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20 Nutrition in the Surgical ICU Patient
243
No nutrition support
(re-evaluate daily)
Start PN early if:
Severe malnutrition or high
nutrition risk
Start PN post 7 days if:
Well-nourished
Is patient hemodynamically stable?
No
GI tract now functioning
Patient tolerating
EN>60 % of goal d/c PN
Yes
Yes
Yes
Are any of the following present?
Bowel obstruction/discontinuity
High output fistula
Non-contained anastomotic leak
High risk of bowel ischemia
No
Start/Resume EN if not:
Expected to start oral diet in 24 hours
on comfort care only
Gastric Feeding
Absence of ileus
Short-gut
Vasopressor use
Small Bowel feeding
High NGT output (ileus)
History of GERD
Severe acute pancreatitis
Supine/Prone position
Intolerance to gastric feeding
Start/Continue
supplemental PN
Fig. 20.1 Determining the route of nutrition support
Route of Nutrition
The benefi t of EN in the ICU patient goes beyond the provision of macro- and micronutrients. Early EN (within 24–48 h
of surgical ICU admission) supports both the functional and
structural integrity of the gut. The use of EN decreases the
risk of infection and late multi-organ failure by supporting
the gut-associated lymphoid tissue and subsequently the
mucosal-associated lymphoid tissue [ 26 , 27 ]. Those patients
at highest nutrition risk have increased gut permeability, and
thus, EN is more likely to have a positive impact on infection, organ failure, and length of stay [ 28 , 29 ].
In the past, there has been concern that the use of PN would
further increase the risk of infection in those patients with a
nonfunctioning GI tract. However, in the age of glycemic control and standard protocol medical management, the differences in infectious complications between the use of early EN
or early PN are becoming narrower [
sis of ICU patients that included >60 % of surgical patients,
early (with 48 h of admission) PN versus no nutrition or early
EN showed no difference in infectious complications or
60-day mortality, suggesting safe provision of PN [
However, the long-term effect of early PN in postoperative
30 – 32 ]. In a meta-analy-
32 ].
Yes
EN<60 % of goal after 7
patients has yet to be studied on a large scale. An algorithm
outlining the decision process in determining the preferred
route in surgical ICU patients is presented in Fig. 20.1 .
Enteral Nutrition
In the surgical ICU population when feasible, early (24–48 h
post admission to the surgical ICU) EN remains the fi rst
choice over parenteral nutrition (PN) and delayed feeding. In
2009, Lewis et al. performed a meta-analysis of early aggressive use of EN involving 13 trials and 1,173 patients that
showed mortality was reduced from 6.8 % to 2.4 %, with use
of early EN postoperatively versus STD (RR = 0.42, 95 % CI
0.18–0.96, p = 0.030) [ 29 ]. A subsequent meta-analysis by
Osland included 15 studies and 1,238 postoperative patients
and demonstrated complications were reduced in the group
receiving early EN (RR 0.53, 95 % CI 0.33–0.86); however,
mortality and LOS were not signifi cantly different [
Based on these data, EN should be provided within
24–48 h of surgery. Clearly, in those patients with evidence
of continued obstruction, bowel discontinuity, ongoing peritonitis, and high risk of bowel ischemia, early EN would be
not be appropriate. A general approach to formulation
33 ].
244
B.E. Taylor and C.M. Coopersmith
Standard high protein
formula
Renal failure
Hemodialysis - low electrolyte,
moderate protein
continuous dialysis - Standard
high protein product
Diagnosis includes:
Trauma, GI surgery, Burn or
morbid obesity
No soluble or mixed
fiber for 1
post GI surgery
Protein Modular should
be used if needed to
meet protein goal
After 1st week - mixed fiber formula
st
week
Resistant Diarrhea
(non-infectious)
st
1
week - small peptide formula
Specialty formula
Trauma, GI
Surgery, Burn
Formula with
arginine, fish oil and
antioxidants
Morbid obesity
Hypocaloric, high
protein formula
Severe fat malabsorption or
chyle leak
Free amino acid
based, low fat
Formula
Fig. 20.2 Determining enteral nutrition (EN) formulation
selection in the surgical ICU patient is presented in Fig. 20.2 .
Noncomplicated well-nourished surgical and trauma patients
requiring a short stay in the surgical ICU who can tolerate an
oral diet should be allowed solid food as tolerated as opposed
to starting with clear liquids. Even patients having undergone gastrointestinal (GI) surgery may tolerate solid foods.
A RCT of over 400 patients post major GI surgery showed
that giving solid food on the fi rst postoperative day did not
increase morbidity or mortality [ 34 ]. Another RCT demon-
strated that postoperative nausea and complications occur
with the same frequency whether patients are advanced fi rst
to a clear liquid or solid diet [ 35 ]. In fact, early start of solid
foods may lessen risk of ileus as evidenced by passage of gas
and stool [ 34 ]. Future use of clear liquids should be primarily
based on patient preference with advancement to solid foods
as soon as possible.
Immunonutrition
Immunonutrition (IMN) components, particularly arginine,
omega-3 fatty acids, and antioxidants, have been shown to be
benefi cial in patients who have experienced trauma or major
surgery. Studies to date suggest the benefi t of IMN compared
to standard enteral formulas (intact proteins with a general
amino acid profi le and omega-6 fatty acids) in surgical ICU
patients is derived in part from the synergistic effect of fi sh
oil and arginine. A meta-analysis of 35 RCTs showed that
use of an arginine/fi sh oil-containing formula given postoperatively reduced infectious complications (RR = 0.78, 95 %
CI 0.64–0.95, p = 0.01) but not mortality compared to a stan-
dard formula [
36 ]. Similar fi ndings were noted when the
IMN and standard formulas were given perioperatively (both
prior to and following surgery) in a meta-analysis of 21
RCTs representing 2,005 patients with signifi cant reductions
in infection (OR = 0.61, 95 % CI 047–0.79, p < 0.01) [ 37 ].
Another meta-analysis of 26 RCTs in 2,496 patients undergoing open gastrointestinal surgery resulted in decreased
postoperative infections (RR = 0.64, 95 % CI 0.55, 0.74, no
p-value provided) [ 38 ]. In these trials, use of the IMN prod-
uct was generally restricted to 7–10 days.
Of the IMN components, arginine remains the most controversial and potentially the most benefi cial to trauma and
postoperative patients. The controversy lies within the use of
arginine in septic patients. There is a theoretical concern that
supplemental arginine will lead to upregulated nitric oxide
synthase (NOS) enzyme activity in a postoperative septic
patient [ 39 ]. However, this has not been proven in clinical
trials [ 40 ]. Nitric oxide (NO) is a prominent compound nec-
essary for proper cardiovascular function. NO production is
driven by both arginine availability and NOS inhibitor asymmetric dimethylarginine (ADMA), a product of protein
20 Nutrition in the Surgical ICU Patient
245
methylation [ 41 ]. ADMA inhibits NO production by com-
peting with arginine for NOS binding, and it is suggested
that the net production of NO likely depends on the
arginine:ADMA ratio [ 42 ].
A multicenter RCT of 176 septic patients compared the
use of a standard enteral formula to another containing fi sh
oil and arginine. A signifi cant reduction in mortality (28 of
87 vs. 17 of 89; p < 0.05), incidence of bacteremia (19 of 87
vs. 7 of 89; p = 0.01), and nosocomial infection (17 of 87, 5
of 89; p = 0.01) was noted [
of 10–15 were associated with the group realizing benefi t;
therefore, it is unclear how these results would translate into
patients with severe sepsis or septic shock. To date, no defi nitive answer exists for or against the use of arginine in sepsis,
and therefore, arginine should be avoided in these patients.
The potential benefi t of arginine is based on the theory
that following major surgery or injury, specialized immune
myeloid suppressor cells rapidly increase the levels of arginase 1, making the supply from endogenous arginine inadequate leading to a relative arginine defi ciency making it a
conditionally essential amino acid [ 44 ]. Arginine stimulates
release of anabolic hormones such as growth hormone, prolactin, and insulin and initiates proliferation and activation of
T-cells.
The benefi t of IMN may be affected by timing, severity of
malnutrition and nutrition risk, as well as diagnosis. A
double- blinded RCT trial in 120 patients undergoing liver
transplantation randomized to IMN or an isocaloric standard
enteral formula given pre- and postoperatively demonstrated
no signifi cant differences in total body protein, muscle function, complications, or mortality [ 45 ]. Conversely, in another
RCT of 305 malnourished (weight loss of at least 10 % body
weight or BMI <18) patients undergoing resection for pancreatic or gastric cancer, differences were noted [ 46 ]. All
patients received 2 weeks of PN preoperatively, given all
patients were not candidates for EN. Then at 12 h postoperative, 152 patients were started on a small peptide IMN product, and 153 were started on an isocaloric small peptide
product. Infectious complications were observed in 43
patients (28.3 %) in the IMN and 60 (39.2 %) in the SEN
group ( p = 0.04). Signifi cant differences were also noted in
overall morbidity (33.5 % vs. 47.1 %, p = 0.01) and mortality
(1.3 % vs. 5.9 %, p = 0.03) [ 46 ].
43 ]. However, APACHE II scores
EN Access
The majority of surgical ICU patients can be fed via the gastric route. Historically, clinical concerns regarding ileus,
aspiration, and increased risk of pneumonia with gastric
feeds in postoperative patients often led to a delay in feeding
until small bowel access could be obtained. However, a multicenter RCT found that small bowel feeding did not decrease
rates of pneumonia [
following GI surgery leading to a need for prolonged gastric
decompression. In these patients, small bowel feeding should
be considered. A team-based approach to small bowel tube
placement has been shown to lessen time to placement and
decrease risk of complications [ 48 ]. In surgical ICUs where
timely bedside placement of small bowel tubes is not an
option and patients display intolerance of gastric feeds, a
trial of slow continuous infusion and use of prokinetics
(metoclopramide or erythromycin) should be considered.
Erythromycin and metoclopramide have been associated
with undesirable effects including cardiac toxicity, tachyphylaxis, tardive dyskinesia, and QT prolongation and
should be used cautiously with monitoring and continued trials of discontinuation. Placement of a gastrostomy, jejunostomy, or gastrojejunostomy should be considered at time of
laparotomy in patients with major trauma or large GI resection in whom EN is expected to be needed for 4 weeks or
greater.
47 ]. Gastroparesis may occur in patients
Protocolized Management of EN
EN protocols addressing starting infusion rate, advancement,
fl ushes, how to handle intolerances (gastric residual volumes, diarrhea, emesis, etc.), and circumstance under which
EN should be adjusted or stopped have been shown to
increase the overall percentage of EN provided [ 49 – 52 ]. In
the surgical ICU, EN infusions are often interrupted for
return trips to the operating room and diagnostic testing.
Volume-based feeding protocols empower the nurses to
increase feeding rates to “make up” for volume lost while
EN is held [ 52 ]. An example of one such surgical ICU proto-
col was used in a pre- and post-study design and demonstrated a signifi cant increase in percent of EN goal provided
(63–89 %, p < 0.0001) [ 53 ].
EN in Complex Situations
The optimal timing and use of different EN formulations in
complex situations (new anastomosis, prolonged ileus, brain
injury, open abdomen, vasopressor therapy) must be individualized. Baseline energy and protein requirements are
determined as previously outlined. Although limited,
increasing surgical experience and RCTs have demonstrated
safety and effi cacy using EN in complex surgical
conditions.
New Anastomosis
A meta-analysis of early EN versus late EN showed no
increase in anastomotic dehiscence (RR = 0.75; 95 % CI
0.39–1.4, p = 0.39) with the direction favoring early EN sug-
246
B.E. Taylor and C.M. Coopersmith
gesting potential increased anastomotic strength with
greater collagen and fi brin deposition and fi broblast infi ltration [
33 ]. A small RCT in 2014 designed to study reduction
of postoperative ileus also commented on anastomotic leakage as a secondary outcome under the heading of “complications.” Patients were divided into early enteral (study) or
early parenteral (control) nutrition, with both groups being
allowed liquids the day after surgery with progression to a
normal diet as tolerated [ 54 ]. The ICU length of stay was
not different between the groups. Of the reported surgical
complications, there was signifi cantly less anastomotic
leakage noted in the EN group compared to the PN group
(one patient vs. nine patients, p = 0.009) suggesting EN
across a new anastomosis may not increase the risk of anastomotic breakdown [ 54 ].
Postoperative Ileus
A postoperative ileus is associated with bowel manipulation
leading to a localized, as well as a systemic, infl ammatory
response [ 55 ]. Experimentally, early feeding following sur-
gery has been shown to reduce ileus by attenuating dysmotility and preventing bowel wall edema. In intention-to-treat
analysis, a RCT of 123 patients undergoing major rectal surgery reported fi rst time to defecation was signifi cantly
shorter ( p = 0.04) in patients randomized to early EN (study
group) versus early PN (control group) [ 54 ]. Although sev-
eral other studies have questioned the need for nasogastric
decompression and delay of EN in bowel surgery patients,
further research is needed in those requiring admission to the
surgical ICU [ 56 – 59 ].
Vasopressor Support
Hemodynamic instability in critically ill patients may warrant the use of vasopressor support. Because splanchnic
blood fl ow is highly dependent on cardiac output, redistribution during hypotension and sepsis decreases blood fl ow to
the mucosal region that is highly vascularized due to the
microvilli. The absorption of nutrients and oxygen exchange
happen within the microvilli. In the absence of adequate
blood fl ow, mucosal ischemia may result. Volume resuscitation in the postoperative patient does not immediately reverse
blood fl ow to the gut. Delivery of EN increases mucosal oxygen requirements. If perfusion demand is higher than supply,
nonocclusive bowel necrosis may result. Although this is a
rare complication (<1 %), the mortality may be as high as
80 %; however, this is primarily based on case reports and
retrospective data [ 60 , 61 ]. Reported cases occur primarily in
trauma and postoperative patients fed via a post-pyloric tube
[ 62 – 67 ]. When the small bowel is hypoperfused and peristal-
sis is lessened, the stomach may act as a buffering chamber.
Experts suggest surgical ICU patients receiving low, stable
doses of vasopressors (a dose often based on clinical judgment and other signs of end-organ perfusion) may be started
on a low or trophic rate of feeding into the stomach, with
close monitoring of gastric tolerance or signs of worsening
hemodynamic instability [
advanced slowly to goal with vigilant monitoring of abdominal exam every 4–6 h.
60 ]. The feeding rate should be
Traumatic Brain Injury
Initiation of EN should be within 24–48 h of injury, and similar to other critically ill patients, practitioners should have a
low threshold for adding supplemental PN in patients with
baseline malnutrition or with EN intolerance lasting greater
than 7 days. These patients are often very catabolic with
energy expenditure ranging from 100 % to 200 % of resting
energy expenditure with the presence of other injuries.
Protein requirements are in the range of 1.5–2.5 g/kg/day
[ 68 , 69 ].
Temporary Abdominal Closure
The temporary abdominal closure technique is commonly
used following damage control laparotomy post resuscitation to avoid abdominal compartment syndrome. Although
the goal is timely fascial closure, patients may have an open
abdomen for days to weeks. A multicenter retrospective
review of 597 patients with a temporary abdominal closure
reported 39 % of the patients were provided EN prior to closure [ 70 ]. In a subgroup analysis of the 307 patients with no
bowel injury, use of EN was associated with signifi cant
reductions in time to abdominal fascial closure, pneumonia,
intra-abdominal complications, and mortality as compared
to those patients receiving no EN (all differences, p < 0.02)
[ 70 ]. Another retrospective review compared early EN
(≤4 days) with late EN (>4 days) and found earlier fascial
closure ( p < 0.02) and less fi stula formation ( p < 0.05) in the
early EN group [ 71 ]. These studies suggest if no known con-
traindication (bowel discontinuity, high-output fi stula, etc),
patients with a temporary abdominal closure can be safely
fed with EN. Energy requirements are similar as for other
surgical ICU patients. However, patients with an open
abdomen have the equivalency of a large open wound that
produces a high-protein exudate. A range of 15–30 g of
protein/L of exudate has been reported and should be
replaced with use of high-protein EN formulas or protein
supplements [ 21 – 23 ].
Parenteral Nutrition
Laparotomy with bowel manipulation combined with an
infl ammatory response leads to gut dysfunction (decreased
mucosal blood fl ow, ileus, etc.) that may be compounded by
ICU interventions (fl uid resuscitation, vasopressor use, etc.)
[ 72 ]. Continued gut disuse with PN may worsen gut dysfunc-
tion and allow the gut to become a reservoir for bacteria and
20 Nutrition in the Surgical ICU Patient
247
toxins. It has been theorized these toxic products can be aspirated or translocated late in the hospital course causing late
complications of nosocomial infections and multisystem
organ failure [ 72 ]. For these reasons, use of PN should be
reserved only in those patients with a nonfunctioning GI
tract. Once PN is started, continued efforts should be made to
initiate EN as soon as the patient’s medical status allows,
continuing “supplemental” PN until the patient is able to tolerate 60 % of their goal EN rate [
73 ].
Regardless of the ability to use the GI tract, initiating PN
in a patient who is well nourished (low nutritional risk) and
continuing PN for less than 7 days provided no further benefi t over no nutrition [ 74 ]. In contrast, patients who are
severely malnourished (high nutritional risk) appear to benefi t from early PN (within 48 h of admission) without
increased infectious complications when EN is not feasible
75 – 77 ].
[
One caveat is the high nutrition-risk patient in the early
or acute phase of sepsis, in which PN should be avoided.
There is a lack of data specifi cally addressing the use of PN
in septic patients, and insights must be drawn from subset
analysis of larger populations. In a mixed ICU study by
Casaer et al., early supplemental PN added to hypocaloric
EN resulted in increased infectious complications and longer length of ICU stay in the subset of patients with a diagnosis of sepsis [
78 ]. A prospective single-day
point-prevalence trial in 415 patients with a diagnosis of
severe sepsis or septic shock showed that hospital mortality
was signifi cantly higher in patients receiving PN alone
(62.3 %) or EN with supplemental PN (57.1 %) compared to
those receiving EN alone (38.9 %) ( p = 0.005) [ 79 ]. However,
both the mean APACHE II and SOFA scores were signifi cantly higher in the PN alone group. A secondary analysis
of a RCT multicenter trial analyzed 353 patients with severe
sepsis or septic shock who received EN, PN, or EN + PN
and found patients with EN alone had lower mortality than
those given EN and supplemental PN [ 80 ]. At present, only
hypothesis-generating results are available for early PN in
patients with severe sepsis or septic shock. Confi rmation is
needed with a RCT.
Oral Diet
The concept of advancing a postoperative patient fi rst to a
clear liquid diet has no physiologic basis. Although clear liquids may leave the stomach more rapidly than solid foods,
they are also the texture easiest to aspirate [ 35 ]. In 241
patients who had undergone an abdominal operation, a RCT
demonstrated no difference in dietary intolerance between
those receiving a clear liquid diet (N-135) or regular diet
( N = 106) [ 81 ]. In a RCT of over 400 patients who underwent
major GI surgery and were successfully extubated within
24 h of surgery, solid foods on postoperative day 1 did not
increase morbidity or mortality [
34 ]. Early advancement to
solid foods appeared to decrease risk of ileus as evidenced by
early passage of gas and stool [
34 ]. Potentially, a clear liquid
diet should only be used in the surgical ICU based on patient
preference or when the surgeon has a high level of concern
regarding the integrity of the anastomosis.
Probiotics
Over the past decade, there has been increased understanding that the intestinal microbiome infl uences the immune
function, physiology, nutritional status, and overall health of
the host [ 82 , 83 ]. In trauma and surgical patients, within
hours of injury or insult, the microbiome is substantially
altered due in part to changes in intravascular volume, blood
fl ow to the GI tract, and widespread use of antibiotics and
artifi cial nutrition support [ 82 , 84 , 85 ]. Initial efforts to use
probiotics to maintain the “normal” microbiome in critically
ill patients have had varying success [ 86 ]. Although a sys-
tematic review of both medical and surgical ICU patients
demonstrated an association between probiotic use and
decreased infectious complications and ventilator-associated
pneumonia, there is diffi culty in extrapolating the results of
different probiotic species provided among the studies [ 86 ].
Therefore, use of probiotics should be restricted to select surgical ICU patient populations where RCTs have documented
safety and outcome benefi t.
A double-blind RCT was done in patients undergoing a
pylorus-preserving Whipple procedure [ 87 ]. The use of a
commercial probiotic product Synbiotic 2000 (Medipharm,
Des Moines, IA) (consisting of 10 10 CFU of each of
Pediococcus pentosaceus 5–33:3, Leuconostoc mesenteroi-
des 32–77:1, L. paracasei ssp paracasei 19 and L. plantarum
2362, as well as 2.5 g inulin, oat bran, pectin, and resistant
starch) led to a signifi cant reduction in infection when the
probiotic preparation was started 1 h postoperatively
compared to controls receiving placebo (12.5 % vs. 40.0 %,
p < 0.05) [ 87 ]. In a pre- and post study of 67 liver transplant
patients, 34 received fi ber, and 33 received fi ber plus mixed
probiotics. Ten patients in the fi ber-only group developed
bacterial infections, compared to three in the group receiving
fi ber plus mixed probiotics ( p < 0.005) [ 88 ]. Until more data
are available using a single strain or commercially prepared
readily available probiotic, general recommendations regarding the use in surgical ICU patients cannot be made.
Conclusion
Timely nutrition intervention leads to positive clinical
outcomes in critically ill patients who have experienced
insult or injury and are at high nutritional risk or unable to
resume adequate oral intake within 7 days. Current data
248
B.E. Taylor and C.M. Coopersmith
and expert consensus support the following recommendations for nutrition in the surgical ICU:
1. Use EN in preference to PN in the presence of a functioning GI tract.
2. Start EN (containing arginine, fi sh oils, and antioxidants) within 24–48 h of trauma or surgery in nonseptic patients, and continue for 7–10 days.
3. Adopt volume-based EN protocols.
4. Hold small bowel EN in patients with increasing vasopressor requirements and consider trophic (10–
20 ml/h) gastric feeds if not contraindicated for other
reasons.
5. Begin PN in severely malnourished or high nutritionrisk patients early in those with nonfunctioning GI
tracts or within 5–7 days if not tolerating at least 60 %
of goal of EN prescribed.
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Antibiotic Strategy and Stewardship
Sarah M. Kolnik and Heather L. Evans
2 1
Antibiotic stewardship is the optimization of antibiotic regimens to ensure the best treatment selection for individual
patients with minimization of side effects and cost, while
attempting to limit the development of resistance [
Comprehensive antibiotic management strategies may use a
variety of methods to limit antibiotic use in volume, duration, and spectrum. These strategies should also include multidisciplinary efforts to monitor compliance with clinical
practice guidelines, policies, and protocols. Formulary
restriction, antibiotic cycling, selective reporting of culture
susceptibilities, and decision support tools to aid in drug
selection are among the means by which antimicrobial use
can be directed. Equally important in the critical care setting
is the prevention and treatment of nosocomial infections
common to critically ill patients.
1 , 2 ].
Preventing Resistance
Antibiotic resistance has been as a public health concern for
decades. In 2014, the World Health Organization (WHO)
published a global surveillance report fi nding very high rates
of bacterial resistance in each of the WHO geographic
regions [
where simple infections once again contribute to signifi cant
mortality, is a possibility within the next century. With the
acknowledgment that a signifi cant contributing factor to
antibiotic resistance is the overuse and misuse of antibiotics,
the Centers for Disease Control and Prevention (CDC) has
highlighted improving antibiotic usage in health-care settings as one of four key strategies to slowing the development of resistance [
recommends that health-care facilities that develop multidisciplinary antibiotic stewardship programs and core elements
S. M. Kolnik , MD, MPH (*) • H. L. Evans , MD, MS, FACS
General Surgery , University of Washington ,
Seattle , WA 98195 , USA
e-mail:
3 ]. The report concluded that a “post-antibiotic era,”
4 ]. First and foremost, the CDC
Kolnik@uw.edu; hlevans@uw.edu
should include a leadership commitment, institutional
accountability, drug expertise, action plan, infection tracking, reporting, and provider education. A recent metaanalysis found that antibiotic stewardship programs, either
prescription restrictive or prescriber persuasive, were effective in decreasing antibiotic resistance and hospital-acquired
infections [
program demonstrated a 50 % reduction in the number of
Clostridium diffi cile infections within its fi rst year of inter-
vention [ 6 ]. The implementation of antibiotic stewardship
programs is often multifaceted, and despite encouraging
results from individual studies and demonstrated effectiveness in meta-analyses, it is diffi cult to identify the components of the programs that are the most benefi cial. Carling
and colleagues [ 7 ] reported that the ultimate success of their
stewardship effort depended on a high degree of provider
acceptance, attributed to having noninfectious disease personnel involved in the effort. Successful stewardship requires
multidisciplinary cooperation, systems-based change, and
support from hospital leadership [ 8 ].
5 ]. A community-based antibiotic stewardship
Antibiotic Formulary Restriction
Antibiotic restriction is an external control over clinician prescribing instituted to address antimicrobial resistance in the
face of provider noncompliance with clinical practice guidelines. Restrictions may be applied at various levels, from limiting drugs available on formulary, to requiring prior approval
from infectious disease experts, to other predefi ned dispensing criteria. In the setting of increasing Gram- negative resistance to aminoglycosides in the 1980s, the association
between a change in antibiotic usage and alteration of antibiotic sensitivities was recognized in the initial reports of antibiotic restriction in the intensive care unit (ICU) [ 9 ]. Early
studies that restricted antibiotics by requiring infectious disease or pharmacy consultant preapproval found decreased
resistance and cost savings through the imposed use of less
expensive unrestricted antibiotics [
10 ]. Over the following
© Springer International Publishing Switzerland 2016
N.D. Martin, L.J. Kaplan (eds.), Principles of Adult Surgical Critical Care, DOI 10.1007/978-3-319-33341-0_21
251
252
S.M. Kolnik and H.L. Evans
decades, the majority of studies evaluating antibiotic restriction have demonstrated a reduction in the targeted antibiotic
with associated improvements in resistance rates. However,
most also report that one consequence of restriction is signifi cantly increased prescribing of alternative agents. For example, a 6-month restriction of fl uoroquinolones in the intensive
care unit (ICU) setting was associated with a decrease in
resistant Pseudomonas aeruginosa from 71.3 to 52.4 % that
was maintained for up to 12 months following restriction
[
11 ]. This study also showed a twofold increase in aminogly-
coside use and a fi vefold increase in macrolide use. In addition to improved resistance rates, some antibiotic stewardship
programs have demonstrated improved clinical outcomes.
May and colleagues found a reduction in vancomycin-resistant Enterococcus spp. and Clostridium diffi cile infections
following restriction of cephalosporin use [ 12 ].
In contrast to the initial reports of reduction in resistant
organism isolation, subsequent studies have shown the converse. “Squeezing the balloon” [ 13 ] describes the phenome-
non where resistance to the alternatively chosen replacement
antibiotic classes develops in the time period of their use
[ 14 ]. A nationally representative survey of hospitals in the
United States found that restricted formularies were associated with an overall higher rate of antibiotic resistance [ 15 ].
Implementation of antibiotic restriction through a variety of
mechanisms has been shown to decrease rates of use of
intended drugs and lower resistance prevalence, though these
practices are also associated with increased use of alternative
classes and variable effects on overall rates of resistance.
Antibiotic Cycling
An alternative to restricting specifi c antibiotic use is the scheduled periodic withdrawal and reintroduction of different antibiotic classes within a clinical environment. This practice is
known as “antibiotic rotation” or “cycling.” Empiric antibiotic
regimens are designed to address selective antibiotic pressure,
preventing the preferential selection of resistant microbes
through single-class antibiotic overuse. Resistant bacterial
strains are assumed to have a growth disadvantage when
homogenous antibiotic pressure is withdrawn, and exposure to
the new class of antibiotics should eliminate resistance
selected during the previous cycle. In an early analysis on
cycling from the 1990s, Gerding and colleagues [ 16 ] observed
that gradual increase of gentamicin use after formulary restriction was not associated with increase in resistance to any of the
aminoglycosides in use. After encouraging results in decreasing resistance patterns with cycling antibiotics over months–
17 ], more intricate cycling schedules were developed
years [
and evaluated. Using predominant resistance patterns as the
basis for the drug choices, Gruson and colleagues [
a comprehensive effort to control rising quinolone and cepha-
18 ] detailed
losporin resistance in a medical ICU through a combined
cycling and antibiotic restriction schedule devised each month,
based on the previous month’s antibiotic use and microbial
resistance pattern. Although the drugs chosen for the rotation
schedule were again targeted against Gram-negative organisms, the incidence of MRSA pneumonia decreased during the
study period. This report also found improved drug sensitivities for several commonly resistant Gram-negative organisms
responsible for ventilator-associated pneumonia (VAP) following the initiation of cycling.
Despite the encouraging results from these early studies
of single antibiotic class cycling, mathematical models suggest that the temporal cycling of antibiotics is inferior to
mixing, a strategy whereby multiple antibiotic classes are
used simultaneously in the environment to increase antibiotic heterogeneity [
designed a study that combined antibiotic mixing and rotation, with two antibiotic classes used in the environment
simultaneously for the empiric treatment of suspected intraabdominal infection, pneumonia, or sepsis of unknown origin. They found a decrease in the incidence of all infections,
infections caused by resistant Gram-negative organisms, and
in-hospital mortality during the rotation period. At the same
time, there was a reduction in hospital-acquired and resistant
hospital-acquired infection rates on the non-ICU wards, suggesting that the infl uence of antibiotic rotation on resistance
patterns in one unit may be sustained after the patients are
transferred to a new location [ 21 ].
It is important to note that whether one employs cycling
or mixing, the degree of variation in prescribed antibiotics is
always greater than what one would achieve with formulary
restriction alone; formulary restriction of necessity constraints provides choices to those available for use instead of
allowing selection from an unconstrained menu of therapeutic agents. This variation has been denoted using a concept
called the antibiotic heterogeneity index with complete heterogeneity equal to 1. A target of an AHI of 0.85 has been
suggested as a means of reducing selection pressure for multiple drug resistance bacterial growth [ 22 ].
19 ]. Raymond and colleagues [ 20 ]
Preventing Infection
Critically ill patients are at increased risk for health-careassociated infections due to their underlying pathology, poor
nutritional status, indwelling devices, and frequent contact
with health-care providers caring for other infectious
patients. An antibiotic stewardship program for the critically
ill must also include best practices for the prevention, diagnosis, and appropriate treatment of common health-careassociated infections. The common infections in the ICU
setting include ventilator-associated pneumonia (more
recently termed ventilator-associated infection), central line-