The dynamics of vascular volume and fluid shifts of lactated Ringer's solution and hypertonic-saline-dextran solutions infused in normovolemic sheep.

UNLABELLED: Infusions of hyperosmotic-hyperoncotic solutions such as hypertonic saline dextran (HSD) are used in Europe for resuscitation of traumatic shock and perioperative volume support as an adjunct to conventional isotonic crystalloids. Whereas plasma volume expansion of HSD has been measured at single time points after the intravascular volume expansion, the detailed time course of fluid shifts during and after infusions have not been reported. We compared the time course of volume expansion during and after 30-min infusions of 4 mL/kg HSD and 25 mL/kg lactated Ringer's solution (LR) in normovolemic conscious splenectomized sheep. Peak plasma volume (Evans blue and hemoglobin dilution) expansion was similar for HSD (7.8 +/- 0.9 mL/kg) and the larger sixfold volume of LR (7.2 +/- 0.5 mL/kg). However, 30 min after the 30-min infusion (T60), plasma expansion remained larger after HSD (5.1 +/- 0.9 mL/kg) than after LR (1.7 +/- 0.6 mL/kg). Both solutions caused an equivalent diuresis. Intravascular volume expansion efficiency (VEE), defined as milliliter plasma expansion/milliliter fluid infused at 0 (T30), 30 (T60), and 60 (T90) min after infusion ended was 1.8, 1.3, and 0.8, respectively for HSD, whereas LR provided a VEE of only 0.27, 0.07, and 0.07. The relative expansion efficiency of HSD versus LR, calculated as the ratio (VEE(HSD)/VEE(LR)), was 7-fold that of LR at the end of infusion T30, and 20-fold at T60, but decreased to 9-fold by T120. Intravascular volume dynamic studies of different volume expanders in animals and patients may provide anesthesiologists with a new tool for monitoring the effectiveness of fluid therapy. IMPLICATIONS: Hypertonic saline dextran (HSD) is a new plasma expander recently approved for clinical use in Europe. We compared the plasma volume expansion of HSD versus lactated Ringers (LR) in normovolemic sheep. After a 30 min infusion, HSD was 7 times as effective at expanding volume as an equal volume of LR, but for the next 90 minutes the relative effectiveness of HSD increased to 10-20 times.

Quantitative assessment of a circulating depolarizing factor in shock.

Sustained depolarization of cell membranes and cellular edema are known to accompany various forms of circulatory shock and probably contribute to hypovolemia and cellular dysfunction. It has been proposed that a circulating protein is responsible for these effects. In the present study we have confirmed the existence of a circulating depolarizing factor (CDF) in hemorrhagic shock, burn shock, sepsis, and cardiopulmonary bypass. Plasma samples from pigs or sheep in shock were quantitatively assayed for depolarizing activity using a microelectrode method on rat diaphragm in vitro. The depolarizing effect of CDF in vitro was similar in magnitude to that of shock in situ. We conclude that CDF can entirely account for membrane depolarization during shock. The depolarizing effect of CDF was dose-dependent and saturable; it could be reversed by rinsing the diaphragm with Ringer's or control plasma. CDF activity was detectable in plasma within 5 min after a severe scald and gradually increased over the next 25 min. Resuscitation of hemorrhaged pigs, but not burned sheep, eliminated plasma CDF activity.

Effects of hemoglobin-based blood substitutes on vasoactivity of rat aortic rings.

Our objective is to characterize the vasoactive properties of a 10% alphaalpha diaspirin cross-linked human hemoglobin (alphaalphaHb) and to test the hypothesis that sodium nitroprusside (SNP)-induced relaxation is inhibited in the presence of alphaalphaHb. Experiments were performed on aortic rings from 18 Wistar rats; the rings were suspended in aerated Krebs solution. Changes in isometric tension were measured to increasing concentrations of alphaalphaHb (1.8 x 10(-9) to 10(-4) M) on phenylephrine (PE)-induced contraction (3 x 10(-7) M), on acetylcholine (ACh)-induced relaxation (10(-8) to 10(-6) M), on SNP-induced relaxation (10(-9) and 10(-8) M), and on PE-induced contraction with an endothelin-1 (ET1) receptor antagonist, BQ123 (10(-5) M). Control rings received no alphaalphaHb. A concentration-dependent increase of the PE-precontraction (1.3%, 6.8%, 17.4%, and 34%, respectively) as well as the inhibition and reversal of ACh-induced relaxation was observed after alphaalphaHb. The presence of alphaalphaHb decreased the SNP-induced relaxation in the presence or absence of endothelium. The relaxation induced by SNP was reduced with time in the presence, but not in the absence, of alphaalphaHb. In conclusion, although pharmacological modulation of the vasoconstriction is possible with nitric oxide donors, our findings suggest that in the clinical setting, large sustained donor doses may be required.

Resuscitation of severe thermal injury with hypertonic saline dextran: effects on peripheral and visceral edema in sheep.

BACKGROUND: Edema of tissue not directly injured by heat is a common complication after resuscitation of burn shock. Hypertonic 7.5% NaCl 6% dextran (HSD) infusion reduces early fluid requirements in burn shock, but the effects of HSD on peripheral and visceral tissue edema are not well-defined. METHODS: We measured the microcirculatory absorptive pressures of burned and nonburned skin and tissue water content of skin and other tissues in anesthetized sheep after 70% to 85% total body surface area scald and resuscitation. Fluid infusion was initiated 30 minutes after injury using 10 mL/kg HSD (n = 11) or lactated Ringer's (LR) (n = 12), with infusion rates titrated to restore and maintain preburn oxygen delivery (DO2). Thereafter, both groups received LR infusions as needed to maintain DO2 until the study's end at 8 hours. Colloid osmotic pressure was measured in plasma, and combined interstitial colloid osmotic and hydrostatic pressures were measured in skin. RESULTS: Both treatments successfully restored DO2, but fluid requirements were less with the HSD group than with the LR group (43+/-19 mL/kg vs. 194+/-38 mL/kg, respectively, p < 0.05). The peripheral and visceral tissue water contents at 8 hours postinjury until the end of the study in both burn groups were significantly higher than in nonburn controls. However, HSD-treated sheep had significantly less water content in the colon (less 28%), liver (less 9%), pancreas (less 55%), skeletal muscle (less 21%), and nonburned skin (less 12%) compared with LR-treated sheep (p < 0.05 for each). HSD-treated sheep maintained significantly higher (3 to 5 mm Hg) plasma colloid osmotic pressure than LR-treated sheep. CONCLUSION: There were no observed differences in edema in burn skin between the two treatment groups. The early volume-sparing effect of HSD and reduction in tissue edema are likely attributed to an increased extracellular osmolarity and a better maintenance of the plasma oncotic pressure.

Burn resuscitation with two doses of 4 mL/kg hypertonic saline dextran provides sustained fluid sparing: a 48-hour prospective study in conscious sheep.

BACKGROUND: The large fluid volumes usually required for burn resuscitation can be suppressed for 8 to 12 hours by intravenous infusion of 4 mL x kg(-1) hypertonic saline dextran (HSD) 1 hour after burn. We hypothesized that a double (8 mL x kg(-1)) dose of HSD or two repeated doses of 4 mL x kg(-1) could enhance or prolong the volume sparing. METHODS: We produced a full-thickness flame burn covering 40% of the body surface on 18 anesthetized sheep. One hour after the burn, the animals were awake and resuscitated with either (1) lactated Ringer's solution (LR) only, (2) 8 mL x kg(-1) HSD followed by LR, or (3) 4 mL x kg(-1) HSD followed by LR, with a second dose of 4 mL x kg(-1) HSD administered when net fluid accumulation increased to 20 mL x kg(-1). For all regimens, infusion rates were adjusted to produce a urine output of 1 to 2 mL x kg(-1) x h(-1). RESULTS: Animals resuscitated with only LR required fluid volumes identical to that predicted by the Parkland formula for the first 12 hours. Infusion of 8 mL x kg(-1) HSD initially created a net fluid loss (urine output > infused volume), followed by a rebound fluid requirement eventually equaling that of animals treated with LR only. Animals treated with two separate doses of 4 mL x kg(-1) HSD generally did not experience a net fluid loss or a rebound fluid requirement. Also in the HSD x 2 group, peak and net fluid accumulation was less than that of the other two groups from 18 hours through 48 hours, although the difference was not significant. CONCLUSION: An initial 4 mL x kg(-1) dose of HSD reduces fluid requirements early after burn, and a second dose administered after an appropriate interval may prolong volume sparing through 48 hours. An 8 mL x kg(-1) continuously infused initial dose was without prolonged fluid sparing effect. The volume-sparing effect of HSD is thus dependent on all of the following: dose, dosing interval, and infusion rate.

Hypertonic saline dextran produces early (8-12 hrs) fluid sparing in burn resuscitation: a 24-hr prospective, double-blind study in sheep.

OBJECTIVE: Resuscitation of large burn injuries must quickly restore and maintain cardiovascular function and fluid balance while minimizing secondary edema-related damage. We tested the hypothesis that two 4-mL x kg(-1) doses of hypertonic saline dextran (HSD; 7.5% NaCl/6% dextran-70) can produce prolonged reduction in fluid requirements after burn injury. DESIGN: Prospective, pseudo randomized, double-blind study. SETTING: Animal research laboratory. SUBJECTS: Female adult Merino sheep (n = 12). INTERVENTIONS: Sheep were given a 40% total body surface area full-thickness flame burn under halothane anesthesia. One hour after the burn, the conscious animals received an initial dose of 4 mL x kg(-1) HSD (n = 6) or normal saline (NS; NaCl 0.9%) (n = 6) intravenously during 30 mins. This was followed by lactated Ringer's solution, infused to a target urine output of 1 mL x kg(-1) x hr(-1) throughout the 24-hr study. A second 4-mL x kg(-1) dose of HSD or NS was started at 12 hrs, and infused during 5 hrs. MEASUREMENTS AND MAIN RESULTS: Hourly urine output measurements were used to guide the infusion rate of the lactated Ringer's. The initial infusion of HSD 1 hr after the burn injury promptly restored cardiac index, promoted diuresis, and reduced fluid requirements compared with the NS controls (73% reduction for HSD relative to NS at 8 hrs). Subsequent rebound fluid accumulation resulted in similar net fluid balances in both groups within 12 hrs after the burn. The second dose of HSD, given at 12 hrs, was without effect on hemodynamics and fluid balance. CONCLUSIONS: We conclude a considerable initial, but not sustained fluid-sparing effect of early HSD, and no effect of a late, slowly infused HSD dose in this two-dose regimen.

A novel approach to monitor tissue perfusion: bladder mucosal PCO2, PO2, and pHi during ischemia and reperfusion.

PURPOSE: The purpose of this study is to determine if monitoring urinary bladder PCO2, PO2, and calculated intramucosal pH would be a reliable index of tissue perfusion. MATERIALS AND METHODS: This nonrandomized controlled study was conducted in a laboratory at a university medical center. Eight immature female Yorkshire pigs were studied with T-9 aortic cross-clamping for 30 minutes followed by a 60-minute period of reperfusion. Cystotomy was performed for placement of a Foley catheter and Paratrend 7 O2/CO2 sensor. RESULTS: Baseline hemodynamic and metabolic measurements were obtained along with measurements of bladder mucosal PO2 and PCO2 (mean+/-SEM). Blood flow measured with microspheres confirmed absence of blood flow during occlusion and hyperemia during reperfusion. Bladder mucosal PO2 decreased from 42+/-14.0 mm Hg (5.6 kPa) to 1.3+/-1.3 mm Hg (1.4 kPa) during the 30-minute interval of ischemia. This was followed by an increase of bladder PO2 to greater than baseline values at the end of the reperfusion period. Bladder mucosal Pco2 increased from 57+/-4.7 mm Hg (7.6 kPa) to 117+/-7.1 mm Hg (15.6 kPa) (P < .05) during ischemia. During reperfusion the Pco2 returned to baseline levels (55+/-4.0 mm Hg [7.3 kPa]). Calculated bladder mucosal pHi declined from 7.31+/-0.04 to 7.08+/-0.05 (P < .05) during the ischemic period and after reperfusion pHi was 7.17+/-0.03. CONCLUSIONS: Monitoring urinary bladder PO2, PCO2, or calculating pHi may provide a simple and reliable means of monitoring tissue perfusion.

Plasma volume expansion with solutions of hemoglobin, albumin, and Ringer lactate in sheep.

We have measured plasma volume expansion (Evans blue and hematocrit changes) and hemodynamic responses in conscious hemorrhaged and normovolemic splenectomized sheep after a 30-min infusion of either 20 ml/kg of diaspirin cross-linked hemoglobin (DCLHb), 20 ml/kg of human albumin (Alb), or 60 ml/kg of a solution of Ringer lactate (RL). All regimens expanded blood volume and increased blood pressure and cardiac output after hemorrhage. However, only 15 +/- 3% of the infused volume of RL was evident as intravascular expansion 10-min postinfusion, compared with 67 +/- 16% and 139 +/- 139% for Alb and DCLHb, respectively. DCLHb infusions were associated with higher blood pressures and lower cardiac outputs compared with RL and Alb infusions, but the increased oxygen content of blood with DCLHb resulted in systemic delivery of oxygen similar to that of the other infusions. These differences in hemodynamics and vascular volume continued for 6 h, and at 24 h vascular volume and all hemodynamics were similar in all three groups. The better volume expansion with DCLHb may be due to greater mobilization of endogenous interstitial protein or reduced transcapillary loss as total intravascular endogenous plasma protein increased after infusion of DCLHb, whereas there was an apparent loss of endogenous intravascular protein after infusions of Alb and RL. Vasoconstriction by DCLHb is one mechanism that could lower blood-to-tissue transport of fluid and protein. In addition to its oxygen-carrying capacity and vasoactivity, DCLHb is associated with volume expansion properties out of proportion to its colloid osmotic pressure.

Resuscitation with hypertonic saline dextran improves cardiac function in vivo and ex vivo after burn injury in sheep.

In a 24 h, double-blind, prospective trial, we tested the hypothesis that two 4 mL/kg doses of hypertonic saline dextran (HSD; 7.5% NaCl/6% dextran 70) given in addition to isotonic fluid treatment would produce both immediate and sustained benefit for the heart after large burn injury. 12 instrumented sheep were subjected to a 40% total body surface area full-thickness flame burn under halothane anesthesia. 1 h after burn, when the animals had recovered from anesthesia, the first dose of either HSD (n=6) or normal saline (NaCl .9%; n=6) was infused over 30 min. The test solution was immediately followed by lactated Ringer's solution infused to maintain a urine output of 1-2 mL/kg x h throughout the study. The second dose of test solution was started at 12 h and was infused over 5 h. The initial dose of HSD corrected the burn-induced reduction in cardiac output, cardiac work, an index of myocardial contractility, and restored myocardial blood flow, as measured by the colored microsphere technique, to preburn values. Plasma concentrations of troponin I, creatine kinase (CK), and CK isoenzyme CKMB were increased 1 h after burn, but were not altered after HSD treatment. After euthanasia at 24 h, myocardial glutathione concentrations were higher in HSD-treated animals, whereas other markers of oxidative injury in heart or in plasma did not show systematic differences. The maximum contraction force measured in isolated right papillary muscles ex vivo was significantly greater in HSD-treated than normal saline-treated animals. In conclusion, the first dose of 4 mL/kg HSD infused 1 h after burn improved cardiac function, whereas the second dose of HSD infused at 12 h was without apparent effect on dynamic variables. An overall effect of the HSD treatments was a lasting increase in papillary muscle contraction force.

Effect of cutaneous burn injury and resuscitation on the cerebral circulation in an ovine model.

The aim of our study was to evaluate the effects of a large cutaneous burn injury on the cerebral circulation. Anesthetized sheep (n = 8) were prepared with vascular catheters, a urinary catheter and a Richmond bolt for intracranial pressure monitoring. A scald injury was inflicted on 70 percent of total body surface area with hot water. Resuscitation was started 30 min after scald with Ringer's lactate to restore and maintain baseline oxygen delivery. Resuscitation maintained blood pressure, cardiac output and urine output at normal levels. Brain blood flow was measured with colored microspheres. During resuscitation intracranial pressure rose slowly from 10.6 +/- 1.5 to 17.0 +/- 4.0 mmHg (P < 0.05) and cerebral perfusion pressure was reduced from 86.4 +/- 6.8 to 64.1 +/- 2.8 mmHg (P < 0.05). During early resuscitation cerebrovascular resistance declined to maintain brain blood flow and oxygen delivery at baseline or better. After 6 h, mean cerebrovascular resistance was inappropriately increased during a period of reduced cerebral perfusion pressure which resulted in brain blood flow reductions of half the baseline levels. These data suggest that autoregulation maintains brain blood flow immediately after burn shock and early resuscitation, but the autoregulation may be less effective as burn resuscitation proceeds.

The role of interstitial starling forces in the pathogenesis of burn edema.

The formation and sustainability of burn edema require substantial change in net microvascular forces. We directly measured interstitial hydrostatic pressure (Pi) and total interstitial absorptive pressure (Pi + IIi), in dermis of anesthetized sheep, before and after a 70% to 85% total body surface area scald and during fluid resuscitation. The most rapid change occurred in Pi in the burn wound, which rapidly decreased from its baseline value of approximately -2 mm Hg to -11 mm Hg in the first 5 minutes, and thereafter increased but remained approximately -4 mm Hg through 4 hours of resuscitation. Pi in nonburned skin slowly increased from its preburn level -2 mm Hg, to become positive +1 mm Hg after 4 hours of resuscitation. The total interstitial absorptive pressure, Pi + IIi, slowly declined similarly from 15 to 16 mm Hg to approximately 10 to 11 mm Hg over 6 hours of resuscitation in both burned and nonburned dermis. Taken together, these data suggest that the rapid formation of burn edema is the result of development of a negative Pi in the burn wound, and its sustainability is the result of a large increase in interstitial compliance. Edema in nonburned skin did not start until after fluid resuscitation was initiated, and then developed as the plasma oncotic pressure declined from 21 to 10 mm Hg.

Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies.

BACKGROUND: Individual trials of small-volume resuscitation of 7.5% NaCl (HS) with and without 6% dextran 70 (HSD) for the treatment of trauma have failed to provide convincing evidence of efficacy. We performed a meta-analysis to evaluate the effects of HS and HSD on survival until discharge or for 30 days. We identified eight double-blinded, randomized controlled trials of HSD and six trials of HS. In all cases, administration of 250 ml of HSD or HS was compared with a control group administration of 250 ml of isotonic crystalloid for the treatment of hypotension either in the field or at admission to the emergency department. METHODS: A fixed-effects meta-analysis was performed with the Mantel-Haenszel method of combining results from multiple studies. RESULTS: Overall, HS was not effective in improving survival with a weighted mean difference in survival of the HS group versus the isotonic control group equal to 0.6%. The results with HSD were more positive, with an increase in survival in seven of eight trials. The mean difference in survival rates favoring HSD (n = 615) over controls (n = 618) was 3.5% (p = 0.14, two-tailed; p = 0.07, one-tailed). The odds ratio was estimated to be 1.20 in favor of HSD with a 95% confidence interval of 0.94 to 1.57. CONCLUSIONS: The meta-analysis of the available data shows that HS is not different from the standard of care and that HSD may be superior.

Hemodynamic effects of isovolemic hemodilution during descending thoracic aortic cross clamping and lower torso reperfusion.

BACKGROUND: Isovolemic hemodilution has been suggested for blood conservation and to improve hemodynamic tolerance to abdominal aortic cross clamping. However, the hemodynamic effects of hemodilution during descending thoracic aortic cross clamping (DAC) have not been established. We evaluated them in anesthetized swine. METHODS: Hemodilution (n = 7) was produced by the isovolemic exchange of blood for 6% hetastarch to a target hematocrit of 20%. Hematocrit in control pigs (n = 7) remained at 30%. DAC was performed at the T9 level for 45 minutes. During a 60-minute reperfusion period, control pigs were infused with lactated Ringer's solution; shed blood was returned to hemodilution pigs, followed by lactated Ringer's. If hypotension occurred despite left atrial pressure of 10 mm Hg or greater, boluses of phenylephrine were given to keep mean arterial pressure above 60 mm Hg. RESULTS: Hemodilution caused a marked reduction in hematocrit and in global oxygen delivery (DO2). DAC produced a significant increase in proximal arterial pressure, cardiac index, and DO2 and oxygen consumption (VO2) was markedly reduced in both groups. A significant increase in systemic vascular resistance during DAC occurred only in control pigs. After reperfusion, vascular resistance was significantly lower than baseline in hemodilution pigs, requiring a sixfold greater dose of phenylephrine to avoid hypotension. A lower global DO2 and supply-limited VO2 were also observed in hemodilution pigs. CONCLUSIONS: Isovolemic hemodilution maintains hemodynamic stability during DAC. During lower torso reperfusion, however, hemodilution caused hemodynamic instability, decreased global DO2, and limited VO2, which may offset its potential benefits.

Pulmonary hypertension and systemic vasoconstriction may offset the benefits of acellular hemoglobin blood substitutes.

OBJECTIVE: We tested the hypothesis that the pharmacologic properties of a small volume of alpha alpha-cross-linked hemoglobin (alpha alpha Hb) could effectively resuscitate pigs subjected to hemorrhage. METHODS: Fourteen pigs hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg for 60 minutes were treated with a 4-mL/kg 2-minute infusion of 10 g/dL alpha alpha Hb or 7 g/dL human serum albumin, an oncotically matched control solution. RESULTS: The removal of blood (17 +/- 1.5 mL/kg) caused the typical physiologic responses to hemorrhagic hypovolemia. Infusion of alpha alpha Hb restored mean arterial pressure and coronary perfusion pressure, but cardiac output and mixed venous O2 saturation did not improve significantly. Pulmonary arterial pressure and pulmonary vascular resistance increased markedly and were higher than baseline levels after alpha alpha Hb. Infusion of human serum albumin produced only minor hemodynamic changes. Brain blood flow did improve to baseline values after alpha alpha Hb, but was the only tissue to do so. In the human serum albumin group, superior mesenteric artery blood flow recovered to baseline values, whereas brain blood flow did not. Blood flows to other tissues were similar in both groups. CONCLUSION: Small-volume infusion of alpha alpha Hb restored mean arterial pressure and brain blood flow, but pulmonary hypertension and low peripheral perfusion may offset benefits for trauma patients.

Individual patient cohort analysis of the efficacy of hypertonic saline/dextran in patients with traumatic brain injury and hypotension.

BACKGROUND: Resuscitation with hypertonic saline/dextran (HSD) has been suggested to be efficacious in patients who have traumatic brain injury and are hypotensive. We undertook a cohort analysis of individual patient data from previous prospective randomized double-blinded trials to evaluate improvements in survival at 24 hours and discharge after initial treatment with HSD in patients who had traumatic brain injury (head region Abbreviated Injury Score > or = 4) and hypotension (systolic blood pressure < or = 90 mm Hg). METHODS: All variables and end points were defined before initiation of data handling. Investigators were blind as to the treatment. Case report forms were received from six studies. Of these, 223 patients met the inclusion for traumatic brain injury. Comparisons between HSD and standard of care were made using stratified analysis and logistic regression to assess efficacy, confounding, and interaction. Potential confounding variables of pre-fluid treatment, Glasgow Coma Scale score (3-8 vs. 9-15), injury type, and systolic blood pressure can be considered a priori factors that were known before randomization. Effects of the various trials was also considered. RESULTS: Treatment with HSD resulted in a survival until discharge of 37.9% (39 of 103) compared with 26.9% (32 of 119) with standard of care (p = 0.080). Using logistic regression, adjusting for trial and potential confounding variables, the treatment effect can be summarized by the odds ratio of 2.12 (p = 0.048) for survival until discharge. CONCLUSIONS: Patients who have traumatic brain injuries in the presence of hypotension and receive HSD are about twice as likely to survive as those who receive standard of care.