G. I. Elgjo

High-dose Vitamin C Infusion Reduces Fluid Requirements in the Resuscitation of Burn-injured Sheep

Fluid resuscitation to maintain adequate tissue perfusion while reducing edema in the severely burned patient remains a challenge. Recent studies suggest that reactive oxygen species generated by thermal injury are involved in edema formation associated with burn. The present study tested the hypothesis that adding a free radical scavenger to the resuscitation fluid would reduce total fluid requirements in the treatment of severe thermal injury. Anesthetized chronically instrumented sheep received a 40% total body surface area full-thickness flame burn. At 1 h after injury, animals were resuscitated with lactated Ringers (LR, n = 14) as control, LR containing high doses of vitamin C (VC, n = 6), 1000 mOsM hypertonic saline (HS, n = 7), or 1000 HS containing VC (HS/VC, n = 7) in coded bags so that investigators were blinded to the treatment. Fluids were infused at an initial Parkland rate of 10 mL/kg/h, adjusted hourly to restore and maintain urine output at 1 to 2 mL/kg/h. Sheep in the VC or HS/VC group received 250 mg/kg VC in the first 500 mL of LR or HS, and then 15 mg/kg/h thereafter. Hemodynamic variables and indices of antioxidant status were measured. At 48 h postburn, sheep were euthanized, and heart, liver, lung, skeletal muscle, and ileum were evaluated for antioxidant status. All fluid resuscitation regimens were equally effective in restoring cardiac output to near baseline levels; no treatment effects were apparent on arterial pressure or heart rate. VC infusion significantly reduced fluid requirements and, therefore, net fluid balance (fluid in, urine out) by about 30% at 6 h and about 50% at 48 h in comparison with the LR group (P < 0.05). HS and HS/VC reduced fluid requirements by 30% and 65%, respectively, at 6 h, but the volume-sparing effect of HS was not observed after 36 h and that of HS/VC was lost after 12 h. Plasma total antioxidant potential increased about 25-fold (P < 0.05) at 2 and 3 h in response to VC infusion compared with the LR and HS groups, and remained about 5- to 10-fold higher throughout the rest of the study. VC infusion also prevented the 4-fold increase in plasma thiobarbituric acid reactive substances seen in the LR group early after burn (P < 0.05). Tissue antioxidant status was similar between groups. In this sheep burn model, continuous high-dose VC infusion reduced net fluid balance, reduced indices of plasma lipid peroxidation, and maintained overall antioxidant status in comparison with standard-of-care LR treatment.

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

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 (VEEHSD/VEELR), 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.

Closed-loop resuscitation of burn shock

Fluid therapy for burn shock is adjusted to establish a target level of urinary output. However, the means for adjusting infusion rate are not defined. Our objective was to compare the performance of automated computer-controlled resuscitation with manual control for burn resuscitation. Sheep with a 40% TBSA full-thickness burn, administered under halothane anesthesia, were resuscitated to restore and maintain normal sheep urinary outputs in a target range of 1 to 2 ml/kg per hour over the course of 48 hours using closed-loop resuscitation (n = 10) or manual hourly adjustment of infusion rate (n = 11). The automated closed-loop resuscitation system is based on a proportional—integral—derivative algorithm, which adjusted infusion rate based on continuous monitoring and changes in urinary output. Mean urinary outputs over the course of 48 hours were in target range and were virtually identical at 1.9 ± 0.5 ml/kg per hour for the closed-loop group and 2.0 ± 0.7 ml/kg per hour for the technician group. Mean infusion rates and infused volumes also were similar. The closed-loop group exhibited significantly lower hourly variation for both urinary output and infusion rate compared hourly control. Hourly targets were achieved in 41% of the measurements in technician group compared with 48% for the closed-loop group (P = .23). Hourly urinary output in the technician group was undertarget by 25% as opposed to 16% with the closed-loop group (P = .02). Automated closed-loop control of infusion rates after burn injury produced urinary outputs in target ranges with less variation and less under target values than manual hourly adjustments. Closed-loop resuscitation may provide an improvement over current resuscitation regimens.

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·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·kg−1 HSD (n = 6) or normal saline (NS; NaCl 0.9%) (n = 6) intravenously during 30 mins. This was followed by lactated Ringers solution, infused to a target urine output of 1 mL·kg−1·hr−1 throughout the 24‐hr study. A second 4‐mL·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 Ringers. 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.

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

ABSTRACT 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 Ringers solution infused to maintain a urine output of 1–2 mL/kg-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 micro sphere technique, to preburn values. Plasma concentrations of troponin I, creatine kinase (CK), and CK iso enzyme 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.

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 Ringers 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.

Hyperosmotic-hyperoncotic solutions

Since the first descriptions of the use of 7.5% hypertonic saline for resuscitation of haemorrhage in 1980, there has been substantial animal research and clinical evaluation of small volume resuscitation. Most interest has focused on combined hyperosmotic and hyperoncotic colloid formulations. Infused hyperosmotic NaCl rapidly expands plasma volume, while the hyperoncotic colloid sustains the volume expansion. Other contributing factors to the efficacy of these solutions are increased cardiac effectiveness and peripheral vasodilation. The most often studied solution, 7.5% NaCl/6% dextran 70, offers promise to reduce the mortality of traumatic hypotension and head injury when used as an initial treatment. Future hyperosmotic-hyperoncotic formulations with different solutes may provide specific beneficial pharmacological properties in addition to the established cardiovascular effects of hyperosmolarity. A particularly promising formulation might be a combination solution of an oxygen carrier colloid, for example, haemoglobin, and a hyperosmotic crystalloid.

Hypertonic acetate-ααhemoglobin for small volume resuscitation of hemorrhagic shock

Hypertonic acetate solution in small volumes greatly improves cardiac output and corrects acid-base disturbances in hemorrhaged animals. We hypothesized that the combination of alpha alpha-crosslinked human hemoglobin (alpha alpha Hb), an oxygen carrier and vasoconstrictor, with hypertonic sodium acetate (HAHb), a vasodilator, may be effective for small volume resuscitation of hemorrhagic shock. Six pigs hemorrhaged to a mean arterial pressure of 40 mmHg for 60 min (bled volume: 23.6 +/- 2.5 ml.kg-1) received a single bolus of 4 ml.kg-1 of HAHb infused over two min. HAHb restored arterial pressure, increased systemic vascular resistance and caused a modest increase in cardiac output and SvO2, while pulmonary arterial pressure and vascular resistance were markedly increased. In two animals, transient severe hypotension and low cardiac output may have been due to acute pulmonary hypertension during injection. Compared to our previous study, in which animals received 4 ml-kg-1 of alpha alpha Hb alone, HAHb produced higher cardiac output and a smaller increase in systemic and pulmonary vascular resistance. However, slower, titrated infusions may be needed when hemoglobin solutions are combined with drugs or solutions that cause vasodilation in order to decrease the likelihood of acute hemodynamic instability.

Low-dose Hypertonic Saline (naci 8.0%) Treatment Of Uncontrolled Abdominal Hemorrhage: Effects On Arterial Versus Venous Injury

The present study compared hemodynamic response to hypertonic saline (HTS; NaCl 8.0%) treatment of uncontrolled hemorrhage from a stab injury in the abdominal aorta (A) or vena cava (V), respectively. The hypothesis was challenged that adverse effects of HTS treatment is dependent on the pressure load in the lesioned vessel. Uncontrolled hemorrhage was produced in anesthetized rats by vessel puncture with a syringe needle. After 10 min of hemorrhage, subjects were randomized to HTS infusion, 2.0 mL/kg i.v. given at .4 mL/min (AHTS, n = 10 and VHTS, n = 10), or to no treatment (AC, n = 12 and VC, n = 7). mean arterial pressure (MAP), heart rate, plasma electrolytes, protein, and hematocrit were recorded continuously for 240 min. HTS treatment produced MAP elevation but did not influence the final outcome in either A or V lesions. Thus, evidence of worsened outcome related to HTS treatment was not confirmed. However, one-half of all subjects with arterial hemorrhage died, compared to only 1 of 17 subjects with venous hemorrhage. Spontaneous MAP recovery during hemorrhage, and MAP response to HTS treatment, were shown to have predictive value for survival.