Sepsis

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

FA Manian MD, MPH, , , , , , , , Leave a comment

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?

FA Manian MD, MPH, , , , , , , , Leave a comment

 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. We just need to do proper studies to prove it!

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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)?

FA Manian MD, MPH, , , Leave a comment

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?

FA Manian MD, MPH, , , , Leave a comment

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?

My elderly patient with acute heart failure with preserved ejection fraction (HFpEF) has a low serum albumin. Can hypoalbuminemia be associated with HFpEF?

FA Manian MD, MPH, , , , Leave a comment

Absolutely! As early as 1959, Guyton and Lindsey demonstrated the importance of serum colloid osmotic pressure in the pathogenesis of pulmonary edema1.

Specifically, they found that in dogs with normal plasma protein concentrations fluid began to transudate into the lungs when the left atrial pressure rose above an average of 24 mm Hg vs only 11 mm Hg when plasma protein concentration was reduced by about 50%.

Fast forward to 2003, Arques et al studied serum albumin and pulmonary artery wedge pressures in 4 groups of patients: acute HFpEF, heart failure with reduced ejection fraction (HFrEF), acute dyspnea from pulmonary origin and normal controls2.   Patients with HFpEF were significantly more likely to have hypoalbuminemia , compared to those with HFrEF, pulmonary disease or normal controls.  The main cause of hypoalbuminemia in the HFpEF was malnutrition in 77% and/or sepsis in 41% of patients.   Hypoalbuminemia was inversely related to age and plasma C-reactive protein.

Perhaps, we should pay more attention the nutritional status of our patients with HFpEF!

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References

  1. Guyton AC, Lindsey AW. Effect of elevated left atrial pressure and decreased plasma protein concentration on the development of pulmonary edema. Circ Res 1959;7: 649-657.
  2. Arquès S, Ambrosi P, Gélisse R et al. Hypoalbuminemia in elderly patients with acute diastolic heart failure. J Am Coll Card 2003;42:712-16. http://www.onlinejacc.org/content/42/4/71                                                                                                    
My elderly patient with acute heart failure with preserved ejection fraction (HFpEF) has a low serum albumin. Can hypoalbuminemia be associated with HFpEF?

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?

FA Manian MD, MPH, , , , , , , Leave a comment

Besides the usual causes of rhabdomyolysis such as trauma, drugs, alcohol, sepsis, etc…, cirrhotic patients may also have what some have called “hepatic myopathy”.  

One study involving 99 patients with cirrhosis and myopathy (all with elevated serum myoglobin) found “infections” as the most common cause (47%),  followed by “idiopathic” (27%) sources as well as ETOH, herbal medicine, and trauma-related causes (<10% each) (1).  Whether this is truly an entity  or just a non-causal association is unclear.

Another study reported that ~60% of rhabdomyolysis cases in cirrhosis had no apparent cause (2), with mortality among patient with cirrhosis and rhabdomyolysis significantly higher than that of controls without cirrhosis (27.5% vs 14.5%).

So perhaps we should lower our threshold for checking serum CK in our patients with cirrhosis and weakness.

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Reference

1. Lee O-J, Yoon J-H, Lee E-J, et al. Acute myopathy associated with liver cirrhosis. World J Gastroenterol 2006;12:2254-2258.  https://www.ncbi.nlm.nih.gov/pubmed/16610032 .

2. Baek JE, Park DJ, Kim HJ, et al. The clinical characteristics of rhabdomyolysis in patients with liver cirrhosis. J Clin Gastroenterol 2007;41:317-21.

 

Is there a connection between cirrhosis and elevated CK or rhabdomyolysis?