MH is primarily thought to be an autosomal dominant genetic disorder that causes a hypermetabolic state after administration of volatile anesthetics (i.e. halothane, sevoflurane, isoflurane, desflurane, enflurane) and succinylcholine. The reported incidence ranges from 1:3000 to 1:65000. Conditions such as Duchenne dystrophy, Central Core Disease, Osteogenesis Imperfecta, and burns may also cause MH. Interestingly, an increase incidence has been reported in Wisconsin, Nebraska, West Virginia, and Michigan. Those at risk are patients who have had previous problems with anesthesia, or patients with an immediate family member who has had anesthesia problems.

MH is caused by an abnormal release of calcium in the sarcoplasmic reticulum, usually caused by a defect of the ryanodine receptor. The increased intracellular calcium causes sustained muscle contraction, hypermetabolism, ATP depletion, heat production, and eventually cell death.

The early signs of MH include: unexplained increased ETCO2 and decreased SpO2, hypoxemia, tachycardia, hypertension, and muscular rigidity (specific sign). As MH progresses, acidosis, elevated body temperature, hyperkalemia, rhabdomylosis, myoglobinuria, and dysrhythmias are common. Symptoms usually occur within one hour of administration of triggering substance, although in rare cases, several hours have elapsed.

Treatment of MH includes: call for help, stop volatile agents, hyperventilate with 100% O2, give Dantrolene which blocks the release of calcium from the SR, finish or abort surgical procedure, cool the patient, change to a clean anesthesia circuit, treat hyperkalemia, treat acidosis, increase urinary output.

Know: (1) the ryanodine receptor is located within sarcoplasmic reticulum, (2) dantrolene blocks release of calcium from sarcoplasmic reticulum and (3) dantrolene is first line therapy for MH. - JM

During induction of anesthesia, a gradient of anesthetic partial pressure develops such that the partial pressure of the anesthetic in the lungs exceeds the partial pressure of the anesthetic in arterial blood, which in turn exceeds the partial pressure of anesthetic in the brain. A key concept to grasp is that anesthetic induction will be increased as more anesthetic is delivered to the lung or as less anesthetic is removed from the lung. The partial pressure of the anesthetic in the lung is the principle force driving the anesthetic into the body.

So, factors that increase the rise in anesthetic partial pressure in the lung will speed this process. Important factors include increasing minute ventilation, delivering unusually high concentrations of anesthetic agents (i.e., overpressure), using high gas flows or non-rebreathing anesthetic systems, and having a reduced FRC (functional residual capacity). Coadministering high concentrations of nitrous oxide may also speed induction through the concentrating effect and/or second-gas effect.

Also, factors that decrease the rate at which anesthetics are removed from the lung will speed this process. There are two important factors to consider - cardiac output and the lipid solubility of the anesthetic agent. High cardiac output and high lipid solubility of the anesthetic will slow induction (because anesthetic partial pressure in the lung will rise more slowly), while avoiding high cardiac output and selecting agents with a low blood:gas solubility will increase the rate of induction.

1) Only occur on induction of anesthesia

2) Describes processes whereby the delivery of an inhalational anesthetic can be enhanced by the presence of a large amount of nitrous oxide.

3)Second-gas effect: when a volatile inhalational anesthetic is given with a large concentration of nitrous oxide (for example, this could be 76% N2O, 20% O2 + 4% Sevoflurane), the rapid uptake of nitrous oxide from the alveoli creates a negative pressure that draws more gas into the lung.4) Concentrating Effect: during induction, much more nitrous oxide is absorbed from the alveoli than O2 or volatile anesthetic (eg, sevoflurane). If you measure the concentration of various gases in the alveoli after much of the nitrous has been absorbed you will find that the % O2 and % volatile agent are increased.

The second gas effect brings more anesthetic into the alveoli, the concentrating effect increases the alveolar concentration of O2 and volatile anesthetic.

Induction - the administration of a drug or combination of drugs at the beginning of an anesthetic that results in a state of general anesthesia.

Maintenance – the drugs used to initiate the anesthetic are beginning to wear off, and the patient must be kept anesthetized with a maintenance agent. In this stage the patient must be kept anesthetized enough so the surgeon may perform the operation.

Emergence – Reversing the NMB’s if used, and allowing the patient to wake up. The process of emergence starts several minutes before the surgical team is done. Good communication should be kept with the surgeon to know when to turn off gasses/NMB’s/and so the anesthesia provider can dose narcotics appropriately.

There is a very good website that reviews this information:

http://emedicine.medscape.com/article/1271543-overview

 In 1937 Arthur Guedel published a Depth of Anesthesia Classification System. This original system was described for ether anesthesia following morphine and atropine premedication. It is important to realize that muscle relaxants were not commonly employed in 1937. Describe Guedel's classification system and other limitations of this system.

Stage I (Stage of Analgesia or the stage of Disorientation): from beginning of induction of anesthesia to loss of consciousness. Note - late in stage 1 there is usually amnesia. - JM

Stage II (Stage of Excitement or the stage of Delirium): from loss of consciousness to onset of automatic breathing. Eyelash reflex disappear but other reflexes remain intact and coughing, vomiting and struggling may occur; respiration can be irregular with breath-holding.

Stage III (Stage of Surgical anesthesia): from onset of automatic respiration to respiratory paralysis. It is divided into four planes:

Stage IV: from stoppage of respiration till death. Anesthetic overdose cause medullary paralysis with respiratory arrest and vasomotor collapse. Pupils are widely dilated and muscles are relaxed.

All this info will not be on the test but anyone administering anesthesia should be aware of the stages and planes of ether anesthesia. Note that these stages and planes only really apply to ether anesthesia. For example, 5 stages were described for chloroform anesthesia. You will hear people commonly talk about Stage II for modern anesthetics but this is not technically correct. It is more correct to refer to "excitement stage" than "Stage II" when talking about modern agents. For almost all anesthetics you will have similar stages: first is analgesia (nitrous oxide is given in dental offices for analgesia, not for anesthesia), then a drunken/confused/delirious/excited stage, then surgical anesthesia, and finally medullary paralysis (body does not regulate breathing, bloodpressure, etc). - JM

Local anesthetics are classified in two ways:

1. Chemical structure

2. Duration of Action

Chemically there are divided into two groups determined by the molecule attached to the intermediate chain of the molecule: they are either amides or esters.

The ester type local anesthetics go through rapid hydrolysis by plasma cholinsterases, thus making it less toxic due to its rapid metabolism. However, ester type local anesthetics have a short duration due to their rapid metabolism. Ester-type local anesthetics contain para-amino benzoic acid (PABA) (cocaine is only exception: it contains benzoic acid, not para-amino benzoic acid).

The amides types of local anesthetics are broken down in the liver. Amide types of local anesthetics require hepatic extraction therefore can lead to higher blood concentration causing toxicity.

Duration of action include three subtypes:
1. Short duration: lasting 30 to 60 minutes
2. Intermediate duration: lasting 60-120 min
3. Long acting duration: lasting 2-6 hours

Clinical duration can be dependent on dosage, site of injection, and use of vasopressors.

Local anesthetics bind to voltage gated sodium channels from the INSIDE of the cell, leading to inactivation of the voltage gated sodium channel. This prevents subsequent channel activation leading to influx of sodium intracellularly causing depolarization.

A drug’s time of onset is dependent on its’ pKa, which is the measurement of pH when which the drug is 50% ionized and 50% non-ionized. The non-ionized fraction, which is the lipid soluble, diffuses intracellularly thru the neuronal lipid membrane, and equilibrated back into its ionized form. As the non-ionized fraction move intracellularly, the concentration of non-ionized fractions increases within the neuronal cell. In attempts to maintain balance inside the neuron, the non-ionized fraction converts back to its ionized state. It is the ionized state which attaches to the gated sodium channel, thus preventing the nerve to reach an action potential by inhibiting sodium influx.

Very important!
LAs with a low pKa have a faster onset of action.
LAs with high protein binding have a longer duration of action.
LAs with high lipid solubility are more potent and have a longer duration of action.

Fast onset of action then low pKa.
High potency then high lipid solubility
Long duration of action then high lipid solubility + high protein binding.

There is only one set of doses you must memorize:

The dose of lidocaine when given iv = 1 - 1.5 mg/kg

The maximum lidocaine dose when administered s.q. = 5 mg/kg
The maximum lidocaine dose when administered s.q. with EPI = 7 mg/kg

All nerve fibers are sensitive to LA, but nerve fibers that are larger in diameter and are myelinated tend to be more resistant to LA.

From high sensitization to low sensitization: small myelinated axons, nonmyelinated axons, large myelinated axons.

The mechanism of local anesthetics differ depending on their structure: Ester or Amide

Ester type local anesthetics are metabolized via hydrolysis rapidly by pseudo cholinesterase. Hydrolysis is very rapid, and the water soluble metabolite is excreted thru urine.

 Amide type local anesthetics are metabolized by P-450 enzymes in the liver. The rate of amide metabolism is dependent on the drug, but overall metabolism is much slower than those of the ester LA. Since metabolism is slower than ester LA, amide LA are can lead to toxicity, esp. in patients with hepatic insufficiency. 

The amount of metabolism of lidocaine and some other amides is limited by liver blood flow. If there is more liver blood flow, clearance is increased (and vice versa).

Phase 1 reaction= oxidative metabolism

Phase 2 reaction= conjugation and hydrolysis 

                                 reactions 

Phase 1 more complex than Phase 2 -- patients with liver disease (eg, cirrhosis) are more likely to have problems metabolizing an amide like lidocaine than an ester like tetracaine.

What are the toxic effects of local anesthetics?

 What is the role of intralipid in the treatment of local anesthetic toxicity?

LA toxicity involves the CNS and Cardiovascular system:

CNS: As plasma concentration continues to increase, symptoms of restlessness, vertigo, and tinnitus occur. Further increases in the CNS result in slurred speech and skeletal muscle twitching, which are signals of the imminence of tonic-clonic seizures.

CV: Toxic levels can lead to hypotension due to relaxation of arteriolar vascular smooth muscle and direct myocardial depression. When plasma LA concentrations are excessive, sufficient cardiac sodium channels become blocked so that conduction and automaticity become adversely depressed.

Intralipid (fat emulsion) has been used to treat cardiovascular collapse in LA toxicity. Mechanism of action is that the lipid soluble local anesthetic drugs partition out of plasma and into lipid after intralipid is administered. As plasma levels of the drug fall, toxic symptoms improve.

Prilocaine is a local anesthetic that is metabolised to o-toluidine. This metabolite causes methemoglobinema. Tx of methemoglobinemia is i.v. methylene blue.

 LA solutions are acidic to a pH of 4-5. Which means they have a lower concentration of free base (non-ionized fractions) =slower onset. If you add epinephrine you produce vasoconstriction causing decrease uptake and longer duration of action because it increases. This allows increase of neuronal uptake, enhances quality of analgesia, prolongs duration of action, and limits toxic side effects.

The addition of sodium bicarbonate to LAs causes the solution to become more alkaline which speeds onset onset, improving quality of the block, and prolonging blockage by increasing the amount of free base available in the solution.

Bicarb causes local anesthetics to begin working faster, EPI increases duration of action.

If patient is highly allergic to sunscreen, which of these local anesthetics would you not administer: procaine (Novacaine), tetracaine, lidocaine, bupivacaine (Marcaine), mepivacaine, prilocaine, ropivacaine, 2-chloro-procaine (Nesacaine), piperocaine?

Procaine (Novocaine) is metabolized to p-aminobenzoic acid (PABA). PABA is a common ingredient in sunscreen.

If the generic name has one "i" in it the drug is an ester. If it has two "i's" it is an amide. The exception to this rule is piperocaine (which is an ester). Therefore procaine and tetracaine are both esters (that are metabolized to PABA) and should not be administered to someone with a PABA allergy.

MAC is the minimum concentration necessary to cause unresponsiveness in 50% of the general population (variable age, co-morbidities, metabolism). The higher the MAC, the less potent the anesthetic.

Blood-Gas Solubility refers to how soluble the agent is in the blood. The lower the solubility, the faster the onset and recovery

Nitrous Oxide: MAC 105, BGS 0.47

Clinical Pros: Rapid in/out, provides “second gas effect” for other agents, good analgesia, minimal CV effects, least hepatotoxic, does not trigger MH

Clinical Cons: Increases ICP and CBF, weak general anesthetic

Ether: MAC 2.0%, BGS 12

Clinical Pros: rarely used in the U.S. (still used in 3rd world countries), little respiratory depression or CV effects, bronchodilitation

Clinical Cons: flammable, slow onset/recovery, secretions, PONV

Cyclopropane: MAC 0.77, BGS unavailable

Clinical Pros: very low blood solubility, favorable pharmacokinetics

Clinical Cons: No longer available, highly explosive

Halothane: MAC 0.75, BGS 2.3

Clinical Pros: no chronotropic effect (SA node), no dromotropic effect (AV node), potent, non-flammable

Clinical Cons: highly arrhythmogenic, increases CBF and ICP, hypotension, hepatotoxic

Isoflurane: MAC 1.2, BGS 1.4

Clinical Pros: dilates coronary vessels, not tissue toxic, not arrhythmogenic

Clinical Cons: positive chronotrope (SA node), hypotension, increase CBF and ICP

Sevoflurane: MAC 2.0, BGS 0.65

Clinical Pros: non-irritating to airways (useful for children), fast onset/recovery (recovery is not fast, similar to isoflurane - JM)

Clinical Cons: positive chronotropy (SA node), increases CBF and ICP, nephrotoxicity (nephrotoxic effects are debatable - JM)

Desflurane: MAC 6.0, BGS 0.42

Clinical Pros: fast onset/recovery (fastest of all available volatile anesthetics - JM)

Clinical Cons: positive chronotropy, increases CBF and ICP, pungent/airway irritant.

Xenon: MAC 70, BGS 0.115

Clinical Pros: lowest BGS, rapid induction/recovery, no MH, little CV effects, non-toxic, neuroprotection, environmentally friendly (only agent on this list that is not a major greenhouse gas)

Clinical Cons: High cost, complex delivery systems necessary for administration

*Note: All of these agents decrease blood pressure (except Nitrous and Xenon) and decrease SVR (exception Halothane, Nitrous, Xenon). All increase CBF and ICP (according to Morgan & Mikhail). All increase respiratory rate and decrease tidal volume. All decrease renal and hepatic blood flow.

Know which agents may be used in patients with MH.

Non-flammable and non-explosive

Decrease cerebrovascular resistance resulting in increased perfusion of the brain

Cause bronchodilation

Decrease minute ventilation

Decrease hypoxic pulmonary vasoconstriction

Movement throughout the body depends on their solubility in blood & tissues as well as blood flow

Ketamine is a short acting, non-barbituate anesthetic that induces a dissociated state in which the patient is unconscious but appears to be awake and does not feel pain. It provides sedation, amnesia, and immobility. It works by interacting with the N-methyl-D-asparate receptor. It is Lipophilic and enters brain circulation very quickly. It is metabolized by the liver; in small amounts it can be excreted unchanged.

It is not widely used because it increases cerebral blood flow and induces postoperative hallucinations

Ketamine stimulates sympathetic outflow-->stimulates the heart-->increases blood pressure and cardiac output. Therefore it is used when circulatory depression is undesireable; i.e. hypovolemic/cardiogenic shock as well as patients with asthma.

Know that "the interaction with NMDA receptor" = ketamine is an NMDA antagonist.

Ketamine is a short-acting, lipophilic, non-barbiturate anesthetic. It acts as an uncompetitive NMDA receptor antagonist thus causing anesthesia. Ketamine also binds to opioid receptors giving it an analgesic effect. Indications for Ketamine are based on its capacity to stimulate sympathetic outflow which causes increase heart rate, blood pressure and cardiac output. This property is of value for patients with hypovolemic or cardiogenic shock as well as patients with asthma.

This is a link to a very good tutorial on local anesthetics. This is from a British site so some of the drug names are spelled differently than we spell them.

http://www.4um.com/tutorial/anaesth/Locals.htm

Halogenated anesthetics may produce malignant hyperthermia in :

A. Pts with poor renal function

B. Pts allergic to the anesthetic

C. Pregnant Women

D. Alcoholics

E. Patients with a genetic defect in muscle calcium

    regulation.

E. All patients undergoing anesthesia must be carefully assessed and monitored for possible adverse reaction. MH occurs n a small population who have a genetic defect and also receive succinylcholine (and some inhalation agents).  

Children with asthma undergoing a surgical procedure are frequently anesthetized with sevoflurane, because it:

A. Is rapidly taken up

B. Does not irritate the airway

C. Has a low nephrotoxic potential

D. Does not undergo metabolism

B. Sevoflurane is an inhalation anesthetic with low pungency. It is nonirritative and therefore, less likely to cause laryngospasm.

Which one of the following is most likely to require administration of a muscle relaxant?

A. Ethyl Ether

B. Halothane

C. Methoxyflurane

D. Benzodiazepine

E. Nitrous Oxide

Which one of the following is a potent intravenous anesthetic but a weak analgesic?

A. Thiopental

B. Benzodiazepine

C. Ketamine

D. Etomidate

E. Isoflurane

Which one of the following is a potent analgesic but a weak anesthetic?

A. Methoxyflurane

B. Succinylcholine

C. Diazepam

D. Halothane

E. Nitrous Oxide