in the periphery

at any synapse in the ascending afferent pathway

via descending efferent inhibitory pathways originating at brainstem level

What do afferent (pain) impulses directly evoke in the spinal cord? (2)

2 spinal reflexes

Somatic Efferent Reflex

Sympathetic Efferent Reflex

nocioceptive efferent (reflex) signals induce

 muscle spasm, which initiates more nocioceptive signals creating a positive feedback loop

(more afferent pain fibers are activated)

see picture on slide 11

Where do sympathetic efferent reflex impulses come from?

What do these reflex impulses produce?

from cell bodies in intermediolateral column of SC

produces smooth muscle spasm, vasoconstriction & release of NE in vicinity of wound, resulting in more pain (more afferent pain impulses)

What is dynamic modulation neuroplasticity more accurately described as?

What are the 2 components of this mechanism of pain modulation?

neural activity-dependent plasticity

Primary hyperalgesia

Secondary hyperalgesia

In primary hyperalgesia _______ nocioceptors are sensitized by locally released mediators of injury/inflammation; what are the mediators? (3)

-peripheral

-prostaglandins, bradykinin, K ions

Secondary hyperalgesia is exaggeration of impulse conduction in _____ neurons.

What causes this exaggeration of impulse?

exaggeration of impulse conduction in first-order neurons

1st order neuron release Substance P from their axons into the peripheral tissue

What does Substance P produce? (2)

1. vasodilation

2. mast cell degranulation which releases histamine & serotonin

combine to effectively increase the size of the "injured area" to include adjacent non-injured tissue

 thus increase the number of pain/afferent transmissions to the spinal cord

The increased peripheral nerve firing caused in primary and secondary hyperalgesia produces ___________ in the SC?

This phenomenon alters response of SC neurons to _______ impulses.

central sensitization neuroplasticity

changes in the excitability of neurons in the SC

alters response of SC neurons to afferent impulses

In central sensitization neuroplasticity, once stimulus frequency reaches a critical threshold what occurs with the second order neurons?

What is this called?

the second-order neurons produces bursts of APs rather than a single AP

WINDUP

WINDUP

Results in APs lasting up to 60sec after stimulus removed

Produces changes in SC processing lasting 1-3 hrs

Central Sensitization

What is long-term potentiation?

afferent axons (1st order neurons) release the excitatory NTs:

Glutamate

Substance P

Neurokinin A

Central Sensitization

How would you describe the synaptic potentials of A delta & C fibers?

slow onset

long duration

Central Sensitization

What do accumulation of excitatory NTs from 1st order afferent neurons result in?

What is the end result of central **sensitization**

changes in SC processing

(increased response of spinal cord to pain transmission from the periphery)

END RESULT

Changes in SC processing (central sensitization) occur even after a ___________?

Primary hyperalgesia in response to noxious stimuli at the incision site may persist for ____?

Secondary hyperalgesia is of _______ in adjacent tissues.

minor surgical incision

many days

shorter duration

Supraspinal Modulation

Descending efferent inhibitory pathways originate at _______ level and synapse in _______ of ______ and there they inhibit ascending pain fibers.

Endorphins

Enkephalins

What does the monoamine or alpha-adrenergic descending inhibitory pathway release?

How does this released substance inhibit the ascending afferent nociceptors?

Norepinephrine

By hyperpolarizing nerves and thus preventing transmission of AP & NT release

What is perception?

Can your perception of pain be modulated? What is this called?

conscious awareness & interpretation of noxious stimuli

yes - called cortical modulation of pain

Cortical modulation

What 2 features make up perception?

cognition

attention

Cortical modulation

How does cognition affect pain?

Cortical modulation

How can adjusting attention affect the perception of noxious stimuli?

What are 2 techniques used?

only a fixed number of afferent stimuli can reach cortical centers d/t techniques of adjusting attention:

Biofeedback

Hypnosis

Hyperglycemia - insulin resistance & gluconeogenesis (epi, cortisol, glucagon)

Negative Nitrogen Balance - protein catabolism as a substrate for gluconeogenesis

Increased Peripheral and Pulmonary Extravascular Fluid - sodium & water retention (aldosterone, cortisol, ADH)

Increased Pain Sensation - sensitization of peripheral nocioceptors (catecholamines)

myocardial ischemia

d/t increased O2 demand

coronary vasoconstriction 

hypercoagulability

congestive heart failure

hypertension

tachycardia

dysrhythmias

 -catecholamines, angiotensin II

salt and water retention -aldosterone, cortisol, ADH

combined with effects of catecholamines

In which pts is the respiratory surgical stress response particularly problematic? (4)

thoracic & upper abdominal incisions

pre-existing pulmonary disease

obesity

elderly

decreased lung compliance

splinting

hypoventilation

atalectasis

ventilation-perfusion mismatch

decreased FRC

increased work of breathing

postoperative morbidity including:

septic complications

abnormal wound healing

Immunologic

Pain related surgical stress response suppresses both ____ and ____ immune function

Resulting in?

both cellular & humoral immune function

Resulting in:

lymphopenia

leukocytosis

depression of the RES

How do anesthetics effect the immunologic system?

Many known mediators of the stress response are potent _________?

What may the immunologic system effects from surgery play a role in?

reduce chemotaxis of neutrophils

Many known mediators of the stress response are potent immunosuppresants

May play a role in periop infection

Reduced cytotoxicity of killer T cells 

these cells dont work as well post surgery and thus if any cancer cells are released into the circulation during the resection there may not be enough T cells to kill them off --- leads to risk for cancer to set up somewhere else in the body.

How is coagulation effected by the surgical stress response?

What 3 specific things contribute to this state?

Per Ron what anesthetic technique may decrease this state?

stress-induced promotion of a hypercoagulable state

increased plt adhesiveness

decreased fibrinolysis

increased blood viscosity

RA - increases fibrinolysis = less hypercoagulation

by focusing on preventive rather than therapeutic measures

preemptive analgesia

patients with limited physiologic reserve

procedures involving more extensive surgical trauma

Does GA effectively attenuate the neuroendocrine stress response?

____ techniques may inhibit some components of the stress response

____ MAC of inhalationals reduces intraop catecholamine release, but has no effect on ______ catecholamine response

No - it does not effectively attenuate the neuroendocrine stress response

high dose opioid techniques may inhibit some components of the stress response

1.5 MAC of inhalationals reduces intraop catecholamine release, but has no effect on postop catecholamine response

(remember that emergence (postop) is a period of increased stress and catecholamine release)

How does RA/analgesia effect afferent impulses?

What does RA reduce?

decreases the intensity of afferent impulses reaching the SC

shown to reduce periop release of catecholamines and other hormones for certain surgeries

With RA, when is the blockade of cortisol response the greatest?

*When does RA/postop analgesia have the greatest benefit?

blockade of cortisol response greatest with lower abdominal and lower extremity procedures

RA and postop analgesia have the greatest benefit in patients at highest risk of complications

may reduce myocardial work & oxygen consumption due to reductions in:

HR

BP

LV contractility

How does a thoracic epidural effect the heart?

Thoracic epidurals show significant reductions in CV morbidity following major _____, ______, and ________ surgery?

reduced incidence of MI and dysrythmias in high risk populations

significant reductions in CV morbidity following major thoracic, abdominal, and vascular surgery

In animal models with thoracic epidurals

In animal models with thoracic epidurals

LAs improve epidcardial to endocardial blood flow ratios in the heart.

Reduced infarct size following acute coronary occlusion.

Benefits to the respiratory system with RA/analgesia?

facilitation of chest physiotherapy

improved postop diaphragmatic function

reduced WOB

enhanced ability to cough

FIRE

enhances fibrinolytic activity

speeds return of antithrombin III to normal levels

attenuates postop increase in platelet adhesiveness

block of sympathetic efferent nerves

reduction in circulating catecholamines

anticoagulant properties of systemically absorbed LA

With RA there a reduced incidence of the following coagulation issues

With RA there a reduced incidence of the following coagulation issues

Reduced incidence of vascular graft occlusion following LE revascularization

Reduced incidence of DVT and PE following total hip arthroplasty, possibly related to:

inhibitory effect of plt aggregation

improved LE blood flow

Similar results (reduction of DVT and PE)following TKA and radical prostatectomy

Opioid receptors are present in many different areas of the CNS system; including the _____; where else are they present?

T/F application of opioids at the peripheral nerve terminals is now known to be effective?

Spinal cord

in peripheral nerves

True Ron

Where is the peripheral opioid effect more profound?

more profound in chronically inflamed tissues

transported to and activated on primary afferent neurons in response to inflammation

Is there an analgesic ceiling with opioids?

List 3 common opioid SE that limit their dosage:

no analgesic ceiling, however analgesic effect is limited by tolerance and SEs

N/V

sedation

respiratory depression

Equianalgesic Doses of Opioids:

Parenteral:Oral

Morphine      10:30

Codeine       130:200

Fentanyl       0.1 (no oral)

Meperidine   75:300

The primary mechanism of NSAIDS is inhibition of _____, and therefore inhibition of __________.

Where does this inhibition occur?

The primary mechanism is inhibition of COX, and therefore inhibition of prostaglandin synthesis

primarily peripherally, but also through inhibition of spinal COX

Constituitive

plt aggregation, hemostasis, gastric mucosal protection

Inducible

pain, inflammation, fever

as sole analgesic typically effective for mild to moderate pain

as adjunct, particularly valuable in a multimodal approach by using a different mechanism than opioids or LAs for more severe pain

Reduce opioid dosage and SE

speed return of GI function

reduce incidence of respiratory depression

improve patient satisfaction

Provide an economic benefit to patient & hospital

Decreased Hemostasis

plt dysfunction

inhibition of TXA2

Renal dysfunction

possible with high risk patients

hypovolemia, baseline renal dysfunction

Interference with bone healing and spinal fusion

Increased incidence of GI bleeding

COX-1 inhibition reducing synthesis of cytoprotective gastric mucosal prostaglandins

Bronchospasm

may be induced by NSAIDs

When is the expression of COX-2 increased?

What may COX-2 inhibition produce?

increased during inflammation

selective COX-2 inhibition may produce analgesia without the COX-1 side effects 

What are the benefits of COX-2 specific inhibitors as compared to non specific NSAIDs? (3)

There is no apparent advantage in reducing incidence of _____ complications

lower incidence of GI complications

produce minimal platelet inhibition

may not impair bone healing

There is no apparent advantage in reducing incidence of renal complications

What are the disadvantages of oral delivery of drugs? (3)

Advantage - earlier use of long-acting oral opioids may facilitate...?

Disadvantages:

lack of titratability

prolonged onset and time to peak effect

require a functioning GI system

Advantage - earlier use of long-acting oral opioids may facilitate transition to oral meds & earlier discharge from the hospital

Transdermal fentanyl requires several ____ to reach peak effect so is not good post op; also there are problems with ____ &  __________.

Transdermal fentanyl in combo with PCA reduces number of ____ doses, but NO change in ________ or _____.

transdermal fentanyl requires several hours to reach peak effect

problems with: titratability, unpredictability of absorbtion

Transdermal fentanyl in combo with PCA reduces number of demand doses, no change in total opioid requirements or SE

transdermal

transmucosal

PCTA with E-trans

interpatient variability in analgesic requirement

variability in serum drug levels

administrative delays

Benefits of PCA relative to traditional "prn" analgesic regimens

provides _____ analgesia

improves patient ________

decreases risk of _______ complications

no increase in _____ or _______

Benefits of PCA relative to traditional "prn" analgesic regimens

provides superior analgesia

improves patient satisfaction

decreases risk of pulmonary complications

no increase in total opioid dose or SE

Demand dose

Lockout interval

Background infusion

T/F there is no optimal demand dose established?

What is the lockout interval of a PCA typically?

Variation of interval within above range has minimal effect on ____ or ____.

True, but for opioid naive patients, it is typically:Morphine 1mg or Fentanyl 10-20mcg

typically 5-10 minutes

Variation of interval within this range has minimal effect on analgesia or SE

increases total dose of drug delivered with no improvement in analgesia or night-time sleep patterns

may result in increased SE, including respiratory depression

use of a background infusion

advanced age

concurrent admin. of sedative/hypnotic drugs

coexisting pulmonary disease

OSA (obstructive sleep apnea)

nocturnal hypoxemia may be reduced with the use of supplemental O2...duh!

What are the considerations of central neuraxial analgesia?

Location - subarachnoid vs epidural

Catheter-incision congruent vs incongruent

Drugs Included - LA, Opioids, and adjuvants

lipophylicity vs hydrophilicity

single shot vs continuous infusion

Risk (SE) vs Benefit

CEI vs PCEA

T/F An example of an incongruent epidural cath placement is if the cath is placed at L4 but the incision is at T8.

What is the site of action of hydrophylic opioids?Examples?

(Note: see graphs on slides 47, 55, 59, 63, 64)

True

must give bigger dose to diffuse upward to surgical site in this kind of situation per Ron

Spinal

Morphine

Hydromorphone

Hydrophylic opioids remain in CSF and produce a delayed onset, but prolonged duration of analgesia.

There is a higher incidence of SE due to cephalad spread within CSF.

What is the site of action of lipophylic opioids?

Examples?

The _____ onset and ____ clearance(duration) of lipophilic opioids from CSF _____ cephalad spread.

unclear (spinal vs systemic or both)

Fentanyl

Sufentanyl

The rapid onset and rapid clearance of lipophilic opioids from CSF limits cephalad spread.

Must know table on slide 62 regarding hydro & lipophilic opioids

T/F blood levels of an epidural opioid like fentanyl may be as high or higher than IV administered opioids?

T/F A hydrophilic opioid would be best for a single shot or outpt admin d/t less risk for SE.

True

False - a lipophilic would be better because less SE risks and is cleared by body faster

T/F the larger the volume an opioid mixed in for an epidural injection the more cephalad it will spread?

To reduce cephalad spread of a hydrophilic opioid give it in a small volume (ie 2 ml) not mixed in with a large volume like your LA dose.

But it is okay to give _____ opioids  mixed in a larger volume.

*see drawing on slide 64

True for hydrophilic opioids

Lipophilic

site of action unclear

potentially - spinal nerve and over time the dorsal root ganglion or spinal cord

True 

they are synergistic not additive

What are the benefits of LA + Opioid?

improved ______ analgesia

slower regression of ______ block

decreased ____ of LA required

unclear if incidence of ___ reduced

What are the benefits of LA + Opioid?

improved postop analgesia

slower regression of sensory block

decreased dose (concentration) of LA required

unclear if incidence of SE reduced

Bupivicaine (<0.125%)

Levobupivacaine (<0.125%)

Ropivacaine (<0.2%)

most prefer the lipophylic drugs

-Fentanyl (2-5mcg/ml)

-Sufentanyl (0.5-1mcg/ml)

some use (but not Ron) Hydrophylics

-Morphine (0.05-0.1mg/ml)

-Hydromorphone (0.01-0.05mg/ml)

Are adjuvant drugs widely used for continuous infusions?

What drugs are used on occasion? (3)

No

Clonidine (5-20mcg/hr)

Epinephrine (2-5mcg/ml)

- may improve density of block

Ketamine

What is the MoA of Clonidine?

Significant SE? (3)

Ketamine may decrease _____________?

acts via the descending noradrenergic pathway

significant SE:

hypotension

bradycardia

sedation

central sensitization via NMDA antagonism

superior analgesia

reduced drug dosage

reduced SE (d/t lower dose)

What  2 things are less with a thoracic placement of epidural?

1. Less lower extremity motor block

- improved early ambulation

2. Less urinary retention

- less bladder catheterization & subsequent infection

False, there is NO increase in neurologic complications as compared to lumbar placement

What should you consider with SE of epidural?

Uncommon but possible SE? (3)

More common SE? (3)

Consider the patient, not just the block

Hypotension (0.7-3%)

Motor Block (2-3%)

Resp depression (0.1-0.9%)

urinary retention

N/V

pruritis

Why is hypotension seen with an epidural?

What should you do if you determine the hypotension in your pt is caused by epidural?

sympathetic blockade

volume status?

may reduce LA dose (rate or concentration)

What is the management of a motor block from an epidural?

Persistent (despite changes with epidural) or increasing motor block should raise suspicion of ______ or ________.

lower concentration of appropriate LA

catheter-incision congruent placement

Persistent (despite changes with epidural) or increasing motor block should raise suspicion of hematoma or catheter migration

What are 3 very common SE of epidurals with opioids?

N/V (20-50% w/ opioids)

Pruritis (60% w/ opioids)

*only 15-18% when only LA in epidural

Urinary retention (>50% w/ opioids) 

*only 18% w/ systemic opioids & 10-30%when only LA in epidural

N/V is ____ dependent and less frequent with _____ opioids?

Pruritis has a lower incidence with _____ than with _____.

What is the mechanism of pruritis?

N/V is dose dependent and less frequent with lipophilic opioids

Pruritis has a lower incidence with fentanyl than with morphine.

mechanism: not clear, but unrelated to peripheral histamine release--possibly related to a central mechanism

(previously learned this was directly opioid receptor mediated)

Treatment of N/V and pruritis caused by opioids?

What virus is epidural morphine use associated with reactivating?

antihistamine/naloxone

antiemetic/naloxone

 herpes simplex labialis

Is respiratory depression greater with epidural or systemic opioids?

Resp depression is ______ dependent in epidurals as with IV opioid use.

Treatment?

equal -- incidence is not increased from the numbers seen with systemic opioids

dose dependent

supportive/naloxone

increasing dose

increasing age

concurrent use of systemic opioids or sedative drugs

more hydrophylic drugs

thoracic surgery?

comorbidities?

extensive surgery?

What is the incidence of urinary retention?

 epidural opioids ___%

systemic opioids ___%

epidural LA ___%

Dose dependent?

Treatable?

epidural opioids 50%

systemic opioids ~18%

epidural LA 10-30%

not dose dependent

treatable with low-dose naloxone or cath

T/F an advantage of PCEA over CEI is a reduction in total drug use.

What are the other advantages of a PCEA vs CEI?

True

allows individualization of dose

superior analgesia

improved patient satisfaction

Is PCEA safe for use outside of OR/ICU?

SE?

Is a background infusion useful?

safe for use on regular surgical floor

SE profile similar to CEI

yes, in contrast to IV PCA; PCEA use of a background infusion appears to be advantageous

Reduced Morbidity and Mortality

- decreased incidence of postoperative GI, pulmonary, and possibly cardiac complications

What are the specific benefits of epidural analgesia:

GI - earlier return of GI motility following _____ surgery (may be delayed with inclusion of epidural ______).

Pulmonary - preserved postop pulmonary function, _______ incidence of infection and complications (not seen when _____ included).

Cardiac - thoracic, but not lumbar epidural may decrease the incidence of postop ____.

attenuation of surgical stress response and hypercoagualability

improved analgesia

redistribution of coronary blood flow

What are complications of epidural analgesia? (3)

T/F all are fairly low incidence?

Epidural Hematoma - pay strict attention to patients coagulation status

Epidural Space Infection - increased with longer duration and sicker patient

Catheter Migration - use safety measures: aspiration, test dose, incremental injection

TRUE