KNOWLEDGE COMPETENCIES
1. Discuss advantages and disadvantages of various routes for medication delivery in acutely ill patients.
2. Identify indications for use, mechanism of action, administration guidelines, side effects, and contraindications for drugs commonly administered in acute illness.
Acutely ill adult patients often receive multiple medications during their admissions to an acute care ward or stepdown unit. These patients may be at risk for increased adverse effects from their medications because of altered metabolism and elimination that is commonly seen in the acutely ill patient. Organ dysfunction or drug interactions may produce increased serum drug or active metabolite concentrations, resulting in enhanced or adverse pharmacologic effects. Therefore, it is important to be familiar with each patient’s medications, including the drug’s metabolic profile, drug interactions, and adverse effect profile. This chapter reviews medications commonly used in progressive care units and discusses mechanisms of action, indications for use, common adverse effects, contraindications, and usual doses. A summary of intravenous (IV) medication information is provided in Chapter 22: Pharmacology Tables.
In the care of the acutely ill, the medication use process is particularly complex. Each step in the process is fraught with the potential for breakdowns in medication safety (ie, adverse drug events [ADEs], medication errors). Improvement in medication safety requires interdisciplinary focus and attention. The Institute for Safe Medication Practices (ISMP) has highlighted the following key elements which must be optimized in order to maintain patient safety in the medication-use process:
• Patient information: Having essential patient information at the time of medication prescribing, dispensing, and administration will result in a significant decrease in preventable ADEs.
• Drug information: Providing accurate and usable drug information to all healthcare practitioners involved in the medication-use process reduces the amount of preventable ADEs.
• Communication of drug information: Miscommunication between physicians, pharmacists, and nurses is a common cause of medication errors. To minimize medication errors caused by miscommunication, it is important to always verify drug information and eliminate communication barriers.
• Drug labeling, packaging, and nomenclature: Drug names that look alike or sound alike, as well as products that have confusing drug labeling and nondistinct drug packaging significantly contribute to medication errors. The incidence of medication errors is reduced with the use of proper labeling and the use of unit dose systems within hospitals.
• Drug storage, stock, standardization, and distribution: Standardizing drug administration times, drug concentrations, and limiting the dose concentration of drugs available in patient-care areas will reduce the risk of medication errors or minimize their consequences, should an error occur.
• Drug device acquisition, use, and monitoring: Appropriate safety assessment of drug delivery devices should be made both prior to their purchase and during their use. Also, a system of independent double checks should be used within the institution to prevent device-related errors such as, selecting the wrong drug or drug concentration, setting the rate improperly, or mixing the infusion line up with another.
• Environmental factors: Having a well-designed system offers the best chance of preventing errors; however, sometimes the acute care environment in which we work may contribute to medication errors. Environmental factors that can often contribute to medications errors include poor lighting, noise, interruptions, and a significant workload.
• Staff competency and education: Staff education should focus on priority topics, such as new medications being used in the hospital, high-alert medications, medication errors that have occurred both internally and externally, protocols, policies, and procedures related to medication use. Staff education can be an important error-prevention strategy when combined with the other key elements for medication safety.
• Patient education: Patients must receive ongoing education from physicians, pharmacists, and the nursing staff about the brand and generic names of medications they are receiving, their indications, usual and actual doses, expected and possible adverse effects, drug or food interactions, and how to protect themselves from errors. Patients can play a vital role in preventing medication errors when they are encouraged to ask questions and seek answers about their medications before drugs are dispensed at a pharmacy or administered in a hospital.
• Quality processes and risk management: The way to prevent errors is to redesign the systems and processes that lead to errors rather than focus on correcting the individuals who make errors. Effective strategies for reducing errors include making it difficult for staff to make an error and promoting the detection and correction of errors before they reach a patient and cause harm.
Intravenous administration is the preferred route for medications in acutely ill patients because it permits complete and reliable delivery. Depending on the indication and the therapy, medications may be administered by IV push, intermittent infusion, or continuous infusion. Typically, IV push refers to administration of a drug over 3 to 5 minutes; intermittent infusion refers to 15-minute to 2-hour drug administration several times per day, and continuous infusion administration occurs over a prolonged period of time.
Intramuscular (IM) or subcutaneous (SC) administration of medications should rarely be used in acutely ill patients. This is due to a number of factors, including delayed onset of action, unreliable absorption because of decreased peripheral perfusion, particularly in patients who are hypotensive or hypovolemic, or inadequate muscle or decreased SC fat tissue. Furthermore, SC/IM administration may result in incomplete, unpredictable, or erratic drug absorption. If the medication is not absorbed from the injection site, a depot of medication can develop. If this occurs, once perfusion is restored, absorption can potentially lead to supratherapeutic or toxic effects. Additionally, patients with thrombocytopenia or who are receiving thrombolytic agents or anticoagulants may develop hematomas and bleeding complications due to SC or IM administration. Finally, administering frequent IM injections may also be inconvenient and painful for patients.
Oral (PO) administration of medication in the acutely ill patient can also result in incomplete, unpredictable, or erratic absorption. This may be caused by a number of factors including the presence of an ileus impairing drug absorption, or to diarrhea decreasing gastrointestinal (GI) tract transit time and time for drug absorption. Diarrhea may have a pronounced effect on the absorption of sustained-release preparations such as theophylline, procainamide, or calcium channel–blocking agents, resulting in a suboptimal serum drug concentration or clinical response. Several medications such as fluconazole and the fluoroquinolones have been shown to exhibit excellent bioavailability when orally administered to acutely ill patients. The availability of an oral suspension for some of these agents makes oral administration a reliable and cost-effective alternative for patients with limited IV access.
In patients unable to swallow, tablets are often crushed and capsules opened for administration through nasogastric or orogastric tubes. This practice is time-consuming and can result in blockage of the tube, necessitating removal of the clogged tube and insertion of a new tube. If enteral nutrition is being administered through the tube, it often has to be stopped for medication administration, resulting in inadequate nutrition for patients. Also, several medications (eg, phenytoin, carbamazepine, and warfarin) have been shown to compete, or interact, with enteral nutrition solutions. This interaction results in decreased absorption of these agents, or complex formation with the nutrition solution leading to precipitation and clogging of the feeding tube.
Liquid medications may circumvent the need to crush tablets or open capsules, but have their own limitations. An example is ciprofloxacin (Cipro) oral solution which is an oil-based preparation that should not be given via feeding tube because of the high probability of clogs. Many liquid dosage forms contain sorbitol as a flavoring agent or as the primary delivery vehicle. Sorbitol’s hyperosmolarity is a frequent cause of diarrhea in acutely ill patients, especially in patients receiving enteral nutrition. Potassium chloride elixir is extremely hyperosmolar and requires dilution with 120 to 160 mL of water before administration. Administering undiluted potassium chloride elixir can result in osmotic diarrhea.
Lastly, sustained-release or enteric-coated preparations are difficult to administer to acutely ill patients. When sustained-release products are crushed, the patient absorbs the entire dose immediately as opposed to gradually over a period of 6, 8, 12, or 24 hours. This results in supratherapeutic or potentially toxic effects soon after the administration of the medication, with subtherapeutic effects at the end of the dosing interval. Sustained-release preparations must be converted to equivalent daily doses of immediate-release dosing forms and administered at more frequent dosing intervals. Enteric-coated dosage forms that are crushed may be inactivated by gastric juices or may cause stomach irritation. Enteric-coated tablets are specifically formulated to pass through the stomach intact so that they can enter the small intestine before they begin to dissolve.
Because of the high degree of vascularity of the sublingual mucosa, sublingual administration of medication often produces serum concentrations of medication that parallel IV administration, and an onset of action that is often faster than orally administered medications.
Traditionally, nitroglycerin has been one of the few medications administered sublingually (SL) to acutely ill patients. Several oral and IV medications, however, have been shown to produce therapeutic effects after sublingual administration. Captopril has been shown to reliably and predictably lower blood pressure in patients with hypertensive urgency. Oral lorazepam tablets have been administered SL to treat patients in status epilepticus; preparations of oral triazolam and IV midazolam have been shown to produce sedation after sublingual administration.
Intranasal administration is a way to effectively administer sedative and analgesic agents. The high degree of vascularity of the nasal mucosa results in rapid and complete absorption of medication. Agents that have been administered successfully intranasally include meperidine, fentanyl, sufentanil, butorphanol, ketamine, and midazolam.
Transdermal administration of medication is of limited value in acutely ill patients. Although nitroglycerin ointment is extremely effective as a temporizing measure before IV access is established in the acute management of patients with angina, heart failure (HF), pulmonary edema, or hypertension, nitroglycerin transdermal patches are of limited benefit. Transdermal patches are limited by their slow onset of activity and their inability for dose titration. Also, patients with decreased peripheral perfusion may not sufficiently absorb transdermally administered medications to produce the desired therapeutic effect. Transdermal preparations of clonidine, nitroglycerin, or fentanyl may be beneficial in patients who have been stabilized on IV or oral doses, but require chronic administration of these agents. Chronic use of nitroglycerin transdermal patches is further complicated by the development of tolerance. However, the development of tolerance can be avoided by removing the patch at bedtime, allowing for an 8- to 10-hour “nitrate-free” period.
A eutectic mixture of local anesthetic (EMLA) is a combination of lidocaine and prilocaine. This local anesthetic mixture can be used to anesthetize the skin before insertion of IV catheters or the injection of local anesthetics that may be required to produce deeper levels of topical anesthesia.
Although transdermal administration of medications is an infrequent method of drug administration in acutely ill patients, its use should not be overlooked as a potential cause of adverse effects in this patient population. Extensive application to burned, abraded, or denuded skin can result in significant systemic absorption of topically applied medications. Excessive use of viscous lidocaine products or mouthwashes containing lidocaine to provide local anesthesia for mucositis or esophagitis also can result in significant systemic absorption of lidocaine. Lidocaine administered topically to the oral mucosa has resulted in serum concentrations capable of producing seizures. The diffuse application of topical glucocorticosteroid preparations also can lead to absorption capable of producing adrenal suppression. This is especially true with the high-potency fluorinated steroid preparations such as betamethasone dipropionate, clobetasol propionate, desoximetasone, or fluocinonide.
Sedatives can be divided into four main categories: benzodiazepines, barbiturates, neuroleptics, and miscellaneous agents. Benzodiazepines are the most commonly used sedatives in acutely ill patients. Neuroleptics typically are used in patients who manifest a psychological or behavioral component to their sedative needs, and barbiturates are reserved for patients with head injuries and increased intracranial pressure. Propofol is a short-acting IV general anesthetic that is approved for use as a sedative for mechanically ventilated, acutely ill patients. Dosing of sedatives should be guided by frequent assessment of the level of sedation with a valid and reliable sedation assessment scale (see Chapter 6 Pain and Sedation Management).
Benzodiazepines are the most frequently used agents for sedation in acutely ill patients. These agents provide sedation, decrease anxiety, have anticonvulsant properties, possess indirect muscle-relaxant properties, and induce antegrade amnesia. Benzodiazepines bind to gamma-aminobutyric acid (GABA) receptors located in the central nervous system, modulating this inhibitory neurotransmitter. These agents have a wide margin of safety as well as flexibility in their routes of administration.
Benzodiazepines are frequently used to provide short-term sedation and amnesia during imaging procedures, other diagnostic procedures, and invasive procedures such as central venous catheter placement or bronchoscopy. A common long-term indication for using benzodiazepines is sedation and amnesia during mechanical ventilation.
Excessive sedation and confusion can occur with initial doses, but these effects diminish as tolerance develops during therapy. Elderly and pediatric patients may exhibit a paradoxical effect manifested as irritability, agitation, hostility, hallucinations, and anxiety. Respiratory depression may be seen in patients receiving concurrent narcotics, as well as in elderly patients and patients with chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea (OSA). Benzodiazepines have also been associated with the development of ICU delirium, which has been linked with worse clinical outcomes.
Monitoring Parameters
• Mental status, level of consciousness, respiratory rate, and level of comfort should be monitored in any patient receiving a benzodiazepine. Signs and symptoms of withdrawal reactions should be monitored for patients receiving short-acting agents (ie, midazolam).
Midazolam is a short-acting, water-soluble benzodiazepine that may be administered IV, IM, SL, PO, intranasally or rectally. Clearance of midazolam has been shown to be extremely variable in acutely ill patients. The elimination half-life can be increased by as much as 6 to 12 hours in patients with liver disease, shock, or concurrently receiving enzyme-inhibiting drugs such as erythromycin or fluconazole; and hypoalbuminemia. Midazolam’s two primary metabolites, 1-hydroxymidazolam and 1-hydroxymidazolam glucuronide, have been shown to accumulate in acutely ill patients, especially those with renal dysfunction, contributing additional pharmacologic effects. Geriatric patients demonstrate prolonged half-lives secondary to age-related reduction in liver function.
Dose
• IV bolus: 0.025 to 0.05 mg/kg
• Continuous infusion: 0.5 to 5 mcg/kg/min
Lorazepam is an intermediate-acting benzodiazepine that offers the advantage of not having its metabolism affected by impaired hepatic function, age, or interacting drugs. Glucuronidation in the liver is the route of elimination of lorazepam. Because lorazepam is relatively water insoluble, it must be diluted in propylene glycol, and it is propylene glycol that is responsible for the hypotension that may be seen after bolus IV administration. Large volumes of fluid are required to maintain the drug in solution, so that only 20 to 40 mg can be safely dissolved in 250 mL of dextrose-5%-water (D5W). In-line filters are recommended when administering lorazepam by continuous infusion because of the potential for the drug to precipitate. Finally, lorazepam’s long elimination half-life of 10 to 20 hours limits its dosing flexibility by continuous infusion. Patients requiring high-dose infusions may be at risk for developing propylene glycol toxicity, which is manifested as a hyperosmolar state with a metabolic acidosis.
Dose
• IV bolus: 0.5 to 2 mg q1-4h
• Continuous infusion: 0.06 to 0.1 mg/kg/h
• Oral: 1 to 10 mg daily divided 2 to 3 times/day
Diazepam is a long-acting benzodiazepine with a faster onset of action than lorazepam or midazolam. Although its duration of action is 1 to 2 hours after a single dose, it displays cumulative effects because its active metabolites contribute to its pharmacologic effect. Desmethyldiazepam has a half-life of approximately 150 to 200 hours, so it accumulates slowly and then is slowly eliminated from the body after diazepam is discontinued. Diazepam metabolism is reduced in patients with hepatic failure and in patients receiving drugs that inhibit hepatic microsomal enzymes. Diazepam may be used for one or two doses as a periprocedure anxiolytic and amnestic, but should not be used for routine sedation of mechanically ventilated patients.
Dose
• IV bolus: 2.5 to 10 mg q2-4h
• Continuous infusion: Not recommended
• Oral: 2 to 10 mg bid-qid
Flumazenil is a specific benzodiazepine antagonist indicated for the reversal of benzodiazepine-induced moderate sedation, recurrent sedation, and benzodiazepine overdose. It should be used with caution in patients who have received benzodiazepines for an extended period of time to prevent the precipitation of withdrawal reactions.
Dose
• Reversal of conscious sedation: 0.2 mg IV over 2 minutes, followed in 45 seconds by 0.2 mg repeated every minute as needed to a maximum dose of 1 mg. Reversal of recurrent sedation is the same as for conscious sedation, except doses may be repeated every 20 minutes as needed.
• Benzodiazepine overdose: 0.2 mg over 30 seconds followed by 0.3 mg over 30 seconds; repeated doses of 0.5 mg can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg. With a partial response after 3 mg, additional doses up to a total dose of 5 mg may be administered. In all of the above-mentioned scenarios, no more than 1 mg should be administered at any one time, and no more than 3 mg in any 1 hour. Continuous infusion: 0.1 to 0.5 mg/h (for the reversal of long-acting benzodiazepines or massive overdoses).
Monitoring Parameters
• Level of consciousness and signs and symptoms of withdrawal reactions
Haloperidol is a major tranquilizer that has commonly been used for the management of agitated or delirious patients who fail to respond adequately to nonpharmacologic interventions or other sedatives. This agent has the advantage of limited respiratory depression and little potential for the development of tolerance or dependence. Although its exact mechanism of action is unknown, it probably involves dopaminergic receptor blockade in the central nervous system, resulting in central nervous system depression at the subcortical level of the brain.
Intravenous haloperidol is the most frequently used neuroleptic for controlling agitation in acutely ill patients. Initial doses of 2 to 5 mg may be doubled every 15 to 20 minutes until the patient is adequately sedated. Single IV doses as large as 150 mg as well as total daily doses of approximately 1000 mg have been safely administered to patients. As soon as the patient’s symptoms are controlled, the total dose required to calm the patient should be divided into four equal doses and administered every 6 hours on a regularly scheduled basis. When the patient’s symptoms are stable, the daily dose should be rapidly tapered to the smallest dose that controls the patient’s symptoms. Continuous IV infusions have also been advocated to allow flexible dosing to control the patient’s symptoms. Higher doses and IV administration of haloperidol may prolong the QTc interval in patients, especially those patients receiving haloperidol by IV injection or continuous infusions. Monitoring the QTc interval is mandatory for all patients receiving haloperidol by continuous infusion.
The major side effect of haloperidol is its extrapyramidal reactions, such as akathisia and dystonia. These reactions usually occur early in therapy and may resolve with dose reduction or discontinuation of the drug. However, in more severe cases, diphenhydramine, 25 to 50 mg IV, or benztropine, 1 to 2 mg IV, may be required to relieve the symptoms. Extrapyramidal reactions appear to be more common after oral haloperidol than after IV haloperidol administration. Neuroleptic malignant syndrome may also be seen with this agent, manifested by hyperthermia, severe extrapyramidal reactions, severe muscle rigidity, altered mental status, and autonomic instability. Treatment involves supportive care and the administration of dantrolene. Cardiovascular side effects include hypotension. It is important to note that despite the common usage of this agent to treat delirium, there is no published evidence that haloperidol reduces the duration of delirium. The lack of this supporting evidence is leading to the reconsideration of the role of haloperidol in this setting compared with other potentially more well-tolerated agents (ie, atypical antipsychotics).
Dose
• IV bolus: 1 to 10 mg (titrated up as clinically indicated)
• Continuous infusion: 10 mg/h (not generally recommended)
• Oral: 0.5 to 10 mg bid-tid
Monitoring Parameters
• Mental status, blood pressure, electrocardiogram (ECG), bedside delirium monitoring, and electrolytes (especially with continuous infusions)
Atypical antipsychotic agents such as quetiapine, olanzapine, risperidone, and ziprasidone have been suggested as possible alternatives to haloperidol, due to their similar mechanism of action and more favorable side effect profile, including reduced incidence of extrapyramidal reactions and QT prolongation. The use of atypical antipsychotics to manage ICU delirium has increased during recent years with reported usage as high as 40% in some studies. Despite these increases, additional well-controlled studies are warranted.
Monitoring Parameters
• Mental status, level of consciousness, electrocardiogram (ECG), bedside delirium monitoring
Quetiapine is the most well studied of these agents to this point, with a randomized, placebo-controlled trial demonstrating a reduction in duration of delirium. Quetiapine can be administered as a scheduled dosing, with additional doses of haloperidol as needed. Dose escalation of the scheduled quetiapine may be required in 50 mg increments in patients still requiring breakthrough management with haloperidol. Sedation is the most commonly-associated adverse effect.
Dose
• PO or per tube: 50-200 mg q12h
Monitoring Parameters
• Mental status, level of consciousness, electrocardiogram (ECG), bedside delirium monitoring
Propofol is an IV general anesthetic that has become popular for sedation of mechanically ventilated patients. Propofol use is typically limited to fewer than 3 days because of the rapid development of tolerance or is used as the primary sedative in daily awakening protocols. The advantages of propofol are its rapid onset and short duration of action compared to the benzodiazepines. Propofol is associated with pain on injection, respiratory depression, and hypotension in acutely ill patients, especially those who are hypotensive or hypovolemic. Hypotension can be avoided by limiting bolus doses to 0.25 to 0.5 mg/kg and the initial infusion rate to 5 mcg/kg/min. The fat emulsion vehicle of propofol has been shown to support the growth of microorganisms. The manufacturer recommends changing the IV tubing of extemporaneously prepared infusions every 6 hours, or every 12 hours if the infusion bottles are used. Propofol is formulated in a fat-emulsion vehicle that provides 1.1 calories/mL and its infusion rate must be accounted for when determining a patient’s nutrition support regimen because the fat-emulsion base can be considered as a calorie source. High infusion rates can be a cause of hyper-triglyceridemia. The agent also causes a rare but serious adverse effect known as propofol infusion syndrome (PRIS). PRIS is associated with the use of propofol for more than 48 hours and at doses greater than 75 mcg/kg/min. Hyperkalemia, tachyarrythmia, and bradycardia combined with hypertriglyceridemia as previously described are common signs of PRIS. The bedside nurse should monitor closely for these signs as discontinuance of therapy may avoid the serious outcomes of PRIS: myocardial failure, metabolic acidosis, rhabdomyolysis, dysrhythmias, and renal failure. Propofol is available in 50- and 100-mL infusion vials. To decrease waste, 50-mL vials may be used when changing vials in patients who are scheduled for IV line changes, extubation from mechanical ventilation, and low infusion rates.
Dose
• IV bolus: 0.25 to 0.50 mg/kg
• Continuous infusion: 5 to 50 mcg/kg/min
Monitoring Parameters
• Level of consciousness, blood pressure, lactic acid, creatinine kinase, and serum triglyceride level, especially at high infusion rates
Ketamine is an analog of phencyclidine that is commonly used as an IV general anesthetic. It is an agent that produces analgesia, anesthesia, and amnesia without the loss of consciousness. The onset of anesthesia after a single 0.5- to 1.0-mg/kg bolus dose is within 1 to 2 minutes and lasts approximately 5 to 10 minutes. Ketamine causes sympathetic stimulation that normally increases blood pressure and heart rate while maintaining cardiac output. This may be important in patients with hypovolemia. Ketamine is useful in patients who require repeated painful procedures such as wound debridement. The bronchodilatory effects of ketamine may be beneficial in patients experiencing status asthmaticus. However, ketamine may increase intracranial pressure and should be avoided or used with caution in patients with head injuries, space-occupying lesions, or any other conditions that may cause an increase in intracranial pressure. Emergence reactions or hallucinations, commonly seen after ketamine anesthesia, may be prevented with the concurrent use of benzodiazepines.
Dose
• IV bolus: 0.1 to 1 mg/kg
• Continuous infusion: 0.1 to 3 mcg/kg/min
• Oral: 10 mg/kg diluted in 1 to 2 oz of juice
• Intranasal: 5 mg/kg
Monitoring Parameters
• Levels of sedation and analgesia, heart rate, blood pressure, and mental status
Dexmedetomidine is a relatively selective alpha-2-adrenergic agonist with sedative properties indicated for the short-term (up to 24 hour) sedation of intubated and mechanically ventilated patients. Dexmedetomidine is not associated with respiratory depression but has been associated with reductions in heart rate and blood pressure. Some patients may complain of increased awareness while receiving the drug in the intensive care unit. Dexmedetomidine has minimal amnestic properties and most patients require breakthrough doses of sedatives and analgesics while receiving the drug. The agent has been evaluated for longer term sedation, up to 28 days in a limited number of patients. In this setting, a reduction of the loading infusion is advised to minimize cardiovascular depression. However, a higher maintenance infusion (up to 1.5 mcg/kg/h) may be required compared to short-term sedation.
Dose
• IV bolus: 1 mcg/kg over 10 minutes
• Continuous infusions: 0.2 to 1.5 mcg/kg/h
Monitoring Parameters
• Levels of sedation and analgesia, heart rate, and blood pressure
Opioids, also known as narcotics produce their effects by reversibly binding to the mu, delta, kappa, and sigma opiate receptors located in the central nervous system. Mu-1 receptors are associated with analgesia, and mu-2 receptors are associated with respiratory depression, bradycardia, euphoria, and dependence. Delta receptors have no selective agonist and modulate mu receptor activity. Kappa receptors function at the spinal and supraspinal levels and are associated with sedation. Sigma receptors are associated with dysphoria and psychotomimetic effects.
Monitoring Parameters
• Level of pain or comfort, blood pressure, renal function, and respiratory rate
Morphine is a commonly used narcotic analgesic. Morphine is hepatically metabolized to several metabolites, including morphine-6-glucuronide (M6G), which is approximately 5 to 10 times more potent than morphine. M6G is renally eliminated and after repeated doses can accumulate in patients with renal dysfunction, producing enhanced pharmacologic effects. Morphine’s clearance is reduced in acutely ill patients due to increased protein binding, decreased hepatic blood flow, or reduced hepatocellular function. Morphine possesses vasodilatory properties and can produce hypotension because of either direct effects on the vasculature or histamine release.
Dose
• IV bolus: 2 to 5 mg
• Continuous infusion: 2 to 30 mg/h
• Oral: 10 to 30 mg q3-4h prn
Patient-Controlled Analgesia (PCA)
• IV bolus: 0.5 to 3.0 mg
• Lockout interval: 5 to 20 minutes
Meperidine is a short-acting opioid that has one-seventh the potency of morphine. It is hepatically metabolized to normeperidine, which is renally eliminated and is also a neurotoxin. Normeperidine can accumulate in patients with renal dysfunction, resulting in seizures. Meperidine should be avoided in patients taking monoamine oxidase inhibitors because of the potential for development of a hypertensive crisis when these agents are administered concurrently.
Dose
• IV bolus: 25 to 100 mg
• Oral: 50 to 150 mg q2-4h prn
Fentanyl is an analog of meperidine that is 100 times more potent than morphine. After single doses, its duration of action is limited by its rapid distribution into fat tissue. However, after repeated dosing or continuous infusion administration, fat stores become saturated, thereby prolonging its terminal elimination half-life to more than 24 hours. Fentanyl does not have active metabolites, although accumulation can occur in hepatic dysfunction. Unlike morphine, fentanyl does not cause histamine release.
Dose
• IV bolus: 25 to 100 mcg q1-2h
• Continuous infusion: 50 to 300 mcg/h
• Transdermal: Patients not previously on opioids: 25 mcg/h
• Opioid-tolerant patients: 25 to 100 mcg/h
Patient-Controlled Analgesia
• IV bolus: 25 to 100 mcg
• Lockout interval: 5 to 10 minutes
Naloxone is a pure opiate antagonist that displaces opioid agonists from the mu, delta, and kappa receptor-binding sites. Naloxone reverses narcotic-induced respiratory depression, producing an increase in respiratory rate and minute ventilation, a decrease in arterial PCO2, and normalization of blood pressure if reduced. Narcotic-induced sedation or sleep is also reversed by naloxone. Naloxone reverses analgesia, increases sympathetic nervous system activity, and may result in tachycardia, hypertension, pulmonary edema, and cardiac arrhythmias. Naloxone administration produces withdrawal symptoms in patients who have been taking narcotic analgesics chronically. Diluting and slowly administering naloxone in incremental doses can prevent the precipitation of acute withdrawal reactions as well as prevent the increase in sympathetic stimulation that may accompany the reversal of analgesia. One 0.4-mg ampule should be diluted with 0.9% NaCl (saline) to 10 mL to produce a concentration of 0.04 mg/mL. Sequential doses of 0.04 to 0.08 mg should be administered slowly until the desired response is obtained. Because its duration of action is generally shorter than that of opiates, the effect of opiates may return after the effects of naloxone dissipate, approximately 30 to 120 minutes.
Dose
• Opiate depression: Initial dose: 0.1 to 0.2 mg given at 2- to 3-minute intervals until the desired response is obtained. Additional doses may be necessary depending on the response of the patient and the dose and duration of the opiate administered.
• Continuous infusion: 3 to 5 mcg/kg/h.
• Known or suspected opiate overdose: Initial dose: 0.4 to 2.0 mg administered at 2- to 3-minute intervals if necessary. If no response is observed after a total of 10 mg has been administered, other causes of the depressive state should be determined.
• Continuous infusion: Loading dose: 0.4 mg, followed by 2.5 to 5 mcg/kg/h and titrated to the patient’s response.
Monitoring Parameters
• Signs and symptoms of withdrawal reactions, respiratory rate, blood pressure, mental status, level of consciousness, and pupil size
Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID) that is indicated for the short-term treatment of moderately severe acute pain that requires analgesia at the opioid level. The drug exhibits anti-inflammatory, analgesic, and antipyretic properties. Its mechanism of action is thought to be due to inhibition of prostaglandin synthesis by inhibiting cyclooxygenase, an enzyme that catalyzes the formation of endoperoxidases from arachidonic acid. NSAIDs are more efficacious in the treatment of prostaglandin-mediated pain. Ketorolac is the only currently available NSAID approved for IM, IV, and oral administration, and it is often used in combination with other analgesics because pain often involves multiple mechanisms. Combination therapy may be more efficacious than single-drug regimens, and combinations with narcotics can decrease narcotic requirements, minimizing narcotic side effects.
Ketorolac is associated with the same adverse effects as orally administered NSAIDs, such as reversible platelet effects, GI bleeding, and reduced renal function. Ketorolac is contraindicated in patients with advanced renal failure and in patients at risk for renal failure due to volume depletion. Therefore, volume depletion should be corrected before administering ketorolac. Because of the potential for significant adverse effects, the maximum combined duration of parenteral and oral use is limited to 5 days.
Dose
• Loading dose: <65 years: 60 mg; >65 years or <50 kg: 30 mg
• Maintenance dose: <65 years: 30 mg q6h; >65 years or <50 kg: <15 mg q6h
Monitoring Parameters
• Renal function and volume status
Acetaminophen is an analgesic and antipyretic that is now available in the United States in an IV formulation. This agent has been used extensively in European countries. In the United States, IV acetaminophen is indicated for the management of mild to moderate pain, and management of moderate to severe pain with adjunctive opioid analgesics. The preferred route of administration for acetaminophen continues to be oral, but the IV route has proven beneficial in the perioperative setting when oral is not feasible. The IV form of this agent is not cost-effective for antipyretic usage as better options exist (eg, acetaminophen rectal suppositories). Use of IV acetaminophen should be restricted to post-surgical patients who are unable to take oral or rectal acetaminophen.
Dose
• IV bolus: 1-gm IV every 6 hours for 24-48 hours postoperative (maximum of 4 gm in 24 hours)
Monitoring Parameters
• Liver function test, pain control
Phenytoin is an anticonvulsant used for the acute control of generalized tonic clonic seizures, following the administration of benzodiazepines, and for maintenance therapy once the seizure has been controlled. Phenytoin stabilizes neuronal cell membranes and decreases the spread of seizure activity. Phenytoin may inhibit neuronal depolarizations by blocking sodium channels in excitatory pathways and prevent increases in intracellular potassium concentrations and decreases in intracellular calcium concentrations.
The bioavailability of oral phenytoin is approximately 90% to 100%. Dissolution is the rate-limiting step in phenytoin absorption with peak serum concentrations occurring 3 to 12 hours after a dose. The rate of absorption is dose dependent, with increasing times to peak concentration with increasing doses. In addition, the dissolution and absorption rate depend on the phenytoin formulation administered. The Dilantin Kapseal brand of phenytoin capsules has the dissolution characteristics of an extended-release preparation, whereas generic phenytoin products possess rapid-release characteristics and are absorbed more quickly. Extended-release and rapid-release products are not interchangeable, and only extended-release products may be administered in a single daily dose.
Phenytoin is 90% to 95% bound to albumin. In acutely ill patients the pharmacologically free fraction is highly variable and ranges between 10% and 27% of the total serum concentration. The free fraction has been shown to increase by more than 100% from baseline during the first week of illness and is generally associated with a significant reduction in serum albumin concentration. Alterations in albumin binding also may be seen in hypoalbuminemia (<2.5 g/dL), major trauma, sepsis, burns, malnutrition, and surgery, as well as liver or renal disease, and may result in an increase in a free concentration with potentially toxic effects. Significant alterations in phenytoin metabolism usually do not occur until the serum albumin falls below 2.5 g/dL. Equations used to normalize the phenytoin concentration in patients with hypoalbuminemia are usually unreliable, and direct measurement of the free phenytoin concentration should be used to adjust therapy.
Phenytoin is metabolized by the cytochrome P-450 enzyme system to its inactive primary metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin, which is glucuronidated and renally eliminated. Phenytoin undergoes dose-dependent metabolism such that proportional increases in the dose may result in greater than proportional increases in the serum concentration. It is difficult to predict the concentration at which a patient’s metabolism will become saturated, so that any changes in dose above 400 to 500 mg/day need to be carefully monitored. Because phenytoin displays nonlinear metabolism, half-life is an inappropriate term to describe phenytoin elimination. Phenytoin metabolism is usually referred to as the time it takes to eliminate 50% (t50) of a given daily dose. In normal patients taking 300 mg/day, the t50 is about 22 hours. As the dose is increased, the t50 increases, with the time to reach steady-state becoming progressively longer. The time to steady-state may vary from several days to several weeks depending on the dose and the patient’s ability to metabolize the drug. Phenytoin metabolism can be affected by drugs that induce or inhibit its metabolic pathway. The effects of enzyme induction can occur within 2 days to 2 weeks after starting an agent. Inhibition usually occurs within 1 to 2 days after a drug is started and its effects usually last until the inhibiting drug is eliminated from the body. Phenytoin clearance is increased in acutely ill patients, resulting in serum concentrations less than 10 mg/L. The mechanism for the increase in clearance is unclear, but may be caused by changes in protein binding, induction in phenytoin metabolism, or a stress-related transient increase in hepatic metabolic function.
The recommended phenytoin loading dose of 15 to 20 mg/kg produces serum concentrations between 20 and 30 mg/L. Loading doses of 18 to 20 mg/kg are recommended for treating status epilepticus, and loading doses of 15 to 18 mg/kg are recommended for seizure prophylaxis after head injury or neurosurgery. The serum concentration increases approximately 1.4 mg/L for each 1 mg/kg of phenytoin administered.
The maintenance dose should be started 8 to 12 hours after the loading dose. The usual adult maintenance dose is 5 to 6 mg/kg/day, although acutely ill patients or patients with neurotrauma may require doses of 6.0 to 7.5 mg/kg/day. Intravenous maintenance doses should be administered every 6 to 8 hours to maintain therapeutic serum concentrations.
Phenytoin precipitates in dextrose-containing solutions and should only be mixed in 0.9% sodium chloride solutions. To prevent phlebitis, the maximum concentration for peripheral administration is 10 mg/mL; a final concentration of 20 mg/mL may be used if the dose is being administered through a central venous catheter. Phenytoin solution must be administered through an in-line 1.2- or 5.0-μ filter to prevent the administration of phenytoin crystals into the systemic circulation. Phenytoin doses should not be administered at a rate faster than 50 mg/min because hypotension and arrhythmias may occur because of its propylene glycol diluent. The infusion rate should be decreased by 50% if hypotension or arrhythmias develop.
Oral administration is not usually recommended in acutely ill patients because of the risk of erratic or incomplete absorption. Phenytoin oral suspension may adhere to the inside walls of oro- or nasogastric tubes, reducing the dose delivered to the patient. If phenytoin is administered through a feeding tube, the tube should be flushed with 30 to 60 mL of 0.9% sodium chloride before and after administering the dose. After the dose is administered, the feeding tube should be clamped for an hour before restarting the feeding solution. Oral absorption may be impaired by concomitant administration with enteral nutrition solutions, reducing its bioavailability and resulting in erratic serum concentrations with seizures occurring as a result of subtherapeutic serum concentrations. Phenytoin oral solution must be shaken prior to use to ensure uniformity in the distribution of the phenytoin particles throughout the suspension. If the suspension is not shaken before obtaining a dose, the phenytoin powder settles to the bottom of the bottle producing subtherapeutic doses when the bottle is first opened and toxic doses as the bottle is used.
Hemodialysis and hemofiltration have no effect on phenytoin clearance. Agents known to inhibit or enhance this enzymatic pathway may affect phenytoin’s clearance. Early adverse effects that may be associated with increasing serum concentrations are nystagmus (>20 mg/L), ataxia (>30 mg/L), and lethargy, confusion, and impaired cognitive function (>40 mg/L).
The normal therapeutic range for the total phenytoin serum concentration is 10 to 20 mg/L with the free fraction therapeutic range of 1 to 2 mg/L. Serum concentration of 20 to 30 mg/L may be required in patients who are having seizures. Phenytoin serum concentrations can be obtained 30 to 60 minutes after the loading dose is infused to assess the adequacy of the dose. Trough concentrations should be monitored 2 to 3 times a week, particularly after the first week of therapy. Measurement of free phenytoin concentrations may be indicated in acutely ill patients, patients with serum albumin concentrations less than 2.5 g/dL, renal failure, or receiving drugs known to displace phenytoin from albumin-binding sites. Other monitoring parameters include the patient’s seizure activity and medication profile for agents known to alter phenytoin’s metabolism.
Dose
• Loading dose: 15 to 20 mg/kg IV
• Maintenance dose: 5 mg/kg/day IV or PO
Monitoring Parameters
• Seizure activity, electroencephalogram (EEG), serum phenytoin concentration (free phenytoin concentration if applicable), albumin, liver function, infusion rate, blood pressure, ECG with IV administration, and IV injection site
Fosphenytoin is a phenytoin prodrug with good aqueous solubility that was developed to be a water-soluble alternative to phenytoin. In patients unable to tolerate oral phenytoin, equimolar doses of fosphenytoin have been shown to produce equal or greater plasma phenytoin concentrations. Although phenytoin sodium 50 mg is equal to fosphenytoin sodium 75 mg, phenytoin should be converted to fosphenytoin on a milligram-per-milligram basis (eg, phenytoin 300 mg should be converted to fosphenytoin 300 mg).
Fosphenytoin, administered IM or IV, is rapidly and completely converted to phenytoin in vivo, resulting in essentially 100% bioavailability. The conversion half-life to phenytoin is about 33 minutes following IM administration and about 15 minutes after IV infusion. After IM administration, peak plasma fosphenytoin concentrations occur approximately 30 minutes postdose, with peak phenytoin concentrations occurring in about 3 hours. Fosphenytoin’s peak concentration following IV administration occurs at the end of the infusion, with peak phenytoin concentrations occurring in approximately 40 to 75 minutes. In patients with renal or hepatic dysfunction or hypoalbuminemia, there is enhanced conversion to phenytoin without an increase in clearance. Fosphenytoin is 90% to 95% bound to plasma proteins and is saturable with the percent of bound fosphenytoin decreasing as the fosphenytoin dose increases.
The maximum total phenytoin concentration increases with increasing fosphenytoin doses, but the total phenytoin concentration is less affected by increasing fosphenytoin infusion rates. Maximum free phenytoin concentrations are nearly constant at infusion rates up to 50 mg phenytoin equivalents (PE)/min, whereas they increase with faster infusion rates secondary to phenytoin displacement from albumin-binding sites in the presence of high fosphenytoin concentrations.
For the treatment of status epilepticus, the recommended loading dose of IV fosphenytoin is 15 to 20 PE/kg, and it should not be administered faster than 150 mg PE/min because of the risk of hypotension. Fosphenytoin 15 to 20 mg PE/kg infused at 100 to 150 mg PE/min yields plasma-free phenytoin concentrations over time that approximate those achieved when an equimolar dose of IV phenytoin is administered at 50 mg/min. In the treatment of status epilepticus, total phenytoin concentrations greater than 10 mg/L and free phenytoin concentrations greater than 1 mg/mL are achieved within 10 to 20 minutes after starting the infusion.
In nonemergent situations, loading doses of 10 to 20 PE/kg administered IV or IM is recommended. In nonemergent situations, IV administration of infusion rates of 50 to 100 mg PE/min may be acceptable, but results in slightly lower and delayed maximum free phenytoin concentrations as compared with administration at higher infusion rates. The initial daily maintenance dose is 4 to 6 mg PE/kg/day. Dosing adjustments are not required when IM fosphenytoin is substituted temporarily for oral phenytoin. However, patients switched from once-daily extended-release phenytoin capsules may require twice-daily or more frequent administration of fosphenytoin to maintain similar peak and trough phenytoin concentrations.
The incidence of adverse effects tends to increase as both dose and infusion rate are increased. At doses above 15 mg PE/kg and infusion rates higher than 150 mg PE/min, transient pruritus, tinnitus, nystagmus, somnolence, and ataxia occur more frequently than at lower doses or infusion rates. Severe burning, itching, and paresthesias of the groin are commonly associated with infusion rates greater than 150 mg PE/min. Slowing or temporarily stopping the infusion can minimize the frequency and severity of these reactions. Continuous cardiac rate and rhythm, blood pressure, and respiratory function should be monitored throughout the fosphenytoin infusion and for 10 to 20 minutes after the end of the infusion.
Following fosphenytoin administration, phenytoin concentrations should not be monitored until the conversion to phenytoin is complete. This occurs within 2 hours after the end of an IV infusion and 5 hours after an IM injection. Prior to complete conversion, commonly used immunoanalytic techniques such as fluorescence polarization and enzyme-mediated assays may significantly overestimate plasma phenytoin concentrations because of cross-reactivity with fosphenytoin. Blood samples collected before complete conversion to phenytoin should be collected in tubes containing ethylenediamine tetraacetic acid (EDTA) as an anticoagulant to minimize the ex vivo conversion of fosphenytoin to phenytoin. Monitoring is similar to phenytoin. In acutely ill patients with renal failure receiving fosphenytoin, one or more metabolites of adducts of fosphenytoin accumulate and display significant cross-reactivity with several phenytoin immunoassay methods.
Levetiracetam is a second-generation antiepileptic drug with increasing usage in acute care settings. The agent leads to selective prevention of burst firing and seizure activity. Levetiracetam is commonly prescribed for adjunctive treatment of partial onset seizures with or without secondary generalization. Other approved indications include monotherapy treatment of partial onset seizures with or without secondary generalization, and adjunctive treatment of myoclonic seizures associated with juvenile myoclonic epilepsy and primary generalized tonic-clonic (GTC) seizures associated with idiopathic generalized epilepsy. Seizure prophylaxis in post-traumatic brain injury patients is also an established role for levetiracetam.
Levetiracetam lacks cytochrome P450 isoenzyme-inducing potential and is not associated with clinically significant interactions with other drugs, including other antiepileptic drugs. Sedation is the most common adverse effect noted.
Dose
• Maintenance dose: 250 mg to 1000 mg q12 IV or PO
Monitoring Parameters
• Seizure activity, electroencephalogram (EEG), sedation
Benzodiazepines are the primary agents in the management of status epilepticus. These agents suppress the spread of seizure activity but do not abolish the abnormal discharge from a seizure focus. Although IV diazepam has the fastest onset of action, lorazepam or midazolam are equally efficacious in controlling seizure activity. They are the agents of choice to temporarily control seizures and to gain time for the loading of phenytoin or phenobarbital. Phenytoin may also be used prophylactically in patients who are at risk for seizures after neurosurgery or following head injuries.
Monitoring Parameters
• Seizure activity, EEG, and respiratory rate and quality
Nesiritide is a recombinant human b-type natriuretic peptide, which is a cardiac hormone that regulates cardiovascular homeostasis and fluid volume during states of volume and pressure overload. The agent is effective in reducing pulmonary capillary wedge pressure and improving dyspnea symptoms in patients with acutely decompensated HF who have dyspnea at rest or with minimal activity. The most common adverse effects include hypotension, tachycardia, and/or bradycardia.
Dose
• IV bolus: 2 mcg/kg
• Continuous infusion: 0.01 mcg/kg/min
Monitoring Parameters
• Blood pressure, heart rate, urine output, and hemodynamic parameters
Sodium nitroprusside is a balanced vasodilator affecting the arterial and venous systems. Blood pressure reduction occurs within seconds after an infusion is started, with a duration of action of less than 10 minutes once the infusion is discontinued. Sodium nitroprusside is considered the agent of choice in acute hypertensive conditions such as hypertensive encephalopathy, intracerebral infarction, subarachnoid hemorrhage, carotid endarterectomy, malignant hypertension, microangiopathic anemia, and aortic dissection, and after general surgical procedures, major vascular procedures, or renal transplantation.
If sodium nitroprusside is used for longer than 48 hours, there is the risk of thiocyanate toxicity. However, this may only be a concern in patients with renal dysfunction. In this setting, thiocyanate serum concentrations should be monitored to ensure that they remain below 10 mg/dL. Other potential side effects include methemoglobinemia and cyanide toxicity. Nitroprusside should be used with caution in the setting of increased intracranial pressure, such as head trauma or postcraniotomy, where it may cause an increase in cerebral blood flow. Nitroprusside’s effects on intracranial pressure may be attenuated by a lowered PaCO2 and raised PaO2. In pregnant women, nitroprusside should be reserved only for refractory hypertension associated with eclampsia, because of the potential risk to the fetus.
Dose
• Continuous infusion: 0.5 to 10.0 mcg/kg/min
Monitoring Parameters
• Blood pressure, renal function, thiocyanate concentration (prolonged infusions), acid-base status, and hemodynamic parameters
Nitroglycerin is a preferential venous dilator affecting the venous system at low doses, but relaxes arterial smooth muscle at higher doses. The onset of blood pressure reduction after starting a nitroglycerin infusion is similar to sodium nitroprusside, approximately 1 to 3 minutes, with duration of action of less than 10 minutes. Headaches are a common adverse effect that may occur with nitroglycerin therapy and can be treated with acetaminophen. Tachyphylaxis can be seen with the IV infusion, similar to what is seen after the chronic use of topical nitroglycerin preparations. In patients receiving unfractionated heparin in addition to nitroglycerin, increased doses of unfractionated heparin may be required to maintain a therapeutic partial thromboplastin time (PTT). The mechanism by which nitroglycerin causes unfractionated heparin resistance is unknown. However, the PTT should be closely monitored in patients receiving nitroglycerin and unfractionated heparin concurrently.
Nitroglycerin is the preferred agent in the setting of hypertension associated with myocardial ischemia or infarction because its net effect is a reduction in oxygen consumption.
Dose
• Continuous infusion: 10 to 300 mcg/min
• Oral: 2.5 to 9 mg bid-qid
Monitoring Parameters
• Blood pressure, heart rate, signs and symptoms of ischemia, hemodynamic parameters (if applicable), and PTT (in patients receiving unfractionated heparin concurrently)
Hydralazine reduces peripheral vascular resistance by directly relaxing arterial smooth muscle. Blood pressure reduction occurs within 5 to 20 minutes after an IV dose and lasts approximately 2 to 6 hours. Common adverse effects include headache, nausea, vomiting, palpitations, and tachycardia. Reflex tachycardia may precipitate anginal attacks. Co-administration of a beta-receptor antagonist can decrease the incidence of tachycardia.
• 10 to 25 mg IV q2-4h
• Oral: 10 to 125 mg bid-qid
Monitoring Parameters
• Blood pressure and heart rate
Diazoxide is a nondiuretic that reduces peripheral vascular resistance by directly relaxing arterial smooth muscle. Side effects such as hypotension, nausea and vomiting, dizziness, weakness, hyperglycemia, and reflex tachycardia have been associated with the use of the higher than 300-mg dosing regimen. Using lower dose regimens produces similar but less severe side effects. Caution should be used when diazoxide is administered with other antihypertensive agents because excessive hypotension may result.
Blood pressure reduction occurs within 1 to 2 minutes and lasts 3 to 12 hours after a dose. Blood pressure should be monitored frequently until stable, and then monitored hourly.
Dose
• IV bolus: 50 to 150 mg q5min
• Continuous infusion: 7.5 to 30.0 mg/min
• Oral: 3 to 8 mg/kg/day divided 2 to 3 times/day
Monitoring Parameters
• Blood pressure, heart rate, and serum glucose
Labetalol is a combined alpha- and beta-adrenergic blocking agent with a specificity of beta receptors to alpha receptors of approximately 7:1. Labetalol may be administered parenterally by escalating bolus doses or by continuous infusion. The onset of action after the administration of labetalol is within 5 minutes with duration of effect from 2 to 12 hours. Because labetalol possesses beta-blocking properties, it may produce bronchospasm in individuals with asthma or reactive airway disease. It also may produce conduction system disturbances or bradycardia in susceptible individuals, and its negative inotropic properties may exacerbate symptoms of HF.
Labetalol may be considered as an alternative to sodium nitroprusside in the setting of hypertension associated with head trauma or postcraniotomy, spinal cord syndromes, transverse lesions of the spinal cord, Guillain-Barré syndrome, or autonomic hyperreflexia, as well as hypertension associated with sympathomimetics (eg, cocaine, amphetamines, phencyclidine, nasal decongestants, or certain diet pills) or withdrawal of centrally acting antihypertensive agents (eg, beta-blockers, clonidine, or methyldopa). It also may be used as an alternative to phentolamine in the setting of pheochromocytoma because of its alpha- and beta-blocking properties.
Dose
• IV bolus: 20 mg over 2 minutes, then 40 to 80 mg IV q10min to a total of 300 mg
• Continuous infusion: 1 to 4 mg/min and titrate to effect
• Oral: 100 to 400 mg bid
Monitoring Parameters
• Blood pressure, heart rate, ECG, and signs and symptoms of HF or bronchospasm (if applicable)
Phentolamine is an alpha-adrenergic blocking agent that may be administered parenterally by bolus injection or continuous infusion. Onset of action is within 1 to 2 minutes, with duration of action of 3 to 10 minutes. Potential adverse effects that may occur with phentolamine include tachycardia, GI stimulation, and hypoglycemia.
Phentolamine is considered the drug of choice for the treatment of hypertension associated with pheochromocytoma because of its ability to block alpha-adrenergic receptors. Also, it is the primary agent used to treat acute hypertensive episodes in patients receiving monoamine oxidase inhibitors.
Dose
• IV bolus: 5 to 10 mg q5-15min
• Continuous infusion: 1 to 10 mg/min
Monitoring Parameters
• Blood pressure and heart rate
Beta-adrenergic blocking agents available for IV delivery include propranolol, esmolol, and metoprolol. Propranolol and metoprolol may be administered by bolus injection or continuous infusion. Atenolol typically is administered by bolus injection, and esmolol is administered by continuous infusion. A continuous infusion of esmolol may or may not be preceded by an initial bolus injection.
Esmolol has the fastest onset and shortest duration of action, approximately 1 to 3 minutes and 20 to 30 minutes, respectively. Propranolol and metoprolol have similar onset times, but durations of action vary between 1 and 6 hours. The duration of action after a bolus dose of atenolol is approximately 12 hours.
All agents may produce bronchospasm in individuals with asthma or reactive airway disease and may produce conduction system disturbances or bradycardia in susceptible individuals. Also, because of their negative inotropic properties, they may exacerbate symptoms of HF.
Beta-blocking agents typically are used as adjuncts with other agents in the treatment of acute hypertension. They may be used with sodium nitroprusside in the treatment of acute aortic dissections. They should be administered to patients with hypertension associated with pheochromocytoma only after phentolamine has been given. Also, they are the agents of choice in patients who have been maintained on beta-blocking agents for the chronic management of hypertension but who have abruptly stopped therapy.
Beta-blocking agents should be avoided in patients with hypertensive encephalopathy, intracranial infarctions, or subarachnoid hemorrhages because of their central nervous system depressant effects. They also should be avoided in patients with acute pulmonary edema because of their negative inotropic properties. Finally, beta-blocking agents should be avoided in hypertension associated with eclampsia and renal vasculature disorders.
Dose
• Esmolol: IV bolus 500 mcg/kg; continuous infusion: 50 to 400 mcg/kg/min
• Metoprolol: IV bolus: 5 mg IV q2min × 3 doses or maintenance 1.25 to 5 mg IV q6-12h. Oral: 25 to 450 mg daily divided 2 to 3 times/day
• Propranolol: IV bolus: 0.5 to 1.0 mg q5-15min; continuous infusion: 1 to 4 mg/h. Oral: 30 to 320 mg daily divided 2 to 4 times/day
Monitoring Parameters
• Blood pressure, heart rate, ECG, and signs and symptoms of HF or bronchospasm (if applicable)
Angiotensin-converting enzyme (ACE) inhibitors competitively inhibit angiotensin-converting enzyme, which is responsible for the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor). In addition, these agents inactivate bradykinin and other vasodilatory prostaglandins, resulting in an increase in plasma renin concentrations and a reduction in plasma aldosterone concentrations. The net effect is a reduction in blood pressure in hypertensive patients and a reduction in afterload in patients with HF.
Angiotensin-converting enzyme inhibitors are indicated in the management of hypertension and HF. Adverse effects associated with ACE inhibitors include rash, taste disturbances, and cough. Initial-dose hypotension may occur in patients who are hypovolemic, hyponatremic, or who have been aggressively diuresed. Hypotension may be avoided or minimized by starting with low doses or withholding diuretics for 24 to 48 hours. Worsening of renal function may occur in patients with bilateral renal artery stenosis.
Enalapril is a prodrug that is converted in the liver to its active moiety, enalaprilat, a long-acting ACE inhibitor. Enalapril is available in an oral dosage form, and enalaprilat is available in the IV form. Following an IV dose of enalaprilat, blood pressure lowering occurs within 15 minutes and lasts 4 to 6 hours.
Dose
• Enalaprilat: IV bolus: 0.625 to 1.250 mg over 5 minutes q6h; continuous infusion: not recommended
• Enalapril: Oral: 2.5 to 40.0 mg qd
Monitoring Parameters
• Blood pressure, heart rate, renal function, and electrolytes
Angiontensin receptor blockers (ARBs) selectively block the binding of angiotensin II (a powerful vasoconstrictor in vascular smooth muscle) to the receptors in tissues such as vascular smooth muscle and the adrenal gland. This receptor blockade results in vasodilation and decreased secretion of aldosterone, which leads to increased sodium excretion and potassium sparing effects. ARBs are indicated for both hypertension and HF. ARBs currently available in oral formulations include valsartan, candesartan, irbesartan, azilsartan, eprosartan, losartan, and olmesartan. The most common adverse effects of ARBs are hypotension, dizziness, and headache. Although rare, cough can also be associated with ARBs. This cough can be reversed by discontinuance of therapy. Overall, these agents are relatively well tolerated and thus used quite commonly for the chronic management of stages 1 and 2 hypertension. The role in acute blood pressure lowering is limited due to the lack of a parenteral formulation.
Monitoring Parameters
• Blood pressure and heart rate, and electrolytes
Calcium channel–blocking agents may be used as alternative therapy in the treatment of hypertension resulting from hypertensive encephalopathy, myocardial ischemia, malignant hypertension, or eclampsia, or after renal transplantation.
Nicardipine is an IV calcium channel–blocking agent that is primarily indicated for the treatment of hypertension. Onset is within 5 minutes with duration of approximately 30 minutes. Nicardipine also is available in an oral dosage form so that patients started on IV therapy can convert to oral therapy when indicated.
Dose
• Continuous infusion: 5 mg/h, increase every 15 minutes to a maximum of 15 mg/h
• Oral: 20 to 40 mg q8h
Monitoring Parameters
• Blood pressure and heart rate
Clevidipine is an IV calcium channel blocking agent that is also indicated for the treatment of hypertension. An onset of 2 minutes is faster than nicardipine with a shorter duration of 10 minutes. Clevidipine is delivered as an injectable lipid emulsion (20%), similar to intralipids, and is not available in an oral dosage form. Similar to propofol, vials of clevidipine and IV tubing must be changed every 12 hours during therapy because the phospholipids support microbial growth.
• Continuous infusion: 1 to 2 mg/h, increase by doubling dose every 90-second intervals initially to achieve blood pressure reduction. As the blood pressure approaches goal, increase dose less aggressively every 5 to 10 minutes. Maximum recommended dose is 16 mg/h.
Monitoring Parameters
• Blood pressure and heart rate
Clonidine is an oral agent that stimulates alpha-2-adrenergic receptors in the medulla oblongata, causing inhibition of sympathetic vasomotor centers. Although clonidine typically is used as maintenance antihypertensive therapy, it can be used in the setting of hypertensive urgencies or emergencies. Its antihypertensive effects may be seen within 30 minutes and last 8 to 12 hours. Once blood pressure is controlled, oral maintenance clonidine therapy may be started.
Centrally acting sympatholytics rarely are indicated as first-line agents except when hypertension may be due to the abrupt withdrawal of one of these agents.
Dose
• Hypertensive urgency: 0.2 mg PO initially, then 0.1 mg/h PO (to a maximum of 0.8 mg)
• Transdermal: TTS-1 (0.1 mg/day) to TTS-3 (0.3 mg/day) topically q1wk
Monitoring Parameters
• Blood pressure, heart rate, and mental status
Antiarrhythmic agents are divided into five classes. Dosage information for individual antiarrhythmic agents is listed in Chapter 22 (see Table 22-4).
Class I agents are further divided into three subclasses: Ia (procainamide, quinidine, disopyramide), Ib (lidocaine, mexiletine), and Ic (flecainide, propafenone). All class I agents block sodium channels in the myocardium and inhibit potassium-repolarizing currents to prolong repolarization.
Class Ia agents inhibit the fast sodium channel (phase 0 of the action potential), slow conduction at elevated serum drug concentrations, and prolong action potential duration and repolarization. Class Ia agents can cause proarrhythmic complications by prolonging the QT interval or by depressing conduction and promoting reentry.
Monitoring Parameters
• ECG (QRS complex, QT interval, arrhythmia frequency)
Class Ib agents have little effect on phase 0 depolarization and conduction velocity, but shorten the action potential duration and repolarization. QT prolongation typically does not occur with class Ib agents. Class Ib agents act selectively on diseased or ischemic tissue where they block conduction and interrupt reentry circuits.
Monitoring Parameters
• ECG (QT interval, arrhythmia frequency)
Class Ic agents inhibit the fast sodium channel and cause a marked depression of phase 0 of the action potential and slow conduction profoundly, but have minimal effects on repolarization. The dramatic effects of these agents on conduction may account for their significant proarrhythmic effects, which limit their use in patients with supraventricular arrhythmias and structural heart disease.
Monitoring Parameters
• ECG (PR interval and QRS complex, arrhythmia frequency)
Beta-blocking agents inactivate sodium channels and depress phase 4 depolarization and increase the refractory period of the atrioventricular node. These agents have no effect on repolarization. Beta-blockers competitively antagonize catecholamine binding at beta-adrenergic receptors.
Beta-blocking agents can be classified as selective or nonselective agents. Nonselective agents bind to beta-1 receptors located on myocardial cells and beta-2 receptors located on bronchial and skeletal smooth muscle. Stimulation of beta-1 receptors causes an increase in heart rate and contractility, whereas stimulation of beta-2 receptors results in bronchodilation and vasodilation. Selective beta-blocking agents block beta-1 receptors in the heart at low or moderate doses, but they become less selective with increasing doses.
Class II agents are used for the prophylaxis and treatment of both supraventricular arrhythmias and arrhythmias associated with catecholamine excess or stimulation, slowing the ventricular response in atrial fibrillation, lowering blood pressure, decreasing heart rate, and decreasing ischemia. Esmolol is useful especially for the rapid, short-term control of ventricular response in atrial fibrillation or flutter.
Nonselective beta-blocking agents should be avoided or used with caution in patients with HF, atrioventricular nodal blockade, asthma, COPD, peripheral vascular disease, Raynaud phenomenon, and diabetes. Beta-1 selective beta-blocking agents should be used with caution in these populations.
Monitoring Parameters
• ECG (heart rate, PR interval, arrhythmia frequency)
Class III agents (amiodarone, dofetilide, and sotalol) lengthen the action potential duration and effective refractory period and prolong repolarization. Additionally, amiodarone possesses alpha- and beta-blocking effects and calcium channel–blocking properties and inhibits the fast sodium channel. Sotalol possesses nonselective beta-blocking properties. Although torsades de pointes is relatively rare with amiodarone, precautions should be taken to prevent hypokalemia- or digitalis-toxicity–induced arrhythmias. Sotalol may be associated with proarrhythmic effects in the setting of hypokalemia, bradycardia, high sotalol dose, and QT-interval prolongation, and in patients with preexisting HF. Sotalol is also contraindicated in patients with severe renal impairment.
The antiarrhythmic effect of amiodarone is due to the prolongation of the action potential duration and refractory period, and secondarily through alpha-adrenergic and beta-adrenergic blockade. In patients with recent-onset (<48 hours) atrial fibrillation or atrial flutter, IV amiodarone has been shown to restore normal sinus rhythm within 8 hours in approximately 60% to 70% of treated patients. Although IV amiodarone has been associated with negative inotropic effects, minimal side effects are associated with its short-term administration. Amiodarone is recommended as an option for the treatment of wide-complex tachycardia; stable, narrow-complex supraventricular tachycardia; stable, monomorphic or polymorphic ventricular tachycardia; atrial fibrillation and flutter; ventricular fibrillation; and pulseless ventricular tachycardia.
Monitoring Parameters
• ECG (PR and QT intervals, QRS complex, arrhythmia frequency)
Dofetilide is a class III antiarrhythmic (potassium channel blocker) agent used for rhythm conversion in patients with atrial fibrillation. The agent has been FDA approved with substantial restrictions, as prescribers must undergo drug specific training before being permitted to prescribe. Initiation of drug therapy is also limited to hospitalized patients with continuous ECG monitoring and dosing based on a prespecified dosing algorithm. Proarrhythmic events and sudden cardiac death are the most substantial adverse events associated with dofetilide administration leading to these restrictions. The dose should be adjusted according to QT prolongation and creatinine clearance. If the QTc is greater than 400 millisecond, dofetilide is contraindicated. Dofetilide is also contraindicated in patients with severe renal impairment.
Dose
• Modified based on creatinine clearance and QT or QTc interval. The usual recommended oral dose is 250 mcg bid.
Ibutilide is a class III antiarrhythmic agent indicated for the conversion of recent-onset atrial fibrillation and atrial flutter to normal sinus rhythm. Ibutilide causes the prolongation of the refractory period and action potential duration, with little or no effect on conduction velocity or automaticity. Its electrophysiologic effects are predominantly derived from activation of a slow sodium inward current. Ibutilide can cause slowing of the sinus rate and atrioventricular node conduction, but has no effect on heart rate, PR interval, or QRS interval. The drug is associated with minimal hemodynamic effects with no significant effect on cardiac output, mean pulmonary arterial pressure, or pulmonary capillary wedge pressure. Ibutilide has not been shown to lower blood pressure or worsen HF.
Ibutilide has been shown to be more effective than procainamide and sotalol in terminating atrial fibrillation and atrial flutter. In addition, ibutilide has been shown to decrease the amount of joules required to treat resistant atrial fibrillation and atrial flutter during cardioversion. Depending on the duration of atrial fibrillation or flutter, ibutilide has an efficacy rate of 22% to 43% and 37% to 76%, respectively, for terminating these arrhythmias. Ibutilide is only available as an IV dosage form and cannot be used for the long-term maintenance of normal sinus rhythm.
Sustained and nonsustained polymorphic ventricular tachycardia is the most significant adverse effect associated with ibutilide. The overall incidence of polymorphic ventricular tachycardia diagnosed as torsades de pointes was 4.3%, including 1.7% of patients in whom the arrhythmia was sustained and required cardioversion. Ibutilide administration should be avoided in patients receiving other agents that prolong the QTc interval, including class Ia or III antiarrhythmic agents, phenothiazines, antidepressants, and some antihistamines. Before ibutilide administration, patients should be screened carefully to exclude high-risk individuals, such as those with a QTc interval greater than 440 millisecond or bradycardia. Serum potassium and magnesium levels should be measured and corrected before the drug is administered. The ibutilide infusion should be stopped in the event of nonsustained or sustained ventricular tachycardia or marked prolongation in the QTc interval. Patients should be monitored for at least 4 hours after the infusion or until the QTc returns to baseline, with longer monitoring if nonsustained ventricular tachycardia develops.
Monitoring Parameters
• ECG (heart rate, PR interval, ST segment, T wave, arrhythmia frequency)
Calcium channel–blocking agents inhibit calcium channels within the atrioventricular node and sinoatrial node, prolong conduction through the atrioventricular and sinoatrial nodes, and prolong the functional refractory period of the nodes, as well as depress phase 4 depolarization. Class IV agents are used for the prophylaxis and treatment of supraventricular arrhythmias and to slow the ventricular response in atrial fibrillation, flutter, and multifocal atrial tachycardia.
Monitoring Parameters
• ECG (PR interval, arrhythmia frequency)
Adenosine, digoxin, and atropine possess different pharmacologic properties but ultimately affect the sinoatrial node or atrioventricular node.
Monitoring Parameters
• ECG (heart rate, PR interval, ST segment, T wave, arrhythmia frequency)
Adenosine depresses sinus node automaticity and atrioventricular nodal conduction. Adenosine is indicated for the acute termination of atrioventricular nodal and reentrant tachycardia, and for supraventricular tachycardias, including Wolff-Parkinson-White syndrome.
Atropine increases the sinus rate and decreases atrioventricular nodal conduction time and effective refractory period by decreasing vagal tone. The major indications for the use of atropine include symptomatic sinus bradycardia and type I second-degree atrioventricular block.
Digoxin is indicated for the treatment of supraventricular tachycardia and for controlling ventricular response associated with supraventricular tachycardia.
Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is characterized by elevations in pulmonary arterial pressure in the absence of a demonstrable cause. Vasoconstriction in the pulmonary vasculature is thought to play an important role in the pathogenesis of IPAH. This vasoconstriction occurs secondary to either impaired production of endogenous vasodilators (prostacyclin and nitric oxide), or from increased production of endothelin, an endogenous vasoconstrictor.
Epoprostenol (Flolan), treprostinil (Remodulin), and iloprost (Ventavis) are potent vasodilators, which also inhibit platelet aggregation and smooth muscle proliferation and are the mainstay of IPAH therapy. Epoprostenol is delivered intravenously via continuous infusion. For long-term therapy, a permanently implanted central venous catheter and portable infusion pump are useful for drug administration. Side effects include jaw pain, diarrhea, and arthralgias. The doses are typically titrated based on impact on systemic blood pressure, therefore monitoring is recommended whenever therapy is initiated. Treprostinil has an advantage of continuous SC delivery, a longer half-life (possibly less immediately life-threatening if interrupted), and the lack of a need for refrigeration. A major disadvantage of treprostinil is the high rate of significant infusion site discomfort if the SC rate is used. Iloprost is an aerosolized preparation which is delivered via a specialized nebulizer device. This agent was recently FDA approved with its role yet to be clearly defined compared to other prostacyclin analogues.
Bosentan (Tracleer) works by blocking the vasoconstrictive properties of endothelin and is only available orally. The main adverse event associated with therapy is elevations in liver enzymes, therefore close monitoring of liver function tests is required. Bosentan is often combined with prostacyclin analogues to treat refractory cases of IPAH.
Numerous studies of patients with IPAH have demonstrated improvements in pulmonary hemodynamics after treatment with sildenafil (Viagra, Revatio). Tadalafil (Cialis) and vardenafil (Levitra) have similar mechanisms of action; however, there appear to be some differences in the degree of phosphodiesterase inhibition, leading to questions of whether these agents are interchangeable. Sildenafil is the most widely studied and therefore the most commonly prescribed phosphodiesterase inhibitor. Similar to bosentan, sildenafil’s most prominent role appears to be in combination with prostacyclin analogues.
Nifedipine (Procardia, Adalat), amlodipine (Norvasc), and diltiazem (Cardizem) all have proven beneficial in IPAH therapy due to vasodilatory properties. Relatively high doses are required to see responses, with systemic hypotension and edema being the most significant adverse effects in these patients. The historical role for these agents has been first-line management; however many clinicians currently opt for prostacyclin therapy or phosphodiesterase therapy initially.
The 2012 Surviving Sepsis Campaign international guidelines for management of severe sepsis and septic shock recommend norepinephrine as the first-choice vasopressor in this setting. It is recommended that vasopressor therapy initially target a mean arterial pressure (MAP) of 65 mm Hg. Norepinephrine is a direct-acting vasoactive agent. It possesses alpha- and beta-adrenergic agonist properties producing mixed vasopressor and inotropic effects. Dopamine is recommended as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia). Dopamine is both an indirect-acting and a direct-acting agent. Dopamine works indirectly by causing the release of norepinephrine from nerve terminal storage vesicles as well as directly by stimulating alpha and beta receptors. Dopamine is unique in that it produces different pharmacologic responses based on the dose infused. At doses less than 5 mcg/kg/min, dopamine stimulates dopaminergic receptors in the kidneys. Doses between 5 and 10 mcg/kg/min are typically associated with an increase in inotropy resulting from stimulation of beta receptors in the heart, and doses above 10 mcg/kg/min stimulate peripheral alpha-adrenergic receptors, producing vasoconstriction and an increase in blood pressure. Dopamine and norepinephrine are both effective for increasing blood pressure. Dopamine raises cardiac output more than norepinephrine, but its use is limited by tachyarrhythmias. Norepinephrine may be a more effective vasopressor in some patients, thus the first line designation. Epinephrine is an option for addition to norepinephrine as needed to maintain adequate blood pressure in refractory patients. Epinephrine possesses alpha- and beta-adrenergic effects, increasing heart rate, contractility, and vasoconstriction with higher doses. Epinephrine’s use is reserved for when other, vasoconstrictors are inadequate. Adverse effects include tachyarrhythmias; myocardial, mesenteric, renal, and extremity ischemia; and hyperglycemia. Phenylephrine is not recommended in the treatment of septic shock except in the following circumstances: (a) norepinephrine is associated with serious arrhythmias, (b) cardiac output is known to be high and blood pressure persistently low, or (c) as salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve the MAP target. Phenylephrine is a pure alpha-adrenergic agonist. It produces vasoconstriction without a direct effect on the heart, although it may cause a reflex bradycardia. Phenylephrine may be useful when dopamine, dobutamine, norepinephrine, or epinephrine cause tachyarrhythmias and when a vasoconstrictor is required.
Vasopressin is an emerging therapeutic agent for the hemodynamic support of septic and vasodilatory shock. Vasopressin is a hormone that mediates vasoconstriction via V1 receptor activation on vascular smooth muscle. During septic shock, vasopressin levels are particularly low. Exogenous vasopressin administration is based on the theory of hormone replacement. Vasopressin (up to 0.03 unit/min) can be added to norepinephrine with the intent of raising MAP to target or decreasing norepinephrine dosage. Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension, and vasopressin doses higher than 0.03-0.04 units/min should be reserved for salvage therapy (failure to achieve an adequate MAP with other vasopressor agents). It is important to note that harmful vasoconstriction of the gut vasculature will occur with dose escalation greater than 0.04 units/min.
Dose
• See Table 22-3.
Monitoring Parameters
• Blood pressure, heart rate, ECG, urine output, and hemodynamic parameters
Dobutamine produces pronounced beta-adrenergic effects such as increases in inotropy and chronotropy along with vasodilation. Dobutamine is useful especially for the acute management of low cardiac output states. Adverse effects associated with the use of dobutamine include tachyarrhythmias and ischemia.
A trial of dobutamine infusion up to 20 mcg/kg/min may be administered or added to vasopressors (if in use) in the presence of: (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion, despite achieving adequate intravascular volume and adequate MAP. Norepinephrine and dobutamine can be titrated separately to maintain both blood pressure and cardiac output.
Dopamine in the range of 5 to 10 mcg/kg/min typically produces an increase in inotropy and chronotropy. Doses above 10 mcg/kg/min typically produce alpha-adrenergic effects.
Isoproterenol is a potent pure beta-receptor agonist. It has potent inotropic, chronotropic, and vasodilatory properties. Its use typically is reserved for temporizing life-threatening bradycardia. Adverse effects associated with isoproterenol include tachyarrhythmias, myocardial ischemia, and hypotension.
Epinephrine produces pronounced effects on heart rate and contractility and is used when other inotropic agents have not resulted in the desired pharmacologic response. Epinephrine is associated with tachyarrhythmias; myocardial, mesenteric, renal, and extremity ischemia; and hyperglycemia.
Dose
• See Table 22-3.
Monitoring Parameters
• Blood pressure, heart rate, ECG, urine output, and hemodynamic parameters
There are a wide variety of antibiotic agents used in hospitalized patients. Commonly used antibiotic classes include beta lactams or penicillins (eg, penicillin G potassium, ampicillin ± sulbactam, oxacillin, nafcillin, ticarcillin ± clavulanic acid, and piperacillin ± tazobactam), carbapenems (eg, meropenem, doripenem, and imipenem/cilastatin), monobactams (eg, aztreonam), cephalosporins (eg, cefazolin, cefotetan, cefoxitin, cefotaxime, ceftazidime, ceftriaxone, and cefepime), fluoroquinolones (eg, levofloxacin, moxifloxacin, and ciprofloxacin), macrolides (eg, azithromycin, erythromycin), lincosamides (eg, clindamycin), nitroimidazoles (eg, metronidazole), lipopetides (eg, daptomycin), oxazolidinones (eg, linezolid), glycopeptides (eg, vancomycin, telavancin), and aminoglycosides (eg, amikacin, tobramycin, and gentamicin). Since the development of the first antibiotic (penicillin) in 1944, microorganisms have consistently evolved by developing resistance to these agents. This has led to the need for newer and more innovative classes of antibiotics with different targets and ways to avoid resistance. Selection of the correct agent(s) is a key consideration, along with correct identification of the site of infection, and knowledge of resistance patterns within your institution. In some instances, combinations of different antibiotic classes (eg, aminoglycoside + beta lactam, or fluoroquinolone + beta lactam) may be used as a strategy to address resistance patterns. This is used particularly with gram negative organisms, and may be advocated vs monotherapy for certain indications. Additionally, the antibiotic dose, frequency, and/or length of infusion can also be modified as well.
As noted, there are a number of factors related to optimal antibiotic therapy. A complete review of all antibiotic classes is beyond the scope of this text, and the focus of this section is on aminoglycosides and vancomycin due to the commonality of their usage and the link to therapeutic drug monitoring.
Gentamicin, tobramycin, and amikacin are the most commonly used aminoglycoside antibiotics in acutely ill patients. These agents are typically used with antipseudomonal penicillins or third- or fourth-generation cephalosporins for additional gram-negative bacteria coverage. Occasionally they are added to vancomycin or penicillin for synergy against staphylococcal, streptococcal, or enterococcal organisms.
Aminoglycosides are not metabolized but are cleared from the body through the kidney by glomerular filtration with some proximal tubular reabsorption occurring. The clearance of aminoglycosides parallels glomerular filtration, and a reduction in glomerular filtration results in a reduction in clearance with elevation in serum concentrations. Additional factors accounting for the reduced aminoglycoside clearance in acutely ill patients include the level of positive end-expiratory pressure and the use of vasoactive agents to maintain blood pressure and perfusion. Aminoglycosides are removed from the body by hemodialysis, peritoneal dialysis, continuous renal replacement therapy (CRRT), extracorporeal membrane oxygenation, exchange transfusion, and cardiopulmonary bypass.
The major limiting factors in the use of aminoglycosides are drug-induced ototoxicity and nephrotoxicity. Ototoxicity results from the loss of sensory hair cells in the cochlea and vestibular labyrinth. Gentamicin is primarily vestibulotoxic, amikacin causes primarily cochlear damage, and tobramycin affects vestibular and cochlear function equally. Symptoms of ototoxicity typically appear within the first 1 to 2 weeks of therapy but may be delayed as long as 10 to 14 days after stopping therapy. Early damage may be reversible, but it may become permanent if the agent is continued. Vestibular toxicity may be manifested by vertigo, ataxia, nystagmus, nausea, and vomiting, but these symptoms may not be apparent in a sedated or paralyzed, acutely ill patient. Cochlear damage occurs as subclinical high-frequency hearing loss that is usually irreversible and may progress to deafness even if the drug is discontinued. It is difficult to diagnose hearing loss in the absence of pretherapy audiograms. Risk factors for ototoxicity include advanced age, duration of therapy for more than 10 days, total dose, previous aminoglycoside therapy, and renal impairment.
Nephrotoxicity has been estimated to occur in up to 30% of acutely ill patients and typically develops 2 to 5 days after starting therapy. An increase in serum creatinine of 0.5 mg/dL above baseline has been arbitrarily defined as significant and as possible evidence of nephrotoxicity. Nephrotoxicity is associated with a reduction in glomerular filtration rate, impaired concentrating ability, increased serum creatinine, and increased urea nitrogen. In most cases, the renal insufficiency is nonoliguric and reversible. The mechanism of nephrotoxicity is possibly related to the inhibition of intracellular phospholipases in lysosomes of tubular cells in the proximal tubule, resulting in rupture or dysfunction of the lysosome, leading to proximal tubular necrosis. Risk factors for the development of aminoglycoside nephrotoxicity include advanced age, prolonged therapy, preexisting renal disease, preexisting liver disease, volume depletion, shock, and concurrent use of other nephrotoxins such as amphotericin B, cyclosporine, or cisplatin.
Aminoglycosides are effectively removed during hemodialysis. However, there is a rebound in the serum concentration within the first 2 hours after the completion of hemodialysis as the serum and tissues reach a new equilibrium. Therefore, a serum concentration should be drawn at least 2 hours after a dialysis treatment. Typically a dose of 1 to 2 mg/kg of gentamicin or tobramycin (amikacin 4-8 mg/kg) is sufficient to increase the serum level into the therapeutic range after dialysis. Continuous hemofiltration is also effective at removing aminoglycosides. Up to 35% of a dose can be removed during a 24-hour period of CRRT. Initially, several blood samples may be required to determine the drug’s pharmacokinetic profile for dosing regimen adjustments. If the hemofiltration rate remains constant, aminoglycoside clearance should remain stable, permitting the administration of a stable dosing regimen. In this setting, drug concentration monitoring may only be required 2 to 3 times a week.
Vancomycin is a glycopeptide antibiotic active against gram-positive and certain anaerobic organisms. It exerts its antimicrobial effects by binding with peptidoglycan and inhibiting bacterial cell wall synthesis. In addition, the antibacterial effects of vancomycin also include alteration of bacterial cell wall permeability and selective inhibition of RNA synthesis.
Vancomycin is minimally absorbed after oral administration. After single or multiple doses, therapeutic vancomycin concentrations can be found in ascitic, pericardial, peritoneal, pleural, and synovial fluids. Vancomycin penetrates poorly into cerebrospinal fluid (CSF), with CSF penetration being directly proportional to vancomycin dose and degree of meningeal inflammation. Vancomycin is eliminated through the kidneys primarily via glomerular filtration with a limited degree of tubular secretion. Nonrenal elimination occurs through the liver and accounts for about 30% of total clearance. The elimination half-life of vancomycin is 3 to 13 hours in patients with normal renal function and increases in proportion to decreasing creatinine clearance. In acute renal failure, nonrenal clearance is maintained but eventually declines approaching the nonrenal clearance in chronic renal failure. In acutely ill patients with reduced renal function, the increase in half-life may be due to a reduction in clearance as well as an increase in the volume of distribution.
Vancomycin is removed minimally during hemodialysis with cuprophane filter membranes, so that dosage supplementation after hemodialysis is not necessary. Vancomycin’s half-life averages 150 hours in patients with chronic renal failure. With the newer high-flux polysulfone hemodialysis filters, vancomycin is removed to a greater degree, resulting in significant reductions in vancomycin serum concentrations. However, there is a significant redistribution period that takes place over the 12-hour period after the high-flux hemodialysis procedure with postdialysis concentrations similar to predialysis concentrations. Therefore, dose supplementation should be based on concentrations obtained at least 12 hours after dialysis.
Vancomycin is removed very effectively by CRRT, resulting in a reduction in half-life to 24 to 48 hours. Up to 33% of a dose can be eliminated during a 24-hour hemofiltration period. Supplemental doses of vancomycin may need to be administered every 2 to 5 days in patients undergoing CRRT.
The most common adverse effect of vancomycin is the “red-man syndrome,” which is a histamine-like reaction associated with rapid vancomycin infusion and characterized by flushing, tingling, pruritus, erythema, and a macular papular rash. It typically begins 15 to 45 minutes after starting the infusion and abates 10 to 60 minutes after stopping the infusion. It may be avoided or minimized by infusing the dose over 2 hours or by pretreating the patient with diphenhydramine, 25 to 50 mg, 15 to 30 minutes before the vancomycin infusion. Other rare, but reported, adverse effects include rash, thrombophlebitis, chills, fever, and neutropenia.
Theophylline is a phosphodiesterase inhibitor, which produces bronchodilatation possibly by inhibiting cyclic AMP phosphodiesterase, inhibition of cellular calcium translocation, inhibition of leukotriene production, reduction in the reuptake or metabolism of catecholamines, and blockade of adenosine receptors. The use of theophylline for bronchospastic or lung disease has declined over the past decade. Most clinicians no longer use it as standard therapy for patients admitted to the hospital with bronchospasm; however, occasional patients may benefit from theophylline therapy. Theophylline should be used with caution in acutely ill patients for several reasons. First, theophylline is metabolized in the liver and illnesses such as low cardiac output, HF, or hepatic failure may impair the ability of the liver to metabolize theophylline, resulting in increased serum concentrations. Second, antibiotics and anticonvulsants routinely administered to acutely ill patients are known to alter theophylline’s metabolism.
In patients without a recent history of theophylline ingestion, the parenteral administration of 6 mg/kg of IV aminophylline (aminophylline = 85% theophylline) produces a serum theophylline concentration of approximately 10 mg/L. In patients with a recent history of theophylline ingestion, a serum theophylline concentration should be obtained before administering a loading dose. Once the serum concentration is known, a partial loading dose may be administered to increase the concentration to the desired level. Each 1.2 mg/kg aminophylline (theophylline 1.0 mg/kg) increases the theophylline serum concentration approximately 2 mg/L. The loading dose should be administered over 30 to 60 minutes to avoid the development of tachycardia or arrhythmias.
The maintenance infusion should be started following the completion of the loading dose and should be adjusted according to the patient’s underlying clinical status (smokers: 0.9 mg/kg/h; nonsmokers: 0.6 mg/kg/h; liver failure or HF: 0.3 mg/kg/h). These infusion rates are designed to achieve a serum concentration of approximately 10 mg/L. In most patients, concentrations above 10 mg/L are rarely indicated and may be associated with adverse effects.
When an IV regimen is converted to an oral regimen, the total daily theophylline dose should be calculated and divided into two to four equal doses depending on the theophylline product selected for chronic administration. When switching to a sustained-release product, the IV infusion should be discontinued with administration of the first sustained-release dose to maintain constant serum theophylline concentrations. Overlapping of the oral dose and IV infusion is not recommended because of the increase in serum theophylline concentrations and the potential development of toxicity resulting from the absorption of the sustained-release product.
Adverse effects occur more frequently at serum concentration above 20 mg/L and include anorexia, nausea, vomiting, epigastric pain, diarrhea, restlessness, irritability, insomnia, and headache. Serious arrhythmias and convulsions usually occur at serum concentrations above 35 mg/L, but have occurred at lower concentrations and may not be preceded by less serious toxicity.
Theophylline concentrations should be determined daily until they are stable. In addition, theophylline concentrations should be obtained daily in unstable patients and in whom interacting drugs are started or stopped. Levels may be measured once or twice weekly if the patient, theophylline level, and drug regimen are stable.
Dose
• Loading dose: 6 mg/kg IV or PO (each 1.2 mg/kg aminophylline increases the theophylline serum concentration by 2 mg/L)
• Continuous infusion: Smokers: 0.9 mg/kg/h; nonsmokers: 0.6 mg/kg/h; liver failure, HF: 0.3 mg/kg/h
Monitoring Parameters
• Serum theophylline concentration, signs and symptoms of toxicity such as tachycardia, arrhythmias, nausea, vomiting, and seizures
Albuterol is a selective beta-2 agonist, used to treat or prevent reversible bronchospasm. Adverse effects tend to be associated with inadvertent beta-1 stimulation leading to cardiovascular events including tachycardia, premature ventricular contractions, and palpitations.
Monitoring Parameters
• Heart rate and pulmonary function tests
Levalbuterol is the active enantiomer of racemic albuterol. Dose ranging studies in stable ambulatory asthmatics and patients with COPD have documented that levalbuterol 0.63 mg and albuterol 2.5 mg produced equivalent increases in the magnitude and duration of FEV1. There are no studies evaluating the efficacy of levalbuterol in hospitalized or acutely ill patients. One study assessing the tachycardic effects of these agents in acutely ill patients showed a clinically insignificant increase in heart rate following the administration of either agent.
Monitoring Parameters
• Heart rate and pulmonary function tests
Stress ulcers are superficial lesions commonly involving the mucosal layer of the stomach that appear after stressful events such as trauma, surgery, burns, sepsis, or organ failure. Risk factors for the development of stress ulcers include coagulopathy, patients requiring mechanical ventilation for more than 48 hours, patients with a history of GI ulceration or bleeding within the past year, sepsis, an ICU stay longer than 1 week, occult bleeding lasting more than 6 days, and the use of high-dose steroids (>250 mg of hydrocortisone or the equivalent). Numerous studies support the use of antacids, H2-receptor antagonists, and sucralfate. There are limited prospective comparative studies supporting the use of proton pump inhibitors (PPI) for preventing stress ulcer formation in acutely ill patients. More studies are warranted to highlight the role of PPIs in this setting.
Antacids once were considered the primary agents for the prevention of stress gastritis. Their main attributes were their effectiveness and low cost. However, this was offset by the need to administer 30- to 120-mL doses every 1 to 2 hours. Large doses of antacids had the potential to produce large gastric residual volumes, resulting in gastric distention and bloating, as well as increasing the risk for aspiration. Magnesium-containing antacids are associated with diarrhea and can produce hypermagnesemia in patients with renal failure. Aluminum-containing antacids are associated with constipation and hypophosphatemia. Large, frequent doses of antacids prevent the effective delivery of enteral nutrition. Finally, antacids are known to impair the absorption of digoxin, fluoroquinolones, and captopril. Also, alkalinization of the GI tract may predispose patients to nosocomial pneumonias with gram-negative organisms that originate in the GI tract.
Dose
• 30 to 120 mL PO, NG q1-4h
Monitoring Parameters
• Nasogastric aspirate pH, serum electrolytes, bowel function (diarrhea, constipation, bloating), hemoglobin, hematocrit, and nasogastric aspirate and stool guaiac
Ranitidine and famotidine essentially have replaced antacids as therapy for the prevention of stress gastritis. These agents have the benefit of requiring administration only every 6 to 12 hours or may be delivered by continuous infusion. When they are administered by continuous infusion, they may be added to parenteral nutrition solutions, decreasing the need for multiple daily doses. Each agent has been associated with thrombocytopenia and mental status changes. Mental status changes typically occur in elderly patients or in patients with reduced renal function in whom the doses have not been adjusted to account for the reduction in renal function. Also, similar to antacids, alkalinization of the GI tract with H2 antagonists may predispose patients to nosocomial pneumonias with gram-negative organisms that originate in the GI tract.
Dose
• Ranitidine: Intermittent IV: 50 mg q8h; continuous infusion: 6.25 mg/h. Oral: 300 to 600 mg daily divided 1 to 2 times/day
• Cimetidine: Oral: 300 mg qid or 800 mg qhs, or 400 mg bid
• Famotidine: Intermittent IV: 20 mg q12h; continuous infusion: not recommended. Oral: 20 to 40 mg daily divided 1 to 2 times/day
• Nasogastric aspirate pH, platelet count, hemoglobin, hematocrit, and nasogastric aspirate and stool guaiac
Sucralfate is an aluminum disaccharide compound that has been shown to be safe and effective for the prophylaxis of stress gastritis. Sucralfate may work by increasing bicarbonate secretion, mucus secretion, or prostaglandin synthesis to prevent the formation of stress ulcers. Sucralfate has no effect on gastric pH. It can be administered either as a suspension or as a tablet that can be partially dissolved in 10 to 30 mL of water and administered orally or through a nasogastric tube. Although sucralfate is free from systemic side effects, it has been reported to cause hypophosphatemia, constipation, and the formation of bezoars. Because sucralfate does not increase gastric pH, it lacks the ability to alkalinize the gastric environment and may decrease the development of gram-negative nosocomial pneumonias. Sucralfate has a limited role as an alternative to H2 antagonists in patients with thrombocytopenia or mental status changes.
Dose
• 1 g PO, NG q6h
Monitoring Parameters
• Hemoglobin, hematocrit, nasogastric aspirate, and stool guaiac
Proton pump inhibitors have demonstrated efficacy in preventing rebleeding and reducing transfusion requirements in several randomized-controlled trials. The rationale for adjunctive acid-suppressant therapy is based on in vitro data demonstrating clot stability and platelet aggregation enhancement at high gastric pHs (> 6). High-dose IV PPI therapy in conjunction with therapeutic endoscopy is the most cost-effective approach for the management of hospitalized patients with acute peptic ulcer bleeding.
Pantoprazole and esomeprazole are available in oral and injectable forms, while lansoprazole and omeprazole are available in oral forms only. It is advisable to transition to oral/enteral PPI therapy, if possible, after 72 hours of IV therapy. The 72-hour time period for continuous infusions is the longest duration that has been studied.
Dose
• Pantoprazole and esomeprazole: IV bolus dosing: 40 to 80 mg IV q12h for 72 hours; continuous infusion: 80 mg IV bolus; then 8 mg/h for 72 hours
Monitoring Parameters
• Hemoglobin, hematocrit, and stool guaiac
Upper GI bleeding is a common problem encountered in the intensive care unit. Its mortality remains around 10%. Vasoactive drugs to control bleeding play an important role in the immediate treatment of acute upper GI bleeding associated with variceal hemorrhage.
Vasopressin remains a commonly used agent for acute variceal bleeding. Vasopressin is a nonspecific vasoconstrictor that reduces portal pressure by constricting the splanchnic bed and reducing blood flow into the portal system. Vasopressin is successful in stopping bleeding in about 50% of patients. Many of the adverse effects of vasopressin are caused by its relative nonselective vasoconstrictor effect. Myocardial, mesenteric, and cutaneous ischemia have been reported in association with its use. Drug-related adverse effects have been reported in up to 25% of patients receiving vasopressin. The use of transdermal or IV nitrates with vasopressin reduces the incidence of these adverse effects.
Dose
• 0.3 to 0.9 units/min
Monitoring Parameters
• Hemoglobin, hematocrit, nasogastric aspirate, stool guaiac, ECG, signs and symptoms of ischemia, blood pressure, and heart rate
Octreotide, the longer acting synthetic analog of somatostatin, reduces splanchnic blood flow and has a modest effect on hepatic blood flow and wedged hepatic venous pressure with little systemic circulation effects. Although octreotide produces the same results as vasopressin in the control of bleeding and transfusion requirements, it produces significantly fewer adverse effects. Continuous infusion of octreotide has been shown to be as effective as injection sclerotherapy in control of variceal hemorrhage.
Dose
• Initial bolus dose: 100 mcg, followed by 50-mcg/h continuous infusion
Monitoring Parameters
• Hemoglobin, hematocrit, nasogastric aspirate, and stool guaiac
Propranolol has been shown to reduce portal pressure both acutely and chronically in patients with portal hypertension by reducing splanchnic blood flow. The primary use of propranolol has been in the prevention of variceal bleeding. Propranolol or other beta-blockers should be avoided in patients experiencing acute GI bleeding, because beta-blocking agents may prevent the compensatory tachycardia needed to maintain cardiac output and blood pressure in the setting of hemorrhage.
Monitoring Parameters
• Hemoglobin, hematocrit, heart rate, and blood pressure
Diuretics may be categorized in a number of ways, including site of action, chemical structure, and potency. Although many diuretics are available for oral and IV administration, intravenously administered agents typically are given to acutely ill patients because of their guaranteed absorption and more predictable responses. Therefore, the primary agents used in intensive care units are the intravenously administered loop diuretics, thiazide diuretics, and osmotic agents. However, the oral thiazide-like agent, metolazone, is used commonly in combination with loop diuretics to maintain urine output for patients with diuretic resistance.
Monitoring Parameters
• Urine output, blood pressure, renal function, electrolytes, weight, fluid balance, and hemodynamic parameters (if applicable)
Loop diuretics (furosemide, bumetanide, torsemide) act by inhibiting active transport of chloride and possibly sodium in the thick ascending loop of Henle. Administration of loop diuretics results in enhanced excretion of sodium, chloride potassium, hydrogen, magnesium, ammonium, and bicarbonate. Maximum electrolyte loss is greater with loop diuretics than with thiazide diuretics. Furosemide, bumetanide, and torsemide have some renal vasodilator properties that reduce renal vascular resistance and increase renal blood flow. Additionally, these three agents decrease peripheral vascular resistance and increase venous capacitance. These effects may account for the decrease in left ventricular filling pressure that occurs before the onset of diuresis in patients with HF.
Loop diuretics typically are used for the treatment of edema associated with HF or oliguric renal failure, the management of hypertension complicated by HF or renal failure, in combination with hypotensive agents in the treatment of hypertensive crisis, especially when associated with acute pulmonary edema or renal failure, and in combination with 0.9% sodium chloride to increase calcium excretion in patients with hypercalcemia.
Common adverse effects associated with loop diuretic administration include hypotension from excessive reduction in plasma volume, hypokalemia and hypochloremia resulting in metabolic alkalosis, and hypomagnesemia. Reduction in these electrolytes may predispose patients to the development of supraventricular and ventricular ectopy. Tinnitus, with reversible or permanent hearing impairment, may occur with the rapid administration of large IV doses. Typically, IV bolus doses of furosemide should not be administered faster than 40 mg/min.
Dose
• Furosemide: IV bolus: 10 to 100 mg q1-6h; continuous infusion: 1 to 15 mg/h. Oral: 20 to 600 mg daily divided 1 to 4 times/day
• Bumetanide: IV bolus: 0.5 to 2.5 mg q1-2h; continuous infusion: 0.08 to 0.30 mg/h. Oral: 0.5 to 5 mg qd-bid (maximum of 10 mg)
• Torsemide: IV bolus: 5 to 20 mg qd. Oral: 2.5 to 20 mg qd
Thiazide (IV chlorothiazide) and thiazide-like (PO metolazone) diuretics enhance excretion of sodium, chloride, and water by inhibiting the transport of sodium across the renal tubular epithelium in the cortical diluting segment of the nephron. Thiazides also increase the excretion of potassium and bicarbonate.
Thiazide diuretics are used in the management of edema and hypertension as monotherapy or in combination with other agents. They have less potent diuretic and antihypertensive effects than loop diuretics. Intravenously administered chlorothiazide or oral metolazone is often used in combination with loop diuretics in patients with diuretic resistance. By acting at a different site in the nephron, this combination of agents may restore diuretic responsiveness. Thiazide diuretics decrease glomerular filtration rate, and this effect may contribute to their decreased efficacy in patients with reduced renal function (glomerular filtration rate, < 20 mL/min). Metolazone, unlike thiazide diuretics, does not substantially decrease glomerular filtration rate or renal plasma flow and often produces a diuretic effect even in patients with glomerular filtration rates less than 20 mL/min.
Adverse effects that may occur with the administration of thiazide diuretics include hypovolemia and hypotension, hypochloremia and hypokalemia resulting in a metabolic alkalosis, hypercalcemia, hyperuricemia, and the precipitation of acute gouty attacks.
Dose
• Chlorothiazide: 500 to 1000 mg IV q12h
• Metolazone: 2.5 to 20.0 mg PO qd
Mannitol is an osmotic diuretic commonly used in patients with increased intracranial pressure. Mannitol produces a diuretic effect by increasing the osmotic pressure of the glomerular filtrate and preventing the tubular reabsorption of water and solutes. Mannitol increases the excretion of sodium, water, potassium, and chloride, as well as other electrolytes.
Mannitol is used to treat acute oliguric renal failure, and reduce intracranial and intraocular pressures. The renal protective effects of mannitol may be due to its ability to prevent nephrotoxins from becoming concentrated in the tubular fluid. However, its ability to prevent or reverse acute renal failure may be owing to restoring renal blood flow, glomerular filtration rate, urine flow, and sodium excretion. To be effective in preventing or reversing renal failure, mannitol must be administered before reductions in glomerular filtration rate or renal blood flow have resulted in acute tubular damage. Mannitol is useful in the treatment of cerebral edema, especially when there is evidence of herniation or the development of cord compression.
The most severe adverse effect of mannitol is overexpansion of extracellular fluid and circulatory overload, producing acute HF and pulmonary edema. This effect typically occurs in patients with severely impaired renal function. Therefore, mannitol should not be administered to individuals in whom adequate renal function and urine flow have not been established.
Dose
• 0.25 to 0.50 g/kg, then 0.25 to 0.50 g/kg q4h
Monitoring Parameters
• Urine output, blood pressure, renal function, electrolytes, weight, fluid balance, hemodynamic parameters (if applicable), serum osmolarity, and intracranial pressure (if applicable)
Unfractionated heparin consists of a group of mucopolysac-charides derived from the mast cells of porcine intestinal tissues. It binds with antithrombin III, accelerating the rate at which antithrombin III neutralizes coagulation factors II, VII, IX, X, XI, and XII. Unfractionated heparin is used for prophylaxis and treatment of venous thrombosis and pulmonary embolism, atrial fibrillation with embolization, and treatment of acute disseminated intravascular coagulation.
Subcutaneously administered unfractionated heparin is absorbed slowly and completely over the dosing interval. The total amount of unfractionated heparin required to achieve the same degree of anticoagulation over the same time period does not appear to differ whether the unfractionated heparin is administered subcutaneously or intravenously. The apparent volume of distribution of unfractionated heparin is directly proportional to body weight, and it has been suggested that the dose should be based on ideal body weight in obese patients. Others suggest that in obese patients the dose should be normalized to total body weight.
The metabolism and elimination of unfractionated heparin involves the process of depolymerization and desulfation. Enzymes reported to be involved in unfractionated heparin metabolism include unfractionated heparinase and desulfatase, which cleave unfractionated heparin into oligosaccharides. The half-life of unfractionated heparin ranges from 0.4 to 2.5 hours. Patients with underlying thromboembolic disease have been shown to have shorter elimination half-lives, faster clearance, and require larger doses to maintain adequate thrombotic activity.
A weight-based nomogram is utilized with a loading dose followed by a continuous infusion. The infusion is titrated based on activated PTT monitoring. The main adverse effects may be attributed to excessive anticoagulation. Bleeding occurs in 3% to 20% of patients receiving short-term, high-dose therapy. Bleeding is increased threefold when the PTT is 2.0 to 2.9 times above control and eightfold when the PTT is more than 3 times the control value. Unfractionated heparin-induced thrombocytopenia may occur in 1% to 5% of patients receiving the drug.
The PTT is the test used to monitor and adjust unfractionated heparin doses. Although unfractionated heparin is typically administered as a continuous infusion, it is important that samples are collected as close to steady state as possible. After starting unfractionated heparin therapy or adjusting the dose, PTT values should be drawn at least 6 to 8 hours after the change. Samples drawn too early are misleading and may result in inappropriate dose adjustments. Once the unfractionated heparin dose has been determined, daily monitoring of the PTT for minor adjustments in the unfractionated heparin dose is indicated. Large variations in subsequent coagulation tests should be investigated to ensure that the patient’s condition has not changed or the patient is not developing thrombocytopenia.
Platelet counts should be monitored every 2 to 3 days while a patient is receiving unfractionated heparin to assess for unfractionated heparin-induced thrombocytopenia, thrombosis, or hemorrhage. Hemoglobin and hematocrit should be monitored every 2 to 3 days to assess for the presence of bleeding. Additionally sputum, urine, and stool should be examined for the presence of blood. Patients should be examined for signs of bleeding at IV access sites and for the development of hematomas and ecchymosis. In addition, IM injections should be avoided in patients receiving unfractionated heparin and elective invasive procedures should be avoided or rescheduled.
Dose
• Individualized dosing: Bolus: 80 units/kg followed by a continuous infusion of 18 units/kg/h; infusion rates should be adjusted to maintain a PTT between 1.5 and 2.0 times the control value
Monitoring Parameters
• PTT, hemoglobin, hematocrit, and signs of active bleeding
Low-molecular-weight heparins have a role in the treatment of deep venous thrombosis, pulmonary embolism, and acute MI. Low-molecular-weight heparins are less time consuming for nurses and laboratories and more comfortable for patients by allowing them to be discharged earlier from the hospital. The use of a fixed-dose regimen avoids the need for serial monitoring of the PTT and follow-up dose adjustments. Enoxaparin is the most studied low-molecular-weight unfractionated heparin. Its dose for the treatment of deep venous thrombosis, pulmonary embolism, and acute MI is 1 mg/kg q12h. Dalteparin is another agent that has been shown to be as effective as unfractionated heparin in the treatment of thromboembolic disease and acute MI. Dalteparin 200 units/kg once daily is the typical dose used for the treatment of thromboembolic disease; 120 units/kg followed by 120 units/kg 12 hours later has been used in patients with acute MI receiving streptokinase. Warfarin can be started with the first dose of enoxaparin or dalteparin. Enoxaparin or dalteparin should be continued until two consecutive therapeutic international normalized ratio (INR) values are achieved, typically in about 5 to 7 days.
Both dalteparin and enoxaparin are primarily renally eliminated with the potential for drug accumulation in patients with renal impairment. The approach for managing these patients differs between the two drugs. Because these agents work by inhibiting factor Xa activity, it is possible to monitor their anticoagulation by measuring antifactor Xa levels. This is a useful monitoring tool, particularly when compared with serum drug levels. Doses of either agent may be adjusted based on antifactor Xa levels in patients with significant renal impairment (ie, creatinine clearance, <30 mL/min). The dosing adjustment for enoxaparin in patients with creatinine clearances less than 30 mL/min is to extend the dosing interval from 12 hours to 24 hours in both prophylaxis and treatment of thrombosis. No such dosage adjustment guideline has been approved for dalteparin; thus antifactor Xa levels may be required.
Several studies have documented that acutely ill patients have significantly lower anti-Xa levels in response to single daily doses when compared to patients on general medical wards. Factor Xa activity may need to be monitored in acutely ill patients to adjust doses to ensure adequate anticoagulation to prevent deep venous clots from developing.
Dose
• Enoxaparin: 1 mg/kg SC q12h.
Monitoring Parameters
• Hemoglobin, hematocrit, signs of active bleeding, and antifactor Xa levels
Warfarin prevents the conversion of vitamin K back to its active form from the vitamin K epoxide, impairing the formation of vitamin K–dependent clotting factors II, VII, IX, X, protein C, and protein S. Warfarin is indicated in the treatment of venous thrombosis or pulmonary embolism following full-dose parenteral anticoagulant (eg, unfractionated or low-molecular weight heparin) therapy. Warfarin is also used for chronic therapy to reduce the risk of thromboembolic episodes in patients with chronic atrial fibrillation.
Warfarin is rapidly and extensively absorbed from the GI tract. Peak plasma concentrations occur between 60 and 90 minutes after an oral dose with bioavailability ranging between 75% and 100%. Albumin is the principal binding protein with 97.5% to 99.9% of warfarin being bound.
Warfarin’s metabolism is stereospecific. The R-isomer is oxidized to 6-hydroxywarfarin and further reduced to 9S, 11R-warfarin alcohols. The S-isomer is oxidized to 7-hydroxywarfarin and further reduced to 9S, 11R-warfarin alcohols. The stereospecific isomer alcohol metabolites have anticoagulant activity in humans. The warfarin alcohols are renally eliminated. The elimination half-lives of the two warfarin isomers differ substantially. The S-isomer half-life is approximately 33 hours and the R-isomer half-life is 45 hours.
Warfarin therapy may be started on the first day of unfractionated or low-molecular weight heparin therapy. Traditionally, warfarin 5 mg daily is started for the first 2 to 3 days then adjusted to maintain the desired prothrombin time (PT) or INR. The timing of INR measurements relative to changes in daily dose is important. After the administration of a warfarin dose, the peak depression of coagulation occurs in about 36 hours. It is important to select an appropriate time during a given dosing interval and perform coagulation tests consistently at that time. After the first four to five doses, the fluctuation in the INR over a 24-hour dosing interval is minimal. The time course of stabilization of warfarin plasma concentrations and coagulation response during continued administration of maintenance doses is less clear. A minimum of 10 days appears to be necessary before the dose-response curve shows interval-to-interval stability. During the first week of therapy, two INR measurements should be determined to assess the impact of warfarin accumulation on INR. Several factors should be assessed when evaluating an unexpected response to warfarin. Laboratory results should be verified to exclude inaccurate or spurious results. The medication profile should be reviewed to exclude drug-drug interactions including changes in warfarin product, and the patient should be evaluated for disease-drug interactions, nutritional-drug interactions, and noncompliance.
Bleeding is the major complication associated with the use of warfarin, occurring in 6% to 29% of patients receiving the drug. Bleeding complications include ecchymoses, hemoptysis, and epistaxis, as well as fatal or life-threatening hemorrhage.
Dose
• 5 mg PO qd × 3 days, then adjusted to maintain the INR between 2 and 3.
• To prevent thromboembolism associated with prosthetic heart valves, the dose should be adjusted to maintain an INR between 2.5 and 3.5.
• INR, hemoglobin, hematocrit, and signs of active bleeding
Rivaroxaban is an oral factor Xa inhibitor, indicated for venous thromboembolism (VTE) prophylaxis post hip or knee replacement, or prophylaxis of embolism, or cerebrovascular accident (CVA) in patients with nonvalvular atrial fibrillation. Additionally, the agent is also indicated for PE and deep venous thrombosis (DVT) treatment.
Dose
• VTE prophylaxis post-surgery: 10 mg PO qd
• Atrial fibrillation, nonvalvular-CVA prophylaxis: 20 mg PO qd
• DVT or PE treatment, and secondary prophylaxis: 15 mg PO bid × 21 days followed by 20 mg PO qd
Monitoring Parameters
• Hemoglobin, hematocrit, renal function, and signs of active bleeding
Dabigatran is an oral direct thrombin inhibitor indicated for use for stroke prevention in patients with non-valvular atrial fibrillation. In clinical trials, dabigatran was superior to warfarin in reducing the risk for stroke and systemic embolism with lower minor bleed risk comparatively. Dabigatran also has a developing role as a VTE prophylaxis after total knee or hip arthroplasty, as well as the treatment of DVT and PE. It is important to note that dabigatran capsules cannot be opened for feeding tube or oral administration.
Dose
• 150 mg PO bid
Monitoring Parameters
• Hemoglobin, hematocrit, aPTT, ecarin clotting time (ECT), and signs of active bleeding
Bivalirudin is an anticoagulant with direct thrombin inhibitor properties. Bivalirudin, when given with aspirin, is indicated for use as an anticoagulant in patients with unstable angina undergoing coronary angioplasty. It has been used as a substitute for unfractionated heparin; potential advantages over unfractionated heparin include activity against clot-bound thrombin, more predictable anticoagulation, and no inhibition by components of the platelet release reaction. A study has suggested the efficacy of SC bivalirudin in preventing deep vein thrombosis in orthopedic surgery patients. The place in therapy of bivalirudin will be determined by further comparisons with unfractionated heparin, low-molecular-weight unfractionated heparins, and recombinant hirudin.
Dose
• Bolus: 1 mg/kg
• Continuous infusion: 2.5 mg/kg/h × 4 hours, if necessary 0.2 mg/kg/h for up to 20 hours
Monitoring Parameters
• Activated PTT, activated clotting time (ACT), hemoglobin, hematocrit, and signs of active bleeding
Argatroban is a selective thrombin inhibitor indicated for the prevention or treatment of thrombosis in unfractionated heparin–induced thrombocytopenia and for use in percutaneous coronary interventions (PCIs). It has also shown effectiveness in ischemic stroke and as an adjunct to thrombolysis in patients with acute MI. Further studies are needed to establish effectiveness for other indications. Argatroban is dosed as a continuous infusion that is titrated based on activated PTT, similar to unfractionated heparin. During PCI, the ACT may be used. A notable drug-laboratory value interaction is the increase in PT and INR values that occurs with argatroban therapy, which may complicate the monitoring of warfarin therapy once oral anticoagulation is initiated.
Dose
• Percutaneous coronary intervention: Bolus: 350 mcg/kg; continuous infusion: 25 mcg/kg/min
• Heparin-induced thrombocytopenia with thrombosis: Continuous infusion: 2 mcg/kg/min
Monitoring Parameters
• Activated PTT, ACT, PT, INR, hemoglobin, hematocrit, and signs of active bleeding
Glycoprotein IIb/IIIa inhibitors are recommended, in addition to aspirin and unfractionated heparin, in patients with acute coronary syndrome awaiting PCI. If the glycoprotein IIb/IIIa inhibitor is started in the catheterization laboratory just before PCI, abciximab is the agent of choice.
Dose
• Abciximab: Bolus: 0.25 mg/kg over 10 to 60 minutes; continuous infusion: 0.125 mcg/kg/min for 12 hours (maximum infusion of 10 mcg/kg/min)
• Tirofiban: Bolus infusion: 0.4 mcg/kg/min over 30 minutes; continuous infusion: 0.1 mcg/kg/min for 12 to 24 hours after angioplasty or atherectomy
• Eptifibatide: Bolus: 180 mcg/kg; continuous infusion: 2 mcg/kg/min until discharge or coronary artery bypass grafting (maximum of 72 hours)
• Platelet count, hemoglobin, hematocrit, and signs of active bleeding
Thrombolytic agents may be beneficial as reperfusion therapy in ST-elevation myocardial infarction (STEMI). The 2013 American College of Cardiology Foundation/American Heart Association guidelines for the management of STEMI include the following recommendations in order from most supported by published literature (class I) to least supported (class III):
• In the absence of contraindications, fibrinolytic therapy should be given to patients with STEMI and onset of ischemic symptoms within the previous 12 hours when it is anticipated that primary percutaneous coronary intervention (PCI) cannot be performed within 120 minutes of first medical contact.
• In the absence of contraindications and when PCI is not available, fibrinolytic therapy is reasonable for patients with STEMI if there is clinical and/or electrocardiographic evidence of ongoing ischemia within 12 to 24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability.
• Fibrinolytic therapy should not be administered to patients with ST depression except when a true posterior (inferobasal) MI is suspected or when associated with ST elevation in lead aVR.
Absolute contraindications to the use of thrombolytic agents include any active or recent bleeding, suspected aortic dissection, intracranial or intraspinal neoplasm, arteriovenous malformation or aneurysms, neurosurgery or significant closed head injury within the previous 3 months, ischemic stroke within the previous 3 months (except acute ischemic stroke within 3 hours), or facial trauma in the preceding 3 months. Relative contraindications include acute or chronic severe uncontrolled hypertension, ischemic stroke more than 3 months prior, traumatic or prolonged cardiopulmonary resuscitation greater than 10 minutes in duration, major surgery within the previous 3 weeks, internal bleeding within 2 to 4 weeks, noncompressible vascular punctures, prior allergic reaction to thrombolytics, pregnancy, active peptic ulcer, and current anticoagulation (risk increasing with increasing INR).
Adverse effects include bleeding from the GI or genitourinary tracts, as well as gingival bleeding and epistaxis. Superficial bleeding may occur from trauma sites such as those for IV access or invasive procedures. Intramuscular injections, with noncompressible arterial punctures, should be avoided during thrombolytic therapy.
Monitoring Parameters
• For short-term thrombolytic therapy of MI: ECG, signs and symptoms of ischemia, and signs and symptoms of bleeding at IV injection sites (laboratory monitoring is of little value)
• Continuous infusion therapy: Thrombin time, activated PTT, and fibrinogen, in addition to above-mentioned monitoring parameters
Alteplase (recombinant tissue-type plasminogen activator) has a high affinity for fibrin-bound plasminogen, allowing activation on the fibrin surface. Most plasmin formed remains bound to the fibrin clot, minimizing systemic effects. Alteplase is nonantigenic and should be considered in patients who have received streptokinase or anistreplase in the previous 6 to 9 months. The risk of an intracerebral bleed is approximately 0.5%.
Dose
• Acute MI-accelerated infusion: Patients over 67 kg, total dose 100 mg IV (15 mg IV bolus, then 50 mg over 30 minutes, then 35 mg over 60 minutes)
• Acute MI-accelerated infusion: Patients 67 kg or less, (15 mg IV bolus, then 0.75 mg/kg over 30 minutes, then 0.5 mg/kg over 60 minutes); total dose not to exceed 100 mg
• Acute MI-3-hour infusion: Weight 65 kg or more, 60 mg IV in the first hour (6 to 10 mg of which to be given as bolus), then 20 mg over the second hour, and 20 mg over the third hour
• Acute MI-3-hour infusion: Weight less than 65 kg, 1.25 mg/kg IV administered over 3 hours, give 60% in the first hour (10% of which to be given as bolus), give remaining 40% over the next 2 hours
• Pulmonary embolism: 100 mg IV over 2 hours
Tenecteplase (recombinant TNK-tissue type plasminogen activator) has a longer elimination half-life (20 to 24 minutes) and is more resistant to inactivation by plasminogen activator inhibitor-1 than alteplase. Tenecteplase appears more fibrin specific than alteplase, which may account for a lower rate of noncerebral bleeding comparatively. However, there have been reports of antibody development to tenecteplase. Tenecteplase and alteplase have similar clinical efficacy for thrombolysis after MI.
Dose
• Acute MI: 30 to 50 mg (based on weight) IV over 5 seconds
Reteplase is a recombinant plasminogen activator for use in acute MI and pulmonary embolism as a thrombolytic agent. Reteplase has a longer half-life (13 to 16 minutes) than that of alteplase, allowing for bolus administration. The dosing regimen requires double bolus doses.
Dose
• Acute MI and pulmonary embolism: Two 10-U IV bolus doses, infused over 2 minutes via a dedicated line. The second dose is administered 30 minutes after the initiation of the first injection.
Cyclosporine is used to prevent allograft rejection after solid organ transplantation and graft-vs-host disease in bone marrow transplant patients. Unlike other immunosuppressive agents, cyclosporine does not suppress bone marrow function. Cyclosporine inhibits cytokine synthesis and receptor expression needed for T-lymphocyte activation by interrupting signal transduction. A lack of cytokine disrupts the activation and proliferation of the helper and cytotoxic T-cells that are essential for rejection.
Cyclosporine is poorly absorbed from the GI tract with bioavailability averaging 30%. Its absorption is influenced by the type of organ transplant, time from transplantation, presence of biliary drainage, liver function, intestinal dysfunction, and the use of drugs that alter intestinal function. Cyclosporine is metabolized by cytochrome P-450 isoenzyme 3A to numerous metabolites with more than 90% of the dose excreted into the bile and eliminated in the feces. The kidneys eliminate less than 1% of the dose. There is no evidence that the metabolites have significant immunosuppressive activity compared with cyclosporine and none of the metabolites are known to cause nephrotoxicity.
Because of poor oral absorption, the oral dose is 3 times the IV dose. When converting from IV to oral administration, it is important to increase the oral dose by a factor of three to maintain stable cyclosporine concentrations. The oral solution can be administered diluted with chocolate milk or juice and administered through a nasogastric tube. The tube should be flushed before and after cyclosporine is administered to ensure complete drug delivery and optimal absorption.
The microemulsion formulation of cyclosporine capsules and solution has increased bioavailability compared to the original formulation of cyclosporine capsules and solution. These formulations are not bioequivalent and cannot be used interchangeably. Converting from cyclosporine capsules and solution for microemulsion to cyclosporine capsules and oral solution using as 1:1 mg/kg/day ratio may result in lower cyclosporine blood concentrations. Conversion between formulations should be made utilizing increased monitoring to avoid toxicity due to high concentrations or possible organ rejection due to low concentrations.
Nephrotoxicity is cyclosporine’s major adverse effect. Three types of nephrotoxicity have been shown to occur. The first is an acute reversible reduction in glomerular filtration; second, tubular toxicity with possible enzymuria and aminoaciduria; and third, irreversible interstitial fibrosis and arteriopathy. The exact mechanism of cyclosporine nephrotoxicity is unclear, but may involve alterations in the various vasoactive substances in the kidney. Other side effects include a dose-dependent increase in bilirubin that occurs within the first 3 months after transplantation. Hyperkalemia can develop secondary to cyclosporine nephrotoxicity. Cyclosporine-induced hypomagnesemia can cause seizures. Neurotoxic effects such as tremors and paresthesias may occur in up to 15% of treated patients. Hypertension occurs frequently and may be due to the nephrotoxic effects or renal vasoconstrictive effects of the drug.
Tacrolimus is a macrolide antibiotic produced by the fermentation broth of Streptomyces tsukubaensis. Although it bears no structural similarity to cyclosporine, its mode of action parallels cyclosporine. Tacrolimus exhibits similar in vitro effects to cyclosporine, but at concentrations 100 times lower than those of cyclosporine.
Tacrolimus is primarily metabolized in the liver by the cytochrome P-450 isoenzyme 3A4 to at least 15 metabolites. There is also some evidence to suggest that tacrolimus may be metabolized in the gut. The 13-O-demethyl-tacrolimus appears to be the major metabolite in patient blood. Less than 1% of a dose is excreted unchanged in the urine of liver transplant patients. Renal clearance accounts for less than 1% of total body clearance. The mean terminal elimination half-life is 12 hours but ranges from 8 to 40 hours. Patients with liver impairment have a longer tacrolimus half-life, reduced clearance, and elevated tacrolimus concentrations. The elevated tacrolimus concentrations are associated with increased nephrotoxicity in these patients. Because tacrolimus is primarily metabolized by the cytochrome P-450 enzyme system, it is anticipated that drugs known to interact with this enzyme system may affect tacrolimus disposition.
In most cases, IV therapy can be switched to oral therapy within 2 to 4 days after starting therapy. The oral dose should start 8 to 12 hours after the IV infusion has been stopped. The usual initial oral dose is 150 to 300 mcg/kg/day, administered in two divided doses every 12 hours.
Nephrotoxicity is the most common adverse effect associated with the use of tacrolimus. Nephrotoxicity occurs in up to 40% of transplant patients receiving tacrolimus. Other side effects observed during tacrolimus therapy include headache, tremor, insomnia, diarrhea, hypertension, hyperglycemia, and hyperkalemia.
Sirolimus is an immunosuppressive agent used to the prophylaxis of organ rejection in patients receiving renal transplants. It typically is used in regimens containing cyclosporine and corticosteroids. Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine stimulation. Sirolimus also inhibits antibody production.
Sirolimus is administered orally once daily. The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after cyclosporine modified oral solution or capsules.
Routine therapeutic drug level monitoring is not required in most patients. Sirolimus levels should be monitored in patients with hepatic impairment, during concurrent administration of cytochrome P-450 cyp3a4 inducers and inhibitors, or when cyclosporine dosing is reduced or discontinued. Mean sirolimus whole blood trough concentrations, as measured by immunoassay, are approximately 9 ng/mL for the 2-mg/day dose and 17 ng/mL for the 5-mg/day dose. Results from other assays may differ from those with an immunoassay. On average, chromatographic methods such as HPLC or mass spectroscopy yield results that are 20% lower than immunoassay whole blood determinations.
The elderly population is the fastest growing segment of the population in the United States. Older patients consume nearly 3 times as many prescription drugs as younger patients and therefore are at risk for experiencing significantly more drug-drug interactions and ADEs. The most common risk factors that contribute to adverse events include polypharmacy, low body mass, preexisting chronic disease, excessive length of therapy, organ dysfunction, and prior history of drug reaction. Special attention must be paid on the part of healthcare professionals when dosing medications in these patients with low body mass and potentially impaired metabolism and clearance of drug secondary to age-related organ dysfunction (eg, renal or hepatic impairment). Agents that are of particular interest in this population include sedatives, antihypertensives, narrow therapeutic index drugs, and anti-infectives. These agents often require a decrease in dose or the extension of the dosing interval to facilitate drug clearance and minimize the likelihood of toxicity.
Therapeutic drug monitoring (TDM) is the process of using drug concentrations, pharmacokinetic principles, and pharmacodynamics to optimize drug therapy (see Table 22-5). The goal of TDM is to maximize the therapeutic effect while avoiding toxicity. Drugs that are toxic at serum concentrations close to those required for therapeutic effect are the drugs most commonly monitored. The indications for therapeutic drug monitoring include narrow therapeutic range, limited objective monitoring parameters, potential for poor patient response, the need for therapeutic confirmation, unpredictable dose-response relationship, serious consequences of toxicity or lack of efficacy, correlation between serum concentration and efficacy or toxicity, suspected toxicity, identification of drug interactions, determination of individual pharmacokinetic parameters, and changes in patient pathophysiology or disease state. The specific indication for TDM is important, because it affects the timing of the sample. Timing of sample collection depends on the question being asked.
The timing of serum drug concentrations is critical for the interpretation of the results. The timing of peak serum drug concentrations depends on the route of administration and the drug product. Peak serum drug concentrations occur soon after an IV bolus dose, whereas they are delayed after IM, SC, or oral doses. Oral medications can be administered as either liquid or rapid- or slow-release dosage forms (eg, theophylline). The absorption and distribution phases must be considered when obtaining a peak serum drug concentration. The peak serum concentration may be much higher and occur earlier after a liquid or rapid-release dosage form compared to a sustained-release dosage form. Trough concentrations usually are obtained just prior to the next dose. Drugs with long half-lives (eg, phenobarbital) or sustained-release dosage forms (eg, theophylline) have minimal variation between their peak and trough concentrations. The timing of the determination of serum concentrations may be less critical in patients taking these dosage forms. Serum drug concentrations may be drawn at any time after achieving a steady state in a patient who is receiving a drug by continuous IV infusion. However, in patients receiving a drug by continuous infusion, the serum specimen should be drawn from a site away from where the drug is infusing. If toxicity is suspected, serum drug concentrations can be obtained at any time during the dosing interval.
Appropriate interpretation of serum concentrations is the step that requires an understanding of relevant patient factors, pharmacokinetics of the drug, and dosing regimen. Misinterpretation of serum drug concentrations can result in ineffective and, at worst, harmful dosage adjustments. Interpreting serum concentrations includes an assessment of whether the patient’s dose is appropriate, if the patient is at a steady state, the timing of the blood samples, an assessment of whether the time of blood sampling is appropriate for the indication, and an evaluation of the method of delivery to assess the completeness of drug delivery. Serum drug concentrations should be interpreted within the context of the individual patient’s condition. Therapeutic ranges serve as guidelines for each patient. Doses should not be adjusted on the basis of laboratory results alone. Individual dosage ranges should be developed for each patient as various patients may experience therapeutic efficacy, failure, or toxicity within a given therapeutic range.
Institute of Safe Medication Practices. nwww.ismp.org. Accessed February 8, 2013.
Martin SJ, Olsen KM, Susla GM. The Injectable Drug Reference. 2nd ed. Des Plaines, IL: Society of Critical Care Medicine; 2006.
Sulsa GM, Suffredini AF, McAreavey D, et al. The Handbook of Critical Care Drug Therapy. 3rd ed. Philadelphia, PA: Lippincott William and Wilkins; 2006.
Vincent J, Abraham E, Kochanek P, et al. Textbook of Critical Care. 6th ed. Philadelphia, PA: Elsevier; 2011.
Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41:263-306.
Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. DOI: 10.1097/CCM.0b013e31827e83af.
O’Gara PT, Kushner FG, Ascheim DD, et al. American College of Cardiology Foundation/American Heart Association Guidelines for Management of ST-Elevation Myocardial Infarction. Executive summary. Circulation. 2013;127:529-555.
Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacist, American College of Chest Physicians. Clinical practice guidelines for sustained neuromuscular blockage in the adult critically ill patient. Crit Care Med. 2002;30:142-156.