP measurements in humans receiving rIL-2. In increase in heart rate (156 ±22beats/min), this rate is probably one case example (9) PWP rose significantly during rIL-2 clinically tolerable (Table 1). Although CaCl2 was used in this infusion, but the volume of administered fluid was not given. study, it is potentially more dangerous than the other drugs In another study Silverman et al. (11) reported a fall in PWP because of its multiplicity of effects and its tendency to cause from 6 ±2.9 to 3.4 ±2.6 mm Hg (P < 0.001). The 9 patients conduction abnormalities and arrhythmias (32). Thus, if one in this study received 30 Mg/kg of IL-2 as a bolus i.v. infusion were to use a single inotropic drug, dopamine would probably every 8 h for 5 days. Following i.v. fluid administration the be the drug of choice. PWP increased to 8.3 ±4.8 mm Hg (P< 0.001). Thus, findings However, none of the inotropic agents reversed the low SVR in humans are variable and may depend not only upon the and, in fact, most caused a further small, nonsignificant fall degree and amount of myocardial depression present, the pres (Table 1). For this reason we administered a pure a-adrenergic ence of a vascular leak, the dose and duration of rIL-2 therapy 4425
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F. P., Carrasquillo, J. A., Shelhamer, J. H., Parrillo, J. E., and Rosenberg, but also upon the amount and timing of fluid replacement. S. Cardio-respiratory effects of immunotherapy with interleukin-2. J. Clin. In conclusion, our results suggest that the rIL-2 induced Oncol., 7:7-20, 1989. decreased SVR and SBP can be overcome by a trial of medium 14. Herberman, R. B. lnterleukin-2 therapy of human cancer: potential benefits dose dopamine and low dose methoxamine (2-3 mg over 15 vs toxicity. J. Clin. Oncol., 7:1-4, 1989. 15. Klausner, J. M., Morel, N., Patterson, I. S., Kobzìk,L., Valeri, C. R., min) without impairing CO, £>o2,orVo2. Eberlein, T. J., Sheprow, D., and Hechtman, H. B. The rapid induction by interleukin-2 of pulmonary microvascular permeability. Ann. Surg., 209: 119-128, 1989. REFERENCES 16. Glauser, F. L., DeBIois, G. G.. Bechard, D. E., Merchant, R. E.. Grant, A. J., Fowler, A. A., and Fairman, R. P. 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Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 1989 American Association for Cancer Research. Inotropic and Vasoactive Drug Treatment of Interleukin 2 Induced Hypotension in Sheep
Stuart Zeilender, Donald Davis, R. Paul Fairman, et al.
Cancer Res 1989;49:4423-4426.
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