• Start with low doses and titrate carefully

• Discontinue any nonvital medication on ICU admission. Keep track of this intervention and restart medications as clinically necessary

• Avoid complete discontinuation of drugs with adverse withdrawal syndromes if not contraindicated (e.g., β-adrenergic blockers, clonidine, benzodiazapines, SSRIs, baclofen, etc.).

• Review medication profile daily for drug–drug interactions

• Anticipate common drug side effects

• Avoid intramuscular route of drug administration

• Avoid the subcutaneous and intramuscular route of drug administration in patients in any form of shock

• Avoid enteral route of drug administration in patients with shock when there is an intravenous formulation

• Oxygen is a “drug”—titrate inspired oxygen concentration to provide adequate systemic oxygen delivery, avoiding both hypoxic vasoconstriction and hyperoxic hypercarbia (e.g., 88–92 % in chronic hypercapneic patients)

• Use the lowest inspired oxygen concentration consistent with adequate tissue oxygenation in patients receiving/or having received bleomycin. May also apply to patients receiving amiodarone or chest radiotherapy.

• Water is a “drug”—ensure adequate intake to avoid dehydration (hypernatremia)

• Strict avoidance of hypoglycemia. Ensure an adequate source of dextrose in any patient receiving an insulin product

• Promote appropriate patient sleep–wake cycles

• Practice daily wake-up in patients receiving sedative medications

• Become familiar with the pharmacokinetic and pharmacodynamic principles of medications prescribed in ICU patients

• Become familiar with the principles of safe writing rules as suggested by the Institute of Safe Medication Practice

• Be aware of common sound-alike medications

• Practice good hand hygiene

• Vaccinate carefully selected patients

• Obtain and review one’s institution’s antibiogram

• Always address the need for stress-ulcer prophylaxis, deep vein thrombosis (DVT) prophylaxis, and nutrition support

Resuscitation goals during the first 6 h (early goal-directed therapy)

• Non-invasive strategies targeting early fulfillment of available clinical endpoints have been shown to be equally effective^b

• Target central venous pressures between 8 and 12 mmHg (12–15 mmHg in intubated patients)—all targets should be individualized based on patient/clinical situation (e.g., need higher CVP in patients with increased abdominal pressure)

     ○ Use a crystalloid (normal saline or lactated Ringer’s solution) as the initial fluid of choice. The initial fluid challenge should be a minimum of 30 mL/kg within the first 3 h; more rapid administration and greater amounts of fluid may be needed in some patients. Monitor for evidence of systemic or pulmonary edema

     ○ Can use albumin in fluid resuscitation when a patient requires substantial amount of crystalloid or prior to or during resuscitation if the patient develops significant increased abdominal pressure or pulmonary edema (author’s opinion)

      ○ Hydroxyethyl starches should be avoided

• Target mean arterial pressure ≥ 65 mmHg (if elevated intra-abdominal pressure (IAP) or intracerebral pressure (ICP), target abdominal perfusion pressure (MAP-IAP) or cerebral perfusion pressure (MAP-ICP))

• Target urine output ≥ 0.5 mL/kg/h

• If elevated lactate levels, target resuscitation to normalize lactate levels

• Central venous (superior vena cava) or mixed venous oxygen saturation ≥ 70 % or > 65 %, respectively, using invasive strategy

      ○ A published study would support a mixed venous oxygen saturation of 65 % as similar to a central venous oxygen saturation of 70 %^c

• Blood product administration only when hemoglobin concentrations decrease to < 7 g/dL to target a hemoglobin concentration between 7 and 9 g/dL. In patients with myocardial ischemia, acute hemorrhage, or severe hypoxemia, a goal-directed trial to higher hemoglobin concentrations may be warranted

Diagnosis

• Diagnostic studies should be performed to identify the source of infection, causative pathogen, and any complications (e.g., abscess, empyema, infected intravascular catheter, etc.). A removable or drainable focus should be removed or drained

• After appropriate cultures have been obtained, initiate appropriate spectrum empiric antimicrobial therapy within the first hour of presentation. Consider combination pharmacotherapy targeting the most likely causative pathogens (based on possible sources, previous antimicrobials, immune status, recent stay in a health-care facility, etc.) and select antimicrobials that penetrate into the presumed source of sepsis

      ○ A published trial in bacteremic septic shock patients showed that each hour of delay in effective antimicrobial administration over the ensuing 6 h was associated with an average decrease in survival by 7.6 %

• Reassess pharmacotherapy after 48–72 h and continue or streamline therapy based on microbiological data, clinical response, and clinical judgment

Vasopressors

• Use when an appropriate fluid challenge fails to restore adequate hemodynamics and organ perfusion or in the face of life-threatening shock when fluid challenge is in progress. Should generally be utilized in patients who have been adequately fluid resuscitated

• Intravenous choices (central line preferred by author but controversial)

      ○ Norepinephrine (first-choice vasopressor)

      ○ Start with 0.05 mcg/kg/min or 4 mcg/min continuous IV infusion and titrate to effect. Maximum dose approximately 125 mcg/min or 3 mcg/kg/min

      ○ Epinephrine (added to and potentially substituted for norepinephrine)

      ○ Start with 0.05 mcg/kg/min continuous IV infusion and titrate to effect. Dose range is 2–10 mcg/min

      ○ Doses under 0.05 mcg/kg/min may exacerbate hypotension

      ○ Vasopressin (author’s opinion—added to norepinephrine before epinephrine)

      ○ May be considered in patients with refractory septic shock

      ○ Can be used as the first vasopressor in patients with malignant tachyarrythmias or active coronary ischemia (preferred over phenylephrine in these circumstances [author’s opinion]); see below

      ○ 0.03 units/min (0.01–0.04 units/min) continuous IV infusion

      ○        ○          □ Doses > 0.04–0.67 units/min have been associated with myocardial ischemia, decreased cardiac output, and cardiac arrest

      ○ Dopamine (only in highly selected patients with a low-risk of tachyarrhythmias)

      ○ 2.5–20 mcg/kg/min continuous IV infusion; may require doses above 10 mcg/kg/min for an adequate response

      ○ No role for low-dose (renal) dopamine

      ○ Phenylephrine (not recommended)

      ○ Circumstances where it may be utilized include emergent 100 mcg boluses, norepinephrine-associated arrhythmias, known high cardiac output states, or salvage therapy

      ○ Start with 50 mcg/min continuous IV infusion and titrate to effect; maximum dose around 400 mcg/min

Inotropes

• Potentially useful in resuscitated patients with persistent evidence of systemic or organ hypoperfusion

• Increasing cardiac index to predefined supranormal levels has not been found to improve outcome

• Dobutamine

      ○ 2.5–10 mcg/kg/min continuous IV infusion up to 20 mcg/kg/min

      ○ May cause hypotension and tachycardia

• Milrinone

      ○ 0.2–0.75 mcg/kg/min continuous IV infusion; use lower doses in patients with renal dysfunction (i.e., 0.2 mcg/kg/min)

      ○ Loading dose of 50 mcg/kg over 10 min may be utilized

      ○ Avoid or administer 50 % if tenuous hemodynamics

      ○ Can be used cautiously as a primary inotrope or in combination with dobutamine

      ○ If utilized, may require starting or increased doses of a vasopressor (combination with vasopressin studied)

Corticosteroids

• Administer only if adequate fluid resuscitation and vasopressor therapy are not able to restore appropriate hemodynamic parameters

• Hydrocortisone 50 mg IV q6h or 100 mg IV q8h for 7 days if deemed appropriate (note: these recommended doses are the author’s opinion). Some clinicians advocate dose tapering after shock resolution

• ACTH stimulation test is not recommended

Glycemic control

• Maintain blood glucose levels between 110 and 150 mg/dL (author’s opinion)

      ○ Use a continuous IV infusion of insulin based on an institution-specific protocol

      ○ Should be used with a continuous enteral or intravenous source of dextrose

      ○ Aggressively avoid and treat hypoglycemia

Pain

• Evaluate location, intensity, characteristics, and aggravating/alleviating factors

      ○ Assess intensity by utilizing the Behavioral Pain Scale or the Critical Care Pain Observation Tool in patients whom motor function is intact and behaviors are observable; vital signs should not be used alone for pain assessment

      ○ Establish predetermined end points

• Methods of intravenous administration

      ○ Continuous IV infusion

      ○ Intermittent IV bolus

      ○ Patient-controlled analgesia in non-critically ill patients

      ○ As needed, method (e.g., prn) should be avoided if the patient has continuous analgesic requirements

• Patient hemodynamically unstable

      ○ Fentanyl 0.5–3 mcg/kg/h continuous IV infusion or 25–100 mcg IVP every 30–60 min

      ○ Less histamine release than morphine

• Patient hemodynamically stable

      ○ Fentanyl 0.5–3 mcg/kg/h continuous IV infusion or 25–100 mcg IVP every 30–60 min

      ○ Morphine 1–10 mg/h continuous IV infusion

      ○ For acute pain can administer 2–4 mg IVP every 1–2 h

      ○ Avoid prolonged use or high doses in patients with renal failure

      ○ Hydromorphone 0.5–3 mg/h continuous IV infusion

      ○ For acute pain can administer 0.2–0.6 mg IVP every 1–2 h

• Avoid meperidine, buprenorphine, butorphanol, and nalbuphine

• NSAIDs or acetaminophen may be used as adjunctive agents in the appropriate patient

• Reassess goals daily and titrate/taper dose to desired response (as the patient may accumulate the medication or become tolerant)

      ○ With downward titration, monitor for signs/symptoms of withdrawal

      ○ Tachycardia, hypertension, tachypnea, mydriasis, lacrimation, diaphoresis, rhinorrhea, piloerection, vomiting, diarrhea, yawning, muscle cramps, irritability, and anxiety

Agitation and Sedation

• Address etiology of agitation and/or anxiety

      ○ Sepsis, renal/liver failure, hypoxia, hypercarbia, pain, central nervous system infections, hypoglycemia, electrolyte imbalances, substance withdrawal, sleep deprivation and/or ventilator dysynchrony

      ○ If patient is sleep deprived, consider altering the patient’s environment and possibly a nighttime sedative to promote an appropriate sleep–wake cycle

• Establish predetermined end points using a valid and reliable sedation and agitation scale (see Table 4.4)

      ○ A light rather than a deep level of sedation is recommended; the target level of sedation will be patient dependent

      ○ Bispectral index monitoring may be of some value in patients who are deeply sedated and receiving neuromuscular blocking agents

• Optimize the environment and minimize lighting, noise, and frequent vital sign checks

• Methods of intravenous administration

      ○ Continuous IV infusion

      ○ Intermittent IV bolus

• Management of acute agitation (non-benzodiazepine strategy) in mechanically ventilated patients

      ○ Consider analgesia-first sedation strategies, as pain is common in the critical care setting

      ○ Propofol 5–50 mcg/kg/min continuous IV infusion (preferably through a central line)

      ○ Nutritional considerations : Contains soy bean oil, egg lecithin, and glycerol. Provides 1.1 kcal/mL of emulsion; may need to adjust nutritional regimen. One formulation contains EDTA. Prolonged therapy with the EDTA-containing product may decrease serum zinc levels. May need to monitor serum zinc levels and supplement. Monitor serum triglyceride levels with prolonged infusions

      ○ Propofol infusion syndrome has been described and may result in severe metabolic acidosis, cardiac dysrhythmias, cardiovascular collapse, rhabdomyolysis, and death. The risk may be increased with concomitant catecholamine infusions or when the dose exceeds 60–80 mcg/kg/min

      ○ Dexmedetomidine 1 mcg/kg IV over 10 min, followed by 0.2–0.7 mcg/kg/h continuous IV infusion; doses up to 1.5 mcg/kg/h have been utilized

      ○ Some clinicians omit the bolus dose or administer half the recommended amount; avoid if hemodynamically unstable

      ○ No decrease in respiratory drive; may have an analgesic effect, can be utilized adjunctively in GABA-withdrawal states

• If a benzodiazepine is warranted:

      ○ Midazolam 0.02–0.1 mg/kg/h continuous IV infusion (note: active metabolite may accumulate in patients with renal impairment)

      ○ Lorazepam 0.01–0.1 mg/kg/h continuous IV infusion or 1–4 mg IV every 4–6 h

• Reassess goals daily and titrate/taper dose to desired response (as the patient may accumulate the medication or become tolerant)

      ○ With downward titration, monitor for signs/symptoms of withdrawal

      ○ Anxiety, agitation, delirium, diaphoresis, myoclonus, tremors, and seizures

      ○ Consider daily sedation interruptions as per hospital protocol

      ○ Use sedation protocols and checklists to facilitate sedation management

• The addition of a narcotic analgesic to a sedative may have additive effects. Monitor and titrate to desired level of sedation if used concomitantly

Delirium

• Use the Confusion Assessment Method for the ICU (Table 4.5) to evaluate the patient

• Have a high suspicion for sepsis

• If possible, discontinue any benzodiazepines, as they may be a risk factor for delirium

• Evaluate for reversible etiologies. Drugs that may cause delirium include:

      ○ Benzodiazepines, barbiturates, opioids, corticosteroids, dopamine agonists (e.g., amantadine, bromocriptine, levodopa, pergolide, pramipexole, ropinirole), H₂-receptor antagonists, anticholinergics (e.g., chlorpromazine, diphenhydramine, diphenoxylate, oxybutynin, prochlorpromazine, scopolamine, trihexyphenidyl), β-adrenergic blockers, methyldopa, carbamazepine, phenytoin, baclofen, cyclobenzaprine, lithium, metoclopramide, antidepressants (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors), cefepime (in the setting of a low CrCl), older generation fluoroquinolones, and interleukin-2

• Haloperidol 1–2 mg slow IVP, followed by doubling the dose every 15–20 min until desired effect achieved. For maintenance regimen, add up total loading dose and administer 25 % enterally every 6 h; duration based on clinical judgment (note: author’s opinion)

      ○ Monitor for QT-interval prolongation and extrapyramidal side effects

• Olanzapine 2.5–10 mg intramuscular or enteral daily may be an alternative to haloperidol. Start with 2.5 mg in elderly or debilitated patients

• Dexmedetomidine 1 mcg/kg IV over 10 min, followed by 0.2–0.7 mcg/kg/h continuous IV infusion; doses up to 1.5 mcg/kg/h have been utilized. Some clinicians omit the bolus dose or administer half the recommended amount; avoid if hemodynamically unstable

7

Dangerous agitation

Pulling at endotracheal tube (ETT), trying to remove catheters, climbing over bedrail, striking at staff, thrashing side-to-side

6

Very agitated

Does not calm down despite frequent verbal reminding of limits, requires physical restraints, biting ETT

5

Agitated

Anxious or mildly agitated, attempting to sit up, calms down with verbal instructions

4

Calm and cooperative

Calm, awakens easily, follows commands

3

Sedated

Difficult to arouse, awakens with verbal stimuli or gently shaking but drifts off again, follows simple commands

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

1. Acute onset of mental status changes or fluctuating course

• Is there evidence of an acute change in mental status from baseline?

• Did the abnormal behavior fluctuate during the past 24 h?

• Did the sedation scale (e.g., Riker Sedation–Agitation Scale) or Glasgow Coma Scale fluctuate in the past 24 h?

2. Inattention

• Did the patient have difficulty focusing?

• Is there a reduced ability to maintain and shift attention?

• How does the patient score on the Attention Screening Examination (ASE)?