Dr. Strangelove or How I Learned to Stop Worrying and Sit on the qSOFA: A pathophysiologic approach to qSOFA

Author: Nikolai Schnittke, MD (@nikolaischnittk, EM Resident Physician, Berbee Walsh Department of Emergency Medicine, University of Wisconsin Hospital and Clinics) // Edited by: Alex Koyfman, MD (@EMHighAK) and Brit Long, MD (@long_brit)

The last few months have seen an enormous amount of controversy in the press, in the FOAMsphere, and in our ED hallways regarding the new consensus sepsis definition^1,2. The goal of this post is not to rehash the strengths and weaknesses of Sepsis 3, but rather to explore the pathophysiologic basis of the simplified clinical features of sepsis outlined in the qSOFA score, which might explain why the definition shook out the way it did. Hopefully, such an understanding will help us apply lessons learned from the derivation of Sepsis 3 to the management of these profoundly sick patients.

So what is Sepsis 3? In his “biography of cancer”, The Emperor of all Maladies, Siddhartha Mukherjee writes about how in the mid 1800s Virchow set out to “describe human diseases in simple cellular terms”³. This need for a pathophysiologic, cellular, and molecular explanation of human disease has permeated many of the advances of modern medicine, but has been curiously lacking from our understanding of sepsis. While past definitions sought to define sepsis as a clinical syndrome based on clinical features (SIRS)⁴, Sepsis 3 seeks to define sepsis as a pathophysiologic entity. This was predicated on research done in the past few decades yielding a considerable, albeit still elementary body of scientific study revealing sepsis to be correlated with a dysregulated metabolic^5,6, immunologic⁷, and microvascular response to infection⁸, which leads to organ failure. Thus, the authors defined sepsis as “a life-threatening organ dysfunction caused by a dysregulated host response to infection”.

This cerebral definition, while scholarly and useful in our conceptualization of the essence of sepsis, seems to do little to help the clinician recognize and treat sepsis. After over two decades of consensus sepsis definitions most clinicians have grown familiar and comfortable using SIRS. The three sepsis mega-trials: PROCESS⁹, ARISE¹⁰, and PROMISE¹¹ seem to have validated a simplified approach to identification and treatment of sepsis using SIRS criteria. The authors of Sepsis 3 however, argue that SIRS has unsatisfactory sensitivity and specificity (best demonstrated by the Area Under the Receiver Operating Curve or AUROC) when it comes to the identification of a life threatening disease. That point was hammered home with disturbing force by a study in the NEJM in 2015, which used a large EMR database to check the sensitivity of SIRS in detecting downstream organ failure caused by infection, and found that SIRS missed 1 out of 8 patients (12%) with severe sepsis or septic shock¹².

Moreover the mortality rate for sepsis remains high despite the significant advances of the last three decades. Indeed, the sepsis mega-trials consistently demonstrated a 90 day mortality in the range of 20-30%, which while significantly better than the 46% baseline mortality rate of Dr. Rivers’ initial EGDT trial¹³, is a shockingly high mortality for a disease whose prevalence continues to increase¹⁴. For comparison, consider that as of 2010, 30-day mortality rate for STEMI by one estimate is down to ~4.4%¹⁵. In an attempt to translate Sepsis 3 into a clinically helpful entity, the authors then worked backwards in a statistical tour de force to define the clinical features that might correlate with mortality in sepsis.

This behemoth retrospective derivation from 1.3 million EMR charts and subsequent validation of 700 thousand charts revealed three clinical variables that were strongly correlated with mortality: RR>21, Altered mental status[1], and SBP<100. The AUROC for situations where two of these variables were present was comparable to or better than that of SIRS in both ICU and non-ICU settings². Thus, Sepsis 3 provides not only a pathophysiologic definition of sepsis, but also the first evidence based description of its clinical features, which are predictive of mortality. The goal of this post is to explore how these two realms fit. In other words, why are these three clinical changes so predictive of mortality secondary to organ dysfunction caused by a dysregulated host response to infection?

 1. Altered mental status

Consider the following case seen recently at Janus General:

An 89 year old man is brought to the ED unresponsive to painful stimuli. His VS are: HR 72, BP 112/54, RR 24, SpO2 96% on 2L NC, FSBG 112. This is his third visit to the ED in three days. During each of these visits, neighbors called EMS, because the patient was found on the floor of his trailer. During the last two visits, he would have his eyes closed, moan occasionally, and would not respond to painful stimuli. After about 30-60 minutes he would wake up, curse out the staff, and demand to be discharged home. Because his labs, CXR, and CT head were all within normal limits, he was discharged home.

This visit is not different from the past two days, except you note that he seems to moan a bit more when your press on his abdomen, but is otherwise unresponsive to sternal rub or nasal trumpet. The patient has a history of dementia, and review of recent admissions indicate that he has a habit of becoming belligerent when admitted, cursing at staff and driving several nurses to tears with insensitive and aggressive comments.

Altered mental status has long been recognized as a feature of sepsis where it has gone by other monikers such as Sepsis Associated Encephalopathy and Sepsis Associated Delirium¹⁸. The concept of “delirium” may be particularly useful in understanding this phenomenon and our relationship to it in the ED.

The DSM-5 defines delirium as an acute change in consciousness not explained by a previous neurocognitive disorder, and thought to be due to a medical or toxicologic condition¹⁹.  As sepsis is a medical condition, the alterations in mentation, which often accompany it can be classified as a subset of a broader delirium syndrome.

The pathophysiology of the delirium syndrome is complex and involves neurotransmitter balances (the cholinergic and dopaminergic axes are strongly implicated), underlying dementia (as with any organ failure, the chronic brain failure of dementia is a strong risk factor for developing acute exacerbations of delirium), vasculopathic changes, and inflammatory changes²⁰.  The latter two are very strongly implicated in sepsis associated delirium, and are the same pathophysiologic changes that cause inflammatory and microangiopathic organ dysfunction during sepsis²¹.  Thus, sepsis associated delirium is a powerful indicator of life-threatening organ dysfunction. While other organs require labwork (creatinine, troponin, liver enzymes) to evaluate for damage, the CNS is the one organ whose function is assessed at the bedside.

This seems like a no-brainer: infection is always at the top of our differential when it comes to altered mental status. However, it turns out that EPs are notoriously poor at picking up delirium when “altered mental status” is not listed as the chief complaint. Several studies place us at around 30% sensitivity in the recognition of delirium and many of these patients are discharged home with no specific plan with regard to their mental status^22,23.  This, despite findings that delirium in the ED is likely an independent risk factor for mortality²⁴. Why is it so difficult to recognize a clinical feature, which requires no additional invasive tests and has such a high predictive value for morbidity and mortality? Of course many of these patients are elderly, with dementia at baseline, and it is difficult to establish how truly different from baseline they are at the time of our evaluation. There are few things as frustrating as being on hold with a nursing home while a nurse who knows the patient’s baseline can be found. Moreover subtle changes in attention can require a full assessment such as a Confusion Assessment Method (CAM), which takes several minutes. And yet, this is perhaps the most powerful clinical lesson we can glean from the sepsis 3 derivation:

We cannot afford to miss altered mentation: a clinical state of organ dysfunction that can be assessed at the bedside.

Identifying mental status aberrations is often as simple as paying attention to this part of the clinical exam. In cases where we are not sure if a patient is altered, the following steps might be helpful in assessing altered mentation in the busy ED setting:

I) Obtain the patient’s baseline. It’s impossible to know if the patient is altered without knowing where the patient usually is. This often means contacting family and/or nursing home staff. If you do not have time on a busy shift to be on hold with the nursing home, it’s ok to delegate this step to a nurse or a tech. Do not rely on hospital admission records to establish the patient’s baseline: many of these patients are not at baseline when in the hospital.

II) Use a cognitive forcing strategy. Too often we see documented exams of intubated patients who are “AOx3”. Force yourself to think of the diagnosis of delirium by documenting the mental status appropriately in the exam. If the patient is AOx3, that’s ok, but if you didn’t ask them to tell you the date, don’t write AOx3.

III) Screening test. Han et al designed a Delirium Triage Screen (DTS) outlined in Figure 1²⁵ . This screen can be done in about 20 seconds and when compared to a 30 min psychiatrist evaluation, the sensitivity of the DTS was 98%. This quick screen performs just as well, regardless of whether it is done by a physician or a non-MD research assistant.

IV) Confirmation test. While the DTS is very sensitive, it is only ~55%  specific. In order to confirm delirium use a modified brief Confusion Assessment Method (bCAM), which has a specificity ~96% (Figure 2). This method is a bit more involved, but still takes about 1-2 minutes. Again if you don’t have time, ask the nurse/tech/med student.

 Remember, these two tests are aids to help guide your clinical assessment. You don’t need to do this with every nursing home resident, but if you’re on the fence, it may well be worth the 2 minutes to validate your concerns. On the other hand, you might be surprised: a nursing home resident who hasn’t had to go to a meeting in twenty years might not know the date, but can still be sharp as a tack.

2. Tachypnea

This is the only carryover from SIRS, and yet it continues to get almost no clinical respect in the ED setting. Pathophysiologically, tachypnea is a respiratory regulatory response to increased metabolic stress and primary metabolic acidosis. The metabolic profile of septic patients is rather complex as it seems to be characterized by both an increased level of cellular respiration as well as mitochondrial dysfunction ^26,27. The net balance of these two opposing forces appears to be an increase in the overall energy expenditure through both aerobic and anaerobic pathways²⁶. These pathways result in net overproduction of CO₂ and lactic acid, and subsequent respiratory compensation through tachypnea.

Increased energy expenditure in sepsis seems to be an early feature of the septic response and is mediated by endocrine mechanisms including increased corticosteroid and catecholamine production. As sepsis proceeds to more severe organ failure and shock, energy expenditure actually appears to decrease as a result of mitochondrial shutdown^27,28. The lactate that we measure in the early risk stratification of septic patients is most likely not due to anaerobic glycolysis alone, but rather is a marker of overall increased metabolic demand and sympathetic overdrive²⁹. Adding a lactate level did not seem to add significantly to the predictive value of qSOFA^2,30. This may be because, pathophysiologically, tachypnea addresses the same metabolic processes as the lactate level.

Like altered mental status, and unlike lactate, tachypnea does not require a blood test. Instead, it requires careful measurement of the respiratory rate, an activity that takes an ENTIRE MINUTE, yet, once again gives us immediate information about the patient’s metabolic status with prognostic value comparable to the lactate level. This brings us to the second most powerful clinical lesson of Sepsis 3:

The respiratory rate is the most important vital sign when you think a patient might be sick, but can’t quite tell yet.

3. Hypotension 

This is perhaps the most straightforward clinical feature. All EPs are acutely aware of hypotension and will treat it aggressively. Even in Sepsis 3, persistent hypotension requiring vasopressors is still classified as septic shock with even worse prognostic value than the qSOFA score^2,31. But what about transient hypotension? In trauma patients, we have known for some time that transient hypotension in the field is correlated with increased mortality³². More recently, transient hypotension has been correlated with increased mortality in all comers to the ED, and a small study in 2009 showed that this effect may be more pronounced in septic patients^33,34.  qSOFA now solidifies sepsis as a disease state in which transient hypotension is correlated with adverse outcomes. Yet, when we admit the pneumonia patient with a presenting SBP of 80/40 who responded to IV fluids, we often hear from our medicine colleagues: “great he can go to the obs unit”. Or worse: “sounds like you fixed her, she can follow up with her PCP tomorrow”.

There are at least three pathophysiologic mechanisms which can contribute to hypotension in sepsis: distributive vasodilation, relative hypovolemia due to poor PO intake and potential insensible losses, and sepsis associated cardiomyopathy. When we talk about volume responsiveness, we are referring to the heart’s ability to improve cardiac output when we fill a relatively depleted and functionally expanded tank³⁵. While volume responsiveness is reassuring (it means the heart can still keep up and is a defining difference between sepsis and the more deadly septic shock), it does little in and of itself to improve the process that got the tank empty and dilated enough to cause a drop in blood pressure. Moreover, the observation that a patient was volume responsive in the ED may result in downstream aggressive volume resuscitation, and delay in initiating vasopressor therapy, which can lead to worse patient outcomes. For more on the physiology and dangers of IV fluid therapy in sepsis see these two excellently researched and referenced emdocs posts^36,37. Thus, transient hypotension is a marker of the life-threatening organ dysfunction of sepsis, and should be taken seriously even if the blood pressure improves with initial volume resuscitation.

 Case resolution:

The patient woke up and began to berate staff. While this appeared consistent with his recent presentation during admission for UTI, his daughter informed the ED team over the phone, that he is usually belligerent only when he has health problems, and he normally does not act this way. At this time his total bilirubin came back at 4.1, AST 156, ALT 163, alkaline phosphatase 377. Right upper quadrant ultrasound showed cholecystitis with biliary tree dilatation concerning for cholangitis. He continued to have waxing and waning mental status throughout his stay in the ED, tearing off his clothes, cursing at staff, demanding discharge, and then falling asleep. He was admitted to the ICU for IV antibiotics and ERCP in the morning.

Closing thoughts

For centuries, we have defined sepsis in terms of its clinical features. Sepsis 3 takes a radically different approach: it defines the physiologic essence of sepsis and works backwards to define the clinical features of sepsis. While the resultant clinical features of qSOFA seem intuitive, they are pathophysiologically complex: a complexity that is congruent with the definition of life-threatening organ dysfunction caused by infection.

Although this consortium of critical care physicians “unanimously considered SIRS to be unhelpful”, it is difficult to abandon SIRS altogether. SIRS will continue to help us suspect significant infection and it will be a component of CMS sepsis core measures for some time, however it does not identify life-threatening organ dysfunction very specifically. In order to understand how sick a patient captured by the broad net of SIRS might be, qSOFA provides us with a tool to judge the severity of illness in these patients³⁸. While prospective validation is needed to assess its utility in guiding clinical decision making, this tool includes several key features, which are grounded in pathophysiology. These features are frequently overlooked in the ED setting, and it’s up to us to start taking these symptoms seriously.

Finally, Sepsis 3 and qSOFA have many weaknesses spelled out elsewhere^39,40. However, this is a strong attempt to bring the understanding of sepsis into the modern era of medicine. An era that demands an understanding of the underlying mechanisms of disease. As our understanding becomes more sophisticated we should be able to improve on this definition. Despite its flaws, Sepsis 3 still provides a significant improvement over older definitions, and should not be ignored just because our current “usual care” is just as good as “aggressive care” in losing a quarter of the lives affected by this life-threatening condition.

Acknowledgements: I’d like to thank Jamie Santistevan (@jamie_rae_EMdoc) and Matt Anderson (@CCInquisitivist) for their amazing and detailed comments and suggestions for this post.

[1]Note: The qSOFA derivation actually used a GCS of 13 or less as the formal criteria for AMS², however the GCS has known problems of interobserver concordance and qSOFA has been widely interpreted by the medical community and its authors to include altered mentation in general, or GCS<15.^16,17

References / Further Reading:

1. Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 801–810 (2016).
2. Seymour, C. W. et al. Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 315, 762–774 (2016).
3. Mukherjee, S. The Emperor of All Maladies: A Biography of Cancer. (Simon and Schuster, 2010).
4. Bone, R. C. et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101, 1644–1655 (1992).
5. Zolfaghari, P. S., Pinto, B. B., Dyson, A. & Singer, M. The metabolic phenotype of rodent sepsis: cause for concern? Intensive Care Med Exp 1, 25 (2013).
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