Ascorbic Acid in Sepsis and Septic Shock

Abstract

Septic shock is a common condition that occurs in the intensive care unit (ICU). Sepsis is the most common cause of death with a mortality between 35 and 50%. Several factors are implicated in the increasing incidence of sepsis, including age, immunosuppression, and antibiotic resistance. Gram+ or gram infections are considered as the main causes of sepsis. The prognosis of septic shock is significantly influenced by early treatment. The patient’s hospitalization in the intensive care unit is particularly important, as the complications of shock make it essential to support vital signs. The scope of this chapter is to study the effects of ascorbic acid in the treatment of septic shock and the benefits of its administration.

1. Introduction

The septic shock syndrome has been known since ancient times. With a mortality rate of about 30–45%, it is one of the biggest issues in the medical industry because it affects both community members and hospitalized patients. International guidelines are published by the scientific community for the proper diagnosis and therapeutic care of sepsis patients, such as the “Surviving Sepsis Campaign” in 2012 [1].

The hemodynamic stabilization of the patient is crucial accordingly with the guidelines, the right medication in the right time, primarily antibiotics [2].

In sepsis, the immune response of the host, or the organism, plays a crucial role. According to William Osler (1849–1919), “Except in a few cases, patients die because of their organism’s response to the infection and not because of the illness.” This revelation marked a turning point in our knowledge of how an infection affects the host’s immune system [3].

2. Septic shock-definitions

2.1 Shock

Shock is characterized as abrupt modifications to the mechanisms of life. A clinical example of the body’s inability to effectively perfuse the tissues is cataplexy. Shock can be caused by a variety of factors, including changes in blood circulation volume, changes in the pumping capacity of the heart, and changes in peripheral resistance. Regardless of the shock type, the systemic reaction is detrimental and frequently results in multiple-organ dysfunction syndrome (MODS). The most important thing is to locate and eliminate the shock’s primary source in order to avoid potentially fatal consequences.

2.2 Sepsis

Clinically or microbiologically documented infection, accompanied by at least two of the following:

1. Temperature > 38°C or < 36°C

2. Pulses >90/minute

3. Respirations >20/min

4. WBC >12,000/mm3 or < 4000/mm3

2.3 Serious sepsis

Sepsis accompanied by failure of at least one organ:

1. Respiratory failure

2. Acute renal failure

3. Metabolic acidosis

4. Disseminated intravascular coagulation (DIC)

5. Disorder of the CNS

6. Malfunctions of other organs

2.4 Septic shock

Septicemia that is resistant to fluid replenishment is known as “septic shock”, which leads to hypotension and malfunction of the tissue blood supply. Acidosis, primarily lactic acidosis, oliguria, and changes in consciousness arise from insufficient fluid replacement. When an infectious agent or an infection-activated mediator triggers a systemic and all-encompassing immune response, septic shock results. Systemic vascular resistance (SVR) declines as a result of the body’s response to the infection [4].

2.5 Diagnosis

Finding signs of infection, organ malfunction, and tissue hypoxia from the history, clinical examination, and paraclinical tests are the basis for the diagnosis of sepsis. We can learn about recent interaction with an infectious agent, implanted devices like a pacemaker or defibrillator, immunosuppression, and the presence of catheters like a port-a-cath or pigtail from the history. One of the most typical clinical signs of sepsis is fever. When there is no fever, we start to consider other things, including age, shock, chronic renal failure, and immunosuppression.

Since the majority of sepsis patients exhibit the distinctive symptoms, the search for the Systemic Inflammatory Reaction Syndrome criteria is highly helpful. Prothrombin time and fibrin degradation product testing should be performed on every patient with a suspicion of sepsis to determine whether the coagulation mechanism has been activated (D-dimmers). Keep in mind that we will see elevated D-dimmers and an extended prothrombin time as a result of thrombocytopenia. Because of tissue hypoxia and the initiation of anaerobic metabolism, lactic acid levels have increased.

Finding the infection will be greatly helped by obtaining blood cultures. Keep in mind that two blood cultures must be obtained. Based on clinical findings and signs of inflammation (redness at the catheter entry site) from the clinical examination, cultures should be obtained from other sites if necessary. This is because, in order of frequency, sepsis-causing infections include pneumonia, urinary tract infections, intra-abdominal infections, skin infections, and catheters in central vessels. For sepsis, about 80 diagnostic and prognostic markers (such as protein C, IL-6, procalcitonin, and C-reactive protein) have been studied.

Although an increase in their price is associated with an increase in mortality, none of them are very helpful in the diagnosis of sepsis due to their low sensitivity. Procalcitonin (PCT) and C-reactive protein are largely the markers that are most frequently employed (CRP). It is advised to take the elevated values into account along with the patient’s clinical profile and the findings of any paraclinical testing [2, 5].

2.6 Treatment

The goal of treating a septic patient is to:

• effectively treat the primary infection

• support critical functions; and

• prevent and appropriately manage hospitalization-related complications, should they occur.

Administration of the proper antimicrobial medication for “source control” is a component of treating the original infection. Source control refers to the management of pathogens that, if left untreated, would render antimicrobial therapy ineffective. This includes surgical treatment of surgical infections, removal of catheters (such as central venous catheters or bladder catheters, if the infection is caused by their presence), drainage, etc. After receiving a diagnosis, it is advised to check the outbreak within 6 hours. All measures should be carried out right once because delaying the start of antimicrobial therapy is linked to a higher mortality rate when septic shock is present.

The diagnostic and therapeutic tools available in the intensive care unit (ICU) support the maintenance of vital functions and the restoration of the homeostasis that is based on them [6].

A few examples include constant monitoring of essential bodily functions, extrarenal clearance, and mechanical support for breathing. Admission to the intensive care unit is required when organ dysfunction, which happens in septic shock, is found. The therapy of the septic patient includes several crucial steps, including hemodynamic stabilization and resuscitation. Restoring tissue hypoxia in septic patients is important because it affects their prognosis. Cardiac output, arterial blood hemoglobin saturation, and hemoglobin value are variables that determine the amount of oxygen given. As a result, good management of these parameters enhances the oxygen supply. Restoring preload and myocardial contractility is a part of optimizing cardiac output in this situation. The delivery of a suitable quantity of intravenous crystalloid solutions and the injection of inotropic drugs, such as dobutamine, when necessary, are the ways to accomplish these objectives. The accomplishment of blood pressure enough for the irrigation of peripheral organs runs parallel to the optimization of cardiac output. As long as intravascular volume restoration is insufficient, the aim is to keep mean arterial pressure at 65 mm Hg by administering vasoconstrictor drugs like noradrenaline. While the restoration of the hemoglobin concentration is accomplished with the transfusion of packed red blood cells, the arterial blood’s hemoglobin saturation is ensured through the provision of oxygen or mechanical ventilation. Hydrocortisone, which helps reverse shock more quickly but does not improve prognosis, may be explored if hypotension persists despite efforts to address the aforementioned variables. Its administration is theoretically justified by the fact that septic shock patients exhibit “relative” cortico-adrenal insufficiency. The resuscitation of the septic patient should be quantified and targeted toward achieving specified hemodynamic targets. The so-called early goal-directed therapy (EGDT), which is regarded as an efficient and secure resuscitation technique and is advised in international standards, is the most pervasive embodiment of this viewpoint (Surviving Sepsis Guidelines) [7].

2.7 Antibacterial therapy

• Aztreonam,

• quinolones,

• piperacillin/tazobactam,

• ceftolozane/tazobactam,

• ceftazidime/avibactam,

• carbapenems, colistin,

• third- or fourth-generation cephalosporin.

2.8 Sepsis and septic shock assessment scales

2.8.1 Sofa score

In order to quantify quantitatively and as objectively as possible the degree of organ dysfunction/failure over time in septic patients, ESICM conducted a consensus meeting in Paris in October 1994. The result was the sepsis-related organ failure assessment (SOFA) scale.

Twenty-four hours after ICU admission and every 48 hours after that, the score is calculated [7, 8].

2.8.2 The APACHE score

The intensive care unit (ICU) makes extensive use of the Acute Physiology and Chronic Health Evaluation (APACHE) score as a method of rating patient outcomes. The worst readings within the first 24 hours of ICU admission are used as the usual data to generate the APACHE II score [9]. In APACHE II, the difficulty of using the original APACHE scale led to the development of the APACHE II scale in 1985. It is the scale for disease severity that is most frequently used. The top score is 71, and there are just 17 physiologic variables as opposed to the original’s 34. But even using ICU admission data to calculate, it seems like a good alternative [8, 10, 11, 12].

APACHE III: The APACHE III severity scale, which differs from APACHE II only in the addition of new characteristics, was developed in 1991. The measure was created using information gathered from 17,440 ICU patients. The APACHE III scale’s key characteristic is its daily recalculation of anticipated mortality using the most recent clinical data. This has a higher predictive ability compared to the computation based on the first 24 hours after ICU admission [9].

APACHE IV was developed in 2006 using data from 110,588 patients who were admitted to the ICU between the years of 2003 and 2004. APACHE IV more reliably predicts mortality and the length of an ICU admission than APACHE III [13].

2.8.3 System for logistic organ dysfunction (LODS)

From a database of 13,152 cases, the Logistic Organ Dysfunction System (LODS) scale was created. It was the first scale of its kind to evaluate the severity of organ dysfunction while accounting for the likelihood of in-hospital mortality using multivariate logistic regression. Six organ system dysfunctions (nervous, cardiovascular, renal, respiratory, hematopoietic, and hepatic) are characterized by 11 factors [14, 15].

3. Ascorbic acid

The most well-known water-soluble vitamin is L-ascorbic acid. It is a white to off-white, water-soluble molecule with a carbohydrate chemical structure that mostly participates in animal species’ metabolic activities. L-ascorbic acid is known by the IUPAC nomenclature (5R)-[(1S)-1,2-dihydroxyethyl] -3,4-dihydroxy-furan-2(5H)-one. L-threo-hexo-2-enone-1,4-lactone is also known as vitamin C and also known as L-ascorbic acid. Since it refers to all chemical molecules that display ascorbic acid’s biological activity, vitamin C is a generic term. Given the critical role L-ascorbic acid plays in maintaining animal creatures’ health, vitamin C is regarded as being especially significant. The human body, like that of higher primates, is unable to manufacture vitamin C because it lacks an enzyme. It should therefore consume the required amount through its nutrition on a daily basis [16].

L-ascorbic acid was initially extracted from the adrenal glands in 1928, and it was not until 1932 that it was acknowledged as a treatment for scurvy, a condition characterized primarily by bleeding. In the past, sailors and members of exploration missions have suffered from scurvy because they were denied access to foods like fresh produce—the only natural sources of ascorbic acid—during their lengthy voyages.

L-ascorbic acid is connected to carbohydrates, particularly hexoses, chemically speaking. It is both a potent reducing agent and a mild organic diprotic acid (albeit it is primarily monoprotic). The need of including L-ascorbic acid in one’s diet and the health benefits of this vitamin are well known, but only recently these facts have been reinforced to the point where benefits ranging from lifespan to the prevention of the common could have been attributed to it.

Ten thousand tons of L-ascorbic acid are made industrially each year using a method that is partially biological. It is utilized as an antioxidant food preservative in addition to being used in multivitamin preparations and nutritional supplements together with certain of its salts (with Na, Ca, and Mg) [17].

3.1 Chemical characteristics

There are two groups of ascorbic acid’s chemical characteristics. The first category is concerned with its acidic characteristic, and the second is with its reducing capacity.

3.1.1 Acidity of a substance

Due to the possibility of the two hydroxyls of the five-membered lactone ring dissociating because of the close proximity of a double bond, ascorbic acid functions as a diprotic acid (enolic hydroxyls). Although the second dissociation is incredibly weak (pK2 = 11.57), the initial dissociation is fluent (pK1 = 4.17, or almost four times stronger than acetic acid). When titrated with solutions of strong bases, ascorbic acid behaves as a monoprotic acid in aqueous solutions and produces a single equivalency point.

It should be mentioned that ascorbic acid was classified as a monoprotic acid during the initial experiments that were conducted. Only extremely, alkaline solutions contain the discharged anion because ascorbic acid is now unstable (lactone ring opening + cleavage) and its solutions quickly oxidize in the presence of oxygen from the atmosphere. Delocalization of the electrons of the carbonyl double bond and coordination of its two normal forms stabilize the singly charged ascorbate anion. This explains why ascorbic acid has a high acidity and what causes it to be “reluctant” to experience the second dimension.

3.1.2 Reducing capacity

A mild to moderately potent reducing agent is ascorbic acid. It is substantially more powerful than straightforward reducing sugars because it contains the exceptionally active and rather uncommon enediol group, C(OH) = C(OH)-. Mild oxidizing agents convert it to dehydroascorbic acid as a result. Its total chemical reversibility is what makes this reaction unique. Dehydroascorbic acid is quantitatively reduced to ascorbic acid by reducing agents such as HI, H2S, and thiols. In the body, glutathione and other thiol substances directly diminish it.

Dehydroascorbic acid preserves the biochemical features of vitamin C, with the exception of course of its antioxidant capacity, thanks to the reversible redox system of ascorbic/dehydroascorbic acid’s active participation in a number of biochemical coupled redox processes.

It is distinctive that ascorbic acid, unlike dehydroascorbic acid, cannot enter the brain through the bloodstream.

As a result, the metabolic reduction of dehydroascorbic acid there yields the ascorbic acid that is found in the brain (and in fact in higher amounts compared to other organs of the body). Dehydroascorbic acid can enter cells through the glucose transporter, but ascorbic acid often cannot. In aqueous solutions, ascorbic acid is easily oxidized by oxygen in the air. This reaction is aided by small concentrations of different metal ions, primarily Cu2+, and is more favored in neutral and alkaline solutions. The interaction between acidic liquids and ambient oxygen happens rather slowly.

The following are examples of ascorbic acid oxidation processes [18]:

$$2\text{C}6\text{H}8\text{O}6+\text{O}22\text{C}6\text{H}6\text{O}6+2\text{H}2\text{O}$$

$$\text{C}6\text{H}8\text{O}6+2\text{F}\text{e}3+2\text{C}6\text{H}6\text{O}6+2\text{F}\text{e}2++2\text{H}+$$

$$\text{C}6\text{H}8\text{O}6+\text{I}2 \text{C}6\text{H}6\text{O}6+2\text{I}-+2\text{H}+$$E1

3.2 Ascorbic acid’s biochemical actions

There are two categories of ascorbic acid’s physiological effects on organisms:

It functions as a redox cofactor, making it easier for numerous enzymes to carry out their functions. These enzymes mostly participate in oxidative processes that lead to the introduction of hydroxyl into organic macromolecules. Additionally, due to the reversibility of the ascorbic/dehydroascorbic acid redox system, the oxidized form of ascorbic acid, dehydroascorbate acid, has virtually the same metabolic action as that of ascorbic acid [19].

It functions as an antioxidant with low molecular weight. It takes part in the body’s oxidative homeostasis, working with other antioxidant chemicals to eliminate any potentially harmful excess of reactive oxygen particles.

Ascorbic acid has a number of functions, including the following:

• It helps for the synthesis of collagen, a structural protein that binds and maintains the skin, gums, bones, muscles, cartilage, and internal organs. Collagen is a component of the body’s connective tissue.

• It contributes to the proper growth and maintenance of biological tissues, including the healing and regeneration of wounds and fractures.

• It helps for the hemoglobin synthesis and appropriate iron absorption, a characteristic that makes vitamin C crucial for treating anemia.

• It helps to increase the immune system’s capacity to fight infections by promoting the production of antibodies and white blood cells. Ascorbic acid consumption should be increased to ward off numerous viruses and the common cold. Although its antiviral effectiveness has not been shown, it is thought to lessen uncomfortable symptoms.

• It helps for the biosynthesis of vital neurotransmitters and hormones (dopamine, epinephrine, etc.).

• L-carnitine, a substance involved in the process of turning fat into energy and the metabolism of food components, is one of the body’s essential amino acids.

• It helps neutralize free radicals and prevent detrimental oxidative reactions in the fundamental biomolecules of cells as a low-molecular-weight antioxidant (e.g., lipid peroxidation, DNA damage, and enzymes).

• It supports healthy vascular circulation and blood vessel protection. Blood clots and heart conditions including angina and atherosclerosis are at a lower risk because of it. Ascorbate is also suggested to lower blood pressure, assisting in lowering the dangers associated with hypertension.

• Due to its antihistamine properties, ascorbic acid aids in the treatment of allergic responses [20].

3.2.1 Studies about ascorbic acid in septic shock and sepsis

Vitamin C is considered particularly important as L-ascorbic acid plays a large role in the health of animal organisms. The human body, due to the absence of an enzyme, like other higher primates, lacks the ability to synthesize vitamin C. For this reason, it should receive the necessary daily amount through its diet. A lack of vitamin C is known to cause scurvy, a disease that primarily manifests itself in bleeding. Today, by changing the diet and incorporating fruits and vegetables, the disease tends to disappear. L-ascorbic acid is good for people with sepsis and septic shock, according to research.

Carr et al. [21] studied a sample of 44 critically ill patients, 24 of whom had septic shock, 17 of whom did not have sepsis, and three of whom were unclassified. It turned out that 40% of patients with septic shock were deficient in vitamin C (ascorbic acid), compared to 25% of non-septic patients, and they came to the conclusion that this is likely because of increased metabolism because of the increased inflammatory response seen in septic shock.

Twenty-four patients with severe sepsis were randomly divided into three groups in their study by Fowler et al. [22] at a ratio of 1:1:1. For 4 days, ascorbic acid was intravenously infused into the first group (Lo-AscA, n = 8; Hi-AscA, n = 8; and placebo, n = 8) once every 6 hours. Patients who received ascorbic acid experienced immediate declines in the SOFA test, whereas patients who received a placebo did not. C-reactive protein and procalcitonin (PCT), two pro-inflammatory biomarkers, were considerably decreased. In contrast to patients receiving placebo, thrombomodulin infusion in patients receiving ascorbic acid did not show a significant increase, indicating an attenuation of vascular endothelial damage.

In a study by Marik et al. [23], they divided the 94 patients into the ascorbic acid treatment group (n = 47) and the control group (n = 47). Their results showed that in-hospital mortality was 8.5% (4 of 47) in the ascorbic acid treatment group, compared with 40.4% (19 of 47) in the control group.

Additionally splitting 24 patients into two groups, Natarajan et al. [24] discovered that Cf-DNA readings were greater and persisted above normal for 96 hours. While MtDNA readings fell in the treatment group, they rose in the placebo group. While the expression of antimicrobial proteins increased considerably only in the treatment groups, red cell distribution width (RDW) only significantly increased in the placebo group. Ascorbic acid infusion can improve sepsis outcomes by lowering cf. and mtDNA levels, increasing endogenous antimicrobial proteins, and maintaining Red cell distribution width (RDW), according to the researchers’ findings.

Ascorbic acid, thiamine, and hydrocortisone have been demonstrated in a recent study by Sadaka et al. [25] to have benefits for patients with septic shock in 62 individuals.

In a trial on a sample of 1144 participants, Shin et al. [26] found that timely vitamin C and thiamine delivery did not increase survival in patients with septic shock, but that it might in more severe circumstances such as hypoalbuminemia or acute organ failure. Particularly, there was no difference in fatality rates between the treatment and control groups (18.3% vs. 17.5%).

4. Conclusions

The findings of the research revealed that:

• The majority of studies demonstrated that ascorbic acid has beneficial properties in sepsis and septic shock, and

• Several studies highlight the significance of giving the patient’s body a combination of ascorbic acid and other vitamins and trace elements.