to these patients, including neuromuscular blockers, fentanyl, phenytoin, and

midazolam. It is important to consider that enzyme activity recovers during the

rewarming process, necessitating close monitoring and potential dose adjustment.

29

Hepatic blood flow (perfusion) may also be altered in J.K. Reductions in hepatic

blood flow because of hypotension (shock) or shunting (cirrhosis) may have

significant effects on prolonging the half-life of medications that are dependent on

liver blood flow for metabolism. These medications are defined as having a high

hepatic extraction ratio (E > 0.7) and would include medications such as midazolam

and fentanyl.

17

Protein-binding alterations may also occur in the critically ill and may

subsequently affect the metabolism of select medications. Specifically, albumin

concentrations may acutely decrease, thus increasing the free fraction of medications

that are normally bound. This is especially relevant for medications that have high

extraction ratios, as more medication would be available for removal, causing a net

reduction in drug half-life.

CASE 56-3, QUESTION 5: How should metabolism issues be managed in J.K.?

To properly manage metabolism alterations in the ICU, the pharmacist should first

be aware of the patient populations who are most likely to have altered metabolic

rates/pathways. These include renal dysfunction, burns, therapeutic hypothermia, and

decreased hepatic perfusion. In addition to identifying at-risk patients, the pharmacist

should be aware of those medications that are most likely to have altered

metabolism. These would include medications metabolized through the CYP 450

system as well as those with high extraction ratios (E > 0.7). Increased vigilance in

monitoring for therapeutic effect/toxicity with these medications in at-risk patients is

warranted.

17,29

CASE 56-3, QUESTION 6: How is elimination altered in J.K.?

Elimination is the process by which a drug or its metabolites are removed from the

body. While the kidney is the main organ that eliminates medications, it is important

to remember that there are other organs (liver/lung) that also may contribute to

elimination.

17

In addition, there exist several therapeutic interventions that occur in

the ICU that also contribute to medication elimination, including continuous renal

replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO).

30

Glomerular filtration is the primary method of renal clearance of medications, and

renal drug removal is usually directly proportional to glomerular filtration rate

(GFR). AKI is a common comorbidity in the ICU population, occurring in 1% to 25%

of patients, leading directly to reduced medication elimination.

17 Other factors may

increase the GFR in ICU patients, including trauma, burns, and use of vasopressors.

Renal function assessment is critical to appropriately dose adjusting renally

eliminated medications and proves to be especially difficult in the ICU population.

The serum creatinine measurement often lags behind actual GFR, because there exist

changes in creatinine production and altered tubular secretion. In addition, most

estimates of renal function, including the Cockcroft-Gault (CG) equation and the

Modified Diet in Renal Disease (MDRD) equation, were validated only in patients

with stable renal function.

31,32 Attempting to apply these equations to a patient with

fluctuating serum creatinine measurements will result in inaccurate estimations of

renal clearance.

In addition to renal function, there exist other modalities that contribute to drug

elimination in specific ICU populations. These include CRRT and ECMO. While a

detailed description of these processes is beyond the scope of this chapter, the

clinician should remember that both may remove medications in clinically relevant

quantities.

It is also important that the pharmacist consider not only the elimination of the

parent compound but the presence active/toxic metabolites that require renal

elimination. Examples of medications with clinically significant toxic metabolites are

nitroprusside and meperidine.

33,34 Renal dysfunction may lead to accumulation of

toxic metabolites, causing patient harm. Common medications given in the ICU with

active metabolites are midazolam and diazepam. These active metabolites may

accumulate in renal insufficiency and cause exaggerated/prolonged

sedation/delirium.

35,36

CASE 56-3, QUESTION 8: How should elimination alterations be managed in J.K.?

Estimation of renal function is critical to appropriately dosing many medications in

the ICU. As above, using the usual process of calculating renal function is often

inaccurate, and typical equations (CG/MDRD) should only be used in patients with

stable creatinine values. In patients with unstable creatinine values, consideration

should be given to calculating creatinine clearance using a 24-hour urine collection.

Other data points should also be considered when determining an appropriate dose in

critical illness and include urine output, trends in serum creatinine, and the specific

medication to be dosed. For J.K., this would mean frequent monitoring of

Vancomycin serum concentrations, anti-Xa monitoring for enoxaparin, and daily

assessment of creatinine and urine output trends. Additionally, medications with

active metabolites requiring renal elimination (midazolam) should be avoided if

possible.

Pain, Agitation, and Delirium in the ICU

Pain, agitation, and delirium commonly occur in critically ill patients for a variety of

reasons. Invasive interventions such as intubation and mechanical ventilation, acute

and preexisting disease states, and surgery are just a few of the common causes of

pain in critically ill patients.

37 Patients may become agitated and develop delirium

because of untreated or inadequately treated pain or because of many other reasons,

including drug abuse or withdrawal, adverse effects of medications, sleep

deprivation, and the impact of comorbidities or severe illness.

37 Pain, agitation, and

delirium are interrelated, and it is often difficult to differentiate these conditions

based on symptoms in patients who are severely ill and often unable to communicate.

They require prompt and effective interventions because they can lead to patient

discomfort, heightened sympathomimetic activity, and negative patient outcomes.

Clinicians should judiciously balance management of pain, agitation, and delirium in

order to keep patients lucid, calm, interactive, free of pain, and cooperative with

their care.

38

CASE 56-4

QUESTION 1: J.A. is a 28-year-old male who presents to the emergency room after a severe motor vehicle

accident. He presents with hemorrhagic shock, multiple rib and leg bone fractures, and a traumatic brain injury.

He is immediately intubated and taken to the operating room for control of his bleeding and initial management

of his fractures. His past medical history is significant for opioid abuse and bipolar disorder. After the operation,

J.A. is transferred to the surgical ICU on mechanical ventilation with multiple chest tubes in place for

management of injuries he sustained in the accident.

What causes of pain does J.A. have and what complications might they cause?

p. 1210

p. 1211

Table 56-1

Common Causes of Pain in Critically Ill Patients

Injuries and Diseases Interventions and Monitoring Routine Care

Trauma Endotracheal intubation Turning

Burns Endotracheal tube for mechanical

ventilation

Suctioning of respiratory secretions

Pancreatitis Chest tube placement Physical therapy

Necrotizing fasciitis Wound care

Decubitus ulcers Surgery

Immobility Vascular access (arterial catheter)

Preexisting disease states (e.g.,

cancer, chronic back pain)

Up to 77% of patients discharged from ICUs report experiencing moderate or

severe pain during their ICU stay.

39,40 This pain occurs during rest and with activity

and is the most common memory patients have of their ICU stays.

41 Pain may occur

because of injuries or diseases, therapeutic interventions, routine ICU care, or

monitoring. Common causes of pain are listed in Table 56-1. Patients consistently

report pain as the most traumatic memory from their ICU stay.

42 During the ICU stay,

untreated pain can result in increased energy requirements, hyperglycemia, muscle

breakdown, immunosuppression, increased risk of wound infection, decreased tissue

perfusion, psychological distress, and impaired sleep. Long-term complications of

untreated pain include chronic pain syndromes, neuropathy, posttraumatic stress

disorder, and a decreased health-related quality of life.

37,43

In light of the acute and

long-lasting consequences of pain as well as the prevalence of untreated pain in

critically ill patients, it is important to diligently assess patients and utilize

appropriate analgesics when indicated.

In J.A., potential causes of pain include trauma, postoperative pain, and the

presence of an endotracheal tube and chest tubes. During his ICU stay, he may

experience pain from routine care, including turning, suctioning of respiratory

secretions, and eventually physical therapy.

CASE 56-4, QUESTION 2: How should J.A. be assessed for pain in the ICU?

Since patient-reported pain assessment is the optimal way to assess pain,

whenever possible, clinicians should ask patients to rate their pain on a scale from 0

to 10 with 0 representing no pain and 10 representing the worst pain imaginable. For

patients who cannot communicate with caregivers because of mechanical ventilation

or other limitations, clinicians should assess patients’ pain scores using validated

nonverbal pain assessment tools that utilize patients’ behaviors as indicators of pain.

The two nonverbal pain assessment tools recommended in guidelines are called the

Behavioral Pain Scale and the Critical-Care Pain Observation Tool.

37 The maximum

score on each tool is 12 and 8, respectively, with higher values indicating more

severe pain. Pain assessment should be protocolized such that it routinely occurs

throughout each day of the patient’s ICU stay. Clinicians should set the goal pain

level and utilize analgesics as needed to achieve it while considering potential

adverse effects. Generally, hemodynamic parameters such as blood pressure, heart

rate, and respiratory rate should not be used to assess pain because they can be

affected by other factors and do not correlate with self-reported pain; however,

changes in vital signs may be used as a cue to further assess patients.

37