Sedative agents may be utilized in some patients who remain agitated
after reversible causes of agitation are thoroughly addressed. Propofol
and dexmedetomidine are recommended first-line sedatives in most
patients and should be titrated to achieve light sedation.
Clinicians can reduce the incidence of delirium by minimizing patients’
exposure to risk factors for delirium and by implementing early
mobilization protocols. Limited evidence suggests atypical antipsychotics
STRESS ULCER PROPHYLAXIS IN THE INTENSIVE CARE
Stress-related mucosal damage can lead to occult gastrointestinal
bleeding in high-risk critically ill patients. All ICU high-risk patients
should be evaluated to determine the appropriateness of pharmacologic
GLYCEMIC CONTROL IN THE INTENSIVE CARE UNIT
Both hypoglycemia and hyperglycemia result in negative outcomes for
critically ill patients. Generally, clinicians should target a blood glucose
<180 mg/dL utilizing insulin to manage hyperglycemia.
HOME MEDICATIONS IN THE INTENSIVE CARE
The management of home medications in an intensive care unit (ICU) can be a very
challenging aspect of care for the medical team. Medication reconciliation has
become an increased priority for hospitals, and pharmacists play a vital role. One
study found that 36% of patients admitted to the hospital had at least one medication
error, and 85% originated from the patient’s medication history.
method of obtaining a home medication list is through information obtained in a
patient interview. However, this can be difficult in an ICU because of the fact that
many patients are intubated, sedated, delirious, and/or unable to participate in a
patient interview. Thus, other methods are required, including interviewing family or
friends, calling retail pharmacies, locating outside medical records, or looking at
previous hospital admissions. Medication reconciliation was shown to decrease
discharge medication errors from 57% to 33% on a medical unit and from 80% to
2 The importance of restarting home medications in the ICU
varies among different agents and medication classes. Multiple types of adult ICUs
exist in the United States, including medical, surgical, burn, and neurosurgical. This
section will limit discussion to surgical and nonsurgical ICUs and the role of home
medications for common situations in these ICUs.
ICU patients can be very complex by definition, and it can be difficult to ensure all
important aspects of critical care are addressed daily. To enhance patient care and
safety, the medical field has started to incorporate an effective tool borrowed from
the airline industry: the checklist. One of the most widely used ICU checklists
worldwide is FAST HUG, which stands for Feeding, Analgesia, Sedation,
Thromboembolic prophylaxis, Head of bed elevation, stress Ulcer prophylaxis, and
3 These are issues that should be addressed daily because of their
impact on morbidity, mortality, and length of ICU stay. Clinical pharmacists working
in an ICU have the option to use a personal checklist or other available checklists
including a modified version of FAST HUG, FASTHUG-MAIDENS. This acronym
stands for Feeding, Analgesia, Sedation, Thromboembolic prophylaxis, Hypoactive
or Hyperactive delirium, Medication reconciliation, Antibiotics, Indications for
medications, drug Dosing, Electrolytes, No drug interactions, allergies, duplications,
or side effects, and Stop dates (of medications).
4 These are checklists that could be
used in any ICU; however, each pharmacist needs to find what works best for them to
ensure optimal medical care for their service and patients.
QUESTION 1: S.M. is a 62-year-old male who comes to the ICU with an upper GI bleed. He reports a 2-
/L, INR 5.2, Na 128 mEq/L, K 3.1 mEq/L, SCr 1.9 mg/dL. His current home medications are
brought to the ICU. Which of his home medications should be held after he is admitted to the ICU?
For the nonsurgical ICU patient, the indication for admission is a major determinant
in what medications can be restarted. Often Medical ICU patients come in with
hemodynamic instability, reduced left ventricular ejection fraction, and/or alterations
in renal or hepatic function, which significantly alter baseline pharmacokinetics.
These patients must be evaluated on a case-by-case basis to determine if home
medications should be restarted. Patients are admitted to the ICU because they need
frequent monitoring and are in constant need of reevaluation. The medical team must
consider that withdrawal can manifest from discontinuation of chronic home
medications (e.g., β-blockers, baclofen) or from discontinuation of other illicit
medications (e.g., heroin, cocaine, methamphetamine). Obtaining thorough patient
history helps prevent withdrawal; however, because of the frequent inability to
obtain a medical history the ICU team must determine if withdrawal treatment is
appropriate based on vital signs and physical exam. This section will discuss home
medications and how they should be addressed in common scenarios encountered in
Hemodynamic instability is one of the most common issues encountered in ICUs.
Common causes of hypotension include hypovolemia, heart failure, and infection.
Knowing the patient’s baseline blood pressure can help determine the seriousness of
the hypotension. A drop in baseline blood pressure can result in hypoperfusion and in
the development of shock. If a patient cannot maintain adequate blood pressure,
vasoactive medications (e.g., norepinephrine, epinephrine, phenylephrine,
vasopressin) need to be initiated. Common indicators of lack of perfusion are
monitored in the ICU, including cool skin, metabolic acidosis, change in mental
status, elevated serum lactate levels, and reduced urine output. If a patient comes to
the ICU with hypotension and signs of hypoperfusion, home blood pressure
medications of all classes are held until there is a resolution of the underlying cause
of the hypotension and hypoperfusion. Blood pressure medications should be slowly
added back on at reduced doses to the hospital medication regimen.
Severe cases of hypertension in the ICU must be dealt with urgently to prevent
stroke and/or end organ damage. Common causes of hypertension in the ICU are
missed hemodialysis, medication noncompliance, volume overload, and pain. The
differential of high blood pressure is extensive, so determining the cause of the
elevated blood pressure will help determine the direction of treatment. Hypertensive
emergencies, defined as a large elevation of SBP or DBP (>180 or >120 mm Hg,
respectively), need to be treated immediately because of possible complications,
including cerebral infarction, intracranial hemorrhage, aortic dissection, and renal
Intravenous medications are often required to control blood pressure in the
emergency room or during the early hours of ICU admission. Common medications
used are nicardipine, diltiazem, diltiazem, hydralazine, esmolol, labetalol, and
enalaprilat. These medications work immediately and can be titrated to lower blood
pressures to desired targets. Intravenous medications are used in the short term until
chronic antihypertensives can be administered and titrated. Restarting home blood
pressure medications in the ICU is important unless there is a contraindication (i.e.,
new renal dysfunction) or the patient now has a new condition that warrants a change
in medication class (i.e., β-blockers and ACEI for new heart failure). This topic is
discussed further in Chapter 16, Hypertensive Crisis.
Since renal function is often unpredictable and unstable in the ICU, many classes
of medications are withheld in the ICU. Renal function can change very quickly in the
ICU and classic indicators of renal function such as SCr, which is used in creatinine
clearance equations like Cockcroft and Gault and the Simplified
4-variable MDRD equation, are delayed in acute renal failure or falsely low in the
elderly. For this reason, drugs that can be monitored using therapeutic drug
monitoring (e.g., vancomycin) should be monitored frequently. Other indicators
including urine output, blood pressure, and volume status should be factored into
determining an appropriate dosing for medications that are eliminated through the
kidney. All medications administered in the hospital setting should be monitored
daily and adjusted based on renal function.
Diabetes medications can cause complications in the ICU. Metformin can cause a
metabolic acidosis if given to patients with renal dysfunction and is withheld in most
ICU patients. Sulfonylureas are also withheld because of the frequent changes in diet
in the ICU, which can result in hypoglycemia. As a substitute to prevent
hyperglycemia, most patients are converted to a short-acting sliding scale insulin
regimen, which accounts for poor oral intake or the withholding of nutrition at certain
points in an ICU stay. Sliding scale insulin regimens give varying doses of insulin
based on a patient’s most recent glucose level. Basal insulin can be considered for
known diabetics, who are not receiving adequate control from sliding scale insulin.
Pain and medications used to treat pain are discussed in various chapters in this
textbook (see Chapter 55, Pain and Its Management for more details). For a new ICU
patient, knowing a patient’s home medication pain regimen can be very helpful and
often vital to good patient care. A patient on chronic opioids should be continued on
a pain regimen, which includes opioids unless there is a contraindication to do so.
Often the regimen must be modified to account for renal function and route of
administration. For example, many of the long-acting medications cannot be crushed
and put down a feeding tube, and a patient with renal dysfunction may need a lower
dose or switch to an opioid that is not cleared through the kidney.
The dynamic nature of the ICU can make anticoagulation a very challenging issue
in the ICU. Unless the patient will likely be in the ICU for a short period of time,
vitamin K antagonists (e.g., warfarin) or the new oral anticoagulants (e.g.,
dabigatran, rivaroxaban, apixiban) will often be held in the ICU to prevent
complications surrounding procedures and the altered pharmacokinetics in ICU
patients. A detailed patient history is essential to determine the indication for
anticoagulation. This will help the medical team determine if full anticoagulation
should be continued. The discussion to continue anticoagulation will be determined
on a case-by-case basis after weighing the risks and benefits of anticoagulation and
often discussing the issue with consult services such as cardiology, vascular surgery,
and the primary care provider. If full anticoagulation is required in the ICU,
unfractionated heparin (UFH) may be the best option, because it can be stopped and
reversed if needed. Almost all patients in the ICU are at increased risk for a venous
thromboembolism (VTE) because of lack of mobility, elderly age (≥70 years), heart
failure, respiratory failure, previous VTE, acute infection, obesity, and/or ongoing
hormonal treatment. Because of increased risk for VTE, patients should be placed on
anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH),
low-dose unfractionated heparin (LDUH) BID, LDUH TID, or fondaparinux unless a
One of the biggest complications for a pharmacist in an ICU patient is finding an
ideal medication regimen for a patient who cannot take any medications by mouth or
that have a feeding tube. For patients who have a feeding tube, medications can be
given down the feeding tube in certain circumstances. The pharmacist must determine
which home medications can be crushed or come in a solution or liquid form. Often
long-acting medications must be converted to immediate release or the medication
must be changed so it can be crushed to go down a feeding tube. The ISMP has
created a resource for medications that cannot be crushed:
http://www.ismp.org/tools/donotcrush.pdf. Certain patients in the ICU will be
ordered to not receive anything by mouth including medications. It should always be
clarified with the medical teams whether an NPO or “nothing by mouth” order
includes medications. Many circumstances allow for the patient to receive oral
medications on an NPO order. If medications cannot be given by mouth or there are
concerns about absorption in the GI tract, the ICU teams will request that medications
be converted from oral to intravenous form. While some medications have
intravenous formulations, many do not. A clinical pharmacist can assist with dosage
conversions, frequency of administration, and alternative options for medications that
do not have intravenous equivalents.
Because of the fact that S.M. is actively bleeding, all anticoagulant and antiplatelet
medications should be held. S.M. should have his aspirin, clopidogrel, and warfarin
held. Additionally, because he has an elevated INR, he should receive vitamin K to
reverse the effect of warfarin. Once his bleeding has stopped the team will have to
determine which medications can be restarted and at what time the medications can
QUESTION 1: D.H. is a 68-year-old with a PMH of CAD (drug-eluting stent placed 11 months ago),
surgery team wants your advice on what medications should be continued throughout surgery and what
medications should be stopped.
Consequences of stopping a chronic medication before, or failing to restart that
medication after surgery, can be significant. For example, abrupt discontinuation of a
period. The American College of Cardiology/American Heart Association
(ACC/AHA) recommends continuation of β-blocker therapy in patients undergoing
surgery who are receiving a β-blocker for treatment of conditions with ACC/AHA
Class I guideline indications for the drugs (e.g., angina, symptomatic arrhythmia,
7 Angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin receptor blockers (ARBs) increase the risk of hypotension after induction
of anesthesia when these agents are not withheld 24 hours before surgery.
the ACEI before surgery, however, can result in adverse postoperative effects, such
as rebound hypertension and atrial fibrillation. Therefore, the decision to continue or
stop the ACEI or ARB before surgery is made on an individual basis, taking into
Preoperative withdrawal of a statin in a patient undergoing major vascular surgery,
for example, increases the risk of myocardial infarction and cardiovascular death
9 Diuretics are typically held the morning of surgery to minimize the risk
of hypovolemia and electrolyte abnormalities.
Oral antidiabetic agents and noninsulin injectable agents are typically held the
morning of surgery and not restarted until normal food intake resumes. In patients
with renal dysfunction and those who may receive IV contrast media, metformin
be discontinued 24 to 48 hours before surgery to reduce the risk of perioperative
lactic acidosis. For patients on insulin therapy, a portion of the morning dose of
intermediate- or long-acting insulin is generally administered on the day of surgery
after a check of the patient’s blood glucose. Close blood glucose monitoring guides
subsequent insulin doses to avoid hypoglycemia.
Antiepileptics, antipsychotics, benzodiazepines, lithium, selective serotonin and
norepinephrine reuptake inhibitors (SSRIs and SNRIs), tricyclic antidepressants
(TCAs), and carbidopa/levodopa have a greater risk for withdrawal or disease
decompensation than for perioperative complications. These medications should
therefore be continued up to and including the morning of surgery.
Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit
platelet aggregation and are often stopped 1 to 3 days before surgery, depending on
the duration of action of the drug. Celecoxib does not affect platelet aggregation and
may be continued up to and including the day of surgery. Nonselective NSAIDs and
celecoxib should be held if there is a concern for impaired renal function during or
For patients on anticoagulant or antiplatelet therapy, the risks for
thromboembolism must be balanced with the risk for bleeding during and after the
surgical procedure. For patients on warfarin, who are at high risk for perioperative
thromboembolism, bridging anticoagulation therapy with IV heparin or LMWH
before surgery is recommended. Warfarin may not need to be discontinued if the
patient is undergoing minor surgery (e.g., certain ophthalmic, dental, or dermatologic
procedures). For patients who have had coronary stents recently placed,
discontinuing antiplatelet therapy prematurely can significantly increase the risk of
perioperative stent thrombosis and have catastrophic consequences.
ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management
of Patients Undergoing Noncardiac Surgery: Executive Summary recommends that
patients undergoing urgent noncardiac surgery during the first 4 to 6 weeks after
receiving a bare metal stent or drug-eluding stent implantation should continue dual
antiplatelet therapy (aspirin plus P2Y12 platelet receptor-inhibitor) unless the
relative risk of bleeding outweighs the benefit of the prevention of stent thrombosis.
They also recommend that the management of perioperative antiplatelet therapy be
determined by a consensus of the surgeon, anesthesiologist, cardiologist, and patient,
who should weigh the relative risk of bleeding with those of prevention of stent
Traditionally, it was thought that patients who have been taking long-term
corticosteroid therapy before surgery will experience adrenal insufficiency in the
perioperative period and should receive a supplemental stress-dose of
hydrocortisone or methylprednisolone during and up to 2 to 3 days after surgery.
recent review of the literature, however, found that patients on long-term
corticosteroid therapy only require continuation of their normal daily dose of
corticosteroid in the perioperative period. These patients are generally able to
increase their endogenous adrenal function above their baseline corticosteroid dose
to meet the increased demand from surgery; a supplemental stress dose of
corticosteroid is not necessary. These patients can be closely monitored, and if
hypotension develops, a stress dose of a corticosteroid should be administered at that
time. Patients who have a known dysfunctional hypothalamic–pituitary–adrenal axis
deficiency (e.g., Addison’s disease), on the other hand, will require supplemental
corticosteroid doses in the perioperative period as they cannot increase endogenous
cortisol production to meet the increased demand from surgery.
Opioid-dependent chronic pain patients who undergo surgery often experience
more severe acute pain after surgery. These patients should receive either their
chronic opioid medication or a comparable dose of an IV opioid the morning of
(e.g., acetaminophen, peripheral nerve blockade, epidural analgesia) for
perioperative analgesia should be maximized in a postoperative patient.
since his stent is over 6 weeks old, his clopidogrel should be held 7 days prior to
surgery. His warfarin should also be held 5 to 7 days prior to surgery and likely does
not need bridging with a UFH or LWMH. His aspirin can be continued through
PHARMACOKINETIC ALTERATIONS IN THE ICU
Pharmacokinetics in the Critically Ill
The dynamic nature of critical illness may cause drastic changes in the
pharmacokinetic profile of many medications. Before describing these changes, it is
important to first consider where the majority of available pharmacokinetic data is
As a medication makes its way through the discovery process, pharmacokinetic
data are obtained in phase I trials and in non-critically ill patients. Phase 1 trials in
humans are most commonly done in healthy subjects in highly controlled
environments. When pharmacokinetic data are obtained in phase II/III trials,
critically ill patients are excluded. As a result, errors may arise in assuming that
patients with the disease of interest, and more importantly, critically ill patients have
similar pharmacokinetic parameters. While available pharmacokinetic data should
always be consulted in formulating a therapeutic regimen, the pharmacist should be
attuned to the limitations inherent in the data.
ICU course, J.K. develops acute kidney injury (AKI) secondary to sepsis/hypoperfusion with his serum
What are potential abnormalities of medication absorption in J.K.?
With the exception of intravenous administration, all medications must undergo
absorption in order to reach the systemic circulation. Bioavailability (F) is defined
as the percentage of the administered dose that reaches the systemic circulation.
Gut function may be altered in J.K. for a variety of reasons including delayed
gastric emptying, ischemic bowel, inflammation, and coadministration of interacting
substances. Each of these issues may lead to significant delays and/or decreases in
the amount of orally/enterally administered medication absorption.
Delayed gastric emptying is a common occurrence in the ICU patient population,
occurring in 40% to 60% of patients.
It may be caused by many factors including
postoperative ileus, trauma, head injury, sepsis, burns, or opioid use.
gastric emptying would be evident in J.K. if he was manifesting high gastric residual
volumes or enteral feeding intolerance. Because most
medications are absorbed in the small intestine, delayed emptying would most
likely affect the rate of absorption, slowing the onset of action of medications in J.K.
Ischemic bowel may also cause J.K. to have alterations in his ability to absorb
oral/enteral medications depending on what portion and how much of the bowel is
affected. In J.K., ischemic bowel may be caused by vasopressor use and/or the
presence of a shock state. Because drug absorption occurs primarily in the small
bowel, impaired blood flow to this area would be more likely to decrease the extent
Acute gut inflammation may increase the absorption of certain medications in J.K.
With the development of severe clostridium colitis on day 6, J.K. may experience
increased oral absorption of oral vancomycin. Under normal patient conditions, oral
vancomycin is not orally absorbed because of the ionization and large size of the
molecule. There have been several reports of therapeutic plasma levels of
vancomycin being achieved with oral treatment of severe C. difficile infections.
The postulated mechanism is the severe inflammation in the colon allowing for the
passage of larger, charged molecules into the bloodstream.
Oral medications are not the only route that may have altered absorption in the
ICU. Subcutaneous absorption has also been shown to be remarkably altered in ICU
patients, particularly those on vasoconstrictive (vasopressor) therapy. It is postulated
that vasopressor treatment causes a decrease in subcutaneous tissue perfusion,
resulting in impaired absorption of subcutaneously administered medications. Studies
have shown that patients on LMWH therapy also receiving vasoconstrictive agents
have markedly reduced peak and total anti-Xa activity when compared to other
CASE 56-3, QUESTION 2: How should absorption issues in J.K. be managed?
Generally speaking, when there is a question of gut function in the intensive care
unit, intravenous formulations are preferred when available. In cases where a given
medication would produce an objective response (antihypertensive, hypoglycemic
agents), enteral therapy may be attempted to assess patients’ response. As above, the
pharmacist should be attuned to the specific pharmacodynamic response of a given
medication to assess therapeutic response with oral/enteral dosing.
In the case of J.K., consideration may be given to monitoring anti-factor Xa levels
for enoxaparin, while he remains on vasopressor therapy. Trough levels of <0.1
IU/mL have been associated with increased risk of the development of DVT.
Additionally, if J.K. is deemed suitable for enteral medication therapy, his proton
pump inhibitor therapy could be changed to a dissolvable (solu-tab) formulation,
which generally is preferred to crushing and dissolving oral tablets to prevent
obstructing tubes and for ease of administration. Consideration could also be given to
monitor serum vancomycin concentrations more aggressively, because J.K. may be at
risk for significant vancomycin absorption given his severe C. difficile infection
while also receiving systemic vancomycin therapy.
CASE 56-3, QUESTION 3: What are the potential changes in the distribution of a medication in J.K.?
The distribution of a medication is defined briefly as where the drug goes once it
is absorbed into the bloodstream. The extent of distribution of a medication is
dependent on both physiochemical drug properties and patient-specific factors. The
physiochemical properties of a drug that determine how extensively it distributes to
tissues include lipophilicity and protein binding, with high lipophilicity leading to
extensive tissue distribution, and lower protein binding contributing to more
extensive distribution. Patient-specific factors that determine the distribution of a
medication include weight, volume status, and vascular permeability.
J.K. has a multitude of factors that may affect the distribution of hydrophilic (low
decreased plasma concentrations of hydrophilic medications, leading to potentially
subtherapeutic concentrations.
Patients who have sepsis may possess several factors that would lead to a
decreased plasma concentration of hydrophilic medications. These include the
presence of capillary leak (third spacing), causing intravascular fluid to distribute to
tissues, the administration of large volumes of intravenous crystalloid medications,
and reduced tissue perfusion. This is particularly well-documented with antibiotic
therapy in this patient population. Most infections occur in the interstitial fluid of
tissues, thus interstitial antibiotic concentrations would be most relevant to determine
efficacy. Studies have shown that the interstitial fluid concentration and subcutaneous
concentration of antibiotics is 5 to 10 times lower and 1 to 5 times lower
respectively, in septic patients as compared to normal controls.
Septic ICU patients may also have drastic changes in plasma protein (albumin)
concentration because of reduced liver production and third spacing of albumin into
tissue sites. Low plasma protein will cause an increase in the unbound fraction of
drug, increasing distribution to tissues. Unfortunately, this increased distribution is
more than offset by the increase in fluid concentration (secondary to capillary leak
and volume administration) of the interstitial tissues, causing low concentrations of
antibiotics in interstitial fluid.
Understanding that the distribution of hydrophilic antibiotics in J.K.
(piperacillin/tazobactam, vancomycin) is likely increased in J.K., several strategies
can be employed to offset these changes. Interventions include giving more frequent
doses or continuous infusions with β-lactam therapy, and using large initial doses
(30–40 mg/kg/day) of vancomycin in conjunction with targeting trough levels of 15 to
CASE 56-3, QUESTION 4: What are the potential alterations in metabolism in J.K.?
Drug metabolism can occur in a variety of body tissues, including the kidneys, GI
tract, lung, and liver. The liver is by far and away the predominant metabolizing
organ and is the focus of this section. ICU patients may have alterations in hepatic
enzyme activity, liver blood flow, and protein binding, all of which may influence the
rate at which hepatically metabolized medications are biotransformed.
Liver metabolism is broken into two major categories, phase I and phase II
metabolism, both of which transform drugs into more polar substances that are more
readily excreted. Phase I metabolism refers to the cytochrome p450 enzyme system
that works through oxidation, reduction, and hydrolysis. Phase II metabolism, in
contrast, adds large polar molecules to the parent compound, including
glucuronidation, sulfation, and acetylation.
There may be significant factors that alter phase I metabolism in J.K. These
include kidney injury, inflammation, and hypothermia.
Renal dysfunction can reduce phase I metabolism through reduced hepatic cell
uptake of medications and reduced biliary excretion.
27,28 The inflammatory response
secondary to trauma has shown variable effects on enzymatic activity, with reduction
in CYP 450 3A4, 2C19, and 2E1, with increased 2C9 activity.
Therapeutic hypothermia has been well-documented to reduce cytochrome activity
across all isoenzyme families. This is especially well-documented with medications
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