multiple organ failure in cirrhotic patients is a very important topic to understand especially for the internist and Gastroenterology specialties

1. Multiple Organ Dysfunction inMultiple Organ Dysfunction in
cirrhoticscirrhotics
Acute-on-chronic liver failure
prof.prof.
RAED MANSOUR, MDRAED MANSOUR, MD

2. ILO,S
 In this topic we review :
 The prevalence, risk factors, and pathogenesis
of MOF in cirrhosis.
 BT and ways to prevent infections & ameliorate
the hyperdynamic circulatory state of cirrhosis.
 CP and management of (SBP),
 Role of alb., & antibiotics in the prophylaxis
of high-risk patients.

3.  SIRS, sepsis, and multiorgan failure.
 The role of adrenal insufficiency.
 Utility of intensive care prognostic models
ILO,S

4. ACLF was defined as a syndrome characterized
by AD of cirrhosis
associated to organ failure (OF)
and high short-term mortality rate
(28-day mortality rate 30–40%)
Definition

5. Introduction
 Bacterial infections account for significant morbidity
and mortality in cirrhotic hospitalized patients.
 Cirrhotic pt. are predisposed to infection due to an
impaired immune function together with an increased
passage of bacteria from the gut [BT]
 that is facilitated by altered intestinal immunity & IBO.

6. ACLF occurs in relation to systemic inflammation,
 Systemic inflammation may cause ACLF
through complex mechanisms including:
an exaggerated inflammatory response &
systemic oxidative stress to pathogen

7. Systemic inflammation as a cause of ACLF
 WBC count and plasma (CRP) levels are higher
in patients with ACLF than in those without,
Plus
 The higher white count or CRP levels the higher
the number of failing organs.

8. SIRS-Sepsis-MODSSIRS-Sepsis-MODS
SpectrumSpectrum
 BT (without overt infection) leads to a worsening
in the hemodynamic status of advanced cirrhosis.
 Once an overt infection occurs, it may lead to
systemic inflammatory response syndrome
(SIRS)/sepsis
 SIRSSIRS
 SepsisSepsis
 Severe SepsisSevere Sepsis
 Septic ShockSeptic Shock
 MODSMODS

9. Thus
 Prophylaxis, early recognition, and
rapid management of bacterial
infections and their complications
are essential to improve patients’
survival.

10. BACTERIAL INFECTIONS IN CIRRHOSIS
 The most common bacterial infections are:
SBP (25%),
(UTI) (20%), &
pneumonia (15%).

11.  GI bleeding and the severity of liver
disease, as reflected by the serum
albumin and the Child-Turcotte-Pugh
(CTP) score
are independent predictors of
bacterial infections in patients
with cirrhosis

12.  The main etiologies for ACLF are:
Alcoholism in 60%, hepatitis C in 13% ,
Alcoholism plus hepatitis C in 10% .
Only 5% due to cirrhosis associated with HBV.

13. CLIF-C OFs,
CLIF-C AD, and
CLIF-C ACLFs,
Designed for patients with AD, with and without
ACLF, allows a step-wise algorithm for therapy.
Scoring system for ACLF composed of 3 scores:

14.  The sequential Organ Failure Assessment (SOFA)
Scale was the model selected for the diagnosis of
organ failure & is superior to the Child-Pugh and
MELD score in predicting mortality in patients
with cirrhosis and (OF).

15.  Treatment of ACLF should be carried out in ICU.
 Therapeutic measures involve the treatment for
complications, organ failures support and LT.

16.  OF in patients with ACLF:
renal failure (56%), followed by liver 44%,,
coagulation 28%,, cerebral 24%,,
circulatory 17%,
&
respiratory failures 9%.

17. Some patients develop ACLF
in the absence of any special trigger.
Mortality was independent of the presence and
type of precipitating events.

18. Pathogenesis:
IMMUNE DYSFUNCTION (ID)
ID in cirrhotic is multi-factorial:
 Decrease in bactericidal activity by phagocytic cells
 low complement levels which are critical in
bacterial phagocytosis, mainly in cirrhosis with
ascites.
 Cirrhosis is accompanied by an impaired (RES),
the main defensive system against bacteremia.

19.  RES activity is impaired because of
portosystemic shunting that bypasses the liver
(escaping the action of the RES) & because of
impaired Kupffer’s cell phagocytic activity.
plus
 Failure to clear other bacterial products such
as endotoxins and cytokines.

20. BT IN CIRRHOSIS
 In cirrhosis, enteric gram-v bacteria (E coli) are
more commonly isolated in SBP& UTI,
 Gram+v bacteria are more likely in pneumonia.
 Importance of gram+v pathogens increases in
norfloxacin prophylaxis and invasive procedures

21. BT
BT is the migration of bacteria or
bacterial products
(lipopolysaccharides [LPS]& endotoxins)
from the lumen of the intestine to
extra-intestinal sites such as
the mesenteric lymph nodes (MLN).

22.  The hyperdynamic circulatory state in
cirrhosis associated with splanchnic &
systemic VD, increased COP, and
decreased mean arterial pressure.
Is responsible for variceal growth,
Ascites & (HRS).

23. Mechanisms in the development of bacterial
infections, sepsis, and MOF in cirrhosis.

24.  anaerobic bacteria rarely translocate &
responsible for <1% of bacterial infections
in cirrhosis.

25. MARKERS OF BT IN HUMANS
 One of them is:
 Serum lipopolysaccharide binding protein (LBP),
a protein with a relatively long half-life
synthesized by the liver in response to
bacteremia or endotoxemia.

26.  Patients with elevated LBP levels have a lower
mean arterial pressure, lower systemic vascular
resistance and marked activation of
compensatory hormones (renin, aldosterone),
proinflammatory cytokines
(TNF-a, interleukin- [IL-]) & NO levels.

27.  another potential marker of BT
 Bacterial DNA (b DNA) in biological fluids
 Cirrhotic with ascites and positive bDNA
have more hemodynamic alterations than
those without bDNA

28. MECHANISMS OF BT
 Several factors contribute to BT including:
 Intestinal bacterial overgrowth (IBO),
 Increased intestinal permeability,
 & immune dysfunction.

29. Intestinal Bacterial Overgrowth (IBO)
 IBO is an important factor promoting BT.
 IBO, determined by hydrogen breath tests,
is more common in cirrhotic patients than in
controls, especially in those with CTP B/C
or a previous history of SBP.

30.  Delayed small bowel transit, a major factor in
the pathogenesis of IBO & is more common in
patients with cirrhosis as compared with controls
and improves after LT.

31. Increased Intestinal Permeability
 The structural alterations in cirrhotic patients
(vascular congestion, edema, & inflammation)
may lead to an increase in intestinal permeability.
 This is likely multifactorial, related to
Oxidative damage, endotoxemia, and an increase
in the synthesis of cytokines and NO.

32. Decreased Immunity
 Impaired innate immune system in cirrhotic
patients due to a reduction in phagocytosis,
opsonization capacity, and complement levels.
plus
 Impairment in the adaptive immune response
such as reduced numbers and impaired
activation of T-cells & a reduction in IgA levels
may play a role in the spread of intestinal
bacteria to extraintestinalsites.

33. MEASURES TO DECREASE BT
 Inhibition of BT can be achieved by:
 (1) eliminating gram-v organisms from the gut
(oral nonabsorbable or poorly absorbed
antibiotics,
‘‘selective intestinal decontamination’’(SID),
(2) by changing the composition of gut bacterial
flora using pre/probiotics or bile acids; &
(3) by accelerating intestinal transit (prokinetics or BB)

34. Spontaneous Infections in Cirrhosis SBP

35. SBP TREATMENT
 The mortality of SBP was 90%;
 with early recognition of SBP & prompt antibiotic
therapy, mortality has been reduced to 15 - 20%.
 Since renal insufficiency is the most important
predictor of mortality in SBP,
large vol. paracentesis, diuretic, & nephrotoxins
should be avoided during acute infection.

36.  Cefotaxime 2 g (I.V.) every 12 hours.
Ceftriaxone 1 g I.V. every 12 to 24 hours.
 Amoxicillin/clavulanate may give similar results
 ‘‘uncomplicated’’ SBP
(No : septic shock, grade 2 to 4 (HE), ileus,
GI bleeding ,or creatinine >3 g/dL)
may be treated with oral ofloxacin.

37.  Albumin improves cirrhotic hemodynamics by:
 In addition to plasma expansion & an increase
in the cardiac preload, it binds VD substances
& cytokines and has an antioxidant effect.
 Albumin is administered at a dose of 1.5 g/Kg
I.V. at diagnosis and 1 g/Kg I.V. on day 3 of
therapy but the optimal dose is unknown.

38. SBP PROPHYLAXIS
 prophylaxis is based on SID, mainly through the
use of oral norfloxacin.
 associated with quinolone and trimethoprim
sulfamethoxazole Resistance
 restricted to those at the highest risk of SBP.

39. Hospitalized Patients with GI bleeding
 5 to 7 days antibiotic prophylaxis in cirrhotic
patients presenting with a GI hemorrhage.

40. Patients with an Ascites Protein <1 g/dL
 Patients with low ascitic protein levels
(<1 g/dL) are at an increased risk of SBP

41. Patients Recovered from an Episode of
SBP
 1-year probability of recurrent SBP of 70% and a
1-year survival of 30 to50%.
 significant reduction in SBP recurrence with
norfloxacin 400 mg once daily.

42. SIRS AND SEPSIS IN CIRRHOSIS
 SIRS is defined as two or more of the following:
Temp. >38.8 C or <36.8 C;
HR >90 beats per minute;
RR >20 breaths per minute or
PaCO2 <4.3 kPa;
TLC >12x109/L or <4109/L, or
the presence of >10% immature neutrophils.
Sepsis refers to SIRS associated with a confirmed
bacterial infection (i.e., positive bacteriological culture).

43.  Severe sepsis represents a more marked
imbalance ,with evidence of OD, hypoperfusion,
or hypotension that responds to intravascular
volume loading alone.
 Septic shock is sepsis associated with
hypotension refractory to IV volume loading,
associated with perfusion abnormalities, &
requiring inotropes

44. Pathogenesis
 ‘‘immune paralysis’’ in decompensated cirrhosis.
Immune paralysis is an established entity defined
as a reduction in monocyte human leukocyte
antigen–DR (HLA-DR) expression and therefore
an impairment in LPS-stimulated proinflammatory
cytokine production (IL-1, IL-6, IL-8, TNF-a).
 The correlation of immune paralysis with the
severity of sepsis has been well established.

45. CIRCULATORY ABNORMALITIES, SEVERE
SEPSIS, AND SEPTIC SHOCK,….. the difficulty
 Diagnosis of SIRS, sepsis,or severe sepsis may
be difficult in a patient with advanced cirrhosis
because of baseline hypotension secondary to the
hyperdynamic circulatory state, a reduction in
neutrophil counts secondary to hypersplenism, &
an elevated RR due to HE.

46. RENAL FAILURE
 RF with bacterial infection, but in the absence of
septic shock, is diagnostic of HRS.
 RF in the setting of Infection is related to decline
splanchnic and systemic VD leading to a further
decrease in effective arterial blood vol., with
activation of (renin-angiotensin-aldosterone)
system that leads to renal vasoconstriction & RF.

47.  The administration of albumin results in a
reduction in renal impairment and reduced
in-hospital mortality.

48. ENCEPHALOPATHY
 ‘‘sepsis-associated encephalopathy’’ is
linked to the production of reactive oxygen
species, the direct effect of inflammatory
cytokines on cerebral endothelial cells,
astrocytes and vagal afferents, and a
reduction in cerebral blood flow.

49. COAGULOPATHY
 Coagulation abnormalities in cirrhosis are
attributed to a reduction in the hepatic synthesis
of factors VII, V, X and prothrombin, lack of vit.
K plus quantitative & qualitative platelet defects.
 Coagulation abnormalities are greater in cirrhotic
patients with sepsis, perhaps as a result of more
severe liver dysfunction.

50. ARDS
 (ARDS) refers to hypoxia and bilateral
radiographic infiltrates in the absence of an
elevated left atrial pressure.
 Association between cirrhosis & ARDS has been
linked to an increase in serum cytokines, NO,
and pulmonary leukotrienes

51. DEATH
 Once infection develops, RF, shock, and HE may
follow, which adversely affect survival.
 The in-hospital mortality of cirrhotic patients with
infection is 15%.
 Infection is responsible for 30% of deaths in
cirrhosis

52. Prognostic Models for Cirrhotic Patients
Admitted to the ICU
 Various scoring systems have been proposed but
few have been validated in patients with cirrhosis
and SIRS/sepsis:
 There are liver-specific models such as MELD
score, CTP score, and general prognostic models
such as the APACHE II and III, the organ system
failure (OSF), and the sequential organ failure
assessment (SOFA)

53.  The ideal scoring system is the one that
will predict death early enough so that
measures can be instituted that will
improve survival.

54. Relative Adrenal Insufficiency
 Cortisol is a stress hormone produced by the
hypothalamic-pituitary-adrenal axis in
response to physiologic stress & critical
illness.
 In non cirrhotic patients with septic shock,
insufficient cortisol production results in
increased mortality, and blunted response to
vasoconstrictors.

55.  The administration of stress dose steroids
improves survival and systemic hemodynamics.
 Similar results have been obtained in critically
ill cirrhotic patients with sepsis.

56.  Independent predictors of adrenal insufficiency
included:
serum bilirubin, bacteremia, vasopressor
dependency, and mean arterial pressure

57. Management
 ANTIBIOTICS
 Antibiotics are the core of therapy for sepsis in
cirrhotic patients.
 In case of non response, repeat cultures.

58. ALBUMIN
 I.V. in patients with cirrhosis and SIRS/sepsis,
particularly in patients with evidence of renal
dysfunction and jaundice
 (i.e., those with acute-on-chronic liver failure).

59.  dose of 1 g/Kg of body weight on the first day
(up to a maximum of 100 g),
followed by 20 to 40 g/day in the setting of HRS.
 Albumin should accompany the use of
vasoconstrictors.

60. VASOCONSTRICTORS
 RF that occurs in the setting of ongoing
bacterial infection, but in the absence of septic
shock, should be considered HRS and treated
as such without waiting for complete recovery
from the infection.

61.  Vasoconstrictors such as terlipressin and
octreotide and midodrine all in combination
with albumin have demonstrated an improvement
in renal function in HRS.

62. Site of action of different
therapies

63. HYDROCORTISONE
 I.V. hydrocortisone (50 mg every 6 hours) to
patients with relative adrenal insufficiency
resulted in hemodynamic improvement, &
increased ICU and in-hospital survival rates.

64.  steroid treatment is not without caution
as 2/25 patients treated with
hydrocortisone developed invasive
fungal infections.

65. SUMMARY
 Bacterial infections causes morbidity & mortality in
cirrhotic through relative immunocompromised state.
 BT plays a major role in the pathogenesis of infections
and in the hyperdynamic circulatory state of cirrhosis.
 Hemodynamic alterations worsen with the progress to
overt infection and can progress to severe sepsis and
septic shock.

66.  Endotoxin ,cytokines, and NO are key elements in the
pathogenesis of circulatory error in cirrhosis &sepsis.
 Early diagnosis and prompt treatment of SBP and
other infections can reduce morbidity and improve
survival.
 Antibiotic prophylaxis is indicated in GI bleeding & in
those who have recovered from an episode of SBP.

67.  infection can lead to a SIRS and MOF.
 In these patients treatment is mainly directed at
treating the infection and circulatory abnormalities
with the use of antibiotics, vasoconstrictors, and alb.
 As critically ill septic cirrhotic have a poor prognosis it
will be vital to use prognostic models to better identify
when further care is useless as well as identify optimal
timing and outcomes of LT.

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