Evidence suggests delirium may be prevented with early mobilization protocols, in

which nurses, physical therapists, and other clinicians assist critically ill patients in

getting out of bed and ambulating. Studies of these protocols have demonstrated that

they are safe and associated with significant reductions in

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delirium, hospital and ICU length of stay, and duration of mechanical ventilation

when used in critically ill patients.

87,88 No pharmacologic therapy has been shown to

prevent delirium in heterogeneous groups of critically ill patients.

37

Although haloperidol has been used historically to treat delirium in critically ill

patients, there is an absence of high-quality published literature in broad groups of

critically ill patients. Consequently, current guidelines make no recommendations

regarding the use of haloperidol for treatment of delirium. Atypical antipsychotics

may be considered to help reduce the duration of delirium; however, published

literature supporting their use is very limited.

37,89 Evidence suggests that using

dexmedetomidine instead of a benzodiazepine for management of agitation may result

in less delirium.

68,70,90

Delirium can be prevented in patients like J.A. through the use of early

mobilization protocols and minimizing risk factors for delirium such as

benzodiazepines. No pharmacologic strategy has been convincingly demonstrated to

reduce delirium, although evidence suggests that atypical antipsychotics might have

some role and could be considered.

Stress Ulcer Prophylaxis in the ICU

The development of stress ulcers in critically ill patients is a common complication

of ICU patients. Stress ulcers from critical illness began to be recognized in the

1960s when one study found that 8/150 (5%) of consecutive ICU patients were found

to have massive bleeding resulting from stress ulcers.

91 Stress ulcers usually develop

in the mucosal layer of the stomach after high stress events and can result in

ulceration and progress to clinically significant bleeding.

92 Up to 15% of patients in

the ICU will develop an overt gastrointestinal (GI) bleed if not given SUP, which

makes it a preventable complication of critical illness.

93 Despite there being a large

volume of research in this area, there lacks a consensus on the management and

prevention of stress ulcers.

Patients with serious illness or trauma can develop stress ulceration within hours

of the inciting event. There are various degrees of stress ulceration and they can

develop from hours to weeks after hospital admission. Critical illness often leads to

increased vasoconstriction, decreased cardiac output, and a pro-inflammatory state

which leads to splanchnic hypoperfusion.

94 The cause of stress ulceration in the ICU

evolves from several factors including gastric acid secretion, mucosal ischemia, and

upper intestinal reflux. This leads to lack of perfusion and oxygen delivery to

intestinal cells, resulting in mucosal damage.

CASE 56-7

QUESTION 1: A.K. is a 76-year-old male admitted to the Medical ICU for likely sepsis from a urinary

source. He was acidotic on arrival to the emergency department and intubated. He has a past medical history

of hypertension, diabetes, multiple pulmonary embolisms, several urinary tract infections, and reports drinking 10

to 12 beers/day. His home medications include metoprolol XL 100 mg daily, metformin 1,000 mg twice daily,

atorvastatin 20 mg daily, lisinopril 20 mg daily, and warfarin 7.5 mg daily. Labs on arrival are Na 131 mEq/L, K

3.2 mEq/L, BUN 33 mg/dL, Scr 2.7 mg/dL, Hct 20%, Plt 47 × 10

3

/μL, INR 5.9. What risk factors does A.K.

have that would qualify him for SUP?

Several risk factors have been identified to help determine who should get SUP.

Cook et al.

95

investigated 2,252 ICU patients and found that there were two major

risk factors for clinically important GI bleeding: (1) mechanical ventilation for more

than 48 hours (odds ratio, 15.6) and (2) coagulopathy (odds ratio, 4.3) defined as a

platelet count of <50,000 mm3

, an International Normalized Ratio of >1.5 or a partial

thromboplastin time of >2 times the control value.

95 Other risk factors that have been

identified include head injury, burn involving >35% of body surface area, partial

hepatectomy, hepatic or renal transplantation, multiple trauma with Injury Severity

Score of >16, spinal cord injury, hepatic failure, history of gastric ulceration or

bleeding during year before admission, and two or more of the following: sepsis,

length of ICU stay >1 week, occult bleeding for at least 6 days, and administration of

high dose corticosteroids (>250 mg/day of hydrocortisone or equivalent).

96 Most

clinicians will start SUP in patients who have ≥1 major risk factor. For patients who

have multiple minor risk factors or patient groups excluded from major trials (spinal

cord injury, traumatic brain injury, or thermal injury), SUP is determined by the

primary team on a case-by-case basis. A.K. has a major risk factor in that he is likely

to be intubated for at least 48 hours. For this reason, he should be started on SUP.

CASE 56-7, QUESTION 2: What medication could be initiated in A.K. to reduce his chance of developing a

stress ulcer?

The mechanisms to pharmacologically prevent against stress ulcers are to layer the

gastric lining with a protective coating, lowering the gastric pH by neutralizing

gastric acid secretions, or by preventing gastric acid secretion. The three classes of

medications used for SUP are Histamine 2-receptor antagonists (H2 blockers),

proton-pump inhibitors (PPIs), and protective barrier producing medications. A

fourth class of medication, prostaglandin analogs, have been used for SUP in the past,

but it has not been shown to be beneficial and will not be discussed in this chapter

further.

97

After deciding to start SUP, the next decision to make is what agent to use. The

two most commonly used classes of medications are H2 blockers and PPIs. H2

blockers were found to be superior to antacids and sucralfate in two different

trials.

98,99 There has been a plethora of research comparing PPIs to H2 blockers, but

there still lacks a consensus on what agent to use based on conflicting data. A recent

meta-analysis in over 35,000 ICU patients showed H2 blockers had a lower risk of

GI hemorrhage compared to PPIs (6% vs. 2%; adjusted OR, 2.24; 95% CI, 1.81–

2.76).

100 This differed with a previous meta-analysis of 13 randomized trials showing

reduced GI bleeding in the PPI prophylaxis group compared to the H2 blocker group

(1.3% vs. 6.6%; OR, 0.30; 95% CI, 0.17–0.54).

101 A meta-analysis of 14 trials and

1,720 patients found that PPIs reduced clinically important upper gastrointestinal

bleeding and overt upper gastrointestinal bleeding compared to H2 blockers.

102

Common agents used for SUP are provided in Table 56-4.

An area of debate is whether a patient who is receiving full caloric

supplementation through tube feeds requires pharmacologic SUP. Enteral nutrition

has been shown to increase gastric pH to >3.5 more often than H2 blockers or PPIs.

103

Animal models have shown a protective benefit of alimentation on the gastric mucosa

from stress-related damage. The practice of whether to discontinue pharmacologic

SUP if enteral nutrition has been started varies among different institutions.

CASE 56-7, QUESTION 3: Are there any adverse effects associated with placing A.K. on SUP?

While pharmacologic SUP has shown to decrease bleeding events, it appears this

does not come without risk. Gastric acid plays an important part in sterilizing the

upper gastrointestinal tract, and alterations of physiologic pH have shown adverse

effects. The higher pH level allows increased colonization of potentially pathogenic

bacteria in the gastrointestinal tract.

After the implementation of SUP as a standard of care in ICUs, several studies and

meta-analyses identified an increased risk of nosocomial pneumonia and C. difficile

infections in patients receiving H2 blockers or PPIs. The increased pH levels as a

result of these medications have been proposed as a mechanism of action. Available

data are conflicting on the incidence of nosocomial pneumonia among the agents that

alter gastric pH. Two studies showed an increased risk for H2 blockers compared to

those who did not receive acid-suppressive therapy or sucralfate.

99,104 One metaanalysis showed no difference on the incidence of nosocomial pneumonia when

comparing PPIs to H2 blockers.

101 A recent study showed that PPIs had a higher

incidence of pneumonia compared to H2 blockers.

100 Both PPIs and H2 blockers have

been associated with an increased risk of C. difficile infection.

105 Most of these

studies are observational and did not control for comorbidities, so there is still much

debate in the critical care community.

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Table 56-4

Common Agents Used for Stress Ulcer Prophylaxis

Agent

Trade

Name Adult Dosing Routes Generic Available

Proton Pump Inhibitors

Dexlansoprazole

a Dexilant 30 or 60 mg Oral No

Esomeprazole

a Nexium 20–40 mg once daily ≥1 hour prior to a

meal

Oral, IV Yes

Lansoprazole

a Prevacid 15 or 30 mg once daily before a meal Oral Yes

Omeprazole

a Prilosec 20 or 40 mg once daily on an empty

stomach ≥1 hour before a meal

Oral, IV Yes

Pantoprazole

a Protonix 40 mg once daily (administer suspension 30

minute prior to a meal)

Oral, IV Yes

Robeprazole

a Aciphex 20–60 mg once daily (administer capsule 30

minutes prior to a meal; if capsule is opened

and dispersed on food, administer within 15

minutes of preparation)

Oral Yes

Histamine H2 Antagonists

Famotidine

a Pepcid 20 mg twice daily (20 mg daily for CrCl <30

mL/minute)

Oral, IV Yes

Nizatidine

a Axid 150–300 mg daily (150 mg/day for CrCl

20–50 mL/minute; 150 mg every other day

for CrCl <20 mL/minute

Oral Yes

Ranitidine

a Zantac 150 mg twice daily (150 mg once daily if

CrCl <50 mL/minute)

Oral, IV Yes

Gastric-Coating Agents

Sucralfate

a Carafate 1 g 4 times daily Oral Yes

aOff label indication for stress ulcer prophylaxis.

Source: Facts & Comparisons eAnswers. http://online.factsandcomparisons.com/MonoDisp.aspx?

monoid=fandc-hcp14911&book=DFC. Accessed September 28, 2015.

While sucralfate does not alter gastric pH, it can interfere with the absorption of

many medications including ciprofloxacin, phenytoin, digoxin, and levothyroxine. To

help prevent this, sucralfate should be given 2 hours after these medications.

Sucralfate has been shown to bind to tube feeds and cause bezoars and cannot be

given through duodenal or jejunostomy feeding tubes. There are several options of

SUP for A.K. A PPI or H 2 blocker would be the best choice. Since he is intubated

and does not have a feeding tube yet, an IV H2 blocker such as famotidine (renally

dosed) or IV PPI such as pantoprazole would be appropriate.

Glycemic Control in ICU Patients

Critically ill patients may develop hyperglycemia for a variety of reasons, including

acute illness, preexisting disease states, and the effects of medications. Glycemic

goals and treatments differ for patients managed in the ICU as compared to those

treated in other settings, including patients receiving chronic therapy for diabetes as

outpatients.

CASE 56-8

QUESTION 1: D.M. is a 74-year-old female admitted to the medical ICU for pneumonia and a COPD

exacerbation. Her past medical history includes hypertension, hyperlipidemia, and COPD. On the first day of

her ICU stay, she decompensates and develops respiratory failure requiring intubation. Among other laboratory

abnormalities, her blood glucose concentration is 212 mg/dL. How should clinicians manage D.M.’s

hyperglycemia?

A variety of biochemical mediators, such as cortisol, glucagon, catecholamines,

and growth factor, may rise in critical illness and contribute to hyperglycemia by

increasing glycogenolysis and decreasing gluconeogenesis.

106

In addition to the

effects of critical illness, inadequately treated diabetes, adverse effects of drugs like

corticosteroids, and exposure to caloric loads from nutritional regimens or dextrose

used as a base for intravenous solutions can contribute to hyperglycemia. Although

studies suggest that hyperglycemia of critical illness is associated with poor

outcomes, it is not clear whether hyperglycemia leads to worsened outcomes or if it

is simply an indicator of disease severity.

107–109

In addition to the magnitude of

hyperglycemia, glycemic variability has also been associated with negative

outcomes.

110

The optimal blood glucose range for critically ill patients has not been definitely

established.

111 Uncontrolled hyperglycemia has the potential to cause severe effects.

Single-center studies of surgical and medical ICU patients treated with intensive

insulin therapy to achieve blood glucose concentrations between 80 and 110 mg/dL

initially suggested improved outcomes, but these findings have not been replicated in

subsequent trials.

112,113

In fact, some studies have suggested that aggressive insulin

therapy may increase mortality as compared to liberal blood glucose control

typically targeting 140 to 180 mg/dL.

114–117

It has been suggested

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p. 1217

that the higher rates of hypoglycemia observed in patients receiving intensive

insulin may increase mortality by leading to neurologic complications. On the basis

of these findings, most clinicians attempt to maintain patients’ blood glucose

concentrations between 140 and 180 mg/dL. Since parenteral administration of

insulin achieves more rapid and reliable results than oral therapy, patients are

typically managed with subcutaneous insulin or intravenous insulin infusions while in

the ICU. Subcutaneous regimens typically include as-needed sliding scale insulin

involving rapid or short-acting formulations. Scheduled long-acting insulin may be

combined with sliding scales in some patients; however, clinicians should cautiously

dose insulin in order to avoid hypoglycemia. Some patients with significant insulin

needs may benefit from a continuous intravenous infusion of regular insulin that is

carefully titrated to the blood glucose goal.

Since D.M.’s blood glucose exceeds 180 mg/dL, clinicians should attempt to

achieve better glycemic control. First, dextrose-containing fluids should be

minimized, and any enteral nutrition she is receiving should be evaluated.

Medications, like steroids, that might increase her blood glucose concentrations

should be assessed and minimized as possible. If her blood glucose remains high

after these measures, it would be appropriate to initially consider sliding scale

insulin with regular insulin.

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