Page 1783 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

1252 PART 11: Special Problems in Critical Care

■ CALCINEURIN INHIBITORS an IL-1 associated autoinflammatory disease. Additional agents with
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The use of cyclosporine and tacrolimus outside the setting of clinical longer half-lives have been recently developed but experience is limited.
or dermatomyositis. The mechanism of action and dosing intricacies ■ B-CELL DEPLETION
transplantation is unusual with the possible exception of polymyositis
of both drugs are very similar. There is an accelerating trend favoring Rituximab is a chimeric (mouse/human) monoclonal antibody that
the use of tacrolimus in organ transplantation because the incidence of targets the CD20 molecule on B cells. CD20 is unique to B cells and is a
hypertension, hyperlipidemia, and nephrotoxicity appear to be less than stable transmembrane marker expressed during all stages of their matu-
with cyclosporine. In a critically ill patient, maintenance of therapeutic ration. The monoclonal antibody depletes B cells by activating apoptosis
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plasma levels of a calcineurin inhibitor requires intensive monitoring signals and complement and Fc receptor cytotoxicity. Rituximab has an
of trough drug levels and frequent dose adjustments. A disparate group extensive history of effective use in B-cell lymphomas, and has a surpris-
https://kat.cr/user/tahir99/
of commonly used drugs affect calcineurin inhibitor metabolism and ingly low number of significant side effects that can be characterized as
eternal vigilance is required to prevent sudden decreases to subthera- constitutional symptoms of fever, chills, and rare hypotension attribut-
peutic levels or increases that are toxic. The volume-depleted patient is able to cytokine release. All of the latter are most frequently experienced
especially susceptible to renal failure caused by either calcineurin inhibi- on the first infusion and may be more common in lymphoma patients
tor. Acute, severe gouty arthropathy is extremely common in patients with a large lymphocyte burden. The ability to selectively target and
being treated with cyclosporine. destroy B cells has generated tremendous interest in the rheumatologic
■ INTRAVENOUS GAMMA GLOBULIN community because rituximab may offer a novel way to treat autoanti-
body-mediated autoimmune diseases like SLE, myasthenia gravis, auto-
Intravenous infusion of pooled IgG antibodies from large numbers of immune hemolytic anemia, and Goodpasture syndrome. In critically
normal volunteers activates a diverse spectrum of immunomodulatory ill patients who cannot tolerate or have failed alkylating agent therapy,
rituximab offers the option of suppression of autoantibody production.
effects. The primary mechanism may be mediated by downregulation of
Fc receptors on neutrophils and macrophages and inhibition of B-cell The creative use of rituximab in autoimmune disease will be limited only
by the imagination of the rheumatologist, and the reality is that wide-
antigen receptors, but cytokine, idiotypic, and major histocompatibility
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antibodies may play a role also. The spectrum of immunomodula- spread off-label use is already in progress. However, it is doubtful that
many of its diverse applications will be confirmed by appropriate clini-
tion provides a rationale for the use of intravenous immunoglobulin
(IVIg) in patients who require immunomodulation, but cannot tolerate cal trials. In theory, the focused destruction of B cells could culminate
eventually in hypogammaglobulinemia and put the patient at high risk
other agents because their bone marrow is suppressed or hypoplastic.
High-dose IVIg therapy may be indicated for therapy-resistant immune- for bacterial infection. Careful monitoring of serum immunoglobulin
levels in these patients is warranted.
mediated thrombocytopenia associated with significant bleeding,
transiently elevate platelets or prolong the half-life of transfused platelets ■ INTERLEUKIN-6 INHIBITION
especially gastrointestinal bleeding, or when there is a need to either
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prior to splenectomy. These modified, biologically active immunoglob- Tocilizumab is a newer monoclonal antibody that binds to and inhibits
ulins are given at approximately a 0.4-g/kg dose and followed by platelet interleukin-6 receptors, reducing inflammation. It is approved for use in
transfusions as indicated. Imaginative uses of these expensive biologics the treatment of rheumatoid arthritis as monotherapy or in combination
are frequent, usually in disease settings where all else has failed. Adverse with methotrexate and is given via intravenous infusion. For a creatinine
effects from the use of IVIg include infusion reactions; uncommon but clearance >50 mL/min, there is no dose adjustment. Dosages for creati-
severe effects include nephrotoxicity, large vein thrombosis at the site of nine clearances below 50 mL/min and for active hepatic disease (or base-
IVIg infusion and stroke. line AST/AST >1.5x ULN) have not yet been defined. Serious adverse
■ TUMOR NECROSIS FACTOR INHIBITION reactions include serious infections and cytopenias. Cases of neurologic
dysfunction resembling multiple sclerosis have been reported. Common
The selective targeting of the proinflammatory cytokine TNF-alpha has reactions include upper respiratory infections, headache, elevated trans-
produced a therapeutic revolution in rheumatology. While most widely aminases, rash, mouth ulcers, elevation of lipids, and hypertension.
used in the management of the synovitis of rheumatoid arthritis, these The half-life is 10 to 14 days. The risk for malignancy is not yet well-
agents have been widely applied to a variety of immune-mediated disor- described. 76,78 Tocilizumab has also been used successfully in refractory
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ders including psoriatic arthritis, ankylosing spondylitis, Behcet disease, adult-onset Still’s disease.
monoclonal antibodies and a recombinant TNF receptor Fc fusion ■ BLyS INHIBITION
and sarcoidosis. Several commercial products are available, including
protein. In general, these drugs are extremely well tolerated, having nei- Belimumab is a newer monoclonal antibody directed against
ther renal toxicity nor marrow suppression. They can reactivate granu- B-lymphocyte stimulator (BLyS), which is overexpressed in patients
lomatous infections, notably tuberculosis and histoplasmosis. They must with systemic lupus erythematosus. Belimumab binds to soluble BLyS
be used cautiously in patients with chronic or recurrent infection. They and inhibits its biologic activity leading to a decrease in subset of
should be discontinued in the setting of serious infection or sepsis. CD20 B lymphocytes and plasma cells. It is given as an intravenous
■ INTERLEUKIN-1 INHIBITION infusion and can be associated with infusion reactions. Phase 3 trials
have shown limited clinical efficacy but similar rates of adverse events,
The prototypical therapy directed against the pivotal proinflammatory serious adverse events, infections and fatalities similar between placebo
cytokine IL-1 is anakinra. It is a recombinant human IL-1 receptor and belimumab. There are no dosage adjustments for renal or hepatic
antagonist and binds to IL-1 receptors preventing signal transduction. impairment. Common side effects include nausea/diarrhea, upper
While moderately effective for rheumatoid arthritis, it has not been respiratory infections, leukopenia, fever, depression, and anxiety. The
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nearly as effective as the TNF-α drugs. However, it is finding utility in half-life is 19 to 20 days.
driven, in part, by IL-1. Although it is associated with fewer serious ■ CTLA4-IG INHIBITION
the therapy of autoinflammatory conditions which are thought to be
infections than TNF-directed therapy, when they are used in combina- Abatacept is a biologic agent that inhibits T-lymphocyte activation
tion the increased risk of serious infection outweighs any additional through the CD80/CD86-CD28 co-stimulatory pathway, thereby limit-
therapeutic benefit. The half-life is short (4-6 hours), making its use ing the inflammatory response in rheumatoid arthritis. It is a fusion
(and ease of discontinuation) popular in those suspected of having protein made of the human cytotoxic T-lymphocyte-associated antigen

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