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APROTININ

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Aprotinin is a natural proteinase inhibitor obtained from bovine lung, and acts as an inhibitor of multiple mediators (e.g., kallikrein, plasmin). It is able to modulate the systemic inflammatory response associated with cardiopulmonary bypass surgery, thus decreasing the risk of bleeding.

Specific Substances

    1) Aprotininum
    2) Bayer A-128
    3) Riker 52G
    4) RP-9921
    5) CAS 9087-70-1
    6) Molecular Formula: C(284)H(432)N(84)O(79)S(7)
    7) CAS 9087-70-1 (APROTININ)

Available Forms Sources

    A) FORMS
    1) INTRAVENOUS
    a) Aprotinin is available in 100 mL vials of 1,000,000 KIU and 200 mL vials of 2,000,000 KIU (Prod Info TRASYLOL(R) injection, 2006). The potency of aprotinin is expressed as kallikrein (kallidinogenase) inactivator units (KIU); one KIU is contained in 140 nanograms of aprotinin (JEF Reynolds , 2000).
    b) As of November 5, 2007, the manufacturer has suspended the marketing of aprotinin due to preliminary reports from a Canadian study suggesting an increased risk of death with the use of aprotinin as compared with two other antifibrinolytic drugs used in the study (US Food and Drug Administration, 2007).
    2) DERMAL
    a) As of May 1998, the United States FDA has approved the use of fibrin sealants containing aprotinin in multi-ingredient products (Jackson & Alving, 1999). Two products available in the US are Tissel(R) VH, by Baxter Healthcare, Glendale CA, and Hemaseel APR, Haemacure, Sarasota, FL.
    1) The sealant is a freeze-dried concentrate which is reconstituted separately as a solution of fibrinogen and thrombin (Jackson & Alving, 1999). Because sealants contain ingredients derived from pooled human plasma, procedures are in place to reduce possible viral transmission (donor screening and product pasteurization). At the time of this review, no cases of viral infection have been reported (Dunn & Goa, 1999).
    B) USES
    1) Aprotinin is a hemostatic and is an inhibitor of proteolytic enzymes including chymotrypsin, kallikrein (kallidinogenase), plasmin, and trypsin. It is used to minimize perioperative blood loss and thus, transfusion requirements during and after open heart surgery with extracorporeal circulation (Prod Info TRASYLOL(R) injection, 2006).
    2) Aprotinin has also been combined with other components to be applied topically as a fibrin glue for wound hemostasis, suture support, and tissue adhesion or sealing (Dunn & Goa, 1999) .

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Aprotinin is used to reduce perioperative blood loss and to prevent the need for blood transfusion in patients undergoing coronary artery bypass graft (CABG) surgery and who are at an increased risk for blood loss and blood transfusion. As of November 5, 2007, the manufacturer suspended the marketing of aprotinin due to preliminary reports from a Canadian study suggesting an increased risk of death with the use of aprotinin as compared with two other antifibrinolytic drugs used in the study.
    B) PHARMACOLOGY: As an antifibrinolytic and protease inhibitor, aprotinin attenuates inflammatory responses, fibrinolysis, and thrombin generation, modulating the systemic inflammatory response associated with cardiopulmonary bypass surgery, resulting in decreased bleeding and a reduced need for allogeneic blood transfusions.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, constipation, renal dysfunction, anaphylaxis, coronary and pulmonary thromboses, and death have been reported with aprotinin therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Doses up to 17.5 million Kallikrein Inhibitor Units (KIU), administered within a 24-hour period, have been well-tolerated with no apparent toxicity.
    2) SEVERE TOXICITY: Coronary and pulmonary thromboses are major adverse events that could potentially occur following severe overdose. Hepatic and renal failure, resulting in death, was reported in a patient postoperatively who received greater than 15 million KIU aprotinin in a 24-hour period. The patient had pre-existing hepatic dysfunction. An autopsy indicated hepatic necrosis and extensive renal tubular and glomerular necrosis; however, causality was unclear.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Fatal cardiovascular thrombosis has developed in patients receiving aprotinin.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Severe respiratory distress has occurred in one adult and may be secondary to an anaphylactoid response or microthrombosis in the pulmonary system. Pulmonary thromboses have been reported with aprotinin therapy.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Cerebral infarct has been observed.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Renal dysfunction has been reported with aprotinin therapy.
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Hematologic dysfunction (thrombocytopenia, leukocytosis, and coagulation disorders) has been reported with aprotinin therapy.
    0.2.19) IMMUNOLOGIC
    A) WITH THERAPEUTIC USE
    1) Mild to life-threatening anaphylactoid response has developed following aprotinin therapy. Symptoms have occurred with the use of intravenous therapy or fibrin sealants which may contain aprotinin.

Laboratory Monitoring

    A) Obtain a CBC with differential, PT or INR, and PTT following a significant exposure or as indicated in symptomatic patients.
    B) Monitor for evidence of anaphylaxis.
    C) Monitor renal function and vital signs.
    D) Look for clinical evidence of thromboembolic complications (eg, chest pain, shortness of breath, flank pain, extremity pain). Specific studies (eg, CT, angiography) may be needed to evaluate for thromboembolic complications.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Hypotension is a frequently reported sign of a hypersensitivity reaction. Treat mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Look for clinical evidence of thromboembolic complications (e.g. chest pain, shortness of breath, flank pain, extremity pain) and obtain specific studies (e.g. CT, angiography) to evaluate for thromboembolic complications as needed.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions or pulmonary toxicity.
    E) ANTIDOTE
    1) None
    F) ACUTE ALLERGIC REACTION
    1) MILD/MODERATE: Antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE: Oxygen, aggressive airway management, antihistamines, epinephrine, corticosteroids, ECG monitoring, and IV fluids.
    G) ENHANCED ELIMINATION
    1) Given the large size and molecular weight of aprotinin, hemodialysis is UNLIKELY to be of value following overdose.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, as aprotinin is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Any patient with symptoms should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients with severe symptoms (eg, anaphylaxis, thromboembolic complications) should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    I) PITFALLS
    1) When managing a suspected aprotinin overdose, the possibility of multidrug involvement should be considered.
    J) PHARMACOKINETICS
    1) Following IV administration, aprotinin is rapidly distributed into the extracellular space, leading to a rapid initial decrease in plasma aprotinin concentration. Primarily renally metabolized. Less than 10% is excreted unchanged in the urine. Terminal elimination half-life of approximately 10 hours.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents (eg, oral contraceptives) or disorders (eg, history of deep vein thrombosis, soft tissue injury, immobility, cellulitis) that may result in thromboembolic events.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Although doses up to 17.5 million Kallikrein Inhibitor Units (KIU), intravenously administered over a 24-hour period, have been well-tolerated with no apparent toxicity, a patient, with pre-existing liver dysfunction, received greater than 15 million KIU of aprotinin in 24 hours, developed hepatic and renal failure post-operatively, and subsequently died; however, causality was unclear.
    B) THERAPEUTIC DOSE: TEST DOSE: 1 mL (1.4 mg or 10,000 KIU); LOADING DOSE: 100 to 200 mL (140 to 280 mg, or 1 to 2 million KIU); PUMP PRIME DOSE: 100 to 200 mL (140 to 280 mg; or 1 to 2 million KIU); CONSTANT INFUSION DOSE: 25 to 50 mL/hr ( 35 to 70 mg/hr, or 250,000 to 500,000 KIU).

Clinical Effects

Summary Of Exposure

    A) USES: Aprotinin is used to reduce perioperative blood loss and to prevent the need for blood transfusion in patients undergoing coronary artery bypass graft (CABG) surgery and who are at an increased risk for blood loss and blood transfusion. As of November 5, 2007, the manufacturer suspended the marketing of aprotinin due to preliminary reports from a Canadian study suggesting an increased risk of death with the use of aprotinin as compared with two other antifibrinolytic drugs used in the study.
    B) PHARMACOLOGY: As an antifibrinolytic and protease inhibitor, aprotinin attenuates inflammatory responses, fibrinolysis, and thrombin generation, modulating the systemic inflammatory response associated with cardiopulmonary bypass surgery, resulting in decreased bleeding and a reduced need for allogeneic blood transfusions.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) Nausea, vomiting, diarrhea, constipation, renal dysfunction, anaphylaxis, coronary and pulmonary thromboses, and death have been reported with aprotinin therapy.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Doses up to 17.5 million Kallikrein Inhibitor Units (KIU), administered within a 24-hour period, have been well-tolerated with no apparent toxicity.
    2) SEVERE TOXICITY: Coronary and pulmonary thromboses are major adverse events that could potentially occur following severe overdose. Hepatic and renal failure, resulting in death, was reported in a patient postoperatively who received greater than 15 million KIU aprotinin in a 24-hour period. The patient had pre-existing hepatic dysfunction. An autopsy indicated hepatic necrosis and extensive renal tubular and glomerular necrosis; however, causality was unclear.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER: In controlled trials, fever was reported in 15% of patients receiving aprotinin (n=2002) compared with 14% of patients receiving placebo (n=1084) (Prod Info TRASYLOL(R) injection, 2006)

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fatal cardiovascular thrombosis has developed in patients receiving aprotinin.
    3.5.2) CLINICAL EFFECTS
    A) CORONARY ARTERY THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Coronary and arterial thromboses have been reported in patients following the use of aprotinin during cardiac surgery, as well as, other types of surgery and/or disease processes (Kocak et al, 2000; Alvarez et al, 1999; Baubillier et al, 1994) .
    b) INCIDENCE: In a review of placebo-controlled trials in US Healthcare centers, NO increased risk of graft closure was reported in patients undergoing coronary artery bypass grafting (CABG) after receiving aprotinin (Prod Info TRASYLOL(R) injection, 2006).
    c) CASE REPORTS
    1) Thrombi were present in both native coronary arteries and new grafts in a 63-year-old woman undergoing urgent CABG who had received low-dose aprotinin therapy. The thrombi were removed, but the patient died following unsuccessful attempts to be weaned from cardiopulmonary bypass (CPB) (Alvarez et al, 1999).
    a) Another elderly patient undergoing first time CABG also developed acute hemodynamic collapse within 60 minutes after being weaned from CPB. Normal ECG readings were present at the time of circulatory collapse. Extensive thrombi were observed in the coronary arteries and new grafts; all were redone. The patient survived with a new onset left sided ischemic cerebrovascular accident.
    2) Fatal thrombus occurred in a 38-year-old liver transplant patient following aprotinin administration (Baubillier et al, 1994).
    3) Superficial thrombosis developed in a 14-year-old girl with acute promyelocytic leukemia and positive factor VQ 506 mutation after prophylactic aprotinin was given (30,000 U/kg for 10 days) to prevent bleeding due to hyperleukocytosis. The patient was maintained on low molecular weight heparin (Kocak et al, 2000).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Sudden episodes of hypotension have been rarely reported in trauma victims following the use of fibrin glue containing bovine thrombin and cryoprecipitate (Jackson & Alving, 1999). The authors suggested that it may be secondary to bovine impurities or relatively high concentrations of glue.
    b) Hypotension is the most commonly reported sign in patients experiencing hypersensitvity reactions following aprotinin administration (Prod Info TRASYLOL(R) injection, 2006).
    C) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) In a review of patients undergoing CABG surgery, NO statistically significant increase in the risk of myocardial infarction was reported with the use of aprotinin (Prod Info TRASYLOL(R) injection, 2006; Rich, 1998).
    b) Other cardiovascular events reported during clinical trials with aprotinin use included: ECG abnormalities (atrial fibrillation, atrial flutter, and ventricular tachycardia), hypotension, and heart failure which occurred at similar rates as compared to placebo (Prod Info TRASYLOL(R) injection, 2006).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe respiratory distress has occurred in one adult and may be secondary to an anaphylactoid response or microthrombosis in the pulmonary system. Pulmonary thromboses have been reported with aprotinin therapy.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 24-year-old man with excessive bleeding following a tonsillectomy was given aprotinin, and within 2 hours developed hypotension (BP 80/40) and severe symptoms of ARDS. Despite normal coagulation and hematologic profiles, an infusion of aprotinin 200,000 units/hour was started (the authors suggested that its use was not indicated in this setting). The patient required 48 hours of mechanical ventilation before symptoms resolved. It is suggested that an allergenic/anaphylactoid reaction (with direct degranulation of mast cells and basophils) or microthrombosis of the small pulmonary arterioles was precipitated by aprotinin (Vucicevic & Suskovic, 1997).
    B) PULMONARY THROMBOSIS
    1) WITH THERAPEUTIC USE
    a) Pulmonary thrombosis has been reported in patients following the use of aprotinin during cardiac surgery, as well as other types of surgery and/or disease processes with rare fatal outcomes . Pulmonary thrombosis has also been reported with aprotinin use during post-marketing surveillance (Prod Info TRASYLOL(R) injection, 2006; Kocak et al, 2000a; Alvarez et al, 1998; Baubillier et al, 1994; Hardy & Desroches, 1992).
    b) Fatal pulmonary thrombosis occurred after graft replacement of an aneurysm of the aortic arch and descending aorta of a 69-year-old woman; the thrombotic event was attributed to aprotinin, which had been given at a total dose of 6 x 10(6) kallikrein inactivation units (KIU), before and during cardiopulmonary bypass (CPB). The woman was uneventfully weaned from CPB but developed right ventricular failure 10 minutes later. Efforts to locate the problem were ineffective, and the woman died after 70 minutes. Postmortem examination revealed fibrinous material loosely adhered to the walls of the pulmonary arteries, right ventricle, and within the venous cannulas (Alvarez et al, 1998).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Cerebral infarct has been observed.
    3.7.2) CLINICAL EFFECTS
    A) CEREBRAL ARTERY OCCLUSION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Gitter et al (1996) reported aortic cannula thrombosis in an adequately anticoagulated 64-year-old man after the use of aprotinin during cardiac transplant surgery. The patient required biventricular support for hemodynamic stabilization. The patient was unresponsive postoperatively and a head CT revealed a large infarct in the left hemisphere with generalized edema. The patient died following withdrawal of hemodynamic support (Gitter et al, 1996).
    b) LACK OF EFFECT
    1) CASE SERIES: In a multicenter placebo-controlled double blind study of 287 repeat CABG (coronary artery bypass grafting) patients, stroke was not reported in either the low-dose or high-dose aprotinin groups; only one patient in the pump-prime group developed a stroke (Levy, 1999).
    B) TOXIC ENCEPHALOPATHY
    1) WITH THERAPEUTIC USE
    a) WITHDRAWAL FROM MARKET: Aprotinin has been withdrawn from the Italian market based on concerns that it may transmit a bovine spongiform encephalopathy and/or a new variant Creutzfeldt-Jakob disease (Mannucci, 1998).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Symptoms of nausea, vomiting, diarrhea or constipation have been reported in clinical trials with aprotinin, but the rates appear similar to the placebo group (Prod Info TRASYLOL(R) injection, 2006).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Renal dysfunction has been reported with aprotinin therapy.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Aprotinin was associated with a higher incidence of renal dysfunction in patients treated with aprotinin compared with those treated with placebo, according to a global pool of placebo-controlled studies. The need for dialysis may be increased in the perioperative period, especially in patients with pre-existing renal impairment or those who receive aminoglycoside antibiotics or other drugs that alter renal function (Prod Info TRASYLOL(R) injection, 2006). In a prospective, multinational observational study, aprotinin was associated with renal toxicity (dialysis or increased creatinine). The study assessed three treatments, aprotinin, aminocaproic acid, and tranexamic acid and compared each treatment group to a control group (Mangano et al, 2006). Aprotinin was associated with a greater increase in serum creatinine levels compared with aminocaproic acid or no antifibrinolytic therapy, in a retrospective, observational, cohort study in consecutive patients who underwent coronary artery bypass graft (CABG) surgery (n=10,148) (Shaw et al, 2008). Furthermore, when compared with tranexamic acid, aprotinin had a higher incidence of renal dysfunction when administered during cardiac surgery with cardiopulmonary bypass in high transfusional-risk patients according to a prospective, case-control study (Karkouti et al, 2006). In one study, aprotinin was associated with an increased risk of postoperative renal dysfunction in patients undergoing off-pump cardiac surgery and being treated with preoperative ACE inhibitors (Mouton et al, 2008).
    b) LACK OF EFFECT
    1) In a placebo-controlled, double-blind study, no increased risk for renal dysfunction following the use of aprotinin was found (Levy, 1999a). Even in high doses, aprotinin therapy does not seem to impair renal hemodynamics and function in most patients (Horl, 2000).
    2) Attention has been given to the potential of renal dysfunction in the setting of deep hypothermic circulatory arrest. Early evaluations describe renal dysfunction in 65% of aprotinin-treated patients, compared to 5% in controls (Sundt et al, 1993). A later review suggested that inadequate heparinization have contributed to the renal dysfunction (Royston, 1997).
    3) Several clinical studies employing high-dose aprotinin during cardiopulmonary bypass have not observed adverse renal effects (Lemmer et al, 1996; Hardy & Desroches, 1992; Royston et al, 1987; van Oeveren et al, 1987).

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hematologic dysfunction (thrombocytopenia, leukocytosis, and coagulation disorders) has been reported with aprotinin therapy.
    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) In controlled US trials with aprotinin, an incidence between 1% and 2% was reported for the following: thrombocytopenia, leukocytosis, coagulation disorders (including disseminated intravascular coagulation (DIC)) (Prod Info TRASYLOL(R) injection, 2006).
    B) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 60-year-old patient, admitted for a stable aortic aneurysm repair, received an induction dose of 500,000 IU of aprotinin intravenously, and an additional 1,500,000 units during surgery with 5,000 units of heparin given before cross-clamping. Transfusion was carried out using a Solcotrans system after heparin had been given. Approximately 9 hours after surgery, laboratory evidence of DIC was present. The patient died the following day after cardiac arrest; microthrombi was found in the heart and liver (Milne et al, 1994).
    C) COAG./BLEEDING TESTS ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In the immediate hours following surgery, elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are anticipated due to circulating aprotinin (Prod Info TRASYLOL(R) injection, 2006).

Immunologic

    3.19.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Mild to life-threatening anaphylactoid response has developed following aprotinin therapy. Symptoms have occurred with the use of intravenous therapy or fibrin sealants which may contain aprotinin.
    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) SUMMARY
    1) Since aprotinin is a polypeptide, there is a risk for anaphylaxis following dosing (Levy, 1999). Anaphylaxis has been associated with intravenous aprotinin and instillation of fibrin sealants containing aprotinin following trauma and/or surgical repairs (Prod Info TRASYLOL(R) injection, 2006; Beierlein et al, 2000; Ong et al, 1999; Dietrich, 1998; Scheule et al, 1998) .
    2) Anaphylaxis is not considered an uncommon response to intravenous therapy (Ong et al, 1999), but is a relatively rare response following fibrin sealant use (Beierlein et al, 2000).
    b) INCIDENCE
    1) INTRAVENOUS: 2.8% to 6% of patients previously exposed to aprotinin have developed symptoms of anaphylaxis (Ong et al, 1999). In another study of 215 high-risk repeat CABG patients, only 1 patient (0.5%) developed an allergic reaction with no anaphylaxis (Levy, 1999).
    2) TOPICAL: Hypersensitivity reactions are rare, with an estimated rate of 0.5/100,000 for all reactions and 0.3/100,000 for serious reactions, but may occur following repeated sealant use within a few weeks (Beierlein et al, 2000).
    c) RISK FACTORS: Re-exposure carries a higher risk of anaphylaxis (Dietrich, 1998) . In several reports, the overall trend of developing anaphylaxis was described as (Prod Info TRASYLOL(R) injection, 2006; Dietrich, 1998) :
    Overall incidence1.8% (8/437 pts)
    Re-exposure overall (adult)2.7% (5/183)
    Re-exposure overall (pediatric)1.2% (3/254)
    Re-exposure within 6 months (n=387)5.0%
    Re-exposure after 6 months (n=387)0.9%

    d) INTRAVENOUS
    1) ADULT: A 57-year-old man with unstable angina developed severe symptoms of anaphylaxis five minutes after receiving a 1 milliliter test dose of aprotinin. Two milligrams of adrenaline were required to maintain a systolic BP >80 mmHg, while the patient was immediately placed on CPB. The patient was stabilized and surgery was completed with no further complications reported (Ong et al, 1999).
    2) PEDIATRIC: Following surgical repair of tetralogy of Fallot as a neonate, a 3.5-year-old was undergoing elective replacement of the right ventricular pulmonary artery conduit . A test dose of aprotinin (10,000 KIU) was given with an immediate drop in blood pressure and a sudden increase in peak airway pressure. Inotropic agents were ineffective and the patient was placed on immediate cardiopulmonary bypass and allowed to recover. No neurological deficits were reported; surgical repair was successfully completed 3 months later (Cohen et al, 1999).
    3) CASE SERIES: An incidence of acute anaphylaxis of less than 1% was reported following 136 doses of aprotinin (used as a protease inhibitor) given to 15 patients with gastric cancer. Two cases of acute allergic reaction were reported. Generalized anaphylaxis occurred after a first dose in one patient who recovered following supportive therapy, and another developed as an urticarial reaction (trunk and limbs) that responded to antihistamines (Freeman et al, 1983).
    e) FIBRIN SEALANT
    1) SUMMARY
    a) In a review of five-year post-marketing surveillance data from over 1 million fibrin sealant applications, only 2 reports of anaphylaxis were found. One case resulted in severe hypoxia and bronchospasm in a child. In Japan, 3 cases of anaphylaxis were reported, with one case linked to the bovine aprotinin component of the sealant (Dunn & Goa, 1999).
    2) CASE REPORTS
    a) A 66-year-old man with a history of adenocarcinoma of the rectum requiring coloanal anastomosis developed repeated anaphylactic reactions after the use of a fibrin sealant containing aprotinin due to formation of aprotinin-specific IgE and IgG antibodies. Rash, mild bronchospasm, bradycardia, and circulatory collapse resolved with supportive therapy (Scheule et al, 1998).
    b) An adult woman developed pruritus and generalized erythema following a second local injection of fibrin sealant for skin repair; no circulatory involvement occurred (Beierlein et al, 2000).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Obtain a CBC with differential, PT or INR, and PTT following a significant exposure or as indicated in symptomatic patients.
    B) Monitor for evidence of anaphylaxis.
    C) Monitor renal function and vital signs.
    D) Look for clinical evidence of thromboembolic complications (eg, chest pain, shortness of breath, flank pain, extremity pain). Specific studies (eg, CT, angiography) may be needed to evaluate for thromboembolic complications.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) Obtain a CBC with differential, PT or INR, and PTT following a significant exposure or as indicated in symptomatic patients.
    2) LABORATORY TEST ABNORMAL: In the immediate hours following surgery, elevations in the partial thromboplastin time (PTT) and celite Activated Clotting Time (celite ACT) are anticipated due to circulating aprotinin (Prod Info TRASYLOL(R) injection, 2006). In addition, the celite ACT is considered a more accurate determination of whole blood clotting time in the presence of aprotinin.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor renal function.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for evidence of anaphylaxis.
    b) Monitor vital signs.
    c) Look for clinical evidence of thromboembolic complications (eg, chest pain, shortness of breath, flank pain, extremity pain). Specific studies (eg, CT, angiography) may be needed to evaluate for thromboembolic complications.

Methods

    A) BIOASSAY
    1) Serum ELISA testing was conducted after a child developed an anaphylactic response to a test dose of aprotinin. The results indicated a highly elevated IgE level in response to aprotinin. It is suggested that 50% of all patients given aprotinin develop detectable IgG immunoglobulins within 3 months of exposure (Cohen et al, 1999).
    2) Robert et al (1996) reported that plasma concentrations of aprotinin can be measured by ELISA (Robert et al, 1996).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms (eg, anaphylaxis, thromboembolic complications) should be admitted to an intensive care setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, as aprotinin is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Any patient with symptoms should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Obtain a CBC with differential, PT or INR, and PTT following a significant exposure or as indicated in symptomatic patients.
    B) Monitor for evidence of anaphylaxis.
    C) Monitor renal function and vital signs.
    D) Look for clinical evidence of thromboembolic complications (eg, chest pain, shortness of breath, flank pain, extremity pain). Specific studies (eg, CT, angiography) may be needed to evaluate for thromboembolic complications.
    E) Plasma concentrations are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Although doses up to 17.5 million Kallikrein Inhibitor Units (KIU), intravenously administered over a 24-hour period, have been well-tolerated with no apparent toxicity, a patient, with pre-existing liver dysfunction, received greater than 15 million KIU of aprotinin in 24 hours, developed hepatic and renal failure post-operatively, and subsequently died; however, causality was unclear.
    B) THERAPEUTIC DOSE: TEST DOSE: 1 mL (1.4 mg or 10,000 KIU); LOADING DOSE: 100 to 200 mL (140 to 280 mg, or 1 to 2 million KIU); PUMP PRIME DOSE: 100 to 200 mL (140 to 280 mg; or 1 to 2 million KIU); CONSTANT INFUSION DOSE: 25 to 50 mL/hr ( 35 to 70 mg/hr, or 250,000 to 500,000 KIU).

Therapeutic Dose

    7.2.1) ADULT
    A) APROTININ
    1) IV
    a) TEST DOSE: A test dose of 1 mL (equivalent to 1.4 mg or 10,000 Kallikrein Inhibitor Units (KIU)), administered IV, is recommended at least 10 minutes before administration of a loading dose (Prod Info TRASYLOL(R) injection, 2006).
    b) LOADING DOSE: REGIMEN A: 200 mL (equivalent to 280 mg or 2 million KIU); REGIMEN B: 100 mL (equivalent to 140 mg or 1 million KIU) (Prod Info TRASYLOL(R) injection, 2006).
    c) PUMP PRIME DOSE: REGIMEN A: 200 mL (equivalent to 280 mg, or 2 million KIU); REGIMEN B: 100 mL (equivalent to 140 mg or 1 million KIU (Prod Info TRASYLOL(R) injection, 2006).
    d) CONSTANT INFUSION DOSE: REGIMEN A: 50 mL/hour (equivalent to 70 mg/hr, or 500,000 KIU/hour); REGIMEN B: 25 mL/hour (equivalent to 35 mg/hour, or 250,000 KIU/hour) (Prod Info TRASYLOL(R) injection, 2006).
    e) IV administration of aprotinin is through a CENTRAL LINE only, with no other agents given through the same line (Prod Info TRASYLOL(R) injection, 2006).
    2) TOPICAL
    a) Fibrin sealant is applied topically to produce coagulation and wound healing, and is available in 4 vials as follows (Dunn & Goa, 1999):
    1) Human plasma protein fractions containing 65 to 115 mg fibrinogen and 40 to 80 units of factor XIII activity.
    2) Bovine aprotinin solution 1000 KIU/mL.
    3) Human plasma protein fraction containing 400 to 600 International Units of thrombin activity.
    4) Calcium chloride solution 14.7 mg in 2.5 mL.
    b) APPLICATION: The sealant is reconstituted in 2 parts (fibrinogen and factor XIII with aprotinin, and thrombin with calcium chloride) with sequential application (via double syringe) to small sites or sprayed over larger areas. It can be used alone or with collagen or absorbable or nonabsorbable mesh (Dunn & Goa, 1999).
    c) LIMITATION TO USE: It may require up to 5 minutes for the fibrinogen to be dissolved in a water (Jackson & Alving, 1999).
    B) FIBRINOGEN/APROTININ/THROMBIN/CALCIUM CHLORIDE
    1) TOPICAL
    a) 100 cm(2) skin graft fixation area: 2 mL topically (Prod Info TISSEEL(TM) topical solution, 2013; Prod Info ARTISS(TM) topical solution, 2014)
    b) 200 cm(2) skin graft fixation area: 4 mL topically (Prod Info TISSEEL(TM) topical solution, 2013; Prod Info ARTISS(TM) topical solution, 2014)
    c) 500 cm(2) skin graft fixation area: 10 mL topically (Prod Info TISSEEL(TM) topical solution, 2013; Prod Info ARTISS(TM) topical solution, 2014)
    7.2.2) PEDIATRIC
    A) APROTININ
    1) Safety and efficacy in pediatric patients have not been established (Prod Info TRASYLOL(R) injection, 2006).
    B) FIBRINOGEN/APROTININ/THROMBIN/CALCIUM CHLORIDE
    1) GREATER THAN 6 MONTHS OLD
    a) 100 cm(2) skin graft fixation area: 2 mL topically (Prod Info TISSEEL(TM) topical solution, 2013)
    b) 200 cm(2) skin graft fixation area: 4 mL topically (Prod Info TISSEEL(TM) topical solution, 2013)
    c) 500 cm(2) skin graft fixation area: 10 mL topically (Prod Info TISSEEL(TM) topical solution, 2013)
    2) GREATER THAN 1 YEAR OLD
    a) 100 cm(2) skin graft fixation area: 2 mL topically (Prod Info ARTISS(TM) topical solution, 2014)
    b) 200 cm(2) skin graft fixation area: 4 mL topically (Prod Info ARTISS(TM) topical solution, 2014)
    c) 500 cm(2) skin graft fixation area: 10 mL topically (Prod Info ARTISS(TM) topical solution, 2014)

Minimum Lethal Exposure

    A) A patient, with pre-existing liver dysfunction, reportedly received greater than 15 million KIU aprotinin intravenously in 24 hours, developed hepatic and renal failure post-operatively, and subsequently died. Autopsy revealed hepatic necrosis and extensive renal tubular and glomerular necrosis; however, causality was unclear (Prod Info TRASYLOL(R) injection, 2006).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) A specific minimum toxic dose has not been established.
    2) Doses up to 17.5 million KIU have been given over a 24-hour period without producing any apparent toxicity (Prod Info TRASYLOL(R) injection, 2006).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >50 mL/kg (RTECS , 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) >50 mL/kg (RTECS , 2000)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) >40 mL/kg (RTECS , 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >40 mL/kg (RTECS , 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Aprotinin is a basic polypeptide that is isolated from the bovine lung. It is a broad-spectrum protease inhibitor that modulates the systemic inflammatory response (SIR) associated with cardiopulmonary bypass (CPB) surgery (Prod Info TRASYLOL(R) injection, 2006). The mechanism of action of aprotinin is complex and not fully defined (Robert et al, 1996).
    B) Aprotinin's antiprotease activity distinguishes it from other more specific lysine analogs. By several key processes it can inhibit multiple mediators (e.g., kallikrein, plasmin), and attenuate inflammatory responses, fibrinolysis, and thrombin generation (Levy, 1999).
    C) It also has a role in the inhibition of pro-inflammatory cytokine release and maintains glycoprotein homeostasis. Within the platelets, aprotinin is able to reduce glycoprotein loss (e.g., GpIb, GpIb/IIa) and can prevent the expression of pro-inflammatory adhesive glycoproteins (e.g., CD11b) (Prod Info TRASYLOL(R) injection, 2006).

Physicochemical

Physical Characteristics

    A) Aprotinin is a clear, colorless, sterile isotonic solution or an almost white hygroscopic powder (Prod Info Trasylol(R), aprotinin, 1998; JEF Reynolds , 2000).

Ph

    A) Hydrochloric acid and/or sodium hydroxide is used to adjust an aprotinin solution to pH of 4.5 to 6.5 (Prod Info Trasylol(R), aprotinin, 1998).

Molecular Weight

    A) A molecular weight of 6500 to 6512 daltons is reported (Prod Info Trasylol(R), aprotinin, 1998; Levy, 1999).

References

General Bibliography

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