Critical Care Pharmacotherapy Review PDF

Critical Care (b) F  urthermore, the corticotropin stimulation test should not be used to identify patients with septic shock or acute respiratory distress syndrome (ARDS) who should receive glucocorticoids. (c) Patients should be weaned off steroid therapy once vasopressors are no longe...

Critical Care (b) F  urthermore, the corticotropin stimulation test should not be used to identify patients with septic shock or acute respiratory distress syndrome (ARDS) who should receive glucocorticoids. (c) Patients should be weaned off steroid therapy once vasopressors are no longer necessary. 7. Metabolic resuscitation a. High-dose intravenous ascorbic acid (vitamin C) has anti-inflammatory and antioxidant properties that may be beneficial in sepsis. b. Thiamine deficiency occurs in critically ill patients with sepsis, and supplementation in these patients improves lactate clearance. c. Ascorbic acid and hydrocortisone may have synergistic protective effects on the vascular endothelium. d. A single-center, retrospective before-and-after study assessed coadministration of hydrocortisone, high-dose ascorbic acid, and thiamine (HAT) therapy for patients with severe sepsis or septic shock. HAT therapy was associated with a shorter duration of vasopressors and a 31.9% decrease in hospital mortality. However, other studies assessing hydrocortisone alone (described in the previous section) have consistently shown decreased time to resolution of septic shock and inconsistently shown improved mortality rates. Therefore, it is unclear whether the benefit was a result of HAT therapy or of hydrocortisone alone (Chest 2017;151:1229-38). e. Several randomized controlled trials were subsequently published that failed to reproduce the mortality benefit with HAT therapy. The VITAMINS trial compared HAT therapy with hydrocortisone alone. Results showed no improvement in the duration of time alive and free of vasopressor administration over 7 days (JAMA 2020;323:423-31). The VICTAS trial compared HAT therapy with placebo and found no difference in ventilator-free and vasopressor-free days and no difference in 30-day mortality (JAMA 2021;325:742-50). f. Although these trials had notable limitations, each suggest that HAT therapy should not be routinely administered in sepsis. The 2021 guidelines suggest against the use of ascorbic acid for adults with sepsis or septic shock. III. INTERPRETATION OF ACID-BASE DISTURBANCES A. Normal Arterial Blood Gas Values pH Pco2 Po2 HCO3− Sao2 7.40 (range 7.35–7.45) 35–45 mm Hg 80–100 mm Hg 22–26 mEq/L (or mmol/L) 95%–100% B. Acidosis: Any pH less than 7.35 indicates a primary acidosis. C. Alkalosis: Any pH greater than 7.45 indicates a primary alkalosis. D. Metabolic disorders 1. Acidosis: Decreased HCO3− 2. Alkalosis: Increased HCO3− ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-311 Critical Care E. Respiratory disorders 1. Acidosis: Increased Pco2 2. Alkalosis: Decreased Pco2 F. Compensation: Occurs in an attempt to normalize the pH in response to the primary problem (Table 5) 1. Respiratory compensation occurs immediately with changes in respiratory rate. a. The compensation for metabolic acidosis is respiratory alkalosis (i.e., decrease in Pco2). This is achieved by increasing the respiratory rate to eliminate more CO2, thus making pH more basic (i.e., higher pH). b. The compensation for metabolic alkalosis is a respiratory acidosis (i.e., increase in Pco2). This is achieved by slowing the respiratory rate to retain more CO2, thus making pH more acidic (i.e., lower pH). 2. Metabolic compensation occurs slowly in the kidneys by regulating the excretion and reabsorption of HCO3− and H+. a. The compensation for a respiratory acidosis is metabolic alkalosis (i.e., an increase in HCO3−). b. The compensation for a respiratory alkalosis is metabolic acidosis (i.e., a decrease in HCO3−). Table 5. Predicted Degrees of Compensation in Acid-Base Disturbances Normal Values HCO3− = 24 mmol/L Pco2 = 40 mm Hg Metabolic acidosis Primary Disturbance ↓ HCO3− by 1 mmol/L Compensation ↓ Pco2 by 1.2 mm Hg Metabolic alkalosis Respiratory acidosis Acute Chronic (>3 days) ↑ HCO3− by 1 mmol/L ↑ Pco2 by 0.7 mm Hg ↑ Pco2 by 10 mm Hg ↑ Pco2 by 10 mm Hg ↑ HCO3− by 1 mmol/L ↑ HCO3− by 3.5 mmol/L Respiratory alkalosis Acute Chronic (>3 days) ↓ Pco2 by 10 mm Hg ↓ Pco2 by 10 mm Hg ↓ HCO3− = 2 mmol/L ↓ HCO3− = 4 mmol/L G. Steps to evaluate acid-base disorders (Table 6) 1. Assess pH, Pco2, and HCO3−. a. Acidosis if pH less than 7.35 i. If Pco2 is elevated, the primary disorder is respiratory acidosis. ii. If HCO3− is decreased, the primary disorder is metabolic acidosis. b. Alkalosis if pH is greater than 7.45 i. If Pco2 is decreased, the primary disorder is respiratory alkalosis. ii. If HCO3− is elevated, the primary disorder is metabolic alkalosis. 2. Calculate the anion gap (AG) = [Na+] − [Cl− + HCO3−]. a. Normal range is 6–12 mEq/L. b. If AG is more than 12, there is a primary metabolic acidosis regardless of pH or HCO3−. Some patients have a mixed acid-base disorder in which they have more than one primary disorder. c. Hypoalbuminemia decreases the AG by 2.5–3 mEq/L for every 1-g/dL decrease in serum albumin less than 4 g/dL. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-312 Critical Care 3. Calculate the excess AG = Total AG − Normal AG. Add excess AG to serum bicarbonate. a. If the sum is greater than a normal serum bicarbonate (i.e., more than 30 mEq/L), there is also an AG metabolic alkalosis (this can occur in addition to other primary disorders). b. If the sum is less than a normal serum bicarbonate (i.e., less than 23 mEq/L), there is an underlying non-AG metabolic acidosis. Table 6. Causes of Acid-Base Disturbances Etiology Treatment Respiratory Acidosis Pulmonary edema Cardiac arrest CNS depression Stroke Pulmonary embolus Pneumonia Bronchospasm Spinal cord injury Sedatives Respiratory Alkalosis Anxiety Pain CNS tumor Stroke Head injury Hypoxia Stimulant drugs Reduced oxygencarrying capacity Reduced alveolar oxygen extraction Respiratory rate stimulation Extracorporeal removal Metabolic Acidosis Anion gap (MUDPILES) Methanol Uremia DKA Propylene glycol Intoxication or infection Lactic acidosis Ethylene glycol Salicylate Correct cause Correct cause Non–anion gap (F-USED CARS) Fistula (pancreatic) Uteroenteric conduits Saline excess Endocrine (hyperparathyroid) Diarrhea Carbonic anhydrase inhibitors Arginine, lysine, Cl− Renal tubular acidosis Spironolactone Correct cause Invasive/noninvasive ventilation Oxygen supplementation Invasive/noninvasive ventilation Hypoventilation Sedation Base use in AG metabolic acidosis is controversial (Sodium bicarbonate has traditionally been used, but evidence of clinical benefit is lacking) Metabolic Alkalosis Urine Cl− > 25 (Chloride resistant) Hyperaldosteronism ↑ Mineralocorticoid Urine Cl− < 25 (Chloride responsive) Vomiting NG suction Diuretic Correct cause If urine Cl− > 25 Potassium Aldosterone antagonist Acetazolamide If urine Cl− < 25 0.9% NaCl Use of bases (sodium Consider bicarbonate or THAM) acetazolamide may be considered in Consider HCl non-AG metabolic acidosis (if severe) AG = anion gap; Cl− = chloride; CNS = central nervous system; DKA = diabetic ketoacidosis; HCl = hydrochloric acid; NaCl = sodium chloride; NG = nasogastric; THAM = tromethamine or tris-hydroxymethyl aminomethane. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-313 Critical Care IV. CARDIAC ARREST A. T  raining: Any pharmacist who participates in codes should complete basic life support (BLS) and advanced cardiac life support (ACLS) training. In general, BLS training takes 3–5 hours to complete, and ACLS training takes 2 days. The information presented in this section consists of selected highlights from these training sessions; it should not be used in place of a comprehensive training program. B. 2020 American Heart Association (AHA) Guidelines 1. Medications used during ACLS: See “Acute Care in Cardiology” chapter for information on drugs, indications, and dosages. 2. CAB (compressions, airway, breathing): In an unresponsive patient or a patient who is not breathing, one rescuer should initiate a cycle of 30 chest compressions as soon as possible, followed immediately by 2 rescue breaths. After placement of an advanced airway, it may be reasonable for the provider to deliver 1 breath every 6 seconds (10 breaths/minute) while continuous chest compressions are being performed. 3. Emphasis is on high-quality cardiopulmonary resuscitation (CPR), with a compression rate of 100–120 compressions/minute at a depth of at least 2 inches for adults, and allow complete chest recoil. 4. For ventricular fibrillation or pulseless ventricular tachycardia, electrical therapy (by an automated external defibrillator or defibrillator) should be initiated as soon as it is available. 5. For nonshockable rhythms (i.e., pulseless electrical activity, asystole), epinephrine should be administered as soon as possible. 6. Interruptions in chest compressions should be minimal and and no longer than 10 seconds. Chest compressions and defibrillation should not be interrupted for vascular access, medication administration, or airway placement. 7. End-tidal carbon dioxide (EtCO2) is the partial pressure of exhaled carbon dioxide at the end of expiration. It is measured using waveform capnography. During cardiac arrest, EtCO2 levels reflect the cardiac output generated by chest compressions and myocardial blood flow. EtCO2 levels less than 10 mm Hg immediately after intubation and 20 minutes after initial resuscitation are associated with poor chances of return of spontaneous circulation (ROSC) and survival. 8. Medication administration a. Central venous administration is preferred. b. If medications are administered through a peripheral vein, it is important to follow the medication with 20 mL of intravenous fluid to facilitate drug flow from the extremity to the central circulation. c. Intraosseous administration is preferred to endotracheal administration if intravenous administration is not possible because of its more predictable drug delivery and pharmacologic effect. d. Endotracheal drug administration can be performed by administering 2–2.5 times the standard intravenous dose and diluting in 5–10 mL of sterile water. The following drugs can be administered through an endotracheal tube: naloxone, atropine, epinephrine, lidocaine. C. Post–cardiac arrest care 1. After ROSC, systematic post–cardiac arrest care can improve survival and quality of life. 2. Initial therapy should optimize ventilation, oxygenation, and blood pressure. a. Sao2 should be maintained at 94% or higher. i. Insertion of an advanced airway may be necessary. ii. Hyperventilation and excess oxygen delivery are harmful and should be avoided, especially after ROSC. b. Hypotension (SBP of 90 mm Hg or less) should be treated with fluid boluses and vasopressors if necessary. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-316 Critical Care 3. Avoidance of hyperthermia is recommended because fever in patients after cardiac arrest is associated with poor neurologic outcomes. 4. Targeted temperature management (TTM) a. Induction of hypothermia (32°C–36°C) for at least 24 hours beginning as soon as possible after ROSC can improve neurologic recovery and mortality. The AHA guidelines recommend that all comatose adult patients with ROSC have targeted temperature management. One study (N Engl J Med 2013;369:2197-206) has shown that a standard target temperature (33°C) does not confer a benefit over a higher target temperature (36°C). A single-center, retrospective, before-andafter cohort study showed that 33°C was associated with a 79% increased odds of neurologically intact survival to discharge compared with 36°C but no difference in hospital mortality. However, those in the 33°C group were cooled faster (1.9 hours vs. 3.5 hours, p<0.001), which is a notable limitation that may have affected the results (Crit Care Med 2020;48:362-9). The AHA guidelines allow the clinician to select the exact target temperature. A recent large multicenter study (N Engl J Med 2021;384:2283-94) found targeted hypothermia (33°C) did not result in improved 6-month mortality compared with targeted normothermia after out-of-hospital cardiac arrest. These results suggest the benefit may be due to avoidance of fever rather than hypothermia. b. No single method for inducing hypothermia is recommended over another. Surface cooling devices, endovascular catheters, cooling blankets, ice packs, and cold intravenous fluids can be used. These methods differ in nursing workload, incidence of adverse events, time to target temperature and cost. c. Core temperature should be monitored continuously. d. Many patients will need sedation and analgesia during periods of hypothermia. e. Rewarming should be done slowly (0.3°C–0.5°C every hour), and patients should remain afebrile. f. Complications i. Shivering (a) Shivering causes excess heat production, increased oxygen consumption, and a general stress response; it should be treated and prevented. (b) Shivering can be treated with sedatives (dexmedetomidine, ketamine), anesthetics, analgesics (e.g., meperidine, fentanyl, tramadol), dexamethasone, clonidine, magnesium, ondansetron, buspirone, and paralytics (please see Crit Care Med 2012;40:3070-82 for individual drugs and doses). (c) Note that shivering can be treated without the use of paralytics in many patients. Therefore, paralytics are not mandatory and should be avoided if possible (see disadvantages of paralytics in section VI: Pain, Agitation, Delirium, and Neuromuscular Blockade). Paralytics may be most beneficial during the induction of hypothermia and during rewarming (when risk of shivering is greatest); however, they should be continually reevaluated and discontinued, if possible, once goal temperature is achieved. Pharmacologic antishivering protocols significantly reduce the incidence of shivering and the need for medications that may interfere with neurologic examinations. ii. Altered drug metabolism (a) Drug clearance is typically reduced during hypothermia, including a depressed activity of cytochrome P450 (CYP) 3A4 and 3A5 hepatic enzymes. Hypothermia can also affect the distribution of drugs to their site of action (e.g., propofol). These effects become more pronounced at cooler temperatures. (b) Use bolus dosing during hypothermia induction, and reduce maintenance doses of sedatives (e.g., midazolam, propofol), opiates (fentanyl, remifentanil), phenobarbital, phenytoin, paralytics, and other drugs as needed (see review article Crit Care Med 2007;35:2196-204). iii. Coagulopathy (a) Providers may choose not to cool patients with preexisting coagulopathy because of the increased risk of bleeding. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-317 Critical Care iv. Increased renal excretion of water and subsequent volume depletion v. Arrhythmia and hypotension (a) Usually bradycardia (b) Discontinue or slightly warm patient if life-threatening arrhythmias or persistent hemodynamic instability develops. vi. Hyperglycemia and hypoglycemia (a) Hyperglycemia during hypothermia, hypoglycemia during rewarming. (b) Monitor blood glucose often (i.e., every 1–2 hours) and adjust insulin accordingly. vii. Infection viii. Electrolyte disturbances (a) Reductions in K, magnesium, and phosphate during cooling (b) Hyperkalemia during rewarming (c) Special electrolyte replacement protocols should be used to ensure that patients do not receive too much potassium during cooling such that they are hyperkalemic during rewarming. Electrolyte shifts occur during the induction and rewarming phases of TTM. Frequent monitoring and careful repletion is important to prevent complications from electrolyte abnormalities. Patient Case 7. A 61-year-old woman collapses in front of her family members, who call 9-1-1 and begin CPR. The paramedics arrive and find the victim unresponsive, with an electrocardiogram revealing ventricular fibrillation, and administer two additional rounds of CPR and two defibrillations, which are successful. In the emergency department, the patient’s MAP is 68 mm Hg after fluids and norepinephrine, but the patient remains unresponsive. She is initiated on the hypothermia protocol. After 24 hours of hypothermia (body temperature 33°C), the patient is in the ICU, and the rewarming process has recently begun. The pharmacist arrives in the ICU about 30 minutes into the rewarming process. The patient has been receiving a continuous infusion of insulin throughout the period of hypothermia at an average rate of 4 units/hour, with blood glucose testing every 3 hours. The patient has been sedated with a continuous infusion of propofol and fentanyl and is receiving cisatracurium for neuromuscular blockade. The patient’s vital signs are stable, and her laboratory values are normal. Which pharmacist recommendation is most appropriate at this time? A. Increase blood glucose testing to now and every 1–2 hours during rewarming. B. Adjust cisatracurium infusion to achieve a TOF of 0/4 impulses. C. Discontinue propofol infusion to facilitate extubation. D. Increase insulin infusion to prevent hyperkalemia. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-318 Critical Care V. ACUTE RESPIRATORY FAILURE A. Causes of respiratory failure (Table 7) Table 7. Respiratory Failure Indication for Mechanical Ventilation Hypoventilation (hypercapnic respiratory failure) Hypoxemia (hypoxic respiratory failure) Inability to maintain airway Examples Drug overdose Neuromuscular disease Cardiopulmonary resuscitation Central nervous system injury or disease Pulmonary injury or disease Pneumonia Pulmonary edema Pulmonary embolus Acute respiratory distress syndrome Loss of airway patency (mechanical obstruction, tracheal or chest wall injury) Loss of gag or cough reflex with large-volume aspiration risk (e.g., central nervous system injury, central nervous system depression, cardiovascular accident, seizures, cardiac arrest) B. C  ommon complications associated with mechanical ventilation (see individual sections later in text for prevention of these complications) 1. Ventilator-associated pneumonia 2. Stress ulcers 3. Venous thrombosis VI. PAIN, AGITATION, DELIRIUM, AND NEUROMUSCULAR BLOCKADE A. General considerations 1. Nonpharmacologic strategies to improve patient comfort include normalizing their environment: lighting, music, massage, verbal reassurance, avoidance of sleep deprivation, and patient positioning based on patient preferences. 2. Determine patient goals using validated scales and routinely assess pain and sedation. a. Routine assessment of pain and sedation should be performed in every patient in the ICU. i. Self-reporting is preferred to pain scales for assessing pain in patients who are able to communicate. ii. To assess pain in patients who are unable to communicate, the Behavioral Pain Scale (BPS; Table 8) and the Critical-Care Pain Observation Tool (CPOT; Table 9) are recommended because, compared with other scores, they are more valid and reliable for monitoring pain in adult patients in the ICU (except those with brain injury). (a) The total BPS score can range from 3 (no pain) to 12 (maximum pain). A score of 6 or higher is generally considered to reflect unacceptable pain. (b) The total CPOT score can range from 0 to 8. A score of 3 or higher is generally considered to reflect unacceptable pain. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-319 AL GRAWANY Critical Care Table 8. The Behavioral Pain Scale Item Description Score Facial expression Relaxed Partially tightened (e.g., brow lowering) Fully tightened (e.g., eyelid closing) Grimacing 1 2 3 4 Upper limb movements No movement Partially bent Fully bent with finger flexion Permanently retracted 1 2 3 4 Compliance with mechanical ventilation Tolerating movement Coughing but tolerating ventilation for most of the time Fighting ventilator Unable to control ventilation 1 2 3 4 Adapted from: Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med 2001;29:2258-63. Table 9. Critical Care Pain Observation Tool Indicator Facial expression Body movements Muscle tension Compliance with the ventilator Vocalization (extubated patients) Description Score No muscular tension observed Relaxed, neutral: 0 Presence of frowning, brow lowering, orbit tightening, and levator contraction Tense: 1 All the above facial movements plus eyelids tightly closed Grimacing: 2 Does not move at all (does not necessarily mean absence of pain) Absence of movement: 0 Slow, cautious movements; touching or rubbing the pain site; seeking attention through movements Protection: 1 Pulling tube, trying to sit up, moving limbs or thrashing, not following commands, striking at staff, trying to climb out of bed Restlessness: 2 No resistance to passive movements Relaxed: 0 Resistance to passive movements Tense, rigid: 1 Strong resistance to passive movements, inability to complete them Very tense or rigid: 2 Alarms not activated, easy ventilation Tolerating ventilator or movement: 0 Alarms stop spontaneously Coughing but tolerating: 1 Asynchrony: blocking ventilation, alarms frequently activated Fighting ventilator: 2 Talking in normal tone or no sound Talking in normal tone or no sound: 0 Sighing, moaning Sighing, moaning: 1 Crying out, sobbing Crying out, sobbing: 2 Adapted from: Gélinas C, Fillion L, Puntillo KA, et al. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care 2006;15:420-7. iii. V  ital signs (e.g., elevated heart rate or blood pressure) indicate further assessment of pain is necessary in adult patients in the ICU. iv. To assess sedation, the Richmond Agitation-Sedation Scale (RASS; Table 10) and SedationAgitation Scale (SAS; Table 11) are recommended because, compared with other sedation scores, they are more valid and reliable for monitoring the quality and depth of sedation in adult ICU patients. Goal sedation scores should be individualized for each patient, but generally, a RASS score of 0 to -1 or an SAS score of 3 or 4 is recommended. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-320 Critical Care Table 10. Richmond Agitation-Sedation Scale Scale Term Description +4 Combative Combative, violent, immediate danger to staff members +3 Very agitated Pulls to remove tubes or catheters; aggressive +2 Agitated Frequent nonpurposeful movement, fights ventilator +1 Restless Anxious but movements not aggressive 0 Alert and calm Spontaneously pays attention to caregiver –1 Drowsy Not fully alert but has sustained awakening to voice (eye opening and eye contact for ≥10 s) –2 Light sedation Briefly (<10 s) awakens with eye contact to voice –3 Moderate sedation Movement or eye opening to voice but no eye contact –4 Deep sedation No response to voice but movement or eye opening to physical stimulation –5 Unarousable No response to voice or physical stimulation Information from: Pun B, Dunn J. The sedation of critically ill adults: part 1. Assessment. Am J Nurs 2007;107:40-8. Table 11. Sedation-Agitation Scale Score Term Description 7 Dangerous agitation Pulling at endotracheal tube, trying to remove catheters, climbing over bedrail, striking at staff, thrashing side to side 6 Very agitated Requiring restraint and frequent verbal reminding of limits, biting endotracheal tube 5 Agitated Anxious or physically agitated, calms to verbal instructions 4 Calm and cooperative Calm, easily roused, follows commands 3 Sedated Difficult to arouse but awakens to verbal stimuli or gentle shaking, follows simple commands but drifts off again 2 Very sedated Arouses to physical stimuli but does not communicate or follow commands, may move spontaneously 1 Unarousable Minimal or no response to noxious stimuli, does not communicate or follow commands Information from: Pun B, Dunn J. The sedation of critically ill adults: part 1. Assessment. Am J Nurs 2007;107:40-8. b.  ain and discomfort are primary causes of agitation; therefore, treat pain first and add a sedative P if needed. This is often referred to as analgosedation. i. Use bolus dose analgesics and/or nonpharmacologic interventions before potentially painful procedures. ii. Opioid analgesics are considered first line for the treatment of nonneuropathic pain. Gabapentin or carbamazepine can be considered for neuropathic pain. However, gabapentin is typically preferred because of the adverse effects and drug interactions associated with carbamazepine. iii. Nonopioid analgesics (e.g., acetaminophen, ketamine) can be used in conjunction with opioids as a “multimodal analgesia” approach to optimize pain control and to avoid dose-related adverse effects. iv. Nonsteroidal anti-inflammatory drugs are usually avoided because of the risk of bleeding and kidney injury in critically ill patients. v. Nonbenzodiazepine sedatives may be preferred to benzodiazepines to improve clinical outcomes in mechanically ventilated patients. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-321 Critical Care c. Dosing strategies for analgesics and sedatives i. A nalgesics and sedatives should be dosed to achieve pain and sedation goals. Adjust sedative medications to achieve a light level of sedation (RASS 0 to –1). Light sedation is needed to allow for patient interaction to evaluate pain and delirium and for early patient mobility. ii. Goals can be achieved using intermittent dosing administered routinely or as needed. iii. If unable to achieve goals with intermittent dosing, use a combination of bolus dosing with a continuous infusion. (a) In patients receiving a continuous infusion, use a bolus dose before or instead of increasing the infusion rate (a bolus dose has a faster onset and can eliminate the need for an increase in the infusion rate). An exception is with drugs such as propofol or dexmedetomidine, which can cause hypotension or bradycardia when bolused. (b) Use bolus dosing proactively (e.g., before dressing changes, suctioning, repositioning or other painful procedures). iv. Daily awakening involves an interruption of continuous infusion opioid or sedatives until the patient is awake (SAS score of at least 4 or RASS score of at least 0) or shows discomfort or pain necessitating reinitiation, ideally at a reduced dose. Although evidence is mixed, a scheduled daily interruption of continuous infusions is associated with several important benefits. (a) Assess the patient’s neurologic function. (b) Reevaluate lowest effective opioid or sedative dose. (c) Prevent drug accumulation and overdose. (d) Reduce time on the ventilator (although one randomized study contradicts this by finding no reduction in the duration of mechanical ventilation or ICU stay with sedation interruption; JAMA 2012;308:1985-92). (e) Reduce mortality and ICU length of stay when combined with a spontaneous breathing trial. (f) Reduce symptoms of posttraumatic stress disorder and post-ICU syndrome. B. Analgesics (Table 12) Table 12. Intravenous Analgesics Morphine Fentanyl Hydromorphone Onset (min) Duration of effect (hr) Prolonged in renal failure Prolonged in hepatic failure Elimination half-life (hr) Active metabolites Adverse effects 5–10 2–4 Yes Yes 3–4 Yes 1–2 1–5 No Yes 2–4 No 5–15 2–6 No Yes 2–3 No Hypotension Flushing Bronchospasm Constipation Yes Yes Yes Yes No No No Yes Yes Yes No Yes Pharmacokinetics ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-322