LIRS, SIRS, Sepsis, MODS and Tertiary Peritonitis

MODS and Tertiary Peritonitis

Moshe Schein · John Marshall

The larger the operation – the greater the trauma The greater the trauma – the stronger the SIRS The stronger the SIRS – the sicker the patient The sicker the patient – the higher the M & M

Local and Systemic Inflammation, and Its Consequences

Moshe Schein

In the first paragraph of this book we alluded to your patient being locally and systemically inflamed by his surgical disease, your treatment, and the complica- tions of both. In almost every subsequent chapter you have been reminded that the magnitude of the inflammation correlates with that of the disease process and the operation. You were told that the more inflammation there is – or that you create – the more likely is your patient to develop organ dysfunction or failure, and to die. In this chapter, we’ll concentrate on the inflammation – both local and systemic – and its consequences. The biological events involved are immense and chaotic but let us maintain a simplistic attitude – you did not buy this book to read about cytokines, right?

Background

Matters were much simpler for us surgeons, only a few years ago. Post opera- tive or post-traumatic fever, raised white cell count, deteriorating organ-system function, with or without shock, meant for us only one thing – “sepsis”. And

“sepsis” meant “infection”, usually bacterial in nature, necessitating antibiotic

therapy. So we administered the “strongest”, ever changing, antimicrobial agents

available on the market; we looked for pus, draining it whenever present, and we

prayed for the “infection” to subside. Some of our patients, however, continued to

deteriorate, dying slowly from respiratory and/or renal failure. We buried them,

blaming the death on an “intractable sepsis”, which in our minds always signified

an infection “somewhere”in their blood,abdomen,urine or lungs.Look around you

– isn’t this the way many of your senior colleagues, mentors or teachers still think

and practice?

Then, in the early 1980s, when our supportive care and re-operative efforts became more aggressive, resulting in prolonged survival, we began to note that many of our patients were dying a “septic” death in the absence of “infection”; we did not understand why. Towards the second half of the 1980s, the rapidly develop- ing field of molecular biology produced a huge amount of data to explain that a lot of what we see in clinical practice is not “sepsis” or “infection” but inflammation – which in turn is fueled by pro-inflammatory mediators such as cytokines. This has totally changed the way we look at the surgical patient. We see him being inflamed by the disease and the operative trauma together with the postoperative complica- tions and associated therapies. In fact, most of our postoperative patients who die today do so from inflammation or infection – alone or in combination. But before we go further, we need to clarify a few issues in terminology.

Terminology

Take a knife and cut your finger: sooner or later your finger will manifest the usual signs of inflammation – redness, swelling, warmth and pain, produced by locally generated inflammatory mediators. This is LIRS or local inflammatory response syndrome.

Now take a patient who has suffered multiple, and deeper, knife wounds to the soft tissues. In addition to the local inflammation he’ll experience signs of systemic inflammation: fever, tachycardia and even elevation of his white cell count. This is SIRS or systemic inflammatory response syndrome.SIRS occurs when the locally pro- inflammatory mediators of LIRS spill over to the systemic circulation, affecting the entire organism. In surgical practice most instances of SIRS are secondary to LIRS.

Examples include acute pancreatitis, retroperitoneal hemorrhage, and acute chole- cystitis.Note that the pro-inflammatory cascades leading to SIRS are initially, at least, well compartmentalized locally, with the SIRS representing only the tip of the iceberg.

LIRS and SIRS can be generated by sterile, non-infective causes (e.g., tissue trauma, necrosis, burn) as well as infective causes (e.g. acute appendicitis). The ensuing clinical manifestation are, however, indistinguishable.

 Infection is a microbiological phenomenon characterized by the invasion of normally sterile tissue by microorganisms.The host’s local response to the infection is LIRS, the systemic response is SIRS. And here we arrive at the term sepsis.

 Sepsis is currently defined as the systemic response to infection consisting of

SIRS with microbiological evidence of infection. (Sepsis = systemic inflammation

(SIRS) ± infection). In other words, SIRS and sepsis represent an identical host-

determined response, the former in culture-negative patients and the latter when

infection is documented. Both manifest a continuum of clinical and pathophysio-

logic severity.

According to current consensus SIRS may be diagnosed in any patient who manifests two or more of the following: temperature >38 °C (100.4 °F), heart rate

>90/min, respiratory rate >20/min, white cell count>12,000 cells/mm

. With such a low inclusion threshold, it appears that most of your emergency abdominal post- operative patients, and all your surgical intensive care unit patients, experience a degree of SIRS. (In fact, there was someone who said that even engaging in vigorous sex produces clinical SIRS).

The noxious stimuli,which incite pro-inflammatory mediators leading to LIRS and SIRS, induce in parallel potent anti-inflammatory mediators, to produce what the late Roger Bone (1943–1996,the “father”of SIRS) termed CARS or compensatory anti-inflammatory syndrome.CARS manifests clinically as immunodepression and an increased susceptibility to infection, so typical in the aftermath of major surgery and trauma. Conceptually, the balance between SIRS and CARS determines out- come. When CARS equalizes SIRS – homeostasis results. When SIRS is unopposed, organ dysfunction develops. When CARS is the winner, primary or secondary infections may take their toll.

As with many other essential things in life, too much may be harmful and too little may be not satisfactory. The same is probably true for the inflammatory and anti-inflammatory responses,which in a certain phase and magnitude are beneficial but when out of control are harmful. Understand, however, that these events are extremely complex, chaotic, non-linear and unpredictable; some severely trau- matized patients do not progress from SIRS to organ failure and some do. Your grandmother may be right – genes play a role in everything.

This is of course a highly simplistic version of the reality, much of which we still do not understand, but didn’t Ralph Waldo Emerson (1803–1882) say: “It is proof of high culture to say the greatest matters in the simplest way?”

From SIRS to Multi-organ Dysfunction Syndrome (MODS)

The same pro-inflammatory mediators that locally posses salutary actions, when over-produced and systemically spread, eventually damage the microcircula- tion, resulting in progressive damage to vital organs. The inflammatory mediators released by the circulating macrophages, which are activated by the disease or injury,result in widespread endothelial damage,causing capillary leak and coagula- tion and resulting in cellular damage and then organ dysfunction (lungs, kidneys, liver, gut…). The cytokines (e.g. interleukin-6) not only promote local coagulation but also suppress local fibrinolysis,a compensatory mechanism that attempts to lyse the forming clot.

Thus, your SIRS patient swells, he gains weight, his lungs become wet, the

gastric mucosa bleeds, liver enzymes become elevated, renal dysfunction appears,

and so forth. He becomes autointoxicated with his own inflammatory mediators.

The more severe the damage to the organs, the more organs are involved and for a longer duration, and the less likely is your patient to recover.When three organs fail the prognosis is grim; when the fourth organ joins in, the die is cast.

The Second-Hit Phenomenon

Imagine a boxer in a ring. Having just received a major blow he lifts himself back up to his feet where, almost erect, he receives a second hit, which is softer than the first one, but enough to send the boxer back onto the floor – a fatal knockout.

Similarly,your SIRS patient is susceptible to a second hit; his inflammatory response, switched on by the primary hit, is easily amplified by additional, albeit relatively minor hits. Think of your patient as an aging boxer. The abdominal emergency plus your operation represent the first hit. From now on any additional procedure (or complication) constitutes a potential second hit, which greatly increases the magnitude of the inflammation.

Treatment of SIRS and MODS

The search for the magic bullet to arrest the cascades of LIRS, SIRS and to modulate CARS continues; but meanwhile is there anything we can do for these patients?

 First, we need to use terms accurately, distinguishing between local inflam- mation and infection, between SIRS and systemic sepsis. We must understand that LIRS and SIRS do not always mean infection and thus may not be an indication to administer antibiotics (

Chaps. 7 and 42).

 Second, we must restore and maintain perfusion of end organs to prevent an additional ischemic injury, which will contribute to the inflammation

(

Chap. 6).

 Third, we must avoid adding fuel to the inflammatory fire, appreciating that what we do, and how we do it does matter. A prolonged operation and rough handling of tissues means more inflammation, more LIRS and SIRS. Unnecessary and poorly timed re-interventions may produce a “second hit” in a previously primed host.

 Fourth, we should deal promptly with ongoing infective (e.g. an abscess) and non-infective (e.g. necrotic tissue) sources of LIRS and SIRS.

 Fifth, we should attempt to preserve the integrity of the mucosal layer of

the gut (through early enteral feeding) in order to prevent translocation of bacteria

and endotoxin, which may contribute to SIRS, sepsis and MODS (

Chap. 41).

 Sixth, we should minimize iatrogenic contributors to LIRS and SIRS. The patient must not be continuously injured and crucified in bed with indiscriminate insertion of catheters, tubes and pipes. Blood products may be harmful and should be used judiciously (

Chap. 40). Antibiotics are a double-edged sword and may in fact increase SIRS by various mechanisms.

It is impossible to prove that each of the above measures decreases SIRS and MODS, but proper management as a whole is the mainstay of prevention of this

“horror autotoxicus”.

Tertiary Peritonitis

In

Chap.12 you were introduced to the concepts of peritoneal contamination

and infection and the terms primary and secondary peritonitis. In

Chap. 46 you read: “When peritonitis persists despite adequate source control and repeated re- operations, think about tertiary peritonitis”. What’s that?

The aggressive supportive and operative measures discussed in the previous chapter allowed for the initial salvage of patients who previously would have suc- cumbed early to uncontrolled secondary peritonitis. This success, however, created a new subgroup of patients. Let us take one as an example:

A 75-year-old male underwent an emergency subtotal colectomy with an ileorectal anastomosis for an obstructing carcinoma of the sigmoid colon (

Chap. 25). Six days later he was rushed for a re-laparotomy because of diffuse peritonitis and a documented free anastomotic leak. At operation his abdomen was found to be full of fecal material. It was cleansed and the anastomosis was dismantled; the rectum was closed as in a Hartmann’s procedure and the ileum exteriorized as an end ileostomy. The abdomen was left open as a

“laparostomy” (

Chap. 46). During a planned relaparotomy 48 hours later residual collec- tions of “thin” pus were evacuated. The patient continued to be “septic” and developed MODS. CT of the abdomen showed fluid in the pelvis and gutters; diagnostic aspiration revealed the presence of fungi. An antifungal agent was added to the wide spectrum anti- biotics the patient was already receiving. He continued to deteriorate; a re-laparotomy dis- closed a few hundred milliliters of murky peritoneal fluid, which grew Candida and Staph.

epidermidis. The antibiotic regimen was changed. MODS worsened leading to the patient’s demise 5 weeks after the first operation. The hospital bill was $250,000.

You have seen similar patients, eh? Probably one of them is now fading away

in your ICU. The term tertiary peritonitis was coined to describe this situation,

which develops late in the postoperative phase, manifests clinically as SIRS with

MODS, and is associated with a peculiar peritoneal microbiology consisting of

yeasts and other commensals.These organisms,normally of low virulence,probably

act as a marker of tertiary peritonitis and not its cause. Their presence also reflects

the global immunodepression of the affected patient,allowing superinfection of the re-explored abdomen with organisms resistant to the antibiotic regimen he is receiving. Further antimicrobial administration and operative interventions are futile and may contribute to the peritoneal superinfection.The usually fatal outcome of tertiary peritonitis, which conceptually falls within the SIRS-MODS complex, indicates that current antibiotic-assisted, mechanical answers to severe peritonitis have about reached their limits, and the patient is unsalvageable.

“Our ingenuity in developing terminology exceeds our abilities to take care of these patients once they have developed the syndrome of MOF.The solution to MOF or MODS or SIRS is prevention.” (Arthur E. Baue)

We asked John Marshall of Toronto, who originated many of the terms described above, to tell us more on how to prevent and treat SIRS, MODS and tertiary peritonitis.

[The Editors]

Invited Commentary

John Marshall

The world of the critically ill surgical patient is a strange one. Its genesis lies in the performance of feats of surgical daring that were almost unimaginable even half a century ago, and its progress reflects the expression of processes that have no precedent in evolutionary biology. Could Halsted or Kocher have anti- cipated an age when surgeons would sew the liver of a cadaver into a patient dying of cirrhosis, or salvage a patient who presents in cardiac arrest from a gunshot wound to the heart? The leading surgical minds of their era spoke of “shock” be- cause they believed that wounded patients died of an overwhelming sense of fear, and it was not until the early years of this century that Alfred Blalock refined this view, and showed that shock arose not from the brain, but from a lack of circulating volume within the vascular tree. He set the stage for a bold and unprecedented con- ceit – that the clinician, through the correction of acute physiologic derangements and the support of fundamental physiologic functions – could prevent, or at least forestall, the inevitability of death from acute life-threatening illness.

The late John Border (1926–1996),a trauma surgeon who contributed so much

to contemporary views of the pathogenesis of critical illness, captured this con-

ceptual advance by allusion to a classical motif from American cinema. The scene

is a battlefield during an unnamed war. Surgeons are operating desperately to save

the life of the shy and handsome, but somehow anonymous, soldier who has been

wounded. The urgency of their mission is underlined by rapid cinematic cuts

between the surgeons, and the rubber bag that moves in and out as the patient inhales the ether that provides him with pain relief. The situation becomes desper- ate.Beads of sweat appear on the brows of the operating surgeon,and the movement of the anesthetic bag becomes shallow… then stops. The surgeons bow their heads, and the camera pulls back to show a silent medical team, lost against the sullen sky of the enveloping evening.And Border opines:“They didn’t realize that all you have to do is to squeeze the bag.”

We have squeezed the bag, and much more, and the author of this chapter has beautifully articulated the consequences of that squeezing. It is both incomprehen- sibly complex, and very simple; let me just underline a few of the principles that I hope you will retain from these discussions.

First, patients no longer die of their primary diseases; rather they die of their response to that disease. Shock kills not because of a deficit of circulating intra- vascular volume (a state that we can readily correct with intravenous fluids), but because of the biologic processes that are activated during reperfusion of ischemic tissues. Infection kills not because of uncontrolled proliferation of microorganisms (a process we can easily avert with source control measures and systemic anti- biotics),but because the host responds to the infecting microorganism.This concept was beautifully demonstrated in an animal study performed more than two decades ago by Michalek et al.(1980).Two strains of mice,one known to be sensitive to endo- toxin, and the other resistant because of a point mutation in a single gene, were irradiated and then given bone marrow transplants from the other strain. The lethality of endotoxin, a bacterial product, was transferred to the resistant-strain animals who received bone marrow cells from their sensitive relatives. In other words, the lethality of bacterial endotoxin is not an intrinsic property of the mole- cule, but rather a function of the fact that the host responds. It is not uncommon to see a critically ill, immunosuppressed patient who survives a life-threatening infection, only to become gravely ill as the immunosuppression abates, and he or she is able to respond to the infection.

An important corollary of this principle is that interventions against infection

will not alter the course of a disease process whose pathophysiology reflects the

response to infection. Stated differently, surgical source control and systemic anti-

biotics are anti-infective measures whose objective is to reduce the size of the

microbial inoculum with which the host must contend. Their utility is critically

dependent on establishing a diagnosis by demonstrating that a focus of infection,

or uncontrolled microbial proliferation, is present, and it is incumbent upon the

surgeon to demonstrate conclusively that such is the case,for antibiotics kill not only

the organisms responsible for the infection, but also the normal colonizing flora

of the host. In doing the latter, they facilitate colonization, and ultimately super-

infection, by antibiotic-resistant organisms, a state that is epitomized by the pheno-

menon of tertiary peritonitis, described above.

Equally, the injury experienced by the critically ill surgical patient reflects not only what happened to him or her prior to arrival at the hospital, but also the inter- vention of the surgeon and other clinicians who provided care. Contemporary critical illness is an intrinsically iatrogenic disorder,for it only arises in patients who in the absence of medical intervention would have died,but its evolution reflects the inadvertent consequences of the interventions used to resuscitate the patient and to sustain life. The challenge we face as clinicians is to apply new technologies, but even more importantly, to recognize the potential adverse consequences of these, and to know when to back off.

Yet another concept intrinsic to this discussion is that the “syndromes” of critical illness are not well-defined pathologic entities, but rather metaphors for a process that we only dimly understand.For example,more than a decade ago a group of intensivists met to try to achieve consensus on the definition of sepsis (Bone et al.1992).They coined the phrase “systemic inflammatory response syndrome”out of a desire to assert that the clinical syndrome of sepsis can arise in patients who are not infected, and to recognize that we did not have terminology to describe such a state. However, this concept does not necessarily define a syndrome, if by a syndro- me we are referring to a constellation of signs and symptoms caused by a discrete pathologic process (Marshall 1999), and the criteria proposed to delineate that supposed syndrome were both arbitrary and highly non-specific (Vincent 1997).

SIRS implies a response,and a relatively significant one at that,but its diagnostic im- port is nothing more than that the clinician should consider looking for a cause of that response (Marshall et al. 2000). The notion that there are other syndromes designated as CARS (compensatory anti-inflammatory response syndrome) or MARS (mixed acute response syndrome) (Bone 1996) similarly overstates our basic understanding and descriptive capacity. It is a biological truism that an acute inflammatory response entails the release of both pro- and anti-inflammatory mediators (and even this distinction is simply a matter of conceptual convenience for a human intellect that insists on categorizing), but it far oversteps current understanding to suggest that we can identify discrete syndromes, or clinical mani- festations that point to a particular pattern of mediator response. SIRS and CARS are useful as concepts, but entirely unhelpful as patterns of clinical manifestations that might guide the care of a particular patient, or even shape the design of a clinical trial.

Finally, despite Dr. Schein’s admonition that “you didn’t want to learn about

cytokines”, let me try to convince you that, although the inflammatory response is

complex (and sufficiently complex that no one really understands it in a com-

prehensive way), its basic principles are not only straightforward, but seductively

appealing. Inflammation is mediated primarily by the innate immune system, in

contradistinction to the adaptive immune system that includes T cells and B cells.

Innate immunity is highly conserved through evolution; the same principles that regulate innate immunity in the Pope,also regulate innate immunity in fruit flies and sea slugs, so they have to be simple. The innate immune system evolved to recognize danger both from microorganisms in the environment, and from injured tissues in the host. Cells of the innate immune system – principally neutrophils and macro- phages – recognize molecular patterns that signify danger, e.g. complex lipids and carbohydrates that are found in bacterial, but not mammalian, cells, or molecules such as heat shock proteins or RNA that are normally found within the cell. Recog- nition occurs through a family of ten receptors called toll-like receptors (“toll”is the German word for “cool” – nothing sophisticated here) that bind these substances, and,in doing so,activate a series of intracellular cascades that lead the cell to express genes that encode inflammatory mediators, two of the most important being tumor necrosis factor (TNF) and interleukin-1 (IL-1). These mediators too, can activate cells, leading to the release of a complex mélange of cytokines, prostaglandins, and reactive intermediates of oxygen and nitrogen, and triggering the coagulation cascade.

But let’s return to the world of clinical reality.We don’t need fully to understand the inflammatory process to recognize that we need to minimize exposure of the innate immune system to danger signals, whether by draining an abscess to reduce the bacterial load, providing rapid resuscitation to prevent tissue ischemic injury, or taking steps to limit iatrogenesis through keeping ventilatory volumes low, and minimizing unnecessary exposure to vasoactive drugs and antibiotics.Good clinical care is grounded in common sense and carefully considered intervention, not in esoteric renderings of biology.

References

Bone RC (1996) Sir Isaac Newton, sepsis, SIRS, and CARS. Crit Care Med 24:1125–1128 Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA et al. (1992) Definitions for

sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.The ACCP/SCCM Consensus Conference Committee. Chest 101:1644–1655

Marshall JC (1999) Rethinking sepsis: From concepts to syndromes to diseases. Sepsis 3:5–10 Marshall JC, Baue AE (2000) SIRS and MODS: What is their relevance to the science and

practice of critical care? Shock 14:586–589

Michalek SM, Moore RN, McGhee JR, Rosenstreich DL, Mergenhagen SE (1980) The primary role of lymphoreticular cells in the mediation of host responses to bacterial endotoxin.

J Infect Dis 141:55–63

Vincent JL (1997) Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med 25:372–374