Sepsis = Dysregulated Host Response to Infection

Sepsis = Dysregulated Host Response to Infection

By Cesar M Limjoco, MD
CMO, T-Medicus LLC

Sepsis has been defined as a toxic response to infection. Sepsis-1&-2 defined it as systemic inflammatory response to infection. Sepsis-3 now defines it as life-threatening organ dysfunction caused by dysregulated host response to infection. These definitions are consistent with sepsis’ fundamental pathophysiology. It is the immune system going awry in the face of an infection.

Historically it was thought that the bacteria in the bloodstream is sepsis. All the while it is well known that the bacteria in the blood can also be seen in non-septic patients. Transient bacteremia is regularly seen in patients who are not sick! Procedures that involve instrumentation, e.g., tooth drilling, urethral catheterization, rectal probing, can cause transient bacteremia. It is also seen commonly in pneumonias, acute pyelonephritis, ascending cholangitis, and bacterial endocarditis and other localized infections.

It is not the bacteria in the bloodstream that defines sepsis, but the response of the immune system that has gone awry. In fact, sepsis occurs even when bacteria are not seen in the bloodstream. The immune system gone toxic causes circulatory insult and deficiency to the vital organs, causing ischemia, then organ dysfunction and finally, organ failure. This dysregulated host response to infection manifested as organ dysfunction/failure is sepsis/severe sepsis. So, in order to determine if a localized infection has developed into sepsis, look for signs of organ dysfunction that cannot be explained by some other condition in your patient.

Organ dysfunction vs failure. Many providers do not make a distinction between the two; but there is a finite line where dysfunction reaches a point that the organ becomes unable to perform its unique function of supporting the body. Organ failure is organ dysfunction with parenchymal injury. Every vital organ has its tipping point and when it is reached, sends signals manifested as signs and symptoms and corresponding abnormal lab values. Click on the following link for my past article on Organ Dysfunction vs Failure delves deeper on this subject.

For example, renal dysfunction first manifests as an insufficiency demonstrated by a rising creatinine. Clinical studies have shown when it rises to 1.5 times its baseline value, it is now in failure. Caveat: in small rises of creatinine caused by hypovolemia, hemoconcentration falsely manifests as a mild creatinine bump.  Although creatinine has not increased, the fluid deficiency makes it look like there’s increased concentration. Studies have shown that with volume replacement, creatinine values return to normal within 6 hours and no injury to the kidneys has occurred. But, true acute kidney injury in the same scenario can happen and becomes evident when volume replacement is not able to correct the creatinine bump in 6 hours. Damage to the renal parenchyma has occurred at that point.

Does life-threatening organ dysfunction equate to organ failure? In the Sepsis-3 definition, life-threatening organ dysfunction is intended to differentiate between organ dysfunctions manifested as remediable changes in body temperature, heart and respiratory rates from the more deleterious manifestations, as in hypotension which can lead to septic shock. Is the abnormal procalcitonin or lactic acidosis signaling systemic ischemia or could it be caused by something else? The answer may not be evident right away. One needs to consider the overall picture, patient course and response to interventions in order to unravel the conundrum.

If sepsis is life-threatening organ dysfunction, then what differentiates sepsis from severe sepsis? When the organ dysfunction crosses the threshold of organ failure, the patient is now in severe sepsis. Each vital organ has its respective functions and corresponding severity thresholds. In the respiratory system, hypoxemia becomes acute respiratory failure as manifested by a PaO2 <60 or PaCO2 >50 with pH <7.35 and other equivalent measurements. In the circulatory system, when the mean arterial pressure (MAP = [(2 x diastolic) + systolic] divided by 3) <65 with corresponding physical signs (e.g., cool, clammy skin; pale skin or cyanosis; rapid, shallow breathing; dizziness or faintness; weakness), the hypotension has reached the threshold of septic shock.

Hence, it is crucial to delineate when the immune system goes from appropriately fighting an infection to going crazy and starts becoming self-destructive. The appropriate inflammatory response may consist of the buildup of inflammatory activity and increased basal metabolic rate. Leukocytosis and fever are part and parcel of a normal inflammatory response. (Caveat: in certain circumstances, especially in the very young and the very old, there will be paucity in the inflammatory activity. Leukopenia and hypothermia may be what manifests.)

At its zenith, the two opposing forces of hyper-inflammatory response (SIRS) and compensatory anti-inflammatory response (CARS) epitomize the dysregulated host response. SIRS is the toxic pro-inflammatory syndrome whose objective is to kill infectious organisms by activating the immune system. CARS counters it by deactivating the immune system to restore homeostasis. The toxic response expressed as organ dysfunction, and at its extreme, organ failure defines sepsis and severe sepsis.

In 1991, Sepsis-1 was the first attempt at attaining consensus criteria to decrease sepsis mortality by finding early warning signals that are commonly found in patients who are critically ill. But soon, it became apparent that using it as screening protocol brought a lot of false positives. The 2001 Sepsis-2 criteria attempted to put the reins on it and qualified that other variables need to be considered. It expanded the diagnostic criteria to acknowledge the importance of the provider who is actively taking care of the patient and included other clinical and laboratory parameters; e.g., creatinine, procalcitonin, lactatemia (lactic acidosis), arterial hypoxemia. Still, the confusion in the industry persisted. The 2016 Sepsis-3 recognized the limitations in both Sepsis-1 & -2 and moved towards qSOFA and SOFA as the more definitive criteria. The diagram below from JAMA on the Sepsis-3 criteria elucidates the critical pathway to follow in using qSOFA and SOFA. It shows how qSOFA and SOFA are to be used in cadence to confirm Sepsis. The qSOFA serves as the initial, quick bedside assessment; and, the SOFA as the confirmatory screening 6 hours and more.

The pathway jumps from Sepsis to Septic Shock because SOFA variables span the spectrum of Sepsis to Severe Sepsis. It only takes a SOFA ≥2 to define Sepsis and may have not reached organ failure threshold in the 6 systems captured in SOFA (Respiration, Coagulation, Liver, Cardiovascular, CNS and Renal). See table below. For example, a patient suspected of sepsis may have a CNS Glasgow scale of 14 and a Creatinine of 1.3. These 2 variables add up to a SOFA score of 2, satisfying the requirement for Sepsis; but, neither the CNS or the Renal assessments satisfy organ failure yet.

In the end, we all need to recognize the adage from William Burton Cameron, “Not everything that can be counted counts. Not everything that counts can be counted.” As everyone knows, Medicine is both art and science. Definition, criteria and protocols are attempts to ascertain that which is not black and white. Ultimately, it’s about the Clinical Truth™. In order to determine the patient’s true condition, the provider considers the unique circumstances of every patient and weaves together an assessment and a work plan that evolves as events unfold. The patient narrative has to show the big picture, after study.