(A) Tissue factor (TF) is a protein expressed in extravascular tissue that is exposed after vascular injury. TF activates factor VII (B), which then activates factor X (C) Creating a TF-VIIa-Xa complex. TF-VIIa also produces a small amount of activated factor IXa. Factor Xa forms a prothrominbase complex by binding to factor Va (E), which then catalyzes the conversion of prothrombin to thrombin (E). The activation process is inhibited by tissue factor pathway inhibitor, which binds to and inhibits factor Xa (D). Amplification: Platelets amplify the coagulation process that was activated by TF in four ways: Activating protease-activated surface receptors on platelets (F), activating plasma factor V (F), activating factor Viii by releasing it from the VWF carrier (G), and finally thrombin activates factors XI and IX (H). Propagation: Large amounts of thrombin are produced by two coagulation factor complexes on the phospholipids surface of platelets: Tenase complex (I) and prothrombinase complex (J). Thrombin catalyzes the formation of fibrin from fibrinogen that crosslinks platelets and stabilizes the clot. Thrombin also activates factor XIII (Fibrin-stabilizing factor) that mediates covalent bonding between fibrin monomers and thrombin activatable fibrinolysis inhibitor (TAFI) to prevent destruction of the clot (K). Reproduced from Drummond JC, Petrovitch CT, Lane TA. Hemostasis and transfusion medicine. In: Barash PG, Cullen BF, Stoelting RK, et al., eds. Clinical Anesthesia. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:387, with permission.

    b) Congenital coagulation factor defects

  i) Any coagulation factor may be deficient or have reduced activity, in isolation or in combination.

  ii) Hemophilia A (Factor VIII deficiency) is the most common congenital coagulation factor defect.

  iii) Hemophilia B (Factor IX deficiency) is less common and is clinically indistinguishable from Hemophilia A (Table 89-1) (2).

    c) Acquired coagulation factor defects

  i) Immune-mediated factor defects

(1) Autoantibodies may cause an acquired hemophilia.

(2) Acquired hemophilia A, the most common type, is typically seen in older patients and may cause severe bleeding. About one third of patients will have underlying disorders (autoimmune diseases such as SLE or rheumatoid arthritis) or lymphoproliferative disorders.

(3) Alloantibody factor inhibitors in hereditary hemophilia patients occur in 4% to 30% of hemophilia A and 5% of hemophilia B patients receiving factor replacement (2).

(4) Alloantibody factor inhibitors neutralize the infused factor and may crossreact with endogenous factor, sometimes increasing the severity of the clinical disease.

  ii) Nonimmune-mediated factor defects

(1) Decreased factor production such as in liver disease and newborn infants.

(2) Abnormal production

   (a) Warfarin treatment interferes with the ability of vitamin K–dependent coagulation factors to bind the surfaces where coagulation reactions occur.

(3) Vit K deficiency

(4) Factor loss and sequestration (e.g., Nephrotic syndrome)

(5) Increased factor destruction

   (a) Destruction of fibrinogen in disseminated intravascular coagulation (DIC)

(6) Inactivation by drugs used for thrombolytic therapy (e.g., tissue plasminogen activator) and direct thrombin inhibitor use (e.g., hirudin, argatroban) (2)

    d) Abnormalities of platelet function

  i) Von Willebrand disease (an abnormality of Von-Willebrand (VW) factor) is the most common congenital bleeding disorder, having a prevalence of approximately 1%. There are three main types.

  ii) Difficult to diagnose because of variable inheritance and clinical presentation

  iii) Should be suspected in patients with a history of menorrhagia or postpartum hemorrhage.

(1) Type 1, which has reduced VW factor levels, is a mild disease, inherited in an autosomal dominant manner. These patients usually respond with a two- to fivefold increase in factor VIII-VWF within 30 minutes of desmopressin (DDAVP) treatment (0.3 μg/kg in 50 mL infused over 30 minutes, consult hematologist for dosing) (5).

(2) Type 2, is caused by abnormal VWF, and has several subtypes including 2A, 2B, and 2N. DDAVP has variable effects on factor VIII and VWF release in these patients; consult a hematologist.

(3) Type 3 (severe vWD), these patients have very little or no plasma or platelet vWF and are not responsive to DDAVP. Consider factor VIII-VWF concentrate (50 IU/daily major surgery, 40 IU/daily or every other day minor surgery, consult hematologist for dosing) (5).

    e) Abnormal or deceased platelet production

  i) Hypocellular bone marrow, e.g. aplastic anemia, drug, alcohol, or viral-induced aplasia

  ii) Hypercellular Bone marrow—B₁₂ or folate deficiency

  iii) Myelodysplastic diseases

  iv) Myelofibrosis

  v) Metastatic disease

    f) Increased peripheral platelet destruction ( Table 89-2)

    g) Platelet dysfunction (Table 89-3)

    h) Dilutional coagulopathy due to massive blood transfusion

  i) Sequestration due to liver disease, splenic disease

2) Evaluation and Treatment

    a) Family history

  i) A family history of bleeding disorder may be seen in hemophilia patients and patients with inherited platelet disorders.

  ii) Up to 30% of cases of hemophilia A are spontaneous mutations with no family history. Von Willebrand disease, the commonest bleeding abnormality, is difficult to diagnose because of the variability in inheritance and clinical presentation.

    b) Personal history

  i) Personal history of surgical, dental bleeding, or easy bruising.

  ii) If abnormal bleeding occurs, note the frequency and the duration.

  iii) Location of abnormal bleeding

(1) Bleeding from skin and mucous membranes tends to occur with platelet disorders.

(2) Bleeding in joints and muscles tends to occur with the hemophilias.

    c) Medical diseases associated with bleeding abnormalities (Table 89-4)

Table 89-4
Medical Diseases Associated with Abnormal Bleeding

    d) Medication history

  i) Aspirin, warfarin, heparin, clopidogrel

  ii) Herbal/dietary supplements that may interfere with clotting include fish oil, flax seed oil, garlic, ginger, gingko, saw palmetto

  iii) In the case of known bleeding disorders, a full history of the severity of the disease and required medications/blood products and previous surgical experience should be elicited.

    e) Physical examination

  i) Assess the patient for bruising or petechiae. In particular, note if petechiae appear after application of BP cuff or tourniquet. Be aware of increased bleeding at IV cannula placement or blood testing.

    f) Laboratory testing

  i) Various laboratory tests may be available at your institution. Consultation with a hematologist will best aid you in test selection and interpretation (Table 89-5).

  ii) Blood tests of coagulation

(1) Full blood count and examination, including cell count and morphology.

(2) Whole blood clotting time (rarely performed)

   (a) A clot should occur in 5 to 15 minutes. A weak friable clot suggests hypofibrinogenemia. Early dissolution of the clot suggests enhanced fibrinolysis

(3) APTT (activated Partial Thromboplastin Time)

   (a) Measures the “intrinsic” and common coagulation pathways.

   (b) Normal PTT times require the presence of the following coagulation factors: I, II, III, IV, V, VI, VIII, IX, X, XI, and XII.

   (c) Normal: 25 to 39 seconds

4) PT, INR (Prothrombin Time, International Normalized Ratio)

   (a) Prothrombin time and its derived measure, international normalized ratio (INR), are measures of the extrinsic pathway.

   (b) Normal PT: 12 to 15 seconds, INR: 0.8 to 1.2.

   (c) PT measures factors I, II, V, VII, and X.

5) TT (Thrombin time)

   (a) Thrombin time compares a patient’s rate of clot formation to that of a sample of normal pooled plasma.

   (b) Reflects fibrinogen activity

   (c) Normal: 10 to 15 seconds

(6) ACT (Activated Clotting Time)

   (a) Activated clotting time is a point of care test, used to monitor the effect of heparin.

   (b) A sample of whole blood is added to a tube containing negatively charged particles and time for the formation of a clot

   (c) Normal values are Kaolin: 90 to 150 seconds, Celite: 100 to 170 seconds, Glass: 110 to 190 seconds.

   (d) Platelet dysfunction and factor deficiencies may prolong the ACT

  iii) Coagulation factor assays

1) Coagulation factors are defined by their functional activity rather than absolute value (i.e., the functional activity of the factor in the patient’s plasma compared with that of a calibrator or standard plasma, the latter with a defined assayed activity of 100%) (2).

  iv) Factor inhibitor assay

1) Measures antibodies to factors, which may reduce the activity of both intrinsic and administered factors.

  v) Platelet function tests

(1) CBC gives platelet number and size

(2) Blood film shows platelet morphology

  vi) Assessment of platelet function

1) Bleeding time

   (a) Involves making a standardized incision, or lance on the ventral forearm. A BP cuff is inflated above the wound. The time it takes for bleeding to stop is measured.

   (b) Normal bleeding time is 2 to 9 minutes.

   (c) Rarely performed

2) Aggregometry

   (a) Addition of an agonist (thrombin, ADP, epinephrine, collagen, ristocetin) to platelet-rich plasma to assess platelet aggregation

1) Flow cytometry

   (a) Assesses platelet membrane receptor functional status.

  vii) Thromboelastography

(1) Thromboelastography is a method of testing the coagulation system by measuring clot formation (Fig. 89-2) (1).

(2) It involves either rotating or oscillating a blood sample to initiate clot formation. It is available as a point-of-care test, and is particularly suited for managing transfusion therapy in the operative setting (6,7).

(3) The thromboelastogram (TEG) measures a number of parameters

   (a) R value or Reaction time—the time in minutes from the start of a sample run until the first detectable levels of fibrin clot formation.

     (i) Reaction time generally reflects coagulation factor levels.

   (b) K value—the measure of time from the beginning of clot formation until the amplitude of the TEG reaches 20 mm.

     (i) k factor in conjunction with the alpha angle reflects coagulation factor amplification.

   (c) Alpha angle—the size in degrees of the angle formed by the tangent line to TEG tracing measure at the reaction time.

     (i) The angle reflects the acceleration of fibrin build up and crosslinking.

   (d) Maximum amplitude (MA)—the greatest amplitude of the TEG tracing. It reflects the maximum strength of the final hemostatic plug. MA assesses the combination of platelet count and function plus fibrinogen activity. Amplitude at 60 minutes is the amplitude of the TEG tracing 60 minutes after the MA is recorded and reflects the stability of the clot.

   (e) Clot lysis index—the amplitude at 60 minutes expressed as a percentage of the maximal amplitude (Fig. 89-3) (1).

1) Anesthetic concerns

    a) Preoperative

  i) The involvement of the patient’s hematologist is imperative in the creation of a perioperative management plan. In the case of patients receiving anticoagulants or antiplatelet drugs, particularly in the setting of a recent revascularization, consultation should be made with their cardiologist.

  ii) Thorough history and physical exam should be elicited

  iii) Appropriate laboratory tests for the patient depending on their history should be performed.

  iv) Many patients with bleeding abnormalities may have had multiple blood product transfusions in the past and may have developed antibodies. Be sure you know the status of your patient and the length of time it may take to cross match blood.

  v) A comprehensive care plan should be constructed between the clinicians involved, surgeons, anesthesiologist, hematologist, intensivist as appropriate.

  vi) The type of procedure, location it is performed (e.g., suitability of surgery center, ICU facilities, blood bank capabilities) should be considered.

  vii) The patient and the family must be counseled regarding potential complications.

  viii) Consider the appropriate anesthetic technique for the procedure in the setting of the patient’s coagulopathy: regional, general anesthesia, monitored anesthesia care, or neuraxial blockade.

  ix) Consider the need for pre-emptive therapy with coagulation factors, platelets, or FFP.

  x) Evaluate the patient’s medications to determine if any need to be stopped prior to surgery (e.g., aspirin).

  xi) Consider the need for additional monitoring, for example, arterial line, CVP, PA catheter.

  xii) Ensure adequate IV access and plan for the possibility of large volume resuscitation in the event uncontrolled bleeding.

  xiii) Communicate with the Blood Bank to ensure appropriate resources

    b) Intraoperative management

  i) Monitor blood loss

1) Visual cues, swabs, suction, surgical field.

2) Communicate with the surgical team to get an accurate idea of ongoing blood loss; venous/arterial, speed of bleeding, the likelihood of controlling bleeding.

1) Laboratory monitoring for coagulopathy should include determination of ACT, platelet count, prothrombin time (PT) or INR, and aPTT. Other tests may include fibrinogen level, assessment of platelet function, thromboelastogram, d-dimers, and thrombin time as indicated (8).

  ii) Monitor for adequate perfusion and oxygenation of vital organs.

  iii) Monitor for transfusion indications relative to patient status, and intraoperative course.

  iv) Therapies

(1) Know the transfusion policies in your institution, in particular whether a “Massive Transfusion” policy exists. Know the location of the Blood transfusion services.

(2) Maintain adequate intravascular volume and BP with crystalloids or colloids. When appropriate, intraoperative or postoperative blood recovery and other means to decrease blood loss (e.g., deliberate hypotension) may be beneficial.

(3) Transfusion of allogeneic red blood cells or autologous blood

(4) Transfusion of platelets

   (a) If possible, a platelet count should be obtained before transfusion of platelets in a bleeding patient, and a test of platelet function should be done in patients with suspected or drug-induced platelet dysfunction (e.g., clopidogrel).

   (b) Bleeding and the surgical procedure (e.g., intracranial surgery) rather than absolute platelet count will determine the need for platelet transfusion.

   (c) Prophylactic platelet transfusion is rarely indicated.

(5) Transfusion of fresh frozen plasma.

   (a) If possible, coagulation tests (i.e., PT or INR and aPTT) should be obtained before the administration of FFP (8)

(6) Single coagulation factor administration

   (a) Factor replacement is dosed relative to the activity of the factor and its half-life (e.g., fibrinogen T_1/2 approximately 96 hours, 50% activity required. Factor VIII T_1/2 is approximately 12 hours, 50% activity required, Factor IX, T_1/2 is approximately 24 hours, 30% activity required.)

(7) Transfusion of cryoprecipitate.

   (a) If possible, a fibrinogen concentration should be obtained before the administration of cryoprecipitate in a bleeding patient.

   (b) Transfusion of cryoprecipitate is rarely indicated if fibrinogen concentration is greater than 150 mg/dL (8).

(8) Multiple coagulation factor deficiency therapy

   (a) FFP and platelets are indicated when there are demonstrable multifactor deficiencies associated with severe bleeding and/or DIC.

(9) Drugs to treat excessive bleeding

   (a) DDAVP

     (i) Increases Factor VIII and Von Willebrand Factor. Useful for uremia-induced platelet dysfunction, aspirin, Von Willebrand disease.

   (b) Aprotinin

     (i) Protease inhibitor w improves platelet function, blocks fibrinolysis.

   (c) Antifibrinolytic agents– E-Aminocaproic acid, Transexamic acid

(10) Supportive Measures are extremely important in maintaining organ function and preventing further exacerbation of the coagulopathy and may include:

   (a) Maintenance of normothermia

   (b) Use of blood warmers

   (c) Ensure adequate acid-base balance

   (d) Replacement of calcium and other electrolytes

   (e) Maintenance of hemodynamic stability and oxygenation.

    c) Postoperative management

  i) Postoperative considerations are related to the underlying disease processes and surgical procedure

  ii) Consider the appropriate facilities for postoperative care, including regular ward, step down unit, ICU, or Coronary Care Unit.

  iii) Consider postoperative intubation if large volumes of fluid and blood products have been given and airway edema is suspected.

  iv) A thorough handover to PACU staff is essential in order to inform them of possible issues such as rebleeding, transfusion of remaining blood products, and monitoring of the patient’s vital signs.

  v) A pain management plan should be formulated and discussed with the surgical or acute pain management services, especially with regard to neuraxial catheters left in situ.

  vi) Follow up with your patient. Postoperative rounds on coagulopathic patients are important to insure optimal postoperative patient management.

References

1. Drummond JC,Petrovitch CT, Lane TA. Hemostasis and transfusion medicine. In: Barash PG, Cullen BF, Stoelting RK, et al., eds. Clinical Anesthesia. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:369–412.

2. Wagenman BL, Townsend KT, Mathew P, et al. The laboratory approach to inherited and acquired coagulation factor deficiencies. Clin Lab Med 2009;29:229–252.

3. Watson HG, Chee YL, Greaves M. Rare acquired bleeding disorders. Rev Clin Exp Hematol 2001;5:405–429.

4. Franchini M, Veneri D. Acquired coagulation inhibitor-associated bleeding disorders: an update. Hematology 2005;10:443–449.

5. Hoffman. Hematology: Basic Principles and Practice. 5th ed. Philadelphia, PA: Churchill Livingstone; 2009. ISBN: 978-0-443-06715-0.

6. Depotis GJ, Joist JH, Goodnough LT. Monitoring of hemostasis in cardiac surgical patients: impact of point-of-care testing on blood loss and transfusion outcomes. Clin Chem 1997;43(9):1684–1696.

7. Shore-Lesserson L, Manspeizer HE, DePerio M, et al. Thromboelastography-guided transfusion algorithm reduces transfusion in complex cardiac surgery. Anesth Analg 1999;88(2):312–319.

8. Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies An Updated Report by the American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology 2006;105(1):198–208.

Part F: Skin and Musculoskeletal Diseases

Malignant Hyperthermia

T. Kyle Harrison, MD

1) Pathophysiology

    a) Molecular mechanism

  i) Etiology is thought to be secondary to a genetic mutation in the ryanodine receptor, which affects calcium release in skeletal muscle sarcoplasmic reticulum.

  ii) The abnormal ryanodine receptor is stimulated from exposure to volatile anesthetics or a depolarizing paralytic.

1) Uncontrolled calcium release occurs, producing a hypermetabolic state within the skeletal muscle.

2) This hypermetabolic state produces the signs and symptoms associated with MH.

    b) Prevalence

  i) The prevalence of MH has been reported to be 1:12,000 for pediatric anesthetics and 1:40,000 adult anesthetics (1).

  ii) MH is most commonly a condition of children and young adults.

1) However, cases of MH have been reported for all ages from infants to the elderly.

2) Although two-thirds of MH-susceptible individuals will have an MH event during their first anesthetic, it can occur after several uneventful prior anesthetics (2).

2) Signs and symptoms

    a) Early signs and symptoms

  i) The signs and symptoms associated with MH are related to the hypermetabolic state that occurs in MH.

  ii) The earliest sign is increased CO₂ production with the resultant increase in respiratory rate in the spontaneously breathing patient or a rising ETCO₂ in a mechanically ventilated patient.

  iii) As cellular metabolism outstrips supply, a metabolic acidosis develops, and in fulminant cases hypoxia can develop from the massive consumption of oxygen in the skeletal muscle.

    b) Late signs and symptoms

  i) As the condition progresses, muscle damage occurs releasing potassium and eventually the core body temperature begins to rise from the sustained muscle activity.

  ii) Cardiac arrhythmias can develop secondary to the hyperkalemia and acidosis.

  iii) Myoglobin released from the damaged muscle can result in acute renal failure and DIC.

  iv) The signs and symptoms of MH can occur quickly following a trigger or take hours to fully develop (2).

    c) Associated findings

  i) An associated finding with MH is masseter muscle spasm (MMS).

  ii) Although mild jaw stiffness can be detected in all patients receiving succinylcholine, an exacerbated response with sustained spasm may develop in some patients especially children.

  iii) It has been reported that up to 50% of children that experience MMS go on to develop MH.

  iv) Isolated MMS is not enough to warrant treatment of MH without further signs of hypermetabolism but it would be prudent to change to a nontriggering anesthetic and monitor closely for sign of MH if MMS is noted (3).

1) Treatment

    a) Initial treatment and resuscitation

  i) Mobilize help

(1) Call for help

(2) Once a presumptive diagnosis of MH has been made, one should quickly mobilize additional help and have an MH cart brought to the room.

(3) Consult MH cognitive aid

  ii) Stop triggering agent(s)

(1) After calling for help and turning off the volatile, one should increase the flow rates on the anesthesia machine to 10 L/min of 100% O₂.

(2) The anesthesia machine and the circuit need not be changed. The surgeon should be notified to complete the surgery as quickly as possible.

  iii) Administer dantrolene

(1) The most important treatment step in treating MH, after turning off the triggering agent, is the rapid administration of Dantrolene.

(2) A 20-mg vial of Dantrolene should be mixed in 60 mL of sterile water. Because of its poor water solubility, it takes some time to get each vial into solution.

(3) Assign one team member the sole task of mixing the Dantrolene as quickly as possible.

(4) The loading dose is 2.5 mg/kg and should be repeated up to 10 mg/kg until clinical signs of improvement are noted.

  iv) Monitor and treat signs and symptoms

(1) An ABG should be sent to monitor the acid/base and electrolyte status.

(2) Cardiac arrhythmias should be treated as hyperkalemia with CaCl, insulin-glucose, and sodium bicarbonate.

(3) Institute hyperventilation

   (a) Increase minute ventilation to eliminate excess CO₂ caused by hypermetabolism.

     (i) Monitor patient’s peak inspiratory pressures for signs of air trapping due to insufficient expiratory time because of increased respiratory rate.

(4) Cooling should be instituted.

   (a) The patient’s core body temperature may rise significantly and can result in central nervous system injury.

   (b) In conjunction with arresting the MH event with dantrolene, the patient should be actively cooled to prevent severe hyperthermia.

   (c) Consider the use of

     (i) Chilled saline for the intravenous infusions.

     (ii) Gastric, peritoneal, and bladder lavage with cold saline may also help decrease the patient’s body temperature.

     (iii) Packing the patient in ice can be an effective way to cool the patient.

  v) Maintenance of anesthesia

(1) The patient’s anesthetic should be maintained with either propofol or benzodiazepine/opioids.

(2) Urinary output should be maintained with fluids, mannitol, and lasix to prevent acute renal failure from the myoglobin release.

    b) Postoperative care

  i) The patient should continue to receive treatment for MH for 36 hours with a dose of 1 mg/kg of Dantrolene every 6 hours in an ICU setting.

  ii) In addition, urinary output should be maintained with aggressive IV fluids and diuretics.

  iii) The patient should have frequent arterial blood gases including electrolytes, creatine kinase levels every 6 hours, and they should be monitored for possible DIC.

    c) Follow-up

  i) Further diagnostic testing

(1) Patients who have had a suspected MH event should be referred for a caffeine-halothane muscle biopsy test at one of the regional MH testing centers.

(2) Contact Malignant Hyperthermia Association of American for more information on test sites.

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