Propofol is an intravenous anaesthetic which is chemically unrelated to other anaesthetics. Induction of anaesthesia with propofol is rapid, and maintenance can be achieved by either continuous infusion or intermittent bolus injections, with either nitrous oxide or opioids used to provide analgesia. Comparative studies have shown propofol to be at least as effective as thiopentone, methohexitone or etomidate for anaesthesia during general surgery. The incidence of excitatory effects is lower with propofol than with methohexitone, but apnoea on induction occurs more frequently with propofol than with other anaesthetics. Additionally, a small number of studies of induction and maintenance of anaesthesia have found propofol to be a suitable alternative to induction with thiopentone and maintenance with halothane, isoflurane or enflurane. Propofol is particularly suitable for outpatient surgery since it provides superior operating conditions to methohexitone (particularly less movement), and rapid recovery in the postoperative period associated with a low incidence of nausea and vomiting. When used in combination with fentanyl or alfentanil, propofol is suitable for the provision of total intravenous anaesthesia, and comparative studies found it to be superior to methohexitone or etomidate in this setting. Infusions of subanaesthetic doses of propofol have been used to sedate patients for surgery under regional anaesthesia, and also to provide sedation of patients in intensive care. In the latter situation it is particularly encouraging that propofol did not suppress adrenal responsiveness during short term studies. If this is confirmed during longer term administration this would offer an important advantage over etomidate. Thus, propofol is clearly an effective addition to the limited range of intravenous anaesthetics. While certain areas of its use need further study, as would be expected at this stage of its development, propofol should find a useful role in anaesthetic practice.

https://link.springer.com/content/pdf/10.2165%2F00003495-198835040-00002.pdf

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic.

Controlling the hemodynamic response to laryngoscopy and endotracheal intubation

Perioperative seizures have numerous potential etiologies. In general, when seizures occur during surgery, their onset often coincides with the introduction of a specific anesthetic or analgesic drug. Conversely, postoperative seizures are more commonly due to nonanesthetic causes. However, there have been reports of postoperative convulsions that appeared to be caused by anesthetic or analgesic drugs administered intraoperatively via inhalation or injection (e.g., intravenous, epidural, or peripheral nerve block). Some anesthetics appear to possess both proconvulsant and anticonvulsant properties. One possible factor is an inherent pharmacodynamic variability in the responsiveness of inhibitory and excitatory target tissues in the CNS. This is well illustrated by the anticonvulsant and proconvulsant effects of progressively higher doses of local anesthetic drugs. This variability in neuronal responsiveness could also explain the conflicting findings for low versus high doses of fentanyl and etomidate. Furthermore, biological variation in the individual patient's responsiveness to certain anesthetic drugs could be an additional contributory factor. Differing structure-activity relationships might also explain why some anesthetic agents possess both proconvulsant and anticonvulsant properties. Relatively minor modifications in a drug's structure can influence its affinity for a specific receptor site and its intrinsic pharmacologic activity. For example, when methohexital was first introduced, convulsions were commonly encountered in patients with and without a history of epilepsy. Subsequent fractionation of the original compound into its two isomeric forms resulted in the identification of the isomer primarily responsible for this convulsive activity. In its present formulation (Brevital; Eli Lilly, Indianapolis, Ind.), the epileptogenic properties of methohexital are limited to patients with psychomotor epilepsy. However, compared with thiopental, excitatory effects are still more common with methohexital. The excitatory effects of methohexital are presumably due to its methylated structure. The inhaled anesthetic flurothyl (hexaflurodiethyl) ether and the intravenous anesthetic ketamine also illustrate how subtle changes in stereoisomerism can result in significant changes in structure-activity relationships. Flurothyl, a fluorinated ether analogue, reliably produces convulsions in nonepileptic patients, whereas its structural isomer isoindoklon has not been associated with seizure activity. Other examples of isomer or structural analogue relationships that produce differential effects on neuronal hyperexcitability include enflurane-isoflurane and meperidine-normeperidine. In conclusion, the patient population (epileptic or nonepileptic), the method of documentation (EEG study or clinical observation), and the method of EEG analysis (cortical or depth electrodes) must be considered to properly analyze the proconvulsant and/or anticonvulsant properties of an anesthetic or analgesic drug.(ABSTRACT TRUNCATED AT 400 WORDS)

http://ether.stanford.edu/library/neuroanesthesia/SNACC%20Reading%20List%20articles/Modica_Part%202%20Pro%20and%20anticonvulsant%20effects.pdf

Pro- and anticonvulsant effects of anesthetics (Part I)

The hemodynamic effects of an induction dose of propofol, 2.5 mg/kg, or etomidate, 0.3 mg/kg, were studied in eight dogs. In addition, cardiodynamic changes were measured using a left ventricular catheter and needle force probes. Propofol was associated with significant decreases in systolic (19.9%) and diastolic (25.3%) arterial pressures associated with a 17.3% decrease in cardiac output (CO) and a 11.6% reduction in systemic vascular resistance (SVR) without change in pulmonary capillary wedge pressure (PCWP). These changes were most pronounced 1 min after the injection of propofol. At 5 and 10 min after the administration of propofol, heart rate (HR) decreased significantly. Minimal changes in hemodynamics were observed with etomidate. Propofol lowered systolic left ventricular pressure (LVPsys) by 17.6%. Signals generated by the force probes in the left ventricular myocardium showed a significant reduction (16.3%) in left ventricular force (LVF) and a decrease in early systolic rates of increase in force (dF/dt max) by 23.5% associated with propofol. In the presence of an unchanged preload, an unchanged HR, and a decreased SVR, the reduction in CO suggests that propofol has a negative inotropic effect. This negative inotropic effect was confirmed by a reduction in LVF and dF/dt max.

Hemodynamic and cardiodynamic effects of propofol and etomidate: negative inotropic properties of propofol.

Cardiac output distribution and regional blood flow in 18 dogs during isoflurane and halothane anesthesia were studied in dose-related fashion. Surgical preparation consisted of left thoracotomy and placement of catheters in the left atrium and aorta through a femoral artery. Regional blood flow was studied one week after surgical preparation using a microsphere technique at the three stages: awake, 1 MAC, and 2 MAC of inhalation anesthesia. At each stage of the experiment, two sets of microspheres (15- and 9-micron diameter), labeled with different isotopes, were used simultaneously. Both anesthetics increased cerebral blood flow, decreased blood flow through preportal area, and preserved renal blood flow. Isoflurane increased hepatic artery blood flow at both levels of anesthesia, while halothane preserved the flow during 1 MAC and decreased it at 2 MAC. Apparently, isoflurane provided better oxygenation to the liver than halothane. Myocardial blood flow was increased during isoflurane (despite decrease in blood pressure and cardiac output) and decreased during halothane anesthesia. Isoflurane appears to be a coronary vasodilator with potential beneficial (improvement in myocardial blood supply) as well as hazardous ("steal effect") effects on the heart.

Regional blood flow during isoflurane and halothane anesthesia.

The effects of propofol (emulsion formulation) on cardiovascular dynamics, myocardial blood flow and myocardial metabolism were studied in 12 patients scheduled for elective coronary artery bypass surgery. Measurements were performed with the patient awake, during steady-state maintenance anaesthesia with propofol 200 micrograms kg-1 min-1 at rest, and during sternotomy when the propofol was supplemented with fentanyl 10 micrograms kg-1. Propofol alone decreased mean arterial pressure and cardiac index; heart rate was increased. Myocardial blood flow and myocardial oxygen consumption were decreased by 26% and 31%, respectively. Myocardial lactate production was seen in one patient during this period. Surgical stimulation, under propofol-fentanyl anaesthesia, led to the return of arterial pressure and heart rate towards baseline; cardiac index decreased further. Myocardial blood flow and oxygen consumption increased such that they almost achieved their baseline values. Myocardial lactate production was seen in one patient. These results suggest that propofol may on occasions, lead to myocardial ischaemia in patients with coronary artery disease, but that it is able to block the sympathetic responses to surgical stimulation when combined with a suitable analgesic.

Effects of propofol on cardiovascular dynamics, myocardial blood flow and myocardial metabolism in patients with coronary artery disease

The effects of Disoprivan on cerebral blood flow (CBF), cerebral oxygen consumption, and CO2-reactivity of the cerebral vessels were studied in 11 male patients between 49 and 63 years of age who were about to undergo coronary artery bypass surgery. Mean perfusion pressure was decreased by 25% under anaesthesia by 0.2 mg/kg per minute Disoprivan, but remained within the ranges of autoregulation. CBF decreased by 51% and cerebral vascular resistance (CVR) increased by 55% following a 36% decrease in cerebral oxygen consumption which was associated with a decrease in neuronal activity in the EEG. Hyperventilation led to a 25% further decrease in CBF due to a 43% increase in CVR while cerebral oxygen consumption remained unchanged. Hypoventilation was followed by a 67% increase in CBF and a 44% decrease in CVR cerebral oxygen consumption was decreased by 38%. This study shows that the reactivity of the cerebral vessels to changes in paCO2 is well maintained under Disoprivan.

Effect of Disoprivan (propofol) on the circulation and oxygen consumption of the brain and CO2 reactivity of brain vessels in the human

Cardiac catheters were placed in seven healthy conscious patients so that aortic and left ventricular pressures (and the derivative), cardiac output (thermodilution) and myocardial blood flow (argon washin) could be measured. Blood was drawn for measurement of arterial blood-gas and arterial and coronary venous oxygen, glucose, lactate, pyruvate and fatty acid values. After induction of anesthesia by inhalation of halothane, the measurements were made during administration of low (0.70 per cent) and high (1.54 per cent) end-tidal halothane concentrations. Myocardial function decreased in a dose-related fashion without a change in heart rate. Myocardial blood flow and oxygen consumption were depressed in a similar manner. Myocardial oxygen extraction decreased and lactate did not change, suggesting that myocardial oxygenation was adequate. The heart rate-systolic blood pressure product correlated poorly with myocardial oxygen consumption. Systolic blood pressure and the contractile performance index dP/dt/IP were better correlated with myocardial oxygen consumption, but the value of the coefficient was still low. Without significant changes in heart rate, systolic blood pressure is the best correlate of myocardial oxygen consumption in healthy man during the myocardial depression produced by halothane.

Myocardial metabolism and oxygenation in man awake and during halothane anesthesia.

The influence of thiopental (Trapanal®) on coronary blood flow (MBF), myocardial oxygen consumption (MVO2), and general haemodynamics was investigated in seven patients without heart disease. Besides measurement of MBF, the amount of substrates (glucose, lactate, pyruvate and free fatty acids (FFA)) was also determined in arterial and coronary sinus blood samples. Thiopental was given intravenously in a mean dose of 4 mg/kg b.w. MBF was measured by means of the argon method. After injection of thiopental, all seven patients showed a significant increase of MBF and MVO2, a fact which can essentially be explained by the increase of heart rate.

The effects of thiopental on arterial concentrations, arterio-coronary substrate differences, myocardial uptake, and O2-extraction ratio of the different substrates are discussed.

ZUSAMMENFASSUNG
Die Veranderungen der Koronardurchbluting, des myokardialen O2-Verbrauches, der allgemeinen Hamodynamik sowie der wichtigsten Substrate des Herzstoffwechsels unter dem Einflus von Thiopental wurden an insgesamt 7 herzgesunden Patienten untersucht. Die verabreichte i.v., Dosis von Thiopental betrug 4 mg/kg Korpergewicht. Die Koronardurchblutng wurde mittles der Argon-Fremdgasmethode bestimmt. Nach Injektion von Thiopental in der angegebenen Dosierung kam es bei allen Patienten zu einem signifikanten Anstieg desMBF und des MVO2, eine Tatsache, die im wesentlichen mit der Herzfrequenzsteigerung erklart werden kann.

Der Einfluss von Thiopental auf die arteriellen Substratkonzentrationen, auf die Substrataufnahme und Sauerstoffextraktionsquotienten werden diskutiert.

Effects of Thiopental (Trapanal®) on Coronary Blood Flow and Myocardial Metabolism in Man

The influence of Glaxo CT 1341 (Althesinr) on coronary blood flow (MBF), myocardial oxygen consumption (MVO2), and general haemodynamics was investigated in seven patients who had no heart diseases. Besides measurement of MBF we also determined the amount of substrates: glucose, lactate, pyruvate, and free fatty acids (FFA) in arterial and coronary venous blood samples. The mean dose of 0.075 ml/kg body weight CT 1341 was given intravenously. MBF was measured by means of the argon method.



After injection of CT 1341 all seven patients showed a significant increase of MBF and MVO2, a fact which can essentially be explained by the increase of heart rate. Similarly, substrate uptake and O2-extraction rates were also markedly increased. Because of these results as well as those of the literature, precautions in the application of CT 1341 in cases with heart diseases are discussed.



ZUSAMMENFASSUNG

AN 7 Patienten ohne cardiale Erkrankungen wurde der EinfluB von Glaxo CT 1341 (Althesin) auf die Coronardurchblutung (MBF). den SauerStoffverbrauch des Myocards (MVO2) und die allgemeine Humodynamik untersucht. Neben der Messung des MBF wurden auch die Substramenten von Glucose, Lactat. Pyruvat und freien Fettsauren (FFA) im arteriellen und im Coronarvenenblut bestimmt. Die i.v. verabreichte Dosis von CT 1341 betrug im Mittel 0.075 ml pro kg Korpergewicht. MBF wurde mittels der Argonmethode gemessen.



Nach der Injektion von CT 1341 zeigten aile 7 Patienten einen signifikanten Anstieg des MFB und MVO2, eine Tatsache, die im wesentlichen mit der Schlagfrequenzsteigerung erklart werden kann. Substrat-und SauerStoffverbrauch waren gleichzeitig deutlich erhort. Wegen dieser Befunde und ahnlicher aus der Literatur werden VorsichtmaBnahmen bei der Anwendung von CT 1341 bei Herzkranken diskutiert.

H. D. Schenk

Papers

Effects of propofol on cardiovascular dynamics, myocardial blood flow and myocardial metabolism in patients with coronary artery disease

Effect of Disoprivan (propofol) on the circulation and oxygen consumption of the brain and CO2 reactivity of brain vessels in the human

Myocardial metabolism and oxygenation in man awake and during halothane anesthesia.

Effects of Thiopental (Trapanal®) on Coronary Blood Flow and Myocardial Metabolism in Man

Effects of Althesin (Glaxo CT 1341) on coronary blood flow and myocardial metabolism in man.