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The Immune System and Anesthesia: Part 2 Dr. Tiffany Eye, DNP, MA-B, APRN, CRNA Murray State University Nurse Anesthesia Program NUR 951 NCE/SEE Exam: Immune Content I. Basic Sciences (20%) A. Anatomy and physiology: #9 Immune B. Pathophysiology: #10 Immune 1. Infections disorders (HIV, AIDS) 2....
The Immune System and Anesthesia: Part 2 Dr. Tiffany Eye, DNP, MA-B, APRN, CRNA Murray State University Nurse Anesthesia Program NUR 951 NCE/SEE Exam: Immune Content I. Basic Sciences (20%) A. Anatomy and physiology: #9 Immune B. Pathophysiology: #10 Immune 1. Infections disorders (HIV, AIDS) 2. Hypersensitivity disorders (Type I-IV) 3. Autoimmune diseases IV. Anesthesia for Surgical Procedure and Special Populations (25%) A. Anesthesia for special populations: #6 Immune compromised and oncology patients a. Pharmacology b. Anesthesia techniques/procedures c. Management Angioedema ● ● ● Hereditary or acquired Characterized by episodic, asymmetric subcutaneous, and submucosal edema formation ○ involving the face, extremities, and gastrointestinal tract ○ occurs rapidly and often resolves spontaneously Two types of angioedema ○ release of mast cell mediators ■ urticaria, bronchospasm, flushing, and hypotension ○ bradykinin release ■ does not cause allergic symptoms Hereditary vs Acquired Angioedema Hereditary ● Deficiency or dysfunction of C1 esterase inhibitor (serpin) ○ absence of C1 esterase inhibitor = release of vasoactive mediators that increase vascular permeability and produce edema via bradykinin ● Patients experience repeated bouts of facial and/or laryngeal edema lasting 24 to 72 hours ○ triggered by menses, trauma, infection, stress, or estrogen-containing oral contraceptives ○ Dental surgery can trigger laryngeal attacks ● Diagnosis ○ low C4 level Acquired ● Patients with lymphoproliferative disorders have antibodies to C1 inhibitor ○ Syndrome that closely mimics hereditary angioedema ○ Angiotensin-converting enzyme (ACE) inhibitors can precipitate angioedema ■ 0.2% of patients ■ increased availability of bradykinin made possible by the ACE inhibitor–mediated blockade of bradykinin catabolism Treatment of Angioedema Mast cell–mediated angioedema treatment ● Same as treating allergy and anaphylaxis - epinephrine, antihistamines, glucocorticoids Bradykinin-mediated angioedema ● C1 inhibitor concentrate, a kallikrein inhibitor, or a bradykinin-receptor antagonist ● Fresh frozen plasma to replace the deficient enzyme ACE inhibitor–induced angioedema ● Stop the offending drug ● Administer supportive care ● Glucocorticoids ○ increase the expression of ACE ○ accelerate bradykinin metabolism ● C1 inhibitor concentrate, kallikrein, or a bradykinin-receptor antagonist Management of Angioedema Prophylactic Management ● before a stimulating procedure: surgery requiring endotracheal intubation, dental surgery ○ availability of C1 inhibitor concentrate for IV infusion should an acute attack occur ■ androgens and tranexamic acid previously used to prevent attacks of angioedema ○ Incidental trauma to the oropharynx - suctioning - should be minimized ○ Regional anesthetic techniques are well tolerated Emergent Management ● Secure the airway ○ depends on the severity of swelling ■ Intubate: dyspnea, voice changes, difficulty controlling secretions, altered mental status, respiratory distress, or stridor ○ videolaryngoscope, awake fiberoptic, surgical airway Angioedema How do I manage this? ● object/goal ● concerns/considerations What is my plan? ● equipment needed What do I need to discuss with the patient? Success!! Alloimmunity Alloimmunity (isoimmunity) ● Response of the immune system toward nonself antigen of other members of the same species, called alloantigens or isoantigens ● Two major types ○ Blood group alloantigens ■ Thrombocytopenia ■ Transfusion reactions ○ Histocompatibility alloantigens ■ rejection of solid organ transplantations Autoimmunity ● Self-tolerance ○ ability of the immune system to recognize and avoid destruction of host cells ● Autoimmunity is an abnormal response to self antigens ○ ○ resulting in production of self antibodies or autoantibodies damage to self tissues due to dysfunction of the innate and/or adaptive immune systems ● Genetic predisposition toward developing an autoimmune disorder ○ ○ more than one autoimmune disorder can occur in the same individual higher incidence in females in childbearing years ● Over 80 different types of autoimmune disorders ○ most common: Graves disease, Hashimoto thyroiditis, multiple sclerosis (MS), RA, SLE, and type 1 diabetes mellitus Autoimmune Disorders Graves Disease ● Type V hypersensitivity caused by autoantibodies to the TSH receptor ○ ● Symptoms ○ ○ ○ ● tachycardia, palpitations, tremor, heat intolerance, and anxiety physical symptoms: thyroid enlargement (goiter) and weight loss ophthalmopathy changes (exophthalmos) - distinguishing characteristic of the disease ■ result of TSI binding to TSH retroorbital tissues Diagnosis ○ ● thyroid-stimulating antibody (TSAb) stimulates the thyroid gland ■ excessive production of thyroxine (T4) and triiodothyronine (T3) elevated plasma levels of T3 and T4, low or absent TSH, radioactive iodine (RAI) uptake, and thyroid ultrasound Treatment ○ ○ antithyroid medications (methimazole and propylthiouracil) to normalize production of T3 and T4 thyroidectomy and RAI destruction of the thyroid ■ require replacement therapy Anesthetic Management of Graves Disease ● ● ● ● Euthyroidism should be established preoperatively ○ elective cases: waiting 6 to 8 weeks for antithyroid drugs (propylthiouracil (PTU)) to become effective ○ emergency cases: ■ intravenous β blocker, ipodate, glucocorticoids, and PTU ● No intravenous preparation of PTU - taken orally ■ glucocorticoids (dexamethasone 2 mg IV every 6 hr) ● decrease hormone release and reduce the peripheral conversion of T4 to T3 Airway Evaluation ○ evidence of tracheal compression or deviation caused by a goiter ■ Examination of chest radiographs and CT scans Intraoperative Management ○ need for invasive monitoring is determined by medical condition of the patient ○ adequate anesthetic depth to avoid exaggerated sympathetic nervous system responses ○ avoid drugs that stimulate the sympathetic nervous system (ketamine, atropine, ephedrine, epinephrine) ○ eye protection (eyedrops, lubricant, eye pads) ○ any inhalational agents may be used ○ may have coexisting muscle disease (myasthenia gravis): reduced requirements for nondepolarizing muscle relaxants Postoperative Management ○ half-life of T4 is 7 to 8 days ■ Continue β-blocker therapy Hashimoto Thyroiditis ● Most common thyroid disorder ○ Females are seven times more likely than males ● Etiology ○ Thyroglobulin (Tg) and thyroid peroxidase (TPO) antigens stimulate the production of Tg and TPO antibodies ■ Occurs during acute thyroid inflammation, hemorrhage, or rapid disordered growth of thyroid tissue ○ Results in follicular destruction of the thyroid ■ Diffuse lymphocytic infiltration of the thyroid and activation of the other components of the immune system ● Symptoms ○ Goiter and hypothyroidism ● Diagnostic tests ○ Labs: low plasma levels of total T4 and elevated TSH levels ○ Tissue biopsy: presence of Tg and TPO antibodies ● Treatment: ○ Thyroid hormone replacement (levothyroxine sodium) Multiple Sclerosis ● Demyelinating disorder of the CNS ○ ● Immune-mediated inflammatory disease that attacks the myelin, oligodendrocytes (myelin producing cells), and the underlying nerve fibers ○ ● ○ fatigue, tingling, numbness, muscle weakness, ataxia, vertigo, tremor, spasticity, bladder and bowel dysfunction, pain, and heat intolerance. periods of relapse (new influx of immune cells) and periods of remission (remyelination) Diagnosis ○ ○ ○ ● CD4 Th1/Th17 cell subsets, B-cell antibodies, NK cells, CD8 Tc, microglia/macrophages, and complement Symptoms ○ ● females are affected two times more than males MS lesions on magnetic resonance imaging (MRI) elevated IgG in the cerebrospinal fluid (CSF) decreased conduction velocity on evoked response studies (visual, auditory, and somatosensory) Treatment ○ ○ ○ disease-modifying agents (DMAMS) ■ IFN-β1b (Betason), IFN-β1a (Avonex, Rebif), and glatiramer acetate (Copaxone) Acute relapses: corticosteroids and plasma exchange (plasmapheresis) Severe progressive: antineoplastic agents - cyclophosphamide (Cytoxan) and mitoxantrone (Novantrone) Management of Multiple Sclerosis General anesthesia Impact of surgical stress ● ● Symptoms and signs of multiple sclerosis exacerbated postop Infection and fever ○ Increase in body temperature (1°C) ■ exacerbation of multiple sclerosis ● complete block of conduction in demyelinated nerves ■ avoid hyperthermia ● ● Regional anesthetic techniques ● Corticosteroid supplementation ● Preoperative chronic immunosuppressive medication should be continued No unique interactions ○ no evidence to support the use of one inhaled or injected anesthetic drug over another Minimize changes in fluid homeostasis, central hemodynamics (preload, afterload) and to maintain respiration ● ● Past hypothesis: intrathecal administration of local anesthetics promoted demyelination in the spinal cord leading to exacerbation of disease Both spinal and epidural anesthesia have been used safely ○ Demyelinated regions of the spinal cord may be more susceptible to the neurotoxic effects of local anesthetics ■ Spinal: Reduce intrathecal dose ○ Epidural: less risk than spinal anesthesia Peripheral nerve blocks: no significant increased risk Management of Multiple Sclerosis Neuromuscular Blocking Agents ● ● Succinylcholine: Avoid ○ Exaggerated potassium release resulting in fatal cardiac arrhythmias Nondepolarizing muscle relaxants: safe ○ Dose cautiously ■ Prolonged responses - increased sensitivity with preexisting muscle weakness ● Coexisting skeletal muscle weakness and decreased skeletal muscle mass ■ Resistance to the effects of nondepolarizing muscle relaxants ● proliferation of extrajunctional cholinergic receptors ○ Use rocuronium with sugammadex to ensure full reversal Postoperative Management ● Patients with severe weakness and respiratory distress (pharyngeal dysfunction) ○ may need extended postoperative care ○ noninvasive/invasive respiratory support ○ intense physiotherapy Rheumatoid Arthritis ● Inflammatory autoimmune disease ○ ○ Synovial inflammation and hyperplasia, cartilage and bone destruction, and systemic features ■ cardiovascular, pulmonary, psychological, and skeletal disorders Affects the smaller joints of the hand and feet but spreads to the larger joints ○ Females are affected three times more often than males ● Innate and the adaptive immune systems ○ ○ T cells - initiation of RA ■ CD4 Th cells - activate macrophages and synovial fibroblasts, the main producers of TNF-α, IL-6, and IL-1 APCs (DCs, macrophages, and activated B cells) activate the T cells ■ abnormal production and regulation of both proinflammatory and antiinflammatory cytokines ■ B cells produce rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) antibodies ● Diagnostic tests ○ ○ ○ Elevated erythrocyte sedimentation rate (ESR) and CRP Presence of RF and anti-CCP antibodies Synovitis, bone erosion, and destruction of cartilage on x-ray and MRI ● Disease-modifying antirheumatic drugs (DMARDs) ○ ○ ○ ■ to control pain and inflammation and reduce joint damage Methotrexate (MTX) inhibits cytokine production, blocks lymphocyte and monocyte proliferation, and prevents osteoclast formation Biologics target specific immune mediators of the inflammatory process and are frequently combined with MTX NSAIDs and corticosteroids are effective in early or mild cases ● Surgical procedures include synovectomy, tendon repair, joint fusion, and total joint replacement ○ Anesthetic considerations: positioning, neck extension Systemic Lupus Erythematosus (SLE) ● Autoimmune inflammatory disease with widespread effects ○ ○ cardiovascular, hepatic, pulmonary, renal, joints, and skin 10 times more common in females ● Early diagnosis - difficult because of widespread and nonspecific symptoms ● Characterized by a large variety of autoantibodies ○ antibodies against coagulation proteins, erythrocytes, lymphocytes, nucleic acids, platelets, phospholipids ● Common findings in SLE ○ ○ butterfly-shaped rash on cheeks/red rash with raised round or oval patches/rash on skin on exposure to sun, mouth sores, arthritis, pleuritis or pericarditis, renal impairment, CNS involvement (seizures, strokes, or psychosis), and abnormal blood tests Laboratory abnormalities: anemia, leukopenia, or thrombocytopenia, elevated ESR and/or CRP levels, and presence of antinuclear antibodies (ANA) ● Diagnostic tests ○ anti–double-strand DNA (anti-dsDNA), anti-Smith (anti-Sm) or antiphospholipid antibodies, lupus anticoagulant (LA), IgG and IgM anticardiolipin (aCL), IgG and IgM anti-β2-glycoprotein, elevated C3 and C4 or CH50 complement levels, and a false-positive blood test for syphilis ● Treatment ○ ○ ○ ○ Avoid triggers: viral infections, sunlight, cigarette smoking NSAIDs: effective in mild cases Corticosteroids or immunosuppressants (azathioprine, mycophenolate, mofetil, MTX) for severe cases MAB belimumab (Benlysta): B-lymphocyte stimulator–specific inhibitor reduces the number of severe flare ups when used in combination with steroids and DMARDs Type I Diabetes Mellitus Type 1A diabetes (T1AD): ● Autoimmune destruction of the insulin-producing β cells of the pancreatic islets of Langerhans ○ ○ ● Onset of the clinical symptom correlates with the end stage of β-cell destruction ○ ● Immune markers are detectable after the onset of the autoimmune process and long before clinical presentation of the disease Pathogenesis ○ ○ ● Diagnosed between 5 and 7 years of age or around puberty Females and males are affected equally T-cell infiltration of the islets (CD8 Tc cells and macrophages) ■ insulitis and destruction of β cells, decreased insulin production, and insulin-dependent diabetes Four autoantibodies are involved in destruction of the β cells ■ islet cell antibodies (ICAs), glutamic acid decarboxylase (GAD-65), insulin autoantibodies (IAAs), and protein tyrosine phosphatase (IA-2A) Treatment ○ Insulin replacement therapy Immunodeficiency Disorders Primary Immunodeficiency Disorders (PIDDs) ● Result of a genetic defect in cells of the immune system ○ lymphocytes, antibodies, phagocytes, and complement proteins ● Characterized ○ ○ ○ low antibody levels, defective antibodies, or defective cells of the immune system ■ T cells, B cells, neutrophils, and complement Increased susceptibility to repeated infections - recurrent, unusual, or difficult to treat infections ■ pneumonia, ear infections, and sinusitis Poor growth patterns or weight loss, recurrent deep abscesses of organs or skin, enlarged lymph glands or spleen, and a coexisting autoimmune disease ● Classification of PIDDs is based on the genetic defect, laboratory findings, and associated features of the disorder ● Treatment ○ ○ ○ largely supportive bone marrow transplantation recent advances in immunobiology, genetics, and availability of biologic modifiers Secondary deficiencies ● Disease (cancer), infections, malnutrition, and medications Acquired Immune Deficiency Disorders Acquired Immune Deficiency (AID) aka Secondary Immune Deficiency ●90% of immune deficiencies are acquired ●Causes of AID worldwide ○severe malnutrition - most prevalent cause ○human T-cell lymphotropic virus type 1 (HTLV-1) infection ○lymphoid cancers such as leukemia and lymphoma ○autoimmune disease such as T1AD ○splenectomy ○aging ○immunosuppressant drugs (corticosteroids, chemotherapy, and DMARDs) ●Affects both the innate and the adaptive immune systems ●Treatment of the primary condition usually results in improvement of the associated AID Acquired Immune Deficiency Syndrome Acquired Immune Deficiency Syndrome (AIDS) ● ● ● ● ● There are two forms and many subtypes of HIV: 90% of HIV-1 infections belong to the HIV-1 group M Mechanism: ○ affects monocytes and macrophage ○ CD4 T-cells are attacked by HIV HIV is a single-stranded RNA molecule = retrovirus ○ reverse transcription: the infected CD4 cell makes a DNA double-stranded helix that contains the viral genetic information ○ Infected cell membranes display viral glycoproteins that can be recognized by APCs for presentation to NK, Tc, and B cells for destruction ○ HIV is capable of changing the amino acid sequences of the antigenic regions of their glycoproteins ■ new version is not recognized by the existing antibodies and escapes destruction ○ Virally infected cells continue to multiply until the immune system is able to produce new, virus-specific antibodies Acute HIV infection: ○ flu like symptoms ■ increased release of inflammatory mediators ■ transient decline in circulating CD4 AIDS: CD4 cell count < 200 cells/mm ○ Symptoms: chills, fever, sweats, swollen lymph glands, weakness, weight loss, and heightened risk of severe opportunistic infections and diseases Acquired Immune Deficiency Syndrome ● ● ● Diagnosis: ○ plasma HIV antigen and HIV antibodies ■ CD4 T-cell count less than 200/mL (normally 600–1500/mL) Treatment: ■ goal is to suppress the viral load to an “undetectable” level ○ Antiretroviral therapy (ART) ● fusion inhibitors that interfere with the HIV’s ability to fuse with a cellular membrane ● entry inhibitors that interfere with the ability of HIV to bind to external cell receptors ● nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) ● faulty DNA building blocks that interfere with HIV DNA synthesis ● nonnucleoside reverse transcriptase inhibitors (NNRTIs) that bind to reverse transcriptase (RT) and prevent the conversion of HIV RNA into HIV DNA ● protease inhibitors (PIs) that interfere with HIV protease, which is essential for cutting long chains of HIV proteins into smaller individual proteins ● integrase strand inhibitors (InSTI) that block the HIV enzyme integrase that is responsible for the integration of viral RNA into the DNA of the infected cell ■ recommended initial ART regimen: two NRTIs and an InSTI ● optional regimen: NNRTI or boosted PI combined with two NRTIs Preexposure prophylaxis (PrEP) ○ daily two-drug combination of emtricitabine, a nucleoside reverse transcriptase inhibitor, and tenofovir alafenamide, a nucleotide reverse transcriptase inhibitor ○ risk of getting HIV from sex is reduced 99% with PrEP, and the risk of drug injection is reduced by 74% Cancers of the Immune System Leukemia ● Uncontrolled clonal proliferation of malignant, dysfunctional leukocytes ○ ○ ● Survivors: ○ ○ ● Malignant lymphoblasts replace the normal marrow elements ■ significantly decreasing production of normal blood cells ● anemia, thrombocytopenia, and neutropenia occur ■ abnormal lymphoblasts proliferate in lymphoid organs - liver, spleen, and lymph nodes Symptoms: ○ ● increased risk of other cancers increased risk for osteonecrosis of the large joints and endocrine abnormalities Mechanism: ○ ● ■ prevent the development of normal hematopoietic cells in the bone marrow Incidence is higher in males and increases with age Increased risk: Down syndrome and neurofibromatosis, environmental exposure to radiation treatments and benzene, cigarette smoking, and a family history of leukemia fever or chills; fatigue; weakness; frequent or severe infections; weight loss; enlarged lymph nodes, liver, and spleen; bruising; recurrent nosebleeds; petechiae; and bone pain Diagnosis: ○ ○ bone marrow biopsy with immunophenotyping Classification: abnormal cell origin (lymphoid or myeloid), rate of the progression (acute or chronic) ■ Lymphoid - lymphocytes of lymphoid or lymphatic tissue ■ Myeloid - precursors of granulocytes or monocytes ■ Acute leukemia involves immature blood cells that multiply aggressively and rapidly ■ Chronic leukemia involves mature blood cells that multiply slowly Lymphoma ● Proliferation of malignant lymphocytes in the lymphoid tissue ● Two groups: non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) ○ ○ Both arise in the head and neck regions Approximately 90% of lymphomas are NHL and 10% are HL ● Etiology ○ Most are malignant B lymphocytes, some are T-cell and NK lymphomas ● Risk factors: ○ environmental chemical exposure (benzene, herbicides, and insecticides), prior chemotherapy, radiation exposure, immune system deficiency or suppression (organ transplantation or autoimmune disease), infections (HIV, HTLV-1, human herpesvirus 8 [HHV8], and Epstein-Barr virus [EBV]), autoimmune disease (RA, SLE, Sjögren disease, and celiac sprue), and chronic immune stimulation (Helicobacter pylori, HBV, hepatitis C [HCV], and Chlamydophila psittaci) ● Symptoms: ○ Similar to common viral illnesses - painless swelling of lymph nodes ● Diagnosis: ○ Lymph node biopsies ● Staging: ○ ○ ○ Computed tomography (CT), MRI, positron emission tomography (PET), bone marrow biopsy, and CSF analysis Stages identify the degree of cancer spread ■ Stage I - the tumor is localized ■ Stage II - limited spread confined to one side of the diaphragm ■ Stage III - regional spread to either side of the diaphragm or to an area near the primary lymph node tumor ■ Stage IV - distal spread beyond the lymphatic system Further divided into A or B ■ B-denoted lymphoma: more advanced ● Treatment: ○ ○ Radiation can be curative for early stages Chemotherapy for advanced stages Multiple Myeloma ● ● ● ● ● ● ● aka Kahler disease Most common type of myeloma Etiology ○ Mutation of plasma B cells results in rapid proliferation of abnormal myeloma cells ■ interfere with the production of WBCs, RBCs, and platelets ○ myeloma cells produce monoclonal proteins or M protein microglobulins ○ M proteins accumulate into plasmacytomas that erode the cortex of the bone resulting in osteoporosis and bone fractures ■ also deposited in organs throughout the body Symptoms: ○ Anemia, bleeding, bone lesions and pain, hypercalcemia, and renal failure Staging I, II, and III ○ degree of anemia, number of M proteins, and renal damage Diagnosis ○ bone marrow biopsy diagnosis Treatment ○ chemotherapy and glucocorticoids ○ targeted drug therapy with proteasome inhibitors (bortezomib) that induce cell death ○ immunomodulating drugs (thalidomide, lenalidomide, pomalidomide) that enhance the immune system’s ability to recognize and destroy the myeloma cell ○ MABs (daratumumab, elotuzumab) that target receptors on myeloma cells ○ IFN can also slow the growth of myeloma ○ Bisphosphonates (alendronate, zoledronic acid), MABs (denosumab), and recombinant parathyroid hormone (teriparatide) are used to increase bone density ○ Autologous or allogeneic HSCT following high-dose chemotherapy may be used for advanced stages Monoclonal Antibodies ● Laboratory engineered molecules that mimic natural antibodies ● Attach to abnormal cells and mark them for identification and destruction by the immune system (immunotherapy) ○ surrounding healthy cells are unaffected by the MAB ● Treatment of cancers and to prevent rejection of transplanted organs ○ ○ ○ ○ ○ Rituximab (Rituxan) attaches to a specific protein (CD20) found only on B cells ■ mark lymphomas arising from these cells and make them visible for destruction by the immune system Cetuximab (Erbitux) attaches to the receptor for epidermal growth factor (EGF) on cancer cells and slows or prevents progression Bevacizumab (Avastin) targets a vascular endothelial growth factor (VEGF) that cancer cells secrete to develop new blood vessels Ado-trastuzumab emtansine (Kadcyla), a MAB combined with a chemotherapeutic drug ■ treat human epidermal growth factor receptor 2 (HER-2)-positive breast cancers Radioimmunotherapy combines a MAB with a radioactive isotope (e.g., ibritumomab [Zevalin]) ■ attaches to cancer cell receptors and destroys the cancer cell through radiation ● Treatment of autoimmune diseases ○ adalimumab (Humira) and etanercept (Enbrel) ■ interfere with TNF ■ treatment of rheumatoid arthritis (RA) and Crohn disease Cancer cells express abnormal antigens (tumor-associated antigens) on their cell surface that can: activate immune cells be used as targets for monoclonal antibodies Surgery and the Immune System Immune surveillance - coordinated activity to destroy cancer cells and infectious organisms ● NK cells of the innate immune system ● cytotoxic CD8+ T cells of the adaptive immune system to destroy cancer cells and infectious organisms Surgery and anesthesia decrease normal immune surveillance ● Results ○ surgical site infections (SSIs), postoperative sepsis, and tumor migration and metastasis ● Immediate postoperative period ○ ○ initial proinflammatory phase quickly followed by a period of immunosuppression ■ surgical stress activation of the sympathetic nervous system (SNS) and the hypothalamicpituitary-interrenal (HPI) axis ■ Increased circulating inflammatory mediators, hyperglycemia, hypothermia, blood transfusions, and anesthetic agents ● Patient factors contribute to perioperative immune system dysfunction ○ ● preexisting immune deficiency, immune suppression therapy for autoimmune diseases or organ transplantation, increasing age, preexisting diseases such as diabetes mellitus, and preoperative sepsis Innate immune system has an earlier recovery from postoperative immunosuppression than the adaptive system Surgical Site Infections ● Infection that occurs at or near the surgical incision within 30 or 90 days of the procedure depending on type of surgery ○ ○ ○ Prolonged hospitalizations and increased patient morbidity and health care costs Staphylococcus aureus, Staphylococcus epidermidis, aerobic streptococci, and anaerobic cocci Causes: patient age, comorbidities, smoking habits, obesity, nutritional status, immunosuppression, malignancies, and postsurgical wound contamination ● Innate immune system ○ ○ Activated within hours of the procedure in response to the tissue damage and blood loss DAMPs promote neutrophil and macrophage migration to the site of injury for removal of tissue debris ■ Activate APCs - monocytes and DCs ■ Inflammatory cytokines, chemokines, and antimicrobial peptides are released ● enhance eradication of injured cells and microbes ● Surgery ○ ○ ○ Intraoperatively: ■ Increased release of Th1 cytokines Postoperatively: ■ Th1 cytokines decrease and Th2 cytokines increase ■ Decrease in T cells that correlates with the duration of the procedure and intraoperative blood loss Stress hormones elevated ■ epinephrine, norepinephrine, and cortisol Surgical Site Infections ● Normally anti-inflammatory mechanisms temper the acute inflammatory response ○ ● Laparoscopic surgery ○ ○ ● If that doesn’t occur: ■ Excessive death of phagocytes and increased susceptibility to infection ■ Vicious cycle ensues ● surgical trauma causing inflammation and immunosuppression ● subsequent infection from invading microbes increasing the inflammatory response ● end result is tissue injury and potential organ failure decreases immune suppression attenuates the cytokine cascade of a decrease in lymphocytes and shift toward a Th2 dominance Immunomodulating diets (IMD) ○ ○ ○ containing ■ supplemental arginine and omega-3 fatty acids ■ Β-blockade reverse the Th1/Th2 imbalance may be beneficial in reducing the immunosuppression associated with surgical trauma Cancer Recurrence ● Surgical excision of tumors stimulates proliferation and metastasis of tumor cells ○ ● Immune and inflammatory processes activated in surgery ○ ● dependent on the normal function of Tc, NK and NKT cells, DCs, and macrophage inflammatory mediators Surgical induced activation of HPA axis and SNS ○ ○ ○ ● surgical suppression of cell-mediated immunity Tumor cells have cell-mediated immunity ○ ● promote the survival and proliferation of cancer cells ■ contributing to the development of metastatic disease Postoperative period = most vulnerable period for metastasis of cancer cells ○ ● Disrupts the blood vessels ■ allowing tumor cells to enter the systemic circulation increases release of cortisol and catecholamines inhibit the proliferation of NK cells and CD8+ T cells necessary to destroy cancer cells promotes proliferation of protumor Treg and Th2 = tumor growth and metastasis Tumor cells express adrenergic β-receptors ○ ○ ○ initiation and progression of cancer β-receptor activation suppresses NK activity and supports metastasis Increased epinephrine and norepinephrine released in the HPA stress response bind to the β-receptors on tumor cells = increased proliferation and survival ■ Current research: use of β-blockers to reduce the progression rate of solid tumors Metastasis Trauma to normal tissue during surgical resection of a tumor ● stimulates an inflammatory response necessary for normal wound healing at the surgical site ○ ○ ● release of humoral factors, such as prostaglandins, cytokines, TNF, and chemokines these factors activate macrophages, neutrophils, and fibroblasts to release additional cytokines and growth factors factors that promote normal tissue healing also stimulate residual cancer cell proliferation and migration ○ ○ combined with the hypothalamic-pituitary-adrenal (HPA) axis inhibition of NK cells and CD8+ T cells inflammatory response supports invasion of surrounding normal tissue by tumor cells as well as inflammatory oncotaxis (metastasis of tumor cells to distant sites) Perioperative Blood Transfusion Blood transfusions ● independent correlate of a poor outcome following cancer surgery ○ ○ depression of the immune system increased metastasis and recurrence of cancer Transfusion-related immunomodulation (TRIM) ● Mechanism ○ donor leukocyte suppression of monocytes, altered lymphocyte function, release of immunosuppressive prostaglandins, inhibition of IL-2, increased suppressor T-cell activity, and a shift toward protumor Th2 cells ● Associated with ○ ○ ○ ○ ○ higher allograft survival rates increased risk of postoperative infections increased tumor recurrence after surgical resection activation of latent viral infections improvement in autoimmune disease ● Irradiated or leukocyte-depleted blood products ○ recommended for cancer patients to offset the depression of the immune system by donor leukocytes ● Intraoperative cell saver ○ contributes to cancer recurrence as the surgical blood can contain tumor cells Perioperative Hyperglycemia ● Increased incidence of SSI and poor patient outcomes ● Mechanism: ○ ○ ○ ○ ○ decreased neutrophil proliferation and function decreases mobilization and adherence of monocytes at the site of infection ■ impedes their bactericidal activity ■ limits their ability to stimulate apoptosis in pathogenic cells decreases the complement response ■ inhibits opsonization by binding to the C3 receptor ■ preventing it from attaching to the microbe and activating phagocytosis increased synthesis and release of cytokines ■ IL-6, TNF, and CRP decreased vasodilation during acute tissue inflammation ■ reducing blood flow and migration of phagocytes to the infected tissue ● Tight glycemic control reduces nosocomial infections and SSIs ○ intraoperative glycemic control - target blood glucose < 200 mg/dL Anesthetic Agents and the Immune System Anesthetic agents ● Impaired immune function ○ depressed function of NK cells, neutrophils, macrophages, DCs, and T cells Intravenous Agents ● Inhalation Anesthetics ● ● ● ● suppress the cytotoxicity of NK cells and macrophages induce apoptosis of T cells decrease IL-2 and restrict proliferation of T cells up-regulate tumorigenic growth factors, hypoxiainducible factor, and IGF ● enhance angiogenesis ● impair adhesion of phagocytes ○ inhibit the respiratory burst necessary for destruction of pathogens Impact of inhalation anesthetics on tumor cells ● Sevoflurane stimulates renal cancer cells and increases risk of metastasis ● Sevoflurane inhibits non-small cell lung carcinoma cells ● ● Midazolam ○ decreases IL-8 necessary for migration and adhesion of neutrophils ○ does not affect cytotoxic T lymphocytes Ketamine and thiopental ○ depress NK cell activity and induce Tlymphocyte apoptosis Propofol ○ protects against immunosuppression ○ promoting the proliferation and cytotoxicity activity of NK cells ○ decreasing proinflammatory cytokines and inhibiting prostaglandin E2 (PGE2) and cyclooxygenase (COX) activity ○ inhibit oncogenes and angiogenesis Opioids and the Immune System Uncontrolled postoperative pain contributes to perioperative immune suppression ● stimulant of the HPA axis and SNS Effective pain control ● attenuates the surgery-induced stress response that promotes metastasis ● Poorly controlled pain and increased opioid requirements = lower survival rates in patients with advanced lung cancer Opioids ● Immune modulatory effects mediated by the mu (μ) opioid receptor (MOR) on lymphocytes ○ ○ ○ ○ suppress NK cells that are vital for the eradication of tumor cells and viruses increase regulatory T cells promote angiogenesis suppress apoptosis ● MOR is overexpressed in some types of cancers ○ ○ direct opioid stimulation of tumor growth, angiogenesis, and metastasis Methylnaltrexone (MNTX), a selective peripheral MOR antagonist, significantly reduces opioid-induced tumor growth and metastasis ● Paradoxically suppress tumor migration and proliferation and induce apoptosis in cancer cells ○ Morphine ■ inhibition of the migration and adhesion of colon cancer cells ■ induction of apoptosis in lung carcinoma and some leukemias ● Opioids differ in their ability to modulate the immune response ○ ○ ○ ○ ○ Morphine and fentanyl suppress NK cell cytotoxicity, increasing the risk for metastasis ■ tramadol increases NK cell cytotoxicity, reducing metastasis ■ buprenorphine has no effect on NK cell cytotoxicity Morphine is associated with the greatest depression of the immune system Codeine, methadone, remifentanil, and fentanyl demonstrate strong immune modulation ■ weaker modulation is seen with hydromorphone, oxycodone, tramadol, and hydrocodone Buprenorphine has minimal or no effect on the immune system Remifentanil increases antiinflammatory cytokines (IL-10) with antitumor activity NSAIDS and the Immune System Postoperative immunosuppression ● causes excess release of prostaglandins ● prostaglandins ○ ○ promotes cancer cell adhesion, migration, and invasion inhibit the activity of Tc and DCs, down-regulate antineoplastic cytokines (TNF-α and INF-γ), and up-regulate immunosuppressive cytokines (IL-10, IL-4, and IL-6) COX ● converts procarcinogens to carcinogens and can initiate cancer cell growth ● COX-2 - overexpressed in some breast and colorectal cancers ○ the product, PGE2, is believed to contribute to the metastatic potential of these cancers NSAIDS ● Beneficial anticancer effects due to inhibition of prostaglandin synthesis by COX inhibition ● Administration of COX-2 inhibitors ○ ○ ○ alone or in conjunction with morphine prevents induced tumor growth and metastasis prevents angiogenesis ● Long-term use of COX inhibitors, especially COX-2 inhibitors = reduced risk of cancer Regional Anesthesia Regional Anesthesia ● attenuates the surgical stress response and supports preservation of normal immune function ○ blocking afferent neural transmission ● associated with decreased cortisol levels, normal NK cell function, and preservation of normal Th1/Th2 balance ● decreases the use of opioids and volatile anesthetics ● lower incidence of SSI compared to general anesthesia ● longer cancer-free time interval and a lower incidence of breast, colon, prostate, and melanoma cancer reoccurrence Local anesthetics ● Amides = cytotoxic effects on cancer cells ● Bupivacaine directly inhibits cancer cell viability, proliferation, and migration ● lidocaine increases NK activity and decreases tumor size and metastasis Combination of general anesthesia and epidural anesthesia ● mitigate the surgical-induced immune suppression ● propofol and paravertebral anesthesia for breast cancer surgery ○ increased infiltration of their tumors by NK and Th cells ● propofol and local or regional anesthesia ○ ○ decrease surgery-induced neuroendocrine responses through HPA axis and SNS suppression less immunosuppression and recurrence of certain types of cancer compared to volatile anesthetics and opioids A combination of propofol, COX antagonists, and regional anesthesia ● decreased immunosuppression Anesthetic Management: Immunocompromised Patient Preoperative tests for immunosuppression ● complete blood counts with a differential smear, serum immunoglobulins, complement assays, T-cell function (skin testing), and B-cell function (antibody titers) Central and peripheral vascular catheters ● 15% to 30% of all nosocomial bacteremias ● central venous catheters (CVCs) are more frequent sources of bacteremia ○ ○ dependent on catheter choice, insertion site, insertion technique, and catheter maintenance Infections are higher for multilumen catheters compared to single-lumen catheters ● CVC : Coagulase-negative staphylococci ● Peripheral catheters: S. aureus and Enterobacteriaceae Reduce infection rate associated with intravascular catheters ● ● ● ● ● Strict aseptic technique and maximum barrier precautions for placement Antibiotic or antiseptic impregnated catheters sutureless securement devices chlorhexidine impregnated dressings disinfection caps References ● ● ● ● Elisha, J.N. S., Heiner, J.S., & Nagelhout, J. J. (2023). Nurse Anesthesia (7th ed.). Elsevier Health Sciences. Gropper, M. (2020). Miller's Anesthesia (9th ed.). Elsevier Health Sciences (US). Hagberg, C. A. (2022). Benumof and Hagberg's Airway Management (5th ed.). Elsevier - OHCE. Hines, R.L. & Jones, S.B. (2021). Stoelting's Anesthesia and Co-Existing Disease (8th ed.). Elsevier - OHCE.