The Case

A 66-year-old woman presented to the emergency department (ED) with acute renal failure, abdominal pain, and watery diarrhea, one month after a prior hospitalization for Clostridioides difficile colitis. After assessment in the ED, including a physical examination that omitted the legs, she was initiated on antibiotics and received fluid resuscitation for suspected urinary sepsis versus recurrent C. difficile colitis. Due to hospital overcrowding, the patient was kept in the ED overnight.

During her stay in the ED, the patient was noted to have persistent hypotension requiring norepinephrine infusion for approximately 12 hours. However, vital signs were notably absent from the medical record, with an 8-hour period during vasopressor administration in which no blood pressure measurements or limb assessments were recorded by nursing staff. Resident notes from the patient’s first hospital day documented palpable pulses. Although attending physicians’ documentation noted possible development of limb ischemia, these notes were not entered into the electronic health record (EHR) until several days later.

After the vasoactive agents were discontinued, the primary service noted that the patient had cool lower extremities and no palpable pulses. Vascular Surgery was consulted in the evening, but their assessment was that she had Rutherford Grade 3 ischemia and her limbs were non-salvageable. She was ultimately transferred to the intensive care unit (ICU), where she was treated for recurrent C. difficile colitis. She underwent bilateral above knee amputations (AKA), and her post-operative course was complicated by recurrent C. difficile colitis symptoms requiring additional antibiotic therapy. Her acute renal failure resolved, and she was ultimately discharged to a skilled nursing facility.

The Commentary

By Mimmie Kwong, MD, MAS

Background: Limb ischemia associated with pressor use

In septic shock, vascular endothelial injury and decreased vascular tone result in hypotension that can often be difficult to control. To address this problem, the Surviving Sepsis guidelines recommend an initial mean arterial pressure goal of 65 mmHg, with a care regimen that involves fluid resuscitation, vasoactive agents, and treatment of the underlying septic source, including empiric use of antibiotics.¹ Yet despite aggressive hospital management, septic shock results in significant mortality, with recent meta-analyses noting 30-day mortality of 35-37%. ^2,3 Even among survivors, there is significant morbidity, including acute or chronic kidney failure, myocardial injury, and stroke. Limb ischemia is a rare but potentially disabling complication that occurs in 1.8-6% of patients with septic shock.⁴ A recent cohort study from 14 major academic and community hospitals reported that 2 of 1000 patients with vasopressor dependent sepsis require an amputation, most commonly involving the lower extremity.⁵ The pathophysiological basis for this phenomenon is thought to be a combination of microvascular thrombosis caused by systemic hypercoagulability and peripheral vasoconstriction caused by pressor use.⁶

Norepinephrine is the recommended first line agent in the treatment of septic shock due to its potent vasoplegic effects. There is no maximal recommended dose although doses over 1 mcg/kg/min are considered high. However, while limb ischemia is associated with more intensive use of vasoactive agents, higher doses and higher blood pressure goals have not been consistently associated with development of peripheral ischemia.^4,7-9 This finding suggests that use of high-dose vasopressors may represent a surrogate for shock severity, and therefore, the intensity of the hypercoagulable state, rather than as a direct driver of limb ischemia.

Optimal treatment of pressor-associated limb ischemia is not well established, and evidence is primarily based on case reports and series.^10,11 Therapeutic options have been extrapolated from treatments for acute and chronic limb ischemia and include down-titration of the vasopressor; use of anticoagulants (heparin)¹² and antiplatelet agents (aspirin)¹³; vasodilators applied topically (nitroglycerin)¹⁴, infiltrated locally (phentolamine)¹⁵, or infused systemically (chlorpromazine hydrochloride)¹⁶; sympathetic blockade (with botulinum toxin)¹⁷; hyperbaric oxygen therapy¹⁸; as well as procedural interventions such as thrombolysis, amputation, skin grafting, and flap reconstruction.¹⁹ The combination of therapies selected is patient and provider/institution-dependent, and certain options may be contraindicated by medical issues such as bleeding diatheses (in the case of anticoagulation or antiplatelet use) or hypotension (in the case of vasodilators). Livesey and colleagues categorized treatment options into three phases of care based on the extent of limb involvement and the duration of presentation, arguing that minimally invasive Phase I options should be employed on all patients, including elevation of the extremity, splinting, warming, topical nitroglycerin, local injections of botulinum toxin and/or phentolamine, and removal of any intravenous or arterial lines in the extremity. Phase II options for patients with extensive, evolving ischemia include fasciotomy, mechanical vasodilation, intraarterial heparin or tissue plasminogen activator, and thrombectomy as needed. Phase III treatments are provided in the setting of tissue necrosis, and include amputation and reconstructive surgery.¹⁰

Approach to Improving Safety

Recognizing vulnerable patients

Early recognition of peripheral ischemia is paramount. In the setting of an acute limb compromise, time is tissue – the longer the duration of perfusion deficit, the greater the extent of tissue necrosis and the lower the likelihood of limb salvage.²⁰ While it may be difficult to identify which septic patients will develop pressor-associated limb ischemia, pre-existing peripheral arterial disease has been cited as a major risk factor for development of limb ischemia in critically ill patients on vasoactive agents.^21,22 Therefore, it is imperative that a thorough vascular exam be conducted early in a critically ill patient’s course to evaluate for the presence of underlying vascular disease and identify vulnerable patients. In this patient’s case, there was poor documentation of the initial vascular exam as well as insufficient monitoring of peripheral perfusion after vasoactive agents were initiated. 

Optimizing resuscitation

Treatment of septic shock centers on identifying and remedying the underlying source of infection, fluid resuscitation, and supportive therapy, including use of pressors if needed. Surviving Sepsis guidelines recommend early, aggressive resuscitation with at least 30 mL/kg of intravenous crystalloid fluid given within the first 3 hours of resuscitation. In patients who remain critically ill, additional resuscitation should be guided by dynamic measures such as cardiac output and stroke volume changes rather than passive indicators like heart rate, blood pressure, and central venous pressure. If such invasive hemodynamic monitoring is not available, observation of skin temperature and appearance as well as capillary refill time may be utilized.¹ In this case, it is unclear whether the patient received adequate fluid resuscitation prior to initiation of vasopressors, and there was no indication that either invasive or non-invasive techniques were utilized to guide initial or ongoing resuscitation. While early initiation of vasoactive agents may improve mortality, pressors should not supplant appropriate fluid resuscitation, as failure to achieve the goal of 30 mL/kg of IV fluids within the first three hours has been associated with increased mortality.^23-25

Monitoring patients closely

Close monitoring of patients in septic shock is critical as their condition can change rapidly and precipitously. Patient outcomes depend greatly on the timeliness of appropriately administered critical care interventions, which are, in turn, reliant on the highly trained multidisciplinary teams caring for these patients.

In recent years, a combination of increasing patient volumes and limited hospital capacity has driven a problematic rise in emergency department (ED) boarding of critically ill patients. Because EDs historically have focused primarily on diagnosing and stabilizing patients, their treatment protocols, staff training, and care paradigms are not well-suited to prolonged management of critically ill patients. ED medical providers and nursing staff have not been specifically trained to nor have they been afforded the staffing ratios and resources to provide prolonged, high intensity care that befits a patient in septic shock. As a result, boarding of critically ill patients in the ED has been associated with longer ICU length of stay and higher hospital mortality, with one study demonstrating increased mortality for patients whose ED stays exceeded 6 hours and another study finding a 1.5% increase in the risk of ICU death for each additional hour that patients waited in the ED.^26,27 Particularly, for patients with sepsis, ED crowding has been associated with increased time to fluid and antibiotic administration and decreased implementation of protocolized care.²⁸ Driven by these findings, Surviving Sepsis guidelines recommend transfer to the ICU within 6 hours after ED arrival.¹ In a resource-limited setting where this might not be possible, patients must receive regular assessments to minimize treatment delays and to identify treatment complications in a timely manner.

In this case, the patient boarded in the ED for a prolonged period due to hospital overcrowding. This situation likely contributed to incomplete examinations, inadequate documentation, and insufficient monitoring, which enabled the development of irreversible ischemia in this patient.     

Systems Change Needed

This patient case highlights areas for improvement on the individual, institutional, and systemic levels. While this critically ill, unstable patient was appropriately diagnosed with sepsis and started on the standard therapy of antibiotics, fluids, and early vasopressor support, she did not then continue to receive the level of care that was needed to avoid one of the most devastating adverse outcomes of septic shock.

On the individual level, this patient was failed by her care team. Her doctors did not appropriately examine and/or document her baseline perfusion nor did they appear to recognize her limb ischemia until it was far advanced. Her nurses similarly did not provide the close intensive monitoring that befitted her situation; such monitoring might have led to earlier re-evaluation of her need for vasopressors and earlier identification of her limb ischemia. It is unclear how the orders for vasopressor titration and monitoring were written, as this commentator does not have access to the electronic record. Additionally, it is uncertain how much non-written communication occurred among the patient’s doctors and between the physician and nursing teams regarding the critical nature of the patient’s condition and the importance of close vascular monitoring and vasoactive medication titration. We suspect that incomplete orders and/or verbal miscommunication may have been contributors, given the delayed recognition of her ischemia that resulted in limb loss. 

At the institutional level, appropriate safeguards were not in place to minimize the risk of this medication-associated adverse event. Physicians and nurses trained in the care of critically ill patients are typically educated on the importance of vascular checks for patients on vaso­pressors. However, caring for complex patients requires focused attention, which can be difficult to achieve in the fast-paced, chaotic, and high-pressure environment of the ED. Paired with staffing shortages and ED overcrowding, this situation creates a perfect storm for errors. Small misses or delays at different phases of care, or on multiple levels, can lead to a catastrophic outcome.

The patient in this case may have benefitted from the implementation of automated electronic health record (EHR) alerts to remind providers to monitor patients on high-dose vasopressors for limb ischemia; to encourage implementation of hemodynamic monitoring; and to de-escalate vasopressor dosing. In recent years, extensive efforts have been made to implement EHR-based programs to identify patients with early sepsis. While these studies have demonstrated improvement in process measures (such as adherence to antibiotic protocols), they have not consistently demonstrated improved mortality or hospital length of stay.²⁹ The EHR not only includes data elements necessary to identify patients at risk of sepsis, but it also has the potential to allow close tracking of patient progression and automated alerts when patients need escalation or de-escalation of care. A recent single-center study described a pilot program utilizing an EHR-based, real-time, sepsis care tracking and alerting platform in the ED to improve adherence to the Centers for Medicare & Medicaid Services Sepsis Core Measures bundle. However, the authors noted variable responses to alerts, with better adherence to alerts regarding some components of the bundle (e.g., repeat lactate) than others (e.g., initiation of antibiotics).³⁰ Additional studies are needed to evaluate the potential of automated EHR-based processes to improve sepsis outcomes.

On a systemic level, hospital overcrowding has led to a problematic shift in the care of critically ill patients out of the ICU and into the ED. In this patient’s case, this resulted in prolonged boarding in the ED that likely contributed to her limb loss. The adverse consequences of limited hospital capacity and ED overcrowding have been well documented, but have never been more apparent than during the recent COVID-19 pandemic. Proposed solutions vary widely and include increasing hospital inpatient staffing and bed space, expanding outpatient services, improving ED diagnostic pathways, and expediting hospital discharge, among others.  However, until solutions are found, efforts must be made to successfully provide ICU-level care to patients outside the ICU setting. One proposal is to implement a Resuscitative Care Unit (RCU), which strives to build an ICU within the ED to focus on triage, resuscitation, and stabilization of critically ill ED patients.³¹ A single center study of the implementation of a RCU demonstrated reductions in mortality and ICU admission rates.³²

Take Home Points

• Limb ischemia is an infrequent but highly morbid complication that stems from microvascular thrombosis due to a combination of systemic hypercoagulability in the setting of sepsis and peripheral vasoconstriction from pressor use.
• Patients with underlying peripheral arterial disease are particularly vulnerable to developing vasopressor-associated ischemic complications and a thorough vascular exam early in the patient’s course is critical in identifying these high-risk patients.
• To achieve optimal outcomes in patients with septic shock, adequate resuscitation, early initiation of appropriate medical and procedural interventions, and close hemodynamic monitoring are critical.
• Despite the limitations created by ED and hospital overcrowding, patients with septic shock need frequent reassessment and timely interventions, regardless of their physical location within the hospital.

Mimmie Kwong, MD, MAS
Assistant Professor
Department of Surgery, Division of Vascular Surgery
UC Davis Health
mdkwong@ucdavis.edu

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