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Use of Steroids and IVIG in ICU

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Use of Steroids and IVIG in ICU Dr. Natalie Leung Dr. KC Chan Feb 2008 IVIG in ICU Immunoglobulins Normal serum contains IgG, IgM, and IgA They are referred to as ... – PowerPoint PPT presentation

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Title: Use of Steroids and IVIG in ICU


1
Use of Steroids and IVIG in ICU
  • Dr. Natalie Leung
  • Dr. KC Chan
  • Feb 2008

2
IVIG in ICU
3
Immunoglobulins
  • Normal serum contains IgG, IgM, and IgA
  • They are referred to as natural antibodies
    because they are induced without deliberate
    immunization and are independent of antigenic
    exposure.
  • They are considered key to the immunoregulatory
    effects of immune globulin in immune-mediated
    disorders

4
IVIG
  • IV intravenous
  • IG immunoglobulin

5
IVIG
  • It is made from large volumes of human plasma by
    a method ethanol fractionation
  • Developed by E.J. Cohn in early 1940s.
  • It is a plasma product  formed by taking
    antibodies from about 3000-10000  donors and
    mixing them together.

6
  • IVIG contains
  • Sterile, purified immunoglobulin
  • 95 unmodified IgG
  • Only trace amounts of IgA or IgM
  • Cytokines
  • Sucrose/ glucose/ some other sugar (based on the
    manufacturers)

7
2 preparations of IVIg
  • Monoclonal
  • Contain a single class of Ig directed against a
    single epitope of those present upon a target
    molecule
  • Predominantly IgG
  • Polycloclonal
  • Containing Igs directed against multiple epitopes
    of the target substance
  • IgG, IgM and minor amounts of IgA

8
IgG
  • IgG
  • A Y shaped antibodies
  • It has intact Fc-dependent effector functions

9
IgG

10
IgG
  • The Fc region of IgG facilitates interaction with
    and signaling through Fc receptors on
  • phagocytes, B cells, and other cells and with
    Fc-binding plasma proteins (e.g. components of
    the complement system).

11
  • Thus, peripheral tissues that are defended mainly
    by IgA antibodies are not fully protected by IVIG
  • Eyes, lungs, gut and urinary tract

12
Possible mechanisms
13
IVIG how does it work?
  • Boost the patients immunological capacilities
  • In those with immune deficiency
  • IVIG  maintain adequate antibodies levels to
    confer a passive immunity
  • In sepsis
  • Increase opsonization and phagocytosis
  • Activation of complement system

14
  • Blunt an autoimmune response
  • Downregulation of the inflammatory response by
    the reduction of TNF and other inflammatory
    mediators
  • Increase the soluble receptors for a number of
    cytokines
  • E.g. Guillian-Barre Syndrome, Myasthenia gravis

15
Why is IVIG so expensive?
  • It is a plasma product  formed by taking
    antibodies from about 3000-10000  donors.
  • Ethanol fractionation is used as an initial step
    in the preparation of pooled immunoglobulin
  • In the past, infusion resulted in a variety of
    serious reactions
  • Need IM injection
  • More painful and slow absorption

16
Why is IVIG so expensive?
  • Several steps were added to the fractionation
    process
  • Extraction at low pH
  • Addition of sugars to decrease aggregation
  • Lots of procedures are needed to remove
  • Protein contaminants (to get the concentrated
    IgG)
  • Deactivate viral contaminants
  • E.g. HBV, HIV

17
How long does it take to have effect?
  • Patients may see a response in their disease
    within 24- 48 hrs after IVIG infusion
  • Some patients will have to wait 3-4 weeks to see
    an effect after IVIG
  • In a few no effect may be seen following IVIG
    infusion.
  • If 4-5 cycles of IVIG do not show any response
    then try a different approach like
    plasmapheresis, cytotoxic or immune suppressants.

18
Side effects
  • Occur in lt5 of patients
  • Common side effects (self-limited)
  • Fever, chlls
  • Myalgias, nausea and dyspnoea
  • Headache (more common in females with history of
    Migraines/ SLE, often 24-72hrs after infusion)
  • Flu like symptoms
  • Fatigue
  • Changes in BP
  • Aseptic meningitis

19
Side effects
  • If this happen
  • Slow down the infusion rate
  • Pre-medicate the patient with antihistamines and
    steroid

20
Other rare adverse reactions
  • Acute renal failure
  • From 6/1985- 11/1988, the US FDA received 120
    reports worldwide
  • It occurs with the sucrose-stablized formulation,
    but not with the D-sorbitol-stabilized
    formulation (? Related to the sugar content and
    osmolality)
  • The FDAs Center for Biologics Evaluation and
    Research (CBER)
  • Issued a warning about ARF and administration of
    IVIG
  • Ensure patients are adequately hydrated

21
Other rare adverse reactions
  • The FDAs Center for Biologics Evaluation and
    Research (CBER) list the risk factors
  • Pre-existing renal insufficiency
  • DM
  • Age gt 65
  • Volume depletion
  • Sepsis
  • Paraproteinaemia
  • Anyone who may be on concomitant nephrotoxic
    drugs

22
Other rare adverse reactions
  • Thromboembolic events
  • E.g. CVA/ TIA/ MI/ DVT
  • Risk factors underlying HT, hypercholesterolemia,
    AF, history of vascular disease
  • Vucic S
  • Thromboembolic complications of intravenous
    immunoglobulin treatment. Eur Neurol. 200452(3)1
    41-4

23
Indication
  • It have been used in a wide variety of diseases
  • Primary and secondary immune deficiency states
  • Autoimmune disorders
  • Prophylaxis and treatment of bacterial and viral
    infection

24
6 conditions approved by FDA
  • ITP
  • Primary immunodeficiencies
  • Chronic B-cell lymphocytic leukemia
  • Pediatric HIV infection
  • Kawasaki syndrome
  • Haematopoietic stem cell transplantation in
    patients older than 20 years

25
Other applications have been outlined by National
Guideline Clearinghouse
  • Hematology
  • Aplastic anaemia
  • Autoimmune hemolytic anaemia
  • Immune-mediated neutropenia..
  • Infectious diseases
  • Conditions in which acquiring an infectious
    disease could be deleterious include low birth
    weight (ie, lt1500 g), solid organ
    transplantation, surgery, trauma, burns, and HIV
    infection.

26
Other applications have been outlined by National
Guideline Clearinghouse
  • Neurology
  • Guillain-Barre Syndrome
  • Myasthenia gravis
  • Chronic inflammatory demyelinating polyneuropathy
  • Lamber-Eaton syndrome
  • Multiple sclerosis

27
Other applications have been outlined by National
Guideline Clearinghouse
  • Obstetrics
  • Recurrent pregnancy loss
  • Respiratory
  • Asthma
  • Chronic chest symptoms
  • Rheumatology
  • RA
  • SLE
  • Dermatomyositis, polymyositis
  • Systemic vasculitis

28
New uses of IVIG lung disease
Role of Intravenous Immunoglobulin in Severe
Steroid-Dependent Asthma Haque S, Boyce N, Thien
FC, O'Hehir RE, Douglass J Intern Med J.
200333341-344
  • Severe Steroid-Dependent Asthma
  • IVIG provides a potentially important adjunctive
    therapy in severe steroid-dependent asthma,
    reducing steroid requirement and decreasing
    hospital admissions, but not improving lung
    function.

29
  • Possible mechanisms
  • The mechanism by which steroid resistance
    develops may be related to elevated levels of
    interleukin 2 (IL-2) and IL-4 in the airways of
    steroid-resistant asthmatic patients
  • IVIG reduces production of IL-2 and IL-4 by T
    cells

30
New uses of IVIG Sepsis
  • Polyclonal IVIG are used off-label either to
    prevent sepsis in at-risk subjects, or to treat
    existing sepsis and its consequences

31
Mechanisms of IVIG in sepsis
  • Blunt the perpetuation of the initial response by
    attenuating the trigger substances
  • Igs against antigens present on the surface of
    the infecting microorganisms
  • It also against the factors that are released
    when the organisms is killed by antibiotics
  • E.g. endotoxin, peptidoglycans

32
  • Inactivate the sepsis mediators that are produced
    and released in a more advanced phase of the
    inflammatory process, or
  • Neutralize the receptors for these substances
    located on the cell surface

33
Why polyclonal IVIG is used?
  • In septic patients, elevated levels of IgM
    anti-endotoxin antibodies are associated with a
    better outcome
  • Thus, IgM-enriched polyclonal IVIG can replicate
    this effect.

34
Why polyclonal IVIG is used?
35
New uses of IVIG Sepsis
Polyclonal Intravenous Immunoglobulin for the
Treatment of Severe Sepsis and Septic Shock in
Critically Ill Adults A Systematic Review and
Meta-analysis Kevin B. Laupland Critical Care
Medicine 200735(12)2686-2692
  • To assess whether adjunctive therapy with IVIG
    reduces mortality among critically ill adults
    with severe sepsis and septic shock

36
  • 14 RCTs published between 1988- 2006 were included

37
  • Characteristics of the included studies

Of the 14 included studies -13 had
intention-to-treat data available - only nine had
adequately concealed randomization - in six the
investigators and patients were blinded to
treatment allocation
38
  • The effect of IVIG on mortality in adult patients
    with severe sepsis or septic shock was 0.66 (95
    confidence interval CI 0.53-0.83 p lt .0005),
    indicating a significant reduction in mortality
    for patients treated with IVIG

39
  • This systematic review demonstrated a significant
    reduction in mortality in critically ill adult
    patients with severe sepsis and septic shock
    treated with polyclonal IVIG

40
In pediatric patients
  • In streptococcal toxic shock syndrome
  • Use of polyclonoal IVIG 2g/kg for 1-2 doses has
    been associated with reduced mortality
  • In vitro evidence suggests that IVIG can
    neutralize superantigen activity
  • Premature newborns of low birth weight
  • Relatives insufficiency of humoral immunity
  • Susceptible to sepsis
  • Meta-analysis showed the use of IVIG marginal
    reduction of early-onset neonatal sepsis

41
Cost
  • IVIG
  • US8050- 40000/ life saved
  • Activated protein C
  • US140000- 170000/ life saved
  • PYNEH 650/ 3g

42
Steroid in ICU
43
  • What is steroid?
  • Common use of steroid
  • Use of steroid in critically ill patients

44
What is steroid?
  • Steroids are small molecules which are
    synthesized in 3 places in human body

Pituitary gld smallest amount
Adrenal cortex
Testicles in men Ovaries in women
45
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46
  • Function of adrenal steroids
  • Influence metabolism (carbohydrate/ protein/
    lipid)
  • Confer resistance to stress
  • Regulation of immune function
  • Modulation of the immune response
  • Electrolyte and water balance (sodium retention/
    alter potassium excretion in urine)

47
  • Function of adrenal steroids
  • Influence metabolism (carbohydrate/ protein/
    lipid)
  • Confer resistance to stress
  • Regulation of immune function
  • Modulation of the immune response
  • Electrolyte and water balance (sodium retention/
    alter potassium excretion in urine)

Glucocorticoid effect Mineralocorticoid effect
48
Synthetic steroid
  • Replacment therapy
  • Low dosage
  • Adrenal insufficiency
  • Treatment of non-endocrine diseases
  • Higher doses

49
Synthetic steroid
  • 2000 years ago, some Roman evaporated the urine
    and get the powdered residue.
  • These residue contains high level of
    testosterone/ estrogen
  • The patients would experience some ve and ve
    effects of these powdered residue

50
  • The Father of modern steroid
  • Adolf Winhaus
  • Synthesized the first steroid
  • Received the 1927 Nobel Prize in Chemistry

51
Synthetic steroids
  • Glucocorticoids
  • Prednisolone/ prednisone
  • Methylprednisolone
  • Dexamethasone
  • Betamethasone
  • triamcinolone
  • Mineralocorticoid
  • Aldosterone
  • Fludrocortisone

52
  • Basic glucocorticoid structure

Increase glucocorticoid and / or
mineralocorticoid activity
53
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54
Pharmacokinetics
  • Most cortisol in serum is bound to proteins
  • Corticosteroid-binding globulin (or transcortin)
  • (Changes in binding proteins level can alter
    total cortisol concentration)
  • The binding affinity of synthetic steroid varies
  • Hydrocortisone 95
  • Prednisolone 60
  • Therefore, they are either bound weakly to
    albumin or as free steroid

55
Pharmacokinetics
  • Administration
  • Oral/ IMI/ IV/ topical/ inhaled
  • Half-life
  • Range from 1 hr for prednisolone to 4hrs for
    dexamethasone
  • Clearance is slower in
  • Elderly
  • Renal and hepatic diseases

56
Measurement of cortisol level
  • Many tests available
  • Serum total cortisol
  • Free cortisol
  • Cosyntropin-stimulated serum total cortisol
  • Which one is recommended in critically ill
    patients?

57
  • Free cortisol should be measured in critically
    ill patient
  • As most critically ill patients are
    hypoproteinemia
  • Binding proteins level is lower, which alter
    meaured serum total cortisol concentration

58
Mechanisms of action
  • Cortisol diffuse into target cells
  • Binds to a cytoplasmic glucocorticoid receptor
  • The activated receptor-drug complex enters the
    nucleus and binds to a specific glucocorticoid
    regulatory element on target DNA molecules,
    initiating or inhibiting gene transcription.

59
Effects of glucocorticoid
  • Metabolic effects
  • Facilitate conversion of protein to glycogen
  • Inhibit protein synthesis and stimulate protein
    catabolism to amino acid
  • Stimulate gluconeogenesis
  • It is vital to prevent hypoglycaemia during
    fasting

60
Effects of glucocorticoid
  • Anti-inflammatory
  • Reduce circulating immunocompetent cells and
    macrophages
  • Reduce formation of inflammatory mediators.
  • E.g. prostaglandins, leukotrienes

61
Effects of glucocorticoid
  • Immunosuppressive effects
  • Depress monocyte/ macrophage function
  • Decrease circulating thymus-derived lymphocytes
    (esp helper T4 lymphocytes)
  • Inhibit the release of interleukins IL-1 and IL-2
  • Inhibit the production of antibody

62
  • Most synthetic glucocorticoids are
  • Higher affinity for the receptor
  • Less rapidly inactivated
  • Have little or no salt-retaining properties

63
Common used glucocorticoids
  • Hydrocortisone
  • The pharmacologic form of cortisol
  • Prednisone/ dexamethasone/ methylprednisolne
  • Additional pharmacologic glucocorticoids
  • Compare to hydrocortisone
  • the other pharmacologic glucocorticoids bind
    cortisol binding globulin (CBG) poorly, resulting
    in more free, physiologically active
    glucocorticoid and greater potency at any given
    dose

64
Corticosteroid preparation
65
Characteristics of common used steroids
  • Hydrocortisone
  • Oral for replacement
  • IV shock/ status asthmaticus
  • Topically ointment for eczema
  • Prednisolone
  • Most widely used in inflammatory disease and
    allergic diseases

66
  • Dexamethasone
  • Very potent (25 times of hydrocortisone)
  • No salt retaining actions
  • Especially useful for high-dose therapy in
    conditions e.g. cerebral edema
  • (as water retention would be a disadvantage)

67
  • Beclomethasone/ budesonide
  • Pass membranes poorly
  • More active topically than when given orally
  • Commonly used in asthma/ eczema

68
Normal serum cortisol production
69
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70
In critically ill patients
  • During physiological stress
  • E.g. major surgery, hypotension, severe infection
  • The HPA axis is activated
  • Diurnal variation is lost
  • Serum cortisol increase

71
In critically ill patients
However, there are circumstances in which
cortisol availability can not be increased
sufficiently to meet demand
72
Circumstances which may affect cortisol production
  • Head injury
  • Infections
  • Malignancy
  • Drugs
  • Etomidate
  • CNS depressants
  • Pituitary infarction
  • Adrenal haemorrhage
  • Previous glucocorticoid therapy

73
In critiically ill
  • Absolute adrenal deficiency is rare
  • However suboptimal production is common

Raise the interest in the possible therapeutic
role of glucocorticoid in severe infection
74
Steroid in critical ill
  • The use of steroid in critical illness has
    existed since the early 20th century.
  • 20th century
  • Adrenal glands are crucial to survival under
    conditions of physiologic stress
  • 80th century
  • The role of steroids in the treatment of septic
    shock has generated significant interest.

75
In the 1980s
  • 3 prospective, randomized, double-blind,
    placebo-controlled studies
  • The effects of high-dose corticosteroids in
    patients with septic shock. A prospective,
    controlled study
  • N Engl J Med 1984 Nov 1311(18)1137-43.
  • A controlled clinical trial of high-dose
    methylprednisolone in the treatment of severe
    sepsis and septic shock.
  • N Engl J Med 1987 Sep 10317(11)653-8.
  • Effect of high-dose glucocorticoid therapy on
    mortality in patients with clinical signs of
    systemic sepsis. The Veterans Administration
    Systemic Sepsis Cooperative Study Group.
  • N Engl J Med 1987 Sep 10317(11)659-65

76
In the 1980s
  • 3 prospective, randomized, double-blind,
    placebo-controlled studies
  • The effects of high-dose corticosteroids in
    patients with septic shock. A prospective,
    controlled study
  • N Engl J Med 1984 Nov 1311(18)1137-43.
  • A controlled clinical trial of high-dose
    methylprednisolone in the treatment of severe
    sepsis and septic shock.
  • N Engl J Med 1987 Sep 10317(11)653-8.
  • Effect of high-dose glucocorticoid therapy on
    mortality in patients with clinical signs of
    systemic sepsis. The Veterans Administration
    Systemic Sepsis Cooperative Study Group.
  • N Engl J Med 1987 Sep 10317(11)659-65

77
  • None of the trials found a mortality benefit
  • Only 1 trial noted decreased duration to shock
    resolution associated with the administration of
    glucocorticoid
  • Remarks
  • All of the trials administrated high dose
    glucocorticoids (e.g. methylprednisolone 30mg/kg
    )
  • Used early endpoints (e.g. 14 days mortality)

78
In 1990s
  • New interest about smaller, more physiological
    doses of steroid for longer duration

79
Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality
in patients with septic shock. JAMA 2002 Aug
21288(7)862-71.
  • The largest double-blind, placebo-controlled
    trial
  • 300 patients were randomized within 8 hrs of the
    onset of septic shock
  • To receive placebo or
  • Hydrocortisone (50mg Q6H) fludrocortisone
    (50mcg QD)
  • Classify the patients to have adequate adrenal
    reserve/ inadequate reserve by ACTH stimulation
    test

80
  • Results
  • In the inadequate adrenal reserve group,
    hydrocortisone administration was associated with
    decreased
  • 28 days mortality
  • ICU mortality
  • Hospital mortality
  • More vasopressor withdrawal within 28days
  • No difference in mortality in adequate adrenal
    reserve group

81
Corticosteroids for treating severe sepsis and
septic shock. Cochrane Database Syst Rev
2004(1)CD002243.
  • A meta-analysis of 15 randomized, controlled
    trials (2023 patients)
  • Examine glucocorticoid administration in severe
    sepsis and septic shock
  • Use of glucocorticoid was associated with
  • Increased shock reversal by days 7 and 28
  • Low dose glucocorticoid used gt 4 days
  • Reduced 28-day mortality
  • Reduced ICU mortality
  • Reduced hospital mortality

82
  • Most studies investigating the therapeutic role
    of glucocorticoid in critically ill patients with
    septic shock
  • Whether these findings can be applied to other
    critical illnesses is unknown

83
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84
  • A multicenter, randomized, double-blind,
    placebo-controlled trial

85
  • Included total 499 patients
  • All with septic shock and remained hypotensive or
    required treatment with vasopressors for at least
    1 hour after adequate fluid resuscitation
  • Study group
  • Hydrocortisone 50mg Q6H for 5 days, then tapered
    during a 6 days period

86
  • Primary end point
  • 28 days mortality in patients who did not
    response to corticotropin
  • Secondary end point
  • 28 days mortality in those response to
    corticotropin and in all patients
  • The rates of death in ICU and in the hospitals
  • The rate of death at 1 year
  • A reversal of organ system failure
  • Length of stay in ICU and hospital

87
Kaplan-Meier Curves for Survival at 28 Days
88
Kaplan-Meier Curves for the Time to Reversal of
Shock
89
  • Hydrocortisone did not improve survival in
    patients with septic shock, either overall or in
    patients who did not have a response to
    corticotropin
  • Use of hydrocortisone resulted in more rapidly
    reversal of shock
  • (However, more rapid weaning from vasopressors
    does not improved survival!)

90
Other common indications of steroid in ICU
  • Chest
  • Asthma/ COPD
  • Other lung condition
  • Autoimmune diseases
  • Newly diagnosed or previously on steroid
  • Neurological condition
  • Brain mass
  • Meningitis

91
Conclusion
  • IVIG
  • Although use of polyclonal IVIG is not
    recommended in current guidelines, recent studies
    found administration of it was associated with
    better outcomes.
  • Further investigation is required before
    introducing it into clinical practice.

92
Conclusion
  • Steroid
  • Steroid is a very common medication being used in
    ICU
  • Different preparations of steroid is recommended
    in different situations
  • Use of steroid is recommended in severe sepsis
    and septic shock according to Surviving Sepsis
    Campaign.

93
The End
  • Thank you
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