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Authors: Brittany T. Jackson, PharmD, W. Anthony Hawkins, PharmD, BCCCP and Sandeep Devabhakthuni, PharmD, BCCP
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, where early identification and appropriate, timely management improve outcomes.1 However, Surviving Sepsis Campaign (SSC) guidelines do not address sepsis management based on the presence of heart failure (HF).2 Sepsis management may differ depending on the type of HF so this blog will focus on patients with heart failure with reduced ejection fraction (HFrEF). Several factors make the management of sepsis in patients with HFrEF uniquely challenging, such as a heightened risk of volume overload and the need for alternative vasoactive regimens to maintain cardiac output (CO). The optimal management of sepsis in patients with HFrEF is undefined. The purpose of this blog is to provide practical considerations in the hemodynamic management of septic patients with HFrEF with a focus on fluid administration and vasoactive agents.
Understanding the pathophysiology in patients with sepsis and HFrEF is crucial to provide safe and effective medication therapy. Many mediators such as pro-inflammatory cytokines (e.g., tumor necrosis factor-a) and reactive oxygen species have been shown to cause cardiac dysfunction, increased vascular permeability, and reduced peripheral vascular resistance, leading to hemodynamic instability and multiple organ injury.3 There is an abundance of literature describing the initial hemodynamic parameters in septic patients without underlying cardiac dysfunction and subsequent hemodynamic changes that occur as the patient is managed (Table 1).4
The hemodynamic differences in septic patients with HFrEF are not well described in the literature. The first major difference for patients with HFrEF is their limited tolerance of rapid changes in volume. In patients with HFrEF, the Frank-Starling curve is relatively flat compared to those without cardiac dysfunction (Figure 1).5 Fluid resuscitation would only be beneficial if patients are on the left side of the preload curve (i.e., low stroke volume), which is rare given that most patients with HFrEF present with volume overload and many patients have at least subclinical congestion.6,7 Because patients with HFrEF are less preload dependent, fluid boluses do not significantly increase stroke volume (and thus cardiac output) if they are on the center or right side of the curve. Instead, additional fluid may only worsen congestive symptoms or cause the patient to “fall off” the curve by causing excess myocardial stretch, leading to a decrease in stroke volume. The second hemodynamic difference in patients with HFrEF is that they have decreased CO at baseline and respond positively to inotropes in the setting of shock (Figure 1).5 Finally, mean arterial pressure (MAP) may be difficult to interpret in patients with HFrEF because systemic vascular resistance (SVR) may be high due to excess neurohormonal activation (resulting in a decrease in CO and thus minimal to no net change in MAP). Consequently, clinicians should not diagnose shock based on MAP alone. Instead, other indices of hypoperfusion should be considered to define shock including signs and symptoms on physical examination (e.g., altered mental status, cool extremities), decreased SCVO2, increased serum lactate levels, and presence of new or worsening end-organ damage. For patients with both HFrEF and sepsis, providers should adopt an individualized approach.3
Current SSC guidelines recommend that at least 30 mL/kg of intravenous (IV) crystalloid fluid be administered during resuscitation from sepsis-induced hypoperfusion within the first three hours. After initial fluid resuscitation, it is recommended that additional administration of fluids be guided by dynamic markers of fluid responsiveness.2 However, data to support administration of 30 mL/kg of crystalloid fluid remain controversial.8,9 Volume overload in sepsis has been associated with respiratory failure requiring mechanical ventilation, thoracentesis, initiation of renal replacement therapy (RRT), and increased mortality.10,11 Literature suggests that compliance with 30 mL/kg crystalloid fluid decreases mortality,12,13 while others have shown no difference.14 A recent study compared outcomes of restrictive (<30 mL/kg) to standard (≥30 mL/kg) fluid resuscitation in septic patients with underlying comorbidities, including HF. This study demonstrated no difference in incidence or time to intubation, duration of mechanical ventilation, or alive ICU-free days between the two groups.15 However, a significant limitation of this study was that all types of HF were included, with only about 20% of patients having HFrEF. This may confound the results because HF with preserved ejection fraction and isolated right ventricular dysfunction are usually more preload-dependent conditions. The heterogeneity of the HF populations included in the study may explain the conflicting findings found in the literature. Administration of 30 mL/kg crystalloid fluid in patients with chronic HF is generally lower.12,14 Notably, administration of less than the 30mL/kg recommendation has not shown to improve outcomes with the exception of decreased incidence of acute kidney injury.16
Taken altogether, these data suggest that fluid resuscitation may be reasonable in the small subset of patients with HFrEF and suspected intravascular depletion.4,8,9,12,15 However, clinicians should monitor volume status closely via physical examination (e.g., capillary refill, skin turgor/dryness, skin perfusion) and continuous monitoring of the patient’s hemodynamic status (e.g., heart rate, MAP, stroke volume variation) and markers of organ function (e.g., creatinine, liver function tests, urine output). In patients with HFrEF, a more conservative approach to fluid resuscitation (e.g., initial fluid of 500 mL over the first hour then up to 2 liters depending on volume status) is suggested.3,4,8,9,12,15 Ultrasonography of the inferior vena cava (IVC) can provide information about diameter and collapsibility, where a flat or highly collapsible IVC would indicate intravascular depletion.3 If the IVC is full and non-collapsible, suggesting intravascular hypovolemia is not present, further fluid administration should be avoided and addition of vasopressor and inotropic agents should be considered instead. If hemodynamic or volume status is still unclear, a pulmonary artery catheter can also be considered to clarify cardiac output (CO) and pulmonary capillary wedge pressure.
Fluid overload and its associated consequences have more recently been identified as a significant contributor to poor patient outcomes, which has warranted a focus on both earlier initiation of vasopressors to minimize fluid resuscitation volumes as well as early and aggressive fluid removal.17,18 Currently, recommended doses of crystalloid for resuscitation in HF patients have not been shown to be detrimental, while a more conservative dosing strategy has not shown benefit, suggesting that a focus on early ‘evacuation’ or ‘de-resuscitation’ could be essential.19
Loop diuretics are a mainstay of treatment in patients with HFrEF, but they should be used with caution in early sepsis if volume status is unclear, as intravascular depletion may result in hypoperfusion. However, if patients have clear evidence of hypervolemia, use of loop diuretics can be considered earlier to prevent worsening congestive symptoms.
The optimal vasopressor in patients with HFrEF remains unclear. In septic shock requiring vasopressors, the SSC guidelines recommend an initial MAP target of 65 mmHg regardless of presence of cardiac dysfunction, with norepinephrine as the vasopressor of choice.2 The SSC guidelines consider epinephrine as a second-line choice because it possesses alpha and beta-agonist activity, which produces both a vasopressor and inotropic effect.2 However, a recent meta-analysis found that epinephrine increased short-term mortality compared to other vasoactive agents in the management of cardiogenic shock.20 Therefore, in patients with HFrEF, epinephrine should probably be avoided when possible, especially in those presenting with mixed septic and cardiogenic shock. SSC guidelines recommend dopamine as an alternative vasopressor in patients with hypotension and bradycardia.2 However, dopamine is associated with an increased risk of arrhythmias and has been shown to increase mortality in patients with cardiogenic shock.21
If target MAP is not achieved, the addition of vasopressin is considered as another second line option in HFrEF patients without evidence of low CO. SSC guidelines state vasopressin can be added to either further augment hemodynamics or reduce the dosage of catecholamines to circumvent tachyarrhythmias.2 However, in patients with HFrEF, vasopressin may not be an ideal agent since it significantly increases systemic vascular resistance (SVR) without simultaneously increasing cardiac contractility (in contrast with norepinephrine and epinephrine), resulting in an imbalance that may worsen CO.22 Also, low doses of vasopressin commonly used in sepsis affect the vasopressin receptor-2 primarily and can result in increased fluid retention. The SSC guidelines recommend phenylephrine only when norepinephrine is associated with serious tachyarrhythmias, CO is known to be high, and blood pressure remains low, or as an adjunctive agent for salvage therapy.2 Phenylephrine is not recommended in patients with HFrEF since it reduces CO similar to vasopressin.
Dobutamine is recommended by the SSC guidelines in patients with persistent hypoperfusion despite adequate fluid resuscitation and use of vasopressors. Although dobutamine is considered a first-line option in patients with cardiogenic shock,23 data supporting its use in patients with concomitant sepsis are limited; however, it may be preferred over epinephrine due to safety concerns.2,20 In patients with HFrEF presenting with mixed septic and cardiogenic shock, it is reasonable to start with norepinephrine as the first-line agent and consider adding dobutamine next if evidence of low CO. Milrinone, a phosphodiesterase III inhibitor, may be used as an alternative in patients with cardiogenic shock, but data for its use in septic shock are limited.24,25 Two features make milrinone a less favorable option in patients with HFrEF and concomitant sepsis. First, milrinone relaxes arterial smooth muscle, which could worsen systemic vasodilation in patients with sepsis. Second, milrinone is renally cleared, increasing the risk of hypotension and arrhythmias in septic patients who develop acute kidney injury.26 Considerations for assessment and management of sepsis in patients with HFrEF are summarized in Figure 2.
Figure 2. Practical Considerations for Hemodynamic Management of Sepsis in Patients with Underlying Cardiac Dysfunction
Patients with underlying HFrEF that present with septic shock are commonly encountered in clinical practice and represent unique challenges. The optimal management of these patients remains unclear, but considerations of comprehensive hemodynamic assessment should influence decisions on resuscitation strategies and vasoactive medications.
Brittany T. Jackson, PharmD
At the time of this writing, Brittany Jackson was a PharmD candidate at the University of Georgia College of Pharmacy. She is now transitioning into a PGY1 residency at Bristol Regional Medical Center. Follow her on Twitter @_btjack .
W. Anthony Hawkins, PharmD, BCCCP
Sandeep Devabhakthuni, PharmD, BCCP
Reviewed by: Trisha N. Branan, PharmD, BCCCP, Stormi E. Gale, PharmD, BCCP and Brent N. Reed, PharmD, BCCP
- Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). Jama 2016;315:801-10.
- Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med 2017;45:486-552.
- Arfaras-Melainis A, Polyzogopoulou E, Triposkiadis F, et al. Heart failure and sepsis: practical recommendations for the optimal management. Heart Fail Rev 2020;25:183-94.
- 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;130:1579-95.
- Chaui-Berlinck JG, Monteiro LHA. Frank-Starling mechanism and short-term adjustment of cardiac flow. J Exp Biol 2017;220:4391-8.
- Adams KF, Jr., Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149:209-16.
- Zile MR, Bennett TD, St John Sutton M, et al. Transition from chronic compensated to acute decompensated heart failure: pathophysiological insights obtained from continuous monitoring of intracardiac pressures. Circulation 2008;118:1433-41.
- Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001;345:1368-77.
- Nguyen HB, Jaehne AK, Jayaprakash N, et al. Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE. Crit Care 2016;20:160.
- Kelm DJ, Perrin JT, Cartin-Ceba R, Gajic O, Schenck L, Kennedy CC. Fluid overload in patients with severe sepsis and septic shock treated with early goal-directed therapy is associated with increased acute need for fluid-related medical interventions and hospital death. Shock 2015;43:68-73.
- Marik PE, Linde-Zwirble WT, Bittner EA, Sahatjian J, Hansell D. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med 2017;43:625-32.
- Leisman DE, Doerfler ME, Ward MF, et al. Survival Benefit and Cost Savings From Compliance With a Simplified 3-Hour Sepsis Bundle in a Series of Prospective, Multisite, Observational Cohorts. Crit Care Med 2017;45:395-406.
- Liu VX, Morehouse JW, Marelich GP, et al. Multicenter Implementation of a Treatment Bundle for Patients with Sepsis and Intermediate Lactate Values. Am J Respir Crit Care Med 2016;193:1264-70.
- Truong TN, Dunn AS, McCardle K, et al. Adherence to fluid resuscitation guidelines and outcomes in patients with septic shock: Reassessing the “one-size-fits-all” approach. J Crit Care 2019;51:94-8.
- Khan RA, Khan NA, Bauer SR, et al. Association Between Volume of Fluid Resuscitation and Intubation in High-Risk Patients With Sepsis, Heart Failure, End-Stage Renal Disease, and Cirrhosis. Chest 2020;157:286-92.
- Hjortrup PB, Haase N, Bundgaard H, et al. Restricting volumes of resuscitation fluid in adults with septic shock after initial management: the CLASSIC randomised, parallel-group, multicentre feasibility trial. Intensive Care Med 2016;42:1695-705.
- Hawkins WA, Smith SE, Newsome AS, Carr JR, Bland CM, Branan TN. Fluid Stewardship During Critical Illness: A Call to Action. J Pharm Pract 2019:897190019853979.
- Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER). A Randomized Trial. Am J Respir Crit Care Med 2019;199:1097-105.
- Silversides JA, Fitzgerald E, Manickavasagam US, et al. Deresuscitation of Patients With Iatrogenic Fluid Overload Is Associated With Reduced Mortality in Critical Illness. Crit Care Med 2018;46:1600-7.
- Léopold V, Gayat E, Pirracchio R, et al. Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients. Intensive Care Med 2018;44:847-56.
- De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010;362:779-89.
- Jentzer JC, Coons JC, Link CB, Schmidhofer M. Pharmacotherapy update on the use of vasopressors and inotropes in the intensive care unit. J Cardiovasc Pharmacol Ther 2015;20:249-60.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:e240-327.
- Schmittinger CA, Dunser MW, Haller M, et al. Combined milrinone and enteral metoprolol therapy in patients with septic myocardial depression. Crit Care 2008;12:R99.
- Sato R, Ariyoshi N, Hasegawa D, et al. Effects of Inotropes on the Mortality in Patients With Septic Shock. J Intensive Care Med 2019:885066619892218.
- Chong LYZ, Satya K, Kim B, Berkowitz R. Milrinone Dosing and a Culture of Caution in Clinical Practice. Cardiol Rev 2018;26:35-42.
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