Clinically significant changes in pain along the visual analog scale.

STUDY OBJECTIVE: We sought to test the hypothesis that the change in visual analog scale (VAS) associated with a clinically significant change in pain is related to the initial VAS score. METHODS: A convenience sample of adults with isolated extremity trauma was enrolled. A VAS score was obtained on entry into the study. Descriptions of change in pain ("lot less," "little less," "about the same," "little more," or "lot more") and VAS scores were then obtained every 30 minutes until the patient was free of pain or discharged or a total of 2 hours had passed. Patients were divided into 3 cohorts on the basis of the initial VAS score: VAS score of less than 34, VAS score of 34 to 66, and VAS score of 67 or greater. The absolute values of VAS changes associated with pain descriptions of a "little less" or "little more" (defined as clinically significant), "about the same" (defined as clinically insignificant), and "lot less" or "lot more" were calculated. RESULTS: The change in VAS associated with clinically significant changes in pain in the cohort with VAS scores of less than 34 was 13+/-14 (mean+/-SD), which was significantly lower than that of the cohort with VAS scores of 67 or greater (28+/-21). There was no statistically significant difference in clinically significant changes in pain between the middle cohort and either the upper or lower cohorts (P =.07 and P =.29, respectively). There was no significant change in VAS for clinically insignificant changes in pain among the 3 cohorts (3+/-4, 6+/-6, and 8+/-16, respectively). CONCLUSION: Patients with greater pain require a greater change in VAS score to achieve clinically significant pain relief.

Post-resuscitative hypothermic bypass reduces ischemic brain injury in swine.

OBJECTIVES: Increasing human and laboratory evidence suggests that post-resuscitative brain hypothermia reduces the pathologic consequences of brain ischemia. Using a swine model of prolonged cardiac arrest, this investigation sought to determine whether unilateral hypothermic carotid bypass was capable of inducing selective brain hypothermia and reducing neurohistologic damage. METHODS: Ventricular fibrillation was induced in common swine (n = 12). After 20 minutes of cardiopulmonary arrest (without ventilatory support or cardiopulmonary resuscitation), systemic extracorporeal bypass was instituted to restore coronary and cerebral perfusion, followed by restoration of normal sinus rhythm. Animals randomized to the normal brain temperature (NBT) cohort received mechanical ventilation and intravenous fluids for 24 hours. The selective brain hypothermia (SBH) cohort received 12 hours of femoral/carotid bypass at 32 degrees C. The bypass temperature was then increased one degree per hour until reaching 37 degrees C and continued at this temperature until completion of the protocol (24 hours). Histopathologic damage was evaluated in two areas of the hippocampus. RESULTS: Normal sinus rhythm was restored in all animals after the systemic (femoral/femoral) bypass was initiated. Nasal temperature (surrogate measure of brain temperature) remained higher than 37.0 degrees C throughout the 24-hour recovery period in the NBT animals. In the SBH cohort, right nasal temperature dropped to the mild hypothermic range (<34 degrees C) two hours after institution of femoral/carotid bypass. This was maintained throughout the 12-hour cooling period without hemodynamic compromise. There was a significant improvement in the neurohistology scores in the CA1 region of the hippocampus of the SBH treated animals as compared with those of the NBT cohort. CONCLUSIONS: Post-resuscitative selective brain hypothermia reduced regional ischemic brain damage in swine with prolonged ventricular fibrillation.

Naloxone blocks transferred preconditioning in isolated rabbit hearts.

We have shown that the cardioprotective benefits of ischemic preconditioning (PC) can be transferred from PC to virgin acceptor hearts via coronary effluent transfusion, implicating the presence of hormonal preconditioning factor(s). Using isolated buffer-perfused rabbit hearts, our aims were to: (1) determine whether the protective factor(s) could be concentrated and recovered by reverse phase chromatography and (2) whether opioid receptor activation contributes to this transferred cardioprotection. Material released into the coronary effluent during PC ischemia/reperfusion or normoxic perfusion was concentrated by reverse phase chromatography. In phase one, hearts received no intervention (controls), PC ischemia, concentrate generated from normoxic hearts (normoxic acceptors) or concentrate from PC hearts (PC acceptors). All hearts underwent 40 min of global ischemia, and area of necrosis (AN) was delineated by tetrazolium staining. In phase two, three additional groups of hearts (control, PC and PC acceptors) received the opioid antagonist naloxone (2 microM) throughout the intervention phase. Treatment with normoxic concentrate had no effect on infarct size: (AN: normoxic acceptors 39+/-8%; control 42+/-8%). In contrast, treatment with PC concentrate evoked cardioprotection equivalent to that afforded by conventional PC (AN 19+/-5% and 21+/-6% respectively P<0.05 v control). Naloxone had no effect on infarct size in controls, and did not inhibit preconditioning. However, naloxone abrogated the protection achieved by transfer of PC concentrate (AN: 44+/-7%). These results indicate that PC concentrate evokes a cardioprotective effect via a mechanism requiring an intact opioid receptor system.

Phentolamine reduces myocardial injury and mortality in a rat model of phenylpropanolamine poisoning.

BACKGROUND: Phenylpropanolamine produces dose-related, life-threatening cardiovascular, and central nervous toxicity from alpha-adrenergic overstimulation. Although some recommend the alpha-adrenergic antagonist, phentolamine, as treatment for such toxicity, its therapeutic efficacy has not been previously studied. We sought to determine if pretreatment with phentolamine could reduce acute myocardial injury and mortality in rats administered an overdose of phenylpropanolamine. METHODS: In the mortality arm of the study, 28 unanesthetized, male Wistar rats (14 animals per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or an equal volume of normal saline diluent (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (150 mg/kg). Mortality was compared at 24 hours. In the myocardial injury arm of the study, 20 unanesthetized rats (10 per group) were randomized to receive an intraperitoneal injection of phentolamine (3 mg/kg) or normal saline (control group). Twenty-five minutes later, all rats received an intraperitoneal injection of phenylpropanolamine (75 mg/kg). Seventy-two hours after phenylpropanolamine administration, all surviving animals were sacrificed and transverse sections of their hearts were graded histologically for injury by a blinded cardiac pathologist. RESULTS: Twelve rats died within 6 hours of phenylpropanolamine administration. Mortality was significantly lower in the phentolamine-pretreated rats (2/14; 14%) as compared to the control group (10/14; 71%; p = 0.006). The degree of myocardial injury was significantly lower in the phentolamine-pretreated rats (0) as compared to the control group (1.4 +/- 1.6; p = 0.012). CONCLUSION: In this rat model, phentolamine pretreatment prevented acute myocardial injury and significantly reduced lethality from an intraperitoneal phenylpropanolamine overdose.

Rapid development of brain hypothermia using femoral-carotid bypass.

OBJECTIVES: Advances in the field of cardiopulmonary resuscitation have led to an increasing number of patients initially surviving sudden cardiac arrest. Unfortunately, most of these patients do not recover from the resultant anoxic brain insult. Several animal and human trials have suggested that post-resuscitative brain hypothermia may improve neurologic recovery after cardiopulmonary arrest. Present cooling methods are slow, induce only brain surface cooling, or result in systemic hypothermia. The authors tested the hypothesis that unilateral hypothermic carotid bypass would induce bilateral brain cooling without evoking systemic hypothermia or hemodynamic instability. METHODS: Anesthetized, ventilated common swine (n = 6, 24-37 kg) underwent right femoral and carotid artery bypass cannulation. Central and peripheral hemodynamic parameters were recorded every 2 minutes throughout the procedure. Thermodynamic parameters included bilateral frontal lobe, bilateral nasopharyngeal, pulmonary artery, and rectal temperatures. Hypothermic femoral-carotid bypass was accomplished by drawing blood from the right femoral artery, cooling it to 24 degrees C, and returning it to the right carotid artery at a flow rate of 5 mL/kg/min for 30 minutes. RESULTS: With initiation of cooling, brain temperatures dropped rapidly from baseline of 37.2 degrees C to 30.6 degrees C (right frontal lobe) and 33.1 degrees C (left frontal lobe) at 30 minutes. Pulmonary artery and rectal temperatures also decreased, but never reached mild hypothermic levels (34 degrees C). There was no significant change in any hemodynamic parameters during brain cooling. CONCLUSIONS: Femoral-carotid hypothermic bypass rapidly induced a state of selective brain hypothermia without causing systemic hypothermia or hemodynamic instability.

Core rewarming via warm lavage liquid ventilation in a swine model of hypothermia-associated ventricular fibrillation.

OBJECTIVES: To determine whether warm lavage liquid ventilation (LV) would provide rapid cardiopulmonary rewarming in swine with severe hypothermia and ventricular fibrillation. METHODS: Intubated common swine (n = 3; mean +/- SEM weight 26+/-1.2 kg) were cooled to a mean aortic temperature of 26.4+/-0.9 degrees C. Ventricular fibrillation was induced by transthoracic electrical shock. Rewarming was initiated by continuous endotracheal instillation of warm (44 degrees C) pre-oxygenated, perfluorocarbon liquid at 5 mL/kg/min. Endotracheal instillation of perfluorocarbon occurred while standard gas ventilation continued. Manual chest compressions were performed throughout the 30-minute rewarming process. Outcome measures were the absolute and relative rates of change of all temperatures. RESULTS: After 30 minutes of warm lavage LV, the mean aortic and pulmonary artery temperatures increased by 6.6+/-0.6 degrees C, respectively. Esophageal, nasal, and rectal temperatures did not change significantly. In one animal, normal sinus rhythm spontaneously returned after 16 minutes of rewarming. CONCLUSIONS: During cardiac arrest, warm lavage liquid ventilation may produce rapid cardiopulmonary rewarming.

An assessment of asbestos body formation in extrapulmonary sites: liver and spleen.

STUDY OBJECTIVES: Asbestos bodies (ABs) form as asbestos fibers become coated by a cellular iron- and protein-rich matrix. ABs have been reported in lymph nodes and a few extrapulmonary sites, but no data exist as to their formation outside of the lung. It is not clear whether the AB found in these extrapulmonary areas have been transported as mature structures from the lung or formed at the extrapulmonary site. This study was designed to determine if ABs are produced in extrapulmonary sites. The guinea pig efficiently forms ferruginous bodies in the lung and so it was chosen as a model to test the coating efficiency of amosite asbestos fibers in lung, liver and spleen. DESIGN: Sized amosite asbestos (5 mg) was administered either endotracheally into lung (n = 2) or directly into liver (n = 4) and spleen (n = 4) of healthy 10-week-old male guinea pigs. The lung, liver and splenic tissues were removed at 40 and 180 days post inoculation and were examined histologically for the presence of AB via light microscopy. Uncoated fibers isolated from the tissues were characterized by electron microscopy. The coating efficiency was calculated as a ratio of uncoated/coated fibers per organ. RESULTS: The coating efficiency ratios of fibers that were collected at 40 days post-injection from the individual sites were: lung - 350:1, liver - 4200:1, and spleen - 220,000:1. At 6 months post-injection the ratios for the individual sites consisted of: lung - 176:1, liver - 11,000:1, and spleen - 1000:1. CONCLUSION: This study indicates that AB can be formed in extrapulmonary sites and that the coating efficiency in the lung is much greater than that within the liver or spleen.

Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart.

Multiple brief periods of ischemia in the mammalian heart elicits protection against morphologic and functional damage caused by longer-duration ischemia. Preconditioning-induced protection against post-ischemic contractile dysfunction has been reported to be depressed with aging of the adult heart. This study was undertaken to determine whether aging of the adult myocardium reduces the preconditioning-induced attenuation of necrosis observed with ischemia. Isolated, perfused hearts obtained from Fischer 344 rats of either 3 (young) or 22 (aged) months of age were paced and instrumented for determination of developed left ventricular pressure. Necrosis was determined with triphenyltetrazolium. In the absence of preconditioning, young and aged adult hearts made globally ischemic for 45 min developed necrosis involving 53+/-6% and 49+/-6% of the myocardium, respectively. Contractile function (+dP/dt(max)) at 90 min of reperfusion was depressed by 80% in young and 52% in aged hearts, compared to values obtained prior to preconditioning. Preconditioning with two 5 min ischemia/5 min reperfusion cycles significantly reduced necrosis development and enhanced reperfusion contractile function in young hearts. However, in aged adult hearts, the preconditioning did not significantly reduce the development of necrosis or enhance reperfusion contractile function. These data suggest that aging reduces the effectiveness of preconditioning in providing cardioprotection against ischemic-induced myocardial necrosis.

"Preconditioning at a distance" in the isolated rabbit heart.

OBJECTIVE: Brief myocardial ischemia evokes a cardioprotective response, referred to as "ischemic preconditioning" (IP), that limits injury caused by a subsequent prolonged ischemic insult. The myocardial IP effect can be induced by ischemia of "distant" cardiac and noncardiac tissue, implicating the involvement of an as-yet-unidentified humoral trigger. If a preconditioning hormone exists, the authors hypothesize that the IP effect should be transferable, via administration of coronary effluent, from a preconditioned donor heart to a virgin non-preconditioned acceptor heart. METHODS: Isolated buffer-perfused rabbit hearts were assigned to one of four treatment groups in a donor/acceptor sequence. Donor hearts underwent either three IP cycles or a matched period of uninterrupted perfusion (control donors). Coronary perfusate collected from IP and control donor hearts was reoxygenated and transfused to virgin acceptor hearts. All hearts then underwent 30 minutes of global ischemia followed by 30 minutes of reperfusion. Left ventricular developed pressure (LVDP) (the authors' index of cardioprotection) was monitored throughout the protocol by a left ventricular (LV) balloon. RESULTS: In donor controls, LVDP assessed at 30 minutes post-reflow was restored to only 49 +/- 5% of baseline values. Recovery of LV function was significantly enhanced in both IP donor hearts (69 +/- 4%*) and IP acceptor hearts (70 +/- 6%*) vs donor controls (*p < 0.05), while, in acceptor controls, intermediate values of LVDP (62 +/- 7%) were obtained. CONCLUSION: The IP effect can be transferred between rabbit hearts, suggesting the presence of a humoral trigger signal for distant preconditioning. Isolating this hormone may have therapeutic and diagnostic implications in the management of acute myocardial ischemia.

Rabbit heart can be "preconditioned" via transfer of coronary effluent.

Brief myocardial ischemia not only evokes a local cardioprotective or "preconditioning" effect but also can render remote myocardium resistant to sustained ischemia. We propose the following hypotheses: remote protection is initiated by a humoral trigger; brief ischemia-reperfusion will result in release of the humoral trigger (possibly adenosine and/or norepinephrine) into the coronary effluent; and transfer of this effluent to a virgin acceptor heart will elicit cardioprotection. To test these concepts, effluent was collected during normal perfusion from donor-control hearts and during preconditioning ischemia-reperfusion from donor-preconditioned (PC) hearts. After reoxygenation occurred and aliquots for measurement of adenosine and norepinephrine content were harvested, effluent was transfused to acceptor-control and acceptor-PC hearts. All hearts then underwent 40 min of global ischemia and 60 min of reperfusion, and infarct size was delineated by tetrazolium staining. Mean infarct size was smaller in both donor- and acceptor-PC groups (9% of left ventricle) than in donor- and acceptor-control groups (36% and 34%; P < 0.01). Protection in acceptor-PC hearts could not, however, be attributed to adenosine or norepinephrine. Thus preconditioning-induced cardioprotection can be transferred between rabbit hearts by transfusion of coronary effluent. Although adenosine and norepinephrine are apparently not responsible, these results suggest that remote protection is initiated by a humoral mechanism.

Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence.

This research was designed to test the hypothesis that ischemic preconditioning can be transferred between animals via whole blood transfusion. Preconditioning at a distance refers to the reduction in myocardial infarct size seen when coronary artery occlusion is preceded by brief ischemic episodes of noncardiac tissue. Isolation of the trigger signal responsible for this effect may be useful in the diagnosis and treatment of acute coronary occlusive syndromes. Rabbits were paired by crossmatching blood samples prior to experimentation. Crossmatched pairs were placed into either preconditioned (P) or control sets. Rabbits in the preconditioned sets were further divided into donor (PD) and acceptor (PA) animals. PD animals underwent five episodes of circumflex and renal artery occlusion followed by reperfusion. Before and after each preconditioning episode, a whole blood exchange was performed between PD and PA animals. Alternatively, control rabbits underwent the same surgical procedures and time-sequenced transfusion without preconditioning. All animals then underwent prolonged circumflex occlusion (60 minutes) followed by reperfusion (30 minutes). The area of myocardium at risk (R) was determined by isotope-labeled microsphere injection. Infarct size (I) was determined by NBT staining. The percent infarct within the risk area (I/R) was then compared. The I/R was significantly lower in the PA (14.0% +/- 12.2) and PD (14.3% +/- 11.2) groups as compared with controls (61% +/- 20. 6). There was no significant difference between the tPA and TPD groups. In conclusion, the ischemic preconditioning effect can be transferred to nonpreconditioned animals via whole blood transfusion, suggesting a humoral mechanism for preconditioning at a distance.

Enhanced mortality from perfluorocarbon administration in a rat model of kerosene aspiration.

BACKGROUND: Aspiration of low-viscosity hydrocarbons may lead to fulminant pneumonitis and acute respiratory distress syndrome. Animal and human studies suggest that partial liquid ventilation with perfluorocarbon improves gas exchange and pulmonary function in acute respiratory failure. The objective of this investigation was to determine the effect of intratracheal perfluorocarbon administration and a brief period of partial liquid ventilation on survival in a rat model of severe hydrocarbon aspiration. METHODS: Two randomized, non-blinded, controlled experiments were performed. First, male Wistar rats (n = 12) were given 0.3 mL/kg kerosene via direct intratracheal instillation and after 5 minutes were randomized to partial liquid ventilation or standard gas ventilation (control) groups. Partial liquid ventilation rats (n = 6) received 20 mL/kg of pre-oxygenated FC-77 intratracheally and positive-pressure gas ventilation (FiO2 = 1.0), and control rats (n = 6) received positive-pressure gas ventilation alone. Animals were observed for survival and 7-day mortality was compared using the Fisher Exact test. The study was then repeated in 12 additional animals using a 15-minute interval between kerosene instillation and treatment (PLV vs control). RESULTS: Mortality was significantly greater in the partial liquid ventilation group (5 of 6; 83%) as compared to the control group (1 of 6; 17% [p = 0.039]). Results were identical in the repeat study. All animals that died succumbed from acute respiratory failure within 24 hours of kerosene instillation. CONCLUSION: In this rat model of severe kerosene aspiration, intratracheal perfluorocarbon administration and a brief period of partial liquid ventilation proved detrimental and significantly increased mortality.

Partial liquid ventilation with perfluorocarbon in the treatment of rats with lethal pneumococcal pneumonia.

BACKGROUND: Partial liquid ventilation with perfluorocarbon is a new therapeutic strategy to treat various lung disorders. The current study was undertaken to determine the efficacy of partial liquid ventilation with a perfluorocarbon (FC-77) in the treatment of pneumococcal pneumonia in rats. METHODS: Male Wistar rats (weight, 275-300 g; n, 75) were infected via direct intratracheal inoculation with ca 10(9) colony-forming units of viable Streptococcus pneumoniae, serotype 3, and 24 h after infection were placed into one of five groups, each containing 15 rats. The groups were (1) no treatment, (2) one intramuscular injection of penicillin G benzathine (200,000 U), (3) partial liquid ventilation with FC-77, (4) partial liquid ventilation with FC-77 and a single intramuscular dose of penicillin G benzathine (200,000 U), and (5) gas ventilation. Animals were observed every 24 h for survival. RESULTS: All untreated or gas-ventilated animals or animals that received only partial liquid ventilation were dead by 7 days. Those receiving only partial liquid ventilation survived longer than untreated controls, but ultimately all succumbed by day 7. Survival was 40% for penicillin-treated rats compared with controls (P < 0.05) and 80% for animals treated with both partial liquid ventilation and penicillin versus antibiotic alone (P < 0.05). CONCLUSIONS: These observations suggest that partial liquid ventilation with perfluorocarbon in combination with antibiotic administration may be an effective therapeutic modality in pneumococcal pneumonia.

Endothelial cell hypoxia associated proteins are cell and stress specific.

Vascular endothelial cells (EC) are one of the initial cells exposed to decreases in blood oxygen tension. Bovine EC respond not only by altering secretion of vasoactive, mitogenic, and thrombogenic substances, but also by developing adaptive mechanisms in order to survive acute and chronic hypoxic exposures. EC exposed to hypoxia in vitro upregulate a unique set of stress proteins of Mr 34, 36, 39, 47, and 56 kD. Previous studies have shown that these proteins are cell associated, upregulated in a time and oxygen-concentration dependent manner, and are distinct from heat shock (HSPs) and glucose-regulated proteins (GRPs). To further characterize these hypoxia-associated proteins (HAPs), we investigated their upregulation in human EC from various vascular beds and compared this to possible HAP upregulation in other cell types. Human aortic, pulmonary artery, and microvascular EC upregulated the same set of proteins in response to hypoxia. In comparison, neither lung fibroblasts, pulmonary artery smooth muscle cells, pulmonary alveolar type II cells, nor renal tubular epithelial cells upregulated proteins of these Mr. Instead, most of these cell types induced synthesis of proteins of Mrs corresponding to either HSPs, GRPs, or both. Further studies demonstrated that exposure of EC to related stresses such as cyanide, 2-deoxyglucose, hydrogen peroxide, dithiothreitol, and glucose deprivation did not cause upregulation of HAPs. Evaluation of cellular damage during hypoxia using phase-contrast microscopy, trypan blue exclusion, chromium release, and adherent cell counts showed that EC survived longer with less damage than any of the above cell types. The induction of HAPs, and the lack of induction of HSPs or GRPs, by EC in response to hypoxia may be related to their unique ability to tolerate hypoxia for prolonged periods.