Hypertonic

Saline of Thermal Injury

Dextran Resuscitation

JURETA W. HORTON, PH.D., D. JEAN WHITE, M.S., and CHARLES R. BAXTER, M.D.

Burn treatment requires large volumes of crystalloid, which may exacerbate burn-induced cardiopulmonary dysfunction. Smallvolume hypertonic saline dextran (HSD) resuscitation has been used for effective treatment of several types of shock. In this study isolated coronary perfused guinea pig hearts were used to determine if HSD improved left ventricular contractile response to burn injuries. Parameters measured included left ventricular pressure (LVP) and maximal rate of LVP rise (+dP/dt max) and fall (-dP/dt max) at a constant preload. Third-degree scald burns comprising 45% of total body surface area (burn groups, N = 75), or 0% for controls (group 1, N = 25) were produced using a template device. In group 2, 25 burned guinea pigs were not fluid resuscitated and served as untreated burns; 20 burns were resuscitated with 4 mL lactated Ringer's (LR) solution/ kg/% burn for 24 hours (group 3); additional burn groups were treated with an initial bolus of HSD (4 mL/kg, 2400 mOsm, sodium chloride, 6% dextran 70) followed by either 1, 2, or 4 mL LR/kg/% burn over 24 hours (groups 4, 5, and 6, respectively). Untreated burn injury significantly impaired cardiac function, as indicated by a fall in LVP (from 88 ± 3 to 68 ± 4 mmHg; p = 0.01) and ±dP/dt max (from 1352 ± 50 to 1261 ± 90 and from 1150 ± 35 to 993 ± 59; p = 0.01, respectively) and a downward shift of LV function curves from those obtained from control hearts. Compared to untreated burns, hearts from burned animals treated with LR alone showed no significant improvement in cardiac function. However hearts from burned animals treated with HSD + 1 mL LR/kg/% burn had significantly higher LVP (79 ± 4 vs. 68 ± 4 mmHg, p = 0.01) and ±dP/dt max (+dP/dt: 1387 ± 60 vs. 1261 ± 90 mmHg/sc, p = 0.01; -dP/dt: 1079 ± 50 vs. 993 ± 59 mmHg/sc, p = 0.01) than hearts from untreated burned animals and generated left ventricular function curves comparable to those calculated for hearts from control animals. Mortality 24 hours after burn was 29% for untreated burns and was 0% for control animals, as well as for groups treated with the Parkland formula or HSD plus 1 or 2 mL/kg/% burn lactated Ringer's. The only deaths after treatment occurred in those animals given HSD plus 4 mL/kg/%

From the Department of Surgery, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

burn, Parkland formula (17% mortality). Our data indicate that HSD + 1 mL/kg/% burn lactated Ringer's was the optimal fluid therapy for maintaining normal cardiac function after burn injury. The exchange of myocardial calcium with 45Ca suggest that enhanced cardiac contractile function after hypertonic resuscitation may be related to increased cellular calcium content.

Po REVIOUS STUDIES HAVE shown that thermal injury promotes edema and significant fluid se-

A portion of this data was presented at Surgical Forum, American College of Surgery Meeting in Chicago, Illinois, November, 1988. Address reprint requests to Jureta W. Horton, Ph.D., Department of Surgery, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75235-9031. Accepted for publication June 4, 1989.

301

questration in burn tissue as well as unburned tissue, producing hypovolemia and hypotension. 1-3 It is well recognized that the first line of defense in treating burn injury is rapid crystalloid volume replacement.2'4'5 The volume of crystalloid fluid required to restore cardiocirculatory function after thermal injury is large, perhaps 14 liters during the first 48 hours.46 Previous studies from our laboratory showed that thermal injury impairs cardiac contractility and slows isovolemic relaxation in adult hearts.7'8 Further study showed that these myocardial defects persisted after adequate isotonic fluid resuscitation from burn injury (4 mL/kg/% burn of lactated Ringer's solution, Parkland formula). Several studies suggest that the large volumes of crystalloid fluid resuscitation lead to edema and extravascular compression of the coronary vasculature. Increased coronary vascular resistance and a resultant myocardial ischemia may contribute to the cardiac depression that occurs after early fluid resuscitation. Recent interest has developed in the use of hypertonic saline dextran solution for the initial resuscitation of several types of shock. These studies have confirmed that an initial bolus of hypertonic saline-dextran (2400 mOsm sodium chloride, 6% dextran 70) improved mean arterial pressure and cardiac output and reduced subsequent fluid requirements after shock.9' Reversal of hypotension with

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hyperosmotic resuscitation has been attributed to a shift of fluid from the intracellular compartment, an increase in plasma volume, and reduced diuresis by vasopressininduced water reabsorption from the tubules. In this study we hypothesized that an initial bolus of hypertonic saline-dextran would prevent myocardial dysfunction after a major burn injury and decrease the subsequent volume of isotonic crystalloid resuscitation. We used an isolated coronary perfused guinea pig heart model to evaluate the contractile response to several regimens of fluid resuscitation from thermal injury in an environment free of alterations in neurohumoral functions as well as altered preload and afterload responses to burn injury. Materials and Methods Experimental Animals Adult albino guinea pigs weighing 300 to 400 g were used throughout the study.* All animals were obtained from Simonsen Laboratories, Inc. (Gilroy, CA) and were allowed 7 to 10 days to acclimate to their surroundings. Commercial guinea pig chow and tap water were available ad libitum before and after the burn procedure. Only healthy animals free from obvious disease were used in this study.

Hemodynamic Instrumentation Guinea pigs were anesthetized lightly with methoxyflurane 18 hours before the burn experiment. Body hair on the abdomen, side, back, and neck was closely clipped, and the neck region was treated with a surgical scrub (Betadine). The left carotid artery was exposed and a polyethylene catheter (PE-50) was inserted into the artery and the tip was advanced retrogradely to the level of the aortic arch. In addition the right external jugular vein was exposed and a polyethylene catheter (PE-50) was inserted for administration of fluids and drugs. The catheters were filled with heparinized saline and exteriorized at the nape of the neck via a subcutaneous tunnel. The catheters were secured with silk sutures and adhesive tape. Furacin powder was placed in the incision and the skin closed with silk suture. After instrumentation, guinea pigs were housed within the laboratory in individual cages, placed on a heating pad maintained at 38 C. Burn Procedure

Eighteen hours after instrumentation, hemodynamic, metabolic, and hematologic measurements were collected for baseline or preburn data. The animals were then deeply All animals included in these experiments were used in accordance with guidelines established by the National Institutes of Health, as well as those required by The University of Texas Southwestern Medical Center's Institutional Review Board for animal use. *

Ann. Surg. * March 1990

anesthetized with methoxyflurane and the animals were, secured in a constructed template device as previously described by this laboratory.'2 The surface of the area of the skin exposed through the device was immersed in 100 C water for 7 seconds on the abdomen and for 12 seconds on the back and on each side. Using this technique, fullthickness dermal burns of specific size were obtained. Sham burn or control guinea pigs were subjected to identical preparation, except they were immersed in room temperature water. After immersion, the guinea pigs were immediately dried and placed in individual cages to recover from anesthesia. Only large burns (approximately 45% total body surface area) were included for study. If an animal died, another was incorporated into the following set of matching experiments to achieve equivalent group N values. Burned guinea pigs did not display discomfort or pain. The anesthetic dose used in this study resulted in a significantly high mortality rate during burn injury, but this was acceptable to avoid unnecessary discomfort in the burned guinea pigs. Immediately after returning the animal to the cage, the external jugular catheter was connected to a swivel device (Holter pump, Model 923, Critikon Inc., Tampa, Florida) for fluid administration during the first 24-hour postburn period. In the control and untreated burn groups, the external jugular vein was cannulated but no fluid resuscitation was administered. Hemodynamic, metabolic, and hematalogic measurements were collected 1, 6, and 24 hours after burn. A small sample of arterial blood (approximately 0.30 mL) withdrawn from the arterial catheter was used for measuring packed cell volume, hematocrit, arterial pH, and blood gases (radiometer, AKB). Body temperature was measured with a rectal temperature probe (YS 1-Tele Thermometer, Model 44TA) and respiratory rate was monitored by counting respiratory movement. Systemic blood pressure was measured using a Gould-Statham (Gould Instruments, Oxnard, CA) pressure transducer (Model IDP23) connected to a Grass (Grass Instruments, Quincy, MA) medical recorder (Model 7D Polygraph). A tachycardiograph (Grass Instruments, Model 7P4F) was used to monitor heart rate. Serum electrolytes were measured by flame photometry (Nova 5 Electrolyte Analyzer, Nova Biomedical, Waltham, MA) and reported as mEq/ liter.

Experimental Groups A total of 25 sham-burned guinea pigs were included for study (group 1). In an additional group of controls (n = 10) a bolus of hypertonic saline dextran 70, 4 mL/kg body weight, was given over 30 minutes. This intervention examined the effects of a hyperosmotic solution in normovolemic animals (group 1 A). Immediately after a third-degree burn comprising 45% of the total body surface area, a total of 75 guinea pigs

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were divided into several experimental groups. In group 2, 25 animals received no fluid resuscitation and served as untreated bums. In group 3, 20 burned guinea pigs were treated with lactated Ringer's alone for 24 hours (Parkland formula, 4 mL/kg/% burn). The remaining 30 guinea pigs received an initial bolus of hypertonic saline dextran 4 mL/kg body weight given over a period of 20 to 25 minutes, and were further divided into three groups for crystalloid fluid resuscitation over 24 hours. In group 4, 10 guinea pigs were given lactated Ringer's, 4 mL/kg/ % burn; group 5 (n = 10) received 2 mL lactated Ringer's/ kg/% burn; and in group 6, 10 guinea pigs received 1 mL lactated Ringer's/kg/% burn.

Isolated Coronary Perfused Hearts

Guinea pigs were anticoagulated before decapitation with sodium heparin (1000 units). Twenty-four hours after burn injury, awake guinea pigs were decapitated with a guillotine, and the heart was rapidly removed and placed in ice-cold (4 C) Krebs-Henseleit bicarbonate buffered solution. The Krebs-Henseleit bicarbonate buffer used in these studies is similar to that previously reported with isolated heart muscle preparations,'3 and identical to that described by Adams et al.7 The solution contained (mmol) NaCl 118, KC1 4.7, NaHCO3 21, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, and glucose 11. All solutions were prepared each day with demineralized, deionized water and bubbled with 95% 02-5% CO2. The pH of this solution is approximately 7.400, PO2 is 583 mmHg, and pCO2 is 38 mmHg. The ascending aorta was cannulated with a 17-gauge cannula, which was subsequently connected via glass tubing to a Krebs-Henseleit bicarbonate reservoir for perfusion of the coronary circulation at a constant flow rate of 6 mL/minute. Hearts were suspended in a temperaturecontrolled chamber maintained at 38 ± 0.5 C. A constant flow pump (Holter, Model 911) was used to maintain perfusion of the coronary artery by retrograde perfusion of the aortic stump cannula. The Krebs bicarbonate perfusate was passed through a bubble trap and heating coil maintained at 38 ± 0.5 C before delivery to the aorta. A pressure transducer, connected to the pressure tubing between the heart and the heating coil, was used to measure coronary perfusion pressure; effluent was collected and measured to confirm coronary flow rate. Contractile function was monitored using a method described by Apstein et al.'3 as modified by Adams et al.7" 4 Intraventricular pressure was measured with a saline-filled latex balloon attached to a polyethylene tube and threaded into the left ventricular chamber through an apical stab wound. This small incision also prevented fluid accumulation between the balloon and the heart. Left ventricular pressure was measured with a Statham P231D pressure transducer attached to the balloon cannula. Left ventricular dP/dt

303

values were obtained using an electronic differentiator (Model 7P20C, Grass Instruments). All parameters were recorded on an ink-writing recording system (Model 7DWL8P, Grass Recording Instruments). The diastolic pressure in the left ventricle was adjusted from -5 to 20 mmHg by filling the intraventricular balloon with saline.

Left Ventricular Function Curves A Starling relationship for hearts from both control and burned animals was determined by plotting left ventricular systolic pressure and dP/dt maximum values against end-diastolic pressure. Left ventricular compliance was determined by plotting changes in intraventricular volume against end-diastolic pressure. Careful attention was devoted to the relationship between balloon size and left ventricular cavity size. The capacity of each balloon was determined by recording the pressure-volume filling curve of the isolated balloon, and experiments were performed on the flat area of the pressure-volume curve. Because heart rate varied after burn injury, hearts were paced as required through an electrode attached to the right atrium (1.8 to 2.0 volts for 4 milliseconds duration; Grass Stimulator, Grass Instruments). The effects of altered coronary flow rate (3 to 12 mL/ minute) on left ventricular performance were studied in hearts from control and burned animals. Peak systolic pressure and ± dP/dt maximum responses were measured after the hearts had stabilized for several minutes at each flow rate. Coronary vascular resistance was calculated and reported as mmHg/sec/mL. The percentage of weight loss during 24 hours after burn was calculated for each animal.

Measurement of Tissue Calcium (45Ca) Two separate groups of animals (burned guinea pigs treated with either lactated Ringer's solution, Parkland formula [n = 6] or hypertonic saline dextran 70, 4 mL/ kg bolus plus lactated Ringer's, 1 mL/kg/% burn, [n = 6]) were used to measure exchange of 45Ca with tissue Ca2+ after resuscitated burn injury. After 24 hours of resuscitation from burn injury, the animals were decapitated and the isolated hearts were perfused in vitro with Krebs as described above. After an in vitro perfusion period of 30 minutes, a tracer amount of 45Ca was added to the Krebs perfusate to produce approximately 13,000 counts/ minute/ 100 yd. 5 Approximately 90 minutes were allowed for exchange of the myocardial tissue calcium content with 45Ca; ventricular function curves were then measured as described above and the hearts were removed from the water bath and blotted with filter paper to remove any perfusate. Hearts were weighed and dissolved in 2 mL of soluene for 18 to 24 hours (Packard Instruments, Downersgrove, IL). At this time scintillation fluid (Insta Gel, Packard Instruments) was added to each vial, and the

Ann. Surg. * March 1990 HORTON, WHITE, AND BAXTER 304 TABLE 1. Comparison of In Vivo and In Vitro radioactivity was determined with a scintillation counter Hemodynamic Parameters (Model LS2800, Beckman Instruments, Palo Alto, CA). One-hundred-microliters sample of the 45Ca Krebs soluControl Control + HSD-70 p (n = 10) (n = 10) Groups Value tion was added to soluene; Insta Gel was added to these reference vials and counted in the same manner as deIn Vivo scribed for tissue. Myocardial radioactivity was expressed 73.7 ± 1.7 65.8 ± 2.5 MAP, mmHg 0.05 338.5 ± 7.1 338.5 ± 7.1 HR, beats/minute NS in mmol calcium/kg wet weight or in mmol/kg dry weight 37.6 ± 0.5 30.7 ± 2.2 PCV, % 0.01 and was based on the assumption that the radioactivity 38.8 ± 0.1 38.9 ± 0.2 BT, °C NS of the Krebs solution represented 2.5 mmol/liter calIn Vitro cium.'5 In addition myocardial samples from each group 87.4 ± 2.5 LVP, mmHg 85.7 ± 2.3 NS were weighed to four decimal places and then dried to a +dP/dt max, mmHg/sec 1351 ± 51 1344 ± 70 NS -dP/dt max, mmHg/sec 1154 ± 34 1193 ± 54 NS constant weight in a drying oven (Thermolyne 1400 FurCPP, mmHg 34.1 ± 0.9 36.7 ± 1.4 NS nace, Thermolyne Corp., DuBuque, IA). Myocardial waCVR, mmHg/mL/ ter content was calculated from the dry wet weight ratio minute 5.67 ± 0.15 6.12 ± 0.39 NS HR, beats/minute 215 ± 7 226 ± 4 NS and reported as milliliter of water per gram dry weight 113 ± 3 TPP, msec 115 ± 3 NS myocardial tissue. 94 ± 2 94 ± 2 NS RT90 (msec) Time to +dP/dt max, Statistical Analysis msec 59 ± 2 57 ± 3 NS Time to -dP/dt max, All values are expressed as mean ± standard error of msec 74 ± 2 69 ± 1 NS the mean. Statistical comparison of group values using a All values are mean ± SEM. MAP, mean arterial pressure; HR, heart Student's t test compared absolute values at similar heart rate; PCV, packed cell volume; BT, body temperature; LVP, left venrate between groups. Relative changes in contractile pertricular pressure; +dP/dt, rate of left ventricular pressure rise and -dP/ formance to altered coronary flow rate were compared, dt, rate of LVP fall; CPP, coronary perfusion pressure; CVR, coronary vascular resistance; TTP, time to peak pressure; RT90, time to 90% reas well as differences or similarities between performancelaxation. NS, not significant. flow relationships achieved in control and burn hearts. * Indicates significant difference between control and experimental Multiple regression analysis of best-fitting curves with test groups at p < 0.05 (analysis of variance and Newman Keuls). evaluation were included. Probability values less than or equal to 0.05 were considered significant. ± 2.9 mmHg, p = 0.001), hypothermia (body temperature fell from 38.8 ± 0.08 to 36.2 ± 0.5, p < 0.05), and heResults moconcentration (hematocrit increased from 34.9 ± 0.9 Hypertonic saline dextran, 4 mL/kg body weight given to 36.3 ± 0.4, p > 0.05). Acid-base derangements included over 30 minutes to normovolemic control guinea pigs a rise in arterial pH (7.47 ± 0.01 to 7.51 ± 0.01, p = 0.001), caused a slight fall in mean arterial blood pressure (from arterial P02 (92 ± 9 to 133 ± 11 mmHg, p = 0.05) and 73.7 ± 1.7 to 68.5 ± 2.5 mmHg, p > 0.05), a significant no change in arterial pCO2 (29 ± 1 mmHg) or serum decrease in packed-cell volume (37.6 ± 0.5 to 30.7 + 2.2%, bicarbonate (22.2 ± 0.8 mmol/1) (Tables 2 and 3). Morp = 0.01), and no change in heart rate (358 ± 9 beats/ tality rate during the first 24 hours after untreated burn minute), body temperature (38.9 ± 0.2 C) nor acid-base injury was 29%. balance. Similarly in vitro comparison of cardiac perforTwenty-four hours after thermal ihjury, hearts were remance in control guinea pigs and control guinea pigs given moved from 25 untreated burn and 25 sham burned conhypertonic saline dextran showed similar LVP, ±dP/dt, trols and perfused at a constant coronary flow rate at 6 coronary perfusion pressure, coronary vascular resistance, mL/minute and a constant LVEDP of 10 mmHg to assess and time to peak pressure, 90% relaxation, and maximal the effects of thermal injury on contractile performance. ±dP/dt (Table 1). Left ventricular function curves (left Compared to control hearts, hearts from burned animals ventricular pressure and ±dP/dt plotted versus increases showed significantly lower LVP (87 ± 3 vs. 68 ± 4 mmHg, in LVEDP from -5 to 20 mmHg) were identical in both p = 0.001), +dP/dt max (1350 ± 51 vs. 1260 ± 96 mmHg/ control groups at all levels of diastolic stretch. In addition second, p > 0.05), -dP/dt max (1154 ± 34 vs. 990 ± 59 left ventricular performance-coronary flow relationships mmHg/second, p = 0.01). In addition, time to peak preswere similar in all control animals, as indicated by sigsure (113 ± 3 vs. 100 ± 2 msecond, p = 0.01), time to nificant and similar increases in LVP and ±dP/dt as cor+dp/dt max (58.9 ± 2.1 vs. 48.7 ± 2.0 msecond) and time onary flow rate was increased from 3 to 12 mL/minute. to -dP/dt max (73.8 ± 3.8 vs. 61.2 ± 3.2, p = 0.01) were significantly shorter after thermal injury (p = 0.001). Burn Response To Untreated Burn Injury injury was associated with a rise in heart rate (215 ± 1 to 222 ± 3 beats/minute, p = 0.01), coronary perfusion All untreated burn animals developed hypotension pressure (from 34.1 ± 0.92 to 42.7 ± 1.6 mmHg, p = 0.01), (mean arterial blood pressure fell from 76.3 ± 1.3 to 62.6

HYPERTONIC SALINE DEXTRAN RESUSCITATION OF THERMAL INJURY

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TABLE 2. Hemodynamic to Burn Injury and Fluid Resuscitation

Hypertonic Saline + Lactated Ringer's Burn Untreated (n =6)

Control

Groups

Treated Burn, LR 4 mL/kg/% burn (n = 6)

4 mL LR/kg (n =6)

2 mL LR/kg (n =6)

1 mL LR/kg (n =6)

± 2.4 8* ± 1.5 ± 0.02 ± 1.1

74.2 ± 2.1 328 8* 43.5 ± 1.8* 7.33 ± 0.04 23.6 ± 2.0

1 Hour After Burn

MAP HR PCV pH

PCO2 MAP HR PVC pH

PC02

72.7 356 37.8 7.39 28.8

± 1.7 ± 7.0 ± 0.4 ± .01 ± 0.6

71.5 298 49.1 7.43 21.9

± 1.4 14* ± 0.6*

73.2 342 37.8 7.41 28.1

± 2.4 ± 13 ± 0.7 ± 0.01 ± 0.7

63.3 293 50.0 7.41 28.4

± 2.0* 15 ± 0.6* ± 0.04 ± 1.5

71.4 ± 2.9 290 ± 11* 44.3 ± 1.5* 7.29 ± 0.04 25.3 ± 0.5

±0.01 ± 0.8

66.1 287 35.5 7.35 30.2

6 Hours After Burn 64.8 ± 2.6* 312.5 ± 13* 43.8 ± 1.6* 7.34 ± 0.03* 26.6 ± 3.1

All values are mean ± SEM. MAP, mean arterial pressure, mmHg; HR, heart rate, beats/minute; PCV, packed red cell volulme, %.

and coronary vascular resistance (from 5.67 ± 0.15 to 7.12 ± 2.7 mmHg/second/mL, p = 0.01) (Table 3). Contractile depression after untreated thermal injury was further evidenced by a shift ofleft ventricular function curves for hearts from untreated burned animals downward and to the right of those curves calculated for control hearts (p = 0.01) (Fig. 1). While burn injury tended to

*

± 2.9 11* ± 1.9 ± 0.02 ± 1.0

71.1 283 40.9 7.37 29.9

64.5 341 44.7 7.43 24.1

62.7 ± 2.6* 326 ± 9 39.1 ± 1.8 7.40 ± 0.01 27.2 ± 1.0

57.1 ± 3.3* 311 ± 9 32.7 ± 1.7* 7.34 ± 0.02* 25.9 ± 2.9

± ± ± ± ±

1.7* 7.3 1.7* 0.01 0.7

Indicates significant difference between groups at p < 0.05.

shift the left ventricular compliance curve to the left of the curve calculated for control hearts, suggesting increased ventricular stiffness, these changes failed to achieve statistical significance. Increasing perfusate calcium concentration from 1 to 8 nmol and increases in coronary flow rate from 3 to 12 mL/minute failed to overcome contractile desparity documented in hearts from burned

TABLE 3. Cardiodynamic Response to Burn Injury and Fluid Resuscitation at 24 Hours

Hypertonic Saline Plus LR Control

Untreated

Treated Burn, LR 4 mL/kg/% burn

75 ± 2 339 ± 1 38±0.5 7.49 ± 0.01 39 ± 0.1 93 ± 1 29± 1

47 ± 3* 334 ± 15 42±1* 7.51 ± 0.02 36 ± 0.5* 110 ± 4* 27± 1

52 ± 3* 368 ± 11* 32±1* 7.48 ± 0.02 37 ± 1.4* 108 ± 6 28± 1

37 ± 4* 307 ± 12* 25±1* 7.43 ± 0.03 36 ± 0.6* 140 ± 10* 23± 1*

46 ± 5* 335 ± 12 29±2* 7.51 ± 0.01 38 ± 0.02* 135 ± 9* 24± 1*

46 ± 3* 370 ± 9* 35±2 7.48 ± 0.02 36 ± 0.3* 115 ± 7* 28±2

88 ± 3 1352 ± 50 1150 ± 35 1.2 ± 0.05 34 ± 1 6.0 ± 0.5 216 ± 2 114 ± 4 94 ± 2 59±2

68 ± 4* 1261 ± 96 993 ± 59* 1.3 ± 0.06 43 ± 2* 7.1 ± 0.3* 222 ± 3 100 ± 2* 90 ± 2 49±2* 61 ± 3* 4.14 ± 0.04

63 ± 4* 1150 ± 60* 909 ± 50* 1.3 ± 0.08 39 ± 3 7.0 ± 0.4 224 ± 3 104 ± 3 94 ± 2 50± 1* 62 ± 2* 4.36 ± 0.01

60 ± 4* 1215 ± 91 832 ± 64* 1.4 ± 0.04* 45 ± 3* 7.4 ± 0.5* 236 ± 7* 99 ± 2* 96 ± 2 48±2* 65 ± 2* 4.31 ± 0.09

71 ± 3* 1320 ± 74 959 ± 50* 1.2 ± 0.06* 47 ± 1* 7.8 ± 0.2* 231 ± 5 101 ± 3* 93 ± 2 53±2 63 ± 2* 4.23 ± 0.03

79 ± 4 1387 ± 60 1079 ± 50 1.3 ± 0.04 38 ± 3 6.3 ± 0.4 247 ± 5* 104 ± 2* 92 ± 2 56± 1 62 ± 3* 4.24 ± 0.04

Burn Groups In Vivo MAP (mmHg) HR (beats/minute) PCV% pH BT (C°)

P02 (mmHg)

PCO2

In Vitro LVP (mmHg)

+dP/dt (mmHg sec-') -dP/dt (mmHg.sec-') Differential Ratio CPP(mmHg) CVR (mmHg mL-' minute) HR (beats/minute) TTP (msec) RT9 (msec) Timetomax+dP/dt Time to max -dP/dt Myocardial water -

74 ± 4

4.37 ± 0.07

MAP = mean arterial pressure; HR = heart rate; PCV = packed cell volume; LVP = left ventricular pressure; +dP/dt = rate ofleft ventricular pressure rise and -dP/dt = fall; CPP = coronary perfusion pressure; CVR = coronary vascular resistance; TTP = time to peak pressure; RT90

4 mL LR/kg

2 mL LR/kg

1 mL LR/kg

= time to 90% relaxation; myocardial water content in ml H20/gm dry weight. * Indicates significant difference between control and experimental groups at p < 0.05 (analysis of variance and Newman Keuls).

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100

Surg * March 1990

-dP/dt max (mmHgsec -1)

+dP/dt max (mmHgsec 1)

LVP (mmHg)

Ann.

1400

1400

1200

1200

1000

1000o

-r TT T

0-

80 [ ;T/

T/

-

-r

60 [

FIG. 1. Left ventricular function curves calculated for sham burn controls, hearts from untreated burns, and hearts from burned animals resuscitated with lactated Ringer's solution for 24 hours. All values are mean ± SEM.

'0

L1

40

800

800 [

20 [

600

600

-5 0 5 10 15 20

-5 0 5 10 15 20

-5 0

5 10 15 20

Left Ventricular End-Diastolic Pressure (mmHg) o-o

Control

o--o

Burns treated with Parkland Formula Untreated Burns

A--A

animals. Furthermore bum-mediated alterations in ventricular performance were not related to the development of myocardial edema because left ventricular water content was lower in nonperfused hearts from burned animals (4.14 0.04 mL/g dry weight) compared to control hearts (4.37 0.07 mL/g dry weight, p = 0.05). After in vitro perfusion, water content increased to a similar extent in all hearts, regardless of bum injury. Effect of Fluid Resuscitation From Burn Injury

Administration of lactated Ringer's solution alone (4 mL/kg/% burn, Parkland formula) or hypertonic salinedextran, plus varying volumes of Ringer's failed to correct hemodynamic defects. Mean arterial blood pressure in all resuscitated groups remained significantly lower than that measured in control animals and was not significantly higher than that measured in untreated burns (Tables 2 and 3). Hemodilution occured in all groups, as indicated by a similar fall in hematocrit. Contractile depression persisted in the burns treated with lactated Ringer's alone, as indicated by a reduced left ventricular pressure and + dP/dt max responses compared to control values, and a persistent rightward shift of left ventricular function curves from those calculated for sham burn controls (Fig. 1). An initial bolus of hypertonic saline dextran added to

the Parkland formula (lactated Ringer's, 4/mL/kg/% burn) did not improve cardiac performance more than the Parkland formula alone. However a reduced volume of Ringer's plus hypertonic saline-dextran significantly improved LVP and ±dP/dt maximum response to burn injury and resuscitation (Table 3). The Starling relationship was examined in all groups of guinea pigs resuscitated with either lactated Ringer's solution alone or hypertonic saline-dextran plus varying volumes of lactated Ringer's during the 24-hour postburn period. As seen in Figure 2, reducing the subsequent volume of lactated Ringer's solution from 4 to 2 to 1 mL/ kg/% burn after an initial bolus of hypertonic saline-dextran progressively improved left ventricular performance as indicated by a shift of the left ventricular function curves upward and leftward ofthose calculated for both untreated burned animals or burned animals treated with the Parkland formula alone. It was of interest that the combined therapy of hypertonic saline-dextran plus 1 mL/kg/% burn of lactated Ringer's solution produced left ventricular function curves that were not significantly different from those curves calculated for control or sham burned animals. To determine coronary flow and left ventricular performance relationships, isolated hearts from all experimental groups were studied as coronary flow rate was var-

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FIG. 2. Left ventricular function curves calculated for control hearts and for hearts from burned animals treated with either lactated Ringer's alone (Parkland formula) or hypertonic saline dextran 70 bolus, 4 mL/kg (HSD) plus lactated Ringer's solution given as either 4, 2, or mL/ kg/% burn for 24 hours after burn. All values are mean ± SEM.

-dP/dt max (mmHgsec .1)

+dP/dt max (mmHgsec-1)

LVP (mmHg)

307

1400

1400

1200

1200

1000

1000

800

800

600

600

T

80 /

--'o AD41n

60 1

40

f

20

-5 0

5 10 15 20

-5 0

5 10 15 20

-5 0

5 10 15 20

Left Ventricular End-Diastolic Pressure (mmHg) o-o Control *-HSD + 1 mILR - HSD + 2 mILR o--oParkland Formula *-- HSD + 4 mILR ied from 3 to 12 mL/minute. As shown in Figure 3, increases in coronary flow rate improved left ventricular function in all hearts, but to a significantly greater extent in those animals treated with hypertonic saline-dextran and a reduced volume of lactated Ringer's solution (1 mL/kg/% burn). In examining the effects of burn injury and fluid resuscitation on coronary vascular reactivity, Figure 4 shows that incremental increases in coronary flow rate increased coronary perfusion pressure to a similar extent in all animals, regardless of either burn injury or the regimen of fluid resuscitation. These data suggest that hearts from burned animals retain the ability to autoregulate coronary vascular resistance equal to that measured in hearts from control animals. In examining the weight gain during the 24-hour postburn period, untreated burned animals showed a significant weight loss compared to sham burn controls. In contrast all burned animals treated with either the Parkland formula alone or with a bolus of hypertonic salinedextran plus a reduced volume of lactated Ringer's solution had a weight gain similar to that documented in the control animals. Only those animals given a bolus of hypertonic saline-dextran plus the full Parkland formula had a weight gain greater than that documented in control animals (Table 4). To examine the hypothesis that large volumes of crystalloid fluid resuscitation produced myo-

cardial edema, contributing to extravascular compression of the coronary vasculature and producing a resultant myocardial ischemia, we examined the myocardial water content per gram of dry weight tissue in all treated groups. As shown in Table 4, there was no significant difference in water content of hearts from either control, untreated, or burned animals treated with any regimen of fluid resuscitation. There were no deaths in control animals subjected to anesthesia, instrumentation, and sham burn. The mortality rate after untreated thermal injury was 29%. The only death observed in fluid-treated burns occurred in the group treated with the hypertonic bolus plus the full Parkland formula (17% mortality rate). Hypertonic salinedextran caused a significant rise in serum sodium in all groups; despite a significant rise in serum sodium 1 hour after burn in groups 4, 5, and 6, all electrolyte derangements were corrected by 24 hours after burn. There was no correlation between mortality rate and the significant rise in serum sodium in the group given the Parkland formula plus HSD (Table 5).

Myocardial 45Ca Exchange After 90 minutes of perfusion of the hearts with Krebs containing tracer amounts of 45Ca, all tissue calcium ex-

308

HORTON, WHITE, AND BAXTER

-dP/dt max (mmHgsec -1)

+dP/dt max (mmHgsec- 1)

LVP (mmHg)

Ann. Surg. March 1990

0

1500

1500

vt 1300[

IT

* -4TriT

1300

11001

3 .

8

.

900

.0,

700

I

FIG. 3. The effects of incremental increases in coronary flow on left ventricular performance.

1

34 6 8 10 12

34 6 8 10 12

3 4 6 8 10 12

Flow Rate (ml/min) o-o Control *--* HSD + 1 mILR o--oParkland Formula *--o HSD + 2 mILR *-- HSD + 4 mILR changed with radioactive calcium and further incubation

hours did not increase myocardial tissue calcium content. Tissue calcium content in hypertonic-treated up to 2.5

60 50

Coronary 40 Perfusion Pressure

(mmHg)

30

hearts tended to be higher at 1.65 ± 0.21 mmol/g wet weight compared to that measured in lactated Ringer'streated hearts ( 1.52 ± 0.1 1 mmol/g dry weight), but this difference failed to achieve statistical significance. The question arose as to whether the tendency for higher tissue calcium content per gram wet weight tissue after hypertonic resuscitation was a consequence of cell shrinkage. To address this issue, we normalized myocardial tissue calcium content for dry weight tissue and showed a significantly higher calcium content in hypertonic-treated hearts (7.52 ± 0.10 mmol/g dry weight) compared to Ringer's-treated hearts (6.99 ± 0.11 mmol/g dry weight, p = 0.001). In addition water content in mL water per gram dry weight of tissue was significantly lower in HSDtreated hearts (4.06 ± 0.01) compared to Ringer's-treated hearts (4.34 ± 0.09) (p = 0.01).

20

10 3

4

6

8

10

Flow Rate (ml/min) o-o Control

o-cParkland Formula

1 mILR HSD + 2 mILR *-- HSD + 4 mILR

*--* HSD + *--*

FIG. 4. Vascular reactivity after resuscitation from burn injury.

Discussion Previous studies have shown that hypertonic salinedextran can resuscitate several types of experimental shock,9"16-22 as well as severly injured patients.'0 In addition several studies have examined the hemodynamic effects, electrolyte and water balance, serum and urine osmolalities in adults23 and children24 resuscitated from burn injuries with concentrated sodium solutions. These clinical burn studies suggest that reducing the total water load during resuscitation by giving hypertonic, hyperon-

Vol. 211I NO. 3

HYPERTONIC SALINE DEXTRAN RESUSCITATION OF THERMAL INJURY

309

TABLE 4. Fluid Distribution After Burn Injury and Resuscitation

*

Groups

Weight Gain (%)

p Value

Control (n = 25) Untreated burn (n = 25) Burn + 4 mL LR (n = 20) Burn + HSD + 1 mL LR (n = 10) Burn + HSD + 2 mL LR (n = 10) Burn + HSD + 4 mL LR (n = 10)

2.19 ± 0.32 -4.84 ± 0.56 4.01 ± 0.99 0.14 ± 0.95 2.99 ± 1.09 7.12 ± 1.42

* * *t NS

Indicates a significant change from control values at p

Hypertonic saline dextran resuscitation of thermal injury.

Burn treatment requires large volumes of crystalloid, which may exacerbate burn-induced cardiopulmonary dysfunction. Small-volume hypertonic saline de...
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