Managing sepsis

Oranges are a proven source of vitamin C, but is vitamin C a proven treatment for sepsis in animals? Photo: sam-21/Bigstock Sepsis is currently defined as a life-threatening organ dysfunction secondary to a dysregulated physiologic response to infection. There are widely used, evidence-based guidelines for diagnosing and managing sepsis in human medicine,1 but there is no single guideline or consensus statement on sepsis management in veterinary medicine. The guidelines most veterinarians follow, and those which we use at my hospital, are derived from expert opinion and the adaptation of human sepsis protocols employed at several academic veterinary institutions. Managing sepsis is a great example of the challenge of practicing evidence-based medicine in an evidence-poor environment. Extrapolation from evidence in humans and reasoning from physiologic first principles are rational and necessary strategies, but, of course, they sometimes lead to practices that turn out to be ineffective or even counterproductive in veterinary patients. Such approaches should always be viewed as a starting point, a provisional strategy pending the development of better evidence in clinical studies of the target patient population. Human medicine, though often blessed with much higher quality evidence we can typically expect, still finds itself mired in controversies over questionable practices that become widespread. This is despite limited or poor-quality evidence which later turn out to have been ineffective. A condition such as sepsis, which is acutely life-threatening and for which no universal, highly effective therapy is yet available, is fertile ground for such disputed approaches. These often spill over into veterinary medicine when we adopt new practices in human patient care, and it is important for us to keep an eye on the evolution of ideas and evidence regarding such practices. In the case of sepsis, for example, the use of vitamin C, alone or in combination with steroids and other vitamins, is an example of a controversial practice that has been ported into our patient care protocols to some extent based on limited, and controversial, early evidence which we may now want to rethink. Diagnosis of sepsis Confirming sepsis and identifying a source of infection can be challenging. However, the emphasis in sepsis management is now on early initiation of therapy since this has been associated with lower mortality in human patients, so diagnostic criteria have been developed to favor rapid diagnosis and therapy. Based on the definition of sepsis given above, a tentative diagnosis of sepsis should be made whenever there is a known or suspected infection and evidence of organ dysfunction or a systemic inflammatory response. Suspicion of infection should be based on history and physical examination of findings. Suggested criteria for identifying organ dysfunction and an inflammatory response in dogs and cats, adapted from those used in humans, include: Therapy The emphasis on early intervention for sepsis has led to the development of treatment and monitoring “bundles;” that is sets of tests and treatments to be implemented universally when sepsis is suspected. There are no validated guidelines or consensus statements to define sepsis bundles in veterinary patients; however, many institutions use treatment protocols adapted from those recommended for humans. The priorities for sepsis treatment are: Early institution of antibiotic therapy2 Hemodynamic stabilization Identification and control of the source of infection Supportive care and recovery Immediate therapy for sepsis. Following a tentative diagnosis of sepsis, recommended immediate care should include: Culture samples. Samples for culture should be obtained before antibiotic administration if this does not delay the use of antibiotics more than 45 minutes. Samples should be specific to the site of infection if this has been identified and can be accessed. If the site is unknown or inaccessible, blood and urine cultures can be taken. Both aerobic and anaerobic cultures should be run. Antibiotics. A de-escalation approach is currently favored in treating human sepsis patients. This involves early initiation of broad-spectrum antibiotic therapy and then a reduction in antibiotic coverage as soon as possible as indicated by culture results. Recommended duration of antibiotic therapy for humans is seven-10 days unless the source of infection cannot be definitively controlled. There are no evidence-based guidelines for antibiotic use in veterinary sepsis patients. Ideally, antibiotic selection should be based on culture results, local population susceptibility patterns, and the history and condition of the individual patient. Common empiric protocols used in veterinary sepsis patients include: Ampicillin/sulbactam and amikacin Ampicillin/sulbactam and enrofloxacin Cefazolin and cefotaxime Cefoxitin Clindamycin and enrofloxacin Lactate measurement. Lactate is an important biomarker for sepsis management. Values > 2.5 mmol/L should be interpreted as an indicator of inadequate perfusion. Fluid therapy. Crystalloids are the initial fluid of choice, and aggressive fluid therapy (e.g. boluses of 20-30mL/kg over 15 minutes) should be initiated for patients with evidence of hypotension (e.g. mean arterial pressure 4.0 mmol/L or consistent physical exam findings) unless there is a clear contraindication (e.g. primary cardiac disease, evidence of overhydration). Fluid therapy should be titrated to endpoints, including: Normalization of heart rate Normalization of respiratory rate Normalization of blood pressure (mean arterial pressure> 65mmHg, systolic > 100mmHg) Normalization of lactate ( 1mL/kg/hr) Hetastarch is not recommended in human sepsis patients due to some evidence of increased mortality and risk for acute kidney injury. It is unclear the extent to which this applies to veterinary patients;3 however, many experts recommend avoiding synthetic colloids, if possible. Canine albumin is preferred as a colloid, though it is often unavailable or unaffordable. Additional therapies Continued hemodynamic stabilization. If the targets for fluid therapy (blood pressure, lactate, etc.) are not met with initial crystalloid treatment, vasopressors should be started early because hypotension in sepsis is often due to decreased peripheral vasomotor tone. Based on guidelines for humans, and limited evidence in veterinary patients, the following are common recommendations for use of vasopressors in sepsis patients: Warning! Some vasopressors can cause ischemic necrosis due to extreme vasoconstriction. They should ideally be given through a central line, and clients should be advised of this possible complication. Norepinephrine; 0.1-0.5mcg/kg/min. Start low and titrate upwards in 0.1mcg/kg/min increments every five-10 minutes until blood pressure (BP) targets are reached (e.g. MAP>65mmHg) or 2-3mcg/kg/min is reached. Vasopressin is often recommended as a second-line pressor or to reduce the dose of norepinephrine in humans, but it is often unavailable to veterinary patients due to cost. Epinephrine; 0.05-mcg/kg/min. This can be added to norepinephrine if needed and titrated upwards every 5-10 minutes until BP targets are reached. Dopamine has historically been the pressor of choice in veterinary patients, but recent practice has shifted to norepinephrine based largely on extrapolation from research in human sepsis patients. Dobutamine is primarily an inotrope and is only recommended if there is evidence of poor contractility because it decreases vascular tone and can decrease BP. Goal-directed monitoring and treatment of key physiologic parameters. It is important to identify all physiologic abnormalities that can be treated in patients with sepsis and septic shock. These may include: Electrolytes Blood glucose Lactate Packed cell volume/total protein/albumin Coagulation: prothrombin time/partial thromboplastin time/platelet counts Blood pressure Vital signs: heart rate, respiratory rate, body temperature, pulse quality, mucous membrane color, capillary refill time SPO2 ECG Pain score and mental status. Analgesia should be provided if there is evidence of pain. Non-steroidal anti-inflammatory drugs should be avoided if there is hemodynamic instability or evidence of gastrointestinal or renal impairments. Urine output and renal values. Body weight. This is a key measure for assessing fluid balance. Source control. Once a patient has achieved hemodynamic stability, early control of the infection source is recommended. Surgical treatment of septic foci should be performed as soon as the patient is reasonably stable for the procedure. Nutritional support. Early and aggressive enteral nutritional support should be considered whenever possible. Oral feeding and nasogastric tube feeding can be instituted if there are no apparent contraindications, and esophageal tube placement should be considered if the patient is anesthetized for source control. Corticosteroids. In human patients who have failed to reach targets for blood pressure and other measures of hemodynamic stability with fluid therapy and vasopressors, corticosteroids are recommended. There is weak evidence showing improved resolution of shock and survival with low-dose hydrocortisone in humans with relative adrenal insufficiency due to sepsis. It is known adrenal insufficiency occurs in veterinary patients, but there are no studies showing the effects of steroid treatment. Physiologic doses of a mixed glucocorticoid/mineralocorticoid such as hydrocortisone for five to seven days in patients with shock refractory to fluids and vasopressors is reasonable. Other medications. There are variety of medications commonly used in septic or other critically ill patients for which there is little or no clear evidence of benefits Gastroprotectants (e.g. pantoprazole) These can be considered if there is evidence of gastrointestinal lesions or symptoms. Anti-emetics (g. maropitant, ondansetron). These can be considered if there is evidence of nausea or vomiting. Promotility drugs (g. metoclopramide, low-dose erythromycin). These can be considered if there is evidence of gastrointestinal hypomotility or ileus. Blood products. There is significant controversy and uncertainty regarding the use of blood products in septic patients. Strict arbitrary cutoff values for use of blood products are now discouraged in human patients due to growing evidence of harm related to transfusion. There are no clear guidelines for veterinary patients. Treatment of anemia. Most critical patients become anemic at some point. Anemia should be treated when associated with significant clinical symptoms (g. hypoxia, tachypnea/tachycardia), ongoing losses of red blood cells, or anticipated losses associated with surgical source control procedures. Though strict cutoffs are discouraged, a hemoglobin of 7.0g/dL is often used as a guideline for when to transfuse in human sepsis patients. Treatment of thrombocytopenia. Platelet-rich plasma is given to humans when there is clinical evidence of bleeding (g. petechiae, ecchymoses, epistaxis), when a surgical procedure is planned and platelet count is < 50k/mm3, or prophylactically when platelet count is <10k/mm3. Treatment of coagulopathy. It is not recommended to give fresh-frozen plasma (FFP) to correct clotting times in the absence of active bleeding. If prothrombin time/partial thromboplastin time are elevated and there is bleeding or a surgical procedure is planned, FFP may be beneficial. Vitamin C Though this is, at best, an ancillary therapy to consider in patients with sepsis, without the acknowledged critical importance of many others and not necessarily widely used in veterinary patients, I want to focus a bit on it because it illustrates the challenges of an evidence-based approach to a complex medical problem. In human medicine, as in the veterinary field, practices may be adopted based on early evidence that is both encouraging and extremely limited. Unlike veterinary medicine, however, follow-up studies are much more common and robust, and better evidence that shows the true state of affairs is often available within a few years. Unfortunately, in our profession, we are more likely to adopt a practice based on a single small study and then employ it widely for a long time before subsequent studies either confirm the benefits or show them to be illusory. Vitamin C for sepsis is a cautionary tale that should encourage us to try harder to confirm our initial assessment of new therapies. In 2017, a study of 94 human patients with sepsis comparing patient given standard treatment and those also given vitamin C, thiamine, and low-dose hydrocortisone (called HAT therapy) was published.4 This was a small by the standards of human medicine, though larger than many equally influential veterinary trials, but it appeared to show dramatic benefits. Mortality was 8.5 percent in the experimental group and 40.4 percent in the control group, and there were apparent benefits in terms of other standardized measures of disease severity. This study had a dramatic impact in the human critical-care field, with reverberations in veterinary medicine. Debate and additional research began immediately in human medicine. In the veterinary profession, there was buzz about this new treatment at conferences5 and online, and some veterinarians began adding it to manage sepsis cases.6 It is unclear how widespread this practice became in veterinary circles, but the published research on vitamin C in critically ill veterinary patients is pretty sparse, and there are not prospective randomized clinical trials specifically comparing HAT to standard care in veterinary sepsis cases.5–7 In contrast, the five years since the publication of the original HAT study has seen a flurry of research in humans, and there are now more than a dozen systematic reviews and meta-analyses evaluating studies in thousands of sepsis patients.4,8–17 Unfortunately, the majority of these have failed to confirm the dramatic results from the original study. Most have found no reduction in mortality from adding HAT to standard care. Some have shown modest improvement in some assessments of disease severity, but many have found no statistically significant nor clinically meaningful effect at all. This is about as clear an example of the Decline Effect as one could ask for. Dramatic effects seen in initial studies of a new therapy get smaller and smaller as subsequent studies attempt to replicate the results until the literature settles on a far less dramatic reality, which surprisingly often turns out to be no effect at all. The explanations for this involve both intentional and, most of the time, unconscious bias on the part of enthusiastic researchers studying a new idea, as well as the limitations of small, often poorly controlled research studies in unrepresentative patient populations. This phenomenon is the main reason we should avoid enthusiastically embracing new therapies before appropriate replication of such initial studies has been done. In the case of HAT, the controversy has grown more dramatic than usual. The primary author of the original study, Dr. Paul Marik, vehemently stands by his results despite all the failed attempts to replicate them. A recent letter to the editorof the journal in which this study was published has alleged that analysis of the results and statistics reported in the original paper is not only suggestive of data fabrication, but clear proof of misconduct. An investigation by the journal is likely, especially in light of a very similar controversy involving the same investigator. Dr. Marik has also published a study purportedly showing a different novel approach with equally dramatic benefits in COVID-19 patients. This paper has recently been retracted due to evidence of data manipulation. The author has also been reprimanded by the Virginia Medical Board for misconduct, resigned his academic position, and become involved in a lawsuit with his hospital over the use of ivermectin as a COVID-19 therapy. Like HAT, the approach Dr. Marik advocates for COVID-19 appeared promising in his early studies, but the elements of it have so far failed to show benefits in subsequent research.18,19 Dr. Marik illustrates starkly how hard the habit of excessive enthusiasm for new therapies based on preliminary evidence is to break. Bottom line Sepsis is a serious and complex problem with numerous possible treatment approaches and mixed, often disappointing, results. An evidence-based approach involves attention to the limited and weak evidence available in veterinary patients and judicious extrapolation from the more robust, but still imperfect, evidence available in humans. The use of vitamin C, alone or in combination, in sepsis patients has evolved from an exciting and promising new idea to an example of failed promise, and of the dangers of unconscious bias, if not outright scientific fraud. The lesson we should draw from this is not merely vitamin C in veterinary sepsis patients is probably not warranted, but also we should proportion our acceptance of and confidence in new therapies to the strength of the evidence for them. For veterinarians, this often means a perpetual state of using treatments in which we can have very little confidence, but this is still preferable to enthusiastic commitment to practices which later prove ineffective or even dangerous for our patients. Brennen McKenzie, MA, MSc, VMD, cVMA, discovered evidence-based veterinary medicine after attending the University of Pennsylvania School of Veterinary Medicine and working as a small animal general practice veterinarian. He has served as president of the Evidence-Based Veterinary Medicine Association and reaches out to the public through his SkeptVet blog, the Science-Based Medicine blog, and more. He is certified in medical acupuncture for veterinarians. Columnists’ opinions do not necessarily reflect those of VPN Plus+. References Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143. doi:10.1097/CCM.0000000000005337. Abelson AL, Buckley GJ, Rozanski EA. Positive impact of an emergency department protocol on time to antimicrobial administration in dogs with septic peritonitis. J Vet Emerg Crit Care. 2013;23(5):n/a-n/a. doi:10.1111/vec.12092. Glover PA, Rudloff E, Kirby R. Hydroxyethyl starch: a review of pharmacokinetics, pharmacodynamics, current products, and potential clinical risks, benefits, and use. J Vet Emerg Crit Care (San Antonio). 2014;24(6):642-661. doi:10.1111/vec.12208. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229-1238. doi:10.1016/j.chest.2016.11.036. Silverstein D. Treating Sepsis with Vitamins? The Risks, Benefits, and Evidence. In: International Veterinary Emergency and Critical Care Symposium. Washington, D.C.; 2019. Taylor SD. Oranges for Horses? Exploring Vitamin C in the Fight against Equine Sepsis. Purdue Equine Heal Updat. 2019;21(2):5. Gordon DS, Rudinsky AJ, Guillaumin J, Parker VJ, Creighton KJ. Vitamin C in Health and Disease: A Companion Animal Focus. Top Companion Anim Med. 2020;39:100432. doi:10.1016/j.tcam.2020.100432. Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock. JAMA. 2020;323(5):423. doi:10.1001/jama.2019.22176. Anderson MJ, Ibrahim AS, Cooper BR, Woolcock AD, Moore GE, Taylor SD. Effects of administration of ascorbic acid and low-dose hydrocortisone after infusion of sublethal doses of lipopolysaccharide to horses. J Vet Intern Med. 2020;34(6):2710-2718. doi:10.1111/jvim.15896. Lee YR, Vo K, Varughese JT. Benefits of combination therapy of hydrocortisone, ascorbic acid and thiamine in sepsis and septic shock: A systematic review. Nutr Health. 2022;28(1):77-93. doi:10.1177/02601060211018371. Wu T, Hu C, Huang W, Xu Q, Hu B, Li J. Effect of Combined Hydrocortisone, Ascorbic Acid and Thiamine for Patients with Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Shock. 2021;56(6):880-889. doi:10.1097/SHK.0000000000001781. Assouline B, Faivre A, Verissimo T, et al. Thiamine, Ascorbic Acid, and Hydrocortisone As a Metabolic Resuscitation Cocktail in Sepsis: A Meta-Analysis of Randomized Controlled Trials With Trial Sequential Analysis. Crit Care Med. 2021;49(12):2112-2120. doi:10.1097/CCM.0000000000005262. Patel JJ, Ortiz-Reyes A, Dhaliwal R, et al. IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2022;50(3):e304-e312. doi:10.1097/CCM.0000000000005320. Fujii T, Salanti G, Belletti A, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16. doi:10.1007/S00134-021-06558-0. Ge Z, Huang J, Liu Y, et al. Thiamine combined with vitamin C in sepsis or septic shock: a systematic review and meta-analysis. Eur J Emerg Med. 2021;28(3):189-195. doi:10.1097/MEJ.0000000000000812. Scholz SS, Borgstedt R, Ebeling N, Menzel LC, Jansen G, Rehberg S. Mortality in septic patients treated with vitamin C: a systematic meta-analysis. Crit Care. 2021;25(1):17. doi:10.1186/s13054-020-03438-9. Somagutta MKR, Pormento MKL, Khan MA, et al. The Efficacy of vitamin C, thiamine, and corticosteroid therapy in adult sepsis patients: a systematic review and meta-analysis. Acute Crit care. 2021;36(3):185-200. doi:10.4266/acc.2021.00108. Popp M, Stegemann M, Metzendorf M-I, et al. Ivermectin for preventing and treating COVID‐19. Cochrane Database Syst Rev. 2021;(7). doi:10.1002/14651858.CD015017.PUB2. Lim SCL, Hor CP, Tay KH, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities. JAMA Intern Med. 2022;182(4):426. doi:10.1001/jamainternmed.2022.0189.

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Managing sepsis

Looking at a rational approach and a cautionary tale

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