Carlo Ori

Clinical anesthesia causes permanent damage to the fetal guinea pig brain.

Exposure of the immature brain to general anesthesia is common. The safety of this practice has recently been challenged in view of evidence that general anesthetics can damage developing mammalian neurons. Initial reports on immature rats raised criticism regarding the possibly unique vulnerability of this species, short duration of their brain development and a lack of close monitoring of nutritional and cardiopulmonary homeostasis during anesthesia. Therefore, we studied the neurotoxic effects of anesthesia in guinea pigs, whose brain development is longer and is mostly a prenatal phenomenon, so that anesthesia‐induced neurotoxicity studies of the fetal brain can be performed by anesthetizing pregnant female pigs. Because of their large size, these animals made invasive monitoring of maternal and, indirectly, fetal well‐being technically feasible. Despite adequate maintenance of maternal homeostasis, a single short maternal exposure to isoflurane, whether alone or with nitrous oxide and/or midazolam at the peak of fetal synaptogenesis, induced severe neuroapoptosis in the fetal guinea pig brain. As detected early in post‐natal life, this resulted in the loss of many neurons from vulnerable brain regions, demonstrating that anesthesia‐induced neuroapoptosis can cause permanent brain damage.

General Anesthesia Causes Long-Lasting Disturbances in the Ultrastructural Properties of Developing Synapses in Young Rats

Common general anesthetics administered to young rats at the peak of brain development cause widespread apoptotic neurodegeneration in their immature brain. Behavioral studies have shown that this leads to learning and memory deficiencies later in life. The subiculum, a part of the hippocampus proper and Papez’s circuit, is involved in cognitive development and is vulnerable to anesthesia-induced developmental neurodegeneration. This degeneration is manifested by acute substantial neuroapoptotic damage and permanent neuronal loss in later stages of synaptogenesis. Since synapse formation is a critical component of brain development, we examined the effects of highly neurotoxic anesthesia combination (isoflurane, nitrous oxide, and midazolam) on ultrastructural development of synapses in the rat subiculum. We found that this anesthesia, when administered at the peak of synaptogenesis, causes long-lasting injury to the subicular neuropil. This is manifested as neuropil scarcity and disarray, morphological changes indicative of mitochondria degeneration, a decrease in the number of neuronal profiles with multiple synaptic boutons and significant decreases in synapse volumetric densities. We believe that observed morphological disturbances of developing synapses may, at least in part, contribute to the learning and memory deficits that occur later in life after exposure of the immature brain to general anesthesia.

RESEARCH ARTICLE: Clinical Anesthesia Causes Permanent Damage to the Fetal Guinea Pig Brain

Exposure of the immature brain to general anesthesia is common. The safety of this practice has recently been challenged in view of evidence that general anesthetics can damage developing mammalian neurons. Initial reports on immature rats raised criticism regarding the possibly unique vulnerability of this species, short duration of their brain development and a lack of close monitoring of nutritional and cardiopulmonary homeostasis during anesthesia. Therefore, we studied the neurotoxic effects of anesthesia in guinea pigs, whose brain development is longer and is mostly a prenatal phenomenon, so that anesthesia‐induced neurotoxicity studies of the fetal brain can be performed by anesthetizing pregnant female pigs. Because of their large size, these animals made invasive monitoring of maternal and, indirectly, fetal well‐being technically feasible. Despite adequate maintenance of maternal homeostasis, a single short maternal exposure to isoflurane, whether alone or with nitrous oxide and/or midazolam at the peak of fetal synaptogenesis, induced severe neuroapoptosis in the fetal guinea pig brain. As detected early in post‐natal life, this resulted in the loss of many neurons from vulnerable brain regions, demonstrating that anesthesia‐induced neuroapoptosis can cause permanent brain damage.

The abolishment of anesthesia-induced cognitive impairment by timely protection of mitochondria in the developing rat brain: the importance of free oxygen radicals and mitochondrial integrity

Early exposure to general anesthesia (GA) causes developmental neuroapoptosis in the mammalian brain and long-term cognitive impairment. Recent evidence suggests that GA also causes functional and morphological impairment of the immature neuronal mitochondria. Injured mitochondria could be a significant source of reactive oxygen species (ROS), which, if not scavenged in timely fashion, may cause excessive lipid peroxidation and damage of cellular membranes. We examined whether early exposure to GA results in ROS upregulation and whether mitochondrial protection and ROS scavenging prevent GA-induced pathomorphological and behavioral impairments. We exposed 7-day-old rats to GA with or without either EUK-134, a synthetic ROS scavenger, or R(+) pramipexole (PPX), a synthetic aminobenzothiazol derivative that restores mitochondrial integrity. We found that GA causes extensive ROS upregulation and lipid peroxidation, as well as mitochondrial injury and neuronal loss in the subiculum. As compared to rats given only GA, those also given PPX or EUK-134 had significantly downregulated lipid peroxidation, preserved mitochondrial integrity, and significantly less neuronal loss. The subiculum is highly intertwined with the hippocampal CA1 region, anterior thalamic nuclei, and both entorhinal and cingulate cortices; hence, it is important in cognitive development. We found that PPX or EUK-134 co-treatment completely prevented GA-induced cognitive impairment. Because mitochondria are vulnerable to GA-induced developmental neurotoxicity, they could be an important therapeutic target for adjuvant therapy aimed at improving the safety of commonly used GAs.

Lipid emulsion is superior to vasopressin in a rodent model of resuscitation from toxin-induced cardiac arrest

Objectives:Lipid emulsion infusion is an emerging antidotal therapy for toxin-induced cardiac arrest. To compare the efficacy of resuscitation from bupivacaine-induced asystole using lipid emulsion infusion vs. vasopressin, alone and with epinephrine. Design:Prospective, randomized, animal study. Setting:University research laboratory. Subjects:Adult, male Sprague-Dawley rats. Interventions:Instrumented rats were given an intravenous bolus of 20 mg/kg bupivacaine to induce asystole (zero time). Rats (n = 6 for all groups) were ventilated with 100% oxygen, given chest compressions, and randomized to receive 30% lipid emulsion (L, 5 mL/kg bolus then 1.0 mL/kg/min infusion) and vasopressin 0.4 U/kg bolus alone (V) or combined with epinephrine, 30 &mgr;g/kg (V + E); boluses (L, V, or V + E) were repeated at 2.5 and 5 minutes for a rate–pressure product (RPP) less than 20% baseline. Measurements and Main Results:The arterial blood pressure and electrocardiogram were measured continuously for 10 minutes when blood was drawn for arterial blood gas analysis, lactate content, and central venous oxygen saturation (ScvpO2). Hemodynamic parameters of the L group at 10 minutes (30,615 ± 4782 mm Hg/min; 151 ± 19.1 mm Hg; 197 ± 8.6 min−1; RPP, systolic blood pressure and heart rate, respectively) exceeded those of the V group (5395 ± 1310 mm Hg/min; 85.8 ± 12 mm Hg; 61 ± 10.8 min−1) and the V + E group (11,183 ± 1857 mm Hg/min−1; 75.5 ± 12.9 min−1, RPP and heart rate, respectively; systolic blood pressure was not different). Metrics indicated better tissue perfusion in the L group (7.24 ± 0.02; 83% ± 3.5%; 2.2 ± 0.36 mmol/L; pH, ScvpO2, lactate, respectively) than V (7.13 ± 0.02; 29.9% ± 4.4%; 7.5 ± 0.6 mmol/L) and V + E groups (7.07 ± 0.03; 26.2% ± 8.9%; 7.7 ± 1 mmol/L). Wet-to-dry lung ratios in V (8.3 ± 0.6) and V + E (8.7 ± 0.2) were greater than that in the L group (6.2 ± 05) (mean ± sem; p < 0.05 for all shown results). Conclusions:Lipid emulsion in this rat model provides superior hemodynamic and metabolic recovery from bupivacaine-induced cardiac arrest than do vasopressors. Systolic pressure was not a useful metric in the vasopressor groups. Vasopressin was associated with adverse outcomes.

A short review of cognitive and functional neuroimaging studies of cholinergic drugs: implications for therapeutic potentials

Summary. In the last 20 years a cholinergic dysfunction has been the major working hypothesis for the pharmachology of memory disorders. Cholinergic antagonists and lesions impair and different classes of cholinomimetics (i.e. acetylcholine precursors, cholinergic agonists and acetylcholinesterase inhibitors) enhance attention and memory in experiment animals, healthy human subjects and Alzheimer disease patients. In addition, acetylcholinesterase inhibitors improve different cognitive (i.e. visuospatial and verbal) functions in a variety of unrelated disorders such as dementia with Lewy bodies, Parkinson disease, multiple sclerosis, schizoaffective disorders, iatrogenic memory loss, traumatic brain injury, hyperactivity attention disorder and, as we recently reported, vascular dementia and mild cognitive impairment. In animals, different cholinomimetics dose-dependently increased regional cerebral metabolic rates for glucose (rCMRglc) and regional blood flow (rCBF), two indices of neuronal function, more markedly in subcortical regions (i.e. thalamus, hippocampus and visual system nuclei). In both healthy human subjects and Alzheimer disease patients acetylcholinesterase inhibitors increased rCMRglc and rCBF in subcortical and cortical brain regions at rest but attenuated rCBF increases during cognitive performances. Hence, acetylcholinesterase inhibitors may enhance cognition and rCMRglc by acting primarily on subcortical regions that are involved in attentional (i.e. thalamus) and memory (i.e. hippocampus) processes; such an effect probably is not specific for Alzheimer disease and can be beneficial in patients suffering from a wide array of neuropsychiatric disorders.

The effects of propofol anesthesia on local cerebral glucose utilization in the rat.

The autoradiographic 14C-2-deoxy-D-glucose method was used to determine local cerebral glucose utilization (LCGU) during propofol anesthesia and recovery in 52 regions of the rat brain. Control rats intravenously received 5 ml.kg-1.h-1 of the egg-oil-glycerol emulsion that constitutes the vehicle for propofol. Anesthetized animals received an iv bolus of propofol (20 mg/kg) followed by continuous infusion of the anesthetic at 12.5, 25, or 50 mg.kg-1.h-1 for 1 h prior to injection of 14C-2-deoxy-D-glucose and for the following 45 min. In addition, a fifth group of animals were studied immediately after awakening from a 20 mg/kg bolus of propofol as indicated by the first reappearance of head lift. All rats were spontaneously breathing room air throughout the experimental procedure. The general pattern of the cerebral metabolic response to propofol anesthesia was a dose-related, widespread depression of LCGU. At the three infusion rates of propofol tested, overall mean LCGU was reduced by 33%, 49%, and 55%, respectively, and significant decreases were observed in 60%, 85%, and 90% of the regions assayed. These effects were rapidly reversible, since in the recovery group, LCGU returned to near control values in the majority of the brain areas. Although all of the anatomofunctional systems (sensorimotor, extrapyramidal, limbic, and reticular) were involved, forebrain structures showed a greater sensitivity to the depressant action of propofol than did hindbrain regions.(ABSTRACT TRUNCATED AT 250 WORDS)

Timing versus duration: Determinants of anesthesia-induced developmental apoptosis in the young mammalian brain

Rapidly accumulating evidence indicates that clinically used general anesthesia causes massive, widespread neuroapoptotic degeneration in the developing mammalian brain. Susceptibility to anesthesia‐induced neurotoxicity has been documented in rats, mice, guinea pigs, primates, and in this study, piglets; in short, anesthesia‐induced developmental neuroapoptosis is not species‐dependent. Our findings with piglets, like those in other immature mammals, demonstrate that relatively short exposure to anesthesia is just as detrimental to species with long periods of synaptogenesis as it is to those with short periods of synaptogenesis. However, the highly reproducible findings in different species also indicate that the timing of exposure to anesthesia is critically important; that is, brain regions that are at the peak of synaptogenesis are most vulnerable even when the exposure to anesthesia is relatively brief. Because the peak of synaptogenesis is characterized by intense, highly programmed neuronal communication that is vital for the survival and proper function of immature neurons, we conclude that anesthesia causes severe disturbances in the fine equilibrium between excitatory and inhibitory neurotransmission in the developing mammalian brain, ultimately leading to neuronal redundancy and death.

Complications of non-invasive ventilation techniques: a comprehensive qualitative review of randomized trials

Non-invasive ventilation (NIV) has become a common treatment for acute and chronic respiratory failure. In comparison with conventional invasive mechanical ventilation, NIV has the advantages of reducing patient discomfort, procedural complications, and mortality. However, NIV is associated with frequent uncomfortable or even life-threatening adverse effects, and patients should be thoroughly screened beforehand to reduce potential severe complications. We performed a detailed review of the relevant medical literature for NIV complications. All major NIV complications are potentially life-threatening and can occur in any patient, but are strongly correlated with the degree of pulmonary and cardiovascular involvement. Minor complications can be related to specific structural features of NIV interfaces or to variable airflow patterns. This extensive review of the literature shows that careful selection of patients and interfaces, proper setting of ventilator modalities, and close monitoring of patients from the start can greatly reduce NIV complications.

Effects of isoflurane anesthesia on local cerebral glucose utilization in the rat.

The effect of isoflurane anesthesia on local rate of glucose utilization was investigated in the rat brain by means of the autoradiographic 14C-2-deoxyglucose method. Local cerebral glucose utilization (LCGU) was measured in 26 neuroanatomic structures of awake and isoflurane-anesthetized rats. Isoflurane anesthesia (1.5% inspired) caused both increases and decreases in LCGU. Significant reductions were found in all cortical areas examined and in primary sensory relay nuclei of central visual and auditory pathways. Among regions of the extrapyramidal motor system, LCGU was increased in substantia nigra pars compacta, and decreased in cerebellum, red nucleus, and ventral thalamus. Large increases in LCGU were observed in some structures of the limbic system such as the medial habenulo-interpeduncular system and the CAs field of hippocampus. LCGU was significantly reduced by isoflurane in the CA1-CA2 field and dentate gyrus of hippocampus. These results are similar to previous findings on the LCGU response to other inhaled and intravenous anesthetics and further confirm the regional specificity of the effects of anesthetics on brain metabolism.