PROPOFOL,THIOPENTAL,SEVOFLURANE,ISOFLURANE IN ANESTHESIA

Part I: propofol, thiopental, sevoflurane, and isoflurane - A randomized, controlled trial of effectiveness byMyles PS, Hunt JO, Fletcher H, Smart J, Jackson T.Department of Anaesthesia and Pain Management,Alfred Hospital, Prahran, Austalia.p.myles@alfred.org.au Anesth Analg. 2000 Nov;91(5):1163-9
ABSTRACT

When compared with thiopental and isoflurane, propofol and sevoflurane are associated with a faster return to wakefulness after anesthesia. Yet their wider usage in inpatient surgery has been restrained by concerns regarding their acquisition costs and by lack of studies demonstrating improved patient outcome. We randomly allocated 453 adult surgical inpatients to one of four anesthetic regimens (thiopental-isoflurane, propofol-isoflurane, propofol induction and maintenance, or sevoflurane induction and maintenance) and measured their rate and quality of recovery. We found no significant differences in the rate and quality of recovery between groups. Propofol was associated with more pain on injection (P: < 0. 0005), but less cough during induction (P: = 0.003), and less early postoperative nausea and vomiting (P: = 0.003). We could not detect any significant advantages with propofol and sevoflurane, when compared with thiopental and isoflurane in adults undergoing elective inpatient surgery. Implications: Propofol and sevoflurane do not offer any significant advantages over thiopental and isoflurane in adults undergoing elective inpatient surgery.

Propofol. A review of its pharmacodynamic and pharmacokinetic properties and use as an intravenous anaesthetic byLangley MS, Heel RC.ADIS Drug Information Services, Manchester. Drugs. 1988 Apr;35(4):334-72.
ABSTRACT
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.

60 years thiopental byHempel V.Anasthesie I und Zentrallabor,Krankenanstalten Konstanz.Anasthesiol Intensivmed Notfallmed Schmerzther. 1994 Nov;29(7):400-7
ABSTRACT

In 1994, thiopentone has been in clinical use as an induction agent for 60 years. For this reason, a literature review is given dealing with its chemical properties and pharmacokinetics with special regard to plasma protein binding, recommended speed of injection, diaplacentar transfer to the foetus in Caesarean section and the transfer to breast milk. The pharmacodynamics of thiopentone are reviewed with emphasis on the effects on the CNS, the cardiovascular system, the respiratory system, renal function, liver and the effect in porphyria. Its side effects such as local reactions and release of histamine are also reviewed. The clinical importance of thiopentone in anaesthesia induction and the present state of cerebral protection are discussed, as well as the results of controlled trials comparing thiopentone to other induction drugs. Thiopentone has the main disadvantage of a slow elimination resulting in minor CNS depression, which seems of very limited clinical importance. In most respects thiopentone seems to be comparable to its younger competitors.

The pharmacology of isoflurane byEger EI 2nd. Br J Anaesth. 1984;56 Suppl 1:71S-99S. ABSTRACTThe physical and pharmacological properties of the structural isomers isoflurane and enflurane differ from each other and from those of other potent inhaled anaesthetics. The minimum alveolar concentration (MAC) for isoflurane (1.15%) is one-and-one-half times that for halothane (0.75%) and two-thirds that for enflurane (1.7%). The blood/gas partition coefficient (1.4) for isoflurane is lower than the coefficients for all other potent inhaled agents. Despite this lower blood solubility, induction of anaesthesia is slightly faster with halothane because of isoflurane's mild pungency. Enflurane depresses ventilation more than isoflurane, which in turn is slightly more depressant than halothane. All these agents dilate constricted bronchi, and thus are useful in the anaesthetic management of patients who have asthma or chronic obstructive pulmonary disease. Isoflurane has the largest circulatory margin of safety of all potent halogenated agents; it produces the least myocardial depression at a given multiple of MAC. Isoflurane may increase heart rate, particularly in younger patients, and occasionally is associated with tachycardia. It decreases total peripheral resistance, thereby decreasing systemic arterial pressure. Although results from one study suggest that isoflurane may produce a "steal" or coronary blood flow in patients with coronary artery disease, results from other studies suggest that, even in the presence of coronary artery disease, coronary blood flow to all parts of the heart remains as adequate with isoflurane as with other anaesthetics. Greater concentrations of isoflurane (1.6 MAC) increase cerebral blood flow less than does halothane. Isoflurane does not produce convulsive activity, but can produce profound muscle relaxation. It enhances the action of tubocurarine or pancuronium, and (to a lesser extent) vecuronium or atracurium. The enhancement is comparable to that produced by enflurane. Less enhancement is produced by halothane or nitrous oxide-narcotic. Only 0.17% of isoflurane taken up in man appears as urinary metabolites. This resistance to biodegradation may explain the minimal or absent hepatotoxicity and nephrotoxicity of isoflurane.

Sevoflurane: an ideal agentfor adult day-case anesthesia? byGhatge S, Lee J, Smith I.Department of Anaesthesia, Keele University/University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, UK.Acta Anaesthesiol Scand. 2003 Sep;47(8):917-31
ABSTRACT

Sevoflurane has several properties which make it potentially useful as a day case anaesthetic. Following induction of anaesthesia with propofol, awakening from sevoflurane is faster compared to isoflurane, faster or similar compared to propofol and comparable (in the majority of studies) to desflurane. Subsequent recovery and discharge is generally similar following all agents. Sevoflurane may also be used to induce anaesthesia, which is generally well-received and causes less hypotension and apnoea compared to propofol. When used as a maintenance anaesthetic, the incidence of postoperative nausea and vomiting after sevoflurane is comparable to other inhaled anaesthetics, but this complication appears more common after inhaled inductions. The tolerability and low solubility of sevoflurane facilitate titration of anaesthesia and may reduce the need for opioid analgesia, which in turn may limit the occurrence of nausea and vomiting.

Molecular mechanisms of anesthesia byUeda I. Anesthesia Service and Research,VA Salt Lake City Health Care System,University of Utah School of Medicine,Salt Lake City, UT, USA. issaku.ueda@m.cc.utah.edu Keio J Med. 2001 Mar;50(1):20-5
ABSTRACT FOR THE MOLECULAR MECHANISMS OF ANESTHESIA IN HUMAN

Anesthesia was a blessing to humankind. It is a miracle that simple molecules such as chloroform (CHCl3), diethyl ether (CH3.CH2.O.CH2.CH3), or nitrous oxide (N2O) induce a state of unconsciousness where patients can tolerate surgery. The diversity of the structures of these molecules indicates that there are no common receptors. The action of anesthetics is nonspecific and physical. After the demonstration by Meyer and Overton that anesthetic potencies correlate to their solubility into olive oil, the nonspecific lipid theories monopolized anesthesia theories for almost a century. The dominance of lipid theories invited repulsions against the nonspecificity idea. Protein theories that stress receptor bindings became the top mode. Nevertheless, the wide varieties of anesthetic molecules and the wide varieties of responding systems are difficult to reconcile with the specific interaction concept. This article discusses the recent progress and controversies on the molecular mechanisms of anesthesia. Anesthetics are unique drugs in pharmacology. They affect all macromolecules. The only comparable drugs are disinfectants. Both are nonspecific drugs. We use alcohols and phenols to wipe off the injection sites. We do not use penicillin or any other antibiotics for this purpose, because they are specific binders. Interestingly, these two nonspecific drugs opened the window for the modern medicine.

Sedation and anesthesia mediatedby distinct GABA(A) receptor isoforms byReynolds DS, Rosahl TW, Cirone J, O'Meara GF,Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, Atack J, Macaulay AJ, Hadingham KL, Hutson PH, Belelli D, Lambert JJ,Dawson GR, McKernan R, Whiting PJ, Wafford KA.Merck Sharp & Dohme Research Laboratories,The Neuroscience Research Centre,Harlow, Essex CM20 2QR, United Kingdom.J Neurosci. 2003 Sep 17;23(24):8608-17
ABSTRACT FOR SPECIFIC MECHANISMS IN CELL THEORY

The specific mechanisms underlying general anesthesia are primarily unknown. The intravenous general anesthetic etomidate acts by potentiating GABA(A) receptors, with selectivity for beta2 and beta3 subunit-containing receptors determined by a single asparagine residue. We generated a genetically modified mouse containing an etomidate-insensitive beta2 subunit (beta2 N265S) to determine the role of beta2 and beta3 subunits in etomidate-induced anesthesia. Loss of pedal withdrawal reflex and burst suppression in the electroencephalogram were still observed in the mutant mouse, indicating that loss of consciousness can be mediated purely through beta3-containing receptors. The sedation produced by subanesthetic doses of etomidate and during recovery from anesthesia was present only in wild-type mice, indicating that the beta2 subunit mediates the sedative properties of anesthetics. These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes.
SOURCE FROM:
http://www.general-anaesthesia.com/comparisons.html

Illustrating the modern anesthesia conceptFramework for the components of anesthesia
This paper presents a graphical framework, which illustrates the modern anesthesia concept, and has been developed according to published scientific theories. It is aimed as an educational tool to visualize what aspects we need to bear in mind when touching the topic of adequacy of anesthesia. Such a framework may be helpful in understanding various components of anesthesia, effects of anesthetics, as well as drug interactions.
The traditional way to visualize anesthesia was to draw a triangle, and then place the terms hypnosis, analgesia, and relaxation in its three corners. However, such a picture was rather simplified, and new theories have further developed the anesthesia concept. In the clinical review articles of this web journal, there is a more detailed information of the evolution of the modern anesthesia concept.
Kindly see the attached figure and note the conceptual circle which has been divided in two.

-On the left side, there are the two cortical anesthesia components (unconsciousness and amnesia).
-The right side semi-circle displays the three subcortical components of anesthesia
(antinociception, motor stability, and autonomic stability).

In the following text, each of the five components will be addressed in more in detail.

CORTICAL COMPONENTS
The cortical components of anesthesia refer to the effects of the anesthetic agents in the brain, particularly in the cerebral cortex, where cognitive processes take place.

Unconsciousness
In this conceptual framework, the term unconsciousness has been taken to denote a component of anesthesia. In this context, many traditional terms have been tried, though not always quite correctly. Some of these terms include "awareness", "wakefulness", "hypnosis", and "depth of anesthesia". In the context of anesthesia, the term consciousness has been defined as a state of awareness of the outside world [1]. Therefore, unconsciousness refers to the lack of this awareness.
Many researches regard unconsciousness as the key component of general anesthesia and hence, much scientific effort has been focused on qualifying anesthesia according to that component. As unconsciousness is a cortical component, obvious indicators for levels of unconsciousness are some forms of neurophysiological measurements of the cortical activity of the brain. Typically, processed EEG and auditory evoked potentials (AEP) have been suggested for this purpose, and there are numerous studies which link them to clinical measures of unconsciousness.
Selected scientific articles have been included in the bibliography listings of the Clinical Window WEB Journal (CWWJ), and more insight into the topic will be given in its clinical articles.

Amnesia
Scientific articles have appeared [2] showing that the sedative and amnesic effects of anesthetic agents actually are two separate phenomena. This makes it clear that amnesia usually occurs at lower drug concentrations than loss of consciousness. [3]
Concerning amnesia, it is important to realize that there are two types of memory: explicit and implicit.Explicit memory refers to the conscious recollection of actual events. Hence, when the patient is considered to be aware during anesthesia, explicit memory plays a role. Implicit memory, on the other hand, is not accessible to conscious mind. However, it has an important influence on human behavior. Moreover, Lubke has shown that some memory formation can occur even during adequate anesthesia [4,5].

SUBCORTICAL COMPONENTS
The subcortical anesthesia components also play an important role. They maintain autonomic and motor stability, and also ensure antinociception.

Antinociception
Antinociception refers to inhibition of the nociceptive processing in the nervous system. Analgesia is the treatment to provide antinociception. In adequate anesthesia, the role of antinociception is crucial; it makes surgical operations possible, and it reduces immediate and long-term negative consequences related to those procedures. With inappropriate analgesia, nociception might cause unfavorable responses of the autonomic nervous system, and involuntary movements in the patient.
Incidentally, in the context of general anesthesia, it is actually not quite ‘correct’ to talk about pain. Merely, the sensation of pain means conscious perception of noxious stimulation. Hence, by that definition, without consciousness, there is no pain.

Motor stability
One of the objectives of general anesthesia is to ensure that the patient does not move involuntarily. In fact, in some procedures like in ophthalmic or neurosurgery, unexpected movements might even compromise patient safety.
Hence, muscle relaxation can be considered as important component of adequate anesthesia. Most often, neuromuscular blocking agents can achieve motor stability, but there are other anesthesia drugs, e.g. inhalation agents, which work to the same direction.
Whenever neuromuscular blocking agents are used, modern practice is to monitor level of neuromuscular block by a peripheral nerve stimulator. Today’s technology allows for an objective assessment of an evoked response, making it possible to maintain steady surgical block and ensure safe restoration of muscle strength at emergence of general anesthesia.
As Rampil has pointed out, movement response of an anesthetized patient seems not to be a cortical phenomenon, but is initiated at the level of the spinal cord [6]. Hence, if the anesthetist takes a patient’s unexpected movement as indication of inadequate hypnosis, that interpretation may not necessarily be true.

Autonomic stability
Autonomic stability is an important component of the adequate anesthesia. In that context, stability of blood circulation is crucial, as sudden hemodynamic changes may indicate nociception, thus being a sign of inadequate analgesia. Concerning an anesthetized patient with a compromised cardiovascular system, it is evident that major hemodynamic variations may no be well tolerated, and all drugs including anesthetics need to be administered by careful titration.

SOURCE FROM:
http://www.clinicalwindow.net/cw_issue_07_article3.htm