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.

Dextrose administration increases sensory/motor impairment and paraplegia after infrarenal aortic occlusion in the rabbit.

Spinal ischemia with resultant cord infarction is a catastrophic complication of surgical procedures involving the thoracoabdominal aorta. A rabbit spinal ischemia model was used to test if glucose administration would increase neurologic deficit of the lower extremity. Rabbits (2 to 3 kg), anesthesized with halothane, had a snare occluder placed around the aorta just below the left renal artery. After a 2-hour recovery, the aorta was occluded for 15 minutes. Before occlusion animals received an intraperitoneal injection of isotonic glucose (2 gm/kg; n = 11), isotonic mannitol (2 gm/kg; n = 3), or an equal volume of saline solution (n = 11). Four sham-operated animals received glucose and an identical surgical procedure, but the aorta was not occluded. Average blood glucose level at the time of occlusion for the glucose group was 249 +/- 15 versus 156 +/- 6 for the control group (p less than 0.01). At 1, 4, 18, and 24 hours, a neurologic impairment score (1 = normal, 2 = partial impairment, 3 = complete impairment) was assigned. At 4, 18, and 24 hours, the glucose group had significantly greater neurologic impairment than did control groups (p less than 0.02). Glucose administration had an adverse effect in a controlled and highly reproducible model of spinal cord ischemia. Exogenous glucose administration should potentially be avoided during complex aortic reconstruction.

Dextrose containing intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in dogs.

Use of dextrose in intravenous resuscitation fluids is common practice; however, this study indicates that 5% dextrose solutions, even if administered in physiologic quantities, greatly worsens the outcome of survivable cardiac arrest. Twelve adult male mongrel dogs were premedicated with morphine, anesthetized with halothane, instrumented, intubated, and ventilated. Each dog was first given 500 ml of either lactated Ringer's (LR) (n = 6) or 5% dextrose in LR (D5LR) (n = 6). Halothane was stopped and fibrillation was induced (60 Hz). Blood glucose just before cardiac arrest was 129 mg/dl in the LR dogs and was increased to 335 mg/dl in the D5LR dogs. After eight minutes of arrest, resuscitation, including internal cardiac massage and standard advanced cardiac life support drug protocols (modified for dogs), was begun. When stable cardiac rhythm was obtained, the chest was closed, and LR or D5LR continued until a total of 1L was given. A neurologic score (0 = normal to 100 = dead) was assigned at 1, 2, 6, and 24 hours. The LR group did not differ statistically from the D5LR group in operative time, number of defibrillatory shocks, time to spontaneous ventilation, time to extubation, or drugs required. Resuscitation was successful in all six LR and five of six D5LR group; however, by 2 hours after resuscitation and thereafter, D5LR group had a significantly greater neurologic deficit (p less than 0.05) than did the LR group. By 9 hours, four of six D5LR dogs displayed convulsive activity and died. At 24 hours the D5LR group had a greater (p less than 0.008) neurologic deficit (82 +/- 11) than did the LR group (21 +/- 7), which walked and ate. We conclude that the addition of 5% dextrose to standard intravenous fluids greatly increases the morbidity and mortality associated with cardiac resuscitation.

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.

Dissociation of the pressor and cerebral protective effects of phenylephrine.

The relationship between the pressor and cerebral protective effects of the alpha-adrenergic agonist phenylephrine was assessed. Sprague-Dawley rats were anesthetized and underwent right carotid artery ligation and placement of arterial and central venous pressure catheters and EEG electrodes. Following a two-hour recovery, the rats were exposed to hypoxia (4.5% chamber O2). Three groups of rats were infused with phenylephrine hydrochloride at 17, 35, and 88 micrograms/kg/min, respectively. A fourth group received normal saline, and a fifth, no infusion. All rats receiving phenylephrine experienced an initial pressor response to 130, 162, and 180 mm Hg, respectively, compared with control animals (119 mm Hg). Cerebral electrical activity was prolonged with the two lower doses of phenylephrine (24 +/- 3 minutes and 21 +/- 4 minutes, respectively), compared with the control response (13 +/- 1 minutes). High-dose phenylephrine decreased survival time (8 +/- 1 minutes), despite higher BP at the time of brain death.

Dextrose administration exacerbates acute renal ischemic damage in anesthetized dogs.

To determine if moderate hyperglycemia produced by dextrose administration was detrimental in normothermic renal ischemia, 15 halothane-anesthetized mongrel dogs underwent right nephrectomy and 60 minutes of left renal artery and vein occlusion. Six dogs received 1 L of lactated Ringer's solution (LR) and six others received 1 L of 5% dextrose in lactated Ringer's solution (D5LR). Three sham-operated dogs received 1 L of D5LR and underwent right nephrectomy but no occlusions. All dogs received 500 mL of fluid before occlusion and 500 mL after occlusion. The blood glucose concentration for the LR group was 7.6 mmol/L (137 mg/dL) after 500 mL and 7.2 mmol/L (130 mg/dL) after 1000 mL. In the D5LR group, the blood glucose concentration was 21.5 mmol/L (387 mg/dL) after 500 mL and 20.2 mmol/L (363 mg/dL) after 1000 mL. In the sham-operated group, the blood glucose concentration was 22.8 mmol/L (410 mg/dL) after 500 mL and 20.7 mmol/L (373 mg/dL) after 1000 mL. At 30 hours, the plasma creatinine concentration rose from 70 to 300 mumol/L (0.8 to 3.4 mg/dL) in the LR group and from 90 to 500 mumol/L (1.0 to 5.8 mg/dL) in the D5LR group; the increase for the D5LR group was significantly greater than that for the LR group. In the sham-operated group, the plasma creatinine concentration was stable throughout the 30-hour period. This study demonstrates a significant detrimental effect of dextrose administration on renal function during normothermic ischemia.

Somatosensory evoked potentials of the dog: recording techniques and normal values.

Median and tibial nerve somatosensory evoked potentials (SSEPs) of 5 sedated dogs were studied to determine their normal features and optimal stimulation and recording techniques. Cortical potentials were mapped from an extensive array of skull electrodes as each limb was independently stimulated with subdermal needles. The effects of bandpass and stimulus intensity and rate were also assessed. Three cortical components (P1, N1, P2) were evoked by median or tibial nerve stimulation and were localized along the coronal suture at lateral and medial electrodes, respectively. SSEP voltage varied much more than morphology, topography, or latency. The inion was a stable, indifferent reference site. Cortical SSEP frequency content was mostly below 250 Hz. Maximal SSEP voltage was achieved only at stimulus intensities 2-3 times motor threshold. Appropriate methods minimize technical difficulties and consistently yield legible SSEPs.

Role of endogenous opioid peptides in the acute adaptation to hypoxia.

A non-lethal, hypoxic conditioning stimulus has been shown by Rising and D'Alecy to increase hypoxic survival time in mice. To determine if endogenous opioids alter the hypoxic conditioning-induced increase in hypoxic survival time, we administered naloxone (0.1, 1.0 mg/kg i.p.) or saline (0.3 ml i.p.) 5 min prior to conditioning. Sixty percent of the mice received the hypoxic conditioning stimulus consisting of three sequential hypoxic exposures (4.5% oxygen balance nitrogen for 1.5, 2 and 2.5 min) separated by 5 min of room air. The remaining mice did not receive hypoxic conditioning but instead remained in room air for this time. All mice were tested for hypoxic survival by first exposing them to 20 s of 8.5% oxygen balance nitrogen followed by exposure to 4.5% oxygen balance nitrogen. The hypoxic survival time was recorded as the time from the onset of the 4.5% oxygen to the cessation of spontaneous ventilation. Naloxone (1 mg/kg) completely blocked the adaptation to hypoxia induced by hypoxic conditioning (P = 0.003). Morphine (1, 5, 10 and 20 mg/kg) had no effect on hypoxic adaptation; however, 50 mg/kg morphine decreased the adaptation induced by conditioning (P less than 0.0001) possibly due to high dose toxicity. These data suggest that endogenous opioids are involved in the protective adaptation to hypoxia induced by prior exposure to non-lethal hypoxia.

Effect of head turning on blood flow in lateral sinuses of nonhuman primates.

The pattern of blood flow leaving the cranium via the lateral sinuses and internal jugular veins is significantly altered by head rotation. This effect is documented in the baboon and macaque monkey by Doppler flow recording and by angiography. This phenomenon may affect the validity of cerebral blood flow data determined by venous sampling and may have significance in angiographic interpretation and in the clinical course of patients with a hypoplastic or occluded lateral sinus or internal jugular vein.

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.

Neurological protection by dichloroacetate depending on the severity of injury in the paraplegic rat.

Hyperglycemia has been shown to exacerbate neurological deficit associated with central nervous system ischemia. Iodoacetate or dichloroacetate was administered intraperitoneally to rats in a study to examine the role of glycolysis in hyperglycemic exacerbation of neurological deficit. Sprague-Dawley rats were injected with saline, iodoacetate, or dichloroacetate and then made paraplegic by temporary occlusion for 10, 12, 13, or 15 minutes of the right and left subclavian arteries and the aorta distal to the left subclavian artery. Glycolytic blockage by iodoacetate was lethal in doses of 15 mg/kg or more, whereas rats receiving 10 mg/kg survived but showed no significant neurological improvement compared to the saline-treated control group. Dichloroacetate, 500 mg/kg, protected neurological function, which suggests a possible detrimental role for lactate accumulation and the benefit of maintaining tricarboxylic acid cycle activity by stimulating pyruvate dehydrogenase. The protection seen with dichloroacetate depended on the severity of ischemic injury. Dichloroacetate administration had a minimal effect on neurological outcome with occlusion periods of 13 and 15 minutes, mild improvement with 12 minutes of occlusion, and a significant protective effect with a 10-minute occlusion period. The dose-response nature of ischemic injury and neurological outcome in this rat model of paraplegia therefore appears to play an important role in determining the effect observed with a specific intervention.

The role of glucose uptake and metabolism in hyperglycemic exacerbation of neurological deficit in the paraplegic rat.

Previous studies indicate that hyperglycemia, particularly that induced by exogenous glucose administration, exacerbates neurological deficits in the rat spinal cord ischemic model. The effect of inhibition of glucose uptake (glucose transporter) and initial metabolism (hexokinase) on neurological outcome was evaluated in the present investigation using the competitive inhibitors 2-deoxyglucose (2-DG) and 3-O-methylglucose (3-OMG). Sprague-Dawley rats, weighing 200 to 300 gm each, received either 0.25, 1, or 2 gm/kg 2-DG; 2 gm/kg 3-OMG; 2 gm/kg glucose; or an equivalent volume of 0.9% saline intraperitoneally. Rats were intubated and ventilated with 1% to 1.5% halothane. The aortic arch was exposed and snares were placed on the right and left subclavian arteries and the aorta distal to the left subclavian artery. The three vessels were occluded for 10, 11, 12, or 13 minutes. Lower-extremity neurological deficits were evaluated at 1, 4, 18, and 24 hours postocclusion based on a 15-point scale (normal = 0, severe deficit = 15). Lower-extremity neurological deficits were significantly less severe in the groups treated with 2-DG (0.25 and 1 gm/kg) at 18 and 24 hours postocclusion (p less than 0.05 for 0.25 gm/kg and p less than 0.005 for 1 gm/kg, Student's t-test with Bonferroni correction). The lower 2-DG dose of 0.25 gm/kg did not significantly increase the plasma glucose level, suggesting that the glucose transporter was not markedly inhibited, and that the improved neurological outcome was more likely due to inhibition of hexokinase. The higher 2-DG dose of 1 gm/kg afforded protection despite significantly increasing the plasma glucose level, implying a strong inhibition of both the glucose transporter and hexokinase. Administration of 3-OMG, which only inhibits glucose uptake and not hexokinase, actually worsened the neurological deficit in a manner similar to that observed in rats treated with glucose. The authors conclude that the activity of the glucose transporter by itself does not significantly contribute to hyperglycemic exacerbation of neurological deficits. In contrast, the hexokinase step, at least in combination with the transporter and possibly alone, plays a significant role in hyperglycemic exacerbation of the lower-extremity neurological deficit in the paraplegic rat.

Continued circulatory support: effect of epinephrine or dopamine on 24-hour survival and neurologic function in dogs.

The effects on 24-h survival and neurologic function were compared following continued postresuscitation circulatory support with epinephrine or dopamine. Cardiopulmonary arrest was induced by ventricular fibrillation. After 10 min, resuscitation efforts were initiated including i.v. infusion of either epinephrine (6 micrograms/kg per min, 11 dogs) or dopamine (10 micrograms/kg per min, 14 dogs) for continued circulatory support. There was no difference detected in duration of circulatory support, although dogs receiving epinephrine required more lidocaine (3.3 +/- 0.4 vs. 1.8 +/- 0.3 mg/kg, P = 0.005). Likewise, there was no statistically significant difference detected in MAP or HR between groups at any time tested. However, dogs receiving epinephrine had significantly worse neurologic function at 6 and 12 h postarrest. Mean survival time (20.3 +/- 1.2 vs. 15.3 +/- 1.9 h, P = 0.028) and overall survival (P = 0.027, survival curve analysis) were significantly longer for dogs receiving dopamine. Plasma glucose in the first 6 h postarrest was significantly higher in dogs receiving epinephrine (P = 0.006). These results suggest that the use of epinephrine for continued vasopressor support in cardiopulmonary resuscitation may contribute to decreased survival and poorer neurologic function in this controlled experimental setting. It is reasonable to propose that similar responses to these commonly used circulatory support agents occur clinically. Therefore, continued vasopressor support with dopamine rather than epinephrine may be justified in the setting of cardiac resuscitation.

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.

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.

Elevated brain lactate accumulation and increased neurologic deficit are associated with modest hyperglycemia in global brain ischemia.

This study determined if hyperglycemia: (1) augments ischemic cerebral cortical lactate accumulation during complete cerebral ischemia; and (2) exacerbates subsequent neurologic morbidity and mortality. Dextrose (D5W, n = 8) or normal saline (n = 6) was administered i.v. prior to 10 min of global cerebral ischemia induced by normothermic cardiac arrest in dogs. Before arrest plasma glucose was significantly higher in the D5W-treated group than saline-infused (407 +/- 31 vs. 11 9 +/- 20 mg/dl, P less than 0.05). By 6 h post-arrest, seven of eight D5W-infused dogs died, compared to one of six saline-infused dogs (P = 0.002). D5W-infused dogs showed significantly greater neurologic deficit at 2, 6, and 12 h post-arrest. In a complementary protocol, dogs were pretreated in the same manner, however, six cerebral cortical brain biopsies were taken before, during, and immediately after cardiac arrest. Plasma glucose was 320 +/- 17 mg/dl in the D5W-infused dogs and lower (P less than 0.001), 140 +/- 5 mg/dl, in the saline-infused group. Cerebral cortical lactate accumulation was slightly but significantly greater during ischemia and early reperfusion in animals receiving dextrose. Neither plasma nor cerebrospinal fluid (CSF) creatine kinase isoenzymes nor plasma or CSF lactate concentrations, measured during and for 25 min after cardiac arrest, served as a good prognostic indicator of 24 h neurologic morbidity or mortality. Therefore, induction of complete cerebral ischemia in the presence of moderate hyperglycemia is associated with profound neurologic dysfunction and striking mortality. A qualitative but not quantitative increase in brain lactate accumulation is consistent with the hypothesis that lactate may contribute to the increased severity of neurologic dysfunction with hyperglycemia.

Thyroid hormone loss and replacement during resuscitation from cardiac arrest in dogs.

Circulating concentrations of thyroxine (T4), triiodothyronine (T3), and reverse triiodothyronine (rT3) were followed in dogs subjected to 9 min of normothermic ventricular fibrillation. Significant decreases were detected 12 h post-arrest when compared to pre-arrest levels in total T4 (P < 0.0005), free T4 (P < 0.0005), total T3 (P < 0.003), and free T3 (P < 0.003), and levels of reverse T3 were significantly elevated (P = 0.0001). Similar changes occurred with only 30 s of arrest. Post-arrest replacement therapy with 7.5 micrograms/kg per h (Rx-7.5) and 15 micrograms/kg per h (Rx-15) levothyroxine sodium (L-T4) increased total T4, free T4, and total T3 (P < 0.01). Free T3 decreased in the Rx-7.5 group (P < 0.01) and did not fall in the Rx-15 group (P = 0.16). Reverse T3 increased with either treatment (P < 0.005). Both treatment groups had higher levels of all five hormones than non-treated animals (P < 0.001). Neurologic function, assessed with a standardized scoring system, showed significant improvement in the treated groups by 6 h (P < 0.05, compared to non-treated group) and remained significant through 24 h post-arrest (P < 0.05). The documentation of rapid and dramatic changes in thyroid hormones immediately following cardiac arrest and resuscitation indicates a significant acute hypothyroid state that may potentially benefit from replacement therapy.

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.

Ibuprofen improves survival and neurologic outcome after resuscitation from cardiac arrest.

Post-ischemic inflammatory changes in the central nervous system (CNS) following cardiac arrest and resuscitation are potentially responsible for ultimate survival and much of the neurologic damage, producing greater morbidity and mortality in successfully resuscitated patients. This study was undertaken to assess the non-steroidal anti-inflammatory agent, ibuprofen, in a controlled and monitored experimental model of canine cardiac arrest and resuscitation. With the investigator blinded as to the intervention, eight of 21 dogs were randomly assigned to receive ibuprofen as an i.v. bolus (10 mg/kg) and a 6-h i.v. infusion (5 mg/kg per h). The other 13 dogs received an equivalent volume of 0.9% NaCl to serve as controls. No statistically significant differences between the two groups were detected in any pre-arrest variables. All 21 dogs were successfully resuscitated. At 24 h, dogs receiving ibuprofen exhibited 100% survival, while control dogs exhibited only 54% survival (P = 0.03). The majority of deaths for the control group occurred within the first 6 h. Neurologic deficit scores were assigned at 1, 2, 6 and 24 h after resuscitation. A general trend occurred such that dogs treated with ibuprofen improved over time, while the control dogs remained severely impaired. A significant difference in neurologic deficit score was detected at 6 h (P = 0.01). At 24 h the ibuprofen group exhibited minimal neurologic deficit (5.9 +/- 3.2), and the control group exhibited significantly more severe neurologic impairment (52.2 +/- 13.0, P = 0.01). These results suggest that ibuprofen may be helpful in the pharmacologic management of cardiac arrest as a means of increasing survival and decreasing neurologic impairment.