Kenneth Messeter

Effects of hypotensive treatment with α2‐agonist and β1‐antagonist on cerebral haemodynamics in severely head injured patients

Therapy of post‐traumatic brain oedema often includes preservation of high arterial blood pressure to avoid secondary ischaemic injuries to the brain. This practice can be questioned since high arterial blood pressure may aggravate brain oedema through raised hydrostatic capillary pressure, causing fluid filtration across the damaged blood‐brain barrier. This latter view is in agreement with our clinical experience and therefore hypotensive therapy with an α2‐adrenergic agonist (clonidine) and a β1‐adrenergic antagonist (metoprolol) has become part of our treatment protocol for severely head injured patients to decrease the post‐traumatic brain oedema. The present study is an attempt to analyse whether there are any direct local cerebrovascular effects of the hypotensive agents used, which also might influence intracranial pressure. Severely head injured patients were investigated. Heart rate, mean arterial blood pressure, intracranial pressure, cerebral blood flow and arterio‐venous difference in oxygen content were measured before and after a bolus dose of clonidine (six patients) and metoprolol (nine patients).

Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig

There are still divergent opinions regarding the pharmacodynamic effects of ketamine on the brain. In this study, the cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRo2) and electroencephalogra‐phic (EEG) activity were sequentially assessed over 80 min in 17 normoventilated pigs following rapid i.v. infusions of anaesthetic (10.0 mg‐kg‐1; n = 7) or subanaesthetic (2.0 mg‐kg‐1; n = 7) doses of ketamine or of its major metabolite norketamine (10.0 mg‐kg‐1; n = 3). The animals were continuously anaesthetized with fentanyl, nitrous oxide and pancuronium. CBF was determined by the intra‐arterial mXe technique. Ketamine (10.0 mg‐kg‐1) induced an instant, gradually reverting decrease in CBF, amounting to ‐26% (P<0.01) at 1 min and ‐13% (P<0.05) at 10 min, a delayed increase in CMRo2 by 42% (P<0.01) at 10 min and a sustained rise in low‐ and intermediate‐frequency EEG voltage by 87% at 1 and 97% at 10 min (P<0.0001). It is concluded that metabolically formed norketamine does not contribute to these effects. Considering the dissociation of CBF from CMRo2 found 10–20 min after ketamine (10.0 mg‐kg‐1) administration, it is suggested that ketamine should be used with caution for anaesthesia in patients with suspected cerebral ischaemia in order not to increase the vulnerability of brain tissue to hypoxic injury. Ketamine (2.0 mg‐kg‐1) had no significant effects on CBF, CMRo2 or EEG. It therefore seems that up to one fifth of the minimal anaesthetic i.v. dose can be used safely for analgesia, provided that normocapnaemia is preserved.

Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow

Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF)by one third, as measured by intermittent133Xewashout. By means of pharmacodynamic models, the effects on the CBFcould be predicted from the arterial drug concentrations. The high-resolution CBFvs. time curves thus generated allowed the calculation of cerebral drug levels from arteriovenous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF,ketamine and midazolam decreasetheir own rateof transport to the brain, the immediate 30-35% drops in CBFgiving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBFis determined mainly by the effects of the anesthetics and by the arterial CO2tension. CBFchanges in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.

Cerebral haemodynamic effects of dihydroergotamine in patients with severe traumatic brain lesions

Dihydroergotamine (DHE) is used in our recently introduced therapy of post‐traumatic brain oedema and is suggested to reduce ICP through reduction in both cerebral blood volume and brain water content. This study aims at increasing our knowledge of the mechanisms behind the ICP reducing effect of DHE by analysing cerebrovascular effects of a bolus dose of DHE in severely head injured patients (GCS<8). Mean hemispheric cerebral blood flow (CBF) calculated from the clearance of i.v. 133Xenon, ICP, and cerebral arterio‐venous difference in oxygen content (AVDO2), were measured before and after hyperventilation and after a bolus dose of DHE (4 μg/kg). The patients were divided into two groups, one with preserved and one with impaired cerebrovascular CO2‐reactivity to hyperventilation, the latter being predictive of poor outcome. The haemodynamic effects of DHE were compared to those of hyperventilation. Regional CBF and brain volume SPECT measurements were performed in two patients.

A porcine model for sequential assessments of cerebral haemodynamics and metabolism

We present a physiologically stable porcine model designed for sequential assessments of pharmacological effects on mean hemispheric cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) at sustained normocapnia. The dynamic influence of continuously administered fentanyl (0.040 mg ˙ kg‐1 ˙ h‐1 i.v.), nitrous oxide (70%) and pancuronium (0.30 mg ˙ kg‐1 ˙ h‐1 i.v.) on these variables was studied in eight normoventilated pigs. CBF was reliably assessable at 10‐min intervals by clearance of intra‐arterially injected 133Xe, monitored by an extracranial scintillation detector. CMRo2 was calculated from CBF and the simultaneously measured cerebral arteriovenous difference in blood oxygen content. The intracerebral distribution of a contrast medium injected into the external and internal carotid arteries was studied by angiography, and the cerebral venous outflow was investigated by measurements of the distribution of an intra‐arterially administered non‐diffusible tracer, [99mTc]pertechnetate, to the internal and external jugular veins. After a 3‐h equilibration period, CBF and CMRo2 were determined on six occasions over a study period lasting 1 h 40 min. The mean ranges of these variables were 56–60 and 1.9–2.0 ml ˙ 100 g‐1 ˙ min‐1, respectively. We conclude that the model enables repeated assessments of CBF and CMRo2 under stable physiological background conditions and thus valid cerebral pharmacodynamic investigations of drugs given for anaesthesia.

Low-dose midazolam antagonizes cerebral metabolic stimulation by ketamine in the pig

In order to test the hypothesis that low‐dose midazolam reduces excitatory cerebral symptoms by attenuating ketamine‐induced increases in the cerebral metabolic rate for oxygen (CMRo2), we compared the cerebral effects of a combination of an anaesthetic dose of ketamine hydrochloride (10.0 mg‐kg1 i.v.) and a subanaesthetic dose of midazolam maleate (0.25 mg‐ kg‐1 i.v., n = 6; or 0.10 mg‐kg‐1 i.v., n = 6) with results recently obtained with ketamine (10.0 mg‐kg‐1 i.v.) in normoventilated pigs anaesthetized with fentanyl, nitrous oxide and pancuronium. Cerebral blood flow (CBF) was measured with the intra‐arterial 133Xe clearance technique, and CMRo2 was calculated from CBF and the cerebral arteriovenous oxygen content difference (Cavo2). The CMRo2 did not increase significantly. In contrast, the maximal increase in cerebral Cavo2 (by 56–59% at 10 min; P < 0.01) was similar to that induced by ketamine, since CBF was more depressed (by 35–45% at 1 min: P < 0.001) by ketamine‐midazolam than by ketamine only. Midazolam was found to increase CVR (P < 0.01) and further depress CBF (P < 0.01), and to antagonize the ketamineinduced increase in CMRo2 (P < 0.05). Ketamine‐induced effects on mean arterial pressure (MAP) and spectral electroencephalographic (EEG) voltage were not significantly altered by midazolam. The pharmacokinetics of ketamine, as measured during an 80‐min period, were not affected by the concomitant administration of midazolam. We propose that a ketamine‐midazolam combination comprising a low‐dose fraction (1/ 100‐1/40) of midazolam is superior to ketamine alone for anaesthetic use.

Cerebral haemodynamic and electrocortical CO2 reactivity in pigs anaesthetized with fentanyl, nitrous oxide and pancuronium

Cerebral haemodynamic, metabolic and electrocortical reactivity to alterations in arterial CO2, tension (PaCO2) was assessed in seven mechanically ventilated juvenile pigs to test an experimental model designed for cerebral pharmacodynamic and pharmacokinetic studies. The animals were anaesthetized with fentanyl, nitrous oxide and pancuronium and sequentially normo‐ and hyperventilated over a 100‐min period. Five measurements were made at 25‐min intervals. The cerebral blood flow (CBF) was measured with the intraarterial 133Xe technique and the cerebral metabolic rate for oxygen (CMRo2) determined from CBF and the cerebral arteriovenous oxygen content difference. A linear correlation (r = 0.845) was found between CBF and PaCO2. The cerebrovascular reactivity to hypocapnia (ΔCBF/ΔPaCO2) was maintained throughout the experimental period and amounted to (95% confidence interval) 9.1 (7.1–11.1) ml · 100 g‐1 · min‐1 · kPa‐1 within the PaCO2 range 3.3–6.3 kPa. The CMRo2 was not influenced by hyperventilation. The baseline electroencephalographic (EEG) pattern was stable at normocapnia (mean PaCO2 5.6 kPa), whereas spectral values for delta and total average voltage increased significantly (P<0.05) at extensive hypocapnia (3.5 kPa). Maintenance of cerebral CO2 reactivity and spectral EEG voltage at a stable plasma level of fentanyl is complementary to the cerebral haemodynamic and metabolic stability previously found at sustained normocapnia in this model.

Effects of dihydroergotamine on cerebral circulation during experimental intracranial hypertension

Different cerebral vasoconstrictors have recently been suggested for the treatment of raised intracranial pressure (ICP) in patients with severe traumatic brain lesions. Such treatment may be associated with severe side effects. A porcine model simulating an intracranial mass lesion was utilized to examine the haemodynamic cerebral effects of dihydroergotamine (DHE), a recently introduced pharmacological treatment for raised intracranial pressure. Intracranial hypertension was induced by inflation of two tonometric gastric balloons placed extradurally covering the parieto‐occipital region bilaterally. The animals were randomized into one group with six animals receiving 1.0 mg of DHE i.v. followed by a continuous infusion of 0.2 mg/h (high dose) and another group of six animals receiving 0.15 mg i.v. followed by 0.03 mg/h (low dose). Measurements of cerebral blood flow (CBF) and arterio‐venous difference in oxygen content (Cavo2) were performed 5, 20, and 60 min after the DHE infusion. Intracranial pressure (ICP), mean arterial blood pressure (MAP) and cerebral electrical activity (EEG) were recorded continuously.

The effect of thiopental on cerebral blood flow, and its relation to plasma concentration, during simulated induction of anaesthesia in a porcine model

The reversible effect of an induction dose of thiopental on the cerebral blood flow (CBF) was characterized by repeated 133Xe washout measurements during stable physiological conditions in anaesthetized pigs. A thiopental effect corresponding to induction of light and transient anaesthesia was confirmed by electroencephalography (EEG). The concentration (arterial plasma) – effect (– % CBF) relationship of thiopental was estimated using a sigmoidal Emax model. The injection caused a rapid 36 4.5% (means.d.) drop in CBF, with return to baseline by 80 min. According to the pharmacodynamic model, the maximal effect of thiopental (Emax) in this experimental set–up was a 58% lowering of the CBF and the concentration at half–maximal effect (EC50) was 25 μg–ml‐1. This study provides a complete characterization of the effect of thiopental on the CBF, including the time–course and concentration–effect relationship. A comparison to limited data in the literature suggests that the findings in the pigs constitute a fair approximation of the action of thiopental during the clinical induction of anaesthesia.

Acid-Base and Energy Metabolism of the Brain in Hypercapnia and Hypocapnia

The metabolism of brain tissue shows some characteristic and specific features (for details and further references, see MCILWAIN [1966], BACHELARD and MCILWAIN [1969], BALACZ [1970]). Thus the organ is active continuously, and in spite of its small weight it is responsible for about 20% of the resting oxygen consumption of the body. Further, although isolated brain tissues can oxidize a variety of substrates in vitro, only glucose can normally pass the blood-brain barrier with sufficient speed to maintain the energy requirements in vivo. Measurements of arteriovenous differences for glucose, oxygen, and carbon dioxide show that the respiratory quotient is close to unity, thus confirming that glucose is the sole substrate. These measurements show that about 95% of the glucose consumed is oxidized to carbon dioxide. The rest of the glucose (about 5%) appears as an arteriovenous difference for lactate (see COHEN [1971]). However, the arteriovenous balance does not reveal the rapid interconversion of glucose carbon between the tricarboxylic acid cycle and the glutamate group of amino acids. In fact, as much as 30% of the 14C administered in radioactive glucose may label these acids (aspartate, glutamate, glutamine, and λ aminobutyrate), but since an equivalent amount of amino acid carbon is fed into the Krebs cycle the end result is compatible with simple glucose oxidation (ROBERTS et al. [1959], VRBA [1962], see also TOWER [1960], BACHELARD [1965]). The rapid turnover of the glutamate group of amino acids, which is partly specific for the brain, may be related to the fact that some of the acids function as excitatory or inhibitory transmitters.