The Journal of Nutrition

Supplement: 9th Workshop on the Assessment of Adequate and Safe Intake of Dietary Amino Acids

Parenteral or Enteral Arginine Supplementation

Safety and Efficacy1–3

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Martin D Rosenthal,4,5 Phillip W Carrott,6 Jayshil Patel,7 Laszlo Kiraly,8 and Robert G Martindale8*
4
Division of Acute Care Surgery, Department of Surgery, and 5Center for Sepsis and Critical Illness Research, University of Florida
College of Medicine, Gainesville, FL; 6Section of Cardiothoracic Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI;
7
Division of Pulmonary Critical Care, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; and 8Division of
Gastrointestinal Surgery, Department of Surgery, Oregon Health and Science University, Portland, OR

Abstract
Arginine supplementation has the potential to improve the health of patients. Its use in hospitalized patients has been a
controversial topic in the nutrition literature, especially concerning supplementation of septic patients. In this article, we
review the relevant literature both for and against the use of arginine in critically ill, surgical, and hospitalized patients. The
effect of critical illness on arginine metabolism is reviewed, as is its use in septic and critically ill patients. Although
mounting evidence supports immunonutrition, there are only a few studies that suggest that this is safe in patients with
severe sepsis. The use of arginine has been shown to benefit a variety of critically ill patients. It should be considered for
inclusion in combinations of immunonutrients or commercial formulations for groups in whom its benefit has been
reported consistently, such as those who have suffered trauma and those in acute surgical settings. The aims of this
review are to discuss the role of arginine in health, the controversy surrounding arginine supplementation of septic
patients, and the use of arginine in critically ill patients. J Nutr 2016;146(Suppl):2594S–600S.

Keywords: arginine supplementation, critical care, surgery, immunonutrition, sepsis

Introduction
Arginine is a nonessential amino acid. During periods of metabolic
or traumatic stress, however, arginine is considered to be condi-
tionally essential amino acid when the endogenous supply is
inadequate to meet metabolic demands (1–4). Over the past 4
decades, arginine has been used in clinical and nonclinical
settings for a wide variety of conditions (Table 1). When
evaluating arginine safety, it must be noted that its beneficial or
detrimental influence will depend not only on the population
and condition being evaluated but also on the dose of supple-
mentation, the duration of therapy, the route of delivery, and the
1
Published in a supplement to The Journal of Nutrition. The 9th Workshop on the
Assessment of Adequate and Safe Intake of Dietary Amino Acids was presented
at the "9th Amino Acid Assessment Workshop" held in Paris, France, 15–16
October 2015. The conference was sponsored by the International Council on
Amino Acid Science (ICAAS). The Organizing Committee for the workshop
included Sidney M Morris Jr., Dennis M Bier, Luc Cynober, Motoni Kadowaki,
and Rajavel Elango. The Supplement Coordinator for this supplement was D’Ann
Finley, University of California, Davis. Supplement Coordinator disclosures:
D’Ann Finley received travel support and compensation from ICAAS for editorial
services provided for this supplement publication. Publication costs for this
supplement were defrayed in part by the payment of page charges. This
publication must therefore be hereby marked "advertisement" in accordance with
18 USC section 1734 solely to indicate this fact. The opinions expressed in this
publication are those of the authors and are not attributable to the sponsors or
the publisher, Editor, or Editorial Board of The Journal of Nutrition.
2 9
The authors reported no funding received for this study.
3
Author disclosures: MD Rosenthal, PW Carrott, J Patel, L Kiraly, and RG
Martindale, no conflicts of interest.
*To whom correspondence should be addressed. E-mail: martindr@ohsu.edu.
nutrient mix with which it is being delivered. According to the
NIH consumer information website, arginine is ‘‘considered
safe’’ when taken appropriately and administered by mouth, by
injection, or when applied to the skin (5). This is intentionally
vague and does not apply when discussing arginine supplemen-
tation in the clinical situation. In the clinical arena, both animal
and human experiments have shown the benefits of arginine in a
wide variety of models and conditions (Table 2). The aims of this
review are to discuss the following: 1) arginine and its role in
health, 2) the controversy surrounding arginine supplementation
in sepsis, and 3) the safety and use of arginine in intensive care
unit (ICU)9 populations.
When studying oral supplementation of L-arginine in healthy
subjects, a bolus dose-response from 3 to 10 g 3 times/d for a
maximal total of 30 g/d was tested and shown to cause minimal
side effects, with the major side effect being diarrhea (7). In a
similar dose-response study, 84 patients with head and neck
cancer were supplemented with L-arginine in a randomized,
single-blind prospective trial. This trial used doses ranging from
5.7 to 18.9 g/d. The investigators reported benefits of decreased
length of hospital stay and a trend toward decreasing fistula
rates. They reported no ill effects even at the highest dose of
Abbreviations used: ADMA, asymmetric dimethylarginine; EN, enteral
nutrition; eNOS, endothelial NO synthase; ICU, intensive care unit; iNOS,
cytokine-inducible NO synthase; nNOS, neuronal NO synthase; PICS, persistent
immunosuppressed inflammatory catabolic state; PN, parenteral nutrition.

ã 2016 American Society for Nutrition.

2594S Manuscript received December 10, 2015. Initial review completed February 1, 2016. Revision accepted October 4, 2016.
First published online November 9, 2016; doi:10.3945/jn.115.228544.
TABLE 1 L-Arginine used in clinical and nonclinical settings for via conversion of citrulline to arginine in the kidney. Third,
multiple conditions1 arginine is available from endogenous protein turnover (16).
Arginine has numerous metabolic fates, and a full discussion is
Chest pain Congestive heart failure beyond the scope of this brief review. Functionally, 2 pathways
Erectile dysfunction Critical illness have been the focus of substantial discussion in the clinical
High blood pressure Memory loss arena: the NO pathway and the Arginase-1 pathway. L-Arginine
Inflammation of the gastrointestinal tract in Cavities is a substrate for NO production and homoarginine increases the
premature newborns availability of NO once it is produced (4, 6, 10, 17–23). This
Nitrate tolerance Diabetes reaction is carried out by 3 isoforms of NO synthase [endothelial

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Leg pain for peripheral arterial disease DM neuropathy NO synthase (eNOS), cytokine-inducible NO synthase (iNOS),
Improved recovery perioperatively Esophageal dysmotility and neuronal NO synthase (nNOS)]. First, NO is a potent intra-
High blood pressure with eclampsia Exercise performance cellular signaling molecule, influencing virtually every mammalian
Renal dysfunction Head and neck cancer organ system. Second, NO is also responsible for improved
Wound healing Infertility bactericidal action within the macrophage, via the L-arginine NO
AIDS-related wasting Bladder inflammation pathway. Next, L-arginine serves as a potent immune function
Altitude sickness MELAS syndrome modulator via its effects on lymphocyte proliferation and
Anal fissures Migraine headaches maturation, as well as lymphocyte and macrophage differentia-
Breast cancer Renal transplant tion (1–3, 24–30). Arginase-1 is an enzyme that rapidly degrades
Chemotherapy side effects Sickle cell disease arginine (31–33), and its concentrations increase rapidly after
1
Data are from reference 5. DM, Diabetes mellitus; MELAS, Mitochondrial Enceph- surgical or traumatic insults. Immature myeloid-derived suppres-
alopathy, Lactic Acidosis, and Stroke-like episodes. sor cells are released simultaneously from the bone marrow into
the circulation and express high amounts of Arginase-1 (31, 34–
39). The endogenous supply of L-arginine is decreased, whereas
18.9 g/d (8). The VINTAGE MI (Vascular Interaction with cellular demand for L-arginine is increased. The accelerated loss of
Age in Myocardial Infarction) study is an often-cited arginine endogenous L-arginine during critical illness is likely due to
supplementation study (9). This was a single-center, double-blind, marked upregulation of Arginase-1 in several tissue beds. In
placebo-controlled trial of L-arginine supplementation after ST- addition, the upregulation of iNOS to yield NO and citrulline
segment elevation myocardial infarction. Patients were supplemented contributes only minimally to arginine depletion (39–43).
with a placebo or 3 g L-arginine 3 times/d (9 g/d) for 6 mo; L-Arginine deficiency or unavailability leads to T lymphocyte
mortality in the treated group (8.6%) was greater than in the suppression and lack of proliferation (24, 25, 27). Consequently,
placebo group (0%). In other studies, there were no reports of T cell dysfunction leads to reduced circulating CD-4 cells,
toxicity when arginine was enterally administered at 28 g/d for increased IL-2, increased IFN-g production, and loss of the
wound healing and at 30 g/d for enhanced blood flow to tissue T cell receptor complex called the z-chain peptide (18, 27, 44, 45).
following flaps requiring vascular anastomosis (Table 3). A Limited L-arginine, coupled with a loss of T cell receptor function,
bolus of 30 g L-arginine parenterally administered over 30 min results in multiple impairments in immune function and response.
for preterm labor decreased uterine contractions, whereas 35 g The resulting immune incompetence is thought to contribute to an
over 45 min normalized vasomotor tone in smokers. The use of a increased risk of infection in critically ill patients (27).
continuous L-arginine infusion of 1.2 mmol
kg21
min21
normalized vascular tone in sepsis (Table 3).
L-Arginine Supplementation in the Clinical
Setting
Physiologic Compared with Pharmacologic
L-Arginine is available to the host from numerous sources, as
Role of Arginine
mentioned above. ‘‘Normal’’ arginine intake from a Western diet
L -Arginine comes from 3 primary sources. First, a typical is between 5 and 7 g/d, whereas the endogenous release of
Western diet contributes 25–30% of the total arginine present in arginine from protein turnover and de novo production of
the circulation. Second, L-arginine is endogenously synthesized arginine combined is estimated at 15–20 g/d. This production

TABLE 2 L-Arginine supplementation in clinical studies (45 y of data)1

Animal models Human studies

Increased survival in sepsis Improved wound healing

Increased survival in tumor-bearing animals Net nitrogen retention during critical illness
Increased number and function of T cells Enhanced lymphocyte proliferative response to mitogens
Increased delayed hypersensitivity 70-fold increase in arginine uptake with stimulation
Increased allograft rejection z chain assembly
Increased macrophage phagocytic activity Necessary for normal myeloid cell function
Macrophages, dendritic cells
Decreased clinical infections
Decreased postoperative length of stay
Decreased intra-abdominal abscess and anastomotic leak
Decreased mortality
1
Data are from references 3 and 6.

Is clinical use of parenteral/enteral arginine toxic? 2595S

TABLE 3 Doses shown to be safe in clinical settings (human
models)1
Enteral
Wound healing: 28 g/d increased collagen deposition (10)
Liver disease with elevated serum ammonia: .100 g/d
Free flap blood flow: 30 g/d increased blood flow to decrease flap loss (11)
Exercise performance: 20–30 g bolus (12)
Parenteral
recommended due to a lack of consistent benefit, as opposed to
being of potential harm or because of safety issues (51). This is a
substantial change from the 2009 Society of Critical Care
Medicine guidelines (52, 53). Two human studies and 1 canine
model were the foundation for the cautionary recommendation
with regard to arginine in sepsis. These studies showed greater
mortality with arginine-containing formulas in sepsis (52, 54).
The increased mortality was attributed to an increased produc-
tion of NO, which would worsen vasodilation and perpetuate

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Citrullinemia type I: doses variable
Preterm labor: 30 g/30 min i.v. decreases uterine contractions (13)
Cardiac: 35 g/45 min i.v. normalized vasomotor tone in smokers
Pulmonary hypertension: 0.5 g/kg decreases pulmonary hypertension
Tram flap: increases flap blood flow (30 g/24-h infusion) (14)
Sepsis: continuous infusion 72 h, 1.2 μmol
kg21
min21 (15)
1
Data are from references shown in parentheses.
results from protein turnover and catabolism, as well as from
renal conversion from citrulline. Numerous studies, which used
differing doses of arginine—from 5 to 30 g/d—in healthy
participants, showed varying results. The current and routinely
used critical care enteral formulas available globally deliver
between 0 and 18.7 g arginine for every liter of formula provided
(Table 4). It is estimated that, on average, an intensive care unit
(ICU) patient receiving L-arginine–supplemented enteral feeding
at goal delivery rates would receive between 15 and 30 g
L-arginine/d. It is difficult to determine the appropriate and safe
level for use in critically ill or hypermetabolic patients because
they are in proinflammatory states. The commercially available
formulations have other ‘‘pharmaconutrients’’ that will alter the
metabolic state, and interactions between these agents have yet
to be determined. At the current level, the arginine available
in commercially mixed formulations appears to be safe and
beneficial (46).
The Arginine Controversy in Sepsis
the shock state through the iNOS pathway (49, 54–59). These
conclusions were unfounded, and as discussed later, NO
production does not drastically increase, nor is it clinically
relevant because mean arterial pressure does not decrease with
L-arginine supplementation. The concept of L-arginine supple-
mentation can at least be partially explained by the ‘‘arginine
paradox.’’ This is essentially the nonintuitive response expected
from supplemental arginine. This was well described by Tsikas
et al. (60), who showed that endogenously produced NO
synthase inhibitors are responsible for the ‘‘paradox.’’
In a canine septic model, Kalil et al. (61) suggested that
‘‘supplemental parenteral L-arginine, at doses above standard
dietary practices, should be avoided in critically-ill patients
with septic shock.’’ A criticism of this trial is that the doses
administered to the dogs in the parenteral nutrition (PN)
formulas (10 or 100 mg
kg21
h21) are equivalent to 90 g/d
for a human and are considered to be supraphysiologic. In
addition, it is unclear whether results obtained in a canine model
of sepsis can be extrapolated to humans. Differences due to
administering L-arginine enterally rather than parenterally also
need to be considered.
Luiking et al. (15, 48), building on several studies that
showed the benefit of supplemental arginine in sepsis, set out to
answer the question, ‘‘Can giving too much arginine in sepsis be
detrimental?’’ In the study, Luiking et al. evaluated 8 critically
ill patients with septic shock and infused varying doses of
L-arginine-HCl in 3 stepwise and increasing supraphysiologic
doses (33, 66, and 99 mmol
kg21
h21) (15, 48). They noted the
following (15):

L-Arginine supplementation has prompted much controversy. ‘‘.septic patients demonstrated elevated protein breakdown at
The theoretical concept that L-arginine may pose a threat to baseline (P value < 0.001 compared with healthy controls),
whereas protein breakdown and synthesis both decreased during
surgical or critically ill patients is based on the perception that
continuous arginine infusion (P < 0.0001). Mean arterial pres-
postoperative or septic surgical patients are often hemodynam-
sure, pulmonary artery pressure, and gastric mucosal perfusion
ically unstable, with a heightened inflammatory response and (as measured by arterial partial pressure of carbon dioxide
upregulated iNOS enzyme activity. It is hypothesized that difference [(Pr-aCO2) gap]) remained stable during arginine
by supplying supplemental L-arginine in metabolic states of infusion (P > 0.05). Stroke volume (SV) increased (P < 0.05) and
upregulated iNOS, an increase in L-arginine will yield additional arterial lactate decreased during the infusion (P < 0.05). In
NO. The potential result of increasing NO is that it may
exacerbate the vasodilation already present in septic patients.
This could worsen hemodynamic stability in a patient with
TABLE 4 L-Arginine in commercially available formulations
refractory hypotension associated with sepsis (2, 40, 47). The
hypothesis that supplementation of L-arginine will dramatically Product Manufacturer Protein, g/L Arginine, g/L
increase NO has been tested in both animal and human models
with severe sepsis and septic shock and has produced contra- Alitraq Abbott/Ross 52.5 4.5
dictory outcomes (15, 48–50). Optimental Abbott/Ross 51.3 5.5
Oxepa Abbott/Ross 62.5 0
Perative Abbott/Ross 66.6 6.5
L-Arginine in Sepsis Crucial Nestlé 94 15
Peptamen AF Nestlé 75.6 0
Septic shock is currently considered an L-arginine–deficient
Impact Nestlé 56 12.5
state, driven by the upregulation of Arginase-1 and -2 and iNOS
Impact (with fiber) Nestlé 56 12.5
(50). In 2016, the American Society of Parenteral and Enteral
Impact Peptide 1.5 Nestlé 84 18.7
Nutrition and the Society of Critical Care Medicine Critical
Impact Glutamine Nestlé 78 16.3
Care Nutrition Support guidelines clearly stated that arginine
Immunex-Plus Victus, Inc. 37 14
supplementation in septic states is not contraindicated but is not
2596S Supplement
 conclusion, a 4-fold increase in plasma arginine during intrave-
nous L-arginine infusion in sepsis stimulated de novo L-arginine
and NO production while reducing whole-body protein break-
down. These potentially beneficial metabolic effects occurred
without negative alterations in hemodynamic parameters.’’
This study questioned the validity of the canine model in study by
Kalil et al. (61), given the numerous observed physiologic benefits.
In another study, Bertolini et al. (49) showed reduced ICU
mortality in a group of 39 patients with severe sepsis or septic
shock who received enteral nutrition (EN) containing low-dose
L-arginine (arginine: 8 g/L; Perative, Abbott Nutrition) com-
pared with those receiving PN (mortality: 44.4% compared with
14.3%; P = 0.039). This study was not blinded and used a
subgroup of a larger multicenter trial, making it difficult to
identify significant mortality differences. Having recognized the
limitations of the former trial in 2003 (49), the same group
of authors revisited whether or not enteral immunonutrition,
compared with PN, in critically ill patients with septic shock was
safe. After analyzing 326 patients in this observational study
they concluded, ‘‘Compared to parenteral nutrition, immune
modulating EN containing L-arginine appears to be beneficial in
critically-ill patients. Parenteral nutrition in these patients
should be abandoned, at least when EN can be administered,
even at an initial low caloric content’’ (62).
López et al. (43) infused nonspecific iNOS inhibitor in septic
patients and showed increased mortality in this group, suggest-
ing that blocking NO synthesis is detrimental and that it is
required for vasoregulation. These investigators reported on
patients with severe sepsis or septic shock with the use of 28-d
mortality as their primary endpoint. The trial was terminated
early because there was a significant increase in mortality when
blocking iNOS, compared with patients receiving 5% dextrose as
placebo, of 59% compared with 49%, respectively (P < 0.001).
It has been suggested that an imbalance of L-arginine and
asymmetric dimethylarginine (ADMA) is detrimental and a
possible culprit of end-organ dysfunction. ADMA is produced as
a post-translational alteration to L-arginine and causes vasocon-
striction, which is thought to counterbalance the vasodilation
effects of NO. ADMA is noted in the blood upon the breakdown
of protein, which increases in most stressed pathophysiologic
states (23). Arora et al. (63) showed that L-arginine supplemen-
tation improved global perfusion in a rodent hemorrhagic shock
model. They also suggested that overcoming the vasoactive
effects of ADMA with supplemental arginine seemed to be the
primary mechanism. Visser et al. (28, 29) reported that elevated
L-arginine and lower ADMA resulted in reduced mortality in
septic patients. A lower L-arginine-to-ADMA ratio resulted in
poor organ perfusion and decreased cardiac output. Gough et al.
(64) evaluated L-arginine-to-ADMA ratios in 109 septic pa-
tients and 50 nonseptic controls. They showed that a declining
L -arginine-to-ADMA ratio was independently associated with
in-hospital mortality (OR: 1.63/quartile; 95% CI: 1.00, 2.65;
P = 0.048) and increased risk of death at 6 mo (HR: 1.41/quartile;
95% CI: 1.01, 1.98; P = 0.043) (64).
Until recently, few studies had evaluated supplemental L-arginine
as a single agent in critically ill septic patients. Luiking et al. (42)
published an elaborate series of tracer studies in a clinical trial that
dealt with citrulline and L-arginine metabolism in septic patients.
The complex metabolic alterations noted in sepsis that contribute
to reduced citrulline and L-arginine availability would suggest
that L-arginine supplementation may be beneficial in the septic
population. In another investigation of metabolic studies that
used tracer technology, Kao et al. (40) again evaluated L-arginine
in sepsis and also concluded that L-arginine may be deficient
in sepsis, via inadequate de novo synthesis, with supplemen-
tation improving end-organ perfusion. These studies underscore
the potential benefits of continuously infused L-arginine, as
reviewed above.
Last, it is unclear if L-arginine should be provided with other
immune-modifying agents (e.g., fish oils, arginine, glutamine,
and/or nucleic acids). Potential metabolic interactions between
L-arginine and other delivered nutrients must be considered
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before administration. In very different models, Bansal et al. (26)
and Alexander and Supp (65) both showed that delivery of an
n–3 FA with L-arginine will significantly alter L-arginine metab-
olism via inhibition of Arginase-1 and variable influences of
iNOS. To date, the vast majority of clinical trials and meta-
analyses that used the L-arginine fish-oil formulations have
proven beneficial in surgical populations (46, 66, 67).
Which Patients May Benefit from L-Arginine
Supplementation?
Pre- and postsurgical and trauma patients appear to have the
most supportive clinical data for L-arginine supplementation.
We are unaware of any reports of toxicity in immune modula-
tion with L-arginine–containing formulations. Patients with
persistent immunosuppressed inflammatory catabolic state
(PICS), a newly defined malady of the ICU population, may
benefit from L-arginine supplementation. Gentile et al. (68) and
Moore et al. (59) first characterized PICS as follows: an ICU
length of stay >14 d, C-reactive protein >1.5 mg/L, total
lymphocyte count <0.80 3 109/L, weight loss >10% during
hospitalization or BMI (in kg/m2) <18, creatinine height index
<80%, serum albumin <3.0 g/dL, serum prealbumin <10 mg/dL,
and retinol binding protein <1 mg/L. If ICU patients survive
acute critical illness and multiple organ failure, they often enter
into a state of chronic critical illness, which is defined as being in
the ICU for >14 d with ongoing low-grade organ dysfunction.
Current literature supports that this population is at risk of
PICS, which is associated with dismal long-term outcomes (6,
17, 35, 68, 69). In patients with critical illness, a rather large
portion of those with chronic critical illness go on to develop
PICS (35, 68). Patients >65 y old with premorbid conditions,
such as heart failure, renal dysfunction, and obesity, are most
susceptible to PICS (35, 60–74). Unfortunately, these patients
lose tremendous amounts of lean body mass, despite optimal
nutrition, leading to profound ICU-associated weakness, recur-
rent nosocomial infections, and poor wound healing (75–77).
L-Arginine supplementation may be beneficial in PICS. To better
understand this, we have to explore the nature of myeloid-
derived suppressor cells, which are immature white blood cells
secreted by the bone marrow after substantial stress, such as
sepsis or trauma. These cells migrate to the spleen, liver, and
lymph nodes and express significant amounts of Arginase-1,
which depletes L-arginine in these tissues (37, 44, 78). Without
adequate L-arginine, lymphocytes cannot proliferate, which
contributes to immunosuppression and, in turn, to an increased
risk of nosocomial infections (27, 79). Recently, Drewry et al.
(80) suggested that persistent lymphopenia on day 4 after
sepsis diagnosis can predict early and late mortality, as well as
increased chances of secondary infection. The authors suggest
that the cause of this is the depletion of L-arginine stores during
severe stress. Thus, early supplementation of L-arginine in this
population could potentially be of great therapeutic value.
Is clinical use of parenteral/enteral arginine toxic? 2597S
 Galbán et al. (81) concluded that immune-enhanced EN
diminished bacteremia and secondary nosocomial infections but
also reduced mortality in septic patients. These formulas were
fortified with L-arginine, mRNA, and n–3 FAs. The L-arginine
supplementation pendulum seems to be swinging back toward
the suggestion of benefit, particularly in the septic population.
Conclusions
The importance of L-arginine in the metabolism of the surgical
and critically ill population cannot be understated. In this
review, we highlighted the clinical safety of L-arginine supple-
mentation in multiple settings, primarily in surgical and septic
populations. It is difficult to theorize the exact influence and
control of all of the metabolic interactions and mechanisms of
the benefits noted, but the biological plausibility may be related
to a combination of L-arginine repletion (of a depleted group),
augmentation of NO, and shifting the L-arginine-to-ADMA
ratio, leading to an improvement in vasoregulation and oxygen
delivery. The elaborate and highly regulated control of L-arginine
within the cell could be the site of multiple mechanistic targets,
including transporters into the cell, multiple enzyme substrates
of L-arginine, colocalization of enzymes, endogenous iNOS
inhibitors, and substrate availability. In addition, new informa-
tion on the role of L-arginine in modulating immune function
must be considered. Numerous reports show inadequate T cell
function with depleted L-arginine availability. Recent data show
the importance of L-arginine in the regulation and conversion
of the M1 proinflammatory to M2 resolution macrophage
classes and may yield yet another indication for supplemental
L-arginine. Adequate cellular L-arginine is associated with M2
class promotion, leading to inflammation resolution and prolif-
eration of repair physiology (82, 83).
The objective of this review was to answer the question, ‘‘Is
there any evidence of toxicity with the clinical use of L-arginine?’’
Our response can be summarized as follows: L-Arginine delivered
via the enteral route shows no toxicity when supplied at the doses
available in commercial formulations. Enteral L-arginine, when
delivered as part of a complete enteral formulation, #30 g/d, and
probably even $40 g/d, is safe and shows no signs of toxicity. When
taken orally as a bolus without other macronutrients >30 g/d, some
gastrointestinal upset and diarrhea may result. Parenteral delivery of
L-arginine appears to be safe at clinical levels, although there are
inadequate studies with dose responses, rates of infusion, or method
of infusion to make a definitive answer. It is clear that arginine is
safe in septic patients when administered by either the enteral or
parenteral route. Supplemental arginine infusions may be beneficial
to septic patients. Further research is needed to define the optimal
dose of arginine and to determine the best methods for making this
decision.
Acknowledgments
MDR, PWC, JP, LK, and RGM wrote the manuscript; and
RGM had primary responsibility for final content. All authors
read and approved the final manuscript.
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