Assessment of tissue oxygenation: ultimate endpoint or simply interesting?
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Publications and source records attributed to George C Kramer.
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OBJECTIVE: NaCl solutions (7.5%) have been reported to be effective for resuscitation in animals and trauma patients, but these solutions are not approved for use in the United States. We hypothesized that infusion of Food and Drug Administration-approved 3% NaCl provides superior cardiovascular and metabolic function while reducing the overall fluid requirement for resuscitation of hemorrhage. Our objective was to compare four groups, hypotensive and normotensive resuscitation of hemorrhage using 3% NaCl (HS) or lactated Ringer's (LR). DESIGN: Sheep were hemorrhaged in three separate bleeds, 25 mL/kg at T0 mins and 5 mL/kg at both T50 and T70 mins. SETTING: University laboratory. SUBJECTS: Instrumented conscious sheep. INTERVENTIONS: Resuscitation was started at T30 mins and continued until T180. Normotensive and hypotensive resuscitation to mean arterial pressures of 90 mm Hg and 65 mm Hg, respectively, was performed with LR or HS using a closed-loop resuscitation system. MEASUREMENTS AND MAIN RESULTS: All four groups were successfully resuscitated to near target levels. Two animals in the hypotensive treatment protocols died during the second and third bleeding, one with the LR65 group and one with the HS65 group. Mean infused volumes were 59.9 +/- 7.0 and 18.0 +/- 5.9 in the LR90 and LR65 groups, respectively, and were 19.6 +/- 2.2 mL/kg and 13.3 +/- 5.7 mL/kg in the HS90 and HS65 treatments (p < .05; LR90 vs. each of the groups). Cardiac indexes were significantly higher with normotensive vs. hypotensive treatment. However, there was no hemodynamic advantage apparent with HS vs. LR when compared with the normotensive or hypotensive treatments. Some animals had high lactate levels (>10 mmol) with both of the hypotensive treatments and also with the HS90 treatment, while not one of the 11 LR90 treatment animals had lactate levels >8 mmol. CONCLUSIONS: Volume sparing was apparent with HS, but no hemodynamic or metabolic advantage was apparent when used for either normotensive or hypotensive resuscitation. Trends toward lower base excess values and higher occurrences of deaths only in the hypotensive treatment protocols suggest that resuscitation to a target mean arterial pressure of 65 mm Hg may be too low.
Hypertonic saline solutions improve cerebral blood flow (CBF) when used for acute resuscitation from hemorrhagic hypotension accompanying some models of traumatic brain injury (TBI); however, the duration of increased CBF is brief. Because the nitric oxide synthase substrate l-arginine provides prolonged improvement in CBF after TBI, we investigated whether a hypertonic resuscitation fluid containing l-arginine would improve CBF in comparison to hypertonic saline without l-arginine in a model of moderate, paramedian, fluid-percussion TBI followed immediately by hemorrhagic hypotension (mean arterial pressure [MAP] = 60 mm Hg for 45 min). Sprague-Dawley rats were anesthetized with 4.0% isoflurane, intubated and ventilated with 1.5%-2.0% isoflurane in oxygen/air (50:50). After preparation for TBI and measurement of CBF using laser Doppler flowmetry and measurement of intracranial pressure (ICP) using an implanted transducer, rats were subjected to moderate (2.0 atm) TBI, hemorrhaged for 45 min, and randomly assigned to receive an infusion of hypertonic saline (7.5%, 2,400 mOsm total; 6 mL/kg; n = 6) or hypertonic saline with 50, 100, or 300 mg/kg L-arginine (2,400 mOsm; 6 mL/kg; n = 6 in each of the three dose groups) and then monitored for 120 min after the end of infusion. CBF was measured continuously and calculated as a percent of the pre-TBI baseline during the hemorrhage period, after reinfusion of one of the hypertonic arginine solutions, and 30, 60, and 120 min after reinfusion. All four hypertonic solutions initially improved MAP, which, by 120 min after infusion, had decreased nearly to the levels observed during hemorrhage. ICP remained below baseline levels during resuscitation in all groups, although ICP was slightly greater (P = NS) than baseline in the hypertonic saline group. CBF increased similarly in all groups during infusion and then decreased similarly in all groups. At 120 min after infusion, CBF was highest in the group infused with hypertonic saline, but the difference was not significant. We conclude that the improvement of MAP, ICP, and CBF produced by hypertonic saline alone after TBI and hemorrhagic hypotension is not significantly enhanced by the addition of L-arginine at these doses.
BACKGROUND: Plasma volume expansion is often performed during adrenergic therapy in the intensive care unit, but little is known about their combined effects. MATERIALS AND METHODS: The influence of three adrenergic drugs (50 microg/kg/min of dopamine, 0.1 microg/kg/min of isoprenaline, or 3 microg/kg/min of phenylephrine) on the relationship between plasma dilution (an index of volume expansion) and the central hemodynamic responses to volume loading with 24 ml/kg of 0.9% saline were evaluated in 6 adult sheep. Kinetic analysis was also applied to the data on plasma dilution and the urinary excretion measured during and after volume loading. RESULTS: The adrenergic agents markedly changed the baseline values for all hemodynamic parameters. The kinetic analysis showed that phenylephrine, which is an alpha-adrenergic receptor agonist, promoted renal excretion of infused fluid at the expense of fluid distribution to the periphery (P < 0.05 versus controls). Isoprenaline, which stimulates adrenergic beta-receptors, had the opposite effect. During volume expansion, cardiac atrial pressures increased by 25 to 90%, cardiac output by 13-80% and the arterial pressures by 2 to 22%. Plasma dilution during and after volume loading correlated, in a linear fashion, with these hemodynamic responses. The correlations were strong (r > 0.80) in the control and phenylephrine groups, but weaker in the dopamine and isoprenaline groups. Dopamine was associated with the most variable hemodynamic responses overall. CONCLUSIONS: Adrenergic drugs altered the hemodynamics at baseline (direct effects), changed the distribution and elimination of infused 0.9% saline (indirect effects) and, finally, modified most hemodynamic responses to plasma dilution (interaction effects).
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 Ringer's (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.
BACKGROUND: The authors studied the influence of alpha, beta, and dopaminergic catecholamines on blood volume expansion in conscious normovolemic sheep before, during, and after a bolus infusion of a crystalloid. METHODS: A 0.9% NaCl bolus (24 ml/kg in 20 min) was infused in four paired experiments each: no drug, dopamine infusion (50 microg . kg . min), isoproterenol infusion (0.1 microg . kg . min), and phenylephrine infusion (3 microg . kg . min). Blood volume expansion was calculated by the dilution of blood hemoglobin concentration. RESULTS: Dopamine had little effect on peak blood volume expansion (12.7 +/- 0.9 ml/kg) compared with 0.9% NaCl (13.0 +/- 2.7 ml/kg); in contrast, isoproterenol augmented blood volume expansion (18.5 +/- 1.8 ml/kg), and phenylephrine reduced blood volume expansion (8.9 +/- 1.4 ml/kg). Two hours after the 0.9% NaCl bolus, sustained blood volume expansion was greatest in the isoproterenol protocol (12.2 ml/kg), whereas the dopamine protocol (6.8 ml/kg) remained similar to the control protocol (4.1 ml/kg), and the phenylephrine protocol had a net volume loss (-1.9 ml/kg). Some blood volume expansion differences were attributed to changes in renal function as phenylephrine infusion increased urinary output, whereas isoproterenol was associated with antidiuresis. However, dopamine caused diuresis and sustained augmentation of blood volume. CONCLUSION: Catecholamines can alter the intravascular volume expansion of fluid therapy. beta-Receptor (isoproterenol) stimulation augmented blood volume expansion, whereas alpha (phenylephrine) stimulation reduced blood volume expansion. Combined dopaminergic, beta, and possibly alpha stimulation with dopamine augmented blood volume expansion and cardiac output while inducing diuresis.
It has been suggested that hyperdynamic (HD) resuscitation improves outcomes. We hypothesized that initial HD resuscitation of burn injury using fluid and inotropes would improve metabolic function as indicated by base excess. We used an anesthetized ovine model of 60% TBSA full-thickness flame burn with delayed resuscitation started at 90 min after burn and continued for 8 h. Three groups (n = 6 each) were included: 1) HD defined as cardiac index (CI) of 1.5x baseline achieved by using Ringer's lactate alone (HD-Fluid); 2) Ringer's lactate and dobutamine (HD-Drug); and 3) Parkland Formula (Parkland) as a control group. Statistical analysis performed using analysis of variance and Tukey's HSD test. Significance accepted at P < 0.05. Higher CI was achieved in both HD-Fluid and HD-Drug groups, e.g., at 8 h the CI was 4.6 +/- 0.4 and 4.7 +/- 0.6 L/min/m respectively, as compared with Parkland 3.6 +/- 0.5 L/min/m. The net fluid balance (fluid infused - urine output) was similar in both Parkland and HD-Drug groups, which were 2.5x more in HD-Fluid (P = 0.001). The mean postburn urinary outputs were similar in both Parkland and HD-Drug groups, e.g., Parkland (0.9 +/- 0.08 mL/kg/h), HD-Drug (1.0 +/- 0.2 mL/kg/h) and increased in HD-Fluid (3.7 +/- 1.0 mL/kg/h; P = 0.0005). Base excess remained positive in both HD-Drug (+2.5 +/- 1 mmol/L) and Parkland (+1.5 +/- 1.7 mmol/L), and declined to -4.0 +/- 3.6 mmol/L in HD-Fluid group (P = 0.036). We conclude that there may be no benefit to using hyperdynamic regimens for the initial resuscitation of burn injury.
Hypotensive resuscitation has been advocated as a better means to perform field resuscitation of penetrating trauma. Our hypothesis is that hypotensive resuscitation using either crystalloid or colloid provides equivalent or improved metabolic function while reducing the overall fluid requirement for resuscitation of hemorrhage. We compared hypotensive and normotensive resuscitation of hemorrhage using lactated Ringer's (LR) with hypotensive resuscitation using Hextend (Hex), 6% hetastarch in isotonic buffered saline. Instrumented conscious sheep were hemorrhaged in three separate bleeds, 25 mL/kg at T0 and 5 mL/kg at both T50 and T70. Resuscitation was started at T30 and continued until T180. Hypotensive resuscitation to a mean arterial pressure (MAP) of 65 mmHg was performed with LR or Hex using a closed-loop resuscitation (CLR) system for a LR-65 and Hex-65 treatment protocol. A control treatment protocol was resuscitation with LR to a MAP target of 90 mmHg, LR-90. All treatment protocols were successfully resuscitated to near target levels. Two animals in the hypotensive treatment protocols died during the second and third bleedings, one in the LR-65 and one in the Hex-65 treatment protocol. Mean infused volumes were 61.4 +/- 11.3, 18.0 +/- 5.9, and 11.6 +/- 1.9 mL/kg in the LR-90, LR-65, and Hex-65 treatments, respectively (*P < 0.05 versus LR-90). Mean minimum base excess (BE) values were +1.9 +/- 1.4, -5.8 +/- 4.3, and -5.9 +/- 4.0 mEq/L in the LR-90, LR-65, and Hex-65 treatments, respectively. Hypotensive resuscitation with LR greatly reduced volume requirements as compared with normotensive resuscitation, and Hex achieved additional volume sparing. However, trends toward lower BE values and the occurrence of deaths only in the hypotensive treatment protocols suggest that resuscitation to a target MAP of 65 mmHg may be too low for optimal outcomes.
BACKGROUND: The combination of isoflurane anesthesia and mechanical ventilation reduces urinary output and promotes redistribution of a crystalloid bolus into the extravascular space. The authors hypothesized that mechanical ventilation rather than isoflurane causes this alteration. METHODS: The fate of a 25-ml/kg, 20-min, 0.9% saline fluid bolus was studied in four different experiments per sheep: while conscious and spontaneously ventilating (CSV), while conscious and mechanically ventilated (CMV), while anesthetized with isoflurane and mechanical ventilated (ISOMV), and while anesthetized with isoflurane and spontaneously ventilating (ISOSV). RESULTS: By calculations based on the indicator dilution and mass balance principles, plasma expansion was similar between protocols. Isoflurane but not mechanical ventilation reduced urinary output and increased interstitial fluid volume (P < 0.001): At 180 min, mean total urinary outputs were 15.6 +/- 2.1 and 15.9 +/- 2.9 ml/kg in the CSV and CMV protocols and 2.7 +/- 0.6 and 3.1 +/- 1.1 ml/kg in the ISOSV and ISOMV protocols, respectively. The net changes in extravascular volume, assumed to be interstitial fluid volume, were 8.6 +/- 3.3 and 8.1 +/- 3.1 ml/kg, and 22.5 +/- 1.5 and 22.1 +/- 1.6 ml/kg in the corresponding protocols. Volume kinetic analysis demonstrated extravascular fluid accumulation associated with isoflurane anesthesia similar to the calculated interstitial accumulation of 20.2 +/- 0.5 and 26.5 +/- 0.3 ml/kg in the ISOSV and ISOMV protocols, respectively. CONCLUSION: Isoflurane, but not mechanical ventilation, decreased urinary excretion and increased interstitial fluid volume. Volume kinetic analysis indicated "third-space" losses due to isoflurane. Perioperative fluid retention may be associated not only with surgical tissue manipulation, but with anesthesia per se.
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BACKGROUND: The purpose of this study was to assess whether the administration of hypertonic saline dextran (HSD) was detrimental when administered to patients who were hypotensive because of penetrating injuries to the torso. The administration of HSD causes an immediate and sustained increase in blood pressure that could contribute to an increase in bleeding in the presence of uncontrolled hemorrhage. We prospectively designed a series of questions to be addressed by a meta-analysis of individual patient data using a computerized data file and case report forms from a multicenter study of HSD. METHODS: The investigators were "blind" as to the treatment the patient received. Patients (n = 230) with penetrating injuries to the torso were studied as to survival until discharge. The patients were administered 250 mL of HSD or normal saline (standard of care [SOC]) as the initial fluid therapy. RESULTS: Of the 120 patients treated with HSD, 82.5% survived compared with 75.5% for 110 SOC patients (p = 0.19). Sixty-eight percent (n = 157) of these patients required surgery. HSD treatment (n = 84) in this population improved survival, 84.5% compared with 67.1% with SOC (n = 73) (p = 0.01). HSD resulted in an increase in blood pressure and a reduction in hematocrit, with no differences noted in fluid requirements or indices of clotting. CONCLUSION: For patients with penetrating injuries to the torso that result in hypotension, initial fluid resuscitation with HSD is beneficial in improving survival, especially if surgery is subsequently required.
BACKGROUND: Endpoint resuscitation has been suggested as a better means to resuscitate penetrating injury. We performed computer-controlled closed-loop resuscitation using invasive cardiac output (CO) or noninvasive skeletal muscle oxygen saturation (SkMusSO(2)) via near infrared spectroscopy (NIRS). METHODS: Conscious sheep received a 4.0-mm aortotomy and uncontrolled hemorrhage at t = 0 min (T0) while resuscitation started at T20 using lactated Ringer's solution. RESULTS: The aortotomy rapidly decreased the mean arterial pressure (MAP) to approximately 30 mm Hg and CO to 20% to 30% of baseline. The SkMusSO(2) endpoint group required only half as much fluid through 4 hours of resuscitation as the CO endpoint group (34.9 +/- 8.4 mL/kg vs. 63.1 +/- 9.4 mL/kg). CO and MAP were lower in the SkMusSO(2) group after T60. Mean infusion volumes were 180% and 100% of the bled volume collected at autopsy in the CO and SkMusSO(2) groups. Brain and muscle oxygenation and base excess were as high or higher in the CO endpoint group. CONCLUSION: Closed-loop resuscitation with either CO or SkMusSO(2) endpoints effectively performs fluid resuscitation of severe uncontrolled hemorrhagic shock. Limited resuscitation may achieve favorable clinical results with volumes less than recommended by Advanced Trauma Life Support guidelines.
Burn injury remains a constant source of morbidity and mortality in the military environment. The logistic constraints of combat casualty care can make it impossible to provide the large volumes of crystalloid typically used for burn resuscitation. Unlike penetrating trauma, the immediate and sustained fluid requirements necessary for resuscitation of thermal injury preclude the use of limited or hypotensive resuscitation. We examine the physiology, traditional resuscitation strategies, and rationales for the use of novel regimens in the resuscitation of thermal injury. Although strategies such as early use of colloids or hypertonic saline may not reduce morbidity or mortality when compared with large-volume infusions of lactated Ringer's, they can be volume sparing for some hours and sustain life until more definitive therapy is initiated. An intriguing hypothesis is that oral resuscitation can effectively restore plasma volume after thermal injury. We present data from recent experiments of gastric and intestinal infusions of an oral rehydration solution in a porcine burn model that demonstrates restoration of plasma volumes and improvement in hemodynamic parameters associated with significant gastric emptying and intestinal absorption.
Hypertonic saline solutions, with or without added colloid, have received extensive evaluation as volume expanders in both animal studies and clinical trials. Most studies have used 7.5% NaCl/6% dextran 70 (HSD). HSD's primary mechanism of action is rapid osmotic mobilization of cellular water into the blood volume. The measured volume expansion efficiency of HSD is equal to 10 times that of lactated Ringer's solution. Part of HSD's effectiveness is because of the hyperosmotic vasodilation of both systemic and pulmonary vessels. Increased cardiac effectiveness occurs because of the combination of increased preload (venous return) and reduced afterload (vasodilation). Increased cardiac contractility also has been reported in several studies and may play a role, but other studies refute a direct effect on contractility. HSD has been shown to be effective and safe with preexisting dehydration. Animal studies of immune function suggest that increased osmolarity prevents T-cell depression and decreases neutrophil activation. Several perioperative and eight randomized, blinded trauma trials have shown safety and reduced volume needs and suggest increased survival, particularly in head- and penetrating-injury patients. Infusion rates for HSD of 10 to 20 minutes may be recommended for the initial resuscitation of hypotensive trauma.
UNLABELLED: We examined whether volume kinetic variables obtained during infusion of a short bolus of 0.9% saline (NS) or 7.5% saline/6.0% dextran 70 (HSD) predict the dilution-time curve resulting from a 20-min infusion of the same fluid. Each of six conscious, splenectomized sheep (mean body weight, 36 +/- 3 kg), on 4 different days, in a random order, received each of 4 IV boluses: NS at a rate of 1.2 mL. kg(-1). min(-1) over 5 min or 20 min or 4.0 mL/kg of HSD over 2 min or 20 min. One, 2, and 3-volume kinetic models were fitted to the dilution of the arterial hemoglobin concentration and the urinary excretion as sampled during 180 min. The maximum dilution of arterial plasma at the end of the 5-min and 20-min infusions of NS was approximately 10% and 22%, respectively, and after the 2-min and 20-min infusions of HSD, maximum dilution was 24% and 21%, respectively. The median absolute performance error was virtually identical when the mean variable estimates from the 5-min infusion of NS were used to predict the individual dilution-time curves of the 5-min (mean, 0.027 dilution units) and 20-min (mean, 0.027) infusions and when the 2-min infusion of HSD was used to predict the dilution during the individual 2-min (mean, 0.050) and 20-min infusions (mean, 0.047). Computer simulations indicated that the difference at the end of infusion between the volume effects of NS and HSD is larger after longer infusions. We concluded that the volume kinetic variables obtained during a short infusion can be used to predict the outcome of a longer one, even if the longer infusion also delivers a larger volume. IMPLICATIONS: Kinetic analysis of a short infusion of 7.5% saline/6% dextran or 0.9% saline accurately predicts the effects of a longer infusion of the same volume (7.5% saline/6% dextran) or of a larger volume (0.9% saline).
Isoflurane-anesthetized sheep were transfused with packed red blood cells (pRBCs) or diaspirin cross-linked hemoglobin (DCLHb) for treatment of intraoperative hemorrhage. A rapid 15-min hemorrhage with lactated Ringer (LR) infusion maintained filling pressure at baseline and reduced blood hemoglobin (Hb) to ~5 g/dl. Sheep received 2 g/kg Hb, DCLHb (n = 6), or pRBCs (n = 7); control group received LR alone (n = 6). After 2 h, anesthesia was discontinued; sheep were monitored in the animal intensive care unit for 48 h. DCLHb expanded blood volume more, but increased total blood Hb less, than pRBCs. Lower Hb and increased methemoglobin resulted in lower arterial oxygen content compared with the pRBCs. DCLHb caused pulmonary hypertension (from 13 to 30 mmHg) and elevated filling pressure (from 6 to 15 mmHg). Cardiac outputs (CO) were similar for all groups during anesthesia; however, during recovery CO increased only in the LR and packed pRBCs groups. DCLHb may limit the reflex ability to increase CO after volume expansion. Hemodynamic effects of DCLHb may be exaggerated when infused after large-volume LR.
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.