Cardiorespiratory Responses to Hypertonic Saline Solution in Cardiac Operations J. Boldt, MD, B. Zickmann, MD, M. Ballesteros, MD, Ch. Herold, F. Dapper, MD, and G. Hempelmann, MD Department of Anesthesiology and Intensive Care Medicine and Department of Cardiovascular Surgery, Justus-Liebig-University Giessen, Giessen, Germany
Infusion of small volumes of hypertonic saline solution (HS) seems to be of benefit in patients with impaired perfusion. The cardiorespiratory response to a 7.2% NaCl solution prepared in hydroxyethylstarch (HES) solution was investigated prospectively in patients undergoing prolonged cardiopulmonary bypass (CPB) (HS-HES group; n = 15); 6% HES 200/0.5 solution was infused in a control group (HES group; n = 15). Volume was given preoperatively to double low pulmonary artery occlusion pressure ( 30 mm Hg), renal malfunction (creatinine level > 130 pmol/L [1.5 mg/dL]), and Pblocking therapy. All patients had a pulmonary artery occlusion 0003-4975/91/$3.50
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pressure (PAOP) of less than 4 mm Hg after induction of anesthesia and the period of cardiopulmonary bypass (CPB) was expected to be greater than 100 minutes (more than five-vessel disease). The patients were randomly divided into 2 groups receiving either a new 7.2% hypertonic saline solution prepared in HES solution (osmolarity 2,400 m o s d ; 60 g/L 6%HES 200/0.5 [Fresenius, Bad Homburg, Germany]) (HS-HES group; n = 15) or a "standard' HES solution (6%;mean molecular weight 200.000; degree of substitution 0.5 [Fresenius]) (HES group; n = 15) to double reduced baseline PAOP value within 20 minutes before onset of the operation.
Anesthesia and Cardiopulmonary Bypass Introduction and maintenance of anesthesia were performed in a standardized manner using weight-related doses of fentanyl (total dose, 33.1 3.0 /*g/kg), midazolam (total dose, 0.61 k 0.1 mg/kg), and pancuronium bromide (total dose, 0.25 0.01 mg/kg); with regard to anesthesia no statistical differences could be demonstrated between the groups. All patients were on controlled mechanical ventilation within the investigation period (inspired oxygen fraction, 1.0; zero end-expiratory pressure). In the intensive care unit, inspired oxygen fraction was adjusted according to blood gas analyses; for better interpretation arterial oxygen tension/inspired oxygen fraction was used. Cardiopulmonary bypass was carried out with a nonpulsatile pump and membrane oxygenators (Sorin 41; Sorin, Turino, Italy). The circuit was primed with 1,000 mL of 5% dextrose solution, 1,000 mL of Ringer's solution, 250 mL of albumin 5% and electrolytes (20 mval potassium, 50 mL sodium 10%); a flow of 2.4 L/min . m2 was maintained during moderate hypothermia (esophageal temperature, 34.2" k 0.5"C). One liter of Bretschneider's cardioplegic solution (based on low sodium [15 mmol/L] and absence of calcium, contains mannitol [20 mmol/L] and is buffered with histidine [180 mmol/L], intracellular type of cardioplegic solution) was given initially for myocardial protection. A two-stage cannula was used for venous return into the circuit, and the operation was performed in "partial bypass" (monoatrial-cannulation technique). During bypass the lungs were kept statically inflated with a positive end-expiratory pressure of 5 cm H,O. Within 20 minutes after start of CPB, blood from the extracorporeal circuit was concentrated using an ultrafiltration device (hemofilter HF-80; Fresenius) to remove as much ultrafiltrate as used cardioplegic solution. When necessary, Ringer's solution was added to the heart-lung machine to maintain filling volume. During weaning off bypass as much pump blood as necessary to keep PAOP greater than 7 mm Hg but less than 13 mm Hg was infused. After termination of CPB, the residual blood of the extracorporeal oxygenation equipment was concentrated using the HF-80 system, and the autologous blood was retransfused until the end of the operation. Volume infusion (Ringer's solution when PAOP was less than 7 mm Hg; packed red cells when the hemoglobin value was less than 90 g/L) as well as administration of
*
*
611
catecholamines during and after weaning off bypass were given as indicated by anesthesiologists not involved in the study.
Data Points and Measured Variables Heart rate, mean arterial pressure, pulmonary arterial pressure, PAOP, cardiac output (thermodilution technique), and right atrial pressure were recorded, and derived variables (cardiac index, total systemic resistance) were calculated as well. Blood gas analyses were carried out from arterial as well as mixed-venous blood samples; oxygen consumption, oxygen delivery, and intrapulmonary right-to-left shunting were calculated by standard formulas [3]. Sodium concentration and blood osmolarity were measured from arterial blood samples. Measurement of hemodynamics was performed and blood samples were taken: 0. After induction of anesthesia (in hemodynamic steady state, before volume infusion = baseline values) 1. After doubling PAOP by volume application 2. 40 minutes after completing volume infusion 3. After termination of bypass (10 minutes after CPB, after decanulation) 4. At the end of the operation (45 minutes after termination of CPB) 5. 5 hours after termination of CPB (in intensive care unit). Fluid balances (volume input, urine output, blood loss) during CPB and in the intensive care unit were also calculated.
S tu tis tics All variables are expressed as mean values and standard deviation. One-factor and two-factor analyses of variance followed by Scheffb's test were used for statistical interpretation. Values of p less than 0.05 were considered significant.
Results Demographic data as well as data from CPB were without differences between the two groups (Table 1). Significantly less hypertonic solution (3.06 ? 0.2 mWkg) than standard HES solution (10.3 k 0.9 mL/kg) was necessary to double the baseline PAOP value. Fluid balance during CPB was negative in the HS-HES patients (-0.08 mL/ kg . min CPB), whereas HES patients had a positive fluid balance (+0.14 mL/kg . min CPB). Fluid balance was even lower in the HS-HES group during the first 5 hours after CPB (see Table 1). In the intensive care unit, less Ringer's solution was used in the HS-HES patients than in the HES patients (see Table 1). The amount of ultrafiltrate removed during and after bypass was without differences between the groups. Autologous blood prepared by the HF system from the pump blood after termination of CPB was comparable for both groups (HS-HES, 870 2 100 mL; HES, 890 k 130 mL). None of the patients received homologous blood or blood products before, during, or after bypass (including the first 5 hours).
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Table 1. Demographic, Fluid Balance, and Cardiopulmonary Bypass Data for the Two Groups" Variable Age (Y) Weight (kg) LVEF LVEDP (mm Hg) CPB (min) Ischemia (min) Fluid balance during CPB (mL/kg . min) Fluid balance 5 h after CPB (mL/kg . min) Ringer's solution 5 h after CPB (mL)
HS-HES
HES
57.1f 6.6 79.5f 6.0 0.71f 0.11 10.2f 4.1 115 f 5.9 79 f 10.1 -0.08 f 0.01"
60.6f 4.1 79.3f 6.3 0.72f 0.07 11.8f 2.5 110 f 6.8 75 f 8.8 +0.14 f 0.02
-0.03 f 0.01"
-0.01
1,000f 200
1,200f 250
f
'p
X
0.01
Q
Values shown as mean f standard deviation. p < 0.05 versus HES POUP. CPB = cardiopulmonary bypass; HES = 6% hydroxyethylstarch ZOO/ 0.5 solution; HS-HES = hypertonic saline solution in hydroxyethylstarch solution; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction.
During weaning from CPB epinephrine was necessary more often and at a higher dosage in the HES group (5 patients, 6.2 1.1 pg/min) than in the HS-HES patients (2 patients, 4.0 2 1.0 pg/min). With regard to hemodynamics no difference in mean arterial pressure, heart rate, and pulmonary arterial pressure between groups could be observed during the entire investigation period (Table 2). Cardiac index (Fig 1) increased in both groups, with a significantly greater increase in the HS-HES group (+40%). Cardiac index was greatest in these patients even after CPB. Total systemic resistance decreased significantly most in the HS-HES patients (-25%) (see Fig 1). Filling pressures (PAOP, right atrial pressure) increased after volume infusion in both groups but remained, however, significantly elevated in the HS-HES patients (Fig 2). After CPB, pulmonary gas exchange (arterial oxygen
*
.
2.3 6
DaSallne
a
0.05 SD
.
3*6L I
+
alter inlusion
1600
-
1300
-
40min alter
mfusion
after CPB
end 01 5 h after ODeration operation
SVR (dyn-rec-cm')
1100 -
900
-
0.05
p
X z SD 700
I
Fig 1 . Changes in cardiac index (CI) and systemic vascular resistance (SVR) in the two groups.
tension) was least compromised in HS-HES group and remained at the baseline level until the end of the investigation, whereas in the HES patients arterial oxygen tension decreased after bypass (Fig 3). Intrapulmonary right-to-left shunting was not changed in the HS-HES
Table 2. Hemodynarnic Changes and Changes in Sodium Concentration and Osmolarity in the Two Groups"
Variable MAP (mm Hg) HR (min-') PAP (mm Hg) Na+ (mmoUL) Osmolarity (mosm/L)
After Volume
40 Minutes After Volume (2)
Group
Baseline (0)
(1)
HS-HES HES HS-HES HES HS-HES HES HS-HES HES HS-HES HES
81.0f 9.2 80.5f 11.1 74.1f 10.2 72.3f 10.4 16.5 f 2.0 15.5f 1.9 143 f 3.5 141 f 2.3 308 f 3.9 307 f 4.1
81.5f 8.2 85.3f 5.1 73.1f 12.1 71.72 10.1 20.8f 4.4 19.3 2 2.5 150 f 1.9b 141 f 4.0 316 f 6.8b 307 4.8
*
85.3 f 11.1 80.0 f 10.1
80.5 f 8.8 85.8f 9.9 20.7f 5.4 19.7-+ 4.0 149 f 2.2b 142 f 3.6 317 f 2.0b 309 2 3.3
5 Hours End of After After CPB (3) Operation (4) Operation (5) 91.8f 8.7 81.2f 10.1 96.3f 12.1 95.6 2 10.1 20.7f 4.8 18.9f 3.0 144 -C 4.0 139 4.1 318 f 3.6 312 f 5.0
*
97.3f 7.4 100.1-+ 5.9 95.3f 11.9 95.2f 9.1 19.05 2.5 19.22 2.8 146 f 3.0 143 f 4.0 314 f 4.5 314 2 4.6
88.3f 8.0 80.1f 6.9 90.3 f 7.7 94.2f 9.6 20.1 2 3.3 19.0f 4.0 144 4.2 142 f 3.9 310 f 4.0 309 f 3.1
Values shown as mean f standard deviation. p < 0.05 versus HES group. HS-HES = hypertonic saline solution in hydroxyethylstarch solution; HR = heart rate; HES = 6%hydroxyethylstarch 200/0.5 solution; PAP = pulmonary arterial pressure. mean arterial pressure;
*
a
MAP =
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Ann Thorac Surg 1991;51:61&5
after 40mm after infusion Infusion
after CPB
end of 5 h after operation operation
10
8
6
4
p
(
0.05
613
of relatively small volumes of hypertonic saline solution in improving hemodynamics and outcome in comparison with much larger amounts of isotonic solution [5, 7, 161. DeFelippe and associates [17] studied the effects of 7.5% NaCl(2,400 m o s d ) in patients with terminal refractory, hypovolemic shock: 11 of 12 patients were successfully treated by infusion of hypertonic NaCl solution. Mazzoni and co-workers [18] documented by a mathematical model that after a 20% hemorrhage the addition of hypertonic solution amounting to one-seventh of the shed blood volume reestablished blood volume within 1 minute. This calculated effect could be verified by subsequent animal experiments. The initial improvement in cardiovascular function represented by an increase in cardiac output seems to be mediated by the hypertonicity of the solution; the solute composition does not seem to be important. However, maintenance of these cardiovascular responses is more dependent on solute than on hypertonicity [S]. Beneficial effects of hypertonic saline solution were reported to be rather transient [13]. Thus, the hypertonic solution was mixed with a colloid, ie, dextran, which resulted in a significant prolongation of its efficacy [6, 141. In the present study, hypertonic solution was prepared in HES solution due to its substantially less anaphylactic potency
E rSD
2
0 infusion
infusion
+HS-HES (11.15)
aiter CPB
end'ol opera!ion
5 h altar operation
pa02 (mmHg)
--s-HES (n-15) 450
Fig 2. Changes in pulmonary artery occlusion pressure (PAOP) and right atrial pressure (RAP) in the two groups. 400
group, but was increased in the HES patients after termination of bypass (see Fig 3). Oxygen consumption was without difference between the groups; oxygen delivery, however, increased significantly in the HS-HES patients. The increase in oxygen delivery remained even after weaning off bypass (Fig 4). Sodium concentration increased after infusion of the HS-HES solution but never exceeded 153 mmoVL (see Table 2), and it returned to values less than 145 mmoYL by the first postoperative day. Osmolarity also increased in the HS-HES patients, without exceeding 320 mosmoYL (see Table 2). After CPB, there were no more differences between the groups with regard to sodium concentration and osmolarity. None of the patients suffered from sequelae attributable to the study. Routinely monitored cerebral function was without differences between the groups. All patients were discharged from the intensive care unit at the third postoperative day at the latest and showed no differences in their postoperative course.
300
250 after 40mln after Infusion infusion
14
The use of hypertonic infusion for treatment of hypovolemia is not new: in 1919 Penfield [15] used hyperosmolar crystalloid injections in severe hemorrhagic shock. Several experimental and clinical data support the superiority
cpe
end o f 5 n after operation operation
lli _.
x
tSD
;1
12
Comment
after
0
1 10
basel,ne
after 40mm after infusion mfusion
+HS-HES (n.15)
after CPB --IT' HES
end o f 5 h after operation OPeralion
(n.15)
Fig 3. Changes in arterial oxygen tension (paO,) and intrapulrnonary right-to-left shunting (QsIQt) in the two groups.
614
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V02 (ml/min)
140
I
L *
p
0.05
x t SD baseline
infuslon
40rnin alter infusjon
infusion
infusion
alter
CPE
end of 5 halter operation operation
after CPE
end 5 alter ooeration operation
after
1400 1300 1200 1100 1000
1
900
800 700 -8- HS-HE5 (n.16)
bf
A
s-H E S (n.16)
Fig 4. Changes in oxygen consumption (VOJ and oxygen delivery (DO,) in the two groups.
and smaller coagulation impairment compared with dextran [19]. We have chosen a "standard" HES solution as control because using it an effective restoration of hemodynamic stability as well as oxygen transport could be achieved. Thus, HES solution is widely accepted for correction of volume deficits, even in cardiac surgery [19]. Fluid administration in our study increased cardiac output promptly in both groups and decreased total systemic resistance significantly, which can be explained by a decrease in viscosity and an increased cardiac index. Both hemodynamic changes were most pronounced in the patients who received HS-HES and were not transient, but lasted until the end of CPB. Oxygen consumption was not changed by infusion of HS-HES solution, whereas oxygen delivery was increased significantly in these patients, most likely due to a more pronounced increase in cardiac output. One of the major findings in this study was the reduction in fluid balance during CPB. This effect of the solution has to be stressed in these patients: according to Utley and Stephens [20], fluid balance during CPB summed up to 800 mL/kg . h of bypass. Breckenridge and associates [21] found a routine fluid accumulation during CPB summing up to a 33% increase in the measured extracellular fluid space postoperatively. In the present
investigation fluid balance was lowest in the HS-HES patients even 5 hours after bypass. When evaluating a new volume therapy in cardiac surgery not only hemodynamic effects are of interest; particular alterations associated with CPB have to be taken into consideration as well. Shires and colleagues [22] outlined the altered physiological function of cell membranes as a result of a low flow state: shock and trauma lead to extravasation of water and electrolytes into the interstitium. Cardiopulmonary bypass has to be regarded as an induced form of shock with an unphysiological nonpulsatile perfusion, low-pressure perfusion, and an impaired microcirculation induced by a release of various mediator systems [23]. In addition to the effective stabilization of macrohemodynamics, another potential beneficial effect of the hypertonic solution is the improvement in microhemodynamics. Besides direct vasodilatory properties, extraction of fluid from the capillary endothelium might be of importance. Mazzoni and associates [18] supposed that the hemodilution and endothelial cell shrinkage result in a decreased capillary hydraulic resistance. By this shrinkage of the endothelium the inner diameter of the capillary will be enhanced, resulting in decreased resistance. The concomitant decrease in viscosity by infusion of hypertonic solution will result in a reduction in hydraulic resistance of the capillaries. As swollen endothelium is observed after ischemia this aspect might be of particular interest in cardiac surgery patients, in whom both the lungs and the myocardium are subjected to a period of sustained ischemia during the period of CPB. Although we did not perform electronic microscopy, the improved pulmonary function after CPB (arterial oxygen tension and intrapulmonary right-to-left shunting not altered, which was in contrast to the control group) in our patients who received hypertonic HES solution before bypass might be explained not only by its fluid-reducing effects but also by an improvement in capillary tissue perfusion. This supports evidence that the lungs seem to be well protected against interstitial fluid accumulation and the negative effects associated with CPB. Moreover, it was demonstrated that application of hypertonic solution for resuscitation prevents an increase in pulmonary vascular resistance often described during the shock state and after CPB [24]. Thus, this hypertonic solution might be advantageous not only by an effective improvement in hemodynamics but also by a reduction in complications secondary to trauma such as CPB. Alterations of the integrity of the capillary membrane seem to be dependent on duration of bypass [25]. Thus, an extensive positive fluid balance during CPB will directly alter pulmonary function thereafter [24]. Bypass times were prolonged, but still moderate (200 minutes) these fluid-reducing effects (and postulated improvement in microhemodynamics) might be even more beneficial. It would be reasonable to assume that less fluid requirements during CPB will be correlated
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Ann Thorac Surg 1991:51:61CL5
with less pulmonary organ impairment and other sequelae [24]. There are, however, some theoretical problems when using hypertonic saline solutions: extreme hypernatremia and hyperosmolarity may result in cerebral dysfunction such as disorientation, confusion, and even seizure by disruption of the blood-brain barrier [7]. However, the sodium concentration in none of our patients exceeded 153 mmoYL, osmolarity was always less than 330 m o s d , and none of our patients had signs of cerebral dysfunction (by electroencephalographic monitoring during operation) or cerebral complications in the postoperative period. Moreover, serum osmolarity of 350 mosm/L without complications has been reported in humans [26]. In the present study, no differences in sodium and osmolarity between the groups were obvious after CPB. Nevertheless, when using hypertonic solutions for volume therapy, close measurements of sodium and osmolarity are of importance. It can be concluded that infusion of hypertonic saline solution prepared in HES solution resulted in an effective, and not only transient, improvement in hemodynamics. Patients undergoing lengthy CPB procedures will profit from this fluid regimen by a less pronounced fluid requirement during bypass and an improvement in microcirculation associated with less pronounced alterations in pulmonary organ function in the period after bypass.
References 1. Miller RD, Bove JR. Acquired immune deficiency syndrome and blood products. Anesthesiology 1983;58:4934. 2. Edwards JD, Nightingale P, Wilkins RG, Faragher EB. Hemodynamic and oxygen transport response to modified fluid gelatin in critically ill patients. Crit Care Med 1989;17:996-8. 3. Shoemaker WC, Hauser CJ. Critique of cristalloid versus colloid therapy in shock and shock lung. Crit Care Med 1979;7:117-24. 4. Shoemaker WC. Relation to oxygen transport patterns to the pathophysiology and therapy of shock states. Int Care Med 1987;13:23C4. 5. Armistead CW, Vincent JL, Preiser JC, DeBaker D, Minh TL. Hypertonic saline solution-hetastarch for fluid resuscitation in experimental septic shock. Anesth Analg 1989;69:714-20. 6. Kreimeier U, MeBmer K. New perspectives in resuscitation and prevention of multiple organ system failure. In: Baethmann A, Messmer K, eds. Surgical research: recent concepts and results. Berlin, Heidelberg: Springer, 1987:39. 7. Maningas PA, Bellamy RF. Hypertonic sodium chloride solution for the prehospital management of traumatic shock: a possible improvement in the standard of care? Ann Emerg Med 1986;15:14114. 8. Smith GJ, Kramer GC, Perron P, Nakayama SI, Gunther RA, Holcroft JW. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res 1985;39:517-28. 9. Velasco IT, Pontieri V, Silva RE, Lopes OU. Hyperosmotic
10. 11.
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14.
15.
16.
17.
18.
19.
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21.
22.
23.
24.
25.
26.
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NaCl and severe hemorrhagic shock. Am J Physiol1988;239: H664-73. Read RC, Johnson JA, Vick JA. Vascular effects of hypertonic solutions. Circ Res 1960;8:53844. Baue AE, Tragus ET, Parkins WM. A comparison of isotonic and hypertonic solutions and blood on blood flow and oxygen consumption in the initial treatment of hemorrhagic shock. J Trauma 1967;774>56. Koch-Weser J. Influence of osmolarity of perfusate on contractility of mammalian myocardium. J Physiol (Lond) 1958; 143:51540. Nakayama SI, Sibley L, Gunther RA, Holcroft JW, Kramer GC. Small-volume resuscitation with hypertonic saline (2.400 mOsm/liter) during hemorrhagic shock. Circ Shock 1984;13: 149-59. Maningas PA, DeGuzman LR, Tillman FJ, Hinson CS, Priegnitz KJ, Vok KA. Small volume infusion of 7.5% NaCU6% dextran 70 for the treatment of severe hemorrhagic shock in swine. Ann Emerg Med 1986;15:1131-7. Penfield WG. The treatment of severe and progressive haemorrhage by intravenous injections. Am J Physiol 1919;48: 121-8. Shackford SR, Sise MJ, Fridlund PH, et al. Hypertonic sodium lactate versus lactated Ringer’s solution for intravenous fluid therapy in operations on the abdominal aorta. Surgery 1983;1:41-51. DeFilippe J, Timoner J, Velasco IT, Lopes OU, Rocha E, Silva M. Treatment of refractory hypovolemic shock by 7.5% sodium chloride injections. Lancet 1980;2:10024. Mazzoni MC, Borgstrom P, Arfors KE, Intaglietta M. Dynamic fluid redistribution in hyperosmotic resuscitation of hypovolemic hemorrhage. Am J Physiol 1988;255:H629-37. London ML. Plasma expansion in cardiovascular surgery: practical realities, theoretical concerns. J Cardiothorac Anesth 1988;6 (Suppl 1):3949. Utley JR, Stephens DB. Fluid balance during cardiopulmonary bypass. In: Utley JR, ed. Pathophysiology and technique of cardiopulmonary bypass, vol I. Baltimore: Williams & Wilkins, 1982:23. Breckenridge IM, Diggerness SB, Kirklin JW. Increased extracellular fluid after open intracardiac operation. Surg Gynecol Obstet 1970;131:53-8. Shires GT, Cunningham JN, Barker CRF. Alterations in cellular membrane function after large hemorrhage. Ann Surg 1972;176:288-95. Chenoweth E, Cooper SW, Hugli, Stewart RW, Blackstone EH, Kirklin JW. Complement activation during cardiopulmonary bypass. Evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 1981;304:497-503. Peters RM. Effects of cardiopulmonary bypass on lung function. In: Utley JR, ed. Pathophysiology and technique of cardiopulmonary bypass, vol 11. Baltimore: Williams & Wilkins, 1983:164. Wisselink P, Feola M, Alfrey CP, Suzuki M, Ross JL, Kennedy JH. Prolonged partial cardiopulmonary bypass and the integrity of small blood vessels. J Thorac Cardiovasc Surg 1970;60:789-95. Monafo WW, Chuntrasakul C, Ayvazian V. Hypertonic sodium solution in the treatment of bum shock. Am J Surg 1973;126:773-80.
Infusion of small volumes of hypertonic saline solution (HS) seems to be of benefit in patients with impaired perfusion. The cardiorespiratory response to a 7.2% NaCl solution prepared in hydroxyethylstarch (HES) solution was investigated prospectively in patients undergoing prolonged cardiopulmonary bypass (CPB) (HS-HES group; n = 15); 6% HES 200/0.5 solution was infused in a control group (HES group; n = 15). Volume was given preoperatively to double low pulmonary artery occlusion pressure ( 30 mm Hg), renal malfunction (creatinine level > 130 pmol/L [1.5 mg/dL]), and Pblocking therapy. All patients had a pulmonary artery occlusion 0003-4975/91/$3.50
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Ann Thorac Surg 1991;51:610-5
pressure (PAOP) of less than 4 mm Hg after induction of anesthesia and the period of cardiopulmonary bypass (CPB) was expected to be greater than 100 minutes (more than five-vessel disease). The patients were randomly divided into 2 groups receiving either a new 7.2% hypertonic saline solution prepared in HES solution (osmolarity 2,400 m o s d ; 60 g/L 6%HES 200/0.5 [Fresenius, Bad Homburg, Germany]) (HS-HES group; n = 15) or a "standard' HES solution (6%;mean molecular weight 200.000; degree of substitution 0.5 [Fresenius]) (HES group; n = 15) to double reduced baseline PAOP value within 20 minutes before onset of the operation.
Anesthesia and Cardiopulmonary Bypass Introduction and maintenance of anesthesia were performed in a standardized manner using weight-related doses of fentanyl (total dose, 33.1 3.0 /*g/kg), midazolam (total dose, 0.61 k 0.1 mg/kg), and pancuronium bromide (total dose, 0.25 0.01 mg/kg); with regard to anesthesia no statistical differences could be demonstrated between the groups. All patients were on controlled mechanical ventilation within the investigation period (inspired oxygen fraction, 1.0; zero end-expiratory pressure). In the intensive care unit, inspired oxygen fraction was adjusted according to blood gas analyses; for better interpretation arterial oxygen tension/inspired oxygen fraction was used. Cardiopulmonary bypass was carried out with a nonpulsatile pump and membrane oxygenators (Sorin 41; Sorin, Turino, Italy). The circuit was primed with 1,000 mL of 5% dextrose solution, 1,000 mL of Ringer's solution, 250 mL of albumin 5% and electrolytes (20 mval potassium, 50 mL sodium 10%); a flow of 2.4 L/min . m2 was maintained during moderate hypothermia (esophageal temperature, 34.2" k 0.5"C). One liter of Bretschneider's cardioplegic solution (based on low sodium [15 mmol/L] and absence of calcium, contains mannitol [20 mmol/L] and is buffered with histidine [180 mmol/L], intracellular type of cardioplegic solution) was given initially for myocardial protection. A two-stage cannula was used for venous return into the circuit, and the operation was performed in "partial bypass" (monoatrial-cannulation technique). During bypass the lungs were kept statically inflated with a positive end-expiratory pressure of 5 cm H,O. Within 20 minutes after start of CPB, blood from the extracorporeal circuit was concentrated using an ultrafiltration device (hemofilter HF-80; Fresenius) to remove as much ultrafiltrate as used cardioplegic solution. When necessary, Ringer's solution was added to the heart-lung machine to maintain filling volume. During weaning off bypass as much pump blood as necessary to keep PAOP greater than 7 mm Hg but less than 13 mm Hg was infused. After termination of CPB, the residual blood of the extracorporeal oxygenation equipment was concentrated using the HF-80 system, and the autologous blood was retransfused until the end of the operation. Volume infusion (Ringer's solution when PAOP was less than 7 mm Hg; packed red cells when the hemoglobin value was less than 90 g/L) as well as administration of
*
*
611
catecholamines during and after weaning off bypass were given as indicated by anesthesiologists not involved in the study.
Data Points and Measured Variables Heart rate, mean arterial pressure, pulmonary arterial pressure, PAOP, cardiac output (thermodilution technique), and right atrial pressure were recorded, and derived variables (cardiac index, total systemic resistance) were calculated as well. Blood gas analyses were carried out from arterial as well as mixed-venous blood samples; oxygen consumption, oxygen delivery, and intrapulmonary right-to-left shunting were calculated by standard formulas [3]. Sodium concentration and blood osmolarity were measured from arterial blood samples. Measurement of hemodynamics was performed and blood samples were taken: 0. After induction of anesthesia (in hemodynamic steady state, before volume infusion = baseline values) 1. After doubling PAOP by volume application 2. 40 minutes after completing volume infusion 3. After termination of bypass (10 minutes after CPB, after decanulation) 4. At the end of the operation (45 minutes after termination of CPB) 5. 5 hours after termination of CPB (in intensive care unit). Fluid balances (volume input, urine output, blood loss) during CPB and in the intensive care unit were also calculated.
S tu tis tics All variables are expressed as mean values and standard deviation. One-factor and two-factor analyses of variance followed by Scheffb's test were used for statistical interpretation. Values of p less than 0.05 were considered significant.
Results Demographic data as well as data from CPB were without differences between the two groups (Table 1). Significantly less hypertonic solution (3.06 ? 0.2 mWkg) than standard HES solution (10.3 k 0.9 mL/kg) was necessary to double the baseline PAOP value. Fluid balance during CPB was negative in the HS-HES patients (-0.08 mL/ kg . min CPB), whereas HES patients had a positive fluid balance (+0.14 mL/kg . min CPB). Fluid balance was even lower in the HS-HES group during the first 5 hours after CPB (see Table 1). In the intensive care unit, less Ringer's solution was used in the HS-HES patients than in the HES patients (see Table 1). The amount of ultrafiltrate removed during and after bypass was without differences between the groups. Autologous blood prepared by the HF system from the pump blood after termination of CPB was comparable for both groups (HS-HES, 870 2 100 mL; HES, 890 k 130 mL). None of the patients received homologous blood or blood products before, during, or after bypass (including the first 5 hours).
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Table 1. Demographic, Fluid Balance, and Cardiopulmonary Bypass Data for the Two Groups" Variable Age (Y) Weight (kg) LVEF LVEDP (mm Hg) CPB (min) Ischemia (min) Fluid balance during CPB (mL/kg . min) Fluid balance 5 h after CPB (mL/kg . min) Ringer's solution 5 h after CPB (mL)
HS-HES
HES
57.1f 6.6 79.5f 6.0 0.71f 0.11 10.2f 4.1 115 f 5.9 79 f 10.1 -0.08 f 0.01"
60.6f 4.1 79.3f 6.3 0.72f 0.07 11.8f 2.5 110 f 6.8 75 f 8.8 +0.14 f 0.02
-0.03 f 0.01"
-0.01
1,000f 200
1,200f 250
f
'p
X
0.01
Q
Values shown as mean f standard deviation. p < 0.05 versus HES POUP. CPB = cardiopulmonary bypass; HES = 6% hydroxyethylstarch ZOO/ 0.5 solution; HS-HES = hypertonic saline solution in hydroxyethylstarch solution; LVEDP = left ventricular end-diastolic pressure; LVEF = left ventricular ejection fraction.
During weaning from CPB epinephrine was necessary more often and at a higher dosage in the HES group (5 patients, 6.2 1.1 pg/min) than in the HS-HES patients (2 patients, 4.0 2 1.0 pg/min). With regard to hemodynamics no difference in mean arterial pressure, heart rate, and pulmonary arterial pressure between groups could be observed during the entire investigation period (Table 2). Cardiac index (Fig 1) increased in both groups, with a significantly greater increase in the HS-HES group (+40%). Cardiac index was greatest in these patients even after CPB. Total systemic resistance decreased significantly most in the HS-HES patients (-25%) (see Fig 1). Filling pressures (PAOP, right atrial pressure) increased after volume infusion in both groups but remained, however, significantly elevated in the HS-HES patients (Fig 2). After CPB, pulmonary gas exchange (arterial oxygen
*
.
2.3 6
DaSallne
a
0.05 SD
.
3*6L I
+
alter inlusion
1600
-
1300
-
40min alter
mfusion
after CPB
end 01 5 h after ODeration operation
SVR (dyn-rec-cm')
1100 -
900
-
0.05
p
X z SD 700
I
Fig 1 . Changes in cardiac index (CI) and systemic vascular resistance (SVR) in the two groups.
tension) was least compromised in HS-HES group and remained at the baseline level until the end of the investigation, whereas in the HES patients arterial oxygen tension decreased after bypass (Fig 3). Intrapulmonary right-to-left shunting was not changed in the HS-HES
Table 2. Hemodynarnic Changes and Changes in Sodium Concentration and Osmolarity in the Two Groups"
Variable MAP (mm Hg) HR (min-') PAP (mm Hg) Na+ (mmoUL) Osmolarity (mosm/L)
After Volume
40 Minutes After Volume (2)
Group
Baseline (0)
(1)
HS-HES HES HS-HES HES HS-HES HES HS-HES HES HS-HES HES
81.0f 9.2 80.5f 11.1 74.1f 10.2 72.3f 10.4 16.5 f 2.0 15.5f 1.9 143 f 3.5 141 f 2.3 308 f 3.9 307 f 4.1
81.5f 8.2 85.3f 5.1 73.1f 12.1 71.72 10.1 20.8f 4.4 19.3 2 2.5 150 f 1.9b 141 f 4.0 316 f 6.8b 307 4.8
*
85.3 f 11.1 80.0 f 10.1
80.5 f 8.8 85.8f 9.9 20.7f 5.4 19.7-+ 4.0 149 f 2.2b 142 f 3.6 317 f 2.0b 309 2 3.3
5 Hours End of After After CPB (3) Operation (4) Operation (5) 91.8f 8.7 81.2f 10.1 96.3f 12.1 95.6 2 10.1 20.7f 4.8 18.9f 3.0 144 -C 4.0 139 4.1 318 f 3.6 312 f 5.0
*
97.3f 7.4 100.1-+ 5.9 95.3f 11.9 95.2f 9.1 19.05 2.5 19.22 2.8 146 f 3.0 143 f 4.0 314 f 4.5 314 2 4.6
88.3f 8.0 80.1f 6.9 90.3 f 7.7 94.2f 9.6 20.1 2 3.3 19.0f 4.0 144 4.2 142 f 3.9 310 f 4.0 309 f 3.1
Values shown as mean f standard deviation. p < 0.05 versus HES group. HS-HES = hypertonic saline solution in hydroxyethylstarch solution; HR = heart rate; HES = 6%hydroxyethylstarch 200/0.5 solution; PAP = pulmonary arterial pressure. mean arterial pressure;
*
a
MAP =
BOLDT ET AL HYPERTONIC VOLUME REPLACEMENT
Ann Thorac Surg 1991;51:61&5
after 40mm after infusion Infusion
after CPB
end of 5 h after operation operation
10
8
6
4
p
(
0.05
613
of relatively small volumes of hypertonic saline solution in improving hemodynamics and outcome in comparison with much larger amounts of isotonic solution [5, 7, 161. DeFelippe and associates [17] studied the effects of 7.5% NaCl(2,400 m o s d ) in patients with terminal refractory, hypovolemic shock: 11 of 12 patients were successfully treated by infusion of hypertonic NaCl solution. Mazzoni and co-workers [18] documented by a mathematical model that after a 20% hemorrhage the addition of hypertonic solution amounting to one-seventh of the shed blood volume reestablished blood volume within 1 minute. This calculated effect could be verified by subsequent animal experiments. The initial improvement in cardiovascular function represented by an increase in cardiac output seems to be mediated by the hypertonicity of the solution; the solute composition does not seem to be important. However, maintenance of these cardiovascular responses is more dependent on solute than on hypertonicity [S]. Beneficial effects of hypertonic saline solution were reported to be rather transient [13]. Thus, the hypertonic solution was mixed with a colloid, ie, dextran, which resulted in a significant prolongation of its efficacy [6, 141. In the present study, hypertonic solution was prepared in HES solution due to its substantially less anaphylactic potency
E rSD
2
0 infusion
infusion
+HS-HES (11.15)
aiter CPB
end'ol opera!ion
5 h altar operation
pa02 (mmHg)
--s-HES (n-15) 450
Fig 2. Changes in pulmonary artery occlusion pressure (PAOP) and right atrial pressure (RAP) in the two groups. 400
group, but was increased in the HES patients after termination of bypass (see Fig 3). Oxygen consumption was without difference between the groups; oxygen delivery, however, increased significantly in the HS-HES patients. The increase in oxygen delivery remained even after weaning off bypass (Fig 4). Sodium concentration increased after infusion of the HS-HES solution but never exceeded 153 mmoVL (see Table 2), and it returned to values less than 145 mmoYL by the first postoperative day. Osmolarity also increased in the HS-HES patients, without exceeding 320 mosmoYL (see Table 2). After CPB, there were no more differences between the groups with regard to sodium concentration and osmolarity. None of the patients suffered from sequelae attributable to the study. Routinely monitored cerebral function was without differences between the groups. All patients were discharged from the intensive care unit at the third postoperative day at the latest and showed no differences in their postoperative course.
300
250 after 40mln after Infusion infusion
14
The use of hypertonic infusion for treatment of hypovolemia is not new: in 1919 Penfield [15] used hyperosmolar crystalloid injections in severe hemorrhagic shock. Several experimental and clinical data support the superiority
cpe
end o f 5 n after operation operation
lli _.
x
tSD
;1
12
Comment
after
0
1 10
basel,ne
after 40mm after infusion mfusion
+HS-HES (n.15)
after CPB --IT' HES
end o f 5 h after operation OPeralion
(n.15)
Fig 3. Changes in arterial oxygen tension (paO,) and intrapulrnonary right-to-left shunting (QsIQt) in the two groups.
614
BOLDT ET AL HYPERTONIC VOLUME REPLACEMENT
Ann Thorac Surg 1991;51:61&5
V02 (ml/min)
140
I
L *
p
0.05
x t SD baseline
infuslon
40rnin alter infusjon
infusion
infusion
alter
CPE
end of 5 halter operation operation
after CPE
end 5 alter ooeration operation
after
1400 1300 1200 1100 1000
1
900
800 700 -8- HS-HE5 (n.16)
bf
A
s-H E S (n.16)
Fig 4. Changes in oxygen consumption (VOJ and oxygen delivery (DO,) in the two groups.
and smaller coagulation impairment compared with dextran [19]. We have chosen a "standard" HES solution as control because using it an effective restoration of hemodynamic stability as well as oxygen transport could be achieved. Thus, HES solution is widely accepted for correction of volume deficits, even in cardiac surgery [19]. Fluid administration in our study increased cardiac output promptly in both groups and decreased total systemic resistance significantly, which can be explained by a decrease in viscosity and an increased cardiac index. Both hemodynamic changes were most pronounced in the patients who received HS-HES and were not transient, but lasted until the end of CPB. Oxygen consumption was not changed by infusion of HS-HES solution, whereas oxygen delivery was increased significantly in these patients, most likely due to a more pronounced increase in cardiac output. One of the major findings in this study was the reduction in fluid balance during CPB. This effect of the solution has to be stressed in these patients: according to Utley and Stephens [20], fluid balance during CPB summed up to 800 mL/kg . h of bypass. Breckenridge and associates [21] found a routine fluid accumulation during CPB summing up to a 33% increase in the measured extracellular fluid space postoperatively. In the present
investigation fluid balance was lowest in the HS-HES patients even 5 hours after bypass. When evaluating a new volume therapy in cardiac surgery not only hemodynamic effects are of interest; particular alterations associated with CPB have to be taken into consideration as well. Shires and colleagues [22] outlined the altered physiological function of cell membranes as a result of a low flow state: shock and trauma lead to extravasation of water and electrolytes into the interstitium. Cardiopulmonary bypass has to be regarded as an induced form of shock with an unphysiological nonpulsatile perfusion, low-pressure perfusion, and an impaired microcirculation induced by a release of various mediator systems [23]. In addition to the effective stabilization of macrohemodynamics, another potential beneficial effect of the hypertonic solution is the improvement in microhemodynamics. Besides direct vasodilatory properties, extraction of fluid from the capillary endothelium might be of importance. Mazzoni and associates [18] supposed that the hemodilution and endothelial cell shrinkage result in a decreased capillary hydraulic resistance. By this shrinkage of the endothelium the inner diameter of the capillary will be enhanced, resulting in decreased resistance. The concomitant decrease in viscosity by infusion of hypertonic solution will result in a reduction in hydraulic resistance of the capillaries. As swollen endothelium is observed after ischemia this aspect might be of particular interest in cardiac surgery patients, in whom both the lungs and the myocardium are subjected to a period of sustained ischemia during the period of CPB. Although we did not perform electronic microscopy, the improved pulmonary function after CPB (arterial oxygen tension and intrapulmonary right-to-left shunting not altered, which was in contrast to the control group) in our patients who received hypertonic HES solution before bypass might be explained not only by its fluid-reducing effects but also by an improvement in capillary tissue perfusion. This supports evidence that the lungs seem to be well protected against interstitial fluid accumulation and the negative effects associated with CPB. Moreover, it was demonstrated that application of hypertonic solution for resuscitation prevents an increase in pulmonary vascular resistance often described during the shock state and after CPB [24]. Thus, this hypertonic solution might be advantageous not only by an effective improvement in hemodynamics but also by a reduction in complications secondary to trauma such as CPB. Alterations of the integrity of the capillary membrane seem to be dependent on duration of bypass [25]. Thus, an extensive positive fluid balance during CPB will directly alter pulmonary function thereafter [24]. Bypass times were prolonged, but still moderate (200 minutes) these fluid-reducing effects (and postulated improvement in microhemodynamics) might be even more beneficial. It would be reasonable to assume that less fluid requirements during CPB will be correlated
BOLDT ET AL HYPERTONIC VOLUME REPLACEMENT
Ann Thorac Surg 1991:51:61CL5
with less pulmonary organ impairment and other sequelae [24]. There are, however, some theoretical problems when using hypertonic saline solutions: extreme hypernatremia and hyperosmolarity may result in cerebral dysfunction such as disorientation, confusion, and even seizure by disruption of the blood-brain barrier [7]. However, the sodium concentration in none of our patients exceeded 153 mmoYL, osmolarity was always less than 330 m o s d , and none of our patients had signs of cerebral dysfunction (by electroencephalographic monitoring during operation) or cerebral complications in the postoperative period. Moreover, serum osmolarity of 350 mosm/L without complications has been reported in humans [26]. In the present study, no differences in sodium and osmolarity between the groups were obvious after CPB. Nevertheless, when using hypertonic solutions for volume therapy, close measurements of sodium and osmolarity are of importance. It can be concluded that infusion of hypertonic saline solution prepared in HES solution resulted in an effective, and not only transient, improvement in hemodynamics. Patients undergoing lengthy CPB procedures will profit from this fluid regimen by a less pronounced fluid requirement during bypass and an improvement in microcirculation associated with less pronounced alterations in pulmonary organ function in the period after bypass.
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