Osmotherapy with hypertonic saline attenuates water content in brain and extracerebral organs

OBJECTIVE: Because of their beneficial effects in patients with hemorrhagic shock and multiple-system trauma, hypertonic saline solutions are increasingly being used perioperatively for volume resuscitation. Although the anti-edema effects of hypertonic saline on brain are well documented in a variety of brain injury paradigms, its effects on the water content on other organs has not been studied rigorously. In this study, we tested the hypothesis that a) hypertonic saline when given as an intravenous bolus and continuous infusion attenuates water content of small bowel, lung, and brain in rats without neuro-injury; and b) attenuation of stroke-associated increases in lung water is dependent on achieving a target serum osmolality. DESIGN: Prospective laboratory animal study. SETTING: Research laboratory in a teaching hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: In the first series of experiments, under controlled conditions of normoxia, normocarbia, and normothermia, spontaneously breathing, halothane-anesthetized (1.0-1.5%) adult male Wistar rats (280-320 g) were treated in a blinded randomized fashion with 7.5% hypertonic saline or 0.9% normal saline in a 8-mL/kg intravenous infusion for 3 hrs followed by a continuous intravenous infusion (1 mL/kg/hr) of 5% hypertonic saline or normal saline, respectively (n=10 each), for 48 hrs. A second group of rats were treated with continuous infusion only for 48 hrs of either 7.5% hypertonic saline or normal saline (1 mL/kg/hr) (n=10 each) without an intravenous bolus. Na?ve rats served as controls (n=10). Tissue water content of small bowel, lung, and brain was determined by comparing the wet-to-dry ratios at the end of the experiment. In a second series of experiments, rats (n=94) were subjected to 2 hrs of transient middle cerebral artery occlusion by the intraluminal occlusion technique. At 6 hrs following middle cerebral artery occlusion, rats were treated in a blinded randomized fashion with a continuous intravenous infusion of normal saline, 3% hypertonic saline, or 7.5% hypertonic saline for 24, 48, 72, and 96 hrs. Surgical shams served as controls (n=7). Hypertonic saline was instituted as chloride/acetate mixture (50:50) in all experiments. Serum osmolality was determined at the end of the experiment in all animals. MEASUREMENTS AND MAIN RESULTS: In rats without neuro-injury that received intravenous bolus followed by a continuous infusion, lung water content was significantly reduced with hypertonic saline (73.9+/-1.1%; 359+/-10 mOsm/L) (mean+/-sd) compared with normal saline treatment (76.1+/-0.53%; 298+/-4 mOsm/L) as was water content of small bowel (hypertonic saline, 69.1+/-5.8%; normal saline, 74.7+/-0.71%) and brain (hypertonic saline, 78.1+/-0.87%; normal saline, 79.2+/-0.38%) at 48 hrs. Stroke-associated increases in lung water content were attenuated with 7.5% hypertonic saline at all time points. There was a strong correlation between serum osmolality and attenuation of stroke-associated increases in lung water content (r=-.647) CONCLUSIONS: Bowel, lung, and brain water content is attenuated with hypertonic saline when serum osmolality is >350 mOsm/L without adverse effect on mortality in animals with and without neuro-injury. Attenuation of water content of extracerebral organs with hypertonic saline treatment may have therapeutic implications in perioperative fluid management in patients with and without brain injury.     

Pentoxifylline attenuates edema formation in proteolytic enzyme-induced lung injury

Ex vivo canine lung lobes were exposed to a pancreatic proteolytic enzyme (chymotrypsin) alone or chymotrypsin after pretreatment with a continuous infusion with pentoxifylline. The lobes exposed to chymotrypsin gained 133 g, while the pentoxifylline-treated lobes gained only 65 g (p less than .05) over the 3-h experimental period. These results suggest that pentoxifylline significantly attenuates the lung weight gain associated with chymotrypsin.     

Experimental spinal cord ischemia: model characterization and improved outcome with arterial hypertension

OBJECTIVE: Paraplegia from spinal cord ischemia is a devastating complication of thoracoabdominal aortic aneurysm repair. Perioperative hypoperfusion of the spinal cord is a critical determinant of residual neurologic deficits. We determined if functional and histologic outcome is dependent on systemic blood pressure in a rat model of spinal cord ischemia. DESIGN: Randomized, controlled, prospective study. SETTING: Research laboratory at a university teaching hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Endotracheally intubated adult male Wistar rats (300-450 g) anesthetized with halothane underwent a thoracotomy and placement of a clip across the descending aorta for 27 mins. Mean proximal arterial blood pressure (MPABP) was monitored with a cannula placed in the left common carotid artery. Halothane was adjusted (1.25-1.5%) to maintain MPABP between 70 and 90 mm Hg (n = 20) or 140 and 150 mm Hg (n = 20). Shamoperated rats (n = 10) had a thoracotomy without aortic clamping at an MPABP of 70-90 mm Hg. Following 1, 24, 48, and 72 hrs of recovery from anesthesia, motor function of the hind paws was scored as follows: 0, no evidence of deficit; 1, toes flat under body when walking but with ataxia; 2, knuckle walks; 3, movements in hind limbs but unable to knuckle walk; 4, no movement, drags hind limbs. Body temperature was maintained between 37 and 38 degrees C throughout the experiment. MEASUREMENTS AND MAIN RESULTS: All sham operated rats with MPABP 70-90 mm Hg recovered without neurologic deficits, whereas those that underwent aortic occlusion with MPABP between 70 and 90 mm Hg emerged from anesthesia with grade 3 and 4 deficits and remained in this condition without improvement at 72 hrs. Histopathology at 72 hrs demonstrated moderate to severe neuronal loss with involvement of dorsal, intermediate, and ventral horns. Only eight of 20 rats that underwent aortic occlusion with MPABP between 140 and 150 mm Hg had grade 1 and 2 deficits on emergence but had no neurologic deficit after 1 hr. Most of the surviving neurons in these animals appeared normal histologically, particularly motor neurons around the periphery of the ventral horn. CONCLUSIONS: Systemic blood pressure is a critical determinant of outcome following spinal cord ischemia, and controlled peri-operative blood pressure augmentation may ameliorate neurologic deficits in patients who undergo thoracoabdominal vascular procedures and are at risk for spinal cord hypoperfusion.     

Effects of combined estrogen and progesterone on brain infarction in reproductively senescent female rats.

Recent data from the Women's Health Initiative have highlighted many fundamental issues about the utility and safety of long-term estrogen use in women. Current hormone replacement therapy for postmenopausal women incorporates progestin with estrogen, but it is uncertain if combined therapy provides major cerebrovascular risks or benefits to these women. No experimental animal stroke studies have examined combined hormone administration. The authors tested the hypothesis that combined hormone treatment reduces ischemic injury in middle-aged female rat brain. Reproductively senescent female rats underwent 2-hour middle cerebral artery occlusion (MCAO) followed by 22 hours reperfusion. Estrogen implants were placed subcutaneously at least 7 days before MCAO, and progesterone intraperitoneal injections were given 30 minutes before MCAO, at initiation, and at 6 hours of reperfusion. Rats received no hormone, a 25-microg estrogen implant, a 25-microg estrogen implant plus 5 mg/kg intraperitoneal progesterone, or 5 mg/kg intraperitoneal progesterone. Cortical, caudoputamen, and total infarct volumes were assessed by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis at 22 hours reperfusion. Cortical and total infarct volumes, except in the acute progesterone-treated group, were significantly attenuated in all estrogen-alone and combined hormone-treated groups. There were no significant differences in caudoputamen infarct volumes in all hormone-treated groups as compared with untreated rats. These data have potential clinical implications relative to stroke for postmenopausal women taking combined hormone replacement therapy.     

Comparison of the effects of positive end-expiratory pressure and jugular venous compression on canine cerebral venous pressure

The confluent sinus pressure was measured in eight mongrel dogs in the head-up position to compare the effectiveness of positive end-expiratory pressure (PEEP) and jugular venous compression in increasing cerebral venous pressure. When the head was elevated 30 cm above the heart, confluent sinus pressure decreased from 9.6 +/- 1.8 (mean +/- SEM) to -5.3 +/- 0.5 mmHg. At constant arterial carbon dioxide tension (PaCO2 = 28 +/- 2 mmHg), PEEP (20 cmH2O) did not increase cerebral venous pressure. However, when the jugular veins were compressed with a neck tourniquet with pressures of 20-140 mmHg, cerebral venous pressure increased rapidly. When neck tourniquet pressure was maintained at 40 mmHg, confluent sinus pressure in all dogs was increased and sustained at 2.4 +/- 0.8 mmHg. Carotid artery pressure measured distal to the tourniquet was not altered. The efficacy of extrathoracic venous pressure elevation (neck tourniquet) is greater than intrathoracic (PEEP), and this may relate to the Starling resistor effects of neck veins and the presence of jugular venous valves. We conclude that prophylactic use of PEEP in the prevention of air embolism during the sitting position may not be as effective as jugular venous compression.     

The beneficial and harmful effects of positive end expiratory pressure.

The effects of increasing levels of positive end expiratory pressure on gas exchange and pulmonary mechanics were determined utilizing an ex vivo ventilated perfused canine pulmonary lobe. When zero positive end expiratory pressure was used, shunting, weight gain and a decrease in compliance occurred over the four and one-half hour experiment. Shunting was eliminated when 5, 10 or 15 centimeters of water of positive end expiratory pressure were used. However, increasing extravascular fluid sequestration and decreasing pulmonary compliance occurred progressively with increasing levels of positive end expiratory pressure above 5 centimeters of water. Pulmonary artery pressure increased immediately along with end inspiratory pressure, an amount approximately equal to the increase in positive end expiratory pressure, and this is thought to be the primary cause of the increased rate of fluid sequestration. These experiments suggest that an optimal level of positive end expiratory pressure exists when the shunt can be reduced and oxygenation improved without increasing the rate of extravascular fluid accumulation to the point where long time deleterious effects could outweigh immediate benefits.