Association of intraluminal thrombus in abdominal aortic aneurysm with local hypoxia and wall weakening.

PURPOSE: Our previous computer models suggested that intraluminal thrombus (ILT) within an abdominal aortic aneurysm (AAA) attenuates oxygen diffusion to the AAA wall, possibly causing localized hypoxia and contributing to wall weakening. The purpose of this work was to investigate this possibility. METHODS: In one arm of this study, patients with AAA were placed in one of two groups: (1) those with an ILT of 4-mm or greater thickness on the anterior surface or (2) those with little (< 4 mm) or no ILT at this site. During surgical resection but before aortic cross-clamping, a needle-type polarographic partial pressure of oxygen (PO2) electrode was inserted into the wall of the exposed AAA, and the PO2 was measured. The probe was advanced, and measurements were made midway through the thrombus and in the lumen. Mural and mid-ILT PO2 measurements were normalized by the intraluminal PO2 measurement to account for patient variability. In the second arm of this study, two AAA wall specimens were obtained from two different sites of the same aneurysm at the time of surgical resection: group I specimens had thick adherent ILT, and group II specimens had thinner or no adherent ILT. Nonaneurysmal tissue was also obtained from the infrarenal aorta of organ donors. Specimens were subjected to histologic, immunohistochemical, and tensile strength analyses to provide data on degree of inflammation (% area inflammatory cells), neovascularization (number of capillaries per high-power field), and tensile strength (peak attainable load). Additional specimens were subjected to Western blotting and immunohistochemistry for qualitative evaluation of expression of the cellular hypoxia marker oxygen-regulated protein. RESULTS: The PO2 measured within the AAA wall in group I (n = 4) and group II (n = 7) patients was 18% +/- 9% luminal value versus 60% +/- 6% (mean +/- SEM; P <.01). The normalized PO2 within the ILT of group I patients was 39% +/- 10% (P =.08 with respect to the group I wall value). Group I tissue specimens showed greater inflammation (P <.05) compared with both group II specimens and nonaneurysmal tissue: 2.9% +/- 0.6% area (n = 7) versus 1.7% +/- 0.3% area (n = 7) versus 0.2% +/- 0.1% area (n = 3), respectively. We found similar differences for neovascularization (number of vessels/high-power field), but only group I versus control was significantly different (P <.05): 16.9 +/- 1.6 (n = 7) vs 13.0 +/- 2.3 (n = 7) vs 8.7 +/- 2.0 (n = 3), respectively. Both Western blotting and immunohistochemistry results suggest that oxygen-regulated protein is more abundantly expressed in group I versus group II specimens. Tensile strength of group I specimens was significantly less (P <.05) than that for group II specimens: 138 +/- 19 N/cm2 (n = 7) versus 216 +/- 34 N/cm2 (n = 7), respectively. CONCLUSION: Our results suggest that localized hypoxia occurs in regions of thicker ILT in AAA. This may lead to increased, localized mural neovascularization and inflammation, as well as regional wall weakening. We conclude that ILT may play an important role in the pathology and natural history of AAA.

Regional low-flow perfusion provides somatic circulatory support during neonatal aortic arch surgery.

BACKGROUND: Regional low-flow perfusion has been shown to provide cerebral circulatory support during neonatal aortic arch operations. However, its ability to provide somatic circulatory support remains unknown. METHODS: Fifteen neonates undergoing arch reconstruction with regional perfusion were studied. Three techniques were used to assess somatic perfusion: abdominal aortic blood pressure, quadriceps blood flow (near-infrared spectroscopy), and gastric tonometry. RESULTS: Twelve patients required operation for hypoplastic left heart syndrome, and 3 required arch reconstruction with a biventricular repair. There was one death (7%). Abdominal aortic blood pressure was higher (12+/-3 mm Hg versus 0+/-0 mm Hg), and quadriceps blood volumes (5+/-24 versus -17+/-26) and oxygen saturations (57+/-25 versus 33+/-12) were greater during regional perfusion than during deep hypothermic circulatory arrest (p < 0.05). During rewarming, the arterial-gastric mucosal carbon dioxide tension difference was lower after circulatory arrest than after regional perfusion (-3.3+/-0.3 mm Hg versus 7.8+/-7.6 mm Hg, p < 0.05). CONCLUSIONS: Regional low-flow perfusion provides somatic circulatory support during neonatal arch surgical procedures. Support of the subdiaphragmatic viscera should improve the ability of neonates to survive the postoperative period.

Hypothermic cardiopulmonary bypass alters oxygen/glucose uptake in the pediatric brain.

OBJECTIVES: Neurologic morbidity related to cardiac surgery has been recognized as a major morbidity. A variety of causes related to cardiopulmonary bypass, including microemboli, nonpulsatile flow, hemodilution, and inflammatory mediation, have been proposed. Because oxygen and glucose are the predominant metabolic substrates for the brain, we sought to examine the uptake of these substrates by the pediatric brain during hypothermic cardiopulmonary bypass. METHODS: Eleven children (median age 5 months, range 1 day-17 years) undergoing a variety of cardiac surgical procedures with the use of hypothermic cardiopulmonary bypass were studied. Cerebral arteriovenous differences for oxygen, glucose, and lactate were obtained before, during, and after bypass. On the basis of the predictable stoichiometric relationship for the oxidation of glucose, the relationship of substrate uptake was expressed as the oxygen/glucose index.Oxygen/glucose index (%) = (arteriovenous oxygen difference [micromol/mL]/arteriovenous glucose difference [micromol/mL] x 6) x 100 RESULTS: All children survived with no obvious neurologic sequelae. During cooling on cardiopulmonary bypass, the oxygen/glucose indexes fell significantly from prebypass values (53% +/- 19% at 28 degrees C and 54% +/- 25% at 24 degrees C vs 117% +/- 70%; P <.05, analysis of variance). This decline resulted from decreased oxygen uptake with stable glucose uptake (P <.05). Although oxygen and glucose uptake both increased with rewarming, the net effect was only a slight increase in oxygen/glucose index (62% +/- 16%). Postbypass oxygen/glucose index exceeded prebypass values (149% +/- 83%). CONCLUSIONS: Hypothermic cardiopulmonary bypass alters the relationship between oxygen and glucose uptake in the pediatric brain. The relationship of these findings to bypass-related neurologic morbidity remains to be explored.

Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction.

OBJECTIVE: Because of concerns regarding the effects of deep hypothermia and circulatory arrest on the neonatal brain, we have developed a technique of regional low-flow perfusion that provides cerebral circulatory support during neonatal aortic arch reconstruction. METHODS: We studied the effects of regional low-flow perfusion on cerebral oxygen saturation and blood volume as measured by near-infrared spectroscopy in 6 neonates who underwent aortic arch reconstruction and compared these effects with 6 children who underwent cardiac repair with deep hypothermia and circulatory arrest. RESULTS: All the children survived with no observed neurologic sequelae. Near-infrared spectroscopy documented significant decreases in both cerebral blood volume and oxygen saturations in children who underwent repair with deep hypothermia and circulatory arrest as compared with children with regional low-flow perfusion. Reacquisition of baseline cerebral blood volume and cerebral oxygen saturations were accomplished with a regional low-flow perfusion rate of 20 mL x kg(-1) x min(-1). CONCLUSIONS: Regional low-flow perfusion is a safe and simple bypass management technique that provides cerebral circulatory support during neonatal aortic arch reconstruction. The reduction of deep hypothermia and circulatory arrest time required may reduce the risk of cognitive and psychomotor deficits.

Resuscitative hypothermia.

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.

Suppression of cerebral metabolic rate for oxygen (CMRO2) by mild hypothermia compared with thiopental.

If the efficacy of hypothermia and barbiturates in ameliorating ischemic brain injury lies in reducing the cerebral metabolic rate of oxygen (CMRO2), the greater efficacy of mild hypothermia (34 degrees C) compared with barbiturates is inconsistent with the 15-20% reduction of CMRO2 caused by mild hypothermia compared with 50% caused by barbiturates. This paradox, we hypothesized, derives from the fact that whereas barbiturates lower CMRO2 associated with EEG activity or thiopental (TP)-suppressible CMRO2, not essential for cellular viability, hypothermia lowers CMRO2 associated with providing energy, i.e., adenosine triphosphate, to maintain transmembrane ion gradients or TP-nonsuppressible CMRO2, essential for neuronal viability. To test this hypothesis, we measured whole brain cerebral blood flow (CBF) and CMRO2 in two groups of rats mechanically ventilated with 70% N2O/30% O2 before and after TP-induced isoelectric EEG. In the normothermic group (n = 7), measurements were made at a brain temperature (Tb) of 38 degrees C, while in the hypothermic group (n = 7), they were made at 34 degrees C. In the normothermic group, TP-induced isoelectric EEG reduced CMRO2 by 50%, from 7.92 +/- 1.05 to 3.95 +/- 0.70 ml 100 g-1 min-1 (mean +/- = SD). Thus, at 38 degrees C, TP-suppressible and TP-nonsuppressible CMRO2 were both 50 +/- 4% of total CMRO2. In the hypothermic group, decreasing Tb from 38 to 34 degrees C caused a 17% decline in CMRO2, from 7.62 +/- 1.92 to 6.28 +/- 1.22 ml 100 g-1 min-1 (p > 0.05). AT 34 degrees C, TP infusion lowered CMRO2 to 2.15 = 0.46 ml 100 g-1 min-1. At 34 degrees C, TP-suppressible and TP-nonsuppressible CMRO2 values were 64 +/- 7% and 36 +/- 8% of total CMRO2, respectively. TP lowered CBF by 50% at both 38 and 34 degrees C. In conclusion, mild hypothermia selectively lowers TP-nonsuppressible CMRO2 associated with the maintenance of viability rather than EEG-associated or TP-suppressible CMRO2.

Assessment of hepatic viability during cold ischemic preservation.

A reliable and easy method for assessing the viability of a cold ischemia-preserved donor liver prior to transplantation into the recepient is needed. Based on an earlier study, we hypothesized that liver free fatty acid (FFA) leakage into the preservation fluid may be a useful, atraumatic indicator of irreversible ischemic injury. The aim of the present study was to determine the time course and magnitude of liver FFA release into the preservation solution and its correlation with the duration of cold ischemic preservation compatible with survival after transplantation. Rat livers (n = 48) were flushed and preserved with University of Wisconsin (UW) solution at 4 degrees C for 0, 12, 24, and 48 h. Thereafter, half of the livers were analyzed for preservation fluid FFA (gas-liquid chromatography) and protein. The other half were perfused with Krebs-Henseleit (KH) solution at 37 degrees C for 1 h. Bile secretion and liver enzyme release (SGOT, SGPT, and LDH) were measured in addition to perfusate FFA and protein. Total FFA in the preservation fluid was 24 micrograms/g wet tissue after 12 h; it increased sharply 2.6-fold after 24 h and 3.7-fold after 48 h of preservation. Bile production was normal after 12 h of preservation but fell by 20% and 54% after 24 h and 48 h, respectively. LDH release rose from a value of 20 U/l at 0 time to 120 U/l and 260 U/l after 24 h and 48 h of preservation. These results suggest that liver viability declines sharply between 12 and 24 h of cold ischemic preservation, which corresponds with a sharp decrease in the 1-week survival from 100% to 33% after 12 h and 24 h, respectively, of cold ischemic preservation. We conclude that measuring FFA and LDH in the preservation solution of donor livers may be a useful means of assessing the quality of the cold-preserved liver before insertion into the recipient. We also speculate that a "threshold" FFA level in the UW preservation fluid indicating irreversible damage may be in the order of 35 micrograms total FFA/g liver. Studies on the clinical applicability of our findings are currently under way.

Stable xenon does not increase intracranial pressure in primates with freeze-injury-induced intracranial hypertension.

Stable xenon (Xe)-enhanced computed tomography is a potentially valuable tool for high resolution, three-dimensional measurement of CBF in patients. However, reports that Xe causes cerebrovascular dilation and increases intracranial pressure (ICP) have tempered enthusiasm for its use. The effects of 5 min of 33% Xe inhalation on ICP (right and left hemispheres) were studied in eight fentanyl-anesthetized Rhesus monkeys after right-sided cortical freeze injury. ICP, CBF, and physiological variables were monitored for up to 6 h postinsult. The preinjury (control) right hemispheric ICP was 8 +/- 5 mm Hg (mean +/- SD) and left hemispheric ICP was 5 +/- 2 mm Hg. Postinjury observations were classified into low (less than 15 mm Hg) and high ICP (greater than or equal to 15 mm Hg) groups. Both right and left ICP values averaged 9 +/- 3 mm Hg in the low ICP group. In the high ICP group, the right ICP was 20 +/- 4 mm Hg and left ICP was 21 +/- 6 mm Hg. ICP was unchanged by Xe inhalation under control conditions as well as in both low and high ICP groups postinjury. Postinjury, the MABP decreased 10-15 mm Hg in the low ICP group and 10-17 mm Hg in the high ICP group 2-3 min after the start of Xe inhalation (p less than 0.05). These results show that 33% Xe inhalation does not increase ICP in fentanyl-anesthetized monkeys but could decrease MABP in stressed states, presumably because of the anesthetic effects of Xe.

Mechanisms of cerebrovascular dilation by ether in monkeys.

We hypothesized that when the depth of ether anesthesia is increased from 2 to 5%, cerebral vessels dilate secondary to circulating catecholamine stimulation of cerebral metabolism. Cerebral blood flow (CBF) by 133Xe clearance and cerebral metabolic rate for oxygen (CMRO2) were measured on 2% and then 5% ether in air in two groups of seven monkeys each during mechanical ventilation. Propranolol, 0.5 mg/kg i.v., was infused over 5 min in one group, and the other received saline. All measurements were repeated on 5% and 2% ether. Cerebrovascular resistance (CVR) fell by 30%, from 2.28 +/- 0.61 (mean +/- SD) to 1.51 +/- 0.28 mm Hg ml-1 100 g-1 min-1 (p less than 0.01), with the increase in ether from 2 to 5%. CBF and CMRO2 were unaltered from values of about 45 ml 100 g-1 min-1 and 2.3 ml 100 g-1 min-1, respectively. During 5% ether anesthesia, propranolol had no effect on CBF, CMRO2, or CVR. On 2% ether, it increased CVR twofold, from 1.5 +/- 0.30 to 3.0 +/- 1.0 mm Hg ml-1 100 g-1 min-1, and decreased CBF by 33%, from 48 +/- 8 to 32 +/- 10 ml 100 g-1 min-1. Plasma epinephrine was two-fold higher on 2% compared to 5% ether, both before and after saline or propranolol infusion. In monkeys, cerebrovascular dilation by ether at 5% compared to 2% is not secondary to catecholamine stimulation of CMRO2. It may result from a direct effect of either plasma catecholamines or ether on the cerebrovasculature.

Detrimental cerebrometabolic effects of hyperoxia in newborn rats.

To investigate the pathogenesis of oxygen toxicity in the newborn brain, we exposed one-day-old Sprague-Dawley albino rats to 100% O(2) and measured whole-brain high-energy phosphates, glucose, lactate, and free fatty acids (FFA) after 0, 15, 30, 60 and 120 min. Whole-brain adenosine triphosphate and creatine phosphate fell significantly from about 4.5 to 2.5 ?mol-mg(?1) protein. Brain lactate remained at about 0.3 ?mol.mg(?1) protein in hyperoxic rats, but increased in normoxic rats, from 0.3 to 1.3 ?mol.mg(?1) protein at 120 min. Total FFA decreased from 30 to 15 nmol.mg(?1) protein during normoxia, but increased to 40 nmol.mg(?1) protein during hyperoxia. Undetectable in normoxic rats, arachidonic acid increased to between 4 and 6 nmol.mg(?1) protein during hyperoxia while oleic acid increased by two to threefold. In normoxia, palmitate decreased by 70% from 12 to 4 nmol.mg(?1) protein whereas in hyperoxia it remained at 10 nmol.mg(?1) protein. Normobaric 100% O(2) has detrimental metabolic effects on the neonatal brain which cannot be attributed to cerebral vasospasm or seizure-induced cerebral anoxia because lactic acidosis was not observed. FFA changes suggest that a likely explanation is membrane lipid peroxidation from O(2)-induced free radicals.

Comparison of the effects of succinylcholine and atracurium on intracranial pressure in monkeys with intracranial hypertension.

The effects of succinylcholine (1.5 mg X kg-1 IV) administered five minutes after a defasciculating dose of curare (0.05 mg X kg-1 IV), were compared with the effects of atracurium (0.5 mg X kg-1 IV) on intracranial pressure (ICP) in 13 cynomolgus monkeys with intracranial hypertension (ICP approximately 25 mmHg). Neither succinylcholine nor atracurium increased ICP during general anaesthesia with 60 per cent N2O/O2, 0.5-1 per cent halothane. During a rapid sequence induction and intubation with thiopentone 5 mg X kg-1 IV, ICP increased equally with intubation following both atracurium (25 +/- 1 to 32 +/- 2 mmHg) and succinylcholine (25 +/- 1 to 31 +/- 2 mmHg) (p less than 0.05). Intubation was also associated with significant increases in PaCO2, CVP and MAP. We conclude that in this primate model of intracranial hypertension, neither atracurium nor succinylcholine (when given following a defasciculating dose of curare) elevates ICP. In terms of the elevation of ICP associated with intubation, atracurium was found to offer no advantage over succinylcholine.

Noradrenalin-inducible cyclic-AMP accumulation in rat cerebral cortex: changes during complete global ischemia.

Neurologic dysfunction after cerebral ischemic insults may be due not only to neuronal death, but also to a possibly reversible failure in synaptic transmission. Because noradrenaline (NA)-inducible cyclic-AMP (cAMP) accumulation in brain may reflect the integrity of synaptic transmission mechanisms and brain viability, we studied its changes in cerebral cortex after various durations of decapitation ischemia. Unanesthetized rats were decapitated and the brains were kept at 37 degrees C for times ranging from 0 to 60 min. Cerebral cortical slices were incubated in vitro and NA (11.2 microM)-induced cAMP accumulation was evaluated over 10 min. At 0 min of ischemia, NA-induced cAMP accumulation was 56 pmol/mg protein/10 min. Between 0 and 20 min of ischemia, a linear eightfold increase, to 435 +/- 49 pmol/mg protein/10 min, occurred in NA-induced cAMP accumulation, with no further increase after longer durations of ischemia. The mechanisms modulating the increase in cortical NA-inducible cAMP accumulation with a maximum response after 20 min of ischemia remain to be defined.

Brain cyclic-AMP and possible mechanisms of cerebrovascular dilation by anesthetics in rats.

Barbiturates decrease both cerebral metabolic rate (CMR) and cerebral blood flow (CBF) and thereby preserve CBF and CMR coupling. However, many inhalation agents and ketamine uncouple CBF and CMR by virtue of inducing disproportionate increases in CBF. Adenosine 3',5'-monophosphate (cyclic-AMP) reportedly mediates uterine and aortic smooth muscle relaxation by halothane and may also mediate CBF-CMR uncoupling by anesthetics. Therefore, the authors studied the effect of various doses of halothane and ether on brain cyclic-AMP and compared them with the effects of ketamine and pentobarbital anesthesia. Both halothane 1.5 and 2.0 per cent and ether, 2.5 to 7.5 per cent (inspired concentrations) increased whole brain cyclic-AMP above unanesthetized levels (1,046 +/- 75 pmol/g wet brain) in a dose-related manner. Ketamine, 150 mg/kg, ip, increased brain cyclic-AMP twofold, whereas an apparent increase by 60 mg/kg pentobarbital, ip, was not significant. These results show a dose-related effect of ether and halothane on brain cyclic-AMP levels and suggest a causal relationship to their cerebrovasodilatory effects.