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The Paradigm Shift and Scurvy – As Related to Sepsis

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The Burden of Sepsis

The global burden of sepsis remains substantial with an estimated 32 million cases and 5.3 million deaths per year [1]. In addition to short-term mortality, septic patients are noted to suffer from numerous long-term complications with a reduced quality of life [2]. Therefore, the early detection and the judicious administration of suitable antibiotics are considered to be the most likely important factors in improving the outcome of patients with sepsis. [2].

The problem however is that the initial signs and symptoms of sepsis are frequently nonspecific, leading to a delay in diagnosis [2]. Over one-third of patients with septic shock presented to the emergency department, they complained of and presented with vague symptoms that were not specific for infection resulting in a delay in the administration of antibiotics [1, 3]. It is important to understand that patients who presented with vague symptoms were twice as likely to die [2]. The most common vague symptoms include malaise, fatigue, shortness of breath, and related altered mental status. Since sepsis is principally a disease of the elderly – age, 60 and up, clinicians should maintain a high degree of suspicion in the elderly population who present with these vague symptoms [2].

We recognize the early signs of sepsis as: tachycardia, hypotension, abnormal temperature, tachypnea with a respiratory alkalosis, abnormal leukocyte count – with left shift, bandemia – an increase in white blood cells, thrombocytopenia, or elevated lactate level [2, 4]. Additionally, an elevated procalcitonin would further support the diagnosis of sepsis [2, 5] and the trend of the procalcitonin level is useful in monitoring the response to treatment as well as the decisions involving the discontinuation antibiotics [2, 6].

The Paradigm Shift

Clinicians have known for some time that the timely diagnosis of sepsis is critical, predominantly once hypotension develops. The delay in the administration of antibiotics in the hypotensive septic patient is associated with an increased risk of death [2, 7]. Therefore, the endorsed concept for the presumptive septic patient is that, “the administration of each antibiotic ordered should be initiated promptly, with healthcare systems working to reduce that time to as short a duration as feasible” [2, 9] as opposed to imposing an aggressive, fixed time period “from the time of recognition” which could lead to unintended consequences [2, 8]. Additionally, there is a lack of support for the concept that aggressive fluid resuscitation is considered crucial for the stabilization of sepsis-induced tissue hypoperfusion, including septic shock [2]. The concern with this concept is that while having minimal effect on blood pressure, fluid resuscitation via boluses may actually cause a fall in the effective arterial elastance potentiating arterial vasodilation in addition to the hyperdynamic state characteristic of septic shock [2, 10, 11, 12]. We now know that the administration of large fluid volumes is likely to result in organ edema as well as late hemodynamic compromise. For this reason, early initiation of Norepinephrine is preferred and recommended (there a demonstratable increased risk of death with each passing hour in which the initiation of Norepinephrine is delayed) [2].

The Notion of Scurvy

Most clinicians do not think of scurvy when it comes to sepsis. Scurvy has been described as, “a disease of antiquity” [13] dating back to the Egyptians who are known to have depicted the disease through their hieroglyphs. During the Renaissance, scurvy was responsible for the deaths of thousands of sailors [13]. Today however, the disease is very uncommon and generally seen only in patients with, “extreme dietary deficiencies” [13].

Marik and Hooper (2018) estimate that approximately 40% of patients admitted to the ICU with septic shock meet the supporting criteria for scurvy with a vitamin C serum level of less than 11.3 u/mol/l. The remaining 60% along with nearly half of all non-septic ICU patients are likely to have ‘hypovitaminosis C’ – a corresponding vitamin C serum level of less than 23 u/mol/l [13].

However, this is not new information. The critical care realm has known for over two decades that acute illness results in an acute deficiency of vitamin C leading to low serum and intracellular levels [14]. Low plasma concentrations of vitamin C have been associated with: more severe organ failure and an increased risk of mortality [13].

But Why?

Marik and Hooper describe the most likely explanation for this acute deficiency, referred to as ‘acute scurvy’ that occurs in patients with sepsis as well as other critical illnesses as a, “consequence of metabolic consumption” [13]. They go on to remark the fall in serum and cellular levels befall too rapidly in order to be explained by a decrease in gastrointestinal absorption or increased urinary loss [13]. The evidence for this was observed in a guinea pig model where myocardial ascorbate had been depleted within hours of the administration of an endotoxin [13]. An interesting anthropological fact regarding this observation is that primates and guinea pigs are the only mammals that are unable to synthesize ascorbic acid in their livers, they have lost the ability to synthesize ascorbic acid due to the L-gulono-γ-lactone oxidase or GULO gene which known for encoding the enzyme responsible for catalyzing the final step of vitamin C biosynthesis [13]. All other mammals increase the synthesis of ascorbic acid during stress; therefore, vitamin C has been considered as an authentic stress hormone [13]. This inability to synthesize ascorbic acid may partially explain why humans and guinea pigs have an increased vulnerability to sepsis as well as dying from sepsis [13].

Experimental models of sepsis have established that, treatment with ascorbic acid can limit ruinous consequences of sepsis through multiple mechanisms and includes the weakening of the proinflammatory response, the enhancement of the endothelial and epithelial barrier function as well as the prevention of sepsis-associated coagulation aberrations [13].

Sepsis is branded by the extreme production of reactive oxygen species (or ROS for short) by way of enzyme induction which include: nicotinamide adenine dinucleotide phosphate-oxidase and the uncoupling of mitochondrial oxidative phosphorylation and inducible nitric oxide synthetase

[13, 14]. Therefore, ascorbic acid is considered to be a, “key cellular antioxidant which counteracts these ROS” [13]. Additionally, ascorbic acid is known to reprocess other antioxidants such as α-tocopherol, recognized as vitamin E and tetrahydrobiopterin or BH4 (BH4 is said to play a critical role in the function of endothelial nitric oxide synthase or eNOS – a deficiency in ascorbic acid ultimately results in an incomplete regeneration of BH4 leading to the uncoupling of eNOS and the generation of superoxide and peroxynitrite) [13, 14].

Lastly, ascorbic acid inhibits the activation of nuclear factor kappa-B, which is a major nuclear

transcription factor involved in release of many proinflammatory mediators [13]. Ascorbic acid is said to be an essential cofactor in the activity of monooxygenase and dioxygenase

enzymes; this comprises enzymes involved in the synthesis of catecholamines and vasopressin in addition to binding to adrenergic receptors increasing catecholamine sensitivity – in short ascorbic acid acts like a vasopressor agent [13, 15].

More Paradigm Shift

With these facts, we are provided with the scientific foundation for the treatment of sepsis with intravenous ascorbic acid. The severe total body depletion of ascorbic acid requires rapid correction and since there is a limited gastrointestinal absorption – which is due to the saturable vitamin C transporter; ascorbic acid must be administered intravenously. The ‘adequate’ dose specified by Marik and Hooper is noted to be 1.5 g every 6 hours [13].

There is a strong belief that benefit of ascorbic acid is enhanced with the concurrent administration of low-dose corticosteroids and thiamine and will yield better patient outcomes. The benefits of these neoadjuvant therapies are likely to be time dependent. From a historical point of view, the treatment for sepsis would typically start with the administration of antibiotics and fluids. After a significant volume, 4 liters – usually; followed by the reluctancy to initiate a vasopressor. Following a delay of a two to three hours, the placement of a central line with x-ray confirmation would take place. Much later on, in the event where the vasopressors were not working, a steroid might be considered – the entire treatment process escalation described could take twelve or more hours [13].

Now, the paradigm shift becomes even more clear with the following concept in the treatment of sepsis – antibiotics, fluid and a peripheral vasopressor (norepinephrine preferred) are all initiated immediately. Additional vasopressors are added within the following minutes if required. At this point, metabolic resuscitation is immediately initiated and includes hydrocortisone, ascorbic acid and thiamine. As the septic patient improves, both the vasopressor(s) and metabolic resuscitation are weaned off – the rapid escalation in treatment not only stabilizes the patient faster but also contributes to an overall reduction in length of stay in the ICU as well as a reduction in organ failure and death [13].

References

  1. Fleischmann C, Scherag A, Adhikari NKJ, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. American Journal of Respiratory and Critical Care Medicine. 2016;193(3):259–72.
  2. Marik PE, Farkas JD. The Changing Paradigm of Sepsis. Critical Care Medicine. 2018;46(10):1690–2.
  3. Filbin MR, Lynch J, Gillingham TD, Thorsen JE, Pasakarnis CL, Nepal S, et al. Presenting Symptoms Independently Predict Mortality in Septic Shock. Critical Care Medicine. 2018;46(10):1592–9.
  4. Marik PE, Farkas JD. The Changing Paradigm of Sepsis. Critical Care Medicine. 2018;46(10):1690–2.
  5. Schuetz P. Procalcitonin Algorithms for Antibiotic Therapy Decisions. Archives of Internal Medicine. 2011;171(15):1322.
  6. Iankova I, Thompson-Leduc P, Kirson NY, Rice B, Hey J, Krause A, et al. Efficacy and Safety of Procalcitonin Guidance in Patients With Suspected or Confirmed Sepsis. Critical Care Medicine. 2018;46(5):691–8.
  7. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock*. Critical Care Medicine. 2006;34(6):1589–96.
  8. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle. Critical Care Medicine. 2018;46(6):997–1000.
  9. Kalil AC, Gilbert DN, Winslow DL, Masur H, Klompas M. Infectious Diseases Society of America (IDSA) POSITION STATEMENT: Why IDSA Did Not Endorse the Surviving Sepsis Campaign Guidelines. Clinical Infectious Diseases. 2017;66(10):1631–5.
  10. Glassford NJ, Eastwood GM, Bellomo R. Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data. Critical Care. 2014;18(6).
  11. García MIM, González PG, Romero MG, Cano AG, Oscier C, Rhodes A, et al. Effects of fluid administration on arterial load in septic shock patients. Intensive Care Medicine. 2015;41(7):1247–55.
  12. Pierrakos C, Velissaris D, Scolletta S, Heenen S, Backer DD, Vincent J-L. Can changes in arterial pressure be used to detect changes in cardiac index during fluid challenge in patients with septic shock? Intensive Care Medicine. 2012;38(3):422–8.
  13. Marik PE, Hooper MH. Doctor—your septic patients have scurvy! Critical Care. 2018;22(1).
  14. May JM, Harrison FE. Role of Vitamin C in the Function of the Vascular Endothelium. Antioxidants & Redox Signaling. 2013;19(17):2068–83.
  15. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Critical Care. 2015;19(1).
Chris Farnady

Chris Farnady

Chris is a graduate of Loyalist College’s Primary Care Paramedic program (Bancroft, ON), Durham College’s (Oshawa, ON) Advance Care Paramedic and currently pursuing his Bachelor of Health Science from Thompson Rivers University. Chris began his prehospital care career in 1997 working as an EMR in Alberta’s oil and gas industry and has enjoyed the privilege of working as a Primary Care and Advanced Care Paramedic in Ontario, Northern Manitoba and Alberta. In April 2018 Chris accepted a position with Advanced Paramedic Ltd. and returned to Northern Alberta as an Advanced Care Flight Paramedic for Alberta Health Services’ transport medicine program. In his time away from work, Chris enjoys being at home with his wife and two children. Chris can be reached for comment at chris.farnady@gmail.com.

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