MODS

MULTI ORGAN DYSFUNCTION SYNDROME : 

MULTI ORGAN DYSFUNCTION SYNDROME JOYDEEP GHOSH MEDICINE IPGMER

Background : 

Background In the late 1960s, several reports appeared describing remote organ failure (eg, pulmonary failure, liver failure) as a complication of severe sepsis In 1975, a classic editorial by Baue was entitled "Multiple, progressive or sequential systems failure, a syndrome of the 1970s."

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Terminologies: multiple organ failure, multiple system organ failure, and multiple organ system failure, More recently, the term multiple organ dysfunction syndrome (MODS) has been proposed as a more appropriate description.

Associated terminologies : 

Associated terminologies SIRS  :  Two or more of: Temperature > 38°C or <36°C Tachycardia > 90 beats/minute Respiratory rate > 20 breaths/minute or PaCO2 < 32mm Hg White blood count > 12000 or < 4000 or > 10% immature (band) forms Sepsis : SIRS due to infection Severe sepsis : Sepsis with evidence of organ hypoperfusion

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Septic shock :Sepsis with hypotension (arterial blood pressure <90 mmHg systolic, or 40 mmHg less than patient's normal blood pressure) for at least 1 h despite adequate fluid resuscitation; or Need for vasopressors to maintain systolic blood pressure 90 mmHg or mean arterial pressure 70 mmHg

Definition : 

Definition MODS is the presence of altered organ function in a patient who is acutely ill homeostasis cannot be maintained without intervention development of progressive and potentially reversible physiological dysfunction in 2 or more organs or organ systems -ACCP/SCCM consensus conference 1991

Organ dysfunction assessment : 

Organ dysfunction assessment How many? APACHE II, APACHE III SOFA Disadvantages of APACHE: Mainly determines the ICU outcome Cumbersome Does not incorporate the extent of damage How severe? SOFA

SOFA SCORE : 

SOFA SCORE

Causes : 

Causes Sepsis Trauma Shock due to any cause- cardiovascular/hemorrhagic Severe derangement in any particular organ system Other: Burns Pancreatitis Massive blood transfusion Poisoning Eclampsia Acute CTDs, severe vasculitis Atrial myxoma, cholesterol emboli, SJS-TEN

Epidemiology : 

Epidemiology Knaus et al: 15% (n=5815) Ecmo et al varies from 7-15% Fry et al Montogmery et al Pine et al: 20% (only surgical patients were taken) 80% of ICU death can be accounted for MODS

Natural history : 

Natural history Progressive rapid MODS and death Progressive rapid MODS and death Recovery

Classification : 

Classification Primary : Dysfunction is happened simultaneously in two or more organs due to primary disease. Secondary : Dysfunction happened in a organ, other organs sequentially happened dysfunction or failure.

Outcome of primary and secondary MODS : 

Outcome of primary and secondary MODS

Pathogenesis : 

Pathogenesis Theories put forward: Gut hypothesis Endotoxin macrophage hypothesis Tissue hypoxia-microvascular hypothesis Integrated hypothesis

Gut hypothesis (Doig et al.) : 

Gut hypothesis (Doig et al.) The most popular hypothesis to explain MODS in critically ill patients is the gut hypothesis. Due to splanchnic hypoperfusion subsequent mucosal ischaemia there occurs structural changes and alterations in cellular function. This results in increased gut permeability, changed immune function of the gut and increased translocation of bacteria. Hepatic dysfunction leads to toxins escaping into the systemic circulation and activating an immune response. This results in tissue injury and organ dysfunction.

Endotoxin macrophage hypothesis : 

Endotoxin macrophage hypothesis Gram-negative infections in MODS patients are relatively common, hence endotoxins have been advanced as principal mediator in this disorder. It is thought that following the initial event , cytokines are produced and released. The pro-inflammatory mediators are: tumor necrosis factor-alpha (TNF-α), interleukin-1, interleukin-6, thromboxane A2, prostacyclin, platelet activating factor, and nitric oxide

Tissue hypoxia-microvascular hypothesis : 

Tissue hypoxia-microvascular hypothesis As a result of macro- and microvascular changes insufficient supply of oxygen occurs. Hypoxemia causes organ dysfunction and cell death.

Integrated hypothesis : 

Integrated hypothesis Since in most cases no primary cause is found, the condition could be part of a compromised homeostasis involving the previous mechanisms.

Cellular and tissue mechanisms : 

Cellular and tissue mechanisms Direct injury to cells: LPS fraction of endotoxin of GNB can directly damage endothelial capillary cells leading to disruption of tissue barrier.

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Activation of serum factors: Trauma, ischemia, endotoxins…….all of them can lead to activation of the complement system, which might culminate in a generalized microvascular coagulation leading to tissue perfusion defects

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Cellular activation: TNF-alfa, IL-1, IL-6 released as a byproduct of injury/insult lead to widespread activation of platelets, PMN leucocytes and macrophages, which in turn can be deleterious

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Endothelial injury: Injury to endothelium can be direct as in case of endotoxemia, or indirect in case of shock. This creates a favorable atmosphere for processes like coagulation ,inflammation and fibrinolysis.

Slide 23: 

Infective diseases Non-infective diseases MODS

Slide 24: 

Pro-inflammatory reaction TNF-a, IL-1, IL-6, IFN TXA2, PAF Cell activation Anti-inflammatory reaction IL-10, IL-4, TGF-β IL-1ra ,Lipoxin Cell elimination

Slide 25: 

SIRS and MODS An uncontrolled inflammation process Pro-inflammatory signals exceed its normal domain or degree Result in end-organ damage and multi-system failure.

Slide 26: 

Infection/ injury Local inflammatory cell activated (M,PMN,VEC,) Pro-inflammatory mediators released Inflammatory stimulator Tissue injury Systemic inflammatory cell activated (M,PMN,VEC,)

Risk factors for the development of MODS : 

Risk factors for the development of MODS Severity of the disease Sepsis on admission Age >65yrs Severe persistent shock (any etiology) for >24 hours Major surgery, trauma, devitalized tissue Severe burns Persistent liver or renal dysfunction Uncontrolled diabetes Immunocompromised Malnutrition

Clinical manifestations : 

Clinical manifestations

Clinical course : 

Clinical course Stage 1 Stage 2 Stage 3 Stage 4

Stage 1 : 

Stage 1 General appearance: normal or mildly restless Cardiovascular function: increased vol. req Respiratory function: mild resp alkalosis Renal function: oliguria-limited diuretic response GI function: distention Hepatic function: normal or mild cholestasis Metabolism: hyperglycemia, insulin req CNS: confusion Hematology: variable

Stage 2 : 

Stage 2 General appearance ill appearing, restless Cardiovascular function: hyperdyanamic volume dependent Respiratory function: tachypnoe, hypocapnia, hypoxemia Renal function: fixed output, minimal azotemia GI function: intolerance to enteral feed Hepatic function: hyperbilirubinemia, prolonged PT Metabolism: severe catabolism CNS: lethargy Hematology: thrombocytopenia, leucopenia/cytosis

Stage 3 : 

Stage 3 General appearance: unstable Cardiovascular function: shock, edema Respiratory function: severe hypoxemia, ARDS Renal function: azotemia, indication for RRT GI function: ileus, stress ulcer Hepatic function: clinical jaundice Metabolism: acidosis, hyperglycemia CNS: stuporous Hematology: coagulopathy

Stage 4 : 

Stage 4 General appearance: moribund Cardiovascular function: drug dependent Respiratory function: hypercapnia, barotrauma Renal function: anuria, instability on RRT GI function: diarrhoe, ischemic colitis Hepatic function: deep jaundice, increased OT/PT Metabolism: lactic acidosis, muscle wasting CNS: coma Hematology: uncorrectable coagulopathy

Chronology of dysfunction : 

Chronology of dysfunction The progressive dysfunction of organ systems that characterize MODS usually occurs in a predictable manner. During the first 72 hours of the original insult, respiratory failure commonly occurs. This is followed by hepatic failure (5 to 7 days), gastrointestinal bleeding (10 to 15 days), and finally renal failure (11 to 17 days)

Metabolic alterations in MODS : 

Metabolic alterations in MODS Hypercatabolism Gluconeogenesis Lipolysis Glycolysis

Prognosis : 

Prognosis Directly proportional to the number and extent of organ involvement. Knaus et al Indian data: SOFA score of 16 is associated with mortality of 50% in contrast to study by Vincent et al, where the figure is 74 % Tropical problems --shown have better prognosis

Treatment : 

Treatment Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. Identify the source of infection and treat with antimicrobial therapy, surgery, or both. Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiorgan system dysfunction.

Features of therapy : 

Features of therapy Largely supportive: Etiology control Maintenance of oxygen transport Use of activated protein C Corticosteroids Metabolic support Organ support

Etiology control : 

Etiology control Infection - antibiotics Trauma - wound care/amputation if required Abscess: - drainage Burns – skin grafting

Antibiotic choice : 

Antibiotic choice Immunocompetent : Ceftriaxone (2 g q24h) or ticarcillin-clavulanate (3.1 g q4–6h) or piperacillin-tazobactam (3.375 g q4–6h); Imipenem-cilastatin (0.5 g q6h) or meropenem (1 g q8h) or cefepime (2 g q12h). Gentamicin or tobramycin (5–7 mg/kg q24h) may be added to either regimen. If the patient is allergic to beta-lactam agents, use ciprofloxacin (400 mg q12h) or levofloxacin (500–750 mg q12h) plus clindamycin (600 mg q8h). If the institution or the community has a high prevalence of MRSA isolates, add vancomycin (15 mg/kg q12h) to each of the above regimens

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Neutropenic : imipenem-cilastatin (0.5 g q6h) ormeropenem (1 g q8h) or cefepime (2 g q8h) ticarcillin-clavulanate (3.1 g q4h) or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) Vancomycin (15 mg/kg q12h) should be added if the patient has an infected vascular catheter, if staphylococci are suspected, if the patient has received quinolone prophylaxis if the patient has received intensive chemotherapy that produces mucosal damage, if the institution has a high incidence of MRSA infections, or if there is a high prevalence of MRSA isolates in the community.

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Splenectomy Cefotaxime (2 g q6–8h) or ceftriaxone (2 g q12h) should be used. If the local prevalence of cephalosporin-resistant pneumococci is high, add vancomycin. If the patient is allergic to beta-lactam drugs, vancomycin (15 mg/kg q12h) plus ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) or aztreonam (2 g q8h) should be used. IVDU: Nafcillin or oxacillin (2 g q8h) plus gentamicin (5–7 mg/kg q24h). If the local prevalence of MRSA is high or if the patient is allergic to beta-lactam drugs, vancomycin (15 mg/kg q12h) with gentamicin should be used.

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AIDS Cefepime (2 g q8h), ticarcillin-clavulanate (3.1 g q4h), or piperacillin-tazobactam (3.375 g q4h) plus tobramycin (5–7 mg/kg q24h) should be used. If the patient is allergic to -lactam drugs, ciprofloxacin (400 mg q12h) or levofloxacin (750 mg q12h) plus vancomycin (15 mg/kg q12h) plus tobramycin should be used.

Oxygen support : 

Oxygen support Objective is to achieve supramarginal oxygen level in the tissues so that the increased needs are fulfilled Maintaining a high oxygen content of 70mm hg Oxygen saturation over 90% Hemoglobin at 11g/dl ------------- a good indicator is the serum lactate levels.

APC : 

APC A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group drotrecogin-alpha, activated resulted in lower mortality rates (24.7% vs 30.8%) in the treated group compared with placebo. reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by 6.1%, (P =.005).

Bernard GR et al. N Engl J Med 2001;344:699-709. : 

Bernard GR et al. N Engl J Med 2001;344:699-709.

Indications : 

Indications Risk of death high APACHE II 25 sepsis-induced multiple organ failure septic shock sepsis-induced ARDS with no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit to APC

Corticosteroids : 

Corticosteroids Intravenous corticosteroids (hydrocortisone 200-300mg/day, for 7days in three or four divided doses or by continuous infusion) are recommended inpatients with septic shock who, despite adequate fluid replacement, require vasopressor therapy to maintain adequate blood pressure. ----- ‘surviving sepsis’ guidelines SCCM 2004

Metabolic support : 

Metabolic support Calorie around 30-50 cal/kg/day with no more than 5 gm/kg/day of glucose Increased carbohydrate causes excessive lipolysis and CO2 production Fat emulsion (W-6 PUFA) not more than 0.5-1 gm/kg/day Proteins 1.5-2gm/kg/day Vitamins, minerals and trace elements

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The enterocyte requires glutamine for cell differentiation and division. The early institution of a glutamine-supplemented enteral diet may play an important role in maintaining the gut mucosal barrier function and preventing bacterial translocation The institution of enteral nutrition within 36 hours of admission to the ICU has been shown to reduce infectious complications in critically ill patients In a small randomized, prospective pilot study, Angstwurm et al. [71] demonstrated an improvement in clinical outcome in patients with SIRS who received selenium replacement

Selective decontamination of digestive tract (SDD) : 

Selective decontamination of digestive tract (SDD) Prevents bacterial translocation Involves the use of nonabsorbable and intravenous antibiotics Despite the publication of more than 50 controlled trials, it remains a controversial subject Most individual studies, however, have shown no effect on mortality, but meta-analyses suggest a 10% overall reduction in mortality

And lastly, rather most importantly-Organ support : 

And lastly, rather most importantly-Organ support Lungs -Mechanical ventilation Kidneys -Renal replacement therapy CVS -Dopamine, dobutamine, IABP CNS – supportive care Liver – supportive care, liver assist devices Hematology - transfusions

At the end of the day… : 

At the end of the day… We should always be able to identify the worsening features at the earliest and intervene We should not have a hopeless attitude towards patients having various organ involvement Critical care can be truly rewarding if the principles are followed diligently….. ------------------- Thank you all