Sepsis with Comorbidities: Management Strategies

Author: William Fox, MD (EM Attending Physician, Baylor University Medical Center, Dallas, TX) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

Case:

Midway through your shift at a small community Emergency Department, the triage nurse alerts you to a patient coming in by EMS from a nursing home who is febrile, altered, and tachycardic.  Your mind runs through your standard differential, and the patient’s initial presentation in your ED confirms your primary suspect: sepsis.  But over the course of your physical exam, you notice a fistula in the patient’s left arm.  You start to wonder how your management will differ now that you know the patient has end stage renal disease.  Can any strategies help you individually tailor the sepsis treatment to impact this patient’s outcome?

Treating sepsis has become one of the cornerstones of effective emergency medicine practice.  The advent of early goal directed therapy coupled with the linkage of reimbursement schemes with adherence to treatment protocols have encouraged providers to adopt a “one size fits all” approach to sepsis treatment.  In an otherwise healthy individual, a standardized fluid resuscitation, antibiotic, and vasopressor guideline may very well be the most appropriate treatment for the initial infectious insult and the resultant systemic organ dysfunction.  In patients with concomitant or preexisting organ dysfunction due to another issue, a standardized approach may be inadequate or harmful.  The goal of this post is to review some of the more common end-organ dysfunctions that can complicate sepsis diagnosis and management and discuss treatment strategies and nuances that may be more beneficial for patients.   The format of the post will include discussion of pathogenesis of specific chronic illness, how it changes overall physiology, what those physiologic changes mean in the context of sepsis, and specific treatment options and adjuncts.

End Stage Renal Disease

End stage renal disease (ESRD) is the gradual destruction of nephrons leading to an impairment in the kidney’s ability to create and maintain an electrolyte gradient.  This chronic illness affects approximately 661,000 Americans.¹ The nephron is the functional unit of the kidney, consisting of glomeruli, arterioles, and parallel fluid circuits that generate electrolyte and osmotic gradients between blood and urine.  These gradients maintain the optimal functional environment for body systems while serving as the most efficient and effective controlled way of eliminating fluid from the body.  A variety of insults may cause damage to the basement membranes of the nephron that assist in the development of the gradient.  Damage to basement membranes lead to failure of the nephron, cumulatively resulting in electrolyte and volume imbalances.  The end result can include uncontrolled hypertension, cardiac dysfunction, and further secondary end organ damage.  The failure of this organ system is not immediately fatal, however, as a suitable replacement for the organ’s functional status can be attained via dialysis.

Two of the most common methods for dialyzing patients include peritoneal dialysis and intermittent hemodialysis.  Peritoneal dialysis relies on the instillation of fluid into the peritoneal space via a surgically placed catheter and facilitates the passive diffusion of electrolytes and fluid through the walls of the body tissues.  Hemodialysis involves extracorporeal flow of blood past a semipermeable membrane.  The flow of blood from systemic to the extracorporeal membrane is facilitated by either catheters or fistulae.  The catheters are usually a temporary, large bore, dual lumen catheter placed at the bedside (Quinton catheter) or a more permanent catheter placed under CT guidance by interventional radiology (Permacath).  A fistula is a surgically joined systemic artery and vein, frequently in either an upper or lower extremity, that creates a high flow, low resistance system which can be accessed multiple times via large-bore cannulae.  These treatment strategies, though effective, create multiple opportunities for pathogens to infect a patient while simultaneously modulating the effectiveness of textbook sepsis treatment strategies.

Sepsis is a leading cause of death in patients with ESRD due to increased immunosuppression risk associated with comorbidities, electrolyte imbalances (i.e. uremia) and, for some patients, advanced age.² Additionally, frequently accessing systemic circulation and bypassing a number of barrier immunologic defenses patients are susceptible to inoculation which later can develop into unchecked infection.  Understanding the timeline of access placement and type of access can help localize the source of infection.  A few elements of the history may be considered:

• If the patient has a catheter, how long has it been in place? Has the dressing been changed regularly by qualified personnel? Is there any discharge, redness, or pain? Did the patient’s dialysis team successfully dialyze through the line recently, or have there been issues? Was the line placed emergently or in a controlled environment?  Has the patient had line infections in the past?
• If the patient has a fistula, how long ago was it placed? Has it matured yet?  Is there a palpable thrill?  Any new changes aside from the normal postoperative redness/swelling?
• If the patient does peritoneal dialysis, has the patient been adherent with his or her normal schedule? Does the patient have access to a clean and appropriately evaluated water source?  Any change in the effluent after the patient has infused the dialysate?  Is it cloudy or a different color?

The ESRD patient’s impaired ability to regulate blood volume and electrolyte composition necessitates judicious fluid resuscitation and volume status monitoring.  Loss of one of the most valuable markers of fluid balance in urine output limits the emergency clinician’s ability to assess volume accurately and objectively.  Aggressive fluid rehydration will induce fluid leakage through more permeable membranes, most commonly in the lungs and dependent extremities.  This will further compromise the patient’s ability to compensate for the associated acidosis related to sepsis.  Consider smaller increments of 500ccs with frequent and careful reassessment of volume status using easily evaluated physical exam findings:

• JVD
• B lines (aka “comets” or “rockets”) on pulmonary ultrasound
• IVC collapsibility
• Work of breathing/dependent lung sounds
• Dependent edema

Still, a subset of ESRD patients who received early goal directed therapy did better than ESRD patients receiving standard care.³  Under-resuscitation and delay in antibiotic administration have led to worse outcomes in these patients.  An important point to consider, echoed in many separate pieces of primary literature, conclude that complications arising from fluid resuscitation (i.e. pulmonary edema) can be corrected with fluid removal via dialysis once septic episode has resolved.  Once identified, the septic episode is usually the biggest threat to the life of the patient.⁴

End Stage Liver Disease

Cirrhosis results from repeated cycle of hepatocellular injury, healing/fibrosis, and remodeling.  The initial insult can be environmental (as in alcoholic hepatitis), infectious (as in chronic viral infections), or immune (as in autoimmune hepatitis).  For ease of discussion, we will only consider the end stage liver disease, or cirrhosis, as opposed to waxing-waning cycle of chronic injury that many patients experience.  Based on census data, there were 633,323 Americans with cirrhosis (prevalence of 0.27%) between 1999 and 2010.⁵  The etiology of liver insult is multifactorial, but in the U.S. it is most commonly due to viral hepatitis, followed by alcohol and diabetes.⁵  Repeated healing/fibrosis cycles influence both intrinsic function of liver and systemic hemodynamics.  Increased portal venous resistance (due to fibrosis) results in development of shunting from portal system to systemic venous circulation via venous plexus in the gut (usually in the distal esophagus or rectum) due to changes in hydrostatic pressure.  Changes in oncotic pressure secondary to failing intrinsic liver function leads to decreased overall intravascular osmotic pressure.  Decreased osmotic pressure intravascularly leads to fluid shifts into other areas, mainly the abdominal cavity, in the form of ascites.  Loss of normal circulating protein production coupled with the initial insult (viral, environmental, or metabolic) further modulates immune activity.⁶

In considering sepsis, cirrhosis has been shown to be a risk factor for hospitalization and death.⁷  Thus, early and appropriate identification of the infection site is critical for targeted treatment and can have measurable impact on patient mortality.⁶ One of the most obvious but overlooked infectious sources is development of secondary bacterial peritonitis (SBP) via translocation of bacteria through the gut.  SBP is most commonly caused by gram negative flora like Klebsiella or Escherichia, but occasionally may be gram positive organisms such as Enterococcus from the bowel lumen.  Improved bacterial yields from ascitic fluids have been found via inoculation of blood culture bottles with fluid as soon as possible after removal from the peritoneal cavity.¹⁶  Source control is important, and “conventional” antibiotic dosing may not be enough to treat an infection sourced in the abdomen.  The standard antibiotic dosing consists of 2g of a third generation cephalosporin, usually cefotaxime or ceftriaxone.  It is important to consider the patient’s medication regimen, as if the patient was previously on floroquinolones for SBP prophylaxis, then you MUST use alternative regimen as treatment is (likely) no longer effective.⁸ Several studies have shown that providers may consider albumin supplementation in patients with concomitant renal dysfunction.  A dose of 1.5g/kg within initial 6 hours, if creatinine >1mg/dL, may prevent further renal decompensation, though these results are not without controversy.⁹ Additionally, some studies suggest steroids could shorten sepsis time and improve survivability, but no RCT has confirmed this.⁶

Pulmonary Hypertension

Pulmonary hypertension (PH) patients have unique circulatory abnormalities that limit resuscitation and treatment options.  The right ventricle functions as the pump for the “low pressure” circuit of the human body.  Upon exposure to oxygen at birth, the right heart pumps through low pressure system modulated by oxygen exposure, which is augmented by left heart to right heart flow until the ductus arteriosus closes shortly after birth.  A French physician, André Cournand, was awarded the Nobel Prize in Medicine or Physiology in 1956 for his work recording right ventricular pressures with a catheter.  It is accepted that normal right ventricular pressures are approximately 25/0 mm Hg.¹⁰ The right ventricle (RV) in a resting, healthy person is often described as a “conduit” for a blood volume equal to the total systemic circulation moving in a high flow, low resistance circuit.¹¹

The RV’s comparison to a simple conduit should frame a clinician’s thinking as to the vessel’s relative inability to work against the increasing afterload seen in pulmonary hypertension.  The RV relies heavily on preload for forward flow, but too much may induce distention, eventually inhibiting its ability to perfuse the thin wall of myocardium, leading to further dysfunction due to ischemia.¹⁷ A consideration of the five classes of pulmonary hypertension can provide more history relating to the initial insult (if known) resulting in RV dysfunction.

5 Types of Pulmonary Hypertension by WHO criteria:

Group 1- Pulmonary arterial hypertension

Group 2- PH due to left ventricular failure

Group 3- PH due to lung disease

Group 4- PH due to thrombotic disorders (i.e. PEs)

Group 5- PH due to other causes

When considering the influence of volume on pulmonary hypertension patients, both hypovolemia and hypervolemia can be damaging.¹² Hypovolemia may reduce the volume of blood reaching the right and left ventricle, thus decreasing the overall systemic cardiac output.  Hypervolemia may cause further right ventricular strain and dysfunction.  The source of infection is significant, as end-organ responses in infection may impact the failing RV differently.  For example, pyelonephritis may be “easier” to manage in these patients due to the physiologic distance between the failing R heart/constricting vessels and the source.  This can be contrasted with pneumonia, which induces physiologic and pathologic changes in the lung parenchyma and in pulmonary blood flow.  Hypoventilated segments will further constrict, potentially worsening RV afterload exposure.  Positive pressure ventilation may help recruit atelectatic and infected lung segments but will continue to tax the right ventricle. Thus, interventions such as noninvasive (or invasive) ventilation may worsen condition.

This leaves emergency clinicians between a rock and a hard place, especially in patients who could benefit from ventilator support.  Early augmentation of RV function to match changes in already compromised pulmonary circulation may be the key to promoting improved circulation and ultimately improving patient outcome.  Vasopressors with ionotropic properties may be reasonable (norepinephrine vs dobutamine) but at the expense of increased likelihood of developing arrhythmias.  Continued fluid loading may be dangerous, and early vasopressor initiation may improve patient status, but ultimately these patients may require medications with dilatory effects specifically on pulmonary vasculature as a temporizing measure, which may be best addressed in an ICU setting.  Prostacyclin or inhaled nitric oxide are two options for pulmonary vasoactive medication but are not usually offered in an emergency medicine practitioner’s armamentarium.  Finally, an understanding of the underlying cause of the patient’s pulmonary hypertension may provide some benefit, but ultimately may be limited as chronic conditions can rarely be reversed in an emergent setting.

Congestive Heart Failure

Congestive heart failure (CHF) affects an estimated 2% of the adult population, with most resulting from coronary artery disease.¹³ It exists in two “flavors,” either limiting the systolic or diastolic function of the heart, with the latter category possessing a delineation between preserved and reduced ejection fraction.  On a more basic level, an “index event” leads to myocardial damage and impairment of the contractility and normal functioning of myocytes.¹⁸ Poor blood flow induces a cascade of signaling molecules resulting in poor systemic circulation, decreased end-organ perfusion, and increased volume retention.  Though a chronic CHF patient’s appearance may lead a provider to reconsider aggressive intervention in sepsis, research has shown an overly-cautious approach may lead to worse outcomes for these patients.

Retrospective studies have shown that under-resuscitation of hypotensive patients with sepsis and CHF leads to higher mortality and higher intubation.¹⁴ Additionally, other data suggest no difference in intubation rates in case-matched studies of patients with left ventricular dysfunction compared to patients with normal ejection fraction.¹⁵ Cardiac dysfunction is a predictable side effect of disseminated bacteremia and the concept of septic cardiac dysfunction has been discussed elsewhere.  In brief, left ventricular systolic dysfunction due to sepsis can stack with existing CHF with depressed ejection fraction leading to further decreases in cardiac output.¹⁹ Volume retention due to systemic compensatory mechanisms may make guideline-driven resuscitation more complicated as patients may be more susceptible to developing pulmonary edema, anasarca, etc.  Augmentation of cardiac with vasopressors in patients maintaining vascular tone can be accomplished with dobutamine.  Still, norepinephrine remains the preferred agent in sepsis for peripherally vasodilated patients who remain hypotensive, as this medication can counter both sepsis-induced myocardial dysfunction and loss of vascular tone.²⁰  In contrast to the considerations in pulmonary hypertension patients, assisted ventilation via BiPAP or intubation may augment left ventricular function and assist in forward flow, while simultaneously improving the ventilatory status that may be faltering or failing after fluid resuscitation.

Conclusion

The understanding and adoption of fluid resuscitation in patients with sepsis has improved outcomes and the level of care so much so that provider compensation may now be tied to meeting certain metrics guiding resuscitation.  Though providers may find solace in the relative simplification of sepsis treatment regimens, adopting therapies as a panacea without critical thought and applicability will inevitably doom complicated or outlier patients to substandard or dangerous care.  The goal of this review is to understand the implications of chronic physiologic abnormalities that can confound providers and limit the effectiveness of the “standard of care”.  An understanding of these nuances of end-organ disease can give providers a general framework to approach the care of complicated sepsis cases in an intelligent, methodical, and patient-centered manner.

Take Home Points

• Despite comorbidities, sepsis is the primary threat to the life of the patient and must be treated
• SBP should not be overlooked in cirrhotic, and valuable culture data can be gleaned from inoculating culture bottles immediately after sample collection
• Early vasopressor usage in pulmonary hypertension and avoidance of positive pressure ventilation can preserve compromised right ventricular function
• Congestive heart failure patients, conversely, may benefit from positive pressure ventilation used judiciously during resuscitation

References / Further Reading

1. Kidney disease Statistics for the United States. https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease. Accessed June 10, 2017.
2. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney International. 2000;58(4):1758-1764. doi:10.1111/j.1523-1755.2000.00337.x.
3. Otero RM, Nguyen HB, Huang DT, et al. Early Goal-Directed Therapy in Severe Sepsis and Septic Shock Revisited: Concepts, Controversies, and Contemporary Findings. Chest. 2006;130(5):1579-1595.
4. Dagher GA, Harmouche E, Jabbour E, Bachir R, Zebian D, Chebl RB. Sepsis in hemodialysis patients. BMC Emergency Medicine. 2015;15(1). doi:10.1186/s12873-015-0057-y.
5. Scaglione S, Kliethermes S, Cao G, et al. The Epidemiology of Cirrhosis in the United States. Journal of Clinical Gastroenterology. 2015;49(8):690-696. doi:10.1097/mcg.0000000000000208
6. Gustot T, Durand F, Lebrec D, Vincent J-L, Moreau R. Severe sepsis in cirrhosis. Hepatology. 2009;50(6):2022-2033. doi:10.1002/hep.23264.
7. Foreman MG, Mannino DM, Moss M. Cirrhosis as a Risk Factor for Sepsis and Death. Chest. 2003;124(3):1016-1020. doi:10.1378/chest.124.3.1016.
8. Runyon B. Spontaneous Bacterial Peritonitis: Treatment and Prophylaxis. Spontaneous bacterial peritonitis in adults: Treatment and prophylaxis. http://www.uptodate.com. Published January 4, 2016. Accessed May 25, 2017.
9. Sort P, Navasa M, Arroyo V, et al. Effect of Intravenous Albumin on Renal Impairment and Mortality in Patients with Cirrhosis and Spontaneous Bacterial Peritonitis. New England Journal of Medicine. 1999;341(6):403-409. doi:10.1056/nejm199908053410603.
10. Rajpal S, Buber Y, Landzberg MJ. Pulmonary Hemodynamics and Right Heart Catheterization. Diagnosis and Management of Pulmonary Hypertension Respiratory Medicine. 2015:225-264. doi:10.1007/978-1-4939-2636-7_10.
11. Tapson VF. The Pulmonary Circulation. Diagnosis and Management of Pulmonary Hypertension Respiratory Medicine. 2015:1-20. doi:10.1007/978-1-4939-2636-7_1.
12. Poor HD, Ventetuolo CE, Bull TM. Pulmonary Hypertension in Critically Ill Patients. Diagnosis and Management of Pulmonary Hypertension Respiratory Medicine. 2015:413-436. doi:10.1007/978-1-4939-2636-7_18.
13. Dar O, Cowie M. The Epidemiology and Diagnosis of Heart Failure. In: Hurst’s The Heart. 13th ed. New York, NY: McGraw-Hill; 2011.
14. Duttuluri M, Rose K, Shapiro J, et al. Fluid Resuscitation Dilemma in Patients with Congestive Heart Failure Presenting with Severe Sepsis/Septic Shock. D45 Critical Care: Circulatory Hemodynamics, Shock, Cardiovascular Disease, and Fluid Management Poster Session American Journal of Respiratory Critical Care. 2016;193.
15. Ouellette DR, Shah SZ. Comparison of outcomes from sepsis between patients with and without pre-existing left ventricular dysfunction: a case-control analysis. Critical Care. 2014;18(2). doi:10.1186/cc13840.
16. Koulaouzidis A, Bhat S, Karagiannidis A, Tan WC, Linaker BD. Spontaneous bacterial peritonitis. Postgraduate Medical Journal. 2007;83(980):379-383. doi:10.1136/pgmj.2006.056168.
17. Wilcox SR, Kabrhel C, Channick RN. Pulmonary Hypertension and Right Ventricular Failure in Emergency Medicine. Annals of Emergency Medicine. 2015;66(6):619-628. doi:10.1016/j.annemergmed.2015.07.525.
18. Mann D, Chakinala M. Heart Failure: Pathophysiology and Diagnosis. In: Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2014.
19. Vieillard-Baron A, Cecconi M. Understanding cardiac failure in sepsis. Intensive Care Medicine. 2014;40(10):1560-1563. doi:10.1007/s00134-014-3367-8.
20. Backer DD, Scolletta S. Clinical Management of the Cardiovascular Failure in Sepsis. Current Vascular Pharmacology. 2013;11(2):222-242. doi:10.2174/1570161111311020011.