By

Prof. M. Ezzat Moemen 

Founder

of the department of anaesthesia and intensive care,

Faculty of Medicine, Zagazig University, Egypt

·        Introduction

·        Pathogenesis

·        Diagnosis

Clinical staging

Scoring

·        Management

Prophylaxis

Treatment of underlying insult

Immunomodulation

Nutrition

Global-oriented haemodynamic therapy

Regional-oriented haemodynamic therapy

·        Opinion

Introduction:

The multiple organ dysfunction syndrome  (MODS) is common in critically ill patients and represents an actual challenge to critical care physicians. The strategies for prevention and management of the syndrome necessitate proper understanding of its pathogenesis and evaluation of on-going studies of different authors.

 

Pathogenesis:

The MODS complicates a diffuse generalized inflammatory response of the host to a variety of infections by bacteria, fungi, viruses, parasites and toxins or to non-infectious stimuli by pancreatitis, trauma, burns, haemorrhage, massive blood transfusion and others. This response is termed the systemic inflammatory response syndrome (SIRS), which aims, basically, to protect the host against the effects of the injurious stimuli. However, when the response is severe, it may injure the host by overwhelming its normal protective mechanisms.

The SIRS induces activation of macrophages, endothelium and arachidonic acid with liberation of cytokines, release of oxygen free radicles and nitric oxide (NO), leading to progressive inflammatory damage, and if the response is severe, it may induce hypotension, hypoperfusion and organ dysfunction as oliguria alteration of mental function and lactic acidosis.

Clinically, SIRS can be diagnosed by the presence of two or more of criteria including: body temperature (> 38^oC or < 36^oC), heart rate (> 90 b/m), respiration rate (> 20 b/m or PaCo₂ < 32 mmHg) and Wbc (> 12000/mm³ or < 4000/mm³ or presence of > 10% of immature forms). We should always remember that we frequently meet this syndrome in our daily practice i.e. tonsillitis with fever and leucocytosis, acute haemorrhage with tachycardia and tachypnea…

The clinician should always appreciate that Allah creates controlling balancing powers in the human being, and that any disturbance of these balances induce discomfort, injury or disease, and that the aim of the intelligent clinician is to return such balances back to normal. Based on this, a stimulus may initiate the SIRS with its proinflammatory mediators or cytokines as TNF, ILI, IL6, IL8 together with activation of complement and coagulation cascade. As a second phase response, this same stimulus initiates an anti-inflammatory response with cytokines as IL4, IL8, IL10 and PGE₂ to counteract and balance the ongoing inflammation. This is the compensatory anti-inflammatory response syndrome (CARS).

If SIRS predominates, the patient may suffer from MODS or if CARS predominates, the balance will be normalized with patient cure. When infection is the underlying cause of SIRS, the condition is called sepsis. When sepsis is accompanied by hypotension that responds to volume loading or by dysfunction of one or more organ, the condition is called severe sepsis. When severe sepsis is accompanied by hypotension that is refractory to volume loading and needs inotropic support, the condition is called septic shock..

 

Diagnosis:

The MODS is diagnosed in patients with SIRS or septic syndrome in whom circulatory, respiratory, renal, hepatic or neurological functions are so altered that homeostasis cannot be maintained without an intervention. It is usually noted that many organs show dysfunction more or less equally and simultaneously. However, these organs do not fail equally or simultaneously, but  they fail in sequence.  So, multiple organ failure (MOF) is actually a progressive sequential organ failure (SOF).

Of particular interest is the association of SIRS or septic syndrome with adult respiratory distress syndrome (ARDS) as the pulmonary system may be an early sufferer from SIRS or sepsis. Actually, ARDS can be considered the pulmonary manifestation of SIRS or sepsis. When ARDS is the primary syndrome due to external chest trauma or to direct insult by aspiration, smokes, burns or drowning, a secondary SIRS with or without sepsis usually proceeds to the MODS.

 

Clinical staging:

The MODS is a progressive process and one may design an arbitrary model to describe how different organs show dysfunction simultaneously and in four stages.

In stage 1, the patient appears normal, but on close examination it is clear that his volume requirements are a little higher than expected. Mild abnormalities in function appear by investigations. In Stage 2, the patient becomes ill and a careful examination shows an occult dysfunction in each organ. Unfortunately, treatment may start in this stage in some patients, and this is late. In stage 3, the patient is sick or very ill as clear to any observer. In this stage, each organ has an overt dysfunction and requires support. Starting treatment in this stage is very late. In stage 4, the patient dies from sequential organ failure.

Scoring:

Recently, a score of the MODS has been suggested by Marshall and Colleagues ⁽¹⁾. It includes 6 parameters with a maximum of 24 points (Table 1). When applied to critically ill ICU patients, mortality was approximately 25% at 9-12 points, 50% at 13-16 points, 75% at 17-20 points, and 100% at 20-24 points.

 

Table (1) : The Multiple Organ Dysfunction Score ⁽¹⁾

*PAR (pressure-adjusted heart rate) = HR x (CVP/MAP); HR= heart rate, CVP= central venous pressure. MAP= mean arterial pressure

** The best estimate in the absence of sedation

 

Other severity of illness scoring systems have been developed to estimate the probability of hospital mortality including APACHE II and III, Mortality Probability Model (MPM) and Organ Failure Index (OFI).  Inflammatory markers have been also used for assessment of organ dysfunctions, including acute phase proteins, cytokines, complement and coagulation factors and other markers as albumin, cholesterol and transferrin. Although the number of scoring systems is large and the number of suggested markers of organ dysfunction are rising, we think that tissue oxygenation and tissue perfusion parameters with testing of organ functions is the most proper for the clinical follow up of patients with MODS. This is because, for diagnosis of tissue hypoxia, there is no gold standard, no specific clinical signs, no single laboratory test but a combination of several methods and regular clinical assessment are the most adequate diagnostic tools.

 

Management:

Prophylaxis, if possible, plays a major role in the treatment of MODS. Examples are avoiding aspiration with induction of general anaesthesia and early surgical evacuation of any pus collection in the human body. 

Treatment of underlying diseases or insults is also of great importance in the management of the MODS. Examples are early treatment of pancreatitis, haemorrhage or any organ or metabolic disease. So, by blocking the stimulus, one can block the mediators initiating SIRS or septic syndrome. Immunomodulation, antibiotics, non-steroidal anti-inflammatory drugs (NSAID’s) and nutrition play pivotal roles in patient outcome.

The basic management of the MODS depends on improving tissue perfusion and oxygenation, to treat supply dependency and hyperlactatemia. Tissue hypoxia is defined as a condition in which the cells have abnormal oxygen utilization, such that they experience anaerobic metabolism.

 

Global-oriented Haemodynamic Therapy:

The Shoemaker concept ^(2-8) aims at improving survival in critically ill patients through therapeutically driving oxygen delivery (DO₂) and oxygen consumption (VO₂) to supranormal levels by early and aggressive fluid therapy and by vasprossors and inotropes. Volume loading is initially titrated to BP and subsequently to CVP to optimize cardiac filling pressures. If vasopressors are needed to maintain BP, they should be weaned as early as possible.

This type of therapy aims to attain certain goals including m² cardiac index (CI) > 4.5L/m2, DO₂>600ml/m/m², VO₂> 170ml/m/m² and oxygen extraction ratio (O₂ER) < 31%.

The Shoemaker concept starts by fluid loading by crystalloids, colloids, blood and or hypertonic solutions. If the goals are not achieved, inotropes as dobutamine may be added in small doses to increase myocardial performance and DO₂ sufficient to maintain a hyperdynamic state. Vasoconstrictors as noradrenaline may have a place in those patients who need and can tolerate them to achieve an adequate pressure head for proper tissue perfusion. It is clear that this concept for management is fulfilled through invasive monitoring by pulmonary and radial artery cannulations.

This concept got encouragement by different authors ^(9-13). On the other hand, the concept has been criticized and did not improve survival as shown by other authors ^(14-16).

The shoemaker concept considered DO₂ of > 600ml/m/m² as a goal of therapy. This figure cannot be considered as a supernormal value but rather a normal value as the normal range of DO₂ is 540-720 ml/m/m².  The Shoemaker concept uses the Fick principle for determination of DO₂ and VO₂. So, mathematical coupling of items included in both DO₂ and VO₂ as arterial oxygen content (CaO₂) and CI may show correlation between DO₂ and VO₂ which may not actually exist. To avoid mathematical coupling and to show more accurate, correlation, if present, VO₂ should be measured by direct calorimetry or spirometrey, with an additional advantage of including VO₂ of the pulmonary system.

Again, the Shoemaker concept may be criticized on its global basis of VO₂/DO₂ relationship. Such global relationship ignores important physiological rules in critical illness. Regional VO₂/DO₂ differs from one organ to another. Cardiac extractability of oxygen is 60-70% at rest, while oxygen extractability of splanchnic organs is less than 25%. At the stress of haemorrhage or critical illness in general, autonomic redistribution of blood is ignored by the Shoemaker concept, which exhibits a global VO₂/DO₂/ relationship.

A main problem with the Shoemaker concept is that attaining supranormal oxygenation values by fluids, vasopressors and inotropes is hazardous for patients with compromized myocardium. That is why if myocardial performance does not allow attaining supranormal values, only normal values should be aimed at. However, the ability to achieve supranormal levels of DO₂ and VO₂ in critically ill patients, means that these patients have greater physiological reserves and are less sick and have better prognosis. This denotes that myocardial performance is the end-point of resuscitation because when VO₂ increases and DO₂ decreases and the heart does not or cannot increase its work to compensate, a defacto-state of heart failure exists.

Regional-oriented haemodynamic therapy:

It is clear that the Shoemaker concept addresses a global VO₂/DO₂ relationship as a goal for haemodynamic therapy in critical illness. Although this may be important, it is also clear that we should also address a regional VO₂/DO₂ relationship as a goal which should not be ignored in the management, being the other side of the coin.

In that domain the gastro-intestinal tract (GIT) is a major focus in the pathophysiology of MOD and MOF. It plays an important role in the SIRS and the septic syndrome by initiating and maintaining tissue damage through the gut starter ⁽¹⁷⁾ or the gut motor hypothesis ⁽¹⁸⁾.

In critical illness with autonomic alterations, blood redistribution leads to splanchnic vasoconstriction with ischemia of the GIT, barrier stress failure and bacterial translocation. An important pathophysilogic change is a decrease in the intramucosal PH (PHi). Persistently abnormal PHi values signal different mediators including free oxygen radicals that result in reperfusion injury and MOD as such radicals have high reactivity and short half life with high degree of tissue damage.

PHi can be evaluated by a minimally invasive monitor, the gastric tonometer with saline or air-filled balloon. Against its drawbacks, a fiberoptic CO₂ sensor in the stomach to facilitate continuous monitoring of PHi is being tested nowadays.

Continuous follow up of the pattern of PHi changes, may be considered as an early marker of tissue hypoxia in the mesenteric region based on regional VO₂/DO₂ relationship. So, it may be wise and logic to orient haemodynamic therapy in critically-ill patients towards this regional relationship, aiming to normalize PHi as an end-point of resuscitation.

In relation to the GIT, it is important to use enteral feeding for the critically ill patients because it decreases complications. Again, selective digestive decontamination (SDD) can share in the prevention and amelioration of bacterial overgrowth and translocation.

Against splanchnic ischemia-reperfusion injury a Miami, USA, protocol ⁽¹⁹⁾ for prevention of MODS in trauma patients was tested. Because ischemia-reperfusion injury generates different inter-related products, blocking a single pathway or chemical does not prevent the deleterious effects of reperfusion. So, the protocol included multiple agents for multiple objects. The agents included folate, mannitol, vit. A, vit. C, vit. E, selenium, acetyl cysteine, lidocaine, glutamine, polymyxin-B and hydrocortisone. The multiple objects dealt with the ongoing intestinal injury by attacking the generation of free radicles, providing free oxygen scavengers, and augmenting natural body defenses. This treatment protocol could normalize PHi in 88% of patients, and 97% of them did survive.

Opinion:

The present article may suggest that the management of MODS includes :

(1)   Prophylactic and preventive measures.

(2)   Treatment of underlying etiology.

(3)   Splanchnic-directed haemodynamic therapy .

(4)   Global-oriented haemodynamic therapy to treat supply dependency and combat hyperlactatemia.

(5)   Immunomodulation.

(6)   Antibiotics.

(7)   Enteral feeding and other supportive measures.

References

1.          Marshall JC, Cook DJ, Christou NV, Bernard GR, Sprung CL. Sibbald WJ. (1995): Multiple organ dysfunction score: a reliable descriptor of a complex clinical outcome. Crit Care Med Oct; 23(10): 1638-52.

2.          Shoemaker W C, Montogomery E S, Kaplan E et al (1973): Physiologic patterns in surviving and nonsurviving shock patients. Arch Surg 106: 630-636.

3.          Shoemaker W C , Appel P L, Bland R D (1983): Use of physiologic monitoring to predict outcome and to assist in clinical decisions in critically ill postoperative patients. Am J Surg 146: 43-50.

4.          Shoemaker W C , Appel P L, Waxman K, Schwartz S and Chang P (1982) Clinical trial of survivors’ cardiorespiratory patterns as therapeutic goals in critically ill postoperative patients. Crit Care Med 10: 398-403.

5.          Shoemaker W C , Appel P L, Kram H B (1986): Haemodynamic and oxygen transport effects of dobutamine in critically ill surgical patients. Crit Care Med 14: 1032-1037.

6.          Shoemaker W C , Appel P L, Kram H B (1988a): Tissue oxygen debt as a determinant of lethal and non lethal postoperative organ failure. Crit Care Med 16: 1117-1120.

7.          Shoemaker W C , Appel P L, Kram H B et al (1988b): Prospective trial of supranormal values of survivors and therapeutic goals in high risk surgical patients. Chest 94: 1176-1186.

8.          Shoemaker W C , Kram H B, Appel P L, et al (1990): The efficacy of central venous and pulmonary artery catheters and therapy based upon them in reducing morbidity and mortality. Arch Surg 125: 1332-1338

9.          Fleming A, Bishop M, Shoemaker W et al (1992): Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 127: 1175-1181.

10.      Tuchschmidt J, Fried J, Astiz M et al (1992): Elevation of cardiac output and oxygen delivery improves outcome in septic shock. Chest 102: 216-220.

11.      Boyd O, Grounds R M, Bennet E D (1993): A randomised clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 270: 2699-2707.

12.      Vallet B, Chopin C, Curtis S E et al (1993): Prognostic value of the dobutamine test in patients with sepsis syndrome and normal lactate values: a prospectie multicentre stdy. Crit Care Med 21: 1868-1875.

13.      Bishop M H, Shoemaker W C, Appel P L et al (1995): Prospective randomized trial of survivor values of cardiac index, oxygen delivery and oxygen consumption as resucitation end points in severe trauma. J Trauma, Injury, Infection and Critical Care 38: 780-787.

14.      Yu M, Levy M M,Smith P et al (1993): Effect of maximinsing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomised, controlled study. Crit Care Med 21: 830-838.

15.      Hayes M A, Timmins A C, Yau E H S et al (1994): Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 330: 1717-1722.

16.      Gattinoni L, Brazzi L, Pelosi P et al (1995): A trial of goal-oriented haemodynamic therapy in critically ill patients. N Engl J Med 333: 1025-1032.

17.      Moore EE, Moore FA, Francoise RJ, Kim FJ, Biffi WL, Bagerjee A. (1994): The post ischemic gut serves as a priming bed for circulating neutrophils that provoke multiple organ failure. J Trauma, 37:881-887.

18.      Marshall JC, Christou NV, Mcakins JL. (1993): The gastrointestinal tract: the undrained abscess of multiple organ failure. Ann Surg, 218: 111-118.

19.       Barquist E, Kirton OC, Civetta JM. (1998): Gastric intramucosal pH in the assessment of adequacy of resuscitation after trauma. Curr Opin Crit Care, 259-262.