Toshizoh Ishikawa

Cerebral circulation and metabolism in patients with septic encephalopathy

Cerebral circulation and metabolism in septic encephalopathy have not been well documented. The authors measured cerebral blood flow (CBF) and metabolic rate for oxygen (CMRO2) in six patients with septic encephalopathy associated with multiple organ failure (three to five organs). They found that CBF and CMRO2 were significantly lower than awake control values of 46 +/- 2 to 28 +/- 3 mL/100g/min (mean +/- SEM) and 3.1 +/- 0.2 to 1.2 +/- 0.2 mL/100g/min, respectively. Cerebral vascular resistance (CVR) and cerebral circulatory index (CCI:CBF/CMRO2) were significantly higher than the control values of 2.0 +/- 0.1 to 3.0 +/- 0.4 mm Hg/mL/100g/min and 15.1 +/- 0.8 to 24.2 +/- 3.3, respectively. At the time of cerebral circulatory and metabolic measurements, their consciousness varied between 4 and 10 as evaluated by the Glasgow coma scale. The electroencephalogram showed diffuse slow wave activity and the latency of the auditory brain stem evoked response was prolonged in four of six patients. Computed brain tomography showed either no abnormality or mild atrophy. It is concluded that CBF and CMRO2 are disproportionally decreased during septic encephalopathy in association with dysfunction of the CNS and decreased electrical activity.

Local Cerebral Glucose Utilization during Nitrous Oxide and Pentobarbital Anesthesia in Rats

Local cerebral glucose utilization was measured in rats during nitrous oxide and pentobarbital anesthesia, using the 2-[14C]-deoxyglucose method. During nitrous oxide anesthesia, 67%, marked heterogeneity of glucose utilization was observed. During pentobarbital anesthesia (30 mg/kg), glucose utilization decreased, the decrease being pronounced in the structures where glucose utilization was high during nitrous oxide anesthesia. During combined use of nitrous oxide and pentobarbital (30 mg/kg), with an electroencephalogram (EEG) consisting of 4–6 Hz wave superimposed by 10–15 Hz wave, glucose utilization was higher in many brain structures, including the midbrain reticular formation, than that observed during pentobarbital (30 mg/kg) anesthesia alone. With pentobarbital, 125 mg/kg, the EEG became nearly flat and a dose-related decrease in glucose utilization was observed in the cerebral cortices and inferior colliculus but not observed in any other structures. During the combined use of nitrous oxide and pentobarbital (125 mg/kg), the EEG was nearly flat, and no statistically significant differences in glucose utilization were observed as compared with those during pentobarbital (125 mg/kg) anesthesia in any of the structures examined. The results suggest that nitrous oxide and pentobarbital affect local cerebral glucose metabolism differently and that nitrous oxide acts as cerebral metabolic stimulant in the presence of cortical function during pentobarbital anesthesia.

Nicardipine increases cerebral blood flow but does not improve neurologic recovery in a canine model of complete cerebral ischemia

The effects of the calcium entry blocker nicardipine on CBF, CMRO2, and neurologic outcome following 10 min of complete cerebral ischemia were examined in dogs. In CBF and CMRO2 studies, the CBF in the untreated group (seven dogs) and the nicardipine group (seven dogs; 20 μg kg−1 at 30 min postischemia and a subsequent infusion of 2 μg kg−1 min−1 for 90 min) initially increased to 300–400% and then returned to preischemic values at 30 min postischemia. Thereafter the CBF in the untreated group significantly decreased to 50% of preischemic values for the following 90-min period (hypoperfusion), while the CBF in the nicardipine group did not differ from preischemic values. The CMRO2 in both groups decreased to ∼50–80% of preischemic values after 15 min postischemia and did not differ between the groups throughout the study. In neurologic outcome studies, 18 dogs were divided into three groups (of six dogs each): untreated; saline infusion only, posttreated; nicardipine as in CBF and CMRO2 studies, pretreated; nicardipine 20 μg kg−1 at 2 min preischemia and a subsequent infusion of 2 μg kg−1 min−1 from immediately postischemia to 120 min postischemia. Nicardipine treatment initiated either before or after ischemia failed to improve neurologic outcome at 48 h postischemia. Thus, the increase of postischemic global CBF by nicardipine is not accompanied by neurologic recovery in a canine model of complete cerebral ischemia.

Local cerebral glucose utilization in septic rats.

To identify cortical and subcortical structures in the brain which are associated with septic encephalopathy, local cerebral glucose utilization (LCGU) in the 31 discrete regions were evaluated with a quantitative (14C)-2. deoxyglucose autoradiographic method in the septic rat model. Sepsis was produced by cecal ligation and punctures. Forty rats were subjected to behavioral study and divided into two groups (control, n = 15; sepsis, n = 25). Septic rats died within 36 h, and the rats developed behavioral depression, and showed EEG slowing and an increase in pain threshold. The latter was evaluated by a tail flick method within 8 h after the surgical procedures, while control rats did not show significant change in either behaviors or pain threshold. In another study, LCGU was measured when behavioral depression, increase in pain threshold, and EEC slowing developed in the sepsis group (n = 7). In this group, the mean LCGU in auditory and parietal cortices, lateral geniculate, superior colliculus, hippocampus, and locus ceruleus was 95, 74, 67, 69, 72, and 53 μmol.100 g−1. min−1, being lower by 23%, 22%, 18%, 19%, 14%, and 27% than that in the sham-operated control group (n = 7), respectively. However, the mean LCGU in septal and raphe nuclei was 52 and 84 μmol.100 g−1. min−1, being significantly higher by 27% and 33% than that in the control group, respectively. These results suggest that septic encephalopathy is associated with metabolic changes in the discrete brain regions, which are related to the serotonergic or noradrenergic system. (Crit Care Med 1990; 18:423)

Cerebral Circulatory and Metabolic Stimulation with Nitrous Oxide in the Dog Reconfirmation by the Simultaneous Measurement of Ckrebral Blood Flow using Direct and Kety‐Schmidt Methods

In both the presencc and the absence of nitrous oxide (57%, end‐tidal), cerebral blood flow (CBF) was measured by a direct method in dogs, and compared to an indirect method (Kety‐Schmidt method), using argon as the tracer. Eighteen comparisons were made in five dogs at flows ranging from 45 to 123 ml per 100 g per minute. There was no systematic difference in CBF between the direct and indirect mcthods, and the ratio of direct CBF to indirect CBF was 1.03. The cerebral circulatory and metabolic stimulation effect of N2O in the dog was reconfirmrd.

Responses of EEG, cerebral oxygen consumption and blood flow to peripheral nerve stimulation during thiopentone anaesthesia in the dog.

The effects of sciatic nerve stimulation on the electroencephalogram (EEG), cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) were investigated during thiopentone anaesthesia in dogs. Anaesthetic levels at 15, 35, 65, 95 and 125 minutes after the start of thiopentone infusion (23 mg.kg-1.hr-1) were designated levels I, 11, III, IV and V, respectively. The effects of stimulation for 5 min were tested at each level. At level 1 (plasma thiopentone concentration; 15 ± 2 μg.ml-1), the EEG was activated with stimulation and CMRO2 and CBF increased by a maximum of 16 and 15 per cent, respectively. The increase in CMRO2 and CBF was significant for five and four minutes, respectively, though the increase became less with time. At level II (27 ±3 μg.ml-1), the CMRO2 and CBF increased at one minute by eight and nine per cent, the increase being accompanied by transient EEG activation. At the three deepest levels III, IV and V (37 ± 6, 42 ± 6, 49 ± 6 μg.ml-1). the EEG, CMRO2 and CBF remained unchanged with stimulation. The results suggest the existence of the tight coupling between the EEG, CMRO2 and CBF and of a threshold level of thiopentone to block the response to peripheral stimulation during thiopentone anaesthesia.RésuméLes effets de la stimulation du nerf sciatique sur l’électroencéphalogramme (EEG), consommation d’oxygène par le cerveau (CMRO2) ainsi que le flot cérebral (CBF) ont été investigués lors de l’ anesthésie au thiopentone chez les chiens. Les niveaux d’ anesthésie à 15,35,65,95 et 125 minutes après le début de la perfusion du thiopentone (23 mg-kg-1-hr1) ont été définis comme étant les niveaux I, II, III, IV et V. Les effets d’une stimulation de cinq minutes ont été étudiés à chaque niveau. Au niveau I (concentration plasmatique de thiopentone; 15±2 µg.ml-1), IéEEG a été activeé par la stimulation et la CMRO2 et le CBF ont augmenté de 16 et 15 pour cent respectivement. L’augmentation de la CMRO2 et du CBF a été significative pour cinq et quatre minutes respectivement même si l’augmentation a diminué avec le temps. Au niveau II (27 ± 3 µg.ml-1), le CMRO2 et le CBF ont augmente a une minute de huit et neuf pour cent, I’augmentation étant accompagnée par une activation transitoire de I’EEG. Aux trois niveaux les plus profonds III, IV et V (37 ± 6, 42 ± 6, 49 ± 6µg.ml-1), I’EEG, la CMRO2 et le CBF sont restés inchangés avec la stimulation. Les résultats suggèrent une liaison étroite entre I’EEG, la CMRO2 et le CBF ainsi que les niveaux du thiopentone qui bloqueraient la réponse à une stimulation périphérique.

CO2 Responses of the Cerebral Circulation During Drug-Induced Hypotension in the Cat

Concern has often been expressed that hypocapnia produced by controlled hyperventilation might further reduce cerebral perfusion during drug-induced hypotension. In the present studies, hypotension was induced in cats with either practolol/trimetaphan (five experiments) or practolol/nitroprusside (five experiments) together with controlled haemorrhage. Arterial Pco2 was altered between 17 and 51 mm Hg by varying inspired CO2 during constant-volume ventilation, first during control conditions of light halothane/nitrous oxide anaesthesia and then during hypotension to mean blood pressure of 36–37 mm Hg. Cerebral cortical perfusion was measured by the krypton clearance technique and pial artery diameter by the image-splitting method. Cerebral cortical blood flow did not alter with Paco2 changes during trimetaphan hypotension, but some responsiveness to CO2 persisted during nitroprusside hypotension, though at less than half control levels. No changes in pial artery diameter were seen with CO2 during hypotension under either technique. It is postulated that CO2 responsiveness persisted with nitroprusside because cerebral blood flow (CBF) values were higher when hypotension was produced with this drug, as compared with trimetaphan. It would appear that hypocapnia does not further reduce CBF during trimetaphan hypotension but does do so with nitroprusside. However, the combination of hypocapnia and nitroprusside hypotension did not in any instance lower CBF below the values found during trimetaphan hypotension.

Blood-brain barrier function following drug-induced hypotension in the dog.

To examine the effects of hypotension induced either with trimethaphan (TMP) or nitroprusside (NTP) on blood-brain barrier (BBB), penetration of Evans blue (EB) was observed in dogs anesthetized with halothane. Dogs given TMP were divided into two groups: Group 1, seven dogs rendered hypotensive to mean cerebral perfusion pressure (CPP) of 45 mmHg for 45 min and then of 30 mmHg for 45 min; Group 2, three dogs examined 3 days after arterial hypotension identical to that in Group 1. Dogs given NTP were divided into four groups: Group 1, seven dogs rendered hypotensive with NTP (at dose < 1 mg/kg) identical to the TMP-Group 1; Group 2, three dogs examined as the TMP-Group 2; Group 3, seven dogs rendered hypotensive to CPP 45 mmHg for 45 min; Group 4, seven dogs rendered hypotensive with NTP (at dose > 1 mg/kg) identical to the NTP-Group 1. In all dogs, the dorsal cortical surface and standardized serial coronal sections were examined for evidence of EB penetration. The mean EB penetration score (±SEM) for TMP-Groups 1 and 2 was 12 ± 6, 0 ± 0, respectively, and for NTP-Groups 1, 2, 3, and 4 was 105 ± 14, 30 ± 7, 6 ± 6, and 125 ± 26, respectively. These results suggest that dysfunction of the BBB in the NTP group was more pronounced than in the TMP group.

Epidural Bupivacaine Suppresses Local Glucose Utilization in the Spinal Cord and Brain of Rats

Using the 2-[14C]deoxyglucose method, the effects of analgesic doses of epidural bupivacaine (300 micrograms) on local spinal cord glucose utilization (SP-LGU) of the cervical, thoracic, and lumbar regions and local cerebral glucose utilization (BR-LGU) in 38 brain structures were examined in conscious rats. In addition, the effects of intramuscular bupivacaine (300 micrograms) and the spinal cord transection (T2) were examined to determine whether the induced metabolic changes, if any, are related to the drugs systemic effect and/or deafferentation. Lumbar epidural bupivacaine sufficient to produce analgesia decreased SP-LGU in the thoracic (18-28%) and lumbar (21-29%) spinal cord but not in the cervical cord. Epidural bupivacaine decreased BR-LGU (15-26%) in 35 of 38 structures examined. With intramuscular bupivacaine, SP-LGU remained unchanged in almost all regions, while BR-LGU was significantly decreased (11-23%) in 23 structures. Plasma concentrations of bupivacaine in the epidural and intramuscular groups were comparable. With spinal cord transection alone, SP-LGU significantly decreased with varying degrees depending on the structure examined, but BR-LGU did not decrease in 36 of 38 structures examined. These results indicate that analgesic doses of epidural bupivacaine decrease SP-LGU, probably reflecting decreased neuronal activity of the spinal cord, and that reduced BR-LGU by epidural bupivacaine is most likely due to the drugs systemic effect rather than deafferentation.

Effects of Dichloroacetate on Survival Rate, Brain ATP, Lactate, and Water Content Following Cerebral Ischemia in Spontaneously Hypertensive Rats

Previous reports have demonstrated that brain acidosis associated with the accumulation of lactate may aggravate ischemic-hypoxic brain damage [1,2]. Therefore, measures preventing or attenuating lactate accumulation may be protective against the ischemic brain damage. Dichloroacetate (DCA) is known to activate the pyruvate dehydrogenase (PDH) complex in various tissues in vitro by inhibiting PDH kinase [3] and to reduce serum levels of lactate and pyruvate by its action on PDH [4]. A recent in vivo investigation revealed that DCA significantly lowered the lactate and glucose concentrations of the brain [5] and that it has therapeutic potential in brain ischemia. Subsequently, Biros and colleages [6–8] have demonstrated that the increase in brain lactate content following incomplete ischemia was reduced by both pre- and post-treatment with DCA. However, the effect of DCA on the neurological outcome of animals subjected to brain ischemia has not been investigated.