Good for muscle building and wound healing, plus …

Arginine Helps Fight Septic Shock

Which if contracted may decrease your risk of survival by 50%

By Will Block

S eptic shock is a severe medical condition that results from sepsis, the presence in tissues of harmful bacteria and their toxins, typically caused through infection of a wound. In response, septic shock is an overwhelming immune response to infection, when immune chemicals released into the blood to combat the infection trigger widespread inflammation, which leads to blood clots and leaky vessels. This results in impaired blood flow, which damages the body’s organs by depriving them of nutrients and oxygen.

The Elderly Are the Prime Targets of Sepsis

At its vilest, septic shock can cause multiple organ failure (MOF), which can simultaneously destroy many of the body’s organs, resulting in death. Systemic inflammatory response syndrome (SIRS) leads to multiple organ dysfunction syndrome (MODS) — and in the worst-case scenario, to MOF (see Fig. 1). Among its common victims are children and immune-compromised individuals. However, the elderly are primary targets, as their immune systems cannot deal with the infection as effectively as those of healthy adults. Patients suffering from septic shock are frequently treated in hospitals and intensive care units, where sepsis is a major cause of mortality. The mortality rate from septic shock is as high as 50%.


The mortality rate from septic shock
is as high as 50%.


In addition to the inflammatory response to infection and multiple organ failure, septic shock is characterized by hemodynamic instability and increased protein turnover. Although global volume-related hemodynamic variables can be stabilized, regional disturbances in organ perfusion — the restoration of blood to an area denied its benefits — are the most important predictors of the worst outcome. Dysfunctional organ perfusion occurs at the microcirculatory level and contributes to the syndrome, along with cell damage and impaired tissue oxygenation.

The Septic Problems Associated with Too Little NO

Inadequate nitric oxide (NO) production in endothelial cells is thought to be of key importance to maintain microcirculation. This is supported by the observed decrease in endothelium-dependent NO in the microcirculation during experimental endotoxemia in humans.


In animal models of endotoxemia,
manipulation of arginine-NO
metabolism improved perfusion and
increased NO production in
various organs.


The researchers of a new study2 suggest that observed changes in the arginine pathway during sepsis is the underlying metabolic cause for impaired NO production and dysfunctional microcirculation. The mechanism of the reduced plasma arginine levels is most likely to be a combination of impaired endogenous arginine production and increased arginine clearance. The reduction of arginine availability in sepsis is related to impaired NO production, which is further deprived by elevated levels of endogenous NO synthase (NOS) inhibitors. In animal models of endotoxemia, manipulation of arginine-NO metabolism improved perfusion and increased NO production in various organs.

To date, however, there has been no study that has measured NO production and protein metabolism in patients with sepsis during arginine administration in the post-absorptive state. Therefore, a new study2 investigated the dose-response effect of intravenous arginine supplementation in patients with septic shock in the post-absorptive state on arginine-NO and protein metabolism and on global and regional hemodynamics. As a reference, metabolic data were compared with those in healthy control subjects.


The aim of the Texas A&M University
study was to investigate the dose-
response effect of intravenous
arginine supplementation in post-
absorptive patients with septic shock
on arginine-NO and protein
metabolism and on global and
regional hemodynamics.


Up to 570,000 Deaths

The Center for Disease Prevention and Control’s National Center for Health Statistics estimates that the number of times people were in the hospital with sepsis or septicemia (another word for sepsis) increased from 621,000 in the year 2000 to 1,141,000 in 2008.1 And of those who get sepsis, between 28 and 50 percent die. That’s between about 320,000 to 570,000 deaths per year.

Yet when you examine the latest leading causes of death published at the CDC, this is what you get:

1. Heart disease: 611,105

2. Cancer: 584,881

3. Chronic lower respiratory diseases: 149,205

4. Accidents (unintentional injuries): 130,557

5. Stroke (cerebrovascular diseases): 128,978

6. Alzheimer’s disease: 84,767

7. Diabetes: 75,578

8. Influenza and Pneumonia: 56,979

9. Nephritis, nephrotic syndrome, and nephrosis: 47,112

10. Intentional self-harm (suicide): 41,149

Where on this list is sepsis? The CDC figures1 for sepsis give us reason to conclude that there are a great many invalid suppositions in the causes of death computations. Take Alzheimer’s disease, for example. A paper published in Neurology last year challenges the Alzheimer figures. According to the report, the figures given by CDC would translate into about 503,400 deaths from Alzheimer’s if misdiagnosis is taken into consideration. As an example of this, President Ronald Reagan’s death certificate stated that he died of pneumonia, rather than Alzheimer’s.

The adjustment computes that the real Alzheimer’s figure is nearly six times higher than the more than 83,000 (the figure available when the paper was written) reported Alzheimer’s deaths. The researchers reported that it is clear from the findings that Alzheimer’s disease and other forms of dementia are underreported on death certificates and in medical records. (See “Alzheimer’s Deaths Rival Cancer’s” in the May 2014 issue.) If a person is admitted to a hospital suffering from heart disease, which may not necessarily be deadly, and if they then develop septic shock, and die from it, then the cause of death is sepsis and not heart disease (see Fig. 2).

Arginine Deficiency

Figure 1. Multi-organ failure (MOF) occurs during septic shock.
LEM1504argininefig1_274.gif
(click on thumbnail for full sized image)

The recent, hitherto referenced, clinical trial — conducted in The Netherlands by the Center for Translational Research in Aging & Longevity, Department of Health and Kinesiology, Texas A&M University — started with the observation that arginine deficiency in sepsis may impair nitric oxide (NO) production for local perfusion and add to the catabolic state, the break-down of molecules into smaller units to release energy.2 Of some concern, excessive NO production has been related to global hemodynamic instability. But this is true of anything in excess. Said Paracelsus (1493 – 1541), the Renaissance physician, botanist, and father of modern pharmacology: “All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.”


Sepsis patients demonstrated elevated
protein breakdown at baseline
compared with healthy controls,
whereas protein breakdown and
synthesis both decreased during
arginine infusion.


The aim of the Texas A&M University study was to investigate the dose-response effect of intravenous arginine supplementation in post-absorptive patients with septic shock on arginine-NO and protein metabolism and on global and regional hemodynamics. Plasma levels of arginine are known to decrease in sepsis, due to impaired endogenous NO production and increased arginine clearance. Could increasing levels of arginine reduce the damage of sepsis?

Dietary and “Made in the Body” Arginine

Arginine is available in the western diet from numerous sources. Normal arginine intake is between 5 and 7 g/day, and endogenous production of arginine is estimated to be 15 – 20 g.3 Numerous studies using differing doses of arginine from 5 to 30 g/day in the normal subject have shown varying results. It appears that orally delivered arginine supplementation up to 30 g/d is safe with few gastrointestinal side effects.

In the study, eight critically ill patients with a diagnosis of septic shock participated in a short-term (8 hours) dose-response investigation. L-Arginine-HCl was continuously intravenously infused in three stepwise-increasing doses (33, 66, and 99 μmol/kg/hour). Whole-body arginine-NO and protein metabolism were measured using stable isotope techniques, and baseline values were compared with healthy controls.

Global and regional hemodynamic parameters were continuously recorded during the study. After arginine infusion, plasma levels were increased by more than a factor of three. This coincided with increased de novo arginine and increased NO production. Sepsis patients demonstrated elevated protein breakdown at baseline compared with healthy controls, whereas protein breakdown and synthesis both decreased during arginine infusion.

In other words, the near 4-fold increase in plasma arginine with intravenous arginine infusion in sepsis stimulated new arginine and NO production and reduced whole-body protein breakdown.

Since these metabolic effects are already apparent at 66 µmol/kg/hour arginine infusion (~21 g of arginine), this amount seems appropriate for future studies. While these potential beneficial metabolic effects occurred without negative alterations in hemodynamic parameters, the improvement in regional perfusion could not be demonstrated in the eight patients with septic shock who were studied. The researchers thought this might have been because the sample was so small.

Dr. Barbul and the Case for Arginine Use in Sepsis

The distinguish surgeon and medical author Dr. Adrian Barbul has been writing about the healing qualities of arginine for two generations. In addition to the following papers:

• Arginine: a thymotropic and wound-healing promoting agent

• Supplemental arginine, wound healing, and thymus: arginine-pituitary interaction

• Arginine: an essential amino acid for injured rats

• Immunostimulatory effects of arginine in normal and injured rats

• Thymic stimulatory actions of arginine

• Arginine stimulates lymphocyte immune response in healthy human beings

• Metabolic and immune effects of arginine in post-injury hyperalimentation

• Wound healing and thymotropic effects of arginine: a pituitary mechanism of action

• Optimal levels of arginine in maintenance intravenous hyperalimentation

• High arginine levels in intravenous hyperalimentation abrogate post-traumatic immune suppression

• Intravenous hyperalimentation with high arginine levels improves wound healing and immune function.

• Arginine: biochemistry, physiology, and therapeutic implications

• Arginine metabolism in wounds

• Arginine and immune function

• Arginine enhances wound healing and lymphocyte immune responses in humans

There are these 5 articles:

• Use of exogenous arginine in multiple organ dysfunction syndrome and sepsis

• Sepsis impairs anastomotic collagen gene expression and synthesis: a possible role for nitric oxide

• Reduced intestinal absorption of arginine during sepsis

• Sepsis impairs gut amino acid absorption

• Role of arginine in trauma, sepsis, and immunity

In Dr. Barbul’s sepsis articles, he explains the case for arginine to combat sepsis, and the misunderstandings that have kept it out of research consideration. However, with the publication of the recent paper, hopefully other researchers will resume further investigation.

Galantamine Controls Inflammatory Response

A recent paper reported that alpha7 nicotinic cholinergic receptors might be a novel therapeutic target for inflammation-based disease. Other studies suggest that the inflammatory response in sepsis can be controlled by activating the cholinergic system. Furthermore, they point out that cholinesterase inhibitors can control the inflammatory response in experimental sepsis, significantly improving survival if administered immediately after induction of sepsis — but not if treatment is delayed. “A number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines.” The cholinesterase inhibitor nutrient galantamine is an alpha7 nicotinic cholinergic agonist (activating the cholinergic anti-inflammatory pathway via the alpha7 nicotinic cholinergic receptor).4

Melatonin Suppresses the Release of Inflammatory Cytokines

Figure 2. Septic shock appears as a leading cause of death
LEM1502argininefig2_274.gif
(click on thumbnail for full sized image)

A very recent paper reports that melatonin may be useful as a treatment for Ebola because of certain of its effects that have been reported in published peer-reviewed scientific papers that includes suppression of the release of inflammatory cytokines (TNF-alpha, IFN-alpha, IL-6, IL-8, TF (tissue factor) and MCP-1 (monocyte chemoattractant protein-1), as well as the downstream events triggered by the release of these molecules such as the initiation of blood coagulation by TF. Melatonin acts as an anti-coagulation agent. In the paper, Ebola infection is considered to be similar to septic shock, a condition that results from a runaway immune inflammatory response to infection. The authors predict in this 2014 paper that death from Ebola virus disease “may be significantly reduced as a result of melatonin administration.” They discuss the uncertainty of the proper dose because of limited dose response studies with melatonin, suggesting that early intervention with a large dose (20 mg or more for a single dose) might be necessary. In fact, if necessary and under severe conditions of an infection, melatonin could be taken in doses of 20 mg three or four times a day.

Dextromethorphan, an Effective Treatment of Endotoxic Shock in Mice, Rats

According to Durk Pearson & Sandy Shaw, an inexpensive over-the-counter cough medicine has been shown to be effective in rats and mice for the treatment of sepsis (see “Keep a Supply On Hand for … When You Need It But Can’t Get It” in the July 2013 issue). Sepsis often occurs, “… in hospitals where large areas of the body can be exposed to bacterial invasion (as in surgical procedures and large area burns) or as a result of catheters or other devices that enter the body through the skin, allowing bacteria to enter.”

Over-the-counter cough medicine contains dextromethorphan (DXM), and frequently guaifenesin, which is often included for chest congestion (forget that and buy the version containing only DXM). This provided significant, very impressive protection against endotoxin shock in mice. No prescription required, and it’s cheap.


After 14 days, the survival rate of
GAS-infected mice without DXM
treatment was only 10%, while the
DXM treated GAS infected mice
showed approximately 72% survival.


In one study,5 endotoxin shock was induced in mice by administering a single intraperitoneal dose of lipopolysaccharide (LPS). Controls received injections of saline. Pretreatment with DXM (30 minutes prior to LPS) at 25 and 12.5 mg/kg, subcutaneously, significantly increased the survival rate up to 90%, while even at the lower dose, survival was increased to 67%.

The researchers found that TNF-alpha (tumor necrosis factor-alpha), a powerful proinflammatory cytokine associated with sepsis, was significantly decreased by dextromethorphan in both liver and serum.

“[DXM] may be a novel compound for the therapeutic intervention for sepsis,” noted the researchers.

Another paper6 reported that pretreatment with DXM reduced the damaging effects in rats treated with LPS (a component of bacterial cell walls). The researchers suggested that, “DM can possibly be used as a prophylactic agent for sepsis in the future.”

Then, in 2011, another paper7 on the antimicrobial and antisepsis effects of dextromethorphan was published. In this study of gram-positive Group A streptococcus (GAS) infections, dextromethorphan was found in mice to increase survival, enhance bacterial clearance, and reduce systemic inflammatory response and organ injury. The animals were inoculated in the air pouch with a lethal dose of GAS NZ131 microbes with or without DXM treatment (12.5 mg/kg) 30 minutes before and 1, 12, and 24 hours after bacterial inoculation.


The bacteria used in this experiment
are one of the infamous “flesh eating
bacteria” that rapidly devour human
flesh and often require limb
amputation.


After 14 days, the survival rate of GAS-infected mice without DXM treatment was only 10%, while the DXM treated GAS infected mice showed approximately 72% survival.3 Liver damage (as shown by fatty degeneration of liver cells, in which the cytoplasm was filled with foamy vacuoles of fat) was inhibited by DXM, which was also reflected by lower serum levels of AST (a liver enzyme increased under conditions of liver injury) in the GAS infected, DXM-treated mice as compared to the GAS infected (but no DXM) mice. The researchers explain: “Although infecting bacteria can be taken care of by antibiotics, the bacterial components released from dead bacteria, such as peptidoglycans, lipoproteins, lipoteichoic acids, and LPS, may be responsible for systemic inflammation and cause organ failure and sepsis.”3 By contrast, DXM reduces the inflammatory response. With respect to dosage, the authors say, “[c]ombined with antimicrobial agents, the dosage of [DXM] may be reduced comparably to the recommended doses as a cough suppressant, but this issue needs to be tested.”

The bacteria used in this experiment are one of the infamous “flesh eating bacteria” that rapidly devour human flesh and often require limb amputation.

Interestingly, one of the papers3 reports that DXM has been shown in previous studies to decrease ROS at least in part through the inhibition of NADPH oxidase, a major source of oxidative stress.


The authors of this paper suggest that
their findings offer a “novel
therapeutic concept of using ‘ultra-
low’ drug concentrations for the
intervention of inflammation-related
neurodegenerative diseases.”


This is a medicine that could be stockpiled for use when you or a loved one are threatened by sepsis and either the infection is antibiotic-resistant (a rapidly growing problem due to out-of-control drug approval costs) or supplies of antibiotics are limited due to health care system rationing or other problems. DXM is stable, and can be stored for many years.

Also, in an earlier study,8 scientists found that the death of dopaminergic neurons in neuron-glia cell culture by inflammation induced by activated microglia could be decreased by DXM at the unbelievably low levels of micromolar and even femtomolar concentrations. This is far lower than the dose used in the control of cough. The authors of this paper suggest that their findings offer a “novel therapeutic concept of using ‘ultra-low’ drug concentrations for the intervention of inflammation-related neurodegenerative diseases.” Durk & Sandy have pointed out the human-equivalent dose for humans is 10 ml (2⁄3 teaspoon) of the liquid cough suppressant.

References

  1. Sepsis Questions and Answers. Centers for Disease Control and Prevention. May 22, 2014. http://www.cdc.gov/sepsis/basic/qa.html. Accessed March 25, 2015.
  2. Luiking YC, Poeze M, Deutz NE. Arginine infusion in patients with septic shock increases nitric oxide production without haemodynamic instability. Clin Sci (Lond). 2015 Jan;128(1):57 – 67. doi: 10.1042/CS20140343.
  3. Zhou M, Martindale RG. Arginine in the critical care setting. J Nutr. 2007 Jun;137(6 Suppl 2):1687S – 1692S.
  4. Bencherif M, Lippiello PM, Lucas R, Marrero MB. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci. 2011 Mar;68(6):931 – 49.
  5. Li G, Liu Y, Tzeng NS, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol. 2005 Jan 15;69(2):233 – 40.
  6. Wang CC, Lee YM, Wei HP, Chu CC, Yen MH. Dextromethorphan prevents circulatory failure in rats with endotoxemia. J Biomed Sci. 2004 Nov-Dec;11(6):739 – 47.
  7. Li MH, Luo YH, Lin CF, Chang YT, Lu SL, Kuo CF, Hong JS, Lin YS. Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents group a streptococcal sepsis. Antimicrob Agents Chemother. 2011 Mar;55(3):967 – 73.
  8. Li G, Cui G, Tzeng NS, Wei SJ, Wang T, Block ML, Hong JS. Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. FASEB J. 2005 Apr;19(6):489 – 96.


Will Block is the publisher and editorial director of Life Enhancement magazine.

Featured Product

  • Learn more about Arginine benefits and implementation strategies.

Ingredients in this Article

FREE Subscription

  • You're just getting started! We have published thousands of scientific health articles. Stay updated and maintain your health.

    It's free to your e-mail inbox and you can unsubscribe at any time.
    Loading Indicator