Alternatives to TIVA for Propofol Shortage.pdf The supply conservation strategy presented herein is to augment or substitute propofol with ketamine, etomidate and/or dexmedetomidine.

Anesthesia :

Intracranial pressure

• Normal Intracranial Pressure (ICP) is defined the pressure inside the lateral ventricles/lumbar subarachnoid space in supine position.

• The normal of ICP is 10-15 mm Hg in adults. It is around 2-4 in neonates and infants.

• About two thirds of patients with severe head injury have intracranial hypertension (ICP>20 mmHg).

• Elevated ICP is associated with reduced amplitudes and increased latencies of cortical SSEPS

Transcranial doppler

• Transcranial Doppler sonography is used to measure the blood flow velocity in the major cerebral blood vessels.

• Normal skull offers barrier for ultrasonic beam. An examination carried out through the temporal window, orbital foramen or foramen magnum by using a 2 MHz probe has been found to provide clinically useful information that has a good correlation with the cerebral blood flow (CBF) changes.

• Middle cerebral artery is commonly chosen for examination as it can be easily insolated and 75 80% of ipsilateral carotid blood flow, flows through MCA.

The amplitude of the normal EEG is 10-100 mV.

Clinically, the EEG activity can be divided into four frequency bands:

Beta - 13-20 Hz

Alpha - 8-13 Hz

Theta - 4-8 Hz

Delta - 2-4 Hz.

An isoelectric EEG represents total abolition of cortical electrical activity.

Manual interpretation of EEG consists of eliminating the artifacts followed by appreciation of the

predominant frequencies and the amplitudes of the sine waves in the recording. The record is also examined for abnormal patterns such as spikes. Since this form of analysis is cumbersome during the course of continuous monitoring, the signal is normally subjected to computer processing and the interpretation is carried out based on some of the measures obtained from the processed EEG.

In time domain analysis, the raw EEG is split into small epochs of a given duration, usually about 1-4 sec. The frequency and/or amplitude information contained in each epoch is depicted graphically. A change in the value of the variables derived form this display is expected to represent a change in the raw EEG.

Compressed Spectral Array: Note shift of EEG power from high to low frequencies over time

Compressed Spectral Array (CSA) and Density Modulated Spectral Array (DSA). CSA displays frequency Vs power plots of successive epochs as lines one over the other.

In DSA, power in various frequency bands of each epoch is represented by dots, the density of which is proportional to the power; successive epochs are plotted one above the other.

Some of the measures derived from the power spectrum that are clinically used are:

Peak Power -Frequency, the frequency with maximum power in an epoch

Mean Power Frequency-the frequency that divides the power spectrum of the epoch into equal halves

Spectral Edge Frequency-the frequency below which 95% of the power in the epoch is contained.

Burst Suppression Ratio: This parameter represents the percentage of time the EEG is suppressed (isoelectric) in a given epoch.

Anesthesia Affects on EEG:

Though anaesthetic agents have been documented to have variable effects on the EEG, there exists a general pattern which is characterised by an initial excitation resulting in a high frequency low amplitude activity followed by a progressive decrease in the frequency and increase in the amplitude, and finally, a decrease in both frequency and amplitude until an isoelectric trace occurs at high doses.

Inhalational Anaesthetics:

During induction, halothane, enflurane,  isoflurane, sevoflurane  and desflurane cause loss of occipital ? activity and genesis of frontal synchronised _ to b activity. In surgical planes of anaesthesia, the anaesthetics differ in their effects on EEG.

Isoflurane  and desflurane,  at1.2 MAC concentration, cause burst suppression without any further slowing in the frequency of the EEG activity in the bursts.

Enflurane causes spike and wave complexes/seizure-like activity at 1.5 MAC.

Halothane causes linear slowing of frequency without burst suppression in clinical

concentrations.

When used alone, nitrous oxide, in subanaesthetic concentrations, causes fast rhythmic activity in frontal region with a peak frequency of 34 Hz. When combined with volatile agents, it has been shown to antagonise or potentiate the EEG effects of volatile agents. In some studies, nitrous oxide decreased the amplitude and increased the frequency of the volatile agent-induced fast activity and decreased the duration of burst suppression suggesting antagonism between nitrous oxide and volatile agents.

In other studies, nitrous oxide increased the delta activity and decreased the alpha to beta activity at non-burst suppressing doses of volatile agents suggesting a potentiation of the two agents.24

Intravenous Anaesthetics:

• Barbiturates, in small doses cause drug-induced fast activity. In higher doses

• they cause EEG suppression. Very high doses cause burst suppression.

• Methohexital enhances interictal epileptiform activity in patients with seizure disorders.

·         Etomidate and propofol cause myoclonic activity at induction. Etomidate increases interictal epileptiform activity when used in small doses and causes burst suppression at high doses.

• Propofol in anaesthetic doses may increase or decrease  interictal epileptiform activity. High doses of propofol cause burst suppression.

• Ketamine causes high amplitude theta activity and a significant increase in beta activity. Seizures may be caused in epileptic patients.

EEG changes during cerebral ischemia

Under stable anesthetic conditions, any change in EEG may represent cerebral ischemia and hypoxia.

Slowing and flattening of EEG progressing to isoelectricity are the characteristic changes seen during ischemia. Loss of slow activity may be one of the earliest signs of ischemia. Seizure activity could be another manifestation of cerebral ischaemia.

Intraoperatively, the CBF threshold for signs of cerebral ischemia depends on the background anaesthetic;

ischemic changes occur at a CBF of:

• 10mL 100gm–1.min–1 under isoflurane anaesthesia

• 15-20 mL 100gm–1.min–1 under halothane anaesthesia.

Clinical applications of EEG

1. EEG is a gold-standard for monitoring cerebral ischaemia. A 16-channel EEG has been shown to be as sensitive as direct CBF measurement intraoperatively during carotid endarterectomy.

2. Intraoperative EEG monitoring could be helpful to identify cerebral ischaemia during procedures associated with temporary vessel occlusion and during cardioplumonary bypass procedures

3. In the intensive care unit, EEG monitoring may be helpful to monitor seizure activity in patients with status epilepticus under the effect of muscle relaxants. Subclinical seizures causing neurological deterioration may also be diagnosed by EEG.

4. EEG has also been used to prognosticate the outcome of coma. It is also an ancillary tool for confirmation of brain death.

5. Various mathematical measures derived from EEG have been investigated for their potential to quantify the depth of anaesthesia. These include median frequency, spectral edge frequency, bispectral index and approximate entropy.

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Anesthetic agents work as the result of direct inhibition of synaptic pathways or the result of indirect action on pathways by changing the balance of inhibitory or excitatory influences

Narcotics

depress electroexitability by increasing inward K+ current and depressing outward Na+ current via a G-protein mechanism linking the receptors to the ion channel

• Non-synthetic opiate
  •   Morphine

   

• Synthetic opiates
  • Fentanyl
  • Sufentanyl
  • Afentanyl

The effects of opiods can be reversed by giving nalaxone- suggesting that the effects are related to µ-receptor activity.

Sedation

• Inhalents
  • Usually effective at low concentration (<10%)
  • potency varies with lipohilicity- suggesting the mechanism depends on changes in the membranes of tissues such as alteration of synaptic function-may alter conformational shape of the receptor ion channel at the protein-lipid interface

  Hallogenated Agents

   

• Produce a dose related increase in latency and reduction in amplitude of cortical SSEPs

  • Isoflurane -most potent
  • Enflurane -intermediate potency
  • Halothane -least potent
  • Sevoflurane and Desflurane -similar potency to isoflurane but has a more rapid onset and offset (more insoluble than ISO) so they may be more potent than ISO when concentrations are increasing.
  • MEPs are easily abolished by halogenated agents
  • When recordable, MEPs may occur only at low concentrations (i.e. >.2 to .5% ISO)
  • Affects are likely the result of depression of synaptic transmission either in the anterior horn cell synapses on alpha motor neurons or in the cortex on the internuncial synapses with a loss of I waves

   

  • Nitrous Oxide (requires higher concentration than halogentatied to be effective anesthetic (~50%)

  Common MAC values

  • Nitrous oxide - 104^[5]
  • Desflurane - 6^[5]
  • Sevoflurane - 2^[5]
  • Enflurane - 1.7
  • Isoflurane - 1.2^[5]
  • Halothane - 0.75^[5]
  • Methoxyflurane - 0.16

   

• Injectables - IV sedatives

  Barbituates, etomidate, althesin, propofol and benzodiazapines work primarily by enhancing the inhibitory effects of GABA (gamma-aminobutyric acid). They are known to bind to the GABA receptor where activiation increases chloride conduction- hyperpolarizing the membrane and producing synaptic inhibition

   

  • Propofol (non-barbituate sedative)
  • Thiopental – barbiturate sedative
  • Pentathal – barbiturate sedative

 Barbituates - sedative-hypnotics

• often used for induction (i.e. Thiopental)- will cause transient decreases in amplitude and increased latencies of cortical response

• have effects similar to that of inhalational agents on evoked potentials

• MEPs are sensitive to barbituates- effects last a long time - poor choice for MEP monitoring

• effects caused by up regulation of the NMDA receptors

• Phenobarbital is a barbituate

 

Benzodiazapines:

Midazolam- has desirable properties of amnesia and has been used for monitoring cortical SSEPs.

Doses consistent with induction (.2mg/kg) in the absence of other agents, produces mild depression of cortical SSEPS but may produce marked depression of MEPs suggesting that it may be a poor induction choice for MEP monitoring.

        Ketamine

• Can heighten synaptic function - higher amplitude cortical SSEP responses

• Inhibits NMDA receptor- thereby reducing sodium influx and intracellular calcium levels

• Can provoke seizure activity in patients with epilepsy- but not in normal individuals

• Can cause severe hallucinations postoperatively

• Can cause increased intracranial pressure

    Etomidate

• Can heighten synaptic function at low doses

• can produce seizures in low doses (.1 mg/kg) in patients with epilepsy

• can produce myoclonic activity at induction-suggesting heightened cortical activity

• Been used for induction and a component of TIVA combined with opiods

Propofol

• Propofol produces amplitude depression in cortical SSEPs with rapird recovery after termination of infusion. 

• Studies show MEPS are depressed with an effect on response amplitude consistent with a cortical effect.

• Rapid metabolism allows rapid adjustment of depth of anesthesia and effects on evoked responses.

• Component in TIVA combined with opiods is thought to produce acceptable conditions for monitoring SSEPs/MEPs

Paralytics

2 catagories based on function:

• Depolarizing agents:

  •  Succinylcholine

   

• Non-Depolarizing agents: End Plate Blockers

  • Vecruronium Bromide (Norcuron)

  • Rocurinmium

  • Atracuronium (Traccurium)

They are also compared by length of action including short vs long acting. Shortest acting agent is Succinylcholine.

 TOF-train of four

• Involves examining muscle response where 4 peripheral motor nerve stimuli are delivered at a rate of 2 Hz. In this technique, the amount of ACH released decreases with each stimulation such that its effectiveness to compare with the neuromuscular blocking agent is reduced with each stimulation.

• Quantitatively the TOF can be measured by comparing the amplitude of the M wave of the fourth twitch (T4) with that of the first (T1) in the T4:T1 ration.

• Practically, the number of visible twitches produced is usually recorded with declining numbers of twitches as the blockade increases.

• Accepatble CMAP monitoring has been conducted with 2/4 twitches.

•  The mechanism of muscle activation differs for the M response from peripheral nerve stimulation (TO4) and TceMEP, and the relationship between the 2 and neuromuscular blockade is non-linear. The MEP response is much larger because centrally applied pulses lead to repetitive activiation of spinal motor neurons, with attendant spatial and temporal summation. For this reason, MEPs are more robust during the blockade and may not be abolished as markedly as the M response (T1).

• Goals of neuromuscular blockade with MEP testing is to prevent sufficient patient movement so that stimulation is not distracting or hazardous during the surgery (particularly when the scope is used). Furthermore, some relaxation may be required to allow surgical manipulation of structures adherent to or over peripheral nerves, or to reduce muscle artifacts that may be interpreted as neural responses (i.e. paraspinous muscle responses seen in epidural recordingss of MEP. A T1 blockade of 10-20% of baseline appears to accomplish this goal adequately (this corresponds to 2/4 twitches).

• Because of varying muscle sensitivity to muscle relaxants, the neuromuscular blockade should be evaluated in specific muscle groups for monitoring.

 

 

Blood Flow

 

Numerous studies have demonstrated a threshold relationship between regional blood flow and cortical evoked responses.

Cortical SSEP remains normal until blood flow is reduced to approzimately 20 mL/min/100 g.

At more restriced blood flow between 15 and 18 mL/min/100g of tissue, the SSEP is altered and lost.

 

As with anesthetic effects, subcortical responses appear less sensitive than cortical responses in blood flow.

Because MEPS and SSEP tracts are removed topigraphically from one another, they may have different sensitivities to ischemic events.

 

Blood Rheology

Changes in hematocrit can alter both O2 carrying capacity and blood viscosity, the maximum O2 delivery is often thought to occur in a midrange hematocrit (30-32%). 

 

Ventilation

Temp

 

Drug Administration and Models

Application & Measurement of Inhalents

MAC: Minimum Alveolar Concentration

1.0 MAC is the concentration of inhalational anesthetic required to blunt the muscular response to surgical skin incision of 50% of a population of unparalyzed patients.

Intubation Tube & Respirator

N20 is mixed with 02 and administered through a respirator. 02 or N20/02 mix are blown across volatile inhalants like isoflorine.

Specifics of Inhalant Measurements

ET: End Tidal is the amount of anesthetic agent exhaled; thus present in the patient’s circulation.

IT: Inhaled Tidal is the % of gas going into the lungs

Factors that Decrease MAC:

• Hypotension
• Anemia (PCV < 13%)*******
• Hypothermia
• Metabolic Acidosis
• Extreme Hypoxia (Pa O2<38 mm/Hg)
• Age- older animal requires less anesthetic
• Pre-medication (opiods, sedatives, tranquilizers)
• Local Anesthetics
• Pregnancy
• Hypothyroidism

Factors that Increase MAC:

o      Increasing body temp – increases cerebral metabolic rate of brain

o      Hyperthyroidism

o      Hypernatrimia

Factors NOT affecting MAC:

o      Duration of anesthesia

o      Speciea (MAC varies by only 10-20% from species to species

o      Gender

o      PaCO2 between 14-95 mm/Hg

o      Metabolic Alkalosis

o      PaCO2 between range of 38-500 mm/Hg

o      Hypertension

 Anesthetics act at the neuronal cellular membrane and synapse at both cortical and spinal neurons. In general, synapses are more sensitive to anesthetics than are axons. Specifically, ligand gated channels are more sensitive than are voltage-gated channels. Channels are the most widely studied protein target for anesthetics but that doesn’t mean that other proteins are not involved.

Stages of Anesthesia

Stage 1

• The cerebral cortex is inhibited
• The onset of analgesia & loss of conciousness

Stage 2

·       This is the excitement phase

·       There is an overall increase in sympathetic tone including;

o      Increase in BP, HR, respiration and muscle tone

o      Side effects include possible cardiac arrhythmias that anesthesiology will be monitoring for

Stage 3

·       This is the surgical anesthesia stage at which surgery is most efficiently performed

·       Four panes of surgical anesthesia reflect progressive CNS depression

·       The cardiovascular and respiratory functions return to normal

·       No skeletal muscle contractions

Stage 4

• This is the overdose of anesthesia leading to medullary paralysis
• The cardiovascular and respiratory centers are inhibited leading to death

A “Complete” anesthetic produces all stages.

Routes of Administration

Inhalation

• Halogenated volatile drugs administered through the lungs mixed with respiratory air or oxygen and NO2 mixture.

Intravenous

• Drugs administered`via venous vascular supply either by infusion (continuous over time) or bolus (single dose or doses)

Intramuscular

• Drug administration through syringe injection into the muscle

General Anesthesia Pharmacologic Effects

CNS specific effects of general anesthesia include:

• Voluntary motor function is inhibited
• Involuntary (autonomic) motor function is inhibited
• Respiratory function is depressed centrally

Cardiovascular specific effects of general anesthesia include:

• Heart muscle contractility and BP are depressed

Salivary and bronchial secretions effects of general anesthesia include:

• Secretions of mucous increases
• /The breathing tube and some inhalational agents stimulate coughing but coughing but coughing is surpressed during general anaesthesia

Skeletal muscle specific effects of general anesthesia include:

• Spinal reflexes are depressed
• Also some agents block acetylcholine leading to neuromuscular inhibition

Gastrointestinal tract effects

• Nausea and vomiting effects depend on specific agents and usually occur during recovery f at all.
• Also decreased intenstinal motility causing constipation are side effects of specific agents

Liver specific effects of general anesthesia include:

• Hepatotoxic  effects
  • Altered enzyme production
  • Jaundice and hepatic necrosis

Administered Types of Standard Anesthesia

Inhalation Agents (volatile anesthetics)

• Administered in % concentration value
• Typically, when administered alone, inhalation concentration of less than 1 MAC has little effect on neurophysiological testing
• Examples: isoflurane, desflurane, sevoflurane, N20 (non-volatile)
• There is a relationship between soluability of inhalent – the less soluable the higher the MAC (<1% isoflurane, < 2% sevoflurane and < 6% desflurane).

Cardopulmonary Aspects:

·       Overall all inhalant anesthetics depress cardiopulmonary function in a dose dependent manner as shown by deceases in cardiac output, BP, respiratory rate and increase partial pressure in CO2 concentrations.

Myocardial Depression’:

·       Halothan

Injectable Agents

• Administered either bolus or drip infusion methods

MEPs are susceptible to aneshtetic agents at 3 sites:

1. The motor cortex: stimulation of neurons associated with movement such as pyramidal cells is either by direct stimulation to these cells (D-waves) or indirect stimulation via internuncial neurons (I waves). The D Waves are relatively unaffected by anesthetics because no synapses are involved in their production. I waves are markedly affected.

2. Anterior Horn Cells - where D and I waves summate. Partial synaptic blockade at the anterior horn cell can make it more difficult to reach threshold. The combination of the cortical blocking of I wave generation and reduced transmission at the anterior horn may inhibit synaptic transmission regardless of the composition of the descending spinal cord volley of activity.

3. The NMJ- fortunately with the exception of NMJ blocking agents, anesthetics have little effect at the NMJ