Aging and arteriosclerosis. I. Development of myointimal hyperplasia after endothelial injury.

Old Fischer 344 rats are more susceptible to vascular lesions after arterial endothelial injury than are young animals. Thus, 20-26-mo-old Fischer 344 rats developed greater and more persistent intimal proliferative lesions than did 2-5-mo-old rats after aortic endothelial denudation. 3 d after deendothelialization, intimal thickness was increased two-fold in both old and young animals. However, 14 d after endothelial injury, intimal thickness had increased nearly five times in old animals, but had regressed to normal in young animals. Intimal thickness of young aortic grafts transplanted into young recipients did not differ significantly from adjacent host aorta or autotransplanted aortic segments 6 wk after surgery. In contrast, intimal thickness of old grafts transplanted into young recipients was eight times greater than adjacent young host aorta 6 wk after surgery. The density of cell nuclei in the intima of old grafts was also much greater than that in young grafts. Thus, in two experimental models of vascular injury, old rats have consistently had greater myointimal hyperplasia than young rats. The increased proliferative response of aortic smooth muscle cells after vascular injury of old animals may contribute to the increased prevalence of vascular disease with age.

Shock and tissue injury induced by recombinant human cachectin.

Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

Alterations of pulmonary gas exchange after superimposed carbon monoxide poisoning in acute lung injury.

BACKGROUND: Smoke inhalation injury produces substantial morbidity and mortality caused both by immediate catastrophic pulmonary failure and by the subsequent development of pneumonia. Although carbon monoxide (CO) poisoning is present to a degree in nearly all instances of smoke inhalation, the importance of CO in the pathogenesis of smoke inhalation injury remains controversial because smoke contains numerous other potential pulmonary toxins such as aldehydes, chlorine gas, and hydrochloric acid. This study was performed to determine whether CO poisoning acts as a cofactor in the evolution of inhalation injury. METHODS: Four groups of anesthetized dogs received ventilation with 1% CO in room air alone, intratracheal instillation of 2.0 ml/kg 0.1 N hydrochloric acid (HCl) alone, or acid either immediately or 30 minutes before CO. Ventilation/perfusion relationships were measured for 4 hours thereafter with the multiple inert gas elimination technique. RESULTS: Acid instillation established 30 minutes before CO poisoning resulted in significantly decreased carboxyhemoglobin concentrations after ventilation with 1% CO in air for 10 minutes. However, CO elimination was markedly delayed in both acid-challenged groups ventilated with CO. Moreover, acid instillation immediately before CO poisoning significantly exacerbated the development of ventilation/perfusion inequality caused by the acid, because the development of shunt was accelerated. CONCLUSIONS: CO poisoning is an important cofactor in the development of inhalation injury by acceleration of the development of ventilation/perfusion inequality after inhalation.

Utility of routine chest radiographs in the surgical intensive care unit. A prospective study.

OBJECTIVES: To correlate patient condition and reasons for obtaining chest radiographs (CXRs) with the utility of CXRs in critical illness and to determine the potential impact of stricter criteria for obtaining a CXR in a surgical intensive care unit (ICU). DESIGN: Inception cohort study of 1003 CXRs examined prospectively. PATIENTS AND SETTING: A total of 157 consecutive patients admitted to the general surgical ICU of a 780-bed, urban, university-affiliated, tertiary care hospital. INTERVENTION: Nothing was done to influence the ordering of CXRs. OUTCOME MEASURES: Influence of CXR findings on clinical management. RESULTS: The likelihood of a clinically important finding was 17% for CXRs obtained for no clear clinical indication (routine), 26% for those obtained to verify the position of a medical device, and 30% for those obtained for suspected clinical conditions. By univariate analysis, suspected pathophysiologic condition, admission APACHE II (Acute Physiology and Chronic Health Evaluation II) score, presence of a central venous or Swan-Ganz catheter, and length of ICU stay were all predictors of a significant finding. By multivariate analysis, the only independent predictor of a finding was a suspected clinical condition, and the only indwelling medical device that was an independent predictor of a finding was a Swan-Ganz catheter. If the criterion that routine CXRs should only be obtained in patients with Swan-Ganz catheters had been used, 200 CXRs would have been avoided during the 3-month study period. The only findings missed by not obtaining those CXRs would have been two malpositioned nasogastric tubes and one malpositioned central venous catheter. CONCLUSIONS: Chest radiographs should only be obtained on surgical ICU patients for specific indications. Routine CXRs for ICU patients are justified only for patients with indwelling Swan-Ganz catheters.

The square-wave approach to impedance measurement of brain tissue water dynamics.

Electrical properties of living soft tissue have been used to analyze their structure and function. Presently, the 'admittance locus' method, with the sine-wave signal of changing frequency, is the most informative continuous method for analyzing extra-and intracellular water content in brain tissue. Using the square-wave signal in lieu of the sine-wave signal, we can avoid cumbersome and costly measurements and facilitate real-time data processing. An isolation-calibration device was developed for the present study in order to condition and stabilize electrical current through the brain cortex. This device was also used for impedance calibration before and after the experiments. We propose a simple algorithm for data analysis on the basis of equivalent circuit approach, which allows to develop a computer program for data processing. Preliminary experiments on rat brains were carried out with a 0.2-0.5 mm stainless-steel tetrapolar electrode system. These studies showed good linearity between stimulating currents (I = 5-30 microA) through the external electrodes in the brain cortex and a drop in voltage which was measured by 2 inner electrodes. The results of the device and the program accuracy tests allow us to choose the optimal range for the working current. We can recommend this method for usage in animal experiments.

Traumatic injury induces interleukin-6 production by human astrocytes.

The brain is being evaluated as a de novo source of cytokines. Because recent evidence indicates that interleukin-6 (IL-6) may influence blood-brain barrier function and vascular permeability, we have sought to determine whether mechanical injury can directly induce in situ cerebral IL-6 production. Adult human astrocyte cultures were subjected to mechanical injury by the in vitro method of fluid percussion barotrauma, developed in our laboratory. Serial supernatant samples were collected for 8 h and evaluated for IL-6 activity using a proliferation assay employing the dependent B cell hybridoma cell line, B9. At optimum injury, the IL-6 level became significantly (P < 0.0001, analysis of variance) elevated from baseline 2 h after trauma and continued to increase over the observation period. Our study shows that following mechanical injury human astrocytes produce IL-6, which may contribute to post-traumatic cerebrovascular dysfunction. Elucidating the precise role of intracerebral cytokines is essential to our understanding of the mechanism responsible for post-traumatic cerebrovascular dysfunction.

A method for monitoring intracranial temperature via tunneled ventricular catheter: technical note.

A simple technique for monitoring intracerebral temperature in humans via a ventricular catheter is described. This differs from a previously described method by enabling such measurements to be accomplished with a commercially available thermistor, a standard ventricular catheter, and common hospital supplies. In contrast to the earlier device, this system allows for the subcutaneous tunneling of the distal ventricular catheter. This is an easily assembled and cost-effective technique with which to conduct investigations on human intracerebral temperature.

Effect of low dose gamma-butyrolactone therapy on forebrain neuronal ischemia in the unrestrained, awake rat.

Low dose gamma-butyrolactone (GBL) therapy alters the natural history of experimental forebrain ischemia in the awake rat. After 30 minutes of four-vessel ischemia, repeated hydrogen cerebral blood flow determinations in awake rats over 72 hours revealed that low dose GBL therapy prevented the development of regional cerebral hyperemia and later the prolonged cerebral hypoperfusion that was experienced by the nontreated controls. Moreover, the low dose GBL-treated group had significantly less neuronal tissue loss than that in comparable brain regions of the nontreated controls. Before the stroke studies, GBL dose-response experiments performed on normal rats indicated that high dose GBL therapy produced seizures, systemic hypertension, metabolic acidosis, hyperthermia, and death.

Effect of naloxone on cerebral perfusion and cardiac performance during experimental cerebral ischemia.

Transient global cerebral ischemia (TGI) was induced in awake rats using the "four-vessel" occlusion model of Pulsinelli and Brierley. Blood pressure, arterial blood gases, cerebral blood flow, and cardiac output were measured during the acute (up to 2 hours) and chronic (2 to 72 hours) postischemic time periods. Coincident with the onset of TGI, cardiac output and caudate blood flow were depressed. The former returned to baseline within 30 minutes after the conclusion of TGI, and the latter progressed to hyperemia at 12 hours (81.8 +/- 4.9 vs 68.6 +/- 3.9 ml/min/100 gm tissue (mean +/- standard error of the mean] and oligemia at 72 hours (45.5 +/- 4.8 ml/min/100 gm tissue) post-TGI in the untreated control rats. Arterial blood gases and blood pressure were unchanged. Naloxone (1mg/kg) given at the time of TGI or as late as 60 minutes post-TGI and every 2 hours thereafter for 24 hours or bilateral cervical vagotomy prevented the depression in cardiac output and blocked the hyperemic-oligemic cerebral blood flow pattern that was predictive of stroke in this rat model. Changes in cardiac output after TGI in this model appear to be mediated by parasympathetic pathways to the heart from the brain stem. Opiate receptor blockade probably blocks endogenous opioid peptide stimulation of these brain-stem circulatory centers, which results in inhibition of parasympathetic activity and improvement in cardiac output. The usefulness of naloxone in the treatment of experimental stroke may be a function of its ability to improve cerebral perfusion in pressure-passive cerebrovascular territories. Variations in cardiac output during experimental stroke may explain the dissimilar responses to naloxone treatment reported by other investigators of experimental stroke.

Traumatic brain injury, hemorrhagic shock, and fluid resuscitation: effects on intracranial pressure and brain compliance.

Intracranial hypertension following traumatic brain injury is associated with considerable morbidity and mortality. Hemorrhagic hypovolemia commonly coexists with head injury in this population of patients. Therapy directed at correcting hypovolemic shock includes vigorous volume expansion with crystalloid solutions. It is hypothesized that, following traumatic brain injury, cerebrovascular dysfunction results in rapid loss of brain compliance, resulting in increased sensitivity to cerebrovascular venous pressure. Increased central venous pressure (CVP) occurring with vigorous crystalloid resuscitation may therefore contribute to the loss of brain compliance and the development of intracranial hypertension. The authors tested this hypothesis in miniature swine subjected to traumatic brain injury, hemorrhage, and resuscitation. Elevated CVP following resuscitation from hemorrhage to a high CVP significantly worsened intracranial hypertension in animals with concurrent traumatic brain injury, as compared to animals subjected to traumatic brain injury alone (mean +/- standard error of the mean: 33.0 +/- 2.0 vs. 20.0 +/- 2.0 mm Hg, p < 0.05) or to animals subjected to the combination of traumatic brain injury, hemorrhage, and resuscitation to a low CVP (33.0 +/- 2.0 vs. 24.0 +/- 2.0 mm Hg, p < 0.05). These data support the hypothesis that reduction in brain compliance can occur secondary to elevation of CVP following resuscitation from hemorrhagic shock. This may worsen intracranial hypertension in patients with traumatic brain injury and hemorrhagic shock.

Human astrocyte production of tumour necrosis factor-alpha, interleukin-1 beta, and interleukin-6 following exposure to lipopolysaccharide endotoxin.

The cytokines, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6, have been found in the human central nervous system. Recent studies have demonstrated that murine astrocytes produce these cytokines when induced with lipopolysaccharide endotoxin (LPS). The present study investigates the kinetics of TNF-alpha, IL-1 beta, and IL-6 production by normal adult human astrocytes when exposed to LPS.

Management of pediatric head injury.

This article on management of pediatric head injury reviews the pathophysiology and current therapy for traumatic brain injury in children. There is an emphasis on clinical protocols and algorithms that guide therapy to prevent or attenuate the deleterious effects of secondary brain injury as intracranial hypertension, hypotension, and hypoxia.

Cerebral edema.

Cerebral edema continues to plague clinicians caring for patients with acute catastrophic neurologic disease. The defect responsible for the accumulation of water in the brain appears to reflect loss of the strict permeability barrier of the cerebral vasculature. A greater understanding of the physiologic mechanisms at work in the blood-brain barrier have helped target therapies at the vascular interface between the circulating blood and the brain. The mounting evidence which implicates inflammatory events as causally related to the loss of cerebrovascular impermeability supports the clinical strategy of suppression of acute inflammation. Clearly, further advances in the management of cerebral edema will be strongly influenced by the development of specific anti-inflammatory pharmaceuticals.

Changes of MPO activity and brain water accumulation in traumatic brain injury experiments.

Comparison of brain tissue water content (BWC) data with myeloperoxidase activity assay (MPO) allows for analysis of the complex pathophysiological mechanisms of cerebral edema following catastrophic brain injuries. The neuroprotective effect of an experimental anti inflammatory drug (FL1003, butyrolactone) was tested in a traumatic brain injury (TBI) model using BWC and MPO analysis. We conducted these studies on a mini-pig model of severe TBI that is well characterized in our laboratory. The animals were divided into three animal groups: no injury, no treatment (control), injured and treated with FL1003, and injured, untreated with FL1003. They were maintained with fluids for 24 hours under general anesthesia. We employed the MPO assay to identify the degree of inflammatory cellular response (polymorphonuclear leukocytes, PMNLs) 24 hours following TBI and calculated brain density from the data of the gravimetric (Percoll) column method for BWC on brain samples. Our results demonstrated increased infiltration of PMNLs and a shift of water into the extravascular space in the injured animals. These changes were significantly (P < 0.05) attenuated in the animal group treated with FL1003.

Mechanisms of cerebrovascular dysfunction.

Cerebrovascular dysfunction characterized by the loss of endothelial integrity has been observed following ischemic and traumatic insults to the brain, resulting in the net movement of fluid and solute out of the intravascular space and into the interstitium. Following traumatic brain injury, the development of intracranial hypertension secondary to cerebral edema plays a major role in the high morbidity and mortality in these patients. Although the precise mechanisms responsible for the disruption of the normally tightly regulated cerebrovascular tissue interface remain unclear, there is increasing evidence implicating inflammatory events in this process through the transient opening of tight junctional complexes. This article will examine the interaction of astrocytes, activated neutrophils, and inflammatory mediators in inducing endothelial contraction, thereby physically opening the permeability barrier and allowing the net movement of fluid out of the intravascular space.

Dual-ended, multifunction tools for microsurgery.

A new concept in microsurgical instrumentation is herein described and the rationale for its design presented in the context of surgical efficiency. This new concept employs bipolarity or dual-endedness as a means to enable the microsurgeon to have access to various instruments without the need to exchange tools. The elimination of instrument exchange has increased the speed with which a microsurgeon can perform a variety of procedures as well as decrease fatigue associated with continuous visual reaccommodation between the microscope and surrounding operating room. Following considerable modification through several prototypical stages and long periods of laboratory testing, these instruments boast ideal balance in the hands of the surgeon, and the capacity for modification by the user, allowing a variety of instrument combinations. Hence, personal preference can dictate the ultimate tool configuration, thereby allowing customization of the instruments to the procedure as well as the surgeon, by virtue of an interlocking mechanism between instrument components. The resulting economy of movement and reduced instrument handling engendered by the use of these instruments reduces operating time and often eliminates the need for a highly trained surgical assistant. These instruments can be fitted with a removable extension allowing unipolar use or extended instrument length. Simplicity of design makes these instruments conducive to standard cleaning and sterilization procedures.

Alterations in intracranial pressure and cerebral blood volume in endotoxemia.

Marked deterioration of neurologic function accompanies organ dysfunction in systemic sepsis. Although previous hypotheses have suggested that cerebral hypoperfusion, anoxia or progressive edema of the brain may be causative, the pathogenesis remains unknown. Patients with sepsis with stable or supported hemodynamics and adequate oxygenation may manifest confusion, stupor or coma. Recent evidence has demonstrated that the brain is the source of many classical mediators of inflammation after various forms of injury. These mediators, including the leukotrienes, have pronounced effect on cerebrovascular function. Endotoxin is known to stimulate the release of arachidonate from cell membranes, the rate limiting step in leukotriene synthesis. The current studies were performed to test the hypothesis that neurologic dysfunction associated with endotoxemia is characterized by alterations in cerebrovascular permeability or vasomotor function manifested by intracranial hypertension, or both. We studied the response of miniature swine to experimental endotoxemic shock and compared this response with hemorrhagic hypotension. We observed a dramatic elevation of intracranial pressure in swine subjected to endotoxemic shock, despite arterial hypotension. Moreover, estimation of cerebral blood volume (CBV) by reflectance infrared photoplethysmography demonstrated a dramatic increase in CBV, which corresponded to this elevation in intracranial pressure. However, cerebral cortical oxygen saturation was significantly reduced despite this net increase in CBV, indicative of an increase in the venous volume of the brain, while arterial volume remained the same or decreased from baseline levels. Oxygen extraction across the brain decreased during this same period compared with baseline and control values. These results demonstrate that endotoxemia is associated with the development of intracranial hypertension and an increase in CBV secondary to elevation of cerebrovascular venous volume coupled with reduced oxygen extraction across the brain. This evidence of cerebrovascular dysfunction probably represents blood flow maldistribution, similar to that seen in other organs with sepsis, suggesting a cause for altered neurologic function in systemic sepsis.

A square signal wave method for measurement of brain extra- and intracellular water content.

Brain tissue electrical impedance is a commonly used method to evaluate the dynamics of brain edema. We have found the square wave impedance method simpler and more cost-effective than the currently used sine wave impedance method. This square wave method avoids the necessity for expensive frequency control and amplitude-phase measuring devices as well as simplifying on-line data processing. In our experiments the electrical impulse was generated by a pulse generator of Macintosh data acquisition system. The signal (I = 11 muA, t = 2-20 ms) was delivered every 2-3 s external electrodes of a tetrapolar system through a specially designed isolation-calibration device. This electrode system was inserted into the cerebral cortex of experimental animals (rat). The cerebral cortex was found to have linear electrical properties in the 5-30 muA range. Our impedance measurement system was tested in calibration trials, and showed system reliability and accuracy. The system was also tested in pilot experiments, in vivo, in a rat brain osmotic edema model.

Fluid percussion barotrauma chamber: a new in vitro model for traumatic brain injury.

Advances in the understanding of the pathophysiology of traumatic brain injury have implicated a number of cellular events as fundamental to the evolution of neurologic dysfunction in this process. Following the primary biomechanical insult, a highly complex series of biochemical changes occur, some of which are reversible. The development of fluid percussion injury as an in vivo model for traumatic brain injury has greatly improved our ability to study this disease. However, a comparable in vitro model of biomechanical injury which would enable investigators to study the response to injury in isolated cell types has not been described. We have developed a model of transient barotrauma in cell culture to examine the effects of this form of injury on cell metabolism. This model employs the same fluid percussion device commonly used in in vivo brain injury studies. The effect of this injury was evaluated in monolayers of human glial cells. Cell viability by trypan blue exclusion and the production of leukotrienes following increasing barotrauma was investigated. This model provided a reproducible method of subjecting cells in culture to forces similar to those currently used in animal experimental head injury.

Incomplete recovery of muscle cell function following partial but not complete ischemia.

A simultaneous comparison of the effect of partial and total ischemia on skeletal muscle was made in dogs. The totally ischemic muscle had larger changes in adenosine triphosphate (ATP), creatine phosphate (CP), and cellular transmembrane potential difference (PD) during the 3-hour ischemic period than the partially ischemic muscle. Following recovery, all measured parameters in the totally ischemic muscle returned to normal, but paradoxically the PD in the partially ischemic muscle remained depressed despite the return to normal levels of ATP and CP. Contrary to the results in partially and totally ischemic brain tissue there was no evidence for higher levels of lactic acid in the partially ischemic muscle that could explain the persistent alteration in muscle cell function.