Hypertonic saline dextran: efficacy and regulatory approval.
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Dextrans↗
Biomedical subjects
D S Prough
Publications and source records attributed to D S Prough.
L-arginine and superoxide dismutase prevent or reverse cerebral hypoperfusion after fluid-percussion traumatic brain injury.
To determine whether treatment with L-arginine or superoxide dismutase (SOD) would prove effective in reducing cerebral hypoperfusion after traumatic brain injury (TBI), we measured cerebral blood flow (CBF) using laser Doppler flowmetry (LDF) in rats treated before or after moderate (2.2 atm) fluid-percussion (FP) TBI. Rats were anesthetized with isoflurane and prepared for midline FP TBI and then for LDF by thinning the calvaria using an air-cooled drill. Rats were then randomly assigned to receive sham injury, sham injury plus L-arginine (100 mg/kg, 5 min after sham TBI), TBI plus 0.9% NaCl, TBI plus L-arginine (100 mg/kg, 5 min post-TBI), TBI plus SOD (24,000 U/kg pre-TBI + 1600 units/kg/min for 15 min after TBI), or TBI plus SOD and L-arginine. A second group of rats received TBI plus saline, L-, or D-arginine (100 mg/kg, 5 min after-TBI). After treatment and TBI or sham injury, CBF was measured continuously using LDF for 2 h and CBF was expressed as a percent of the preinjury baseline for 2 h after TBI. Rats treated with saline or D-arginine exhibited significant reductions in CBF that persisted throughout the monitoring period. Rats treated with L-arginine alone or in combination with SOD exhibited no decreases in CBF after TBI. CBF in the SOD-treated group decreased significantly within 15 min after TBI but returned to baseline levels by 45 min after TBI. These studies indicate that L-arginine but not D-arginine administered after TBI prevents posttraumatic hypoperfusion and that pretreatment with SOD will restore CBF after a brief period of hypoperfusion.
Animals↗
Effects of nalmefene, CG3703, tirilazad, or dopamine on cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and hemorrhage.
Hemorrhage after traumatic brain injury (TBI) in cats produces significant decreases in cerebral oxygen delivery (DcereO2) and electroencephalographic (EEG) activity. To determine whether effective treatments for the separate insults of TBI and hemorrhagic shock would also prove effective after the clinically relevant combination of the two, we measured the effects of a kappa-opiate antagonist (nalmefene), an inhibitor of lipid peroxidation (tirilazad), a thyrotropin-releasing hormone analog (CG3703), a clinically useful pressor agent (dopamine) or a saline placebo on cerebral blood flow (CBF), and EEG activity after TBI and mild hemorrhagic hypotension. Cats (n = 40, 8 per group) were anesthetized with 1.6% isoflurane in N2O:O2 (70:30) and prepared for fluid-percussion TBI and microsphere measurements of CBF. Cats were randomized to receive nalmefene (1 mg/kg), tirilazad (5 mg/kg), CG3703 (2 mg/kg), dopamine (20 microg x kg(-1) x min[-1]) or a saline placebo (2 ml, 0.9% NaCl). Animals were injured (2.2 atm), hemorrhaged to 70% of preinjury blood volume, treated as just described and resuscitated with a volume of 10% hydroxyethyl starch equal to shed blood. CBF was determined and EEG activity recorded before injury, after hemorrhage, and 0, 60, and 120 min after resuscitation (R0, R60, and R120). CBF increased significantly after resuscitation (R0) in the nalmefene- and CG3703-treated groups. CBF did not differ significantly from baseline in any group at R60 or R120. DcereO2 was significantly less than baseline in the saline-, dopamine-, and tirilazad-treated groups at R60 and in the dopamine-, tirilazad-, and CG3703-treated groups at R120. EEG activity remained unchanged in the nalmefene-treated group but deteriorated significantly at R60 or R120 compared to baseline in the other groups. Nalmefene and CG3703 preserved the hyperemic response to hemodilution (otherwise antagonized by TBI), and nalmefene prevented the deterioration in DcereO2 and EEG activity that occurs after TBI and hemorrhage.
Animals↗
Cerebral blood flow during experimental endotoxemia in volunteers.
OBJECTIVE: To measure cerebral blood flow, cerebral metabolic rate for oxygen, cerebral oxygen delivery, and cerebral vascular resistance during experimental endotoxemia in volunteers. DESIGN: Experimental, prospective study. SETTING: University general clinical research center. SUBJECTS: Healthy volunteers (six male, four female, 30.1 +/- 1.9 yrs of age). INTERVENTIONS: Volunteers had radial, pulmonary arterial, and jugular venous bulb catheters inserted. All volunteers received a bolus of Escherichia coli endotoxin (4 ng/kg). Cerebral blood flow was measured, using the Kety-Schmidt technique. MEASUREMENTS AND MAIN RESULTS: Cerebral and systemic hemodynamics and oxygenation variables were measured at baseline and hourly for 5 hrs after endotoxin administration. A systemic hyperdynamic response characterized by an increase in body temperature (97.9 +/- 0.02, 100.2 +/- 0.02, and 99.7 +/- 0.02 degrees F [36.6 +/- 0.01, 37.9 +/- 0.1, and 37.6 +/- 0.1 degrees C] at baseline, 3, and 5 hrs, respectively), cardiac index (3.7 +/- 0.2, 6.2 +/- 0.2, and 5.7 +/- 0.2 L/min/m2 at baseline, 3, and 5 hrs), and heart rate (70 +/- 2.6, 96 +/- 2.6, and 93 +/- 2.9 beats/min at baseline, 3, and 5 hrs), and a decrease in mean arterial pressure (99.3 +/- 2.2, 84.4 +/- 2.8, and 84 +/- 3.4 mm Hg at baseline, 3, and 5 hrs) and systemic vascular resistance (1498 +/- 53, 788 +/- 37, 849 +/- 36 dyne.sec/cm5.m2 at baseline, 3, and 5 hrs) followed the endotoxin bolus. Cerebral blood flow (65.4 +/- 4.3, 57.7 +/- 3.1, and 58.6 +/- 3.0 mL/100 g/min at baseline, 3, and 5 hrs), cerebral oxygen delivery (11.6 +/- 0.7, 9.8 +/- 0.6, and 9.5 +/- 0.6 mL/100 g/min at baseline, 3, and 5 hrs), cerebral metabolic rate for oxygen (3.8 +/- 0.4, 3.3 +/- 0.3, and 3.0 +/- 0.3 mL/100 g/min at baseline, 3, and 5 hrs), and cerebral vascular resistance (1.4 +/- 0.2, 1.4 +/- 0.2, and 1.3 +/- 0.2 mm Hg/mL/100 g/min at baseline, 3, and 5 hrs) were unchanged throughout the 5-hr study period. Signs of cerebral dysfunction were not apparent, although the volunteers appeared drowsy during the latter part of the study. CONCLUSION: A dose of endotoxin sufficient to induce systemic vasodilation in healthy subjects does not influence cerebral blood flow or the cerebral metabolic rate for oxygen.
Adult↗
Global cerebral ischemia in humans: how long is too long?
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Adolescent↗
Therapy of patients with head injuries: key parameters for management.
BACKGROUND: Secondary brain injury, presumed secondary to ischemia, increases the mortality and morbidity of traumatic brain injury. Although many mechanisms appear to be involved, many potential ischemic insults results from changes in readily observable physiologic variables. METHODS: A focused search of scientific articles published in English to determine what data are available to suggest parameters within which key physiologic variables should be maintained. RESULTS: Few data demonstrate that maintenance of variables within specific ranges alters outcome; however, considerable evidence establishes association with poor outcome and hypotension, intracranial hypertension, and cerebral venous saturation. Key parameters vary somewhat based upon the phase of treatment after injury. Other variables, such as systemic oxygen delivery and brain saturation measured by near-infrared spectroscopy, are less well linked to outcome. CONCLUSIONS: Further research is necessary to establish that manipulation of physiologic variables to maintain them within preset ranges improves outcome.
Brain Injuries↗
Acute alterations in growth hormone-insulin-like growth factor axis in humans injected with endotoxin.
The purpose of the present study was to characterize the acute changes in the insulin-like growth factor (IGF) system in humans after administration of endotoxin (lipopolysaccharide; LPS). Escherichia coli LPS (4 ng/kg) was injected intravenously into healthy adults, and serial blood samples were collected for the next 5 h; subjects injected with saline served as time-matched controls. LPS administration resulted in a gradual decrease in the total extractable IGF-I concentration, which was reduced by approximately 20% over the final 2 h of the experiment; levels of free IGF-I were not significantly altered. LPS also produced a marked but transient elevation in growth hormone (GH) concentration. IGF-binding protein (BP)-1 levels were elevated more than fivefold 2 h after LPS injection, and thereafter levels gradually returned toward baseline. IGFBP-2 concentration also increased after LPS injection, but the maximal increase (approximately 50% above basal) was observed during the final 2 h of the protocol. In contrast, IGFBP-3 levels did not vary over the period examined in response to LPS, and there was no apparent increase in number of BP-3 proteolytic fragments. Cortisol levels were increased early and remained two- to threefold above baseline throughout the protocol. No significant alterations in serum concentration of glucose or insulin were noted. LPS also produced an early elevation in tumor necrosis factor and a later increase in interleukin-6. These data indicate that the acute changes in the GH-IGF axis in humans in response to LPS are comparable with those observed in humans in other traumatic conditions and in animal models of endotoxemia and infection.
Adolescent↗
Determinants of cerebral perfusion during cardiopulmonary bypass.
The risk of postoperative neurologic dysfunction in patients undergoing cardiac surgery remains high despite continued improvements in myocardial protective strategies. Part of this neurologic morbidity can be attributed to patients' increased age and underlying pathology, but other factors adversely affecting cerebral blood flow and cerebral metabolism during cardiopulmonary bypass may also contribute. Particulate microembolization during cardiopulmonary bypass appears to be a major cause of postoperative neurologic dysfunction and the pH-stat method of carbon dioxide management during hypothermia may potentiate neurologic damage by allowing a greater embolic load to be delivered to the brain. Echocardiography and transcranial Doppler methods may contribute to reducing the incidence of cerebral embolization by recognizing the timing and number of microemboli. Although hypothermia confers cerebral protection, rewarming may unmask and perhaps potentiate any ischemic damage that occurred with embolization during hypothermia. Both the degree and speed of rewarming may be important factors contributing to the extent of ischemic damage and ultimately neurologic function. In addition, many other factors related to cardiopulmonary bypass can alter cerebral perfusion and metabolism, such as nonpulsatile flow, hemodilution, pressure autoregulation, anesthetic and cerebroprotective drugs, and the neuroimmune response to bypass. In this review, the major factors affecting cerebral blood flow during cardiopulmonary bypass are discussed and their relative importance evaluated with regard to postoperative neurologic function.
Brain↗
Validation in volunteers of a near-infrared spectroscope for monitoring brain oxygenation in vivo.
Cerebral oximeters based on near-infrared spectroscopy may provide a continuous, noninvasive assessment of cerebral oxygenation. We evaluated a prototype cerebral oximeter (Invos 3100; Somanetics, Troy, MI) in 22 conscious, healthy volunteers breathing hypoxic gas mixtures. Using the first 12 subjects (training group), we developed an algorithm based on the mathematic relationship that converts detected light from the field surveyed by the probe to cerebral hemoglobin oxygen saturation (CSfO2). To develop the algorithm, we correlated the oximeter result with the estimated combined brain hemoglobin oxygen saturation (CScombO2, where CScombO2 = SaO2 x 0.25 + SjO2 x 0.75 and SjO2 = jugular venous saturation). We then validated the algorithm in the remaining 10 volunteers (validation group). A close association (r2 = 0.798-0.987 for individuals in the training group and r2 = 0.794-0.992 for individuals in the validation group) existed between CSfO2 and CScombO2. We conclude that continuous monitoring with cerebral oximetry may accurately recognize decreasing cerebral hemoglobin oxygen saturation produced by systemic hypoxemia.
Adult↗
The influence of carbon dioxide and body position on near-infrared spectroscopic assessment of cerebral hemoglobin oxygen saturation.
Near-infrared spectroscopy may allow continuous and noninvasive monitoring of regional brain hemoglobin oxygen saturation by measuring the differential absorption of infrared light by oxyhemoglobin and deoxyhemoglobin. We have previously examined the correlation between the spectroscopic signal generated by a prototype cerebral oximeter (Invos 3100; Somanetics, Troy, MI), and global brain hemoglobin oxygen saturation calculated from arterial and jugular venous bulb oxygen saturations. Because the technology does not distinguish between arterial and venous hemoglobin saturation, changes in the proportion of cerebral arterial and venous blood volume, which may result from changes in blood flow or venous distending pressure, may confound measurements. In eight conscious volunteers breathing hypoxic oxygen mixtures, we examined the influence of supine, 20 degrees Trendelenburg, and 20 degrees reverse Trendelenburg positions on the correlation of the spectroscopic measurement of cerebral oxygen saturation in the field assessed by the probe (CSfO2) and the calculated brain hemoglobin oxygen saturation (CScombO2), estimated as 0.25 x arterial saturation plus 0.75 x jugular venous bulb oxygen saturation. We found that changes in position did not influence the association between CSfO2 and CScombO2 (r2 = 0.69-0.885) during hypoxic challenge. In a second set of eight volunteers, we studied the influence of hypercapnia and hypocapnia and body position on the association between CSfO2 and CScombO2, and found that they were less well correlated (r2 = 0.366-0.976) in individual patients. Because changes in body position and Paco2 confound the relationship between CSfO2 and CScombO2, changes in CSfO2 can best be assessed if position and Paco2 are constant.
Adult↗
Signal extraction technology: a better mousetrap?
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Anesthesia Recovery Period↗
Cerebral near-infrared spectroscopy: a plea for modest expectations.
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Brain↗
Hypertonic saline does not improve cerebral oxygen delivery after head injury and mild hemorrhage in cats.
OBJECTIVES: To investigate the effects of hypertonic saline for resuscitation after mild hemorrhagic hypotension combined with fluid-percussion traumatic brain injury. Specifically, the effects of hypertonic saline on intracranial pressure, cerebral blood flow (radioactive microsphere method), cerebral oxygen delivery (cerebral oxygen delivery = cerebral blood flow x arterial oxygen content), and electroencephalographic activity were studied. DESIGN: Randomized, controlled, intervention trial. SETTING: University laboratory. SUBJECTS: Thirty-four mongrel cats of either sex, anesthetized with 1.0% to 1.5% isoflurane in nitrous oxide/oxygen (70:30). INTERVENTIONS: Anesthetized (isoflurane) cats were prepared for traumatic brain injury, and then randomly assigned to the following groups: moderate traumatic brain injury only (2.7 +/- 0.2 atmospheres [atm], group 1); mild hemorrhage (18 mL/kg) only, followed immediately by resuscitation with 10% hydroxyethyl starch in 0.9% saline in a volume equal to shed blood (group 2); or both traumatic brain injury (2.7 +/- 0.1 atm) and mild hemorrhage, followed immediately by replacement of a volume equal to shed blood of 10% hydroxyethyl starch in 0.9% saline (group 3); or 3.0% saline (group 4). MEASUREMENTS AND MAIN RESULTS: Data were collected at baseline, at the end of hemorrhage, and at 0, 60, and 120 mins after resuscitation (or at comparable time points in group 1). Intracranial pressure in group 1 was significantly increased by traumatic brain injury at the end of hemorrhage, immediately after resuscitation, and 60 mins after resuscitation (p < .02 vs. baseline). In group 2, intracranial pressure increased significantly only immediately after resuscitation (p < .0001 vs. baseline). Groups 3 and 4 exhibited higher, although statistically insignificant, intracranial pressure increases at 60 and 120 mins after resuscitation. During resuscitation, cerebral blood flow increased significantly (p < .02 vs. baseline) in the uninjured cats. In contrast, cerebral blood flow failed to increase during resuscitation in the cats subjected to traumatic brain injury before hemorrhage and resuscitation. Although cerebral oxygen delivery in group 2 decreased significantly immediately, 60 mins, and 120 mins after resuscitation (p < .001 vs. baseline) both groups 3 and 4 had significantly lower cerebral oxygen delivery at 60 and 120 mins after resuscitation (p < .01 and p < .005, respectively, vs. group 1 at 60 mins after resuscitation, and p < .01 and p < .01, respectively, vs. group 1 at 120 mins after resuscitation). CONCLUSIONS: After a combination of hemorrhage and traumatic brain injury, neither 10% hydroxyethyl starch nor 3.0% hypertonic saline restored cerebral oxygen delivery. Although neither trauma alone nor hemorrhage alone altered electroencephalographic activity, the combination produced significant decreases in electroencephalographic activity at 60 and 120 mins after resuscitation in groups 3 and 4, suggesting that cerebral oxygen delivery is inadequately restored by either resuscitation fluid. Therefore, traumatic brain injury abolished compensatory cerebral blood flow increases to hemodilution, and neither hydroxyethyl starch nor 3.0% hypertonic saline restored cerebral blood flow, cerebral oxygen delivery, or electroencephalographic activity after hemorrhagic hypotension after traumatic brain injury.
Animals↗
Still lethal after all these years.
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Acute Kidney Injury↗
Solutions in search of problems.
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Craniocerebral Trauma↗
Neuroprotective properties of calcium-channel blockers.
Increases in intraneuronal Ca2+ concentration, which accompany cerebral ischemia and traumatic brain injury, initiate a cascade of biochemical events that can eventually result in cell lysis and death. Calcium-channel blockers, in certain experimental models of focal and global ischemia, attenuate the increase in intracellular Ca2+ concentration and thereby ameliorate neurologic damage. Clinical efficacy varies among disease states. After nontraumatic subarachnoid hemorrhage, nimodipine has become a standard of care. Calcium-channel blockers improve outcome, whether given before or after onset of vasospasm. Although the precise mechanism of their beneficial effect remains unclear (vasodilation vs. attenuation of increases in intracellular Ca2+ concentrations), numerous studies have demonstrated decreased neurologic morbidity. Although there also is suggestive evidence of benefit in human stroke, these results have not been sufficiently impressive to result in the widespread use of these drugs as neuroprotectants. In clinical trials after cardiac arrest, calcium-channel blockers have been ineffective. In clinical traumatic brain injury, data suggest moderate efficacy in younger patients and those with post-traumatic subarachnoid hemorrhage, although overall outcome is not changed. The future role of calcium-channel blockers as neuroprotectants appears bright. Newer classes of compounds, with greater specificity and fewer side effects, may provide greater clinical benefit.
Animals↗
Cerebral metabolic consequences of hypotensive challenges in hemodiluted pigs with and without cardiopulmonary bypass.
We tested the hypothesis that progressive aortic hypotension with bicarotid occlusion produces greater reductions in cerebral blood flow (CBF) and more flow-metabolism mismatching with hemodilution during cardiopulmonary bypass (CPB) than with hemodilution alone. In Yorkshire pigs randomized to hemodilution with CPB (n = 10) or hemodilution without CPB (control; n = 9), the effects of bicarotid ligation and graded hypotension on CBF (microspheres), the electroencephalogram (EEG), and cortical energy metabolites were examined. After bicarotid ligation, systemic flow was reduced for 15-min intervals of 80, 60, and 40 mm Hg aortic pressure, followed by a cortical brain biopsy. At baseline, CBF was lower in CPB (58 +/- 3 mL.100g-1.min-1) than control (90 +/- 3 mL.100 g-1.min-1., P < 0.05) animals, as was cerebral oxygen metabolism (3.1 +/- 0.1 vs 4.2 +/- 0.2 mL.min-1.100g-1; P < 0.05). Although CBF remained 40% lower at each level of hypotension in CPB than control animals (P < 0.05), EEG scores showed no intergroup differences, indicating similar flow-metabolism matching. Brain metabolites were similar between CPB and control groups (adenosine triphosphate, 9.6 +/- 2.4 vs 12.4 +/- 1.9 mumol/g; adenosine diphosphate, 6.0 +/- 0.7 vs 6.3 +/- 0.4 mumol/g; adenosine monophosphate, 4.8 +/- 0.9 vs 3.8 +/- 0.8 mumol/g; creatine phosphate, 8.3 +/- 1.8 vs 7.9 +/- 1.0 mumol/g; and lactate, 178.4 +/- 20.2 vs 150.8 +/- 13.9 mumol/g). Thus, despite significantly lower CBF during hypotension with bicarotid occlusion in hemodiluted animals during normothermic CPB, cortical electrical activity and the balance between flow and metabolism did not differ from those in control animals without CPB.
Adenine Nucleotides↗
Hyperglycemia during hypothermic canine cardiopulmonary bypass increases cerebral lactate.
BACKGROUND: Hyperglycemia frequently occurs during cardiopulmonary bypass (CPB), although its direct effects on cerebral perfusion and metabolism are not known. Using a canine model of hypothermic CPB, we tested whether hyperglycemia alters cerebral blood flow and metabolism and cerebral energy charge. METHODS: Twenty anesthetized dogs were randomized into hyperglycemic (n = 10) and normoglycemic (n = 10) groups. The hyperglycemic group received an infusion of D50W, and the normoglycemic animals received an equal volume of 0.9% NaCl. Both groups underwent 120 min of hypothermic (28 degrees C) CPB using membrane oxygenators, followed by rewarming and termination of CPB. Cerebral blood flow (radioactive microspheres) and the cerebral metabolic rate for oxygen were measured intermittently during the experiment and brain tissue metabolites were obtained after bypass. RESULTS: Before CPB, the glucose-treated animals had higher serum glucose levels (534 +/- 12 mg/dL; mean +/- SE) than controls (103 +/- 4 mg/dL; P < 0.05), and this difference was maintained throughout the study. Cerebral blood flow and metabolism did not differ between groups at any time during the experiment. Sagittal sinus pressure was comparable between groups throughout CPB. Tissue high-energy phosphates and water contents were similar after CPB, although cerebral lactate levels were greater in hyperglycemic (37.2 +/- 5.7 mumol/g) than normoglycemic animals (19.7 +/- 3.7 mumol/g; P < 0.05). After CPB, pH values of cerebrospinal fluid for normoglycemic (7.33 +/- 0.01) and hyperglycemic (7.34 +/- 0.01) groups were similar. CONCLUSIONS: Hyperglycemia during CPB significantly increases cerebral lactate levels without adversely affecting cerebral blood flow and metabolism, cerebrospinal fluid pH, or cerebral energy charge.
Adenine Nucleotides↗