Carbon Dioxide and the Cerebral Circulation

Update on bispectral index monitoring.

ObjectiveTo assess the new "Lund therapy" of posttraumatic brain edema, based on principles for brain-volume regulation and improved microcirculation.DesignA prospective, nonrandomized outcome study over a 5-yr period on severely head-injured patients with increased intracranial pressure, comparing

Improved outcome after severe head injury with a new therapy based on principles for brain volume regulation and preserved microcirculation.

Daily and seasonal variation in response to stress in captive starlings (Sturnus vulgaris): corticosterone.

BACKGROUND: The potential adverse effects of ketamine in neurosurgical anesthesia have been well established and involve increased intracranial pressure (ICP) and cerebral blood flow. However, reexamination of ketamine is warranted because data regarding the effects of ketamine on cerebral hemodynamics are conflicting. METHODS: Eight patients with traumatic brain injury were studied. In all patients, ICP monitoring was instituted before the study. Control of ICP (less than 25 mmHg), hemodynamic values, and blood gas tension (partial pressure of carbon dioxide in arterial blood between 35-38 mmHg) was obtained with propofol infusion (3 mg x kg(-1) x h(-1)) and mechanical ventilation. The effects of three doses of ketamine, 1.5, 3, and 5 mg/kg, respectively, on ICP, cerebral perfusion pressure, jugular vein bulb oxygen saturation, middle cerebral artery blood flow velocity, and electric activity of the brain (EEG) were measured. The three doses were administered intravenously at 6-h intervals over 30 s through a central venous line. Systemic and cerebral hemodynamics and end-tidal carbon dioxide were continuously monitored and recorded at 1-min intervals throughout the 30-min study periods. RESULTS: Ketamine, in all three doses studied (1.5, 3, and 5 mg/kg) was associated with a significant decrease in ICP (mean +/- SD: 2 +/- 0.5 mmHg [P < 0.05], 4 +/- 1 mmHg [P < 0.05], and 5 +/- 2 mmHg [P < 0.05]) among the study patients regardless of the ketamine dose used. There were no significant differences in cerebral perfusion pressure, jugular vein bulb oxygen saturation, and middle cerebral artery blood flow velocity. Ketamine induced a low-amplitude fast-activity electroencephalogram, with marked depression, such as burst suppression. CONCLUSIONS: These results suggest that ketamine may not adversely alter cerebral hemodynamics of mechanically ventilated head-trauma patients sedated with propofol. These encouraging results should be confirmed in larger groups of similar patients.

Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation

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 alpha 2-adrenergic agonist (clonidine) and a beta 1-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 arteriovenous difference in oxygen content were measured before and after a bolus dose of clonidine (six patients) and metoprolol (nine patients). Clonidine decreased mean arterial blood pressure and cerebrovascular resistance without affecting other parameters measured. Metoprolol decreased heart rate and mean arterial pressure, but had no effect on the cerebrovascular parameters. The results show that clonidine and metoprolol have no, or only minor, direct influence on local cerebral haemodynamics in severely brain injured patients. This implies that if there is an intracranial pressure reducing effect of these drugs, as suggested, this must be due to other mechanisms, namely a reduction in capillary hydrostatic pressure secondary to decreased arterial blood pressure and heart rate.

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

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 electroencephalographic (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 133Xe 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.

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

At the turn of this century both ether and chloroform were used as anaesthetic agents. However, while Sir Victor Horsley, a British neurosurgeon, preferred chloroform (I) , Harvey Cushing believed that ether was a better choice for neurosurgical procedures ( 2 ) . At that time general anaesthesia was frequently associated with brain protrusion, which led de Martel (3) and later Cushing (4) to recommend that neurosurgery should be carried out under local anaesthesia. However, general anaesthesia for neurosurgical procedures was frequently employed. It is uncertain when N 2 0 was introduced in neuroanaesthesia, but in the late 1940s a combination of N20 barbiturates and trichloroethylene was widely used. N 2 0 possesses advantages superior to most other anaesthetics regarding adjustability of anaesthetic depth and speed of recovery, which is vital in the postoperative surveillance of most neurosurgical patients. Furthermore, since N 2 0 was considered physiologically “inert” with only minor effects on cerebral circulation and metabolism, it became a natural component of anaesthetic gas mixtures during neurosurgical procedures. During the past two decades a substantial amount of information has been presented showing adverse effects of N 2 0 on cerebral blood flow (CBF‘) and intracranial pressure (ICP). Experimental studies using both humans and experimental animals have documented increases in CBF (5-7), cerebral metabolism (CMRO,) (5), and ICP (8, 9). The magnitude of these changes has vaned as a consequence of species differences and interactions with other drugs (10, 11). There is, however, an increasing amount of evidence showing that N 2 0 itself has cerebral vasodilating properties. In a recent study using single photon emission computer-aided tomography (SPECT) after injection of ‘33Xenon (12) administration of a 50% N20, 30% O2 and 20% N2 gas mixture to healthy spontaneously breathing volunteers was associated with a 21% increase in global CBF during normocapnia and an almost identical flow level during hypocapnia. An uneven flow distribution was recorded with increased perfusion mainly in the frontal brain structures, including regions anatomically associated with the limbic system. The mechanism responsible for the cerebrovascular response to N 2 0 is still unclear. Some investigators support the concept of increased cerebral metabolism due to a stimulatory effect by N20, leading to cerebral vasodilation. The uneven flow distribution favouring the frontal parts of the brain and other reports suggesting an increased electrocortical activity in the limbic system during N20 inhalation (1 3) are in line with this theory. Another theoretical explanation for the above mentioned observations is that N 2 0 exerts a direct effect on the cerebral arteries caused by a release of endothelium derived relaxing factor (EDRF‘) from vascular sources, or a direct relaxation of arterial smooth muscle via a nitric oxide resembling mechanism. However, these mechanisms of action seem less plausible since N 2 0 does not influence contractions in isolated human pial arteries (1 2 ) . This in vitro observation does not exclude the possibility that N 2 0 causes liberation of vasoactive substances in vivo as proposed for the rat (4) and in isolated perfused canine brain (1 5). On the other hand, liberation of vasoactive substances would presumably lead to a uniform increase in CBF and therefore not fit with the data suggesting an uneven CBF distribution during N20 inhalation. Today, 150 years after the introduction of N20, we must conclude that further studies are most certainly warranted to clarify the effect of N 2 0 on cerebral circulation and metabolism. However, based on our present knowledge, we can no longer support the use of N 2 0 in patients with reduced intracranial compliance.

Cerebrovascular response to nitrous oxide.

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 micrograms/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. DHE increased cerebrovascular resistance (CVR) by about 20% and significantly reduced ICP in both groups of patients, resulting in unchanged AVDO2. Hyperventilation with preserved CO2-reactivity caused a similar decrease in ICP as by DHE but with a much larger increase in CVR (by 70%) and a substantial increase in AVDO2. Hyperventilation with impaired CO2-reactivity reduced ICP but otherwise had no significant cerebrovascular effects. The study supports the concept that the ICP reducing effect of DHE results more from constriction of the large veins than from arterial vasoconstriction, also implying a relatively smaller risk of ischaemia with DHE than with hyperventilation.

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

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.

K Messeter

Papers

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

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

Cerebrovascular response to nitrous oxide.

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

A porcine model for sequential assessments of cerebral haemodynamics and metabolism