Gender differences in 24-hour outcome following resuscitation after 9 minutes of cardiac arrest in dogs.

OBJECTIVE: To examine possible gender-specific differences in 24-hr outcome following resuscitation from 9 mins of controlled cardiac arrest. DESIGN: Preclinical, prospective study comparing two similarly prepared, independent control groups (one female group, one male group) included in a larger series of studies. SETTING: Physiology research laboratory at a major medical center. SUBJECTS: Male and female mongrel dogs (Canis familiaris), weighing 16 to 22 kg. INTERVENTIONS: Cardiopulmonary-cerebral resuscitation following 9 mins of normothermic cardiac arrest in male vs. female dogs. MEASUREMENTS AND MAIN RESULTS: Mean arterial blood pressure, heart rate, urine output, arterial blood oxygen, and PCO2 values, arterial pH, temperature, plasma glucose concentrations, and hematocrit were measured and recorded at the precardiac arrest and postcardiac arrest period, and at 30 mins, and 1, 4, 6, 12, and 24 hrs following resuscitation. Neurologic dysfunction was assessed using a well-standardized neurologic deficit score assigned at 6, 12, and 24 hrs after arrest. Plasma concentrations of malonaldehyde, 4-hydroxynonenal, and erythrocyte-reduced glutathione were measured at the precardiac arrest period, and 6, 12, and 24 hrs following resuscitation. Additionally, serum concentrations of alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase, gamma-glutamyl transferase, creatinine kinase, creatinine, albumin, and total protein were measured before arrest, and at 6, 12, and 24 hrs after resuscitation. Plasma concentrations of inorganic phosphorus, blood urea nitrogen, and electrolytes (sodium, chloride, calcium, and potassium) were measured. The estrous cycle phase in the female dogs enrolled in the study was determined by physical examination and vaginal cytology. No prearrest differences were detectable between males and females in basic physiologic variables. No differences in neurologic deficit were detectable between males and females across the 24-hr recovery period following resuscitation. No detectable differences in malonaldehyde, 4-hydroxynonenal, and erythrocyte-reduced glutathione occurred between groups. Serum concentrations of aspartate aminotransferase (p = .02), alanine aminotransferase (p = .009), creatinine kinase (p = .01), total bilirubin (p = .05), and plasma concentrations of inorganic phosphorus (p = .03), blood urea nitrogen (p = .0003), and creatinine (p = .02) all were significantly and dramatically higher in female than male dogs at the 24-hr time point. The trend of increase in these values began at the 6- and 12-hr time points and was consistent with a steadily decreasing trend in mean arterial pressure and an increasing trend in heart rate in the female group. CONCLUSIONS: An extensive history with this preclinical canine model (restricted to male dogs) had indicated little or no change in standard clinical chemistry markers of systemic dysfunction following 9 mins of cardiac arrest. However, when compared with male dogs, the female dogs tested here appear to have sustained a more significant hepatic and renal ischemic injury with no differences in the neurologic deficit.

Thyroid hormone in neural rescue.

Serum thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (rT3) were followed for 24 h in dogs resuscitated following 9 min of controlled cardiac arrest (CA). Total T4, free T4, total T3, and free T3 decreased, while reverse T3 was elevated in the 24 h following resuscitation. Similar changes occurred with only 30 sec of CA. Levothyroxine sodium (L-T4) post-CA (7.5 micrograms/kg/h = CA + 7.5 or 15 micrograms/kg/h = CA + 15) increased total T4, free T4, and total T3. Free T3 decreased in the CA + 7.5 group but did not fall in CA + 15 group. Neurologic function improved significantly by 6 through 24 h (p < 0.05). Follow-up studies infusing T3 or rT3 failed to improve neurologic outcome. Systemic oxygen consumption (VO2) and delivery was assessed in a separate group of seven dogs that received a pre-CA L-T4 infusion of 15 micrograms/kg/h for 1.5 h and L-T4 infusion for 6 h afterward while controls (n = 7) received saline. Systemic VO2, VCO2, and RQ were calculated from blood contents and cardiac output and serum levels of circulating TSH, T4, FT4, T3, FT3, and rT3 were measured before L-T4 and periodically over 6 h. L-T4 maintained significantly higher T4, FT4, T3, FT3, rT3, VO2, and cardiac output compared to controls. No change in canine TSH was detected. Rapid and dramatic decreases in thyroid hormones following resuscitation indicate a significant acute serum hypothyroid state that may benefit from L-T4 treatment. L-T4 enhances systemic oxygen consumption and delivery and these changes may contribute to L-T4's neural protective effect.

Acute thyroid hormone administration increases systemic oxygen delivery and consumption immediately following resuscitation from cardiac arrest without changes in thyroid-stimulating hormone.

This study determined the acute effects of intravenous levothyroxine sodium (LT4) on systemic oxygen delivery and consumption for 6 h following resuscitation from 9 min of normothermic cardiac arrest in dogs. Male mongrel dogs (15-25 kg) were randomly assigned to two groups of seven. The treated group received a pre-cardiac arrest infusion of 15 micrograms/kg per h of LT4 for 1.5 h prior to arrest and for 6 h after, while controls received a comparable volume of 0.9 N saline infusion. Neurologic outcome was recorded at 1, 2 and 6 h following resuscitation. Systemic oxygen consumption (VO2), carbon dioxide production (VCO2) and respiratory quotient (RQ) were calculated from directly measured cardiac output, arterial and mixed venous blood gases and contents. Serum levels of circulating canine thyroid-stimulating hormone (cTSH), total thyroxine (T4), free thyroxine (FT4), total 3,5,3'-triiodothyronine (T3), free 3,5,3'-triiodothyronine (FT3), reverse 3,3',5'-triiodothyronine (rT3), and plasma markers of oxidant injury (malonaldehyde (MDA), 4-hydroxynonenal (4-OH) and erythrocyte GSH) were measured before administration and after resuscitation. Following resuscitation, treated dogs maintained significantly higher cardiac output when compared with their control counterparts at 4 h (5.5 ml/g per h vs. 2.9 ml/g per h, respectively, P < 0.05) and at 6 h (5.5 ml/g per h vs. 3.0 mg/g per h, respectively, P < 0.05). The level of VO2 was significantly higher in treated dogs than control dogs at 1, 4 and 6 h (P < 0.05). Treated dogs had significantly elevated levels of T4, FT4, T3, FT3 and rT3 (P < 0.01), compared with control dogs. No changes in cTSH were detected between groups or over time. Acute administration of LT4 enhances systemic oxygen delivery and apparently, therefore, oxygen consumption following resuscitation.

Acute administration of T3 or rT3 failed to improve outcome following resuscitation from cardiac arrest in dogs.

Documentation of profound changes in serum thyroid hormone concentrations associated with cardiac arrest and resuscitation, as well as other acute emergencies, have spurred evaluation of possible therapeutic thyroid hormone administration. Acute and significant, this state, characterized by abnormally low serum thyroid hormone concentrations, may indicate selective thyroid replacement therapy. In a previous investigation, post-resuscitation infusion of levothyroxine sodium (L-T4) to normalize serum 3,5,3'-triiodothyronine (T3) concentrations was associated with significant reduction of neurologic deficit caused by severe global cerebral ischemia. Since L-T4 has been reported to act directly or via one of its metabolites, most likely T3, this most active form of thyroid hormone was tested. When L-T4 reduced the neurologic deficit, an increase in 3,3',5'-triiodothyronine (rT3) was also observed. This study therefore determined whether a post-resuscitation treatment with either T3 (n = 8) or rT3 (n = 8) provided protection against global cerebral ischemia comparable to that of L-T4. Global cerebral ischemia was achieved with 9 min of ventricular fibrillation. Following resuscitation, one of three solutions (saline group as a control) was infused for 24 h at rates that reproduced the normal serum T3 concentrations or the rT3 concentrations achieved previously during the L-T4 therapy. The successful elevation of T3 and mimicking rT3 concentrations was assessed and confirmed by radioimmunoassay (RIA). In addition, TSH levels were measured by a novel RIA specific for canine thyroid-stimulating hormone (cTSH). Neurologic deficit was assessed with a well-standardized neurologic deficit examination. In contrast to previous studies using L-T4 infusion, no significant reduction of neurologic deficit was observed. Serum thyroid hormone changes confirmed previously described decreases and in no case did changes in cTSH appear causal in these changes. Thus, we concluded that L-T4 may offer a therapeutic advantage over T3 or rT3.

Systemic pressor response during hindlimb ischemia is inversely related to femoral artery pressure and fractional inspired oxygen.

BACKGROUND: Delayed-onset reflex increases in mean arterial pressure (MAP) occur during clamping of the infrarenal aorta. This study investigated the afferent limb of the reflex by independently altering femoral artery blood pressure (FBP) or fractional concentration of inspired oxygen (FIO2) while monitoring systemic arterial blood pressure. METHODS: The infrarenal aorta was divided, and an occlusive roller pump delivered incremental flow to the distal aorta thus controlling FBP. In six dogs the FBP was reduced in random order to 50, 40, 30, 20, and 10 mm Hg and held constant for 30 minutes. In another six dogs the FBP was held at 20 mm Hg, whereas the FIO2 was randomly varied among 0.13, 0.21, and 1.0 for 30-minute intervals. RESULTS: Under these conditions MAP was significantly and inversely correlated with FBP (MAP was 172 +/- 8 mm Hg when FBP was 10 mm Hg, p < 0.0001; MAP was 158 +/- 8 mm Hg when FBP was 20 mm Hg, p = 0.0001; MAP was 138 +/- 7 mm Hg when FBP was 30 mm Hg, p = 0.0048; and MAP was 130 +/- 7 mm Hg when FBP was 40 mm Hg, p = 0.0045). MAP was significantly and inversely related to the FIO2 value when FBP was fixed at 20 mm Hg (MAP of 186 +/- 9 mm Hg at FIO2 of 0.13 and was significantly higher than MAP of 163 +/- 11 mm Hg at FIO2 of 0.21, p = 0.01; and MAP of 157 +/- 10 mm Hg at FIO2 of 1.0, p = 0.0001). CONCLUSIONS: The magnitude of the delayed systemic pressor response is inversely proportional to the FBP. We suggest that this pressor response is also particularly sensitive, in part, to arterial blood oxygen tension when hindlimb perfusion pressure is low.

High resolution magnetic resonance imaging of the rat spinal cord.

A two turn saddle shaped surface coil receiver was developed that allowed high resolution magnetic resonance imaging of the rat spinal cord. This is particularly important in laboratory animals where central nervous system regions of interest are relatively small. A continuous copper wire 1.5 mm in diameter was wound into two turns 28 mm in diameter. The saddle shape of the second turn improved the homogeneity of the signal within the region of interest and maintained sufficient field of view and depth of penetration. The quality factor (Q) for the surface coil was Q = 199 unloaded, and Q = 60 loaded. Using this surface coil with a GE CSI II 2.0 Tesla small bore magnet, spin echo T1 (TR = 500 msec, TE = 25 msec) and T2 (TR = 2000 msec, TE = 100 msec) weighted images were obtained in cross section, using 2 mm slice thickness with 2 excitations per phase encoding step. A sagittal gradient echo (rapid scan, TR = 85 msec, TE = 10 msec) was used to document reestablishment of vascular flow following ischemia. Spinal cord ischemia was induced by 14 minute temporary occlusion of spinal cord blood supply. MRI was performed at 18 hours following ischemia. There was a 1.4 fold increase in T2 image intensity in ischemic rat spinal cord (n = 4), consistent with edema formation, compared to normal rat spinal cord (n = 4). Preliminary studies show that similar high resolution images can be performed on the rat brain. This technique uses standard MRI equipment and the surface coil is made from inexpensive readily available materials. There are various animal models of cerebral and spinal cord injury that would benefit from improved high resolution MRI. This coil design may have application in larger animal models and the clinical setting.

Central and peripheral effects of asymmetric dimethylarginine, an endogenous nitric oxide synthetase inhibitor.

We tested the hypothesis that the endogenous nitric oxide synthetase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), regulates cardiovascular function by central mechanisms. In in vivo studies, rats received intracerebroventricular (i.c.v.) injection of isotonic saline, ADMA (1 mg), l-arginine (3 mg), and N omega-nitro-l-arginine methylester (l-NAME, 1 mg). Baroreflex function was then assessed by intravenous (i.v.) injection of phenylephrine. Central application of exogenous NOS inhibitor, l-NAME, increased mean arterial blood pressure and decreased heart rate. However, application of the endogenous NOS inhibitor, ADMA, decreased mean arterial blood pressure and heart rate simultaneously (-39 +/- 6 mm Hg and -50 +/- 8 beats/min, respectively). Both l-NAME (i.c.v.) and ADMA (i.c.v.) significantly inhibited the baroreflex function, indicating a regulatory role of central nitric oxide in controlling baroreflex function. In contrast to the central effect, intravenous injection of ADMA caused dose-dependent increases in mean arterial blood pressure that could be blocked by l-NAME pretreatment. In vitro studies using aortic rings demonstrated that ADMA (10(-4)M) significantly increased the concentration of acetylcholine for the threshold response (EC15) and half-maximal response (EC50). This indicates that ADMA inhibits the constitutive isoform of NOS in the endothelium. ADMA may have functional importance in regulating cardiovascular function by mechanisms in addition to the inhibition of nitric oxide synthesis.

Infrarenal aortic clamp hypertension is exacerbated by baroreceptor blockade.

Aortic clamp-induced hypertension has long been implicated in the cardiovascular mortality and morbidity following infrarenal aortic operations. We studied the physiologic mechanisms leading to clamp-induced hypertension. Mean arterial pressure (MAP), cardiac output, heart rate, and left ventricular pressure were measured in alpha-chloralose-anesthetized dogs. Animals received alpha, beta, both alpha and beta, or no adrenergic blockade (n = 3, 4, 12 and 7, respectively). The infrarenal aorta was clamped following ligation of the infrarenal collateral vessels (lumbar, circumflex iliac, and tail arteries). Statistical analysis used paired t tests within groups, and ANOVA and unpaired t tests between groups, with Bonferroni's correction as indicated. Following placement of the clamp, MAP increased immediately in all groups, with magnitude of the increase related to the extent of adrenergic blockade. MAP increased 5.6 +/- 0.8 mm Hg with no blockade (P = 0.0005), 6.7 +/- 0.8 mm Hg with alpha blockade (P = 0.0153), 15 +/- 3.1 mm Hg with beta blockade (P = 0.0163), and 16.7 +/- 1.3 mm Hg with combined alpha and beta blockade (P < 0.0001). The increase in MAP immediately following infrarenal aortic clamping was most pronounced with combined alpha and beta blockade. We suggest that acute intraoperative hypertension associated with infrarenal aortic clamping is caused by the attenuation of compensatory baroreceptor reflex mechanisms.

Alkaloid delta agonist BW373U86 increases hypoxic tolerance.

Activation of delta opioid receptors increases survival time during acute, lethal hypoxia in mice. delta Agonists therefore present a promising avenue for therapeutic application to reduce the morbidity and mortality associated with clinical hypoxia in settings such as drowning, head injury apnea, and complicated childbirths. However, most delta agonists now available are peptides, and may have limited clinical utility. In the present study, we evaluate the neuroprotective ability of an alkaloid delta agonist, BW373U86. Alkaloid compounds, due to increased stability and increased systemic distribution, may be more favorable for clinical use. We found that BW373U86, like the peptide delta agonist, DPDPE ([D-Pen2, D-Pen5]-enkephalin), increases survival time of mice during lethal hypoxia. The mechanism of neuroprotection induced by delta receptor activation appears to involve decreasing body temperature. Further, using selective opioid receptor antagonists, it appears that BW373U86 exerts these neuroprotective effects by acting at delta-opioid receptors.

Calcium channel activity increased by plasma from ischemic hindlimbs of rats: role of an endogenous NO synthase inhibitor.

We tested the hypothesis that an endogenous nitric oxide synthase (NOS) inhibitor released from ischemic hindlimbs increases the activity of calcium channels in vascular smooth muscle, thus contributing to the increased contractile response to calcium agonists. Hindlimb ischemia was generated in rats by infrarenal aortic cross clamping for 5 h, after which plasma was obtained from femoral vein blood. Incubating naive aortic rings (endothelium intact) for 2 h in plasma collected from ischemic rats significantly reduced relaxation to acetylcholine in precontracted rings and increased contraction to the calcium channel agonist, BAY K 8644. However, in isolated smooth muscle cells (without endothelium) loaded with fura-2, no difference was noted in BAY K 8644-stimulated intracellular calcium concentration. The contractile responses to sodium fluoride, serotonin, and calcium ionophore A23187 were not different in either ischemic or control plasma-incubated rings. The augmentation of the contractile response to BAY K 8644 was significantly inhibited by nitroglycerin (10-8 M) and by exposure to calcium-free solution. N omega-nitro-L-arginine (without plasma incubation)-pretreated rings also demonstrated hyperresponsiveness to BAY K 8644. The increase in responsiveness to BAY K 8644 exhibited a negative correlation with the maximal relaxation to acetylcholine (r = -0.99), suggesting that the apparent increase in activity of calcium channels is mediated through inhibition of nitric oxide by an endogenous NOS inhibitor on endothelium.

Stimulation of endogenous nitric oxide pathway by L-arginine reduces declamp mortality and attenuates hypertension associated with aortic cross-clamp-induced hindlimb ischemia in rats.

We tested the hypotheses that maintaining the activity of nitric oxide by L-arginine infusion would counteract the release of an endogenous nitric oxide synthase inhibitor, improve survival, and decrease intraoperative hypertension after infrarenal aortic cross-clamp surgery. Hindlimb ischemia was generated by infrarenal aortic cross-clamping and tying of the left femoral artery for 5 hours in rats with bilateral femoral and sciatic nerves cut. Mean blood pressure significantly increased during the 5-hour ischemic period in ischemic rats (no drug treatment). Baroreceptor function was inhibited in ischemic rats assessed by intravenous dose response to phenylephrine and nitroprusside after 5 hours of ischemia, suggesting baroreceptor resetting. In ischemic rats infused with L-arginine the intraoperative hypertension was prevented during the 5-hour period, suggesting that this hypertension may be mediated by nitric oxide inhibition. The rates of survival and arrhythmias 2 hours after declamping were 50% in ischemic rats and 100% in ischemic rats treated with N omega-nitro-L-arginine (a nitric oxide synthase inhibitor) 10 minutes before declamping. In ischemic rats infused with L-arginine the survival rate was significantly increased to 100% and the arrhythmic rate was inhibited. We conclude that L-arginine prevents hypertension during cross-clamping and decreases the mortality rate and arrhythmias after declamping by maintaining nitric oxide synthesis. These results suggest that humoral factors released from the ischemic hindlimb may inhibit endogenous nitric oxide production, thus contributing to intraoperative hypertension, arrhythmias, and high mortality rate after aortic cross-clamp surgery.

Inhibition of vascular nitric oxide-cGMP pathway by plasma from ischemic hindlimb of rats.

The hypothesis was tested that plasma from ischemic hindlimbs facilitates hypertension. Ischemia-induced hypertension was generated in rats by infrarenal aortic cross clamping for 5 h after which plasma was obtained from femoral vein blood. In vitro contractile activity of naive aortic rings incubated for 2 h in plasma collected from ischemic rats demonstrated reduced relaxation to acetylcholine and nitroglycerin. Methylene blue (10(-5) M) induced greater contraction in rings incubated in control vs. ischemic plasma, suggesting that endogenous guanylate cyclase activity is decreased by ischemic plasma. However, 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP) relaxed equally strips incubated in ischemic or control plasma. Acetylcholine-induced nitrite release was significantly lower in ischemic vs. control plasma-incubated strips (8.6 +/- 2.7 vs. 28.2 +/- 2.3 ng/10 mg tissue wt, respectively). The impaired relaxation to acetylcholine in ischemic plasma-incubated rings was significantly increased by L-arginine but not by prior treatment of ischemic plasma with heating or superoxide dismutase and catalase. These findings suggest the impaired relaxation is mediated through inhibition of the nitric oxide-cGMP pathway. Prolonged blunting of vasodilation by ischemic plasma may therefore contribute to maintenance of a sustained vasoconstriction and ischemic hypertension.

Hypoxic cardiopulmonary-cerebral resuscitation fails to improve neurological outcome following cardiac arrest in dogs.

Hyperoxic cardiopulmonary resuscitation (CPR) is associated with an increase in neurologic dysfunction upon successful resuscitation with much of the damage attributable to an increase in reperfusion oxidant injury. We hypothesized that by contrast, hypoxic ventilation during resuscitation would improve neurologic outcome by reducing available substrate necessary for oxidant injury. Specifically, this study investigated the effects of 2 levels of hypoxic ventilation during resuscitation: F1O2 = 0.085, PaO2 = 26.6 +/- 3.4 mmHg, (HY8), and F1O2 = 0.12, PaO2 = 33.0 +/- 4.2 mmHg, (HY12), and normoxic resuscitation: F1O2 = 0.21, PaO2 = 60.6 +/- 17.0 mmHg, (N) on survival and neurological outcome following 9 min of normothermic cardiac arrest. Concentrations of malonaldehyde (MDA) and 4-hydroxynonenal (4-OH) in plasma and concentrations of glutathione (GSH) in erythrocyte lysates were measured to quantify possible radical damage. Physiological variables including arterial blood gases were followed for 24 h after resuscitation. Neurologic outcome was assessed using a standardized scoring system. Hypoxically (HY8) resuscitated dogs tended to have a greater neurologic deficit than normoxically resuscitated dogs and had reduced overall survival (16.9 +/- 8.9 h) compared to N dogs (24.0 +/- 0.0 h). Overall survival time correlated negatively (-0.693) and significantly (P = 0.0018) with plasma glucose concentration. Arterial plasma glucose concentrations were higher in the HY8 group compared to the N group immediately (HY8, 312 +/- 86 mg/dL; N, 196 +/- 82 mg/dL; P = 0.17) and 30 min (HY8, 331 +/- 109 mg/dL; N, 187 +/- 74 mg/dL; P = 0.077) following resuscitation. No statistically discernible differences in markers of oxidant injury were apparent among the 3 groups, but pooled data increased significantly with time for MDA and 4-OH. Pooled data for GSH showed a significant drop at 1 h following resuscitation and returned to normal by 6 h. Data from these markers suggested attendant oxidant injury in all groups. Thus, hypoxic ventilation at 2 depths of hypoxia during resuscitation failed to improve neurologic outcome beyond that achieved by ventilation with air, suggesting that normoxia rather than hyperoxia or hypoxia is the ideal target for arterial oxygenation during resuscitation.

Prevention of paraplegia during thoracic aortic cross-clamping: importance of patent internal mammary arteries.

PURPOSE: Unexplained anatomic and physiologic factors account for the unacceptably high rate of paraplegia/paresis after thoracoabdominal aortic reconstruction. We assessed the neurologic significance of patent internal mammary arteries (IMAs) in a novel rat model of aortic clamping in which the aortic origins of the intercostal arteries (ICAs) were occluded. METHODS: Twenty anesthetized, intubated, and halothane-ventilated adult male rats had catheters placed in the carotid and femoral arteries. ICAs arising from the aorta were divided at their origins through a left thoracotomy. IMAs were either divided (IMA-OUT, n = 10) or left intact (IMA-IN, n = 10). Proximal and distal descending aortic clamps were placed for 7 minutes. A neurologic deficit score (NDS) was assigned at 1, 4, 18, 24, and 48 hours by use of an established scoring system. RESULTS: The mean IMA-IN NDS was statistically better than the mean IMA-OUT NDS at 1, 4, 18, and 24 hours with p = 0.0005, 0.0014, 0.0098, and 0.0151, respectively. Moreover, the mortality rate in the IMA-OUT group was statistically greater than in the IMA-IN group (p = 0.0036). CONCLUSION: In this model, patent IMAs prevent paraplegia when the ICAs are occluded at their aortic origin and the aorta is clamped for 7 minutes.

Potential adaptations to acute hypoxia: Hct, stress proteins, and set point for temperature regulation.

Severe, intermittent hypoxia (hypoxic conditioning, HC) increases survival time during subsequent lethal hypoxia in mice. This protective effect was blocked by naloxone, suggesting an opioid-dependent mechanism. We proposed and evaluated three potential mechanisms of this acute adaptation: 1) increased hematocrit (Hct), 2) protein synthesis, and 3) decreased set point for temperature regulation (set point). Increased hematocrit is a well-studied adaptation to chronic hypoxia and could be acutely initiated by sympathetically mediated splenic contraction. Survival during stress can be prolonged by synthesis of stress proteins. We tested this hypothesis using two protein synthesis inhibitors, anisomycin and cycloheximide. Our third hypothesis is that set point is decreased after HC. A regulated decrease in body temperature would lower oxygen demand during hypoxia. Our studies indicate that hematocrit and protein synthesis are not dominant mechanisms of acute adaptation to hypoxia. However, we have observed a naloxone blockable decrease in set point after HC, supporting a mechanism in which acute adaptation involves an endogenous opioid-dependent decrease in set point. These studies also demonstrate that set point could be a more dominant contributor than body temperature to hypoxic tolerance.

Systemic hypertension induced by aortic cross-clamping: detrimental effects of direct smooth muscle relaxation compared with ganglionic blockade.

PURPOSE: Infrarenal aortic cross-clamping performed during vascular reconstructive procedures is often accompanied by systemic supraclamp hypertension. Much of the disease and death that attend aortic cross-clamping centers around hypertension. Many different strategies have been developed to attenuate intraoperative hypertension, and a host of pharmacologic agents are regularly used to lessen the heart-related, cerebral, and systemic effects of clamp-induced hypertension. This study was performed to evaluate two such strategies; the intravenous administration of either trimethaphan camsylate or nitroprusside. METHODS: We used a highly controllable and reproducible model of aortic cross-clamping in which we have previously shown the hypertension associated with clamping to be an active process mediated by means of a reflex arc. Ten dogs, five treated with nitroprusside (NP group) and five treated with trimethaphan camsylate (TC group), underwent 90 minutes of aortic cross-clamping. During this 90-minute period each group received 30 minutes of antihypertensive therapy. RESULTS: Control mean arterial pressure +/- SEM was 80 +/- 5 mm Hg for both groups and increased to 140 +/- 5 mm Hg with clamp application. With antihypertensive treatment the elevation in mean arterial pressure produced by cross-clamping was reduced to preclamp levels in the TC group and only partially (52%) in the NP group, despite very high doses of nitroprusside. Cardiac output (CO) increased in the NP group by 115% and decreased by 36% in the TC group. This increase in CO translates into a large (101%) increase in cardiac minute work for the NP group. CONCLUSIONS: The attenuation of clamp-induced hypertension by nitroprusside is associated with a dramatic increase in CO and cardiac work whereas the use of trimethaphan camsylate is not. The use of this ganglionic blocker may be more appropriate in this setting.

Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs.

This study investigated the effects of normoxic (FIO2 = 0.21), hyperoxic (FIO2 = 1.0), and hyperoxic (FIO2 = 1.0) plus antioxidant pretreatment (tirilazad mesylate) [corrected] resuscitation on neurologic outcome following 9 min of normothermic (39 +/- 1.0 degrees C) cardiac arrest. Physiologic variables including arterial blood gases and neurologic outcome, which was assessed using a standardized scoring system, were followed over a 24-h period following resuscitation from cardiac arrest. Hyperoxically resuscitated dogs sustained significantly worse neurological deficit at 12 and 24 h (mean scores: 39 +/- 3 and 49 +/- 8, respectively) than did antioxidant pretreated hyperoxically resuscitated dogs (mean scores: 22 +/- 1, P = 0.0007 and 22 +/- 1, P = 0.004, respectively) and normoxically resuscitated dogs (mean scores: 28 +/- 4, P = 0.025 and 33 +/- 8, P = 0.041 respectively). These data suggest that oxidant injury has a major role in central nervous system dysfunction following successful resuscitation from 9 min of cardiac arrest. Also, resuscitation from cardiac arrest with hyperoxic FIO2's may contribute to and further exacerbate neurologic dysfunction.

Hormonal profiles in a canine model of the brain-dead organ donor.

PURPOSE: The aim of the present study was to determine the effect of brain death on the circulating hormone levels. METHODS: Serum total thyroxine (TT4), total 3,3,5' triiodothyronine (TT3), free thyroxine (FT4), free 3,3,5' triiodothyronine (FT3), reverse 3,3',5' triiodothyronine (RT3) and plasma cortisol (CORT), norepinephrine (NE), epinephrine (EPI), dopamine, insulin (INS), and glucagon (GLUC) concentrations were measured before and for 5 hours after the maintenance of brain death (BD, n = 8), sham-brain death induction (SHAM, n = 3), and the operative procedure alone (time control, n = 3). Brain death in the canine model was induced by increasing and maintaining intracranial pressure above systolic arterial pressure. RESULTS: Brain death led to a persistent, significant decrease in mean arterial pressure (121 +/- 6 v 40 +/- 4 mm Hg at 5 hours). A significant decrease in the TT4, TT3, FT4, and FT3 concentrations was seen during the experiment for all three groups with the exception of TT4 in the SHAM group; no significant difference was found among the three groups for any of the time points. RT3 was found to increase after the induction of brain death in the BD (n = 5) group. The CORT levels in the BD group were significantly less than the other two groups for all time points 30 minutes after the induction of brain death. The mean 30- to 300-minute plasma NE and EPI levels in the SHAM group were statistically greater than the BD group. The plasma glucose in the BD group was maintained between 60 and 140 mg/dL whereas the trends of the INS/glucose and GLUC/glucose ratios in the BD group were appropriate for the plasma glucose level. CONCLUSIONS: The operative procedure alone led to the decrease in the plasma thyroid hormone levels. The inability of the BD group to increase plasma CORT, NE, and EPI may contribute to the hemodynamic deterioration and eventual somatic death.

Delayed onset hypertension with infrarenal aortic cross-clamping in dogs.

The time course and mechanism of systemic hypertension associated with infrarenal aortic cross-clamping were investigated in 31 chloralose-anesthetized dogs after ligating the tail artery, the paired infrarenal lumbar arteries, and the circumflex iliac arteries bilaterally. Cardiac output, renal blood flow, and suprarenal and infrarenal mean arterial blood pressure were continuously monitored. Infrarenal aortic clamping (90 min) in the standard group (n = 6) consistently decreased infrarenal blood pressure from 90 +/- 6 to 13 +/- 1 mm Hg within 1 min, while suprarenal blood pressure gradually increased over 20-30 min from 88 +/- 7 to 144 +/- 8 mm Hg, where it remained until declamp. The SHAM group (identical operation and instrumentation, without aortic clamping) (n = 5) showed no statistically significant changes. After 90 min of clamp total peripheral and renal resistance nearly doubled but no statistically significant changes in cardiac output, heart rate, central venous pressure, renal blood flow, renin, or glomerular filtration rate were detected. Upon declamping, pressures returned to control levels within 20 min. Groups with bilateral nephrectomy (n = 9) or unilateral iliac artery clamping (n = 7) produced similar time courses and patterns of hemodynamic change. Ablation of afferent nerves from the left hind limb (n = 4) eliminated the hypertension produced by left iliac artery clamping. The substantial delay (20-30 min) to the onset and full development of suprarenal hypertension, with near immediate infrarenal hypotension, is not consistent with a direct mechanical impedance effect. Hypertension in the presence of a bilateral nephrectomy or unilateral iliac artery clamping combined with its full reversal by nerve section strongly suggests that this is a reflex hypertension. This reflex mechanism of hypertension development has implications for intra- or perioperative events associated with hypertension management.