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The effect of low concentrations of halothane dissolved in saline (equivalent to 0.34% halothane) on the oxygen electrode was examined using a multi-wire Clark type electrode, consisting of eight platinum wires, each of 15 microns tip diameter. On the first exposure of the day to saline equilibrated with halothane in 10% oxygen or air, the output of the oxygen electrode increased by 40% over 56 min. On the second and subsequent exposures the increase in output was much less, but was still 10% greater than the correct values. After immersing the electrode overnight in saline without halothane the high sensitivity to halothane was present again next morning, even if neither membrane nor electrolyte was changed.

The increasing use of shorter-acting hypnotic agents to control intracranial pressure (ICP) following severe head injury has prompted a prospective double-blind controlled trial comparing the efficacy of etomidate and Althesin, given by i.v. infusion. Over the dose ranges used, the two drugs appeared equipotent in decreasing ICP whilst preserving cerebral perfusion pressure. However, in two patients (one in each group) ICP did not respond to hypnotic infusion, a feature noted in other studies to occur in a minority of patients. With the cessation of Althesin manufacture and the discussion about the use of etomidate infusions, it is timely to document the effectiveness of etomidate in decreasing ICP.

A comparison of the blood flow and electrical power and an area of parietal cortex has been made in cats subjected to controlled hypotension induced with either practolol and trimetaphan or practolol and nitroprusside. In both groups it was necessary also to remove blood to achieve the required low values of arterial pressure (AP). It was found that cerebral cortical blood flow was significantly greater at mean AP of 40, 35 and 30 mm Hg during nitroprusside (NTP) as compared with trimetaphan (TMP) hypotension. The total power in the e.e.g. as assessed by the cerebral function monitor (CFM) was less depressed at mean AP 35 and 30 mm Hg during NTP hypotension. Even at mean AP 26 mm Hg with NTP, electrical power, although significantly reduced, was still 66 +/- 3% of control values. Correlation of cortical blood flow with CFM activity indicated that electrical power tended towards zero at flow values of 20-25 ml min-1 per 100 g. It is concluded that, in the parietal cortex of the lightly-anaesthetized cat, cortical blood flow and electrical power are better-maintained when hypotension is induced with NTP than with TMP.

Baboons anesthetized with halothane and N2O/O2 were given an intravenous steroid anesthetic (Althesin; Glaxo Laboratories Ltd., U.K.). The drug bolus was labeled with 99mTc, and the time from central venous injection to peak radioactivity in the brain was designated drug brain arrival (DBA-peak). The electroencephalogram slowed 1.2 +/- 0.9 s after DBA-peak (P greater than 0.2), and approximately 2 s after DBA-peak, internal carotid blood flow (ICarBF) decreased and calculated internal carotid vascular resistance (ICarVR) rose. During this 2-s delay in the cerebrovascular response to the arrival of a cerebral metabolic depressant in the brain, the decrease in mean cortical Pco2 was calculated to be less than 0.26 mmHg from cortical CO2 solubility, and less than 0.32 mmHg from cortical CO2 diffusivity, which indicated that mean cortical Pco2 changes do not control cerebral blood flow (CBF). The unaltered time course of the changes in EEG, ICarBF, and ICarVR after acute cervical sympathectomy and alpha-adrenergic receptor blockade excluded the involvement of the sympathetic nervous system in the vasoconstrictor response. Intracarotid Althesin showed that the cerebral vasoconstriction was not a direct effect of the drug. The postulated link between the effects of Althesin on CBF and cerebral metabolism remains to be elucidated but is probably indirect, involving the brainstem.

Ten patients presenting for carniotomy were studied. Each was anaesthetized with thiopentone or Althesin followed by tubocurarine and the lungs were hyperventilated with nitrous oxide in oxygen. Fentanyl 0.2 mg was administered i.v. and the intracranial pressure (i.c.p.) and mean arterial pressure were recorded continuously for 10 min. At the time of administration of fentanyl nine of the 10 patients were hypocapnic (PaCO2 less than 4 kPa). The changes in i.c.p. were small. Cerebral perfusion pressures less than 50 mm Hg were observed in two patients who had moderate hypotension before the drug was given. We conclude that fentanyl is a valuable agent in the hyperventilation technique in patients with intracranial space-occupying lesions, provided that hypotension is absent.

Baboons anaesthetized with halothane and nitrous oxide in oxygen were given Althesin 0.05 ml kg-1 i.v. Cerebral blood flow (c.b.f.) was measured by an electromagnetic flowmeter and by xenon clearance whilst extracellular fluid (e.c.f.) pH of the parietal cortex was measured with a micro pH electrode. Carotid blood flow (carBF) began to decrease and carotid vascular resistance (carVR) to increase 2.0 s (SEM 0.3) after the slowing of the e.e.g. produced by Althesin, while e.c.f. pH began to change to alkaline 10.5 s (SEM 1.0) after the e.e.g. change. The first statistically significant increase in mean e.c.f. pH occurred 25 s after the Althesin-induced change in the e.e.g. The duration of the changes in carVR and e.c.f. pH were 7 and 5 min respectively. It is concluded that the change in e.c.f. pH cannot have initiated the increase in carVR which followed the cerebral matabolic depression produced by Althesin. The later alkaline shift in e.c.f. pH may, however, have maintained the increased carVR during the duration of cerebral metabolic depression produced by Althesin.

Ten patients with cerebral tumours were anaesthetized with thiopentone, 70% nitrous oxide in oxygen and fentanyl. Ventilation was controlled to give mean PaCO2 4.8 (range 3.6-6.7) kPa. Enflurane 2% was administered and ICP and MAP were recorded continuously for 10-15 min. The changes in ICP were not significant and ranged from -18.5 to 5.5 mm Hg. There were significant decreases in MAP (P less than 0.001) and CPP (P less than 0.001) during the administration of enflurane. In four patients the administration of enflurane had to be terminated prematurely because of a low CPP. Thus, enflurane has very little effect on ICP in patients with cerebral tumours and low concentrations of enflurane can safely be used during anaesthesia for intracranial operations, provided that the arterial pressure is monitored carefully.

The effects of discrete increases in the volume of an artificial space-occupying lesion on intracranial pressures and the systemic circulation were studied in six anaesthetised and artificially ventilated dogs. Each increase in volume, accompanied by an increase in supratentorial intracranial pressure, a decrease in supratentorial perfusion pressure, and an increase in transtentorial pressure gradient, induced alterations in the systemic circulation. There were a decrease in heart rate, marked alterations in the arrhythmia index, and increases in stroke volume and systemic vascular resistance. A period of transient systemic hypertension was noted to accompany each discrete increase in intracranial pressure.

In Leeds a screw device is used to monitor surface subarachnoid pressure following severe head injury. The possibility that such measurements may under-read true intracranial pressure (ICP) has led to the development of an infusion test to confirm free communication with the surface subarachnoid space. The results of 69 infusion tests using 18 devices reveal that the device was reading accurately on 33 of 69 occasions. In 31 of the remaining 36, correction of the problem was possible. Particularly at ICP values exceeding 20 mm Hg the Leeds device may under-read, and possible causes for this are discussed. Reliable readings can usually be obtained using the infusion sequence described.

The effects of some general anaesthetics, for example thiopentone, Althesin (alphaxalone + alphadolone) and ketamine, on cerebral vascular smooth muscle are those which would be expected from their metabolic actions. With other anaesthetics, mainly those administered by inhalation, and especially the volatile agents, cerebral blood flow increases in excess of the metabolic activity, which is usually depressed to varying degrees. During general anaesthesia with any of these agents, responses to changes in arterial Pco2 or blood pressure are maintained. Furthermore, when seizure activity occurs during enflurane administration, there is a flow response to the associated metabolic stimulation. The time course of the flow response to the metabolically depressant drug Althesin has been measured in baboons and shown to be very rapid. Wtih this drug cerebrovascular resistance begins to increase within 2 s of its arrival in the brain. This rapid flow change occurs also after sympathetic denervation. Extracellular fluid pH of the cortex does not alter until after the initiation of the vascular smooth muscle response.

Chest physiotherapy causes increases in intracranial pressure (ICP) in patients with severe head injuries. In mechanically hyperventilated severe head injuries (PaCO2 3.3 - 4 kPa) 50% nitrous oxide in 50% oxygen exacerbated ICP increases associated with chest physiotherapy, while thiopentone and Althesin reduced these changes in ICP.

The effects of hypotension induced by trimetaphan (TMP) or nitroprusside (NTP) together with controlled haemorrhage on cerebral electrical activity, cerebrospinal fluid pressure (CSFP) and systemic circulatory and metabolic variables were measured in 10 mongrel dogs anaesthetized with halothane (end-tidal, 0.88 +/- 0.03%). Induced hypotension was maintained at cerebral perfusion pressure (CPP) of 45 mmHg for 45 min and then at 30 mmHg for 45 min. In five TMP dogs, there were significant decreases in EEG-power and slowing of peak power frequency from the frontal area, but not from the occipital area. The CSFP did not change significantly except for an increase during the induction stage of hypotension. In five NTP dogs, there were no significant changes in EEG-power and peak power frequency throughout the study from either frontal or occipital areas, but CSFP increased significantly. With both drugs, an increase in glucose, lactate and lactate pyruvate ratio (L/P), and a decrease in PaO2 were more pronounced at 30 mmHg than 45 mmHg. With NTP, there were sustained increases in lactate and L/P, even after restoration of arterial pressure. The same magnitude and duration of the decrease in CPP induced by either TMP or NTP produced different effects on cerebral and systemic function.

Intracranial pressure has been measured in 45 patients undergoing neurosurgery during the induction of deliberate hypotension using either sodium nitroprusside or trimetaphan. A statistically significant increase in intracranial pressure (ICP) occurred during the early stages of the infusion of nitroprusside in normocapnic patients. A non-significant increase in ICP was obtained in hypocapnic patients. The mean ICP increased from 6.3 mm Hg to 11.7 mm Hg when the arterial pressure was reduced slightly, but the response in individual patients varied widely (range -1.6 mm Hg to +20.9 mm Hg). When the arterial pressure (BP) had decreased to 70% of the value existing before infusion of nitroprusside, mean ICP returned to control values and thereafter decreased with further reductions in BP. In patients rendered hypotensive with trimetaphan, there was no change in mean ICP but two patients showed moderate increases (+9.3 mm Hg and +5.7 mm Hg). The mechanism of the increase in ICP with nitroprusside is thought to be expansion of the intracranial blood volume as a result of cerebral vasodilatation. Trimetaphan does not usually produce ICP changes except when intracranial compression is severe, for in these circumstances a small change in intracranial blood volume consequent upon autoregulation may trigger an increase in ICP.

CO2 responsiveness of the cerebral circulation has been measured in baboons before, during, and after halothane-induced hypotension. At a systolic blood pressure (BP) of 60 mmHg, C02 responsiveness was abolished, but was maintained at higher levels of BP. After hypotension, CO2 responsiveness returned to control values. Autoregulation to BP increases induced by intravenous noradrenaline was impaired when cerebral perfusion pressure during the hypotensive period had been below 30-40 mmHg. It is concluded that at levels of halothane-induced hypotension commonly employed clinically, CO2 responsiveness of the cerebral circulation may be absent. The return of CO2 responsiveness in the post-hypotensive phase argues in favour of controlled hyperventilation after neurosurgery which has involved induced hypotension.

The conflicting evidence concerning the influence of high-dose steroids on intracranial pressure (ICP) and outcome following severe head injury has led to the institution of the prospective double-blind controlled trial reported here. Severely head-injured patients admitted to intensive care during a 3-year period were randomly allocated to a dexamethasone- or placebo-treated group. Adults in the steroid group received dexamethasone, 50 mg intravenously, as a bolus on admission to the neurosurgical unit, then 100 mg on Days 1, 2, and 3, 50 mg on Day 4, and 25 mg on Day 5 on continuous intravenous infusion. Children received proportionate intravenous dosages calculated on a weight basis. Severity of head injury was assessed from admission Glasgow Coma Scale (GCS) scores and the appearance of the admission computerized tomography scan. Intracranial pressure (ICP) was monitored in all patients from the surface subarachnoid space. Outcome at 6 months was assessed using the Glasgow Outcome Scale. Steroid and placebo groups were similar in terms of admission GCS score, intracranial pathology, incidence of associated injuries, and time interval from injury to admission to intensive care. The ICP generally increased during the first 48 hours of intensive therapy; there was no difference in this trend between the steroid and placebo groups. A poorer outcome was observed in patients with elevated ICP who received steroids. No increase in the incidence of pulmonary, gastrointestinal, or other extracranial complications was seen in the steroid group. The 6-month outcome did not differ between the steroid and placebo groups. No advantage of high-dose dexamethasone on ICP trends or clinical outcome in the treatment of severe head injury has emerged from this study.

In a randomized trial nitrous oxide 50% in oxygen (Entonox) or oxygen 100% was given during chest physiotherapy on 23 occasions to three mechanically ventilated patients with severe head injuries. Intracranial pressure (i.c.p.) increased by 22.7 mm Hg (SD 10.62) during chest physiotherapy with Entonox, compared with 10.5 mm Hg (SD 10.4) with oxygen 100% (P greater than 0.02). A further nine mechanically ventilated patients with severe head injuries were given Entonox without chest physiotherapy. There was a mean increase in i.c.p. of 3.8 mm Hg (SD 2.4) (P less than 0.001) when Entonox was given, and a mean decrease of 4.6 mm Hg (SD 2.8) when the nitrous oxide was withdrawn. End-tidal carbon dioxide concentration showed almost no change during nitrous oxide administration (decrease of 0--0.1%). We conclude that nitrous oxide causes an increase in i.c.p. in patients with severe head injuries and exacerbates the increases in i.c.p. occurring during chest physiotherapy.

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.

Hypotension induced with nitroprusside is compared with the same degree of hypotension produced by trimetaphan in terms of cerebral perfusion, oxygenation and brain electrical activity. It is concluded that in all these respects nitroprusside has advantages over trimetaphan. On the other hand, nitroprusside increases intracranial pressure whilst trimetaphan does not. Both these drugs have a place in hypotension for neurosurgery.

Ten patients with intracranial lesions, anaesthetized with thiopentone and nitrous oxide (70%) in oxygen (30%) received etomidate 0.2 mg kg-1 i.v. Ventilation was controlled in each patient. Intracranial pressure (i.c.p.) and mean arterial pressure (m.a.p.) were recorded. I.c.p. decreased significantly in all patients (0.01 greater than P greater than 0.001). Although PaCO2 decreased during the period of measurement, the extent and time-course of this change suggested that it was not mainly responsible for changes in i.c.p. M.a.p. decreased in most patients, but the decrease was statistically significant only at 3 and 4 min after the administration of etomidate (0.05 greater than P greater than 0.02). The changes in cerebral perfusion pressure (c.p.p.) and heart rate were not clinically or statistically significant. We conclude that etomidate can be used for the induction of anaesthesia in patients with intracranial space-occupying lesions without increasing i.c.p. or seriously reducing c.p.p.

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 less than 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 greater than 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.

Cerebral cortical blood flow, electrical activity, and extracellular fluid (ECF) pH and K+ ion activities were measured in anesthetized cats (0.7% halothane 65% N2O in O2) subjected to hypotension (mean BP 30-32 and 26-28 mmHg), induced by either practolol and trimetaphan (TMP) or practolol and nitroprusside (NTP). Limited blood withdrawal was also necessary to achieve these blood pressure (BP) levels. Cerebral cortical blood flow during hypotension was greater with NTP than with TMP, and hyperemia occurred in the recovery phase after NTP but not TMP. Electrical activity also was maintained better with NTP. ECF K+ increased in five of six TMP experiments but in only one of six NTP experiments. Values of K+ greater than 15 mM were only seen in the TMP group. Release of K+ into the ECF space occurred at values of cerebral cortical oxygen delivery below 3 ml 100 g-1 min-1. ECF K+ partially recovered after the end of hypotension in all except the experiment with the highest value. A progressive and severe cerebral acidosis was seen in all experiments during induced hypotension, and values below pH 6.50 were present at the stage of K+ increase in the ECF space. It is concluded that the ability of cell membranes in the cat's cortex to maintain normal ionic gradients is depressed by hypotension to these levels with TMP, but not with NTP, and that this difference is related to better-maintained oxygen supply values during NTP hypotension.

Seventy-six severely head-injured patients, 67% of whom had Glasgow Coma scores of five or less on admission, were managed according to an intensive treatment regime which included controlled hyperventilation (under full muscular paralysis), high-dose steroids, dehydrating agents, diuretics and hypnotics (Althesin and thiopentone). Intracranial pressure (ICP) was measured throughout the period of controlled ventilation. Treatment was directed to keeping the mean ICP below 25-30 mmHg and to the prevention of increases in ICP during chest physiotherapy and other noxious stimulation. Six months after injury 46% of patients had died and 4% were vegetative survivors, whilst 43% had made a good recovery or were only moderately disabled. Features associated with worse than average prognosis were: low coma score, pupillary abnormalities, respiratory dysrhythmia and ICP greater than 30 mmHg. Spontaneous hyperventilation was a relatively good initial feature. These results support the employment of intensive care in severely head-injured patients, particularly those with diffuse brain injury.

1 In the baboon the blood levels of pentazocine between 1 and 60 min after intravenous injection of 0.5 mg/kg were measured by a gas chromatographic technique. From cerebral arteriovenous differences it was shown that the peak of the brain concentration occurred within 15 min and probably within 10 min of intravenous injection. At the time of peak concentration about 10% of the injected dose was in the brain, while the corresponding value at 60 min was 2%.2 The concentration of pentazocine in the brain was an order of magnitude greater than the concentration in cerebral venous blood both at 5 min and 60 min after injection. No major brain interregional differences were demonstrated. Cerebrospinal fluid from the cisterna magna did not yield values from which the cerebral concentration of pentazocine could be predicted.

Continued expansion of an artificial space-occupying lesion produced further increases in mean supratentorial and infratentorial pressures associated with increases in mean arterial pressure, heart rate, and systemic vascular resistance-the `Cushing' or systemic hypertensive response. These primary changes resulted in an increase in transtentorial pressure gradient and a decrease in arrhythmia index. Immediately before the onset of the systemic hypertensive response, supratentorial perfusion pressure was low, and the period of systemic hypertension did not appear to produce any worthwhile improvement in the perfusion pressure or in the blood flow in the supratentorial compartment. The studies demonstrated also that the systemic hypertensive response was a pre-terminal event and was followed rapidly by circulatory failure.

Hypotension to a mean blood pressure of 33 mmHg for periods of 70 to 187 minutes was induced by increasing the inspired halothane concentration in 11 baboons which were already anaesthetized with 0·5% halothane, nitrous oxide, and oxygen. During hypotension, cerebral blood flow, measured by Xenon clearance and by a carotid electromagnetic flowmeter, decreased by more than half, and sagittal sinus oxygen saturation was 46%. Cerebral oxygen uptake fell from 5·15 to 3·56 ml./100 g/min at this deeper level of halothane anaesthesia. Cerebral hyperaemia developed after hypotension in those animals which regained a mean blood pressure greater than 70 mmHg. Acidbase measurements on CSF from the cisterna magna revealed no metabolic acidosis during or after hypotension. In all four animals with intact autoregulation before hypotension, this was absent or impaired afterwards.

Intracranial pressure (i.c.p.) and mean arterial pressure (m.a.p.) were studied in 20 patients during the induction of anaesthesia for craniotomy. Tubocurarine was administered as the muscle relaxant and either thiopentone or Althesin for the induction of anaesthesia. No significant differences were found in the i.c.p. changes with induction, intubation or pharyngeal packing, between the thiopentone and the Althesin groups. Except for two patients (one in each group) the increases in i.c.p. associated with intubation were small. In these two patients moderate increases from normal values to 28 and 37 mm Hg were recorded, but in one of these patients coughing and straining followed intubation. Marked decreases in m.a.p. were noted in both groups, but the recovery of m.a.p. was significantly more rapid in the Althesin group. Only two patients had i.c.p. values greater than 20 mm Hg before operation and in neither did i.c.p. increase above control values during induction and intubation. Packing the pharynx produced minimal changes in i.c.p. in all patients.