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Lecture Title: Acute Pain Management. Lecturer name: Osama Ibraheim MD,SOB. Lecture date:. Lecture Objectives. Fundamental Considerations. Millions of patients worldwide undergo surgery.

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slide1

Lecture Title: Acute Pain Management

Lecturer name:Osama Ibraheim

MD,SOB.

Lecture date:

fundamental considerations
Fundamental Considerations
  • Millions of patients worldwide undergo surgery.

Although developing more effective techniques for postoperative analgesia, many patients experience pain.

slide4
PAIN

An unpleasant sensory and emotional experience associated with actual

or potential tissue damage.

IASP, Subcommittee on Taxonomy, 1979

etiolgy of pain
ETIOLGY OF PAIN
  • HEAT
  • COLD
  • CHEMICAL
  • MECHANICAL

TORSION STRETCH CUT PINCH PRICK COMPRESS CRUSH

typology of pain
TYPOLOGY OF PAIN
  • Acute
  • Chronic benign
  • Chronic cancer
chronic pain vs acute pain
Chronic Pain vs Acute Pain

Acute: A Symptom of Injury or Disease

Chronic Benign: Pain itself is the disease

Chronic Cancer: Actual Tissue destruction

adverse effects of pain
Adverse Effects of Pain
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Renal
  • Extremities
  • Endocrine
  • CNS
  • Immunologic
adverse effects of pain1
Adverse Effects of Pain

Cardiovascular: Tachycardia, hypertension, increased SVR, increased cardiac work, increased myocardial O2 demand.

Pulmonary: Hypoxia, hypercarbia, atelectasis, decreased cough, decreased vital capacity and function residual capacity, V/Q mismatch.

Gastrointestinal: Nausea, vomiting, ileus, intolerance for oral intake.

Renal: Oliguria, urinary retention.

adverse effects of pain2
Adverse Effects of Pain

Extremities: Skeletal muscle spasm, limited mobility, thromboembolism.

Endocrine: Excessive adrenergic activity, vagal inhibition, catabolic metabolism, increased O2 consumption.

CNS: Sedation, fatigue, anxiety, and fear cause central sympathetic stimulation.

Immunologic: Inhibited cellular immunity, increased risk of infection, ?? impaired wound healing ??

algogenic substances released by pain
ALGOGENIC(substances released by pain)

SEROTONIN POTASSIUM

HISTAMINE ACETLYCHOLINE

BRADYKININS LEUKOTRIENES

PROSTAGLANDINS SUBSTANCE P29

NOREPINEPHRINE

slide14
THE RECEPTORS IN THE FREE NERVE ENDINGS RESPOND TO THE SUBSTANCES BY BECOMING CHARGED ELECTROCHEMICALY
nociception
NOCICEPTION

This electrochemical event that occurs between the site of tissue damage or injury sets off a series of neural transmissions that eventually results in the perception of pain……Collectively this known as nociception

nerve fiber pain classification
NERVE FIBERPAIN CLASSIFICATION

A FIBER……..SHARP-STABBING-LOCAL

“ FIRST PAIN”

B FIBER....PHYSIOLOGIAL REACTION

C FIBER....DULL-ACHE-BURN-THROB

NONLOCALIZED-RADIATE

“SECOND PAIN”

nerve fiber classifcation
NERVE FIBER CLASSIFCATION

TYPE FUNCTION

A a myelinated motor

A alpha myelinated touch-pressure

A beta myelinated touch-pressure

A delta myelinated pain-temperature

A gamma myelinated proprioception

a delta
A Delta
  • 1 - 4 micrometers diameter
  • Myelinated, Rapid conduction
  • Sharp, localized
  • Heat, cold
  • “First pain”
slide20

B myelinated

preganglionic autonomic

C non-myelinated

pain-temperature

c fibers
C Fibers
  • Small
  • Slow Conduction
  • Unmyelinated
  • Postganglionic autonomic
c fibers1
C Fibers
  • Dull pain, burning, Aching throbbing
  • Nonlocalized - radiating - diffused
  • Temperature,Touch,Mechanical
  • “Second pain”
gate theory
Gate Theory

Balance between A delta and C fibers to dorsal horn determines the intensity of the stimulus that is passed to higher brain center

area of high nociceptor concentration
Area of High Nociceptor Concentration
  • Mucosal membranes
  • Periosteum
  • Deep fascia
  • Ligaments
  • Joint capsules
  • Cornea
  • Subcutaneous tissue
areas of moderate nociceptor concentration
Areas of Moderate Nociceptor Concentration
  • Skeletal muscle
  • Cardiac muscle
  • Smooth muscle
physiologic processes of nociception
Physiologic Processes of Nociception
  • Detection
  • Transduction
  • Transmission
  • Modulation
  • Perception
detection
Detection
  • “First pain”
  • “Second pain”
transduction
TRANSDUCTION

NOXIOUS STIMULI TRANSLATED INTO ELECTRICAL FIRING AT THE SENSORY NERVE ENDINGS

transmission
TRANSMISSION
  • PROPAGATION OF IMPULSE TRAVELS VIA NEURAL PATHWAYS.
  • SENSORY AFFERENT NEURONS PROJECT INTO THE SPINAL CORD
  • ASCENDING NEURONS RELAY TO BRAINSTEM AND THALAMUS
  • THALAMUS RELAYS TO CEREBRAL CORTEX
modulation
MODULATION

INTRINIC PAIN MODIFICATION

1.DIFFERENT IN INDIVIDUALS

2.DEPENDS ON.....

PAST EXPERIENCES

CULTURE

PSYCHIC

modulation cont
MODULATION-CONT
  • STIMULUS PRODUCED ANALGESIA
  • NEUROENDOCRINE ANALGESIA
  • CNS/PNS ANALGESIA
  • OPIOID ANALGESIA
  • SITUATION
  • PATHOLOGY
  • PHYSIOLOGY
modulation excitatory substances
Modulation – Excitatory Substances
  • Peripheral

Prostaglandins, bradykinins, histamine, K, substance P, serotonin (5HT2)

  • Spinal

Glutamate, aspartate, amino acids, substance P, norepinephrine (alpha 1)

modulation inhibitory
Modulation - Inhibitory

Supraspinal

  • Endorphins, enkephalins, dynorphins, norepinephrine (alpha 2), GABA, somatostatin (5HT1), neurotensin
first neuron pain
First Neuron Pain

Peripheral afferent fibers to dorsal horn

Second Neuron Pain

Dorsal horn to thalamic

Third Neuron Pain

Thalamus to cortex

pain pathways
Pain Pathways:
  • Tissue damage>>>Algesic substanses release>>>Noxious stimuli>>>A delta and C fibers>>>to the Neuraxis>>>Many to Ant. and Anterolat.Horns>>>Segmenal reflex responses , and others via the Spinothalamic and Spinoreticular tracts>>>Suprasegmental and cortical responses.
classification function of peripheral nerve fibers
Classification & Function of Peripheral Nerve Fibers

A. Myelinated A- Fibers:

  • a: Motor , Proprioception (afferent)
  • b: Motor, Touch (afferent)
  • g: Muscle spindles (efferent)
  • d: Pain, Temperature (afferent)

B. Myelinated B-Fibers:

  • Pre-ganglionic Sympathetic Fibers

C. Non-Myelinated C- Fibers: Pain, Temperature.

nociceptive pathways peripheral sensory nerves

Spinothalamic tract

Dorsal horn of spinal cord

  • Nociceptive sensory fibres are C-fibres and Ad fibres
  • C-fibres umyelinated
  • Ad myelinated
  • Slow conduction velocity
  • Signal variety of noxious stimuli - polymodal

Dorsal Root

Ganglion

Peripheral nerve

Sympathetic ganglion

Viscera

Blood vessels

Skeletal

muscle

Tendon bundle

C and Ad

fibres

Nociceptive terminals

Muscle and skin receptors

Nociceptive pathways: peripheral sensory nerves
ascending pain pathways

Cortex

Thalamus

Mesencephalon

Medulla oblongata

Spinal

cord

Ascending Pain Pathways
  • Topographic representation maintained
  • Sites for pain modulation are spinal cord and thalamus

Pons

slide40

Segmental reflex responses:

Increased skeletal muscle tone , Increased oxygen consumption , Lactic acid production

  • Suprasegmental
  • reflex responses:

Increased Sympathetic tone , Hypothalamic stimulation.

chemical mediators

Chemical Mediators

Membrane ion channels of Nociceptive neurons

Directly coupling to membrane receptors

Hydrogen

ATP

Serotonin

5HT3

Indirectly (more commonly) mediating intracellular secondary messages

Bradykinins B1, B2

Cytokines

Prostanoids

Histamine H1

Serotonin

5HT1

factors that modify perioperative pain
Factors that modify perioperative pain :
  • 1- Site ,nature and duration of surgery.
  • 2- Type and extent of incision.
  • 3- Physiologic and psychologic makeup of the patient.
  • 4- Pre operative preparation of the patient.
  • 5- Presence of complications of surgery.
  • 6- Anesthetic management.
  • 7- Quality of perioperative care.
  • 8- Preoperative treatment of painful stimuli .
preemptive analgesia
Preemptive Analgesia :
  • Antinociceptive treatment of that prevents the establishment of altered central prossesing, which amplifies postop. Pain.
  • Windup:functional changes in the dorsal horn because of pain .
  • This type of therapy ,in addition to reducing acute pain ,attenuates chronic postop. Pain.
principles of pain management

Principles of Pain Management

Anticipate pain

Recognize patient:

Ask the patient

Look for signs (HR, BP, facial grimacing, tears, sweating, etc)

Find the source

Quantify pain (mild, moderate, severe)

Treat:

Quantify the patients perception of pain

Correct the cause where possible

Give appropriate analgesics regularly as required

Remember most sedative agents do not provide analgesia

Reassess

modalities of pain relief

Modalities of Pain Relief

Non-opioid analgesics+opioid analgesics

Regular injections of opioids

Continuous IV or SC infusion of opioids

Patient controlled analgesia (PCA)

Extradural opioids & or local anesthetics

Combined exrtadural + spinal analgesia

Long acting oral opioids

Long acting regional blocks

Ketamine (S+)

modalities of pain relief1

Modalities of Pain Relief

Pharmacological

Non-pharmacological

drugs

DRUGS

NSAID’s

COX-1 Minor – Moderate pain

COX-2rofecoxib, parecoxib-inj Severe pain

Actions:

Inhibit synthesis of PG-E

Direct analgesic effect on higher centers

Modify nociceptive responses-bradykinins

Antiplatelet

Hypothrombinaemia

Lowers body temp

Hypoglycemia

Metabolic acidosis

Adverse gastrointestinal effects

Lower doses only

systemic opioids
Systemic Opioids :

Analgesic effects of opioids : via receptors in the CNS.

Roots of administeration :I.M. ,I.V. ,Transdermal ,Oral ,Topical ,I.V. regional ,Perineural ,etc.

I.M. root is the most treatment choice after surgery.

The” As Needed” part of the order is often interpreted to mean “As little as possible” .

No relation exists between Gender and opioid requirement.

analgesic opiates
Analgesic Opiates
  • Morphine
  • Pethidine
  • Fentanyl
  • Sufentanil
  • Alfentanil
  • Remifentani
  • ANTIDOTE : Naloxone
routes of administration of analgesics

Routes of administration of analgesics

Oral Intravenous

Sublingual/buccal Epidural (opioid)

Oral transmucosal Intrathecal (opiod)

Intranasal Intra articular (opioid)

Transdermal Topical - EMLA cream

Rectal Intradermal

Inhalational Peripheral N block

Subcutaneous Nerve plexus block

Intramuscular Intravenous regional

modalities of pain relief2

Modalities of Pain Relief

Non-pharmacological

Transcut. Electrostimulation

Cryoanalgesia(obselete)

Acupuncture

Hypnosis

new modalities of systemic drug administration
New Modalities Of Systemic Drug Administration

The goals of new methods are:

1.Precise,controlled delivery of the prescribed dose

2. A rapid onset of action

3. Avoidance of first-pass hepatic metabolism

4. Maintenance of a steady-state concentration of drug

5. An improved side-effect profile and

6. Improved patient compliance

transdermal route advantages
Transdermal Route Advantages
  • Decreased first-pass hepatic metabolism
  • Decreased gastrointestinal degradation
  • Stable plasma concentrations,and
  • Improved patient compliance
treatment methods
Treatment methods :
  • 1-Systemic opiods.
  • 2-Patient-controlled analgesia.
  • 3-Regional anesthetic techniques .
  • . a : Intraspinal analgesia.
  • b :Patient-controlled epidural analgesia.
  • c :Combined spinal-epidural technique.
  • 4-intraarticular analgesia.
  • 5-Nonopioid analgesics.
  • 6-Cryoanalgesia.
  • 7-T.E.N.S.
  • 8-Psychologic and other methods.
patient controlled analgesia
Patient-Controlled Analgesia:

PCA was originally developed to minimize the effects of pharmacokinetic and

Pharmacodynamic variability among patients.

A negative feedback loop exists: experiencing pain>>>Medication demanded>>>Reducing pain >>>No further demand .

  • If Nurses, Relatives,or Parents assume responsibility for drug administration,or if using this device by the patient is for reasons other than pain relief ,this loop fails.
slide56

Cases of respiratory depression during PCA use have been reported.

  • Causes :advanced age, hypovolemia, large doses, use of background continuous-infusion mode.
  • No difference in respiratory mechanics between PCA and IM opioids (FEV1,FRC,PFR)is seen.
side effects of pca
Side effects of PCA:
  • Nausea ,Vomiting ,Itching.
  • Treated by changing opioid or using drugs that provide symptomatic relief.
  • A pre printed set of standard orders can facilitate a uniform standard of care.
regional anesthetic techniques
Regional Anesthetic Techniques:
  • Advantages:
  • Positive respiratory, cardiovascular and neuroendocrine effects; reduced thromboembolic complications and blood loss; and reduced convalescence
ideal components
IDEAL COMPONENTS
  • Block SENSORY feeling
  • Immobilize MOTOR responses
  • Obtund REFLEXES
  • wipe out MEMORY
  • Control VC and CTZ
  • Not permanent
  • Cause sense of well-being
regional anesthesia
REGIONAL ANESTHESIA

SEGMENTAL LOSS OF SENSATION

BY BLOCKING NERVE CONDUCTION

regional
REGIONAL

1. SPINAL

2. EPIDURAL

4. INTRAVENOUS ( BIER )

5. AXILLARY (INFILTRATION)

6. RETROBULBAR

local anesthetics
LOCAL ANESTHETICS

AMIDES MAX / DOSE

  • BUPIVACAINE 2 MG/KG
  • LIDOCAINE 7 MG/KG
  • ROPIVACAINE 4 MG/KG
  • MEPIVACAINE 7 MG/KG
  • PRILOCAINE 6MG/KG
local anesthetics1
LOCAL ANESTHETICS

ESTERS MAX /DOSE

CHLOROPROCAINE 20 MG/KG

COCAINE 3 MG/KG

NOVOCAINE 12 MG/KG

TETRACAINE 3 MG/KG

local anesthetics2
LOCAL ANESTHETICS

Local anesthetics are the drugs, which reversibly block the generation, propagation and oscillations of electrical impulses in the excitable tissues.

mechenism of action
MECHENISM OF ACTION
  • Block nerve fiber conduction by acting directly on nerve membranes to inhibit sodium ion from crossing the membrane
    • Nerves cannot depolarize
    • Conduction of impulses is blocked
mechanism of action
Mechanism of Action
  • Decrease or prevent transient increase in the permeability of excitable membranes to Na+ ions
  • Direct interaction with voltage gated Na+

channels

  • Increase in threshold
  • Decrease in the rate of rise of A.P.
  • Slows down the conduction
mechanism of action1
Mechanism of Action
  • Site of action - Inside the membrane
  • Binding sites within the Na+ channel
  • Heterotrimeric complexes of glycosylated proteins ( 300 k Da)
  • 3 sub units- a, b1& b 2
  • a has I- IV homologous domains
  • Each domain has 6 transmembrane domains
  • Bind with S6 transmembrane domain.
slide68

CONTRAINDICATIONS

  • RELATIVE
    • Patient Appropriateness
    • Local Infection near injection site
    • Hypovolemia
    • CNS Disease
    • Chronic Back Pain or Prior Lami
    • Prior SAB with difficulty
slide69

Nerve Fiber and Local Anesthetic Setup

Sequence of clinical anesthesia

Sympathetic block (vasodilate & skin T0)

Loss of pain and temperature sensation

Loss of proprioception

Loss of touch and pressure sensation

Loss of motor function

slide70

Interscalene brachial plexus blocks :analgesia for 12-24 hrs.

Sciatic and Femoral n. blocks :similar results.

Intercostal n. blocks : 6-12 hrs. analgesia.

Administration of long acting L.A.s from a catheter into pleural cavity :unilat. Analgesia with little or no sensory block.

L.A. infusion into Axillary sheath, Femoral sheath, and the vicinity of the Sciatic n.:analgesia and particularly useful to facilitate perfusion after extensive revascularization.

Interscalene

l a boluses or infusions
L.A. boluses or infusions :
  • Advantages over parenteral opioids:
  • Early ambulation, improve bowel function, higher arterial O2 tension, fewer pulmonary complications.
  • For optimal results, the catheter tip should be near the segments innervating the insicision.
slide74

Segmental Level of Block Required

    • T-4 to T-6

IntraAbdominal

  • T-6 to T-8

GU, Low Abdominal

  • T-8 to T-10

GU, A/R, Legs

T-4

T-6

T-10

intraspinal analgesia
Intraspinal analgesia:

With:

  • Opioids
  • Opioid-L.A. mixture
  • Ketamine
  • Clonidine
  • Neostigmine
opioids
Opioids:
  • Initial reports in 1979.
  • Single injection of intrathecal Morphin provides about 24 hrs. analgesia.
  • Epidural root uses more, because:
  • Popularity of technique during surgery, ability to leave catheter in place, familiarity with technique, no risk of PDPH.
slide79

Elderly patients require remarkably small doses of epidural morphine.

  • Fentanyl is useful when rapid onset of epidural analgesia is important.
  • Epidural meperidine is widely used in some parts of the world and as with other opioids, respiratory depression can occure.
respiratory depression
Respiratory depression
  • early:
  • In the first two hrs.
  • Is the result of vascular uptake and redistribution.
  • Delayed:
  • Between 6 and 12 hrs.
  • Consequent of rostral spread of opioid in CSF to respiratory center in the floor of 4th. Ventricle.
slide81

Pruritus is a common side effect and is seen more in obstetrics patients.

  • Face is a common site of itching.
  • Although it is not due to histamine release, antihistamines provide symptom relief.
  • Nalbuphine is also of value.
  • Naloxone is consistently effective (repeated doses or infusion).
slide82

Urinary retention is higher in volunteers than in patients and in men than in women.

  • Naloxone prevents or reverses it but may require doses that antagonizes analgesia.
  • Most patients are able to void spontaneously when the catheters are removed.
slide83

Nausea and vomiting: due to rostral spread of opioid in CSF to the vomiting center and the CTZ .

  • Treatment:
  • first line: antiemetics (may produce unwanted sedation and resp. depression ) , Scopolamine patches.
  • Second line: I.V. droperidol, Ondansetrone.
slide84

Sedation produced by intraspinal opioids may be the result of spread of the drug in CSF to receptors in the thalamus, limbic system or cortex and hypercarbia can augment it.

  • Epidural buprenorphine 0.15 mg. produces prolonged depression of the CO2 response that lasts 8-12 hrs.
ketamine
Ketamine:
  • Produces analgesia via interaction with cholinergic, adrenergic, and serotonergic systems.
  • Side effects: sedation, blurred vision, tachycardia, hypertension, and hallucinations.
  • In some studies on baboons : neurotoxic changes.
  • The routine use of intrathecal ketamine in humans is not recommended.
clonidine
Clonidine:
  • If administered by the oral route can augment spinally mediated opioid analgesia.
  • Epidural or intrathecal clonidine can provide effective analgesia alone.
  • Intrathecal clonidine does not provide surgical anesthesia.
intra articular analgesia
Intra-Articular analgesia
  • Following arthroscopic surgery, a combination of systemic Ketorolac and intra-articular bupivacaine decreased analgesic requirement and pain.
nitrous oxide
Nitrous oxide:
  • Useful, especially for painful experiences of short duration (dressing changes, debridements).
  • Rapid onset of analgesia and rapid recovery.
  • In concentrations of 30-50% is as potent as 10 mg. I.M. morphine.
  • “Anesthesia” may occur>>>risk of aspiration.
slide89

Long term administration: causes bone marrow suppression and leukopenia (reversible when detected early).

  • Entonox:50%mixture of N2O with oxygen.
cryoanalgesia
Cryoanalgesia:
  • Temp.s between -5 and -20`causes disintegration of axons and breakdown of myelin sheaths while the perinurium and epinurium remain intact.
  • Is used most common for thoracotomy pain and hernia repair pain.
  • Residual neuropathic pain has been seen following cryoanalgesia.
transcutaneous electrical nerve stimulation t e n s
Transcutaneous electrical nerve stimulation(T.E.N.S.)
  • Uses both for chronic pain and acute perioperative pain.
  • Advantages: absence of opioids side effects (resp. depression, sedation, nausea and vomiting, urinary retention)
  • It is simple, noninvasive and free of toxicity.
slide92

The mechanism of analgesia by TENS is not known and it may be by:

  • Modulation of nociceptive impulses in the spinal cord (gate control theory).
  • Activation of inhibitory area in the brain stem.
  • Stimulation of the release of endorphins, or a combination of these mechanisms.
  • A placebo effect may play a role.
psychologic and other methods
Psychologic and other methods:
  • After surgery patients may suffer ”discomfort” due to headache, NG tubes, drains, IV catheters, or anxiety, fear, and insomnia.
  • Therapy of these problems may result in reporting of less “pain”.
  • Preoperative discussion, reassurance and provision information results in less anxiety, less opioid use and shorter hospital stay.
pediatric patients
Pediatric patients:
  • Misconceptions about pain in children are common (e.g. children don’t feel pain, or if it is felt it is not remembered.
  • Pain causes suffering and psychologic abnormalities in children of all age.
  • Special scales are available for young children (self reporting of pain).
  • In preverbal children, the interpretation of behavior must be used to estimate intensity of pain.
slide97

Because of fear of IM injections alternatives are: sublingual, rectal and transdermal routs.

  • I.V. PCA is effective in children.
  • Caudal opioid analgesia can be used in children.
  • Regional techniques: dorsal nerve block of the penis, or lidocaine jelly, or EMLA creams for circumcision, ilioinguinal and iliohypogastric nerve blocks for pains after orchiopexy and herniorrhaphy, etc.
elderly patients
Elderly patients:
  • The average age of surgical patients will increase in the future.
  • Older patients have more complex cases than younger.
  • PCA & PCEA is ineffective in some elderly patients because of their reluctance.
slide100

Treatment of perioperative pain in elderly remains inadequate because:

  • Fear of complications associated with treatment of pain.
  • Pain is reported less in elderly.
slide101

NSAID,s may have benefits in elderly because:

  • Different site of action that may be more effective.
  • Opioid sparing.
  • An additional anti-inflammatory effect.
  • But they have increased risk of side effects because of decreased renal clearance>>>they doses must be decreased.
advantages of regional anesthesia
Advantages of regional anesthesia:
  • Minimizing physiologic trespass.
  • Pharmacologic simplicity.
  • Reduced blood loss.
  • Fewer thromboembolic complications.
  • Reduced stress response.
  • Less confusion.
  • Less postoperative pain.
slide104

General principles:

  • 1-expect high self-reported pain scores.
  • 2-base treatment decision on objective pain assessment (deep breathing, coughing, etc.).
  • 3-recognize and treat nonnociceptive sources of suffering.
  • Continue opioids for as long as is appropriate for acute pain.
addiction
Addiction:
  • A chronic disorder characterized by compulsive use of a substance resulting in physical, psychologic, or social harm to the user and continued use despite that harm.
clinical triad suggestive of addiction
Clinical triad suggestive of addiction:
  • 1-high self-reported pain scores.
  • 2-high opioid use compared with other patients having similar procedures.
  • 3-a relative absence of opioid-induced side effects.
slide107

PCA is not good for providing basal opioid replacement.

  • PCA is good for extra opioids needed for postoperative pain.
slide109

Anesthesiologists are a logical choice to provide periop. Pain relief, because they are:

1-familiar with the pharmacology of analgesics and L.A.s.

2-aware of short- and long-term effects of drugs given intraoperatively.

3-knowledgeable about pain pathways and their interruption.

4-are skilled in techniques available to provide superior pain control.

lest you forget

LEST YOU FORGET

Discomfort from:

Full bladder/bowel/gasses

Noise

Alarms

Visitors

Painful IV site

Multiple lines

Repeated disturbance from medical personnel

Complications of analgesic drugs

Other pathological complications

t hank you

Thank You 

Dr.

Date: