Medicaldump.com_Sickle cell disease _ pain crisis.pptx

7/27/2019 Medicaldump.com_Sickle cell disease _ pain crisis.pptx

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SICKLE CELL PAINFUL CRISIS


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HEMOGLOBIN

Normal hemoglobin consists of2 beta-globin protein chains

2 alpha-globin chains

heme

Hb S An abnormal, mutated B1-globingene, the sickle hemoglobin gene, in which

valine replaces glutamine in position 6 of thebeta globin chain


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Courtesy: Noguchi CT, NIH


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Sickle cell trait (Hb AS) Inheritance of onenormal hemoglobin gene (HbA) from oneparent and one abnormal Hb S from another

parent

Sickle cell disease Inheritance of Hb S andone other abnormal hemoglobin. Commonvariants include:Sickle Cell Anemia (HbSS)Sickle--ThalassemiaSickle-C Disease (HbSC)


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Source: Bridges KR & Pearson HA. Anemias and other red cell disorders. McGraw Hill Medical Publishing division,

2008, p.247


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Major Haplotypes

Asian (Arabo-Indian) haplotype originated

in Central India or Saudi Arabia

Benin haplotype

Central West Africa Senegal haplotype West African region

above the Niger river

Bantu (or CAR) haplotype - south centralAfrica. Associated with severe disease.

(Powers et al. Am J Pediatr Hematol Oncol 1994; 16: 55-61)


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RBC SICKLING

RBC sickling and

polymerization occurs in

Severe tissue hypoxia

Acidosis

Increased viscosity

Dehydration

Hypothermia

Severity of

polymerization depends

on % HbS


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VASO-OCCLUSION

Also involves

Adherence of WBCs and other circulating blood

elements to endothelial cells

Hypercoagulability Endothelial dysfunction

Altered nitric oxide metabolism

Ischemia-reperfusion injury


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Nociceptive pain involves Transduction tissue damage generates noxious

mediatorsthat activate nociceptors in primary afferent nervefibers

Transmission

the painful stimulus is transmitted to thedorsal horn of the spinal cord and to the thalamic and limbicsystem

Modulation descending fibers from the midbrain to thedorsal horn can inhibit transmission of the painful stimuli

Perception- final pain perception is subjective and involves

a complex interplay the enhancing and inhibitory factors atlevel of CNS in addition to a host of co-existing psychosocialand environmental factors


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PAIN TYPES

SOMATIC - e.g. bones, joints, muscles

VISCERAL e.g. liver, spleen

NEUROPATHIC aberrant processing in the

central or peripheral nervous system. No truenerve damage

IATROGENIC healthcare related

-Tolerance associated

- withdrawal associated-Pseudoaddiction


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Pain Intensity, by Percentage of Pain Days*.

Smith W R et al. Ann Intern Med 2008;148:94-101

2008 by American College of Physicians


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Mean Percentage of Days When Each Patient Reported Crises, Utilization, or Both.




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Breakdown of diary days.Total diary days (n = 31 017) are reported by percentage in 4mutually exclusive categories of pain severity, and mean pain intensity is reported by

category.




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ACUTE PAINFUL CRISIS

New onset of pain that lasts at least 4 hours

for which there is no explanation other than

vaso-occlusion and which requires therapy

with parenteral opiods or ketorolac in amedical setting

Ballas SK et al. Am J Hematol 2010; 85:6-13


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PAINFUL CRISIS

Hallmark of the disease

Episodic and variable in intensity

Unpredictable

Triggered by known and unknown risk factors

Prognostic significance more frequent

episodes predict poorer survival


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TRIGGERS

Stress Emotional and physical

Cold weather

Infections

Physical exertion

Hypoxia

Menstruation

Pregnancy


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VASO-OCCLUSIVE PAIN

Mainly nociceptive

Pain from tissue

ischemia Occurs in a variety

of vascular beds

Most often affected

sites Deep muscle

Periosteum

Bone marrow


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Painful Crisis Frequency

Platt OS et al. N Engl J Med 1991;325:11-16


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Painful Crisis Frequency(continued)

Platt OS et al. N Engl J Med 1991; 325:11-16


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Crisis frequency predicts survival

Patients with morefrequent painful

crises have poorer

survival

Platt OS et al. N Engl J Med 1991; 325:11-16


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Serjeant GR et al. Br J Hematol 1994; 87: 586-591


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TIME COURSE

Recurrent self limited, discrete episodes that

occur as isolated events

Persistent

painful episodes continue for longerthan usual duration despite treatment


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.

Ballas, S. K. Hematology 2007;2007:97-105

Figure 2. A typical profile of the events that develop during the evolution of a severe sicklecell painful crisis in an adult in the absence of overt infection or other complications


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MANAGEMENT (standard)

Oxygenation

Hydration

Nonpharmacologic approaches Pharmacologic Pain management

Non-opiods Opiods

Adjuvants


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Management (non-standard)

PRBC transfusion Simple blood transfusion

Exchange transfusion

Chronic transfusions

Anti-Sickling agents Niprisan

Anticoagulation

Others Steroids

Magnesium sulfate


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OXYGENATION

Keep oxygen saturation above 96%

No benefit from excessive oxygenation

Oxygen can be harmful

Suppreses erythrocyte production

Depresses reticulocytosis

Causes rebound sickle cell crisis

Embury SH et al. N Engl J Med 1984; 311:291-5


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HYDRATION

Hypotonic fluid is preferable over saline Hyposthenuria leads to free water loss

Infusion of large quantitities of saline can inducehyperchloremic metabolic acidosis

Induced hyponatremia leads to less sickling

Decreased viscosity leads to less sickling

Total fluid about 1.5 X maintenance(45ml/kg/24hrs).

Overhydration contributes to onset of acute chestsyndrome

(Keitel et al. 1956; Rosa et al. 1980, 1982)


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NON-PHARMACOLOGIC APPROACH

Relaxation

Music

MassageDistraction

Self-hypnosis

Heat or ice packs

Music

Acupuncture


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Pain Management

Mainstay of management

Non-opiods have a ceiling effect, a dose above

which no additional analgesic benefit is

attained Opiods are often required and necessary for

effective pain control. Have no ceiling effect.


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ISSUES WITH OPIOD USE

Choice and dose should be based on past

history and experience

Titrate dose to adequate pain relief

Tolerance

a state of adaptation in which moredrug is needed to produce the same effect.

May lead to requirement of exceptionally high

doses of medication over time.


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PSEUDOADDICTION

Undertreatment of pain may lead to the patient

exhibiting drug seeking behaviors like

exagerating response to pain in the presence

of physician or frequently asking for more painmedications


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Opiod-induced hyperalgesia

Chronic administration of opioid to treat pain

may contribute to or cause pain

More common with morphine

Pain often involves the same sites involvedwith the vaso-occlusive crisis

Tends to be neuropathic pain with minor

ambient stimuli inducing severe pain


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Blunted Opiod response

Seen at days 4-6 in some patients

Patients remain in severe pain despite high

doses of opiods

Transgenic sickle cell mouse models founddecreased expression of mu opiod receptors

after 3 days of opiod therapy


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Transition to chronic pain

Intractable chronic pain, with no obvious

sign, may result from inadequate treatment

of recurrent severe acute painful crises

Results from central sensitization, whereby

pain threshold is lowered

Once chronic pain sets in, it becomes

independent of vaso-occlusion andpercentage of Hb S


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Chronic pain syndrome can still be punctuated

with superimposed acute painful crises due to

vaso-occlusion

Must be managed like other chronic painsyndromes


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MORPHINE

Strong opioid agonist

Has active metabolites, M6G and M3G

M6G is 4-times more potent than morphine

and has a longer half-life than morphine Hydrophilic rapidly distributes to tissues

Histaminergic causes severe pruritus

Accelerates retinopathy and renal injury intransgenic sickle mice


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Methadone

Has a long half-life of at least 36 hours but shortduration of analgesic effect (4-6 hrs)

Prolongs QTc interval and associated with fatalarrythmia

Associated with mortality more than any otheropioid

EKG monitoring useful in prolonged use

Useful in treating chronic pain

Oral and parenteral preparations are available Oral absorption rate is twice that of morphine


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MEPERIDINE

Use is controversial

Associated with seizures in 1%-12%

A subset of adult patients with SCD obtain

relief from pain with only meperidine


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ADJUVANTS

Antihistamines Antidepressants

Anticonvulsants Benzodiazepines

Phenothiazines Antiemetics

Laxatives Clonidine


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SIMPLE BLOOD TRANSFUSION

Higher H/H values areassociated with morepainful episodes

Transfusion dilutes Hb Sbut increases viscosity

Transfusion is needed insymptomatic anemia,

sequestration crisis, andin aplastic crisis

Do not exceed Hb of

10g or Hct of 30


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EXCHANGE TRANSFUSION

Acute Chest syndrome

Priapism

Stroke

Retinal arterial vaso-occlusion

Hepatic failure

Septic Shock

Refractory painful crisis Chronic transfusion

regimen

Wayne A et al. Blood 1993; 81(5):1109-1123


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16% Early Readmission rate

Inappropriate management of the

hypercoagulable state, evident at the stage of

resolution.

Premature discharge Opioid withdrawal syndrome after discharge


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NOVEL THERAPIES


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NIX-0699 (NIPRISAN)

Extracts from 4 medicinal plants used forcenturies in Nigeria

Active ingredients and exact mechanism ofaction unknown

In vitro, inhibits RBC sickling and produces leftshift of the oxygen-dissociation curve

In phase 2 cross-over study, effective in

reducing painful crises over a 6 month period No serious side effects noted

Wambebe C et al. Phytomedicine 2001; 8(4): 252-61


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TINZAPARIN

Low molecular weight heparin

Decreases p-selectin-mediated cell adherence

to vessel wall

Decreases coagulation activation

Decreases overall duration of painful crisis

Recommended dose: 200-240IU/kg daily.

No renal dose adjustment is needed.

Qari MH et al. Tromb Haemost 2007; 98(2): 392-396


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Magnesium Sulfate

Significantly shorter hospital stay reported in a

single study of 19 hospitalized patients

Variable doses used in that study (40mg/kg (max

2.5g/dose) q8hrs for 4 days vs 3 doses (max 1.5g/ dose) only)

Unclear if response is dose-dependent

Brousseau DC et al. Acad Emerg Med 2004; 11: 968-972

STEROIDS


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STEROIDS

No effect on RBC sickling in-vitro

Probable beneficial anti-inflammatory effect

Short courses of dexamethasone (0.3mg/kg),prednisone (2mg/kg/day), or methylprednisone(15mg/kg/day) associated with

Decreased hospital stay

Decreased number of opioid dosesDecreased need for transfusions

Griffin TC et al. N Engl J Med 1994; 330(11):733-7; Bernini JC etal. Blood 1998;

92(9):3082-9; Kumar et al. J Pediatr Hematol Oncol 2010; 32 (3):e91-4.


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Steroids - Disadvantages

Higher rates of rebound pain and readmission

within 72hrs

Increased risk of avascular necrosis

Mental status changes

Pancreatitis

COMPLICATIONS


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COMPLICATIONS

Fat embolism

Priapism

Stroke Acute Chest syndrome

Infections

Site-Specific Infarcts

Bone marrow Phalangeal

Renal Medulla

Pulmonary

Chronic

Leg ulcers

Pulmonaryhypertension

Proliferativeretinopathy

Aseptic hip necrosis

Renal failure


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Definitions of pain-related terminology

Nociception The neural processes of encoding and processing noxiousstimuli

Nociceptors A receptor on primary afferent fibers preferentially sensitiveto a noxious stimulus or to a stimulus that would become

noxious if prolonged

Hyperalgesia An increase in pain to a stimulus that is normallypainful

Allodynia Pain evoked by a stimulus that does not normally provokepain

Central Enhanced excitability of nociceptive neurons in theSensitization dorsal horn of spinal cord resulting from tissue damage or

inflammation

Neuropathic pain Pain initiated or caused by a primary lesion ordysfunction in the nervous system

Nocifensive behavior Behavioral responses to noxious stimuli


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Papillary necrosis

Medicaldump.com_Sickle cell disease _ pain crisis.pptx

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