Plasma atrial natriuretic peptide concentrations during induction of anesthesia and acute volume loading in patients undergoing cardiac surgery

Plasma Atrial Natriuretic Peptide Concentrations During Induction of Anesthesia and Acute Volume Loading in Patients Undergoing Cardiac Surgery Markku Hynynen, MD, Ilkka Tikkanen, MD, Markku Salmenper~, MD, Jussi Heinonen, MD, and Frej Fyhrquist, MD Induction of anesthesia with fentanyl for coronary artery bypass grafting decreased (P < .05) plasma atrial natriuretic peptide (ANP) concentrations from awake values in twelve patients. During a steady state of anesthesia before surgery, isotonic saline solution (10 mL/kg) was infused simultaneously with the elevation of the lower extremities in six patients, while six subjects served as controls receiving no volume loading and having no leg raising. The ANP levels returned to the awake values in the volumeloaded patients, while plasma ANP remained at anesthetized baseline levels in the control subjects

(P < .01 between the groups). Ten minutes after the end of the loading procedure, plasma ANP had begun to decrease again towards the postinduction level in the loaded group, but a significant (P < .05) difference was still observed between the groups. These changes in ANP levels parallelled those of cardiac filling pressures. In conclusion, the results suggest that the degree of distention of the atria regulates the secretion of atrial natriuretic peptide into the circulation in patients anesthetized with fentanyl. © 1987 by Grune & Stratton, Inc.

P E C I F I C G R A N U L E S of mammalian atrial cardiocytes contain polypeptides that have diuretic, natriuretic, hypotensive, and vasorelaxant properties. 13 They also inhibit the secretion of aldosterone, renin, and vasopressin. 47 These peptides, known as atrial natriuretic peptide (ANP), have been shown to bind to specific receptors in renal? adrenal, 9 and vascular 8'1° tissues, and may play a role in the regulation of sodium and volume homeostasis." Increased plasma A N P concentrations have been measured as a response to intravenous fluid infusion in conscious animals ~2 and humans. 13 Various anesthetics, including morphine 14 and halothane, 12 have also been shown to increase plasma A N P level in experimental animals. On the other hand, the secretory response of A N P to fluid infusion was blocked in animals by anesthesia with halothane? z but not with pentobarbital. ~5 Since the effects of anesthetic drugs or saline infusion during anesthesia on plasma A N P level have not been studied in man, the possible changes in plasma A N P level caused by induction of anesthesia with fentanyl and subsequent acute volume loading in patients scheduled for coronary artery bypass grafting (CABG) was studied.

their nitrates and calcium channel blocking or beta-adrenergie blocking drugs on the morning of surgery. The patients were premeditated with scopolamine and morphine in doses of 6 and 200 #g/kg, respectively, intramuscularly one hour before arrival in the operating room. Before the induction of anesthesia, peripheral intravenous, radial artery and flow-directed pulmonary artery thermodilution catheters were inserted under local anesthesia in the supine horizontal position. After a stabilizing period, anesthesia was induced with fentanyl, 48 #g/kg, given over ten minutes. Simultaneously, at the beginning of the ten-minute induction infusion, a maintenance infusion of fentanyl was started and continued throughout the study at a rate of 0.3 t~g/kg/min. The fluid volumes given in association with fentanyl administration were approximately 1 mL/kg (bolus) and 0.3 mL/ kg/10 rain (infusion). After loss of consciousness, pancuronium, 0.1 mg/kg, was given as the muscle relaxant, and the tracheas of the patients were intubated. Ventilation was controlled with a mixture of oxygen and air (FlO2 - 0.5) using the non-rebreathing cireuit of a Servo 900 B ventilator (Siemens-Elema, Sweden). The respiratory rate was 12/rain, and the minute volume was adjusted to maintain normocarbia as measured by the end-tidal CO2 concentration and arterial blood gas analysis.

S

PATIENTS AND METHODS Twelve men scheduled for elective CABG were studied. The study protocol was approved by the ethical committee of the institute, and each patient gave his consent for the study. Patients with significant valvular disease or critical narrowing of the left main coronary artery were excluded from the study. After overnight fasting, the patients received Journal of Cardiothoracic Anesthesia,

From the Department of Anesthesia and IVth Department of Medicine, Helsinki University Central Hospital and the Unit of Clinical Physiology, Minerva Foundation Institute for Medical Research, Kauniainen, Finland. Supported by grants from the Finnish Foundation for Cardiovascular Research; the Ida Montin Foundation, the Paavo Nurmi Foundation, the Paulo Foundation, and the Sigrid Jusklius Foundation. Address reprint requests to Dr Markku Hynynen, Department of Anesthesia, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland. © 1987 by Grune & Stratton, Inc. 0888-6296/87/0104-0005503.00/0

Vol 1, No 5 (October), 1987: pp 401-407

401

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HYNYNEN ET AL

During a steady state, about 30 minutes after the start of induction of anesthesia, a rapid infusion of isotonic saline solution, 10 mL/kg, was started in six patients. The electrolyte contents of this solution were: sodium 130, potassium 4, calcium 1.5, chloride 109, and acetate 28 mmol/L. During the infusion, the legs of the patients were lifted about 60° from the horizontal level. The other six patients served as controls; they received no loading with fluids and their legs were not raised. The V5 lead of the electrocardiogram was monitored continuously and various limb leads were reviewed intermittently. Hemodynamic measurements were performed (1) before induction of anesthesia, (2) after induction but before volume loading, (3) after volume loading, immediately after the legs were again in the horizontal position, and (4) ten minutes after the end of the volume loading. The measurements were performed at the end-expiratory phase of respiration and included heart rate (HR), mean arterial pressure (MAP), mean and diastolic pulmonary artery pressures (PAP), central venous pressure (CVP), and cardiac output (CO) by thermodilution. During volume loading, HR, CVP, and systemic and pulmonary arterial pressures were recorded continuously. Blood samples for hormonal analyses were drawn from the pulmonary artery during the above-mentioned hemodynamic measurements. The blood samples were collected into prechilled EDTA tubes, centrifuged, and stored at -20°C until assayed. Radioimmunoassay was used to measure plasma atrial natriuretic peptide,16plasma renin activity (PRA), 17and arginine vasopressin (AVP). 18The radioimmunoassay of plasma ANP has been described in detail previously, ~6but a short description of the method is given here. Rabbit anti-a-ANP serum (Peninsula Laboratories, Belmont, CA) was used. The crossreactivity of the antiserum is 100% with human ANP (1-28 Met-ANP), rat ANP (1-28 Ileu-ANP), and rat atriopeptin III (5-28 ANP); 90% with human 8-33 ANP; 57% with human 18-28 ANP; 50% with rat 13-28 ANP; 27% with rat atriopeptin II (5-27 ANP); 3% with rat atriopeptin I (5-25 ANP); and there is no reactivity with argS-vasopressin, oxytocin, or somatostatin. The sensitivity of the method is <10 pg/mL, with 95% confidence limit. When 250 or 1,000 pg of ANP was added to disodium edetate-plasma, diluted one in five in assay buffer, percent-

age recoveries (mean _+SEM) were 68% _+ 5% (n = 7) and 74% _+2.9% (n = 7), respectively. For two plasma pools prepared for samples obtained during ANP infusion in healthy subjects, intra-assay coefficients of variation were 10.6% (mean ANP concentration 92 pg/mL, n = 10) and 7.8% (104 pg/mL, n = 10). Interassay coefficients of variation for the same plasma pools were 10.3% (n = 4) and 9.6% (n = 4). Because of laboratory error and missing of samples,

DPAP 30 (mmHg)

10

0CVP

15

ANP

210~-

PRA

20 -

(pglml)

~

Table 1. Characteristics of the Patients

1-

Group Controls

n Age (yr) Height (cm) Weight (kg) No. of diseased vessels Ejection fraction Medication beta-adrenergic blockers calcium channel blockers long-acting nitrates diuretic digitalis

Volume-Loaded

6 59 (2) 171 (3) 81 (5) 2,5 (0.3) 0.58 (0.03)

6 53 (2) 175 (3) 86 (5) 2.7 (0.3) 0.55 (0.06)

4 4 5 1 1

6 4 6 1 1

Values are means (SEM) or number of patients,

(pg/ml) 4

0

t

"l'.

I C

I Pre

Fig 1. Diastolic pulmonary artery pressure (DPAP), CVP, ANP, plasma renin activity (PRA), and AVP (individual responses and mean _+ SEM) before and after induction of anesthesia in twelve patients anesthetized with fentanyl for myocardial revascularization. Abbreviations: C, control (awake); Pre, after induction of anesthesia. Significant change from control: ~ P < .05, ~ P < .01.

403

ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS

Table 2. Mean (SEM) Values of Hemodynamic Variables Before and After Induction of Anesthesia in 12 Patients Anesthetized for Coronary Artery Bypass Grafting. MAP (mmHg)

MPAP (mmHg)

DPAP (mmHg)

Control (awake)

92.9 (6.3)

20.4 (2.2)

14.7 (1.9)

ARerinduction

86.3 (4.6)

14.4" (1.7)

9.6* (1.4)

CVP (mmHg)

CI (L/min/m 2)

HR (beats/rain)

SVR (dyne • s • cm -5)

PVR (dyne • s • cm -5)

6.5 (1.0)

3.1 (0.3)

62.3 (6.0)

1149 (57)

122 (21)

4.1" (0.6)

2.9 (0.1)

71.6 t (4.4)

1181 (61)

110 (18)

Abbreviations: MPAP, mean pulmonary artery pressure. CI, cardiac index. PVR, pulmonary vascular resistance. *P < .01 when compared with control value. t P < .05 when compared with control value.

AVP analysis could be completed only in ten patients, five subjects in each group. The t test for paired data was used to identify significant changes in all twelve patients from awake values to those obtained after induction of anesthesia. Two-way analysis of variance (ANOVA) was used to assess whether the courses of the measured variables differed significantly between the groups of six subjects in each from the preloading values onwards, in case of significance after ANOVA, the changes from the preloading values were compared between the groups using the t test for two independent means. The linear regression analysis was used to assess the interrelationship between the changes in plasma ANP concentration and the corresponding changes in diastolic pulmonary artery pressure or central venous pressure, respectively. P values less than .05 were considered statistically significant. The results are expressed as the mean _+SEM. RESULTS

T h e d e m o g r a p h i c d a t a of the patients a r e given in T a b l e 1. T h e two study groups were c o m p a r a b l e . T h e volume loading period lasted 12 +_ 1 minutes in the loaded patients, while the corresponding period in the control patients was d e t e r m i n e d to be 13 minutes.

( mDPAP m H g ) 15 f 10

5 CVP

1

ANP

70

(mmHg)

8

2L (pg/ml)

~

~

~

50 30 10

PRA

1Or-

AVP

4

nglm,l.

~

Effects o f Induction o f Anesthesia T h e d a t a o b t a i n e d in all 12 patients were used to assess the effect of the induction of anesthesia on p l a s m a h o r m o n e levels and hemod y n a m i c variables. A significant decrease in the p l a s m a A N P and A V P concentrations and a significant increase in P R A were observed ( F i g 1). A significant decrease in diastolic p u l m o n a r y a r t e r y pressure and central venous pressure also occurred ( F i g 1, T a b l e 2). W h e n the changes from the a w a k e values to those o b t a i n e d after the induction of anesthesia were correlated, no sign i f i c a n t r e l a t i o n s h i p was o b s e r v e d b e t w e e n p l a s m a A N P level and diastolic p u l m o n a r y arterial pressure, or p l a s m a A N P level and central venous pressure. M e a n p u l m o n a r y a r t e r y pres-

3L (pg/ml)

f 0 I II I Pre

Postl-O Postl-lO Max

Fig 2. DPAP, CVP, ANP, PRA, and AVP concentration (mean _+ SEM) before, during, and after acute volume loading in six patients anesthetized for myocardial revascularisation and in six control patients at corresponding stages of anesthesia. Key: O, loaded patients; O, control patients; Pre, before loading; Max, maximal value of filling pressures during loading; Postl-O, immediately after loading; Postl-lO, 10 minutes after loading. ~r P < .05, Yt-tr P < .01, ~rCr P < .001 ; significant difference between the groups in the change from the value before loading.

404

HYNYNEN ET AL

sure decreased and heart rate increased significantly (Table 2), while other hemodynamic variables remained stable during the induction of anesthesia.

Effects of Volume Loading Hormonal changes (Figure 2). Immediately and 10 minutes after volume loading, plasma ANP levels had increased significantly from the preloading value in the study group as compared to the control group. ANOVA revealed no significant differences between the groups in PRA or plasma AVP concentration. Filling pressures of the heart (Fig 2, Table 3). The maximal changes in diastolic pulmonary artery pressure and central venous pressure during the study period were taken into account when the statistical significance between the changes in the two groups was analyzed. In the volume-loaded patient group, these filling pressures were significantly increased during the loading procedure as compared with the control

group. In the case of diastolic pulmonary artery pressure this difference persisted 10 minutes after the loading procedure. A statistically significant relationship was observed betfveen the changes in plasma ANP concentration and diastolic pulmonary artery pressure (r = 0.622; P < .001), and plasma ANP concentration and central venous pressure (r = 0.555;P < .01). Other hemodynamics. Immediately after volume loading, pulmonary vascular resistance was significantly decreased in the study group as compared with the control group. ANOVA revealed no significant differences between the groups in any other hemodynamic variable. DISCUSSION

The results show that patients anesthetized with fentanyl, pancuronium, and oxygen, and mechanically ventilated to normocarbia, do not increase the secretion of ANP; a decrease in ANP was observed during the induction of aries-

Table 3. Mean (SEM) Values of Hemodynamic Variables Before, During, and After Acute Volume Loading in Six Patients Anesthetized for Coronary Artery Bypass Grafting and in Six Control Patients at Corresponding Stages of Anesthesia BeforeLoading (after induction) MAP (mmHg) L C MPAP (mmHg) L C DPAP (mmHg) L C CVP (mmHg) L C CI (L/min/m 2) L C HR (beats/min) L C SVR (dyne • s • cm -5) L C PVR (dyne • s • cm -s) L C

Maximal Value During Loading

Immediately After Loading

Ten Minutes After Loading

84.8 (6.2) 87.8 (7.3)

90.2 (8.3) 89.5 (8.1)

89.3 (6,9) 87.8 (6.9)

12.7 (2.4) 16.2 (2.3)

15.0 (2.3) 16.3 (2.0)

14.7 (1.9) 14.8 (1.9)

10.3 (1.7) 10.7 (2.0)

10.0 (1.3) t 10.3 (1.6)

7.8 (1.6) 11.3 (2.1) 3.8 (0.7) 4.3 (1.1)

14.0 (1.8)* 11.3 (2.1) 8.4 (1.1):1: 4.3 (1.1)

6.4 (1.1) t 4.0 (1.0)

4.8 (1.1) 4.3 (1.0)

2.9 (0.1) 2.8 (0.2)

3.2 (0.2) 2.7 (0.2)

3.0 (0.2) 2.6 (0.2)

72.5 (5.1) 70.7 (7.7)

69.5 (6.0) 67.0 (7.6)

63.8 (3,8) 63.2 (7.1)

1115 (69) 1247 (100)

1058 (30) 1355 (108)

1061 (92) 1346 (102)

97 i32) 123 (17)

82 (26)t 146 (16)

85 (27) 132 (8)

Abbreviations: L, loading group; C, control group. *P < .01 (difference between the groups in the change from the value before loading. t P < .05 (difference between the groups in the change from the value before loading. ~P < .001.

ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS

thesia. Furthermore, during the maintenance of anesthesia with the continuous infusion of fentanyl, plasma A N P concentration remained low in the control patients who were not volume loaded. These observations with fentanyl in patients do not agree with the results of animal studies with morphine 14 and halothane ~2 that showed increased plasma ANP levels. These animal studies did not explain the precise mechanism of the ANP release by the anesthetics. It is possible, however, that secondary hemodynamic changes caused by the anesthetics or respiratory depression might have influenced the A N P levels. Elevated levels of circulating A N P have been reported in states of increased extracellular fluid volume such as congestive heart failure, t6'19'2° end-stage renal disease, 21 and normal pregnancy. 22 Plasma A N P levels have also been shown to correlate with cardiac filling pressures in patients with congestive heart failure. 23'24 These observations suggest that increased atrial distention may stimulate A N P release. Acute blood volume expansion has been shown to release natriuretic peptide from the rat heart-lung preparation 25 and to increase the secretion of this peptide into the circulating blood of rats. 15'26'27 In these studies, increased central vascular pressure was shown to be associated with increased natriuresis 2s or increased secretion of the atrial peptide.15 In human volunteers, an infusion of 500 mL of isotonic saline over 45 minutes, 28 2,000 mL over 60 minutes, ~3or 6 to 18 m L / k g at a rate of 250 m L / m i n 29 increased plasma levels of ANP. Passive leg raising for 20 minutes has also been shown to increase plasma A N P levels in normal volunteers. 3° Parallel changes in plasma A N P levels and cardiac filling pressures were observed in the studied patients. Thus, the induction of anesthesia was associated with decreased cardiac filling pressures 3~ and a decreased A N P level, whereas increases in these variables were observed as a result of volume loading. However, great interindividual variability in the A N P response to the changes in the distention of the atrial wall in the patients was observed. Although increased sodium ion concentration or osmotic pressure has been suggested to mediate the release of A N P during volume loading, 12'32the decrease in A N P level before loading

405

suggests that the change in atrial distention was the effective stimulus in the present study. Furthermore, Anderson et al measured increased circulating concentrations of A N P without changes of plasma osmolality or electrolyte concentrations after infusion of isotonic saline solu~tion. 29 The very rapid tendency of plasma A N P levels to decrease after the end of the loading procedure in the present story differs from the results of volunteer studies by Yamaji et a128and Anderson et al. 29 In their awake subjects, the plasma natriuretic peptide level continued to increase after the discontinuation of the saline infusion, whereas in the anesthetized patients the hemodynamic or other effects of anesthesia attenuated the plasma A N P response to acute volume loading. This attenuating effect of anesthesia in man thus agrees with the results obtained in animal studies. 12 The observed rapid decrease in plasma A N P concentration also indicates the brief half-life of this peptide. 33 At present, the physiologic importance of A N P in the regulation of the body fluid balance is not known. 34'35 Plasma A N P levels measured after volume loading in the present study and in other studies in man ~3'28'29 are distinctly lower than those measured in subjects receiving an infusion of synthetic A N P to cause biologic effects in association with pharmacologic plasma A N P levels. 16'36 It was recently shown that an increase in plasma A N P concentration (within normal range) contributes to the natriuretic response as studied during water immersion in normal subjectsP 7 Whether or not acute volume loading increases plasma A N P to levels causing clinically significant biologic effects in man warrants further studies. Induction of anesthesia has previously been shown to increase PRA, 38 and this renin response was seen in the present study with a simultaneous decrease in A N P level. Saline infusion for one hour has been reported to cause a decrease of PRA in conscious healthy subjects. 13 In the present study, no significant difference could be found in PRA response between the patients receiving and not receiving acute volume loading, although a significant difference between the groups occurred in A N P response to loading. Thus, the behavior of PRA was not entirely opposite to that of A N P in those patients. It

406

HYNYNEN ET AL

s e e m s t h a t P R A r e s p o n s e to a c u t e v o l u m e loading is not as r a p i d as A N P response, at least in anesthetized patients. T h e s m a l l b u t significant d e c r e a s e in a r g i n ine vasopressin level d u r i n g t h e i n d u c t i o n o f a n e s t h e s i a a g r e e s w i t h t h e results o f a p r e v i o u s study, 39 in w h i c h v o l u m e l o a d i n g was not done. T h e p r e s e n t results s h o w t h a t v a s o p r e s s i n does not r e s p o n d to short periods of a c u t e v o l u m e loading during anesthesia. In conclusion, t h e results of t h e p r e s e n t

s t u d y do not s u p p o r t t h e h y p o t h e s i s b a s e d on animal experiments that morphinomimetics i n c r e a s e p l a s m a A N P level. R a t h e r , t h e p r e s e n t results a r e in a c c o r d a n c e w i t h t h e e a r l i e r observations t h a t t h e r e l e a s e o f a t r i a l n a t r i u r e t i c pept i d e into t h e b l o o d s t r e a m is r e g u l a t e d by a t r i a l stretch. ACKNOWLEDGMENT

The authors thank Mailis Himberg, Marja Ylh~iinen, and Ahmet Pekiner for excellent laboratory assistance.

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ATRIAL NATRIURETIC PEPTIDE CONCENTRATIONS

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