652576

research-article2016
NCPXXX10.1177/0884533616652576Nutrition in Clinical PracticePatel et al

Invited Review
Nutrition in Clinical Practice
Volume XX Number X
When Is It Appropriate to Use Arginine in Critical Illness? Month 201X 1­–7
© 2016 American Society
for Parenteral and Enteral Nutrition
DOI: 10.1177/0884533616652576
ncp.sagepub.com
hosted at
Jayshil J. Patel, MD1; Keith R. Miller, MD2; Cameron Rosenthal, MD3; online.sagepub.com
and Martin D. Rosenthal, MD4

Abstract
In health, arginine is considered a nonessential amino acid but can become an essential amino acid (ie, conditionally essential amino
acid) during periods of metabolic or traumatic stress as endogenous arginine supply is inadequate to meet physiologic demands. Arginine
depletion in critical illness is associated with impairments in microcirculatory blood flow, impaired wound healing, and T-cell dysfunction.
The purpose of this review is to (1) describe arginine metabolism and role in health and critical illness, (2) describe the relationship
between arginine and asymmetric dimethylarginine, and (3) review studies of supplemental arginine in critically ill patients. (Nutr Clin
Pract.XXXX;xx:xx-xx)

Keywords
arginine; critical illness; trauma; sepsis; surgery; wound healing; asymmetric dimethylarginine; nitric oxide; arginase

Arginine (ARG; 2-amino-5-guanidovaleric acid) is 1 of 6 con-
ditionally essential amino acids. When Swiss chemist Ernst
Schulze first isolated arginine from lupin seedling extract in
1886, he probably did not anticipate arginine would have the
potential for such widespread application as a nutrition supple-
ment.1 In fact, the importance of arginine was not realized until
Krebs and Henseleit discovered the urea cycle in 1932.2 In
noncritical illness, arginine improves outcomes related to
wound healing, sickle cell disease, treatment of preterm labor
and preeclampsia, the perioperative setting, and pulmonary
hypertension.3–7 Within the critical care setting, arginine sup-
plementation remains controversial. The purpose of this review
is to (1) describe arginine metabolism and role in health and
critical illness, (2) describe the relationship between arginine
and asymmetric dimethylarginine (ADMA), and (3) review
studies of supplemental arginine in critically ill patients.
Arginine Metabolism in Health
In health, arginine is considered a nonessential amino acid but
can become an essential amino acid (ie, conditionally essential
amino acid) during periods of metabolic or traumatic stress as
endogenous arginine supply is inadequate to meet physiologic
demands.8,9 L-arginine is available via 3 sources (Figure 1).
First, dietary sources contribute 25%–30% (5–7 g) of total
daily arginine. Arginine from dietary sources is absorbed in the
small bowel.10 Second, 15–20 g of arginine is synthesized
endogenously through an intestinal-renal axis. Citrulline pro-
duced by enterocytes is extracted by renal tubular cells, where
it is converted to L-arginine via sequential reactions involving
arginosuccinate synthase and arginosuccinate lyase.11
Impairment of small bowel and/or renal function disrupts the
intestinal-renal axis, consequently reducing the endogenous
arginine pool. Finally, arginine is readily available from pro-
tein turnover/breakdown through cellular amino acid recy-
cling. In relation to arginine metabolism and recycling, the
concept of reduced global arginine bioavailability (GABR =
arginine/ornithine plus citrulline) has been identified as a risk
factor in multiple disease entities, including cardiovascular
disease, depression, posttraumatic stress disorder, and sickle
cell anemia.7,12–14
Role of Arginine
Circulating arginine has biosynthetic, precursory, and regulatory
roles (Figure 1). In the nourished state, arginine is funneled
toward protein biosynthesis, including conversion to urea, cre-
atine, and citrulline.15 Arginine is used as a precursor of poly-
amine (putrescine, spermine, and spermidine) and proline
synthesis for cellular proliferation and wound healing,
From the1Department of Medicine, Division of Pulmonary & Critical
Care Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin,
USA; 2Department of Surgery, Division of Trauma Surgery, University
of Louisville, Louisville, Kentucky, USA; 3Department of Pediatrics,
University of Florida, Gainesville, Florida, USA; and the 4Department of
Surgery, University of Florida, Gainesville, Florida, USA.
Financial disclosure: None declared.
Conflict of interest: None declared.
Corresponding Author:
Jayshil J. Patel, MD, Medical College of Wisconsin, Department of
Medicine, Division of Pulmonary & Critical Care Medicine, 9200 West
Wisconsin Ave, Suite E5200, Milwaukee, WI 53226, USA.
Email: jpatel2@mcw.edu

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2 Nutrition in Clinical Practice XX(X)
Figure 1.  Sources of arginine and role of arginine in health. *5–7 g through dietary intake. #15–20 g through renal conversion.
respectively.16 As a regulatory amino acid, arginine stimulates
processes such as collagen synthesis and growth hormone pro-
duction, suggesting arginine has a role in stimulating wound
repair. High arginine concentrations improve glucose tolerance
through insulin release from pancreatic β cells and glucose
uptake by tissues.15 As an immunomodulatory agent, arginine
regulates T-cell function by stimulating lymphocyte prolifera-
tion. In addition, lymphocyte antigen memory is improved by
arginine.17–19 In health, <5% of arginine is used as a substrate for
nitric oxide synthases (NOS) and thus is the only substrate for
nitric oxide (NO) production. Three NOS isoforms—neuronal
NOS (nNOS), endothelial NOS (eNOS), and inducible NOS
(iNOS)—convert L-arginine to NO.20 Through the iNOS path-
way, NO produced serves as an intracellular signaling molecule
that vasodilates blood vessels, increases vascular permeability,
is directly bactericidal, and is used by macrophages and leuko-
cytes to destroy microbial pathogens.15,21,22 Arginase is secreted
in large quantities during states of inflammation by myeloid-
derived suppressor cells (MDSCs) and Th-2 lymphocytes stimu-
lated by interleukin (IL)–4, IL-10, and IL-13. Arginase converts
arginine to ornithine, ultimately shunting arginine away from
NO production. In addition, arginase catabolizes arginine in the
urea cycle to detoxify ammonia.15,22 Clearly, arginine require-
ments increase substantially in any condition that calls for aug-
mented immune function, an increased NO production, and/or
ammonia detoxification.
Arginine in Critical Illness
The metabolic response to critical illness and surgical stress is
complex and involves activation of neuroendocrine, inflamma-
tory/immune, adipose tissue hormone, and gastrointestinal
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(GI) hormone components. The neuroendocrine component
begins within seconds to minutes following stress, activating
the sympathetic nervous system and hypothalamic-pituitary
axis. The inflammatory and immune components are activated
within days and lead to release of cytokines and inflammatory
mediators.23 Trauma and surgery induce a predominant Th-2
response, leading to an increase in IL-4, IL-10, and IL-13.24
These cytokines upregulate arginase production. Increased
arginase in macrophages leads to NO inhibition and reduced
T-cell proliferation, resulting in impaired immune function.18,22
During prolonged critical illness, MDSCs are released from
bone marrow into circulation and amplify circulatory arginase
1 activity, leading to rapid arginine depletion and lack of T-cell
regulatory function.25–27
On the contrary, septic shock leads to a predominantly Th-1
response with IL-1, tumor necrosis factor (TNF)–α, and inter-
feron (IFN)–γ expression.28,29 These host cytokines and bacte-
rial endotoxins upregulate components associated with iNOS
while downregulating eNOS. Consequently, shuffling of argi-
nine from low-output eNOS to high-output iNOS produces
large amounts of NO, leading to widespread vasodilatation and
enhanced tissue permeability. Sepsis is associated with reduced
arginine levels. First, there is a negative nitrogen balance due
to excessive protein catabolism. The proteins from proteolysis
are used for gluconeogenesis. Second, there is reduced renal
citrulline conversion to arginine.11 Third, a concomitant
increase in arginase 1 activity in macrophages reduces avail-
able arginine.30
Consequences of arginine depletion include reduced NO
production, which can potentially affect blood pressure, cyto-
toxicity, and gene expression.20 Other consequences of argi-
nine depletion in the setting of critical illness include the
Patel et al 3
Figure 2.  Production and effect of ADMA. *Physiologic
concentrations of ADMA are 10-fold higher than MMA
and SDMA. ADMA, asymmetric dimethylarginine; MMA,
monomethylated arginine; NO, nitric oxide; PRMT, protein
arginine methyltransferase; SDMA, symmetric dimethylarginine.
potential for poor wound healing, impaired microcirculatory
blood flow, immunosuppression, and, while not specific for
arginine, impaired muscle function from severe catabolism.
Ischemic/reperfusion (I/R) injuries are not uncommon in criti-
cally ill patients, and arginine has been purported to limit endo-
thelial dysfunction in I/R injury, suggesting an additional
beneficial mechanism.31 The rationale for arginine supplemen-
tation is well established in animal models where supplemental
arginine decreased thymus involution, promoted wound heal-
ing and lymphocyte proliferation, improved resistance to bac-
terial infections, and improved survival in sepsis.32
Arginine and Asymmetric
Dimethylarginine Relationship
As discussed previously, critically ill patients are in a cata-
bolic state, leading to increased protein turnover. Increased
protein turnover yields dimethylarginine residues. Protein
arginine methyltransferase (PRMT) proteolysis of dimethyl-
arginine residues forms methylarginines (Figure 2). A single
nitrogen methylation is monomethylarginine (MMA). Type I
PRMT enzymes add 2 methyl groups to a single nitrogen,
forming ADMA. Type II PRMT enzymes methylate the other
terminal nitrogen to form symmetric methyl arginine
(SDMA).33
ADMA is produced 10-fold compared with SDMA and
MMA. Humans normally produce approximately 300 µmol/d
of ADMA.33 The kidneys continuously excrete 10% of ADMA,
but the majority of ADMA is degraded by dimethylarginine
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dimethylaminohydrolase (DDAH) to citrulline and dimethyl-
amine. The liver contains a large concentration of DDAH.
Kidneys, pancreas, spleen, and endothelium also contain
DDAH.33
Since critical illness is accompanied by protein catabolism,
there are increased dimethylarginine residues. In addition, crit-
ical illness leads to hyperglycemia (which impairs DDAH
function), kidney injury, and hepatic dysfunction, all reducing
ADMA clearance. Consequently, ADMA levels are elevated in
critical illness. ADMA’s predominant effects include NO inhi-
bition and competitive inhibition for cationic amino acid trans-
porters (CATs), the effect of which inhibits arginine from
entering the cell (Figure 1).33 Therefore, ADMA accentuates
the process of critical illness through vasoconstriction and
endothelial dysfunction.
The arginine to ADMA ratio (ARG/ADMA) concept has
replaced GABR conceptually as the marker of choice in criti-
cal illness and chronic disease states. In health, the ARG/
ADMA ratio is 183.34 In critical illness, the ratio is lower
secondary to both increased ADMA and reduced arginine lev-
els. In fact, both ADMA level and the ARG/ADMA ratio are
independent markers for intensive care unit (ICU) out-
comes.33,35–38 Davis et al35 demonstrated that the ARG/ADMA
ratio was significantly reduced in sepsis and correlated with
severity of illness and organ failure. In the same study, ele-
vated ADMA levels were independently associated with
reduced microvascular reactivity, severity of organ dysfunc-
tion, and 28-day mortality (odds ratio [OR], 95% confidence
interval [CI] for death in those in the highest quartile [>0.66
mmol/L] = 20.8 [2.2–195.0]; P = .008). Gough et al36 mea-
sured arginine and ADMA levels in 109 patients with severe
sepsis and demonstrated that a decreased ARG/ADMA ratio
was independently associated with both hospital (OR, 1.63
per quartile; 95% CI, 1.00–2.65; P = .048) and risk for
6-month mortality (hazard ratio, 1.41 per quartile; 95% CI,
1.01–1.98; P = .043). Visser et al38 prospectively measured
plasma arginine and ADMA at ICU admission in 17 patients
with cardiogenic shock and 27 patients with septic shock. A
mean (SD) ARG/ADMA ratio of 93.2 (42.5), predominantly
due to reduced arginine, was associated with an increased
risk for mortality (OR, 0.980; 95% CI, 0.963–0.997; P =
.025). Koch et al37 demonstrated that elevated ADMA in a
group of patients with sepsis, compared with those without
sepsis, was an independent prognostic biomarker for short-
term and long-term mortality.
To date, human trials of arginine supplementation have not
risk stratified patients based on reduced ARG/ADMA ratio or
elevated ADMA. In effect, the benefit of arginine supplemen-
tation in those with a reduced ARG/ADMA ratio may be coun-
terbalanced by potential harm in those with a higher ratio,
suggesting no benefit when studied in a heterogeneous popula-
tion. Risk-stratifying septic patients using the ARG/ADMA
ratio and/or ADMA levels may elucidate which patients will in
fact benefit from exogenous arginine supplementation.
4 Nutrition in Clinical Practice XX(X)
Which Patients May Benefit From
Arginine Supplementation?
Immunonutrition (containing arginine) in critically ill patients
has been the subject of numerous trials.39–42 There are a few
concerns with these trials, preventing blanket recommenda-
tions for arginine in critical illness. First, critically ill patients
are a heterogeneous group of medical and surgical patients
with varying disease processes (trauma, postoperative, sepsis).
Second, immunonutrition did not contain arginine alone but
rather had a mixture of immune-modulating agents such as fish
oil and glutamine. To illustrate this point, the largest trial to
date examining “immunonutrition” in the ICU included no
arginine at all.43 Finally, the type of nutrition support provided
to control groups varies widely from study to study. To con-
clude that arginine is safe (or unsafe) in a critically ill patient
would seem naive.
The 2016 Society of Critical Care Medicine (SCCM) and
American Society for Parenteral and Enteral Nutrition
(ASPEN) Guidelines for the Provision and Assessment of
Nutrition Support Therapy in the Adult Critically Ill Patient
provide a very weak recommendation for immune-modulating
formulations containing arginine in severe trauma and in
patients with traumatic brain injury.44 The guidelines also rec-
ommend the synergistic benefit of arginine- and fish oil–con-
taining formulas in postoperative surgical ICU patients.44
Three meta-analyses have demonstrated that, compared with
standard formula, both preoperative and postoperative arginine
and fish oil supplementation reduced infection rate and length
of stay but produced no difference in mortality.45–47 Arginine
supplementation prior to surgical insult provided very little
benefit, while the strongest signal was seen when used in the
postoperative period, suggesting the operative insult may con-
tribute to an arginine deficiency state.48
The benefit of arginine in trauma and postoperative patients
may be due to arginine’s impact on increasing NO production
and improvement in microcirculatory blood flow and T-cell
function by overcoming the effect of myeloid suppressor
cells.44 In addition, arginine has a positive effect on wound
healing. Supplemental arginine provides a substrate for colla-
gen synthesis at the wound site; increases plasma insulin-like
growth factor, which mediates growth hormone; and stimulates
T-cell function toward wound healing.32
A new phenotype of critical illness, termed the persistent
immunosuppressed inflammatory catabolic state (PICS), is
emerging. Some patients survive acute critical illness and mul-
tiple-organ failure, only to enter a state of chronic critical illness
(after 14 days) characterized by low-grade organ dysfunction
and immune suppression, leading to malnutrition, muscle
weakness, recurrent infections, and poor wound healing.49
Individuals with preexisting medical conditions such as heart
failure and obesity are most susceptible to PICS. The immune
suppression in PICS is in part due to immature white blood cell
accumulation. Mentioned earlier, these MDSCs migrate to the
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liver, spleen, and lymph nodes, where they express arginase 1,
depleting arginine in these tissues.49 Arginine depletion leads to
impaired lymphocyte proliferation and proclivity for nosoco-
mial infections. Early arginine supplementation in the PICS
population may be of therapeutic value to restore lymphocyte
proliferation and function. The exact timing, duration, and opti-
mal dose remain to be determined.
Arginine Supplementation in Sepsis
Despite reduced arginine levels in sepsis, arginine supplemen-
tation remains controversial.50 The 2016 SCCM/ASPEN nutri-
tion therapy guidelines suggest that immune-modulating
formulas not be used routinely in patients with severe sepsis
given the paucity of data for positive outcomes.44 Severe sepsis
and septic shock lead to widespread vasodilatation and
increased endothelial permeability, mediated by upregulated
NO. Clinical consequences include hypotension despite effec-
tive circulating volume repletion. Theoretically, arginine sup-
plementation in septic shock can provide a substrate for NO
production, thereby resulting in greater hemodynamic instabil-
ity.44 On the contrary, nonselective NO inhibition has been
demonstrated to be detrimental. Lopez et al51 randomized 797
patients with septic shock across 124 ICUs to receive an NOS
inhibitor or placebo. Mortality in the NOS inhibitor group was
59% compared with 49% in the placebo group (P < .001).
There was an increased proportion of deaths due to refractory
shock in the NOS inhibition group. The authors speculate a
beneficial role for NO in septic shock as overcorrection of vas-
cular tone (through NOS inhibition) may result in an excessive
increase in ventricular afterload, leading to myocardial
dysfunction.51
Animal models of sepsis and supplemental arginine have
yielded mixed results. In a rat septic model, arginine infusion
led to reduced inflammatory markers and increased liver pro-
tein synthesis.52 In Escherichia coli bacteremic sheep, Lorente
et al53 infused L-arginine at 200 mg/kg/h for 300 minutes pre-
bacteremia and demonstrated a significant decrease in blood
pressure and oxygen delivery in the septic sheep. In a canine
sepsis model of E coli peritonitis, Kalil et al54 evaluated the
effects of intravenous (IV) L-arginine (10 mg/kg/h vs 100 mg/
kg/h) alone or in combination with N-acetylcysteine. L-arginine
infusion was associated with lower serum pH, more renal dys-
function, and increased shock and mortality.54
Animal studies are limited by the varying methods, includ-
ing species (pig, sheep, rat, mice, and rabbit), method of sepsis
induction (cecal ligation, peritonitis, or endotoxin challenge),
route of arginine delivery (enteral vs IV), variability of amino
acid metabolism, and studied outcomes.8,20 In the canine sepsis
model by Kalil et al,54 the actualized harm may have been due
to the supraphysiologic arginine dose and method of delivery.
When provided enterally, 40% of arginine is degraded in the
gut during absorption. Indeed, supraphysiologic IV arginine
(not subjected to first-pass clearance) may be harmful.
Patel et al 5
Table 1.  Human Studies of Intravenous Arginine in Sepsis.
Year Authors Study Design Sepsis Population IV Arginine Dose
1993 Lorente PO Mixed medical 200 mg/kg bolus
et al59 surgical
2005 Luiking PO Mixed medical 0.6–1.8 µmol/
et al60 surgical kg/ha
2006 Luiking PRCT Mixed medical 1.2 µmol/kg/hb
et al61 surgical
2015 Luiking PO Mixed medical 33–99 µmol/kg/hc
et al62 surgical
CI, cardiac index; IV, intravenous; MAP, mean arterial pressure; PO, prospective observational; PRCT, prospective randomized controlled trial; SV,
stroke volume; SVR, systemic vascular resistance.
a
Stepwise increase in dose for 2 hours each.
b
Continuous infusion for 3 days.
c
Stepwise increase in dose at 33, 66, and 99 µmol/kg/h for 2 hours.
Most human studies evaluating arginine have used an
immune-enhancing formula containing other immune-modifying
agents such as fish oil, vitamin E, zinc, and selenium; included
heterogeneous ICU patient populations; and compared enteral
immunonutrition with parenteral nutrition (PN).39–42,55–58
In the only study specifically evaluating septic patients,
Galban et al39 randomized septic patients with an Acute
Physiology and Chronic Health Evaluation II (APACHE II)
score of ≥10 to receive either an L-arginine–enriched enteral
formula or a regular high-protein diet. There was a significant
reduction in mortality for those patients receiving the
L-arginine–enriched formula compared with a high-protein
control feed (19% vs 32%, P < .05). The intention-to-treat
analysis also demonstrated a reduction in bacteremia in those
receiving the L-arginine formula.39
Other immunonutrition studies, while demonstrating
improvements in outcomes, such as reduced catheter-related
infections, length of hospital stay, and duration of mechanical
ventilation, examined mixed ICU patient populations.40–42,55,57
Two studies demonstrated harm with arginine supplementa-
tion as part of an immune-enhancing formula. In an unpub-
lished study, Dent et al56 conducted a randomized controlled
trial (unpublished) in critically ill patients using an L-arginine–
containing formula. Enrollment ceased after 53% of the
planned sample showed 23% mortality in the L-arginine group
compared with 9.6% in the standard enteral feeding group (P <
.01). Numerous flaws with the study preclude concluding that
arginine was harmful. For example, a low arginine level was
used in the study group, and there was likely a randomization
error as the experimental group had a significantly higher per-
centage of pneumonia, and mortality in the pneumonia group
was 50%, compared with 0% in the group without pneumo-
nia.8,56 Bertolini et al55 randomized 237 patients across multi-
ple ICUs to an arginine-containing immunonutrition formula
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Outcomes Comments
Transient reduction in MAP and Supraphysiologic arginine,
SVR and increase in CI small cohort (n = 7)
Four-fold increase in plasma Small cohort (n = 7)
arginine and increase in
SV without change in other
hemodynamic parameters
No change in protein nitrosylation Unpublished study
and no hemodynamic instability
Reduced whole-body protein Small cohort (n = 8)
breakdown, increased de
novo arginine production, and
improved hemodynamics
vs standard PN. In a subgroup of 39 patients with severe sepsis,
mortality was higher in those receiving enteral immunonutri-
tion compared with those receiving PN (44.4% vs 14.3%, P =
.039).
Interpretation of outcomes in these large randomized con-
trolled trials should be done in the context of the population
studied (eg, mixed ICU patient population), methodologic
flaws (eg, randomization error), the type and quantity of argi-
nine supplemented, and understanding the benefits and limita-
tions of providing arginine with other immune-enhancing
agents.
Four studies have specifically evaluated arginine infusion
alone in septic shock (Table 1).59–62 Lorente et al59 infused a
200-mg/kg IV bolus of L-arginine in 7 patients with septic
shock, which led to immediate but transient increases in cardiac
index and reduction in systemic vascular resistance. Luiking
et al60 infused IV arginine in 8 patients with septic shock, result-
ing in a 4-fold increase in plasma arginine and improvement in
stroke volume without changes in systemic blood pressure.
Luiking et al61 conducted a (unpublished) prospective random-
ized double-blind placebo-controlled trial evaluating the effect
of arginine infusion in patients with septic shock. The patients
who received arginine infused at 1.2 mcg/kg/min (compared
with alanine) had no adverse hemodynamic effects. More
recently, Luiking et al62 evaluated the dose response of IV argi-
nine ranging from 33–99 µmol/kg/h (equaling arginine 10–31
g/d) in 8 patients with septic shock. IV arginine was associated
with no significant change in pulmonary arterial pressure, mean
arterial pressure, or gastric perfusion. In addition, stroke vol-
ume increased and arterial lactate decreased. Last, tracer studies
demonstrated that IV arginine was associated with a decrease in
net whole-body protein breakdown.62 These studies are limited
by small sample sizes, differences in dose administered, and
studied outcomes (Table 1).
6 Nutrition in Clinical Practice XX(X)
Conclusions and Future Insights
Arginine is an essential amino acid in critical illness, where it
is a key amino acid in several pathways, including NO pro-
duction, protein biosynthesis (for wound healing), and immu-
nomodulation. Arginine deficiency in critical illness has
significant consequences for microcirculatory blood flow,
wound healing, protein synthesis, and T-cell function. Within
the critical care setting, arginine supplementation is recom-
mended for preoperative and postoperative surgical ICU
patients, severe trauma patients, and traumatic brain injury
patients. Despite these recommendations, the role of arginine
supplementation in critical illness remains in evolution.
Arginine supplementation may be beneficial in patients with
PICS, although optimal dose and timing remain to be deter-
mined. Whether arginine should be supplemented alone
or with other immune-modifying agents such as fish oil is
unclear. Potential interactions between arginine and other
immune-modifying agents must be considered. Arginine sup-
plementation in sepsis remains controversial, and interpreta-
tion of data from large randomized controlled trials must take
into context methodologic flaws, the ICU population studied,
and the type of immune-enhancing formula used. In fact, the
2016 SCCM/ASPEN guidelines recommend against routine
use of immune-modulating enteral formulas (which may con-
tain arginine) in medical ICU patients as data to support mor-
tality benefit, reduced infectious complications, and hospital
length of stay are not evident in the medical ICU popula-
tion.44 Small studies suggest that arginine supplementation
in hemodynamically stable septic patients is safe without
hemodynamic impairments. Despite improved hemodynamic
parameters in the small studies evaluating IV arginine in sep-
sis, the optimal route is unknown. Extrapolation from several
studies suggests 15–30 g/d arginine is safe.62 Future studies
of arginine in sepsis should consider risk-stratifying using
ADMA level and/or ARG/ADMA ratio to appropriately iden-
tify which patients will indeed benefit from exogenous argi-
nine supplementation.
Statement of Authorship
J. J. Patel and M. D. Rosenthal contributed to the conception and
design, drafted the manuscript, critically revised the manuscript,
gave final approval, and agree to be fully accountable for all aspects
of work ensuring integrity and accuracy. K. R. Miller and C.
Rosenthal contributed to the conception of the work, critically
revised the manuscript, gave final approval, and agree to be fully
accountable for all aspects of work ensuring integrity and accuracy.
All authors read and approved the final manuscript.
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