Kidney International, Vol. 51(1997), pp. 1867-1875
Ritodrine- and terbutaline-induced hypokalemia in preterm labor: Mechanisms and consequences
GREGORY L. BRADEN, PAUL T. VON OEYEN, MICHAEL J. GERMAIN, DAVID J. WATSON, and BURRITI' L. HG
Departments of Medicine and Obstetrics and Gynecology, Baystate Medical Center, Springfield, and Tufts University School of Medicine, Boston, Massachusetts, USA
Ritodrine- and terbutaline-induced hypokalemia in preterm labor: hypokalemia in these women have not been completely elucidated Mechanisms and consequences. The effects of ritodrine and terbutaline [4—8]. Indeed, B2-adrenergic stimulation has the potential to on potassium homeostasis, renal function, and cardiac rhythm were assessed in women treated with these drugs for preterm labor. Timed affect potassium homeostasis by numerous mechanisms. blood and urine samples were obtained for two hours before and during Ritodrine or terbutaline therapy may increase pancreatic insu- six hours of intravenous ritodrine (N =5)and terbutaline (N =5) lin release either due to direct B2-receptor stimulation of pancre- administered in pharmacologically equivalent doses. No differences were atic islet cells [9] or due to increases in blood glucose resulting found in any parameters affecting potassium homeostasis or renal function between these drugs. A decrease in mean plasma potassium of 0.9from B-adrenergic-mediated glycogenolysis and gluconeogenesis mEq/liter occurred after 30 minutes of drug infusion (4.2 0.1 to 3.3 in the liver [10, 11]. Increases in plasma insulin could stimulate 0.1 mEq/liter, P < 0.005) before any significant changes in plasma glucose cellular potassium uptake [12]. Changes in blood glucose and (75.0 4.7 to 93.7 6.1 mg/dl, P =NS)or plasma insulin (12.4 6.0 to insulin during ritodrine or terbutaline have been the only factors 28.45.1 mU/mi, P =NS).The mean plasma potassium after four hours of drug infusion was 2.5 0.1 mEq/liter. Plasma insulin rose to a level studied to explain the profound hypokalemia produced by these known to induce cellular potassium uptake (39.2 7.7 mU/mi) after 60 drugs. However, 13-adrenergic stimulation in muscle cells may minutes of drug therapy and remained at this level for four hours.directly induce cellular potassium uptake by producing increases Hyperlactatemia occurred at four hours (4.7 0.8 mmol/liter) and the in intracellular cAMP which increase the activity of the Na,K- plasma lactate/pyruvate ratio increased in a 10:1 ratio. Both drugsATPase pump [121. In addition, plasma renin activity may in- significantly reduced glomerular filtration rate, sodium, potassium, and chloride excretion and urinaly flow rate. Changes in acid-base homeosta- crease from beta-adrenergic stimulation leading to increases in sis, plasma aldosterone, or renal potassium excretion did not contribute to plasma aldosterone that could enhance renal potassium excretion ritodrine- or terbu,aline-induced hypokalemia. In 83 women with preterm in the distal nephron [13] or exert a permissive effect on extra- labor randomly assigned to ritodrine (N =42)or terbutaline (N =41),the renal cellular potassium uptake [14]. maximum decrease in plasma potassium occurred after six hours of drug Therapy with ritodrine and terbutaline has been complicated by infusion. During Holter monitoring, 3 of 14 women treated with ritodrine or terbutaline developed symptomatic cardiac arrhythmias at the lowest pulmonary edema, lactic acidosis and tachyarrhythmias in women plasma potassium, while no women treated with saline and morphine (N = treated with these drugs during preterm labor [8]. It is possible 12)developed cardiac arrhythmias (P =0.14).We conclude that ritodrine that these drugs cause significant renal sodium and water reten- and terbutaline induce profound hypokalemia by stimulating cellular tion which could contribute to pulmonary edema. However, the potassium uptake and both drugs cause significant renal sodium and fluid retention and cardiac arrhythmias. Careful monitoring of electrolytes, renal effects of B-adrenergic drugs in pregnant women have not fluid balance, and cardiac rhythm should occur during tocolytic therapy been studied. Whether lactic acidosis is due to tissue hypoperfu- with ritodrine or terbutaline. sion from hypotension associated with B-adrenergic-mediated vasodilation or is due to over-production of lactic acid from B-adrenergic induced muscle glycogenolysis is unknown. Meta- bolic acidosis during infusion of these drugs could attenuate Ritodrine hydrochloride and terbutaline sulfate are the twocellular potassium uptake. Finally, no studies have examined B-adrenergic drugs most commonly used in the United States towhether a decrease in plasma potassium is associated with cardiac inhibit preterm labor [1—3]. Ritodrine and terbutaline are primar- arrhythmias. ily B2-selective in their adrenergic effects, resulting in uterine and The purpose of this study is to examine the effects of ritodrine bronchiole smooth muscle relaxation. Although both drugs mayand terbutaline on potassium homeostasis, renal function, urinary induce profound hypokalemia in women treated with these agentselectrolyte excretion and cardiac rhythm in women being treated for preterm labor, the mechanisms, duration and consequences ofwith these agents for preterm labor in order to better delineate the mechanisms for hypokalemia induced by these drugs.
Methods Received for publication May 4, 1995 and in revised form December 16, 1996 This study was limited to pregnant women age 18 or older, Accepted for publication December 16, 1996 between 24 to 36 weeks of gestation who gave written informed © 1997 by the International Society of Nephrology consent to an IRB-approved protocol. All women had the acute
1867 1868 Bradenet al: Ritodrine and terbutaline hypokalemia onset of preterm labor defined as regular uterine contractionsreceived either intravenous ritodrine or terbutaline for 12 hours occurring at intervals of < 10 minutes, palpated or recorded for atfollowed by conversion to the oral drug form as outlined in least 30 minutes by external tocography and with evidence onProtocol 1. The 10 patients studied during Protocol I are included pelvic exam of cervical effacement or dilation. All women werein this randomization. intitially given an intravenous bolus of 300 ml of 0.45% normal Protocol 3. Effects of ritodrine and terbutaline on cardiac rhythm. saline followed by 100 mllhr of this fluid. Women were excludedTo correlate the hypokalemic effects of ritodrine and terbutaline if they had active vaginal bleeding, preeclampsia, intrauterinewith cardiac arrhythmias, 24-hour Holter monitor recordings of infection, known maternal diabetes mellitus or an admissionthe 10 women above and 4 additional women treated with either blood sugar > 200 mg/dl, maternal cardiac disease, maternal renalritodrine and terbutaline were compared to Holter recordings disease, maternal hypothyroidism, maternal hypertension, anemiaobtained from 12 women admitted in preterm labor who were defined as a hematocrit < 30%, twin gestation, fetal malforma-treated with intravenous 0.45% normal saline at the same rate but tion, or a condition limiting the chance of successful of tocolyticgiven intravenous morphine rather than ritodrine or terbutaline. therapy, such as an incompetent cervix, ruptured membranes,In addition, each patient served as her own control since the advanced labor, or an untreated urinary tract infection. In addi-Holter monitor was placed for two hours prior to initiation of drug tion, no woman had any prior administration of either ritodrine orinfusion. Baseline electrocardiographic diagrams were performed terbutaline during the current pregnancy. before the initiation of either drug. The patients were randomized to receive either ritodrine hydrochloride (Yutopar®, Astra Pharmaceutical Products, West- Laboratory methods boro, MA, USA) or terbutaline sulfate (Brethine®, Geigy Phar- Plasma sodium and potassium were measured by flame pho- maceuticals, Ardsley, NY, USA). Ritodrine therapy was initiated intravenously at 100 j.tglmin and increased by 50 igImin every 10tometry (Instrument Labs, Lexington, MA, USA). Chloride, CO2 minutes up to a maximum of 350 jtgImin or until uterinecontent, glucose and creatinine were measured by spectrophoto- contractions ceased. Terbutaline sulfate therapy was initiated atmetric methods, utilizing Guilford/Corning reagents and a Guil- 10 jsglmin and increased by 5 jtgImin up to a maximum of 35ford semi-automated spectrophotometer (Guilford Systems, jig/mm or until uterine contractions ceased. The doses of rito-Oberlin, OH, USA). Pyruvate and lactate were measured using drine and terbutaline were chosen to be pharmacologically equiv-enzymatic methods [16], utilizing a Dupont Autoanalyzer (Wil- mington, DE, USA). Venous pH was measured on an Instrument alent, since earlier work indicated that terbutaline is 10 times Labs 1302 arterial blood gas machine. Aldosterone was measured stronger than ritodrine in stimulating B-adrenergic receptors [15].on ethyl acetate extracts of plasma after chromatography on Both intravenous infusions were continued for 12 hours, after which the oral form of each drug was initiated and continued untilcelite-ethylene glycol microcolumns. Radioimmunoassay was per- 38 weeks of gestation or childbirth. Oral ritodrine therapy wasformed using aldosterone-1, 2, 6, 7-H3 (New England Nuclear initially started at 20 mg every four hours, and terbutaline sulfateCorp., North Billerica, MA, USA), and a sensitive sheep anti- therapy was initiated at 5 mg every four hours for the first day andaldosterone antibody (Radioassay Systems Laboratories, Carson, thereafter administered every six hours. CA, USA). Separation of unbound aldosterone was performed with a dextran-charcoal suspension. Sensitivity was 5 pg per tube Women in preterm labor were studied utilizing three protocols. or 1.5 ng/dl. Assay recoveries were 93 to 97% using H3 aldoste- Protocol 1. Effects of intravenous ritodrine or terbutaline on rone spiked serum. Intra- and interassay precision was 6% and potassium and acid-base homeostasis and renal function. Ten 9.6% coefficient of variation, respectively. The normal adult women randomly assigned to either drug were studied for tworeference range is 2 to 20 ng/dl. Plasma renin activity was hours before initiation of intravenous ritodrine (N = or 5) estimated using the Rianen Angiotensin I Radioimmunoassay Kit terbutaline (N = and for four hours after initiation of either 5) (New England Nuclear). Recovery of added angiotensin I was 95 drug. Timed, 30-minute urine samples for urinary sodium, potas-to 100%. Intra-assay precision was 8.7% and 5.2% coefficient of sium, chloride, creatinine and osmolality were obtained for two hours before and four hours after initiation of either drug in allvariation for low and high plasma pool replicators. Sensitivity was ten women and for 12 hours in five of the ten women. In theapproximately 30 pglml. Plasma renin activity is expressed as ng of angiotensin I generated/ml/hr. The normal adult reference range 12-hour study, three women received ritodrine and two received is 20 to 160 ng/ml/hr. Insulin was measured using the "Coat-a- terbutaline. When necessary, foley catheters were utilized to count" Insulin Radioimmunoassay Kit (Diagnostic Products assure adequate urine samples. All women were placed in a left lateral position to maximize glomerular filtration and a 24-hourCorp., Los Angeles, CA, USA). The assay is performed on Holter monitor was attached. In addition, blood was obtainedundiluted plasma in antibody-coated tubes. Sensitivity was ap- before ritodrine and terbutaline infusion and at frequent timedproximately 2 jsU/ml and intra-assay precision was 7%. Recovery from insulin spiked sera was 100%. The normal adult reference intervals thereafter for four hours. Blood samples were obtained range was 0 (unmeasurable) to 30 jsU/ml. to measure plasma sodium, potassium, chloride, CO2 content, glucose, creatinine, calcium, phosphorus, uric acid, insulin, venous pH, lactate, aldosterone and renin activity. Statistical analysis Protocol 2. Effects of oral ritodrine and terbutaline on plasma Data were analyzed utilizing the Student's (-test for paired and potassium and glucose homeostasis. To determine whether theunpaired data to examine the effects of both drugs after two hypokalemic effects of ritodrine and terbutaline are sustainedminutes and to examine differences between the two drug groups. upon conversion to the oral medication, 83 women were random-Repeated measures analysis of variance was utilized for changes ized to receive ritodrine or terbutaline, and plasma potassium andin all parameters over time. Fisher's exact test was used to analyze glucose were determined every six hours for 24 hours. All patientsdifferences on the cardiac effects of the two drugs compared to Braden et at: Ritodrineand terbutaline hypokalemia 1869
5.0 drug infusion was 12.46.0 i.tU/mI and increased significantly to 31.5 5.2 tU/m1 after 40 minutes of drug infusion (P < 0.05). '- 4.5 Plasma insulin reached a mean level of 39.2 7.7 jsU/ml after 60 minutes of drug infusion, a level known to induce cellular potassium uptake in non-pregnant patients [171. The insulin level E peaked after 90 minutes of drug infusion and remained elevated E above 40 j.tU/ml for the remainder of the four-hour drug infusion. The early changes in plasma potassium, glucose and insulin 3.0 during i.v. drug infusions are shown in Figure 3. The mean plasma potassium concentration decreased from 4.2 mEq/liter to 3.3 2.5 mEq/liter after 30 minutes (P < 0.005), a change of 0.9 mEq/liter, before any significant changes in glucose or insulin occurred. _t____7/ I I I I There were no significant changes in plasma sodium, chloride, 0 10 20 30 405060 90 120 240 creatinine, calcium, phosphorus, uric acid, or plasma osmolality at Time,minutes any time during the drug infusions. Fig.1. Effects of ritodrine and terbutaline on plasma potassium during the first four hours of intravenous administration of the drugs. Data areEffects of i. v. ritodrine and terbutaline on bicarbonate, lactate and expressed as mean su. < 0.05 vs time 0. pH The mean plasma bicarbonate level measured as CO2 content saline-treated, control patients. A P value < 0.05 was considereddecreased from 19.0 0,7 mEq/liter (mmol/liter) at the start of the drug infusions to 16.2 0.8 mEq/liter after 240 minutes of significant. drug infusion (Fig. 4). Plasma lactate increased from a mean value Results before drug infusions of 1.2 0.3 mmol/liter to 4.7 0.8 There were no significant differences in any blood level or renalmmol/liter after 240 minutes of drug infusion. The plasma lactate: function parameter between the five women treated with ritodrinepyruvate ratio increased in a 10:1 ratio at all time points during and the five women treated with terbutaline during the first fourthe 240 minutes of drug infusion. There was no change in venous hours of drug infusion. This is presumably due to pharmocologicpH during four hours of infusion. The 3 mmol/liter mean decrease equivalency of the two drugs at the dosing concentration used inin serum bicarbonate after 240 minutes of drug infusion was this study [15]. Although terbutaline is 10 times more potent thanequivalent to the mean increase in plasma lactate of 3.7 mmol/ ritodrine, it was used in 1/10 the dose during the infusion periodliter. yielding similar physiologic effects. Thus, for simplicity, the five women treated with ritodrine and the five women treated with Effects of i. v. ritodrine and terbutaline on plasma renin activity terbutaline are grouped together for statistical analysis. The data and aldosterone presented are the mean standard error for all 10 patients. The mean plasma renin activity before drugs was 9.4 1.3 Effects of intravenous ritodrine and terbutaline on plasma ng/ml/hr, and it increased significantly by 90 minutes and peaked at 23.5 1.7 nglml/hr after 240 minutes (Fig. 5). The mean potassium plasma aldosterone concentration decreased as expected with the The effects of ritodrine and terbutaline on plasma potassiumdecrease in plasma potassium during the first 40 minutes of drug, are shown in Figure 1. The mean SEM potassium level before i.v.and then it increased concomitantly as plasma renin activity drug infusions was 4.2 0.1 mEq/liter. Within two minutes ofincreased during the next 80 minutes, but none of these changes starting these drugs, the plasma potassium had decreased to 4.0 in plasma aldosterone were significant (Fig. 5). 0.1 mEq/liter (P < 0.05). After 60 minutes of drug infusion, the mean serum potassium was 2.9 0.1 mEq/liter, for a mean Effects of oral ritodrine and terbutaline on plasma potassium and decrease after one hour of 1.3 0.1 mEq/liter (P < 0.001). Thereafter, the serum potassium decreased but at a much slower glucose rate, and after four hours of drug infusion the mean serum The hypokalemic effects of intravenous ritodrine and terbutal- potassium was 2.5 0.1 mEq/Iiter (P < 0.001). The majority ofme began to diminish during the last six hours of infusion (Table the decrease in serum potassium (76%) occurred during the first1). At 12 hours (end of infusion) and at 18 hours (6 hr after first hour of drug infusion, with only a 24% decrease during the lastoral dose), the mean plasma potassium had returned to approxi- three hours of intravenous infusion. mately 85% and 96% of the pre-drug levels, respectively. At 24 hours the plasma potassium in the ritodrine treated group had not Effects of i. v. ritodrine and terbutaline on glucose and insulin yet increased to the baseline level while the plasma potassium in The effects of these drugs on plasma glucose and insulin arethe terbutaline group was back to baseline. However, there were shown in Figure 2. The baseline plasma glucose before drugno significant differences in plasma potassium at any time period infusion was 75.0 4.7 mg/dl (4.2 mmol/liter) and it increased tobetween the ritodrine and terbutaline treated groups. 103.3 6.1 mg/dl (5.2 mmol/liter) after 40 minutes of i.v. infusion The mean plasma glucose was higher after six hours of intra- (P < 0.05). After 60 minutes of infusion, the mean plasma glucosevenous terbutaline compared to intravenous ritodrine, but the was 108.0 10.4 mg/dl (6.0 mmol/liter) and peaked at 142.09.0physiologic significance of this increase at only one time period is mgldl (7.9 mmol/liter) after 120 minutes. Plasma insulin beforeunclear. 1870 Braden et al: Ritodrine and terbutaline hypokalemia
150 60
125 50 -D a) C/) E100 40 ci) a) 0 75 30 C,)c 0) Ecci 50 Cl) 20 cci ci 25 10 Fig. 2. Effects of ritodrine and terbutaline on I I I I / /1 plasma glucose (0) and plasma insulin (•) 90 120 240 during the first four hours of intravenous 0 10 20 30 40 50 60 administration of the drugs. Data are expressed Time, minutes as mean SE. *p < 0.05 vs. time 0.
5.0 150 60
4.5 125 50 + -D -u 4.0 ci) 3.5 ::I
.0 3.0 50 — 20 0 0. 2.5 25 10
Fig. 3. The early effects of intravenous ritodrine I I and terbutaline on plasma potassium (U), glucose 0 10 20 30 40 (0) and insulin (•). Data are expressed as mean SE. *p < 0.05 potassium vs. time 0; Time,minutes p < 0.05 glucose or insulin vs. time 0.
Effects of i. v. ritodrine and terhutaline on renal flinction 0.01) and to 94/435/5 after 90 minutes of drug infusion (P < The renal effects during the first four hours of intravenous drug0.001). The lower blood pressures were sustained throughout the infusion are listed in Table 2. Both drugs produced significantfirst eight hours of intravenous infusion, but began to increase by decreases in the glomerular filtration rate measured as creatininethe end of the 12 hours intravenous drug infusion and returned to clearance and significant decreases in sodium, potassium, andnormal baseline levels on oral therapy. chloride excretion and the urinary flow rate. The urinary osmo- lality increased from a baseline of 340 mOsm/kg H20 to 663 Effects of ritodrine and terbutaline on cardiac rhythm mOsm/kg H20 after four hours despite no change in plasma The effects of these drugs on cardiac rhythm are listed in Table osmolality. Five out of the 10 women were followed for up to 123. Baseline EKGs were normal in all 14 women treated with either hours after initiation of drug therapy. Although the decreases inritodrine or terbutaline and in the 12 control women who received sodium, potassium and chloride excretion and urinary flow rateintravenous saline and morphine. Holter monitoring before rito- persisted for 12 hours, the creatinine clearance improved todrine or terbutaline infusion demonstrated no arrhythmias while baseline at approximately eight hours after initiating drug infu-these women were in active preterm labor. Thereafter, one sion. The mean fluid gain after 12 hours in these women was 2.3 woman, after three to four hours of i.v. terbutaline, developed 0.2 liters. symptomatic supraventricular tachycardia and junctional rhythms Changes in systemic hemodynamics associated with B2- sympa-at the nadir of her plasma potassium at 2.2 mEq/liter (Table 3). In thomimetic-induced vasodilation were associated with decreasesaddition, this woman developed multifocal aberrant premature in creatinine clearance. The mean blood pressure prior to drugatrial beats and unifocal ventricular premature beats. Another infusion was 119/69 10/4, and decreased to a mean bloodwoman receiving i.v. ritodrine after three hours developed symp- pressure of 97/45 6/3 after 30 minutes of drug infusion (P 25 6.0b.U P<0.05 P<0.001P<0.o01 5.0 — 20 I 7.5 NS 4.0 — 1 4.0 7.4 15 7.3 3.0 — 7.3 7.2 10 2.0 1 7.1 5 1.0H 7.0 I Ohr 4hr Ohr 4hr Ohr 4hr Fig. 4. Effects of ritodrine and terbutaline on acid-base parameters after four hours of Plasma Plasma VenouspH intravenous administration. Data are expressed bicarbonate, mEq/liter lactate, mmol/Iiter as mean SE. 30 250 mEq/liter after 60 minutes. Possible mechanisms for a drug- induced decrease in plasma potassium include a shift of potassium 25 200 ) from the extracellular fluid into the intracellular fluid and/or 0 (I) 20 increased urinary or gastrointestinal potassium excretion. No 150 stool samples were obtained during these studies, so it is unknown whether gastrointestinal potassium excretion is enhanced by these - drugs. Catecholamines modulate extrarenal potassium homeostasis - :°I 18, 19]. Early animal and human studies infusing intravenous ji epinephrine showed an initial transient increase in serum potas- I I I I / I sium due to potassium release from liver cells, but thereafter 0 20 40 60 90 120 240 significant decreases in serum potassium were demonstrated Time, minutes presumably due to B2-adrenergic-mediated cellular potassium Fig. 5. Changes in plasma renin activity and plasma aldosterone during the [20—22]. This bi-phasic response was blocked by B-adrenergic first four hours of intravenous ritodrine and terbutaline. Data are expressed receptor antagonists such as propanolol [20]. However, in our as mean SE. *D<0.05 renin vs. time 0. study a bi-phasic potassium response to either ritodrine or terbutaline was not demonstrated. In addition, the mean plasma potassium 30 minutes after drug infusion decreased by 0.9 mEq/ at the nadir of her plasma potassium at 2.1 mEq/liter (Table 3). Aliter before any significant rise in blood glucose and insulin. These third woman treated with terbutaline developed symptomaticobservations suggest that ritodrine and terbutaline may directly unifocal premature atrial beats. All arrhythmias developed withinstimulate cellular potassium uptake. Beta-adrenergic drugs pre- the first four hours of drug infusion when the plasma potassiumsumably decrease plasma potassium by B2-receptor stimulation of had maximally decreased. The arrhythmias disappeared after the adenylate cyclase which increases intracellular cAMP which acti- plasma potassium increased during conversion to oral therapy. Novates Na,K-ATPase leading to cellular potassium uptake [23]. women in the control group treated with saline or morphine Increases in plasma glucose and plasma insulin levels during developed arrhythmias. However, the incidence of arrhythmias inritodrine and terbutaline infusion may have contributed to a the group treated with ritodrine and terbutaline was not statisti-decrease in plasma potassium in these patients. Beta-adrenergic cally different from the control group (P =0.14). stimulation could increase plasma glucose and insulin by several mechanisms. Beta-adrenergic stimulation in mammalian liver Discussion activitates glycogenolysis and gluconeogenesis, contributing to It is clear from these studies that therapeutic doses of intrave-increases in plasma glucose which could stimulate pancreatic nous ritodrine and terbutaline which inhibit preterm labor rapidlyinsulin release [10]. These effects in cats are blocked by B-adren- induce hypokalemia. Indeed, the plasma potassium decreasedergic antagonists but not a-adrenergic antagonists, suggesting significantly just two minutes after initiation of intravenous rito-specific B-adrenergic effects [24]. In addition, the human liver drine or terbutaline. After 15 minutes of drug infusion, the plasmacontains predominantly B2-adrenergic receptors with a lesser potassium decreased by 0.5 mEq/liter and further decreased by 1.3population of cs1-adrenergic subtypes [25]. Earlier studies utilizing 1872 Braden et al: Ritodrineand terbutaline hypokalemia Table 1. Effects of ritodrine versus terbutaline on potassium and glucose Time hours Parameter Drug N 0 6 12 18 24 Potassium Ritodrine 42 3.67 0.05 2.68 0.04 3.17 0.05 3.560.08 3.520.06 Potassium Terbutaline 41 3.56 0.05 2.520.05 3.03 0.05 3.390.11 3.740.07 Glucose Ritodrine 42 90 4 151 6 167 6 128 6 119 6 Glucose Terbutaline 41 96 5 189 ioa 186 8 139 6 121 5 Data are expressed as mean SE at all times. a P < 0.05 ritodrine vs. terbutaline. Table 2. Effects of ritodrine and terbutaline on renal function Table 3. Results of 24-hour Holter monitoring Drug infusion Time K N hr Pre-drug 1.5 hours 4.0 hours Arrhythmia mEq/liter 1. ia 4 2.20 Creatininc clearance 114.5 16.3 70.86.4a 91.8 11.3 Supraventricular tachycardia 2.Premature atrial beats mi/mm a. Multifocal, aberrant ia 1 2.35 Sodium excretion 199.1 37.9 78.8 17.Oa 80.0 14.8 b. Unifocal, occasional 1h 3 2.10 p.Eq/min 1 1 3.15 Potassium excretion 66.98.9 28.33•5a 30.1 3.8a c. Unifocal, frequent 3.Junctional rhythm i' 3 2.20 p.Eq/min 4.Premature ventricular beats Chloride excretion 181.1 34.2 67.8 21.P 51.3 12.1' a. Unifocal, rare ia 0.5 2.95 p.Eq/min b. Unifocal, occasional 3 2.10 Urine flow rate 3.6 1.4 1.2 0.2 0.9 0.2 l' mi/mm a Same patient. Urine osmolality 340 98 289 31 663 53 Same patient. mOsm/Kg H20 a P < 0.05 compared to pre-drug. a mean plama insulin level of 37 U/ml produced a 0.5 mEq/liter decrease in serum potassium over a two-hour period [35]. In ritodrine or hexoprenaline to inhibit preterm labor demonstratedcontrast, intramuscular and subcutaneous insulin that increased that blood glucose and insulin rise without any significant changesthe plasma insulin to 45 /LU/ml for three hours produced no in glucagon, human placental lactogen or human chorionic gona-decrease in serum potassium in normal subjects [36]. In addition, datotropin [26, 27]. In addition, a fall in plasma alanine occurredintravenous insulin infusion in Type I diabetics produced no during salbutamol therapy to inhibit preterm labor, suggestingdecrease in the serum potassium over several hours despite that hepatic gluconeogenesis was also stimulated by these drugsreaching a mean plasma insulin level of 90 U/ml [37]. In our [281. Thus, pancreatic insulin release could be stimulated by a risestudy, the mean plasma insulin reached 40 .tU/ml after 60 minutes in plasma glucose from hepatic glycogenolysis and/or gluconeo-of drug infusion and that level persisted for the next three hours. genesis. It is possible that the decrease in plasma potassium in our study is Increases in plasma insulin could also occur due to directin part due to insulin-mediated shifts of potassium into the B2-adrenergic stimulation of pancreatic insulin release. Studies inintracellular compartment during ritodrine and terbutaline infu- dogs have shown that B-adrenergic agonists infused directly intosion. No changes in plasma osmolality occurred to attenuate the pancreas stimulate pancreatic insulin release [29]. Similarcellular potassium uptake [38]. changes have been found in rat islet cells incubated with epineph- Both ritodrine and terbutaline induced hyperlactatemia after rine [30] and in sheep given intravenous isoproterenol [31]. Infour hours of drug infusion. Ritodrine and terbutaline have been addition, two human studies have shown that B-adrenergic stim-reported to produce hyperlactatemia by unknown mechanisms ulation directly stimulates insulin release [29, 32]. Thus, B-adren-[39, 40]. In our study, the starting plasma bicarbonate level was ergic agents can raise plasma insulin secondary to either increases19.6 mEq/liter, consistent with the renal adaptation to chronic in glucose or by directly stimulating pancreatic insulin release. respiratory alkalosis which occurs in normal pregnancies [41, 42]. Increases in plasma insulin probably contributed to cellularDuring the first four hours of drug infusion, the mean serum potassium uptake during the infusion of ritodrine and terbutaline.bicarbonate decreased concomitantly with an equivalent increase The basal plasma insulin level mediates cellular potassium uptakein plasma lactate, suggesting that all of the bicarbonate decrease since somatostatin infusion in animals and humans suppresseswas due to acid buffering from the production of lactate. Studies basal insulin levels inducing a rise in serum potassium of 0.5of ketogenesis during ritodrine and terbutaline infusion did not mEq/liter [33]. Additional studies have shown that raising theshow any changes in women treated with these agents for preterm plasma insulin level in the fasting state to approximately 25 jsU/mllabor [26—28]. The mean venous pH in our patients was 7.35 and attenuates the rise in serum potassium after a potassium load [34].this did not change at any time over the first four hours of drug Zierler and Rabinowitz originally calculated that a plasma level ofinfusion, suggesting that increases in pulmonary ventilation oc- 40 1.tU/ml would be required to shift potassium from the extra-curred appropriately to compensate for the decrease in serum cellular into the intracellular compartment [17] and studies ofbicarbonate. A venous pH of 7.35 is consistent with venous pH intravenous insulin by glucose clamp techniques, which producedlevels in normal pregnant women [43]. The plasma lactate/ Braden et al: Ritodrine and terbutaline hypokalemia 1873 pyruvate ratio remained 10 to I throughout the first four hours ofmediates sodium reabsorption in the mammalian kidney. Angio- drug infusion, suggesting that the cause for hyperlactatemia wastensin IL infusion in dogs produces sodium retention without any either overproduction of lactate or under utilization of pyruvate.measurable changes in renal blood flow or glomerular filtration Women in labor may produce lactate but not to the levels seen inrate [59]. In addition, micropuncture and isolated proximal tubule our study [44]. In addition, stimulation of B-adrenergic muscleperfusion studies demonstrated direct stimulation by angiotensin receptors activates muscle phosphorylase, which induces muscleII on proximal tubule sodium reabsorption [60]. Finally, intrave- glycogenolysis and leads to increased production of pyruvatenous infusion of angiotensin II into normal humans decreases the through the Embden-Myerhoff pathways [45]. We have previouslyfractional excretion of lithium, a marker of proximal tubule demonstrated overproduction of lactic acid due to B-adrenergicsodium reabsorption [61]. Thus, it is possible that sodium reten- drugs used to treat acute bronchospasm [46] and lactic acidosistion in women treated with ritrodine or terbutaline could be has been found in catecholamine excess states, such as pheochro-secondary to the direct renal hemodynamic effects of these drugs, mocytoma [47]. Thus, changes in acid-base homeostasis occuror due to a direct B-adrenergic or angiotensin II effect to during ritodrine and terbutaline infusion but do not contribute tostimulate proximal tubule sodium reabsorption. hypokalemia induced by these agents. The decrease in urinary flow rate and significant increase in The pre-drug plasma renin activity and plasma aldosteroneurinary osmolality suggest that enhanced antidiuretic hormone levels were increased above non-pregnant levels to levels found insecretion occurs during infusion of ritrodine or terbutaline. In- normal pregnancies [48]. Plasma renin activity increased signifi-deed, the mechanism of B-adrenergic decreases in renal water cantly during drug infusions either due to activation of barore-excretion in humans and animals is secondary to non-osmotic ceptor mechanisms in afferent arterioles due to B2-mediatedstimulation of ADH. Beta-adrenergic-induced vasodilation de- vasodilation or due to direct stimulation of renin release bycreases carotid and aortic baroreceptor tone leading to increased B-adrenergic-mediated mechanisms [49—Si]. Plasma aldosteroneADH release from the hypothalamus [62]. ADH levels were not levels fluctuated during drug infusions and changes were notmeasured in this study, but fenoterol, an experimental beta- statistically significant. Moreover, changes in plasma aldosteroneadrenergic tocolytic significantly increased plasma ADH levels were not associated with increased renal potassium excretion. and decreased urinary water excretion [54]. The reduced renal Increased urinary excretion of potassium was not a factor insodium, chloride and water excretion during the first 12 hours of ritodrine- and terbutaline-induced hypokalemia. Rather, urinaryintravenous infusion of ritodrine and terbutaline in our study may potassium excretion decreased and remained below baseline forcontribute to the onset of pulmonary edema in women receiving the 12 hours of drug infusion. Epinephrine infusion into humansthese agents [8]. significantly decreases urinary potassium excretion [22,52]. More- In conclusion, ritodrine and terbutaline may induce hyperlac- over, decreased distal nephron potassium secretion may occurtatemia and significant hypokalemia leading to cardiac arrhyth- during ritodrine and terbutaline, since in vitro studies of themias in women treated with these agents for preterm labor. isolated perfused cortical collecting tubule demonstrated thatSignificant arrhythmias may occur when plasma potassium de- isoproterenol directly inhibits potassium secretion [53]. In addi-creases to <2.5mEq/liter. Significant sodium and fluid retention tion, the decreased urinary flow rate during drug infusion couldcan also occur, possibly contributing to pulmonary edema induced have limited urinary potassium excretion. Thus, despite the highby these drugs. Most of these effects occurs within six hours of levels of plasma aldosterone in pregnant women treated withinitiating tocolytic therapy. Cardiac monitoring should be initiated ritodrine or terbutaline, urinary potassium excretion was signifi-for any pregnant woman in preterm labor treated with intravenous cantly diminished. ritodrine or terbutaline. In addition, the blood potassium should Urinary sodium and chloride excretion were significantly de-be checked two to four hours after initiation of drug therapy to creased during intravenous ritodrine and terbutaline. Severalidentify those women prone to severe hypokalemia, who may mechanisms may have contributed to these changes. A decrease inbenefit from potassium supplementation. Further studies compar- glomerular filtration rate may have decreased the filtered load ofing subcutaneous versus intravenous terbutaline and ritodrine to sodium. In addition, B-adrenergic receptors may modulate prox-treat preterm labor are needed to determine whether the side imal tubule sodium reabsorption. Infusion of norepinephrine oreffects of these agents can be minimized while still providing epinephrine into isolated perfused rat kidney induced sodiumtherapeutic efficacy. retention that was blocked by propanolol but not by phenoxyben- zamine, suggesting that sodium reabsorption is mediated by Acknowledgments B-adrenergic receptors [54]. In addition, in vitro experiments in The authors thank Walter Stupak and Ann Vasseur for their technical proximal tubular epithelia demonstrated beta-adrenergic in-assistance and Men Kassanos and Maureen Harbilas for their secretarial creases in fluid absorption and Na,K-ATPase activity [55—57].support for this manuscript. Thus, it is possible that part of the decrease in sodium excretion from these drugs may be secondary to B-adrenergic stimulation of Reprintrequests to Gregoty L. Braden, M.D., Chief Renal Division, proximal tubular sodium reabsorption. 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