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Contemporary Management of Septic Shock: Update for Critical Care and Health-System Pharmacists

Note: Learners completing and receiving credit for the original activity cannot claim credit for reviewing this update.

INTRODUCTION

The Centers for Disease Control and Prevention recently reported that 1.7 million Americans are diagnosed with sepsis each year; 270,000 of those patients will die from sepsis. Of all patients who die within the health system, it is estimated that 33% have sepsis, despite advances in targeted therapies, supportive care, and emphasis on early recognition.¹

In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) were published and marked a landmark departure from previous definitions for the identification and progression of sepsis.² Previous definitions (Sepsis-2) identified sepsis as the presence of 2 or more systemic inflammatory response syndrome (SIRS) criteria in the setting of known or suspected infection. Sepsis was further classified as having progressed to “severe sepsis” in the setting of acute organ dysfunction. Septic shock involved all of the above criteria, as well as persistent hypotension despite adequate fluid resuscitation.³

Unfortunately, SIRS criteria alone are too non-specific for reliable identification of patients with sepsis or septic shock. The SIRS criteria often identify those with adequate and adaptive responses to infection, which is in contrast with the definition of sepsis as the dysregulated, non-homeostatic response to infection. With the latest evolution of the Sepsis-3 consensus, the definition and identification of sepsis is greatly streamlined and targets the life-threatening organ dysfunction caused by the dysregulated host response to infection.² The term “severe sepsis” has been eliminated from the vocabulary, and, now, only “sepsis” and “septic shock” are recognized, since sepsis does not exist without some form of end organ damage and, therefore, all sepsis now falls under the previous definition of “severe sepsis.” The Sepsis-3 task force further defined septic shock as the presence of persistent hypotension, despite adequate fluid resuscitation, requiring vasopressor support to maintain a mean arterial pressure (MAP) of at least 65 mmHg, along with a serum lactate concentration greater than 2 mmol/L².

PATHOPHYSIOLOGY

Sepsis is characterized by an overwhelming and dysregulated host response to pathogen invasion. The response is both complex and not fully understood. Both inflammatory and anti-inflammatory processes occur simultaneously, which can have deleterious effects on the host. Major negative effects include, but are not limited to, widespread inflammation, increased vascular permeability, activation of coagulation pathways, and immune suppression. Cytokine and inflammatory mediators are key targets in the investigational combination therapy of ascorbic acid, thiamine, and hydrocortisone.

Increased levels of inflammatory cytokines induce systemic inflammation and compromise the endothelial glycocalyx. The endothelial glycocalyx is a relatively new concept to clinical practice but is now understood to play a vital role in maintaining the integrity of the vascular endothelium. Damage to this structure occurs commonly in trauma and disease states including sepsis, and is referred to as “glycocalyx shedding,” which results in varying degrees of vascular permeability. This, in combination with inability to maintain vascular tone, results in systemic hypotension⁴. As this hypotension persists, end organs experience hypoperfusion. In response to renal hypoperfusion, the renin-angiotensin-aldosterone system (RAAS) is upregulated to produce fluid/water retention, angiotensin 1 production and conversion to angiotensin 2. This system is a key target of newer sepsis therapies involving angiotensin II.⁵

There are 4 recognized classifications of shock: cardiogenic, neurogenic, hemorrhagic, and distributive. Distributive shock is defined as any shock in which there is inappropriate distribution of intravascular volume. Septic shock caused by persistent hypotension and end organ damage is a subset of distributive shock. In the setting of septic shock, the intravascular volume has difficulty maintaining hydrostatic pressure within the endothelium due to shedding of the glycocalyx.

Septic shock can be divided into 2 phases: an early hyperdynamic phase and a late hypodynamic phase. In the early phase, vascular permeability is observed via low systemic vascular resistance (SVR). However, high cardiac output is observed as an attempted compensatory mechanism. As inflammatory cytokines continue to circulate and overwhelm the host, cardiac output can drastically decline and, therefore, the low SVR becomes uncompensated.⁶ Vasopressors, as well as investigational and newer therapies including angiotensin II and methylene blue, target the persistent low SVR as treatment for septic shock.

MANAGEMENT OF SEPSIS AND SEPTIC SHOCK

The Sepsis-3 consensus emphasizes the early recognition of sepsis through utilization of the Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA) scoring systems.² The SOFA score was developed to evaluate organ dysfunction on the basis of both clinical and laboratory assessments (Table 1),⁷ and any change in score of 2 or more points is considered to identify sepsis.^2,7 Higher SOFA scores are associated with an increased probability of mortality, and a score of 2 or more is correlated with approximately 10% mortality in a general hospital population with suspected infection.²

Rapid calculation of a SOFA score is not always possible due to the laboratory tests involved, and it is in this setting that the qSOFA can be applied. The qSOFA considers 3 clinical variables and the score ranges from 0 to 3 points, with a higher score predicting a poorer outcome (Table 2).⁸ The Emergency Department (ED) is an ideal place to implement widespread use of the qSOFA score to assist with rapid assessment and identification of sepsis in an often-hectic environment with limited available data. Many electronic medical systems have sought to implement electronic triggers to assist with early identification of patients with sepsis. Unfortunately, it is increasingly difficult to reliably capture ‘altered mental status’ early in evaluation charting, and therefore many systems trigger based on SIRS criteria rather than qSOFA.

After recognition of sepsis, the initial resuscitation should begin promptly. This initiative is most commonly referred to as early goal-directed therapy (EGDT) and consists of administration of resuscitative fluid and broad spectrum antibiotics and the use of vasoactive agents with the overall goal of restoring adequate tissue perfusion within 6 hours (Table 3).^9,10 Although EGDT has failed to show a consistent reduction in mortality, it has been associated with higher rates of admission to intensive care units and more frequent receipt of vasopressor therapy, but these interventions are not without consequences of their own.¹⁰ Prior to 2018, the Surviving Sepsis Campaign endorsed 3- and 6-hour bundles (i.e., elements of care) to facilitate early recognition and intervention for patients with sepsis.¹¹ In 2018, however, the Surviving Sepsis Campaign taskforce released a guideline update, consolidating the previous 3- and 6-hour bundles to a 1-hour bundle to further improve recognition and early intervention in sepsis.⁹ Within 1 hour of identification of sepsis, providers should obtain serum lactate levels and blood cultures and administer broad spectrum antibiotics and 30 mL/kg of resuscitative fluid, as well as initiate vasopressor support, if necessary.⁹ Completion of these efforts may take more than 1 hour, but clinicians should work expeditiously to initiate these interventions within that crucial time window as much as possible. This is not without its challenges at bedside, though, and sepsis management requires a multi-disciplinary, systematic approach. Such approach has demonstrated efficacy in the state of New York, where measures were implemented in 2013 requiring all hospitals to develop and implement protocols for early recognition of sepsis, as well as ensuring administration of timely antibiotics and fluids. Not only must the institution develop these protocols, but they must regularly report adherence to said protocols and their clinical outcomes to the state department of health.¹² Kahn and colleagues demonstrated that when compared to patient outcomes in states without mandated sepsis protocol care, those patients without protocolized-care in place had 3.2% higher mortality.¹³ Since the 2013 development in New York, many states have followed suit.

Resuscitative fluid therapy

Initial fluid resuscitation is aimed at reversing and stabilizing sepsis-induced tissue hypoperfusion. Within the first hour after identification of sepsis, 30 mL/kg balanced crystalloid (e.g., Lactated Ringer’s, Plasma-Lyte A) or 0.9% sodium chloride (saline) should be administered rapidly. Balanced crystalloid fluids are crystalloid solutions that also contain additional anions such as acetate or lactate and are, therefore, more representative of plasma composition than sodium chloride. Historically, saline has been the backbone of fluid resuscitation, but it has been found to be associated with hyperchloremic metabolic acidosis, acute kidney injury, and death.^14-16{Yunos, 2011, The biochemical effects of restricting chloride-rich fluids in intensive care} Contemporary practice has moved in the direction of resuscitation with balanced crystalloids, which has been shown to slightly improve rates of acute kidney injury and death.¹⁷

The use of colloids such as albumin may be considered for patients with shock or septic shock who require substantial amounts of crystalloid fluid. During fluid administration, continuous reassessment of hemodynamic status should guide further fluid administration. Dynamic hemodynamic monitoring methods, including both invasive (e.g., FloTrak, arterial catheterization) and non-invasive (e.g., non-invasive cardiac output monitoring, ultrasonography of the inferior vena cava, passive leg raise) methods, are preferred over static methods for assessing fluid responsiveness. The MAP is a key driver of tissue perfusion and may be calculated from blood pressures obtained via blood pressure cuff or arterial transducer. Central venous pressure may also be monitored, but MAP is a more valuable clinical target.

Vasopressor therapy

The recommended initial goal when monitoring hemodynamic status in sepsis and septic shock is a target MAP of 65 mmHg.¹¹ If an MAP of 65 mmHg is not achieved after adequate fluid resuscitation (30 mL/kg), vasopressors should be initiated, with norepinephrine as the recommended first-line vasopressor for septic shock.¹¹ Overall, norepinephrine is associated with fewer tachyarrthymias than dopamine and may be more effective than other vasopressors at increasing blood pressure in patients with septic shock. Dopamine may be considered as an alternative to norepinephrine for a small group of patients with septic shock and with absolute or relative bradycardia who are considered to have a low risk of tachyarrhythmias. However, dopamine has been demonstrated to have a higher incidence of mortality than norepinephrine and should, therefore, be used with caution.¹⁸ If MAP goals are unable to be met with fluids and norepinephrine, vasopressin can be added at a fixed dose of 0.03 units/min. The increase in blood pressure due to the addition of vasopressin is thought to be supplemental in nature, as patients with septic shock may have lower-than-physiologic levels of endogenous vasopressin in addition to pure V₁ receptor stimulation causing vasoconstriction. Hammond et al demonstrated in a retrospective study that the early (within 4 hours of septic shock onset) addition of vasopressin to norepinephrine support resulted in earlier achievement of MAP goal, and reduced time to end organ dysfunction by 72 hours. While retrospective, this data suggests that early addition may be beneficial and warrants further consideration and investigation.¹⁹ In the case of refractory septic shock during norepinephrine and vasopressin therapy, epinephrine can be added to the current regimen. Notably, epinephrine may increase aerobic type B lactate production and may decrease the utility of lactate clearance as a measure of resuscitation adequacy.

Angiotensin II is a novel agent that may be considered in patients who are unable to maintain an MAP of 65 mmHg with norepinephrine/vasopressin alone. Angiotensin II is a naturally occurring peptide and is a main product of the RAAS.²⁰ Angiotensin II elevates blood pressure secondary to direct vasoconstriction of both arteries and veins and increased aldosterone release, and it is indicated to increase blood pressure in adults with septic or other distributive shock.²¹ Angiotensin II has been shown to positively impact MAP effects in patients with septic shock who are unable to maintain target MAPs with norepinephrine ± vasopressin without significant differences in mortality.⁵ The major adverse event seen with angiotensin II therapy is the potential for venous and arterial thrombotic and thromboembolic events, and use of pharmacologic prophylaxis is encouraged. To date, the Surviving Sepsis Campaign guidelines have not included angiotensin II in treatment recommendations, but it may have a place in therapy for patients with shock who cannot achieve a target MAP despite adequate fluid resuscitation and currently available vasoactive agents.⁵

Certain patients, including those with hypodynamic cardiac contractility who have difficulty overcoming the increased SVR as a result of vasopressor therapy, may require inotropic therapy to further improve cardiac output. For these patients, dobutamine is recommended as the first-line choice to increase cardiac output when fluid resuscitation is considered adequate with corresponding MAP, but may require increasing vasopressor doses to combat hypotension²². Milrinone is often difficult to use within the distributive shock setting due to the paradoxical hypotensive effect of phosphodiesterase 3 inhibition.

Vasopressor and inotrope therapy are associated with several risks and adverse effects. First, the cardiac effects may have significant impact on overall patient management and outcomes. Heart rate alterations (both tachycardia and bradycardia) and arrhythmias are of significant concern due to reduction in cardiac output and oxygen delivery.²³ Local harmful effects include extravasation or local skin necrosis, limb necrosis, and ischemic colitis.²⁴ Increasing amounts of data are coming to light regarding the safe administration of vasopressors and the need for central versus peripheral access. Previously, it was regarded as standard practice to obtain central venous access as part of sepsis care for the purpose of monitoring central venous oxygen saturation and for safe administration of vasopressor therapy. However, we are now learning that vasopressors can be safely administered at low to moderate doses through quality peripheral venous access. It is safest when considering this approach to ensure the largest bore possible, preferably in a proximal peripheral location (antecubital fossa), and to have frequent infusion site checks to monitor closely for extravasation. If, however, infusion rates are rising and multiple vasopressors are being added, central venous access remains the safest route of administration. In order to promote patient safety and reduce long-term morbidity and mortality, all healthcare professionals involved in the care of patients with sepsis should have a heightened awareness of potential adverse effects related to therapies and an understanding of early intervention procedures to mitigate or minimize the effects.

For patients who have received adequate fluid resuscitation and are unable to obtain hemodynamic stability despite vasopressor therapy, the addition of corticosteroids, specifically hydrocortisone, may be considered. Several studies have provided weak evidence that the addition of corticosteroids decreases mortality.^25-27 Despite the less-than-compelling data, if restoration of hemodynamics is not achieved, intravenous (IV) administration of hydrocortisone 50 mg every 6 hours or 100 mg every 8 hours is a reasonable addition to already-implemented resuscitative efforts. There is no consensus regarding the optimal duration of treatment, but steroids are typically continued for 5 to 7 days. After vasopressors are no longer required, corticosteroids may be discontinued in an effort to decrease their potential side effects. Tapering therapy has been independently associated with higher incidences of adverse events, including hyperglycemia and hypokalemia. Lack of taper has not been associated with relapse of shock symptoms and is, therefore, preferred over tapering strategies.^28,29 Steroid therapy is indicated for patients who have a history of steroid therapy or those with adrenal dysfunction. 

Antimicrobial therapy

Prior to initiation of antimicrobial therapy, microbiological blood cultures should be obtained, as collection prior to administration of antimicrobials increases the likelihood of pathogen identification and targeted antibiotic therapy. However, this should not delay antimicrobial therapy, since antimicrobials should be administered promptly (i.e., within 1 hour of identification of sepsis). Empiric combination antimicrobials with at least 2 antibiotics from different antimicrobial classes is recommended (and required by the Centers for Medicare and Medicaid Services core measure for sepsis management criteria) during initial management of sepsis and should be administered within the first hour of resuscitation to promote pathogen clearance.¹¹ Strategies to promote compliance with this element of care include, but are not limited to, the use of sepsis alerts; the availability of broad spectrum antimicrobials for immediate preparation in the direct patient care area (e.g., antibiotics for reconstitution and administration as IV push); and the presence of clinical pharmacists in the ED.

The specific antibiotics chosen for sepsis management should consider patient-specific history, previous culture results, comorbidities, immunocompromised state, suspected site of infection, suspicion of viral or fungal infection, and local resistance patterns.³⁰ Typical organisms that are isolated from patients with sepsis include Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Streptococcus pneumoniae.³¹ Methicillin-resistant S. aureus and Pseudomonas species should be considered on a patient-specific basis when the source of infection is unidentified. Additionally, empiric antifungal therapy should be considered when there are risk factors for invasive fungal infections. Early therapy should be initiated prior to definitive identification of a pathogen and take into account these potential causative organisms; after pathogen identification, broad spectrum antimicrobials should be transitioned to targeted antimicrobials according to changes in clinical status such as decreased vasopressor requirement and improved signs of infection on the basis of biomarkers.

Antimicrobial dosing considerations in the critically ill should be instituted when dosing antibiotics in sepsis and septic shock. Secondary to pharmacokinetic changes during the process of sepsis, antimicrobial dosing strategies should be aggressive to optimize the pharmacodynamic properties of each agent. Volume of distribution (V_d) and half-life are dynamic properties in critically ill patients, so attention should be paid to alterations in these parameters: V_d increases after resuscitation secondary to additional volume, fluid shifts, and capillary leak with tissue edema; half-life can also increase secondary to renal or hepatic dysfunction. Patient-specific management requires continuous monitoring of therapy with drug-specific levels (if available), necessary adjustments for organ dysfunction, and changes in fluid status. These properties require dosing strategies to optimize antimicrobial therapy, such as administration of extended interval b-lactams, and therapeutic monitoring of certain antimicrobials (e.g., vancomycin and aminoglycosides) to minimize toxicities.³² Additionally, dosing strategies should adequately address patient body habitus, patient antimicrobial history, and clinical status. 

INVESTIGATIONAL THERAPIES FOR THE TREATMENT OF SEPTIC SHOCK

In an effort to provide a multi-modal management strategy for septic shock and end organ damage, various therapies have been examined and new, investigational treatments are gaining attention.

Combination vitamin C, thiamine, and hydrocortisone

Combination therapy with high-dose ascorbic acid (vitamin C), thiamine, and hydrocortisone has gained traction following the publication of the retrospective before-after study by Marik and colleagues.³³ Sepsis is hypothesized to cause overwhelming creation of free radicals, so ascorbic acid can work as a scavenger for such particles. Humans are believed to be relatively deficient in ascorbic acid during sepsis and, therefore, exogenous replenishment may be beneficial. In the study by Marik and colleagues, patients received a daily dose of 6 grams IV (divided) of ascorbic acid for 4 days, hydrocortisone 50 mg IV every 6 hours for 7 days (followed by a 3-day taper), and thiamine 200 mg IV every 12 hours for 4 days. It is notable that administration of high-dose ascorbic acid may lead to inaccurate readings of blood glucose on point-of-care testing machines. These inaccurate readings occur due to high plasma concentrations of vitamin C interfering with chromagen oxygenation on the testing strip. Depending on the manufacturer of the machine and the presence of the reaction, to obtain accurate blood glucose readings a method of laboratory blood glucose level measurement should occur.³⁴ 

The intervention was applied to patients who received standard of care sepsis management (i.e., resuscitative fluid, vasopressor support, antimicrobial therapy). No patients who received the novel combination of therapies experienced progressive organ failure, and no deaths were attributed to the therapy.³³⁷ Most recently Fowler and colleagues, further investigated the impact of high dose Vitamin C on organ failure and inflammatory biomarkers in patients with sepsis in combination with severe acute respiratory failure. The CITRIS-ALI trial enrolled patients with early onset acute respiratory distress syndrome (ARDS) (<48 hours) and investigated the impact of 96 hours of vitamin C therapy on both a modified SOFA score and various plasma biomarkers such as C-reactive protein and thrombomodulin levels compared to placebo. While they were unable to show any difference in the primary outcomes, they were able to demonstrate a reduction in secondary outcomes of all-cause mortality and ICU/hospital free days in the vitamin C group. ³⁵ This leads to further questions into the divergence of findings between primary and secondary outcomes, and how these findings fit into practice. Further investigation is warranted prior to incorporation of this intervention into primary practice.

Methylene blue

Many mechanisms responsible for vasodilation seen in septic shock have been investigated as targets for treatment, but nitric oxide (NO)-mediated vasodilation has gained specific attention. In the presence of the numerous inflammatory modulators seen in sepsis, NO is readily produced, and downstream cyclic GMP is produced and directly responsible for smooth muscle relaxation and subsequent vasodilation.³⁶ In addition to the loss of systemic vascular tone, NO is associated with a reduction in responsiveness to vasopressor therapy,³⁷ which may be clinically detrimental and, therefore, a potential therapeutic target in the setting of septic shock. While global inhibition of NO synthase has been associated with increased mortality,³⁸ more targeted approaches have been investigated.

Methylene blue is a medical dye that inhibits NO-induced guanylate cyclase activation.³⁹ In all published reports, methylene blue clinically raised MAP, usually within 30 minutes, but effects typically dissipated within 60 to 180 minutes of administration.^40-45 Various dosing schemes are reported, ranging from 1 to 4 mg/kg bolus infusions to 0.25 to 2 mg/kg/h continuous infusions. High bolus doses (3-4 mg/kg) appear to be associated with higher rates of adverse events, primarily increases in pulmonary vascular resistance and worsening of respiratory status. Despite available data, the optimal dosing scheme is not well defined for the use of methylene blue in septic shock and mortality remains high. Further studies are needed to truly define the role of methylene blue in sepsis and septic shock therapy.

PHARMACISTS ROLE

Sepsis and septic shock are medical emergencies that require rapid, targeted interventions. Pharmacists have many opportunities to play a vital role in the team-based approach to sepsis management: they can assure that therapy is initiated promptly after identification of sepsis by assisting with the selection of fluid for resuscitation, evaluating vasopressor selection and titration, and choosing optimal empiric antimicrobial treatment. Pharmacists can also provide valuable input to the care of patients with septic shock by informing care providers of novel and investigational therapies such as angiotensin II; vitamin c, thiamine, and hydrocortisone combination therapy; and methylene blue.

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