Critical Care Pharmacotherapy PDF

Critical Care C. Sedatives 1. Guidelines suggest using propofol or dexmedetomidine over benzodiazepines for sedation in mechanically ventilated adult patients. Benzodiazepines should be avoided when possible to prevent adverse outcomes, including prolonged duration of mechanical ventilation, incre...

Critical Care C. Sedatives 1. Guidelines suggest using propofol or dexmedetomidine over benzodiazepines for sedation in mechanically ventilated adult patients. Benzodiazepines should be avoided when possible to prevent adverse outcomes, including prolonged duration of mechanical ventilation, increased ICU length of stay, and development of delirium (Table 13). 2. Lorazepam a. Intermittent dosing 1–4 mg every 2–6 hours b. Continuous infusion: Start at 1 mg/hour and titrate to goal (e.g., RASS, SAS). Total daily doses as low as 1 mg/kg can cause propylene glycol toxicity. If high-dose continuous infusion is used, monitor for an osmolal gap greater than 10–12 mOsm/L, indicating propylene glycol toxicity. c. Lorazepam is the preferred benzodiazepine in severe hepatic dysfunction because of its metabolism with lack of active metabolites. 3. Midazolam a. Intermittent dosing 1–4 mg every 15 minutes to 1 hour b. Continuous infusion: Start at 1 mg/hour and titrate to goal (e.g., RASS, SAS). c. Often used for procedural sedation or daily dressing changes because of its rapid onset and short duration d. Prolonged infusions of midazolam may accumulate because of its greater lipophilicity and active metabolites compared with lorazepam, especially in patients with renal dysfunction. 4. Diazepam a. Not routinely used as a sedative for mechanically ventilated patients because of accumulation of active metabolites with prolonged administration. b. Often used for the treatment of alcohol withdrawal because of its rapid onset and long half-life. Table 13. Intravenous Benzodiazepines Diazepam Lorazepam Midazolam 2–5 2–4 Yes Yes 24–120 Yes Yes 15–20 4–6 No No 10–20 No No 2–5 1–2 Yes Yes 1–10 Yes Yes Yes Yes No No Maybe Yes No No No Pharmacokinetics Onset (minutes) Duration of effect (hr) Prolonged in renal failure Prolonged in hepatic failure Elimination half-life (hr) Active metabolite CYP3A4 interactions Adverse effects Hypotension Thrombophlebitis Propylene glycol toxicity CYP = cytochrome P450. 5. Propofol a. Rapid onset (1–2 minutes) and short duration (3–5 minutes or longer if prolonged infusion) b. Initiate at 5 mcg/kg/minute and titrate to achieve sedation goals by 5 mcg/kg/minute every 5 minutes. Avoid prolonged infusions greater than 80 mcg/kg/minute because of the patient’s risk of developing propofol-related infusion syndrome. c. Avoid loading doses because of the risk of hypotension. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-323 Critical Care d. e. In general, used in intubated patients because of the risk of respiratory depression Propofol has no significant analgesic activity. If a patient has pain, propofol must be combined with an analgesic. f. Monitoring i. Blood pressure ii. Triglyceride concentrations should be obtained when propofol is administered for longer than 48 hours or at a rate of at least 50 mcg/kg/minute. An alternative agent should be given if severe hypertriglyceridemia occurs because the patient’s risk of developing pancreatitis increases. An exact threshold is uncertain, but clinicians often consider an alternative when serum triglyceride concentrations exceed 500–800 mg/dL. iii. Calories provided from 10% lipid emulsion (1.1 kcal/mL). May need to adjust lipid or calories provided by nutrition support (i.e., EN or PN) iv. Propofol-related infusion syndrome is more likely to occur with infusion rates of at least 80 mcg/kg/minute for at least 48 hours, and is associated with metabolic acidosis, cardiac failure, arrhythmias (e.g., bradycardia), cardiac arrest, rhabdomyolysis, hyperkalemia, and kidney failure. g. Propofol is more commonly used than benzodiazepines because of its shorter duration, easy titration, and predictability. 6. Dexmedetomidine a. Sedative properties through central and peripheral α2-receptor agonist activity b. Extent of analgesic activity in patients in the ICU is not well described. c. Does not cause respiratory depression d. Rapid onset (5–15 minutes if bolus, longer without bolus) and short duration (2-hour half-life). Longer duration in patients with severe hepatic dysfunction e. A loading dose is suggested for patients undergoing surgery; however, loading doses are not recommended for patients in the ICU because of the risk of bradycardia and hypotension. f. Maintenance dose of 0.2–0.7 mcg/kg/hour is approved by the U.S. Food and Drug Administration for a maximum of 24 hours; however, there is evidence showing the safety and efficacy of prolonged infusions at doses of up to 1.5 mcg/kg/hour, and this is most commonly used in practice. g. Compared with benzodiazepines, dexmedetomidine is associated with a lower prevalence of ICU delirium in some studies (Intensive Care Med 2021;47:943-60). h. Results from the MIDEX and PRODEX studies show that dexmedetomidine is noninferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced the duration of mechanical ventilation compared with midazolam but was noninferior compared to propofol (JAMA 2012;307:1151-60). i. A recent multicenter study (N Eng J Med 2021;384:1424-36) compared sedation with dexmedetomidine and propofol in mechanically ventilated adults with sepsis. There was no difference in number of days alive without delirium or coma, and no difference in ventilator free days at 28 days or 90-day mortality. It is still unclear if sedative choice has an impact on clinical outcomes. j. Monitoring: Primary adverse effects are dose-related bradycardia and hypotension. k. Does not cause drug dependency, but withdrawal symptoms (e.g., nausea, vomiting, agitation) have occurred after prolonged use (1 week). l. Dexmedetomidine can be used as an adjunct to ethanol withdrawal, but not as replacement for benzodiazepine use. 7. Ketamine a. N-methyl- d-aspartate receptor antagonist b. Has both analgesic and sedative properties c. Does not cause respiratory depression; however, does cause bronchodilation, which is beneficial in patients with asthma or chronic obstructive pulmonary disease ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-324 Critical Care d. e. f. g. h. i. Dosing and titration strategies vary widely by institution. Minimal effect on bowel motility Risk of emergence delirium when high doses are tapered off. It is unclear whether benzodiazepines will reduce the risk of emergence. Major adverse effects include hypertension, tachycardia, and delirium. Has been associated with an opioid-sparing effect, especially in patients with chronic pain Guidelines suggest using low-dose ketamine as an adjunct to opioid therapy when seeking to reduce opioid use in postsurgical patients. There is no routine use for ketamine in sedation or in prevention and treatment of delirium. D. Assessment and management of delirium 1. Delirium is an acute change in cognitive function characterized by disorganized thought, altered level of consciousness, and inattentiveness. 2. Delirium is associated with increased mortality, prolonged length of stay in the ICU, and cognitive impairment after ICU discharge. 3. Validated tools to proactively identify and assess delirium include the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC). The CAM-ICU is designed to detect delirium at the time of testing, whereas the ICDSC detects delirium during a nursing shift. For a detailed description of delirium monitoring tools, see http://icudelirium.org/delirium/ monitoring.html. 4. Nonpharmacologic interventions are preferred to pharmacologic treatment. These interventions include maintaining communication with the patient, reorienting the patient (to person, place, and time), maximizing uninterrupted sleep (e.g., control light and noise, cluster patient care activities, decrease stimuli at night), providing access to natural lighting (rooms with windows), removing unnecessary equipment from room, correcting sensory deficits (e.g., hearing aids, glasses), removing unneeded invasive devices (e.g., urinary catheters, intravenous lines, endotracheal tubes, enteral feeding tubes), minimizing physical restraint, and encouraging patient autonomy and early mobility. 5. Correctable causes of delirium include hypotension, hypoxia, infection, and electrolyte disturbances. 6. Few interventions have been shown to improve delirium-related outcomes; therefore, a strong focus should be put on minimizing or treating reversible risk factors such as avoiding or minimizing the dose of benzodiazepines and other medications that can cause delirium (e.g., opioids, anticholinergic medications). 7. Guidelines discourage routine use of antipsychotics for the treatment of delirium. However, they should be considered when patients experience significant distress because of symptoms of delirium. Antipsychotics should be used as a short treatment until symptoms resolve and use reassessed at transitions of care. E. Pharmacologic treatment of delirium (Table 14) 1. Haloperidol a. Although commonly used, there is no evidence that haloperidol reduces the duration of delirium. b. Monitoring i. Hypotension ii. Assess QTc interval at baseline and daily during haloperidol administration. In addition, monitor for other drugs that could prolong QTc interval. Prolongations of greater than 500 milliseconds are associated with a higher risk of torsades de pointes. iii. Extrapyramidal effects, including laryngeal dystonia and dysphagia, are more common with chronic oral administration than with intravenous administration. c. Lower initial doses of haloperidol (1–2.5 mg) should be used in older adults because of greater risks of adverse effects, including QTc prolongation. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-325 Critical Care d. 2.  oses of haloperidol for acute agitation can be doubled every 20 minutes until an effective dose is D reached. Atypical antipsychotics a. Atypical or second-generation antipsychotics can reduce the duration of delirium in critically ill patients. b. Atypical antipsychotics are associated with a lower incidence of extrapyramidal symptoms (EPSs) than is haloperidol. c. Differences between agents are half-life, the risk of QTc prolongation, sedation, incidence of metabolic syndrome, and risk of EPSs. i. Sedative effects may be beneficial (e.g., hyperactive vs. hypoactive delirium). ii. Agents with a shorter half-life (quetiapine) generally act faster and can be quickly titrated. iii. Olanzapine and risperidone have less risk of QTc prolongation but should still be monitored. Table 14. Medications Used to Treat Delirium Medication Haloperidol Initial Dosing 2.5 mg every 6 hr Dose Forms Tablet, IM, IV Quetiapine 25 mg twice daily Tablet Olanzapine 5 mg daily Tablet, ODT, IM Risperidone 0.5 mg twice daily Tablet, ODT, solution, IMa Ziprasidone 20 mg twice daily Capsule, IM Half-life (hr) Adverse Effects 18 QTc prolongation EPSs 6 Sedation QTc prolongation 33 Sedation QTc prolongation (less than other agents) 24 EPSs (doses > 6 mg/day) QTc prolongation (less than other agents) 7 Sedation QTc prolongation a IM formulation of risperidone is a long-acting formulation that is not indicated for acute delirium management. EPS = extrapyramidal symptom; IM = intramuscular(ly); IV = intravenous(ly); ODT = orally disintegrating tablet. F. Neuromuscular blockade in patients in the ICU (Table 15) 1. Neuromuscular blockade is typically indicated for intubated patients with severe respiratory failure (e.g., ARDS, status asthmaticus) despite optimization of analgesia, sedation, and ventilator management. 2. In patients with severe ARDS (defined as a Pao2/Fio2 ratio less than 150), a 48-hour infusion of cisatracurium (15-mg bolus followed by 37.5 mg/hour for 48 hours) showed a decreased adjusted 90-day mortality (N Engl J Med 2010;363:1107-16). More recent data analyses using a similar regimen had conflicting results with no difference in mortality or ICU-related weakness, but increased adverse cardiovascular events (N Engl J Med 2019;380:1997-2008). Notable differences between these studies (e.g., the degree of sedation in the control group and differences in use of prone positioning) may have contributed to the discrepancy. Of note, in these studies, the cisatracurium infusion was a fixed dose and was not adjusted on the basis of the monitoring parameters described later (e.g., train-of-four [TOF]). Because of the lack of a clear benefit in ARDS, neuromuscular blockers should be reserved for patients who are persistently hypoxemic or at risk for ventilator injury despite deep sedation. Neuromuscular blockers should be avoided in patients who tolerate ventilation using lighter sedation. 3. Neuromuscular blockers are also used as adjunctive agents to control severe intracranial hypertension in patients with neurologic injury (e.g., traumatic brain injury). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-326 Critical Care 4. 5. 6. 7. 8. Neuromuscular blockers are typically used once efforts to facilitate ventilation have failed (e.g., poor oxygenation, dyssynchrony, high intrathoracic pressures that put the patient at risk for barotrauma) and a combination of high-dose opioids and sedatives have failed (i.e., patient continues to have poor oxygenation). Neuromuscular blockers may be used to attenuate shivering during therapeutic hypothermia. Never use neuromuscular blockers in a patient who is not completely sedated or does not have adequate pain control. Neuromuscular blockers should be used only in conjunction with a continuously infused sedative. Sedatives should have amnestic properties (e.g., benzodiazepines, propofol). Analgesics can also be used as needed in patients with pain. Dexmedetomidine does not provide the depth of sedation required for neuromuscular blocker infusion. Many practitioners insist on the combination of a sedative and an analgesic in paralyzed patients. Patients should be provided with scheduled lubricating eye drops while paralyzed. Neuromuscular blockade in the ICU can be used in cases of elevated intracranial pressure (ICP), tetanus, or intubation and to decrease movement during procedures. Table 15. Neuromuscular Blocking Agents Recommendation Duration of effect (hr) Prolonged in renal failure Prolonged in hepatic failure Loading dose Maintenance dose Adverse effects Tachycardia Hypotension Pancuronium 0.75–1.5 Yes Yes 0.08 mg/kg 0.8-1.7 mcg/kg/ min Vecuronium 0.5–0.75 Yes Yes 0.1 mg/kg 0.8-1.7 mcg/kg/ min Atracurium 0.25–0.5 No No 0.4 mg/kg 4-20 mcg/kg/min Cisatracurium 0.5–1 No No 0.1 mg/kg 2–10 mcg/kg/min Yes No No No No Dose-dependent No No 9. Concerns with neuromuscular blockade a. Can mask seizure activity b. Prolonged use is associated with critical illness poly-neuromyopathy, which is characterized by prolonged muscle weakness, especially with steroid based neuromuscular blocking agents. c. Can mask insufficient analgesia and sedation d. Increased risk of venous thromboembolism (VTE) e. Increased risk of skin breakdown and decubitus f. Corneal abrasions caused by eye dryness and lack of blinking; prevent by applying ophthalmic ointment or drops to eyes every 6–8 hours 10. Monitoring a. Neuromuscular blockers must be monitored to prevent an excessive degree of blockade and prolonged paralysis. b. The goal of neuromuscular blockade is to facilitate safe and optimal mechanical ventilation strategies using the minimal degree of neuromuscular blockade needed. c. Even with appropriate individualized dosing and monitoring of neuromuscular blockade, a principal adverse effect is prolonged muscle weakness after discontinuation. This can dramatically slow patient recovery, increasing the need for health care resources (e.g., physical therapy, rehabilitation). For this reason, it must be emphasized that the need for therapeutic paralysis must be carefully considered and reevaluated every day. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-327 Critical Care d.  simple way to assess the appropriateness of the paralytic is as follows. Regularly (e.g., once A daily) but temporarily discontinue the drug to determine the time needed for the patient to move or breathe spontaneously. Although not applicable to all patients, this “drug holiday” can be useful for the following reasons: i. Assess sedation and adjust sedatives as needed (e.g., if the patient is agitated after the drug is discontinued, he or she is not receiving adequate sedation or analgesia). ii. Assess the need for continued blockade (e.g., if the patient can maintain oxygenation, then perhaps the drug is no longer necessary). iii. Assess the dose of the paralytic (e.g., determine whether the paralysis wore off within the expected time according to the expected drug duration); this is especially important for drugs such as vecuronium because of the long half-life and dependence on end organ clearance. iv. Note that the studies listed earlier (N Engl J Med 2010;363:1107-16; N Engl J Med 2019;380:19972008) used cisatracurium continuously (without a holiday) for 48 hours without an increased incidence of prolonged weakness. e. A peripheral nerve stimulator can be used in conjunction with drug holidays to assess the level of neuromuscular blockade and guide drug dosing. i. The TOF refers to peripheral nerve stimulation using four electrical impulses, usually applied to the ulnar (preferable) or facial nerves. ii. Obtain a baseline TOF before initiation to determine patient sensitivity to impulses. Patients who are not blocked should have one twitch for each impulse (for 4/4 twitches). iii. During neuromuscular blockade infusions for respiratory failure, patients should typically be maintained at one or two twitches, which indicates 85%-90% receptor blockade. iv. Technical problems that limit the accuracy of TOF monitoring include the presence of perspiration or tissue edema. The TOF monitor may no longer be accurate if the electrodes are moved after the neuromuscular blocker is initiated. 11. In addition to the monitoring described, clinical assessment involves adjusting the neuromuscular blocker dose to prevent patient-ventilator dyssynchrony (e.g., “bucking” the ventilator, elevated peak airway pressures). 12. Avoid other medications or electrolyte abnormalities that can potentiate or inhibit paralysis (Table 16). Table 16. Interactions with Neuromuscular Blockers Drugs Electrolyte disorders Potentiate Block Corticosteroids Aminoglycosides Clindamycin Tetracyclines Polymyxins Calcium channel blockers Type Ia antiarrhythmics Furosemide Lithium Hypermagnesemia Hypocalcemia Hypokalemia Antagonize Block Aminophylline Theophylline Carbamazepine Phenytoin (chronic) Hypercalcemia Hyperkalemia ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-328 Critical Care VII. GLUCOSE CONTROL A. History of blood glucose control 1. 2001: Study by van den Berghe et al. of surgical ICU patients showed a significant morbidity and mortality benefit of maintaining blood glucose at 80–110 mg/dL, despite the increased risk of hypoglycemia at 5.1% versus 0.8%. 2. 2006: Study by van den Berghe et al. of primarily medical ICU patients showed no mortality benefit associated with maintaining blood glucose in the range of 80–110 mg/dL in the entire study population. The study showed a reduction in ventilator time, length of stay, and mortality in patients with an ICU length of stay of 3 days or more. The incidence of hypoglycemia (18%) was higher than previously reported. 3. Subsequent investigations of tight glycemic control (80–110 mg/dL) never replicated the mortality benefit seen in the 2001 study. Studies showed much higher rates of hypoglycemia with tight glycemic control. 4. 2009: Results of a large, international, randomized study (NICE-SUGAR) involving more than 6000 critically ill medical and surgical patients showed higher mortality and higher risk of hypoglycemia in patients receiving intensive blood glucose control (goal glucose 81–108 mg/dL) compared with patients having a goal of 180 mg/dL or less (mean blood glucose 142 mg/dL). 5. The 2012 Society of Critical Care Medicine guidelines for using an insulin infusion to manage hyperglycemia in general critically ill patients suggest using a blood glucose of 150 mg/dL or higher as a trigger for insulin therapy, adjusted to keep blood glucose less than 150 mg/dL, and maintaining values less than 180 mg/dL using an insulin protocol that achieves a low rate of hypoglycemia (blood glucose 70 mg/dL or less). 6. The 2021 SSC guidelines recommend a protocolized approach to insulin therapy, initiating insulin therapy at a glucose level greater than 180 mg/dL. A typical target blood glucose concentration range is 144–180 mg/dL for patients with sepsis. B. Treatment strategies to achieve glycemic control in critically ill patients 1. For a continuous insulin infusion approach, use a validated dosing protocol that considers blood glucose concentration, rate of change, and insulin infusion rate. 2. Intravenous insulin is preferred for patients with type 1 diabetes, patients with hyperglycemia who are hemodynamically unstable, and patients in whom long-acting basal insulin should not be initiated because of changing clinical status. Once patients are in stable condition, they can be considered for transitioning to a protocol-driven subcutaneous insulin regimen. 3. Regularly scheduled subcutaneous administration of basal or rapid-acting insulin can prevent hyperglycemia in clinically stable patients who do not need an intravenous infusion of insulin. The use of subcutaneous insulin is not recommended in patients receiving vasopressors, patients with significant peripheral edema, or patients for whom rapid correction of blood glucose is warranted. 4. Subcutaneous sliding-scale or correction factor insulin should not be the sole method of glucose control in critically ill patients. A sliding-scale or correction factor insulin regimen can be used in conjunction with the regularly scheduled subcutaneous doses; however, the baseline of insulin administered should be adjusted daily to prevent hyperglycemia and the need for additional doses of insulin. C. Monitoring blood glucose 1. For a continuous insulin infusion approach, monitoring of blood glucose every 1–2 hours is typically needed to provide safe and effective therapy. 2. Interpret point-of-care testing of capillary blood with caution because it can overestimate plasma glucose values. Overestimation of blood glucose is more common in patients with anemia, hypotension, or hypoperfusion. It is also more common when blood glucose is in the hypoglycemic or hyperglycemic range. 3. Arterial or venous whole blood sampling is recommended instead of fingerstick capillary blood glucose testing in patients with shock or severe peripheral edema and for patients on a prolonged insulin infusion. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-330 Critical Care VIII. PREVENTING STRESS ULCERS A. Mucosal bleeding in critically ill adults 1. The incidence of stress-related mucosal bleeding in critically ill adults is estimated to be 2.5%. 2. Signs and symptoms of stress ulcers include hematemesis, gross blood in gastric tube aspirates, coffee ground emesis or aspiration from gastric tube, and melena. Clinically significant stress ulcers are defined as those that cause hemodynamic compromise or necessitate blood transfusion. B. Prophylactic therapy for stress ulcers 1. Prophylactic medications are recommended for any one of the following major risk factors: a. Respiratory failure necessitating mechanical ventilation (for more than 48 hours) b. Coagulopathy, defined as platelet count less than 50,000 cells/mm3, INR greater than 1.5, or activated partial thromboplastin time greater than twofold the control value. (Note: Prophylactic or treatment doses of anticoagulants do not constitute coagulopathy.) 2. Prophylactic medications or continuing home acid suppressive regimens are also recommended for any patient with a history of gastrointestinal (GI) ulceration or bleeding within 1 year before ICU admission. 3. Prophylactic medications are recommended for patients with two or more of the following risk factors (although data on this approach are lacking): a. Head or spinal cord injury b. Severe burn (more than 35% of body surface area) c. Hypoperfusion d. Acute organ dysfunction e. High doses of corticosteroids (more than 250 mg/day of hydrocortisone or equivalent) f. Liver failure with associated coagulopathy g. Transplantation h. Acute kidney injury i. Major surgery j. Multiple trauma C. Strategies for stress ulcer prophylaxis (SUP) (see Table 17 for specific medications) 1. Efficacy of intravenous histamine-2 (H2)-blockers in preventing stress-related upper GI bleeding has been shown in several clinical trials. These are commonly administered enterally when possible because of excellent bioavailability; however, evidence of efficacy is primarily with the intravenous administration of H2-blockers. 2. Proton pump inhibitors (PPIs) also prevent stress-related mucosal bleeding and are commonly administered enterally, when possible, given their excellent bioavailability. 3. Recent data analyses assessing PPIs versus placebo found no difference in mortality or clinically important events, which were a composite of clinically important GI bleeding, pneumonia, C. difficile infection, or myocardial ischemia. However, of note are the limited therapy duration (median of 4 days) and higher rate of GI bleeding in the placebo group (4.2% vs. 2.5%). Another large study comparing PPIs with H2-blockers found no difference in mortality, but a lower incidence of clinically important GI bleeds with PPIs (1.3% vs. 1.8%; RR 0.73 [95% CI, 0.52–0.92]). However, 20.1% of patients randomized to H2-blockers received PPIs, making it difficult to draw definitive conclusions and apply them to clinical practice (JAMA 2020;323:616-26). 4. A recent meta-analysis compared the efficacy and safety of H2-blockers, PPIs, and sucralfate against each other or placebo. H2-blockers and PPIs had a significant reduction in clinically important GI bleeding in high risk critically ill patients. No differences were found in mortality or infections. There was no benefit found with sucralfate in any endpoint. Although this meta-analysis has limitations of heterogeneous patient populations, definitions, and endpoints, it supports the use of H2-blockers or PPIs in patients with a high risk of bleeding. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-331 Critical Care 5.  egardless of the drug choice or route, it is important to discontinue therapy when risk factors are no R longer present to avoid unnecessary drug interactions, adverse effects (e.g., pneumonia), and increased costs. This step is easily overlooked, with the result that patients are discharged from hospitals and then continue to take acid-suppressive therapy with no indication. 6. Recent studies suggest enteral nutrition may have protective effects against GI bleeding. Pharmacologic prophylaxis may not provide additional benefit to EN, but may increase risk for adverse effects such as pneumonia. Additional studies are needed to confirm these outcomes. 7. Not recommended for prevention a. Antacids. b. Sucralfate is inferior to H2-blockers and is therefore not recommended for preventing stress ulcers. In addition, it can cause obstruction of enteral feeding tubes and aluminum toxicity in patients with renal failure. 8. Safety: The benefits of preventing stress ulcers by increasing the stomach pH must be weighed against an increased risk of infection, including C. difficile, hospital-acquired pneumonia, and community-acquired pneumonia (for patients discharged with a PPI). Table 17. Medications for Stress Ulcer Prophylaxis Class H2-receptor blockers Examples and Dosing Famotidine 20 mg IV or PO every 12 hr Adverse Effects Mental status changes, thrombocytopenia Nizatidine 150 mg PO every 12 hr Notes Excellent bioavailability Low cost Potential for reduced efficacy over time (tachyphylaxis) Cimetidine 300 mg PO every 6 hr Dose adjustment for renal dysfunction Low risk of nosocomial pneumonia Proton pump inhibitors Omeprazole 20 mg PO daily Powder for oral suspension available Headache, diarrhea, constipation, abdominal pain, nausea Esomeprazole 20–40 mg PO or IV daily Cimetidine not routinely used because of drug interactions (strong P450 inhibitor) and adverse effects Solutions of certain PPIs may be compounded; refer to individual package inserts for instructions No adjustment needed for renal or liver dysfunction Lansoprazole 30 mg PO or IV daily Delayed-release orally disintegrating tablets and oral suspension available Higher cost than H2-blockers Administration problems may occur when given by feeding tubes Pantoprazole 40 mg PO or IV daily granules available for oral or tube administration Risk of ventilator-associated pneumonia increased Risk of C. difficile infection (nosocomial or community acquired) H 2 = histamine-2; IV = intravenous; PO = orally; PPI = proton pump inhibitor. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-332 Critical Care Patient Case Questions 12 and 13 pertain to the following case. A 73-year-old woman (weight 84 kg) is admitted to the ICU after a pneumonectomy. Her blood pressure is 104/65 mm Hg, heart rate is 88 beats/minute, and Sao2 values are 98% on 40% Fio2 and positive end-expiratory pressure 5 cm H2O; her Glasgow Coma Scale score is 11. Her other laboratory values are normal. Her medications include simvastatin 20 mg every night, aspirin 81 mg/ day, metoprolol 25 mg twice daily, heparin 5000 units subcutaneously every 8 hours, and 0.9% sodium chloride intravenously at 75 mL/hour. 12. The surgeon would like to initiate SUP. Which is the best recommendation for this patient? A. Administer famotidine 20 mg per tube every 12 hours. B. Administer magnesium hydroxide 30 mL per tube four times daily. C. Administer sucralfate 1 g per tube four times daily. D. SUP is not indicated. 13. O  ne week later, the patient is extubated but still in the ICU. Her Glasgow Coma Scale score is 15, blood pressure is 112/70 mm Hg, and heart rate is 75 beats/minute, but her appetite is poor. Which statement is most appropriate regarding SUP for this patient? A. SUP should continue until the patient is discharged from the ICU. B. SUP should be discontinued now. C. Continue SUP until patient is eating. D. SUP should be discontinued at hospital discharge. IX. PHARMACOLOGIC THERAPY FOR PREVENTING VENOUS THROMBOEMBOLISM A. G  eneral overview: VTE is a common complication of critical illness, with an incidence of deep vein thrombosis of 8%–40% and pulmonary embolism of up to 12%. B. Risk factors for VTE 1. Critically ill patients are usually at high risk of VTE. 2. Additional risk factors include surgery, major trauma, lower extremity injury, immobility, malignancy, sepsis, heart failure, respiratory failure, venous compression, previous VTE, increasing age, pregnancy, erythropoiesis-stimulating agents, obesity, and central venous catheterization. C. Recommendations for critically ill patients 1. American Society of Hematology guidelines a. Recommends low-molecular-weight heparin (LMWH) or low-dose unfractionated heparin (UFH) over no prophylaxis or mechanical prophylaxis. Guidelines also suggest using LMWH over UFH. LMWH compared with UFH appeared to have a moderate impact on mortality and VTE, with a decreased incidence of heparin-induced thrombocytopenia (HIT). b. Nonpharmacologic prevention i. Early mobility is the ideal nonpharmacologic therapy, though the definition of mobility varies. ii. Mechanical prophylaxis with intermittent pneumatic compression or graduated compression stockings is recommended for medical patients at risk of VTE who have a contraindication to pharmacologic anticoagulation (e.g., thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-333 Critical Care c. 2. Suggests pharmacologic or mechanical VTE prophylaxis alone over mechanical combined with pharmacologic prophylaxis. This is because of the potential increased risk of complications with combination therapy without any perceived benefit. d. The guidelines provide separate postoperative recommendations. A detailed assessment is beyond the scope of this text, and readers are encouraged to see the guidelines cited in the References list for more information. SSC recommends pharmacologic VTE prophylaxis with LMWH over unfractionated heparin unless a contraindication to therapy exists. D. Pharmacologic prophylaxis (see Table 18 for dosage) 1. Unfractionated heparin a. Low cost b. Twice- versus three-times daily administration: Two meta-analyses have been completed on the subject. The first, in 2007, concluded that there was no difference in efficacy, but three-times daily administration was associated with a slightly higher risk of bleeding. The second, in 2011, found no difference in efficacy or safety with either regimen. c. Risk of HIT lower than that of full anticoagulation doses 2. LMWHs a. All considered therapeutically equivalent b. Dalteparin is renally eliminated but can be considered in patients with creatinine clearance (CrCl) less than 30 mL/minute/1.73 m2 because of its low accumulation. c. Low risk of HIT d. In the largest trial of VTE prevention in critical care patients, dalteparin 5000 units subcutaneously once daily provided better protection against pulmonary embolism, similar protection against proximal deep venous thrombosis with no difference in bleeding, and less HIT than unfractionated heparin 5000 units twice daily. 3. Fondaparinux a. Can be safe in patients with a history of HIT b. Data on reversal of fondaparinux are lacking c. Contraindicated for CrCl less than 30 mL/minute/1.73 m 2 d. Limited data in critically ill patients 4. Direct oral anticoagulants a. Rivaroxaban was evaluated against enoxaparin in a study of acutely ill medical patients needing hospitalization. Although rivaroxaban was as efficacious as enoxaparin at study day 10, there was an excess risk of bleeding in the rivaroxaban group. Patients with cardiogenic or septic shock with the need for vasopressors were excluded. Rivaroxaban is renally eliminated and is not recommended in patients with significant renal insufficiency. b. Apixaban was evaluated against enoxaparin in a study of acutely ill medical patients needing hospitalization. There was no difference in rates of VTE, but a higher bleeding rate with apixaban. Patients with septic shock were also excluded from this trial. c. Compared with heparins, there is less experience in reversal of Factor Xa inhibitors in clinical practice. d. Rivaroxaban is the only direct oral anticoagulant (DOAC) FDA-approved for VTE prophylaxis in medically ill patients. However, the safety and efficacy in critically ill patients is still unclear. E. Special populations 1. Impaired kidney function a. If estimated CrCl is less than 30 mL/minute/1.73 m2, LMWH dose reduction is usually necessary. If CrCl is less than 20 mL/minute/1.73 m 2 or the patient requires dialysis, dosing information is limited for LMWH; anti-Xa monitoring might not be reliable in patients undergoing dialysis. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-334