Esmolol Infusion During Nitroprusside-Induced Hemodynamics, Ventricular Performance, Nitin Shah, MD, Oscar Del Valle, Deborah

Matarazzo,

MD, Richard

CRNA,

Andre

Edmondson,

Rogatko,

C

ONTROLLED HYPOTENSION is commonly used to produce a bloodless surgical field and/or to reduce intraoperative bleeding and the consequent need for blood transfusion. The most frequently used agent for inducing controlled hypotension is sodium nitroprusside (SNP), although there arc a number of problems associated with its use. Chief among these problems is reflex activation of the sympathetic and renin-angiotensin systems.” which can lead to tachycardia, rebound hypertension,‘,’ tachyphylaxis,‘-’ and SNP overdose.7-‘s In addition, SNP is associated with dose-dependent inhibition of hypoxic pulmonary vasoconstriction, which can cause hypoxemia in the presence of preexisting pulmonary pathology.“~” Esmolol is known to markedly decrease the dose of SNP required for producing deliberate intraoperative hypotension. This effect is associated with improved oxygenation and reductions in heart rate (HR), plasma renin activity (PRA), and norepinephrine levels.” Because esmolol has a time-action curve similar to that of SNP,” it seems to be an ideal agent both for reducing SNP dose requirement and for preventing rebound hypertension. Although esmolol has been shown to reduce cardiac output (CO) in patients undergoing cardiovascular surgery,Z4 its impact on hemodynamic variables, left ventricular performance, and intrapulmonary shunting during SNPinduced afterload reduction has not been investigated. The

From the Division of Biostatistics, Department of Anesthesiology and Cn’tical Care Medicine, Memorial Sloan-Kettering Cancer Center, Cornell UniversityMedical College, New York, NY Address reprint requests to Nitin Shah, MD, Department ofAnesthesiology and Critical Care Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. Copyright o 1992 by I+!B. Saunders Company 1053-0770/9210602-0015$03.0010 fRichard Edmondson, MD, is deceased. 196

MD,’ Gregory

PhD, Alisa Thorne,

The impact of esmolol infusion on hemodynamics, ventricular performance, venous admixture, sympathoadrenal, and rerun-angiotensin system responses during sodium nitroprusside (SNP)-induced hypotension was studied in 11 patients undergoing lymph node dissection during general anesthesia with 60% nitrous oxide and fentanyl. Radial arterial and thermistor-tipped pulmonary catheters were employed for hemodynamic monitoring. Arterial and mixed venous blood gas tensions, arterial plasma renin activity (PRA), and plasma catecholamine levels were measured. Derived hemodynamic parameters and venous admixture (Qs/Qt) data were obtained from standard equations. Transesophageal echocardiography (6 patients) was used to assess left ventricular performance using the relationship between end-systolic wall stress (ESWS) and velocity of circumferential shortening (VCFC). After surgical incision, arterial hypotension was induced with SNP alone. Esmolol was infused at each of the following rates in sequence: 200,300, and 400 pglkgf min. Each esmolol infusion lasted 20 minutes and the SNP dose was adjusted to maintain MAP at 55 to 60 mm Hg. The mean

Hypotension: Impact and Venous Admixture Acampora,

MD, Donna

MD, and Robert

Dwyer,

F. Bedford,

on CRNA,

MD

dose of SNP required to induce hypotension was 5.5 pg/ kg/ min -C 0.5 SE. Compared to prehypotension values, SNP induced significant increases in Qs/Qt and reductions in PaO,, systemic vascular resistance (SW?), and stroke volume index (SVI). Esmolol infusion caused dose-dependent (highest with 400 pg/kg/min) reductions in the SNP requirement, heart rate (HR), SVI, Qs/Qt, and PRA, and also led to significant increases in SVR and left ventricular (LV) internal diameter in diastole as well as systole. Furthermore, esmolol infusion was associated with a dose-dependent downward and leftward shift of the ESWS versus VCFC relationship, implying diminished contractility. These findings indicate that p-blockade with esmolol during SNP-induced hypotension is effective in reducing SNP dose requirement and PRA, while improving arterial oxygenation. However, in this setting, esmolol causes reductions in cardiac inotropic and chronotropic responses, resulting in diminished ventricular performance. Copyright d 1992 by W. B. Saunders Company

present study was instituted to further document the ef’ccts of an esmolol infusion during intraoperative hypotension, using both invasive hemodynamic measurement techniques and two-dimensional (2D) transesophageal echocardiography (TEE).

MATERIALS

AND METHODS

The subjects of this investigation were 1I patients, ASA physical status I or II, with a mean age of 31 years (range, 26 to 44) scheduled for retroperitoneal lymph node dissection. The protocol was reviewed and approved by the Institutional Review Board and

informed consent was obtained from each patient on the day before surgery. Premeditation consisted of meperidine, I mgikg, hydroxyzine, 1 mgikg. and glycopyrrolate, 0.2 mg, intramuscularly. 1 hour before surgery. Radial artery catheters and thermistortipped pulmonary artery catheters were inserted for pressure measurement and for sampling arterial and mixed venous blood. All pressures were transduced and continuously recorded with the zero reference point at the level of the midaxillary line. Anesthesia was induced with thiopental, 3 to 5 mgikg, and fentanyl, S kg/kg, intravenously, and maintained with 60% N,O in O?, supplemented with fentanyl, 10 ugikglhr. Vecuronium was used for muscle relaxation; ventilation was controlled to maintain end-tidal CO1 tension at 35 mm Hg (Perkin Elmer Mass Spectrometer). The following parameters were determined: HR, mean arterial pressure (MAP), right atrial pressure (RAP), mean pulmonary artery pressure (MPAP), pulmonary capillary wedge pressure (PCWP) at end-exhalation, and CO using the thermodilution technique in triplicate. Arterial blood samples were collected anaerobically for the determination of blood gas tensions, PRA (radioimmunoassay, New England Nuclear, Billerica, ME), and plasma catecholamine levels (high-performance liquid chromatography and electrochemical detection assay) using the method of Moyer et al.‘5 Mixed venous and arterial oxygen content were determined directly using a Corning Model 168 cooximeter. Derived parameters and pulmonary venous admixture were calculated from standard formulae. In 6 patients, a Hewlett-Packard 2D TEE machine (model

Journalof Cardiothoracic and VascularAnesthesia,

Vol6, No 2

(April),1992:

pp 196-200

ESMOLOL

197

INFUSION

200

using a transesophageal probe (2D TEE) was placed to make temporal and dimensional measurements. To isolate contractility in a fashion independent of HR, preload, and afterload, the relationship of end-systolic wall stress (ESWS) to rate-corrected velocity of circumferential shortening (VCFC) was used.“Xz7Aortic valve opening time was used to calculate left ventricular ejection time (LVET)**; short-axis 2D M-mode dimensions were used to determine LV posterior wall thickness (PWT) and LV internal dimensions (LVID). VCFC was calculated from the formula: 77020-AC)

PaO, 190 (mm Hg) ,Oo ;;; 100 “‘

PVR (dynewcms)

z!?.m VCFC = LVET where FS is the fractional percentage of shortening and RR is the R-R interval. ESWS was calculated from the formula:

co (L/min)

i)S/&

ESWS =

v=)

PWT x 1 + LVIDS

$t 6

t 1% ??

1

??

6

t

5

where P is the systolic pressure, LVIDS is the LV internal diameter at systole, and PWT is the posterior wall thickness at systole. Echocardiographic data were recorded on standard VHS format videotape. All measurements were made on-line using the internal calipers and software incorporated in the HP-22070-AC. Calculations were completed using a HP-29C hand-held programmable computer to apply the formulae. Data were recorded at 20 minutes after surgical incision had been performed, 20 minutes after MAP was lowered to 55-60 mmHg with SNP infusion, after 20 minutes of esmolol infusion at each of the following rates administered in sequence: 200,300, and 400 kgikgimin, with SNP doses adjusted to maintain MAP at 55 to 60 mm Hg, 20 minutes after termination of both SNP and esmolol. Echocardiographic data (ESWS vs VCFC) were plotted during normotension and during SNP-induced hypotension, without esmolol, and during esmolol infusion at 200 and 400 kgikgimin, and subjected to linear regression analysis. Linear F-tests were performed to compare the regression parameter estimates for the data at each dose of esmolol with the corresponding parameters found in the control condition. Hemodynamic and intrapulmonary venous admixture data were compared using one-sample multivariate profile analysis.29 Pair-wise comparisons were performed by Student’s t-test for paired data using Bonferroni correction for multiple comparisons. The statistical analysis was performed using the SAS statistical package (SAS Institute, Inc). The critical significance level of 5% was chosen.

-J t

SNP dose

4

(uglkglmin)

3 2

t

c- I 1

t

+

2’

t

/

I

SNP+ Incision E=O (Control)

I

SNP+ E=200

SNP+ E=300

t YT

t

t

e\

SNP+ E=400

Hypote”SlO”

Fig 1. Changes in arterial oxygen tension (PaO,), pulmonary vascular resistance (PVR), CO, pulmonary venous admiaure (Gs/Gt), and SNP dose requirement throughout the study. Esmolol (E) expressed in pg/kg/min. All values are mean + SE. ?? P c 0.05 versus control. tf -z 0.05 versus SNP + E =: 0.

RESULTS The hemodynamic and venous admixture data are summarized in Fig 1 and Table 1. Compared with the postincision data, SNP-induced hypotension resulted in a significant increase in QsiQt and significant reductions in PaO,, RAP, and PCWP.. As expected, increasing esmolol doses caused a dose-dependent reduction in SNP requirement. This was associated with significant reductions in HR, CI, Qs/Qt, and elevations in PCWP and RAP, compared with data obtained during SNP hypotension without esmolol. At

Table 1. Hemodynamic and Blood Gas Changes Throughout Study Sodium Nitroprusside

Parameter

Infusion

Post

Esmolol

Esmolol

Esmolol

incision

(Ol

(2001

(3001

MAP (mm Hg)

83 f 4

HR (beats/min)

90 + 14

Esmolol l400)

Normotension

56 2 2s

57 + 2*

56 + ‘I*

56 r 2*

80 t 3

102 + 14

79 ? 15t

74 + ‘l5t

72 + 13t

73 -t 13t

RAP (mm Hg)

821

521

721

8 + ‘I

9 + 1t

9 :t 1t

PCWP (mm Hg)

821

521

721

8+

9 + It

10 :i 1t

Cl (Llmin/m2) SW (dyn . set

5.2 + 0.2

. cmm5)

592 +

42

4.9 5 0.3 445 2 31*

3.8 2 0.3tX 575 * 47

‘It

3.3 + 0.3t* 670 + 89

2.8 2 0.3t*

3.5 + 0.2t*

795 + 122t

853 -c 54t*

SW (mL/mZ)

58.1 + 3.0

48.6 2 2.7*

44.0 2 :3.2t*

39.2 z? 3.7*t

48.7 e 3.7

PaCO, (mm Hg)

36.5 + 0.9

36.6 + 0.5

35.2 f 0.7

35.2 -t 0.9

35.5 + 0.8

37.2 f 0.9

PH PvO, (mm Hs)

7.45 -t .Ol

7.44 -c .Ol

7.45 2 .Ol

7.44 + 01

7.44 f .Ol

7.42 c .Ol*t

48.9 ? 1.5

48.8 + 4.3

43.5 f 3.8*

39.3 f 2.2*

36.9 + 1.7*

40.5 r 1.6’

NOTE. All values are Mean + SE ?? P < 0.05 vs Postincision tP < 0.05 vs Esmolol (0)

479 ? 2.5t

198

SHAH ET Al

1.4

I=

NormotenSion

y = 1.3911 -0.0064x

A = 0.67

2=

.

Esmolol z 0

3= 4=

II 0

[I

Esmolol:ZOO Esmolol=‘loo

y = 1.3531 - 0.005% y = 1.2019 -0.0052x y = 1.0257 -0.0052x

R = 0.76 A = 0.58 R = 0.97

1.2

1.0

significant increases in SVR, LVIDS, LVJD, and 11. and significant decreases in SVI and CJ. The humoral responses to SNP and esmolol infusion are summarized in Table 3. SNP-induced hypotension resulted in significant elevations in norepinephrine, which remained elevated during esmolol infusion at 200 and 300 kg/kg!min. Esmolol infusion at 400 pg/kg/min was associated with a significant reduction in PRA compared with values determined during hypotension before esmolol was begun.

were

0.0

DISCUSSION

0.6 a0

60

40

80

100

ESWS (g/cm’) Fig 2. Changes in LV performance, plotted as end-systolic wall stress (ESWS) measured in grams per cm’ (g/cm*) versus VCFC measured in LV circumferences per second (circ/s). SNP-induced hypotension had no effect on this relationship compared with the data obtained during normotension. In contrast, esmolol at 400 pg/kg/min caused a significant (P < 0.001) downward shift of this relationship, implying diminished LV contractility.

an esmolol dose of 400 bg/kg/min, there was also a significant reduction in SV and a return of PaO, and Qs/Qt to prehypotension values. There were no clinically significant changes in arterial PCO, or pH. The echocardiographic findings and corresponding cardiovascular parameters for the 6 patients studied by 2D TEE are summarized in Fig 2 and Table 2. Compared with the ESWS/VCFC relationship that existed during normotension, SNP-induced hypotension without esmolol caused no change in LV performance; both the slopes and intercepts of the relationships were identical. In contrast, esmolol infusion caused a dose-dependent downward and leftward shift of the ESWS/VCFC relationship, which reached statistical significance at an esmolol dose of 400 pg/kg/min. Specifically, the y-intercept of the 400 pg/kg/min dose of esmolol differed significantly (P < 0.001) from the control condition (y-intercept = 1.0257 versus 1.3911, respectively). The slopes of the regression lines were identical. These data imply diminished LV contractility associated with an esmolol infusion of 400 pg/kg/min; concurrently, there Table 2. Measurements

Esmolol is a logical agent to use for potentiation of SNP-induced hypotension. Unlike longer acting P-adrenergic blocking agents, esmolol has a time action curve similar to that of SNP, with a half-life of approximately 9 minutes.‘2 Thus, it should be possible to avoid the adverse effects of P-blockade, such as the masking of tachycardia caused by hypoxia or hypovolemia. However, this study indicates that the effects of esmolol may outlast those of SNP, because HR, CO, Qs/Qt, SVR, PVR, RAP, and PCWP were unchanged 20 minutes after terminating both SNP and esmolol infusions. Esmolol infusion clearly acts to counteract the reflexes that are thought to mediate both the tachycardia and tachyphylaxis to SNP, the baroreceptor responses and the renin-angiotensin system. In addition, these data confirm canine3” and human” studies suggesting that esmolol impairs myocardial performance. Thus, the potentiation of SNP-induced hypotension by esmolol is mediated by more than simply decreased PRA and norepinephrine levels caused by adrenergic blockade. The plot of ESWS/VCFC, which has been used to show the effects of pharmacological agents on myocardial performance in a load-insensitive fashion? also indicates a dose-dependent reduction in ventricular contractility, thus explaining the observed reductions in CI and SVI and increases in SVR, RAP, PCWP, LVIDS, and LVIDD. The impact of SNP on arterial oxygenation is controversial. Several studies have observed that SNP did not alter Qs/Qt in dogs with normal lungs,“.” and Stone et al” reported the same findings in humans. However, the present data support several other studies,h.2”,” in which

in Six Patients During Echocardiographic Sodwm

SNP dose (pglkglmin) HR (beats/min) MAP (mm Hg) Cl (L/min/m*) SVI (mL/m’) SVR (dyne.

s. cm-“)

PCWP (mm Hg)

Studies

Nitroprusside

Infusion

Post

Esmolol

Esmolol

Esmolol

incision

(0)

(200)

(400)

0

6+1

95 t- 4

105 2 6

6+1 84 5 2*

4t

1+

77 ?z 2f

82 & 4

57 -t 2

57 + 2

56 f 2

5.3 2 .3

5.2 ? .5

4.2 t .3

3.0 ? .3f

55 + 4

49 * 3

50 r 4

39 t 4*

562 + 32

411 5 26

507 2 39*

679 % 66*

622

622

822

LVIDD (cm)

4.6 + .2

4.2 +- .2

4.4 * .2

4.7 f .1*

LVIDS (cm)

3.0 -+ .2

2.6 ? .2

3.0 rt .2*

3.3 t .1*

NOTE. All values are Mean + SE. ?? P < 0.05 vs Esmolol(0).

722

199

ESMOLOL INFUSION

Table 3. Catecholamine

Levels and Plasma Renin Activity Throughout Study Sodium Nitroprusside

Infusion

Esmolol

Esmolol

ESIllOlOl

(0)

~200)

l3W

(4001

1.5 2 0.3t

ESltlOlOl Normotension

PRA (ng/mL/min)

4.3 k 0.8

5.4 + 1.3

2.5 + 0.4

2.1 r 0.4

NE (pg/mL)

246 + 34

420 + 34’

388 ? 46’

382 + 48*

337 2 49

187 + 37t

EPI (pg/mL)

59 + 28

138 + 48

215 f 34

184 + 31

230 ? 33

195 + 41

DOPA (pg/mL)

21 + 13

45 + 6

47% 11

60 r 22

482

10

532

10

1.7 f 0.4t

NOTE. All values are Mean ? SE. Abbreviations: PRA, plasma renin activity; NE, norepinephrine; EPI, epinephrine, DOPA, dopamine. ?? P < 0.05 vs postincision values tP < 0.05 vs esmolol(0)

SNP induced increases in Qs/Qt. It has been hypothesized that this impairment in oxygenation is primarily caused by SNP-induced inhibition of hypoxic pulmonary vasoconstriction (HPV).‘6,21 In the present study, it is likely that esmolol-induced reduction in SNP dose requirement is one reason for the improvement in oxygenation during esmolol infusion. This interpretation is supported by the upward trend in pulmonary vascular resistance with increasing doses of esmolol. However, of interest is the fact that oxygenation did not return to control values until esmolol infusion reached 400 pg/kg/min, despite a significant reduction in SNP dose requirement during esmolol infusion at 300 kg/kg/min. Given the cardiovascular depression present during 400 pg/kg/min of esmolol, it is likely that reduced CO also played a role in decreasing Qs/Qt and increasing PaO,.” Cheney and Colley? in an extensive review of the impact of CO on oxygenation, concluded that changes in CO may have a variable effect, depending primarily on the condition of the lungs. They contended that a decrease in CO is most likely to lead to an improvement in arterial oxygenation, independent of Qs/ Qt, when there is minimal pulmonary pathology, as was the case in the present study. P-Blockade with propranolol has been shown to potentiate SNP-induced hypotension and also to improve arterial oxygenation in patients with chronic lung disease (scoliosis).’ When Miller et aP5 examined this phenomenon in a canine model, they concluded that (1) propranolol did not reverse SNP-induced inhibition of lobar HPV, and (2) improvement in arterial oxygenation was probably related to a reduction in CO. In the present study, because it was only at an esmolol infusion rate of 400 pg/kg/min that PaO, and Qs/Qt returned to control levels, and at this time CO was at its nadir, it is believed that the concurrent improvement in oxygenation was probably the result of reduced CO.

Reduction of CO is not without risk to oxygenation. In the presence of constant oxygen consumption, reduced CO leads to an increase in peripheral oxygen extraction and a reduction in mixed venous oxygen content, reflected in the present study as a decrease in PvO,. As venous blood becomes more desaturated, it will result in a decreased PaO,, corresponding to the amount of venous admixture present.36 In the patients without pulmonary pathology, however, the reductions in PvO, that occurred during high-dose esmolol were well tolerated. It should be pointed out that the order of esmolol infusion was sequential and not randomized. Accordingly, it is possible that some of the effects observed at 300 and 400 kg/kg/min may have resulted from prolonged exposure to esmolol and/or to hypotensive blood pressure levels. Because the half-life of esmolol is only 9 minute? and the duration of each infusion was 20 minutes, it is doubted that there was a cumulative esmolol effect. Accordingly, the observed effects of esmolol on hemodynamics, oxygenation, and humoral parameters in this study were most likely caused by the dose of esmolol administered rather than by the sequence of administration. In conclusion, esmolol is effective in reducing the SNP dose requirement during controlled hypotension. In addition to preventing increases in HR and PRA, esmolol causes dose-dependent reductions in LV performance. Improved oxygenation during esmolol infusion was probably caused by a combination of decreased CO and reduced inhibition of HPV resulting from the decrease in SNP dose requirement. ACKNOWLEDGMENT

The authors thank Ruth Reinsel, PhD for her expertise in performing the statistical analysis of these data, and in memory of our colleague

and coauthor,

Richard

Edmondson,

MD.

REFERENCES

1. Marshall WK, Bedford RF, Arnold WP, et al: Effects of propranolol on the cardiovascular and renin-angiotensin systems during hypotension produced by sodium nitroprusside in man. Anesthesiology 55:277-280, 1981 2. Pettinger WA, Keeton K: Altered renin release and proprano101 potentiation of vasodilatory drug hypotension. J Clin Invest 55:236-243,1975 3. Khambatta HJ, Stone JG, Khan E: Propranolol alters renin release during nitroprusside-induced hypotension and prevents

hypertension on discontinuation of nitroprusside. Anesth Analg 60:569-573,1981 4. Khambatta HJ, Stone JG, Khan E: Hypertension during anesthesia on discontinuation of sodium nitroprusside-induced hypotension. Anesthesiology 51:127-130,1979 5. Amaranath L, Kellermeyer WF: Tachyphylaxis to sodium nitroprusside. Anesthesiology 44:345-348,1976 6. Bedford RF, Berry FA Jr, Longnecker DL: Impact of propranolol on hemodynamic response and blood cyanide levels

200

during nitroprusside infusion: A prospective study in anesthetized man. Anesth Analg 58466469, 1979 7. Cottrell JE, Pate1 K, Casthely P. et al: Nitroprusside tachyphylaxis without acidosis. Anesthesiology 49:141-142, 1978 8. Greiss L, Tremblay NAG, Davies DW: The toxicity of sodium nitroprusside. Cdn Anaesth Sot J 23:4X0-485, 1976 9. MacRae WR, Owen M: Severe metabolic acidosis following hypotension induced with sodium nitroprusside. Br J Anaesth 46795.797, 1974 10. Michenfelder JD: Cyanide release from sodium nitroprusside in the dog. Anesthesiology 46:196-201, 1977 Il. McDowall DG, Keaney NP, Turner JM, et al: The toxicity of sodium nitroprusside. Br J Anaesth 46327-332, 1974 12. Vesey CJ, Cole PL, Simpson PJ: Cyanide and thiocyanate concentrations following sodium nitroprusside infusion in man. Br J Anaesth 48:651-660, 1976 13. Michenfelder JD, Tinker JH: Cyanide toxicity and thiosulfate protection during chronic administration of sodium nitroprusside in the dog: Correlation with a human case. Anesthesiology 471441-448, 1977 14. Posner MA, Rodkey FL, Tobey RE: Nitroprusside-induced cyanide poisoning: Antidotal effect of hydroxocobalamin. Anesthesiology 44:330-335, 1976 15. Cottrell JE. Casthely P, Brodie JD, et al: Prevention of nitroprusside-induced cyanide toxicity with hydroxocobalamin. N Engl J Med 298:809-811, 1978 16. Benumof JL: Hypoxic pulmonary vasoconstriction and infusion of sodium nitroprusside. Anesthesiology 50:481-483, 1979 17. Colley PS, Cheney FW, Hlastala MP: Ventilation-perfusion and gas exchange effects of sodium nitroprusside in dogs with normal and edematous lungs. Anesthesiology 50:489-495, 1979 18. Hodges MR, Stanley TH, Johansen RK: Pulmonary shunt and cardiovascular responses to CPAP during nitroprussideinduced hypotension. Anesthesiology 46:339-341, 1977 19. Stone JG, Khambatta HJ, Matte0 RS: Pulmonary shunting during anesthesia with deliberate hypotension. Anesthesiology 45:508-515, 1976 20. Colley PS, Cheney FW: Sodium nitroprusside increases Qs/Qt in dogs with regional atelectasis. Anesthesiology 47:338341,1977 21. Hill AB, Sykes MK, Reyes A: A hypoxic pulmonaryvasoconstrictor response in dogs during and after infusion of sodium nitroprusside. Anesthesiology 50:481-488, 1979 22. Edmondson R. Del Valle 0, Shah N, et al: Esmolol for

SHAH Ei A

potentiation ot nitroprusside-lndtlced hypotension: lmpaci on II~