My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

 Absolutely! Although trauma, toxins, exertion, and medications are often listed as common causes of rhabdomyolysis, infectious etiologies should not be overlooked as they may account for 5% to 30% or more of rhabdomyolysis cases (1,2).

 

Rhabdomyolysis tends to be associated with a variety of infections, often severe, involving the respiratory tract, as well as urinary tract, heart and meninges, and may be caused by a long list of pathogens (1).  Among bacterial causes, Legionella sp. (“classic” pathogen associated with rhabdomyolysis), Streptococcus sp. (including S. pneumoniae), Salmonella sp, Staphylococcus aureus, Francisella tularensis have been cited frequently (3).  Some series have reported a preponderance of aerobic gram-negatives such as Klebsiella sp., Pseudomonas sp. and E. coli  (1,2).   Among viral etiologies, influenza virus, human immunodeficiency virus, and coxsackievirus are commonly cited (2,3).  Fungal and protozoal infections (eg, malaria) may also be associated with rhabdomyolysis (5).

 

So how might sepsis cause rhabdomyolysis? Several potential mechanisms have been implicated, including tissue hypoxemia due to sepsis, direct muscle invasion by pathogens (eg, S. aureus, streptococci, Salmonella sp.), toxin generation (eg, Legionella), cytokine-mediated muscle cell toxicity (eg, aerobic gram-negatives) as well as muscle ischemia due to shock (1,5).

 

Bonus Pearl: Did you know that among patients with HIV infection, infections are the most common cause (39%) of rhabdomyolysis (6)? 

 

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References

 

1. Kumar AA, Bhaskar E, Shantha GPS, et al. Rhabdomyolysis in community acquired bacterial sepsis—A retrospective cohort study. PLoS ONE 2009;e7182. Doi:10.1371/journa.pone.0007182. https://www.ncbi.nlm.nih.gov/pubmed/19787056.

2. Blanco JR, Zabaza M, Sacedo J, et al. Rhabdomyolysis of infectious and noninfectious causes. South Med J 2002;95:542-44. https://www.ncbi.nlm.nih.gov/pubmed/12005014

3. Singh U, Scheld WM. Infectious etiologies of rhabdomyolysis:three case reports and review. Clin Infect Dis 1996;22:642-9. https://www.ncbi.nlm.nih.gov/pubmed/8729203

4. Shih CC, Hii HP, Tsao CM, et al. Therapeutic effects of procainamide on endotoxin-induced rhabdomyolysis in rats. PLOS ONE 2016. Doi:10.1371/journal.pone.0150319. https://www.ncbi.nlm.nih.gov/pubmed/26918767

5. Khan FY. Rhabdomyolysis: a review of the literature. NJM 2009;67:272-83. http://www.njmonline.nl/getpdf.php?id=842

6. Koubar SH, Estrella MM, Warrier R, et al. Rhabdomyolysis in an HIV cohort: epidemiology, causes and outcomes. BMC Nephrology 2017;18:242. DOI 10.1186/s12882-017-0656-9. https://bmcnephrol.biomedcentral.com/track/pdf/10.1186/s12882-017-0656-9

My patient with sepsis and bacteremia has an extremely high serum Creatine kinase (CK) level. Can his infection be causing rhabdomyolysis?

My hospitalized patient with sepsis has persistently elevated lactic acid despite volume resuscitation, source control, and adequate oxygenation. What could I be missing?

Although the causes of lactic acidosis are legion (eg, sepsis, tissue hypoperfusion, ischemic bowel, malignancy, medications, liver dysfunction), thiamine deficiency (TD) is an often-overlooked cause of persistently elevated serum lactic acid (LA) in critically ill hospitalized patients,1 reported in 20-70% of septic patients.2  Septic shock patients may be particularly at risk of TD because of increased mitochondrial oxidative stress, decreased nutritional intake and presence of comorbid conditions (eg,  alcoholism, persistent vomiting).3

Early recognition of TD in hospitalized patients may be particularly difficult because of the frequent absence of the “classic” signs and symptoms of Wernicke’s encephalopathy (eg, ataxia, cranial nerve palsies and confusion) and lack of readily available confirmatory laboratory tests.4

TD-related lactic acidosis should be suspected when an elevated LA persists despite adequate treatment of its putative cause(s) (4,5). Administration of IV thiamine in this setting may result in rapid clearance of LA.3-5

TD causes lactic acidosis type B which is due to the generation of excess LA, not impairment in tissue oxygenation, as is the case for lactic acidosis type A. Thiamine is an essential co-factor in aerobic metabolism, facilitating the conversion of pyruvate to acetyl-CoA which enters the citric acid (Krebs) cycle within the mitochondria. In TD, pyruvate does not undergo aerobic metabolism and is converted to LA instead, leading to lactic acidosis.

Bonus pearl: Did you know that because of its limited tissue storage, thiamine stores may be depleted within only 3 weeks of reduced oral intake!

References

  1. O’Donnell K. Lactic acidosis: a lesser known side effect of thiamine deficiency. Practical Gastroenterol March 2017:24.   https://www.practicalgastro.com/article/176921/Lactic-Acidosis-Lesser-Known-Side-Effect-of-Thiamine-Deficiency
  2. Marik PE. Thiamine: an essential component of the metabolic resuscitation protocol. Crit Care Med 2018;46:1869-70. https://journals.lww.com/ccmjournal/Fulltext/2018/11000/Thiamine___An_Essential_Component_of_the_Metabolic.23.aspx
  3. Woolum JA, Abner EL, Kelly A, et al. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med 2018;46:1747-52. https://journals.lww.com/ccmjournal/Fulltext/2018/11000/Effect_of_Thiamine_Administration_on_Lactate.5.aspx
  4. Kourouni I, Pirrotta S, Mathew J, et al. Thiamine: an underutilized agent in refractory lactic acidosis. Chest 2016; 150:247A. https://journal.chestnet.org/article/S0012-3692(16)56459-9/pdf
  5. Shah S, Wald E. Type B lactic acidosis secondary to thiamine deficiency in a child with malignancy. Pediatrics 2015; 135:e221-e224. http://pediatrics.aappublications.org/content/135/1/e221

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My hospitalized patient with sepsis has persistently elevated lactic acid despite volume resuscitation, source control, and adequate oxygenation. What could I be missing?

How accurate are peripheral thermometers for estimating body temperature in my patient with chills?

Though convenient, oral, tympanic membrane, axillary, and temporal artery thermometers (AKA “peripheral thermometers”) may not be highly accurate in measuring body temperature.

A 2015 systematic review and meta-analysis of the performance of peripheral thermometers involving 75 studies (mostly in adults) found that compared to central thermometers (eg, pulmonary artery, urinary bladder, rectal), peripheral thermometers had a low sensitivity (64%, 95% CI 55%-72%), but much better specificity (96%, 95% CI 93%-97%) for fever (most commonly defined as 37.8° C [100° F] or greater).1

In the same study, for oral electronic thermometers, sensitivity was 74% with a specificity of 86%. For temporal artery thermometers, sensitivities ranged from 26% to 91%, while specificities ranged from 67% to 100%. For tympanic membrane thermometers, sensitivities ranged from 23% to 87%, with a specificity of 57% to 99%.

A 2016 study involving adult emergency department patients reported the sensitivity of peripheral thermometers (vs rectal temperature 38 C [100.4] or higher) as follows: oral (37%), tympanic membrane (68%), and temporal artery (71%). Specificity for fever was >90% for all peripheral thermometers. 2

So, it looks like while we may be pretty comfortable with a diagnosis of “fever” when our patient with chills has a high temperature recorded by a peripheral thermometer, lack of fever alone by these devices should not veer us away from the possibility of systemic infection. When in doubt and if possible, check a rectal temperature.

References

  1. Niven DJ, Gaudet JE, Laupland KB. Accuracy of peripheral thermometers for estimating temperature: A systematic and meta-analysis. Ann Intern Med 2015;163:768-777. https://www.ncbi.nlm.nih.gov/pubmed/26571241
  2. Bijur PE, Shah PD, Esses D. Temperature measurement in the adult emergency department: oral tympanic membrane and temporal artery temperatures versus rectal temperature. Emerg Med J 2016;33:843-7. https://www.ncbi.nlm.nih.gov/pubmed/27334759

 

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How accurate are peripheral thermometers for estimating body temperature in my patient with chills?

200 pearls and counting! Take the Pearls4Peers quiz #2!

Multiple choice (choose 1 answer)
1. Which of the following classes of antibiotics is associated with peripheral neuropathy?
a. Penicillins
b. Cephalosporins
c. Macrolides
d. Quinolones

 

 

2. The best time to test for inherited thrombophilia in a patient with acute deep venous thrombosis is…
a. At least 1 week after stopping anticoagulants and a minimum of 3 months of anticoagulation
b. Just before initiating anticoagulants
c. Once anticoagulation takes full effect
d. Any time, if suspected

 

 

3. All the following is true regarding brain MRI abnormalities following a seizure, except…
a. They are observed following status epilepticus only
b. They are often unilateral
c. They may occasionally be associated with leptomeningeal contrast enhancement
d. Abnormalities may persist for weeks or months

 

 

4. Which of the following is included in the quick SOFA criteria for sepsis?
a. Heart rate
b. Serum lactate
c. Temperature
d. Confusion

 

 

5. All of the following regarding iron replacement and infection is true, except…
a. Many common pathogens such as E.coli and Staphylococcus sp. depend on iron for their growth
b. Association of IV iron replacement and increased risk of infection has not been consistently demonstrated
c. A single randomized-controlled trial of IV iron in patients with active infection failed to show increased infectious complications or mortality with replacement
d. All of the above is true

 

True or false

1. Constipation may precede typical manifestations of Parkinson’s disease by 10 years or more
2. Urine Legionella antigen testing is >90% sensitive in legionnaire’s disease
3. Spontaneous coronary artery dissection should be particularly suspected in males over 50 years of age presenting with acute chest pain
4. Urine dipstick for detection of blood is >90% sensitive in identifying patients with rhabdomyolysis and CK >10,000 U/L
5. Diabetes is an independent risk factor for venous thrombophlebitis

 

 

 

Answer key
Multiple choice questions:1=d; 2=a;3=a;4=d;5=c
True or false questions:1=True; 2,3,4,5=False

 

200 pearls and counting! Take the Pearls4Peers quiz #2!

Should I use qSOFA to screen for severe infections in my non-ICU patient?

Sepsis-3 qSOFA criteria—systolic BP ≤100 mg Hg, altered mental state, and RR≥22, with ≥2 considered positive— should NOT be used as either a screening or diagnostic tool for sepsis until properly designed prospective studies validate its utility.1

An important issue with qSOFA is its poor sensitivity for identifying patients with sepsis and its complications.  In a retrospective study of over 30,000 hospitalized patients suspected of infection in the emergency department or hospital wards, qSOFA ≥2 had a sensitivity of only 54% and specificity of 67% for in-hospital mortality or ICU transfer vs a much higher sensitivity of 91% but lower specificity of 13% for SIRS ≥2. Interestingly, most patients in this study met qSOFA criteria only 5 h before the studied outcome vs 17 h for SIRS ≥2 criteria.2

In another retrospective study of over 15,000 patients presenting to the Emergency Department with suspected infection, qSOFA ≥2 had a sensitivity of  49% and a specificity of 79% for hospital mortality vs  84% and 35% for SIRS≥2, and 65% and 74% for “severe sepsis” (Sepsis-2), respectively.3

So, using qSOFA alone to decide who needs prompt management of their infection (eg, blood cultures, serum lactate, antibiotics, fluids) may delay timely intervention in a substantial proportion of patients with infection that may become complicated by ICU transfer or death.  As is usually the case in medicine, it pays to look at the entire picture!

References

  1. Machado FR, Nsutebu E, AbDulaziz S, et al. Sepsis 3 from the perspective of clinicians and quality improvement initiatives. J Crit Care 2017:40: 315-17. https://www.ncbi.nlm.nih.gov/pubmed/28478045
  2. Churpek MM, Synder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration n infected patients outside the intensive care unit. Am J Respir Crit Care Med 2017; 195: 906-11. https://www.ncbi.nlm.nih.gov/pubmed/27649072
  3. Lembke K, Parashar S, Simpson S. Sensitivity and specificity of SIRS, qSOFA, and severe sepsis for mortality of patients presenting to the emergency department with suspected infection. Chest Annual Meeting, Toronto, October 29, 2017. http://dx.doi.org/10.1016/j.chest.2017.08.427
Should I use qSOFA to screen for severe infections in my non-ICU patient?

In my patient with sepsis, is administration of proper antibiotics within an hour compared to 1-3 hours associated with better outcome?

The weight of the evidence based on observational studies suggests that the earlier the antibiotics are administered even within the first 3 hrs of the diagnosis of sepsis,  the better the patient outcome.

A 2017 study analyzing data from 37 studies (primarily observational) involving ~20,000 patients with severe sepsis and/or shock found a 10% increase in hospital mortality for every 1 hr delay in initiation of antibiotic therapy1. Two multicenter studies (1 in Pennsylvania2 and another in California3) and a New York State data base study involving patients with severe sepsis or septic shock4 similarly reported decreased survival with each 1- hr delay in antibiotic therapy. Another study of patients with severe sepsis found that each hour delay in first antibiotic dose administration was associated with an 8% increased risk of progression to shock5.

Despite the emphasis on the timing of the first dose of antibiotics, let’s not forget that the second dose of antibiotics should also be given on time in sepsis; a >25% delay is associated with increased mortality, length of stay and requirement for mechanical ventilation6.

So, yes, antibiotics should be given within 3 hours of diagnosis of sepsis, but within an hour followed by a timely second dose is even better!

Final Pearl: Did you know that sepsis is the 3rd leading cause of death in the US and contributes to 1 in every 2 to 3 hospital deaths7?

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References

  1. Kalil AC, Johnson DW, Lisco SJ, et al. Early goal-directed therapy for sepsis: a novel solution for discordant survival outcomes in clinical trials. Crit Care Med 2017;45:607-14. https://www.ncbi.nlm.nih.gov/pubmed/28067711
  2. Seymour CW, Kahn JM, Martin-Gill, et al. Delays from first medical contact to antibiotic administration for sepsis. Crit Care Med 2017;45:759-65. https://insights.ovid.com/pubmed?pmid=28234754
  3. Liu VX, Fielding-Singh V, Greene JD, et al. Th timing of early antibiotics and hospital mortality in sepsis. Am J Respir Crit care Med 2017; 196;858-63. https://www.ncbi.nlm.nih.gov/pubmed/28345952
  4. Seymour CW, Gesten F, Prescott HC, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med 2017;376:2235-44. http://www.nejm.org/doi/full/10.1056/NEJMoa1703058
  5. Whiles BB, Deis AS, Simpson SQ. Increased time to initial antimicrobial administration is associated with progression to septic shock in severe sepsis patients. Crit Care Med 2017; 45:623-29. https://www.ncbi.nlm.nih.gov/pubmed/28169944
  6. Leisman D, Huang V, Zhou Q, et al. Delayed second dose antibiotics for patients admitted from the emergency department with sepsis: prevalence, risk factors, and outcomes. Crit Care Med 2017;45:956-65. https://www.ncbi.nlm.nih.gov/pubmed/28328652
  7. https://www.ecri.org/components/HRC/Documents/Sepsis%20at%20a%20Glance.pdf

 

 

In my patient with sepsis, is administration of proper antibiotics within an hour compared to 1-3 hours associated with better outcome?

My patient with cirrhosis has been admitted to the hospital several times this year with bacterial infections. How does cirrhosis increase susceptibility to infections?

Bacterial infections are a common cause of morbidity and mortality in patients with cirrhosis, affecting about 30% of such patients either at admission or during their hospitalization, with an attendant risk of mortality that is twice that of individuals without cirrhosis1.

Two major mechanisms may account for the observed immune dysfunction in cirrhosis: 1. Compromise of the immune surveillance function of the liver itself through damage of the reticulo-endothelial system (RES) and reduced synthesis of innate immunity proteins and pattern recognition receptors (PRRs); and 2. Dysfunctions of circulating and intestinal population of immune cells2.

Damage to the RES in cirrhosis leads to portal-system shunting, loss/damage of Kupffer cells (specialized hepatic macrophages) and sinusoidal capillarization, all hindering blood-borne pathogen clearance. Cirrhosis is also associated with a defect in hepatic protein synthesis, including complement components, decreased PRRs and acute phase reactants (eg C-reactive protein), which may in turn lead to the impairment of the innate immunity and bacterial opsonization.

Cirrhosis can also cause reduction in the number and function of neutrophils (eg, decreased phagocytosis and chemotaxis), B, T, and NK lymphocytes, and decreased in bacterial phagocytosis by monocytes. In addition, damage to the gut-associated lymphoid tissue (eg Peyer’s patches and mesenteric lymph nodes) may facilitate bacterial translocation.

References

  1. Pieri G, Agarwal B, Burroughs AK. C-reactive protein and bacterial infections in cirrhosis. Ann Gastroenterol 2014;27:113-120. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982625/pdf/AnnGastroenterol-27-113.pdf
  2. Albillos A, Lario M, Alvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014;61:1385-1396. http://www.journal-of-hepatology.eu/article/S0168-8278(14)00549-2/pdf

 

My patient with cirrhosis has been admitted to the hospital several times this year with bacterial infections. How does cirrhosis increase susceptibility to infections?

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?

 UTIs are often considered in the differential diagnosis of causes of delirium in the elderly. Though largely speculative, 2 possible pathophysiologic basis for this association are suggested:1-3

  •  Direct brain insult (eg, in the setting of sepsis/hypotension)
  • Indirect aberrant stress response, involving cytokines/inflammatory pathways,  hypothalamic-pituitary-adrenal [HPA] axis and sympathetic nervous system (SNS). One or both pathways can interact with the neurotransmitter and intracellular signal transduction systems underlying delirium in the brain, which may already be impaired in the elderly due to age-related or other pathologic changes.

The indirect aberrant stress pathway suggests that not only pain and discomfort (eg from dysuria) can contribute to delirium but UTI-associated circulating cytokines may also cause delirium.  Indeed, a large study of older adults undergoing elective surgery found a significant association between delirium postoperatively (postop day 2) and serum proinflammatory cytokine levels such as IL-6. 4  

The corollary is that bacteriuria is unlikely to be associated with delirium in the absence of significant systemic inflammatory response, pain or discomfort.

 

References

1.Trzepacz P, van der Mast R. The neuropathophysiology of delirium. In Lindesay J,  Rockwood K, Macdonald A (Eds.). Delirium in old age, pp. 51–90. Oxford University Press, Oxford , 2002.

2.Flacker JM, Lipsitz LA. Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol A Biol Sci Med Sci. 1999; 54: B239–B246 https://www.ncbi.nlm.nih.gov/pubmed/10411009

3. Maclullich AM, Ferguson KJ, Miller T, de Rooij SE, Cunningham C. Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res. 2008;65:229–38. https://www.ncbi.nlm.nih.gov/pubmed/18707945

4. Vasunilashom SM, Ngo L, Inouye SK, et al. Cytokines and postoperative delirium in older patients undergoing major elective surgery. J Gerontol A Biol Sci Med Sci 2015;70:1289-95. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817082/pdf/glv083.pdf

Contributed by Henrietta Afari MD, Mass General Hospital, Boston, MA

How exactly do urinary tract infections (UTIs) cause delirium in my elderly patients?

What are the potential pitfalls in reliance on serum creatinine levels or urine output in sepsis-associated acute kidney injury (SA-AKI)?

Although serum creatinine and urine output are usually easily measured, several limitations in their interpretation in patients suspected of having sepsis and AKI are worth emphasizing1.

First, there is an inherent lag of hours between a drop in glomerular filtration rate (GFR) and a rise in serum creatinine concentration. Second, in critically ill hypotensive patients with sepsis receiving aggressive fluid resuscitation, hemodilution may mask serum creatinine rise and delay the diagnosis of AKI by a day. Third, sepsis itself may reduce muscular production of creatinine, even in the absence of weight loss, as demonstrated in animal studies2.  Fourth, patients receiving diuretics may fail to meet criteria for AKI diagnosis based on reduced urine output alone because of increased urine output.  

Lastly, as renal function deteriorates, the half-life of serum creatinine increases from several hours to several days3, prolonging the time needed to achieve a new steady-state that may be more reflective of the concurrent GFR.

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 References

  1. Godlin M, Murray P, Mehta. Clinical approach to the patient with AKI and sepsis. Semin Nephrol 2015;35:12-22.
  2. Doi K, Yuen PST, Eisner C, et al. Reduced production of creatinine limits its use as marker of kidney injury in sepsis. J Am Soc Nephrol 2009;20:1217-21.
  3. Chiou WL, Hsu FH. Pharmacokinetics of creatinine in man and its implications in the monitoring of renal function and in dosage regimen modifications in patients with renal insufficiency. J Clin Pharmacol. 1975; 15(5-6):427-34.
What are the potential pitfalls in reliance on serum creatinine levels or urine output in sepsis-associated acute kidney injury (SA-AKI)?

How is the pathophysiology of sepsis-associated acute kidney injury (SA-AKI) different than AKI due to non-septic conditions?

Sepsis accounts for up to one-half of AKI cases in developed countries1.  Although sepsis-mediated hypoperfusion causing tubular necrosis has traditionally been implicated as the primary basis for SA-AKI,  an increasing number of studies have suggested that SA-AKI is a distinct subset of AKI differentiated from other causes by unique hemodynamic and inflammatory/immune-related mechanisms.  

Many animal and limited human studies have found that renal blood flow is an inconsistent predictor of SA-AKI, possibly related to the redistribution of blood in the renal microvasculature to the detriment of the renal medulla in sepsis2.

Cytokine-mediated response in sepsis can also lead to tubular cellular injury without necessarily causing necrosis. Of interest, an autopsy study found histological features of acute tubular necrosis in only 22% of patients with clinical diagnosis of SA-AKI 3.  

Differences in its pathophysiology may at least in part explain why oliguria, renal function recovery, hemodialysis and death are more common among SA-AKI patients4.

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References

  1. Alobaidi R, Basu RK, Goldstein SL, Bagshaw SM. Sepsis-associated acute kidney failure. Semin Nephrol 2015;35:2-11.  https://www.ncbi.nlm.nih.gov/pubmed/25795495
  2. Maiden MJ, Otto S, Brealey JK, et al. Structure and function of the kidney in septic shock. Am J Resp Crit Care Med 2016;194:692-700. https://www.atsjournals.org/doi/abs/10.1164/rccm.201511-2285OC
  3. Langenberg C, Bagshaw SM, May CN, Bellomo R. The histopathology of septic acute kidney injury: a systemic review. Crit Care 2008;12:R38.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2447560/
  4. Cruz MG, de Oliveira Dantas JGA, Levi TM, et al. Septic versus non-septic acute kidney injury in critically ill patients: characteristics and clinical outcome. Rev Bras Ter Intensiva 2014;26:384-391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304467/
How is the pathophysiology of sepsis-associated acute kidney injury (SA-AKI) different than AKI due to non-septic conditions?