Because the AT-III level recovery varies, thus 20 min after infusion of initial dose, recheck AT-III level and recalculate the additional dose necessary to correct AT-III deficiency. Then it is recommended to measure AT-III level every 12 h and maintain AT-III level greater than 80 %. The whole calculated dose should be infused over 10–20 min [4].
(e)
Drug Interactions:
In the presence of heparin, the rate of antithrombin-thrombin inactivation is increased to 1.5 to 4 × 107/M/s; the reaction is accelerated 2,000–4,000-folds. Factor IXa inhibition is increased by 500–1,000-folds.
(f)
Side Effects: Dizziness, chest tightness, chest, shortness of breath, nausea, foul taste in mouth, chills, cramps, hives, fever, and light-headedness.
Protamine
(a)
Introduction: Clinically, protamine is used to antagonize the anticoagulant effects of heparin. Protamine itself is a weak anticoagulant.
(b)
Drug Class: Heparin antagonist.
Mechanism of Action: Protamine binds to heparin to form a stable ion pair.
(c)
Indications:
Reversal of heparin.
Clinical Pearls:
There is a large individual variation in response to protamine infusion; it is better to start with slow infusion, get a sense of patient’s response to protamine, and then set the rate of infusion.
If patient has very unfavorable response to protamine, some alternative strategies may be considered:
Allow heparin effects to dissipate
Intravenous platelet concentrates
Methylene blue
Hexadimethrine
(d)
Dosing Options: IV 1–2 mg per 100 unit of heparin.
(e)
Drug Interactions:
Protamine is not compatible with many antibiotics (the cephalosporins, penicillins).
(f)
Side Effects:
Anaphylaxis
Hypotension and bradycardia
Pulmonary hypertension and dyspnea
Flushing and feeling warm
Tranexamic Acid (Cyklokapron)
(a)
Introduction: Tranexamic acid is an intravenous antifibrinolytic agent used in cardiac surgical procedures. It is ten times as potent as aminocaproic acid (Amicar).
(b)
Drug Class: Synthetic amino acids.
Mechanism of Action:
Competitive inhibitor of plasminogen activator
Noncompetitive inhibitor of plasmin at higher concentrations
(c)
Indications:
Cardiac surgery for reducing blood loss
Hemophilia for short-term use (2–8 days)
Clinical Pearls:
Tranexamic acid solution cannot be mixed with blood.
Dose in renal patients needs to be reduced.
(d)
Dosing Options: 10–20 mg/kg loading dose bolus; then 1–2 mg/kg/h continuous infusion. Tranexamic acid should be started before CPB.
(e)
Drug Interactions:
Tranexamic acid increases the effects of Factor IX by pharmacological synergism. Thus, it may increase the risk of thrombosis.
Tranexamic acid and mestranol increase each other’s effects by pharmacological synergism, thus increasing the risk of thromboembolic event.
(f)
Side Effects: Nausea, vomiting, diarrhea, hypotension, thromboembolic events, pulmonary embolism, and cerebral thrombosis.
Aminocaproic Acid (Amicar)
(a)
Introduction: An intravenous antifibrinolytic agent.
(b)
Drug Class: Synthetic amino acid.
Mechanism of Action: Fibrinolysis-inhibitory effects by inhibition of plasminogen activator and antiplasmin activity.
(c)
Indications: Cardiac or other surgical procedures to reduce blood loss when fibrinolysis is contributing to bleeding.
Clinical Pearls: Infusion before CPB; may have higher plasma level in renal patients.
(d)
Dosing Options: 100–150 mg/kg bolus and then 10–15 mg/kg/h continuous infusion. Or intravenous bolus 5 g and then infuse 1 g per hour.
(e)
Drug Interactions:
Ethinyl estradiol: Concomitant use of aminocaproic acid with ethinyl estradiol may lead to additive hypercoagulability.
Mestranol: Mestranol decrease effects of aminocaproic acid by pharmacological antagonism.
(f)
Side Effects:
Allergic reaction
Edema, headache, and malaise
Cardiovascular: bradycardia, hypotension, and thrombosis
Nausea, vomiting, diarrhea, and abdominal pain
Dyspnea and pulmonary embolism
Myalgia, pruritus, and tinnitus,
Desmopressin Acetate (DDAVP)
(a)
Introduction: DDAVP is a synthetic analog of the pituitary hormone 8-arginine vasopressin (ADH) which is an antidiuretic hormone.
(b)
Drug Class: Synthetic hormone like ADH.
Mechanism of Action: DDAVP increases water permeability in renal tubular cells, thus decreasing urine volume and increasing urine osmolality.
(c)
Indications:
Von Willebrand’s disease and hemophilia: Facilitate the release of platelets from bone marrow
Central diabetes insipidus: For the temporary management of polyuria or polydipsia after head trauma or surgery
Nocturnal enuresis
Renal impairment
Thrombocytopenia
Clinical Pearls: DDAVP is usually given intravenously over 10 min.
(d)
Dosing Options: 0.3 mcg/kg intravenously over 15–30 min.
Intranasal Dosing: 5–40 mcg/day divided to every 8–12 h.
(e)
Drug Interactions:
The concomitant administration of some drugs (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, opiate analgesics, NSAIDs, lamotrigine, and carbamazepine) with DDAVP may increase the risk of water intoxication with hyponatremia.
(f)
Side Effects: Transient headache, nausea, flushing, and mild abdominal cramps.
Recombinant Coagulation Factor VIIa (NovoSeven)
(a)
Introduction: Though NovoSeven is not a pharmacological agent, it is often used in cardiac and other surgical procedures.
(b)
Drug Class: Recombinant coagulation Factor VIIa.
Mechanism of Action: NovoSeven is used to activate the extrinsic coagulation pathway to facilitate hemostasis.
(c)
Indications:
Congenital Factor VII deficiency: Prevention and treatment of bleeding.
Hemophilia A or B patients with inhibitors to Factor VIII or IX.
Clinical Pearls:
NovoSeven is one of the vitamin K-dependent coagulation factors.
NovoSeven is provided with a bottle of dissolvent for its reconstitution.
(d)
Dosing Options: 90 mcg/kg intravenously every 2 h.
(e)
Drug Interactions:
Hemorrhage
Hypertension, hypotension, and angina pectoris
Pain and fever
Headache, cerebral infarct, and cerebral ischemia
Nausea and vomiting
Arthralgia and hemarthrosis
(f)
Side Effects: Thrombotic event, pyrexia, hemorrhage, injection site reactions, headache, hypertension, hypotension, pain, edema, and nausea.
Amnesic Sedatives
Midazolam, Lorazepam, and Diazepam
(a)
Introduction: Midazolam (Versed), lorazepam (Ativan), and diazepam (Valium) are very commonly used as perioperative anxiolytics, intraoperative amnesics, and other sedation purposes. Almost no invasive anesthetic/surgical procedure should be performed without any sedation. There are evidences that preoperative anxiety is associated with poor postoperative outcome for cardiac surgery patients, especially in elderly patients [5]. Tully et al. found that anxiety, stress, and depression are risk factors for postoperative atrial fibrillation [6].
(b)
Drug Class: Benzodiazepine.
Mechanism of Action: All benzodiazepines work by binding to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron, thus activating the inhibitory GABAa receptor complex. GABA is one of the principal inhibitory neurotransmitters in the central nervous system.
(c)
Indications:
Perioperative anxiolysis
Intravenous sedation
Amnesic use
Clinical Pearls:
Midazolam provides more rapid onset amnesia and sedation effects than diazepam.
Midazolam is so widely used in anesthesia practice, and only in few scenarios is midazolam not used.
(d)
Dosing Options:
Midazolam: IV 1–3 mg for adults, 0.05 mg/kg for pediatric patients; 0.4–1 mg/kg PO for preoperative sedation
Lorazepam: IV 1–3 mg for adults
Diazepam: IV 5 mg for adults
Preoperative anxiolysis for pediatric patients: Midazolam: 0.5–0.7 mg/kg orally
(e)
Drug Interactions:
Midazolam and other anesthetic agents like volatile agents (reduce MAC) and opioids potentiate each other.
All drugs which inhibit P450 may prolong the sedative effect of benzodiazepines. These drugs include cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, itraconazole, etc.
(f)
Side Effects:
Oversedation, agitation, dystonia, amnesia, diplopia, ataxia, weakness, dysarthria, and euphoria
Nausea, vomiting, and hiccups
Injection site pain
Hypotension, rash, cardiac arrest, bradycardia, tachycardia, and syncope
Respiratory depression, apnea, paradoxical CNS stimulation, bronchospasm, and anaphylaxis/anaphylactoid reaction
Dexmedetomidine
(a)
Introduction: Dexmedetomidine offers sedation without respiratory depression.
(b)
Drug Class: α2-Adrenergic agonist.
Mechanism of Action: Selective α2-adrenergic agonist with sedative properties.
(c)
Indications:
Procedural sedation: Dexmedetomidine can be used to sedate patient for endoscopy and radiological and other procedures.
ICU sedation: Dexmedetomidine can also be used in ICU sedation for intubated patient or for weaning from ventilation.
Clinical Pearls:
Dexmedetomidine can lower BP in some patients; it may not be indicated for hypotensive patients.
Individual variation in response to dexmedetomidine may necessitate dose adjustments to achieve desired clinical outcome.
Elderly patients (>65 years old) and patients with liver dysfunction need dose reduction.
(d)
Dosing Options: Loading dose 0.2–1 mcg/kg over 10 min. Maintenance infusion dose at 0.2–0.7 mcg/kg/h.
(e)
Drug Interactions:
Dexmedetomidine and anesthetics, opioids, and sedatives likely have synergistic effects.
(f)
Side Effects: Hypotension, hypertension, nausea/vomiting, and bradycardia are common side effects.
Opioids: Fentanyl, Morphine, Sufentanil, and Remifentanil
(a)
Introduction: Opioids are very commonly used in cardiac anesthesia, especially fentanyl and sufentanil, for preoperative sedation, blocking responses to endotracheal intubation, and intra- and postoperative analgesia.
(b)
Drug Class: Opioids.
Mechanism of Action: Working on central opioid receptors.
(c)
Indications:
Preoperative sedation
Intraoperative and postoperative analgesic agents
Clinical Pearls:
There is a trend to decrease the total dosage of opioids during cardiac surgery over the last two decades.
For elderly cardiac surgery patients, opioid dose should be decreased, especially initially to test the patient’s response to opioids.
Meperidine is not indicated for postoperative analgesia now. Meperidine is only indicated for postoperative shivering.
(d)
Dosing Options:
Fentanyl: Bolus 1–3 mcg/kg. Infusion at 0.1–4 mcg/kg/h
Sufentanil: Bolus 1–2 mcg/kg. Infusion at 0.3–1.5 mcg/kg/h
Alfentanil: Bolus 20–50 mcg/kg. Infusion at 0.5–3 mcg/kg/min
Remifentanil: Bolus 1–3 mcg/kg over 1 min. Infusion at 0.05–2 mcg/kg/min
Morphine: Bolus 1–4 mg IV
Meperidine: Bolus 25–75 mg IV. For postoperative shivering 12.5–25 mg IV
(e)
Drug Interactions:
Opioids have synergistic effects with other intravenous anesthetic agents. Other CNS depressants may potentiate the effects of opioids also.
An extremely important drug interaction is the combination of meperidine with MAOI that can cause significant blood pressure change, CNS symptoms, respiratory arrest, and hyperpyrexia.
(f)
Side Effects:
Sedation and dizziness
Nausea, vomiting, constipation, and delayed gastric emptying
Physical dependence, tolerance, and hyperalgesia
Respiratory depression
Immunologic and hormonal dysfunction
Muscle rigidity, chest tightness, and myoclonus
Induction Agents
Etomidate
(a)
Introduction: Etomidate is an intravenous anesthetic agent used for patient who has decreased cardiac function. A well-known side effect of etomidate is its suppression of adrenal gland function. This suppression can even occur after single induction dose [7].
(b)
Class: Carboxylated imidazole
Mechanism of Action: Acts through potentiating GABAa-mediated chloride channels.
Etomidate is very commonly used for induction of general anesthesia in cardiac surgery. Etomidate has less myocardial depressive effects than other induction agents (propofol, thiopental etc.).
(c)
Indication: Induction of general anesthesia or intravenous sedation.
(d)
Dosing:
Anesthesia IV Induction: Children >10 years and adults: initial 0.2–0.6 mg/kg over 30–60 s and total intravenous maintenance of anesthesia 10–20 mcg/kg/ min.
Patients scheduled for cardiac surgery are likely in the situation needing smaller dose of intravenous induction agents, and many times a less cardiodepressive induction agent is chosen. That is the reason that etomidate is often the choice of induction agent for cardiac surgery.
(e)
Drug Interactions: Fentanyl increases its plasma level and prolongs its elimination half-life. Opioids may decrease etomidate-induced myoclonus during induction.
(f)
Side Effects: Adrenal gland suppression, nausea, vomiting, injection site pain, transient myoclonus, averting movements, apnea, arrhythmias, bradycardia, tachycardia, decreased cortisol synthesis (shock), hyper-/hypotension, and laryngospasm.
Propofol
(a)
Currently, the most commonly used intravenous anesthetic agent.
(b)
Class: Isopropylphenol.
Mechanism of Action: Propofol causes global central nervous system (CNS) depression through the potentiation of the chloride current mediated through the GABAA receptor complex. It may also cause reduced glutamatergic activity through NMDA receptor blockade.
(c)
Indication:
Induction of general anesthesia.
Intravenous sedation.
Neurosurgical procedures: Propofol produces a decrease in both CMRO2 and cerebral blood flow (CBF), thus decreasing ICP. Propofol also critically depresses cerebral perfusion pressure (CPP) due to a decrease in both CBF and MAP as a result of systemic peripheral vasodilatation.
Burst suppression: Propofol can produce burst suppression on an EEG which is an endpoint that has been used for the administration of IV anesthetics for neuroprotection.
(d)
Dosing: Bolus 2–2.5 mg/kg. Continuous infusion at 50–200 mcg/kg/min.
(e)
Drug Interactions:
Propofol potentiates non-depolarizing neuromuscular blockers.
Fentanyl and alfentanil plasma concentrations may be increased with administration of propofol.
(f)
Side Effects:
Pain at injection site
Hypotension, bradycardia, and asystole
Involuntary muscle movements and seizures
Respiratory acidosis during weaning, pulmonary edema, hyperlipidemia, rash, pruritus, and anaphylaxis/anaphylactoid reaction
Propofol infusion syndrome
Pancreatitis, phlebitis, and thrombosis
Renal tubular toxicity
Ketamine
(a)
Introduction: Ketamine is a very commonly used induction agent in pediatric anesthesia. It is also used for uncooperative patients by giving intramuscularly.
(b)
Class: Phencyclidine.
Mechanism of Action: Noncompetitive NMDA receptor antagonist that blocks glutamate. Ketamine produces a cataleptic-like state by direct action on the cortex and limbic system. Ketamine also has some analgesic property.
(c)
Indications:
Pediatric anesthesia induction.
Induction of anesthesia in adult patients with asthma or other reactive airway.
Ketamine given intramuscularly for patients who are combative or uncooperative.
Ketamine can also be used for animal anesthesia.
Neurosurgical procedures: Unlike other IV anesthetics, ketamine is a cerebral vasodilator with resultant increases in CBF, CMRO2, and ICP. It is not administered if patients have known intracranial disease due to the risk in increasing ICP.
Clinical Pearls:
Ketamine is very useful for induction of general anesthesia in trauma patients.
Ketamine is relatively contraindicated in coronary artery patient because its potential increase of heart rate.
(d)
Dosing: Bolus 0.5–2 mg/kg. Continuous infusion at 0.1–0.5 mg/min. Pediatric bolus dose 0.5–1 mg/kg/dose IV. Continuous IV infusion: 5–20 mcg/kg/min.
(e)
Drug Interactions:
Ketamine potentiates non-depolarizing neuromuscular-blocking drugs.
Combination with theophylline may predispose patient to seizures.
Diazepam attenuates its cardiostimulatory effects and prolongs its elimination half-life. Sympathetic antagonists may unmask its direct myocardial depressant effects.
Lithium may prolong its actions.
(f)
Side Effects: Sialorrhea, anorexia, nausea, vomiting, hypertension, tachycardia, arrhythmias, diplopia, nystagmus, fasciculations, depressed reflexes, hallucinations, bradycardia, hypotension, cystitis, respiratory depression, laryngospasm, increased intraocular pressure, emergence delirium, tonic-clonic movements, and anaphylaxis.
Muscle Relaxants
This section may be well covered by other book chapters.
Rocuronium
(a)
Introduction: Rocuronium is often used during induction and intubation because of its fast onset and moderate duration, especially in some patients who may not tolerate well to succinylcholine. Pancuronium is often used for the maintenance of muscle relaxation due to its long-acting effect.
(b)
Drug Class: Monoquaternary aminosteroid non-depolarizing neuromuscular blocker.
Mechanism of Action:
(c)
Indications:
Facilitating endotracheal intubation
Maintenance of muscular paralysis during surgery or other clinical scenarios
Substitute to succinylcholine for rapid sequence induction (RSI)
Paralysis of intubated patients in ICU setting
Clinical Pearls:
Its fast onset is only second to succinylcholine.
Currently, rocuronium is very commonly used in clinical anesthesia, for both intubation and maintenance of paralysis.
(d)
Dosing Options: 0.6 mg/kg for intubation and 1.2 mg/kg for RSI.
(e)
Drug Interactions:
Anticonvulsants: Carbamazepine and phenytoin decrease the duration and intensity of rocuronium-induced muscle relaxation.
Antibiotics: Aminoglycosides, vancomycin, tetracycline, bacitracin, polymyxins, colistin, and other antibiotics can enhance the neuromuscular blocking effects.
Lithium can increase the duration of rocuronium.
Local anesthetic agents can increase the duration of rocuronium.
Inhalational agents: Many inhalational anesthetic agents (isoflurane, enflurane) can enhance the neuromuscular block effects of rocuronium.
(f)
Side Effects:
Transient hypotension or hypertension
Allergic reaction, especially in patients with asthma
Cardiac dysrhythmia
Pancuronium (Pavulon)
(a)
Introduction: Pancuronium is the most commonly used long-acting muscle relaxant.
(b)
