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CCM presentation The forgotten area in ICU

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CCM presentation The forgotten area in ICU ..Fertility? Dr. HK Tsang TMH ICU Resident Our case Our case: Cause of coma Hyperammonaemic encephalopathy ... – PowerPoint PPT presentation

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Title: CCM presentation The forgotten area in ICU


1
CCM presentationThe forgotten area in
ICU..Fertility?
  • Dr. HK Tsang
  • TMH ICU Resident

2
Case presentation
  • 55/F
  • Housewife
  • Exsmoker and non drinker
  • Lives with family, ADLI

3
Past medical history
  • Migraine 1982 on aspirin OTC
  • GIB with partial gastrectomy 97 in private
  • Hx of pancreatitis 2001 with Ix in private
  • Stagnant Loop syndrome 2007

4
Past medical history
  • Stagnant loop syndrome 2007
  • Presented with diarrhoea x 3/12
  • BO 3-5x/day
  • No Mucus/PR bleeding/tenesmus
  • Subjective weight loss for few lbs
  • Abd distension
  • Ankle edema

5
Past medical history
  • Initial Ix
  • Albumin 17, ALP 200, ALT 53, normal bilirubin
  • 24hr urine TP 0.3g/d
  • Stool
  • WCC/RBC/Ova and cyst/C/ST/fat globulin/FOB neg
  • Blood
  • Hepatitis serology, CMV pp65 neg
  • Autoimmune markers/Ig pattern/AnitSM/AMA neg
  • Tumour markers normal
  • TSH normal

6
Past medical history
  • Colonoscopy 11/07 colitis from transverse colon
    downward
  • Histology lymphocytic infiltrate, no
    cryptitis/crypt abscess/viral inclusion/malignancy
  • CT abd gross ascites and thickened colonic wall
    suggestive of colitis
  • OGD Food residuePrevious BII with clear base GU
  • Bx active chronic inflammation, no villus
    atrophy
  • Duodenal aspiration AFB smear neg, heavy growth
    of GB/GN bacilli (Aeromonas caviae, E.Coli,
    Enterococcus, Bacteroides)
  • Imp
  • Bacterial overgrowth
  • Aspirin induced lymphocytic colitis
  • dLFT secondary to poor nutrition and starvation
    or PSC secondary to IBD
  • Given ciproxin and flagyl? symptoms improved

7
Past medical history
  • Progressive dLFT with TB 39, ALP 400, ALT 80
  • ERCP 01/08 Previous B II with small gastric
    remnant. Tight stricture over afferent loop and
    unable to pass through it

8
Past medical history
  • Private MRCP 20/01/08 Small GS, IHD not dilated
  • Liver bx 31/1/08 bile duct proliferation ?bile
    duct obstruction?PSC variant
  • Colonoscopy 2/08 NAD
  • Bx from terminal ileum villous atrophy, colonic
    bx non specific inflammation
  • Push enteroscopy 02/08 Moderate villous atrophy
    and giardia neg

9
Past medical history
  • Xylose absorption test borderline normal
  • 5 days stool x Alpha antitrypsin clearance study
    in QMH 18 (NR lt13)
  • Suggestive of Protein losing enteropathy
  • Albumin scan and small bowel enema scheduled
    04/08

10
History of present illness
  • Admitted 4/4/08 for decreased GC x 1/52
  • Irrelevant speechbizarre behaviour in recent 2-3
    days
  • Confused on admission
  • Cough with sputumSOB
  • No fever all along
  • Cachexic
  • WCC 26 (Neutrophil predominent)
  • CXR RUZ pneumonic changes
  • Mx as CAP with Rocephin zithromax
  • Resp failure and intubated

11
History of present illness
  • Tracheal aspirate
  • C/ST, TB PCR, AFB smear, Influenza/parainfluenza
    neg
  • Urine x Legionella Ag neg
  • Mycoplasma lt10
  • Blood x C/ST neg
  • TPN
  • 5/4/08 Clinomel NT 1000
  • Clinically improved with good ventilation
    oxygenation
  • Sedation off 07/4/08
  • Remained comatosegt48hrs ?Reason

12
?Reasons of coma
  • C-CO2 narcosis
  • O-Overdose of medications/Sedations
  • M-Metabolic Hypoglycaemia, DKA, hypothyroidism,
    hypercalcaemia, adrenal failure, uraemia, hepatic
    coma
  • A-Apoplexy HI, CVA, ICH, CNS infection, epilepsy

13
Whats the next Ix?
  • CT brain mild cerebral atrophy
  • EEG episodic frontal prominent sharp and slow
    waves, non specific encephalopathy
  • LP unremarkable

14
Reasons of coma
  • A blood test was performed

15
Reasons of coma
16
Reasons of coma
  • Coagulation profile normal
  • USG abd No evidence of cirrhosis

17
History
  • Stopped and given patient some Px
  • Extubated 11/04/08
  • Sitting out, watching TV
  • ?Happy ending

18
History
  • Sudden ?SOB 12/04/08
  • ECG
  • TnI 9
  • Cardiac arrest and failed CPR

19
The forgotten area in ICUFertility?Hyperammonem
ia in the ICU
20
Ammonia and fertility
21
Ammonia Production
  • Mostly from gut
  • Byproduct of digestion of nitrogenous components
    of the diet
  • Deamination of glutamine by glutaminase
  • Breakdown of urea by urease present in colonic
    flora
  • Kidney
  • Synthesized from glutamine in the proximal tubule
    concentrated in the medullary interstitium
  • Release into systemic circulation
  • Facilitate the excretion of protons
  • Increased in GIB
  • Muscle
  • In seizures or intense exercise

(CHEST 2007 13213681378)
22
Ammonia Degradation
  • Liver
  • Metabolized to urea through the urea cycle
  • If liver fails or inadequate
  • Kidney
  • Decreased NH3 production
  • Muscle Brain
  • Metabolise NH3 to glutamine

23
The urea cycle
24
3 mechanisms of hyperammonemia
  • Capacity of the normal liver to metabolize
    ammonia is overcome
  • Ammonia production gt Metabolic capacity of the
    liver
  • Ammonia bypassing the liver
  • Congenital AVM in liver, portal hypertension in
    cirrhosis
  • Liver is unable to metabolize ammonia
  • Acute liver failure, cirrhosis

25
Causes of hyperammonemia
  • Hepatic causes
  • Acute fulminant hepatic failure/ chronic liver
    disease
  • Precipitating factors
  • GIB, constipation, electrolyte abnormalities,
    high protein diet
  • Non-hepatic causes
  • Drug-associated (e.g. Valproate, 5FU,
    cyclophosphamide salicylates)
  • Inborn errors of metabolism (Urea cycle or fatty
    acid oxidation)
  • Porto-systemic shunts (Weber Rendu Osler disease)
  • Urinary tract infection with urease-producing
    bacteria (e.g. Proteus mirabilis)

26
Causes of hyperammonemia
27
Causes of hyperammonemia
  • Fulminant liver failure
  • Drugs
  • IEM
  • Infection
  • Idiopathic

28
Causes of hyperammonemia
  • Fulminant hepatic failure is the most common
    cause of acute hyperammonemia in adult ICUs
  • Most common causes
  • Acetaminophen toxicity
  • Drug reactions
  • Viral hepatitis (A or B)
  • Idiopathic
  • Other causes
  • Infections (eg, the hepatitides, varicella,
    Epstein-Barr virus CMV)
  • Autoimmune diseases
  • Vascular diseases (eg, Budd-Chiari
    venoocclusive disease)
  • Pregnancy-related (eg, acute fatty liver of
    pregnancy, eclampsia)
  • Toxins (eg, mushrooms and herbs)

29
Causes of hyperammonemia
  • Fulminant liver failure
  • Drugs
  • IEM
  • Infection
  • Idiopathic

30
Causes of hyperammonemia
Hepatotoxic drugs
31
Causes of hyperammonemia
  • Several drugs cause hyperammonemia by disrupting
    the urea cycle
  • Glycine stimulates ammonia production
  • Salicylates can reduce mitochondrial function in
    the liver e.g. Reye syndrome
  • Carbamazepine, ribavirin, sulfadiazine with
    pyrimethamine Mechanisms not known

32
Causes of hyperammonemia
  • Valproate may rarely cause hyperammonemic coma
  • In chronic dosing
  • Asymptomatic hyperammonemia occurs in 50 of
    patients
  • Chronic use leads to carnitine deficiency,
    impairs urea cycle
  • In healthy patients
  • Overdose increases propionic acid levels, which
    inhibit mitochrondrial CPS
  • In heterozygote females with asymptomatic OTC
    deficiency, therapeutic doses of valproate may
    also cause acute hyperammonemia

33
Causes of hyperammonemia
  • Fulminant liver failure
  • Drugs
  • IEM
  • Infection
  • Idiopathic

34
Causes of hyperammonemia
35
Causes of hyperammonemia
  • Inborn errors of metabolism (IEM)
  • Most common UCDs in adults
  • OTC deficiency (X-linked), ASS deficiency(AR),
    and carbamyl phosphate deficiency(AR)
  • Hyperammonemia is most severe when the enzyme
    defect occurs in the early steps of the urea
    cycle (eg OTC deficiency)
  • Clinical presentations of different IEM are quite
    similar
  • In the fulminant form, coma and encephalopathy
  • In the milder forms, intermittent periods of
    confusion or bizarre behavior, presumably from
    hyperammonemia
  • May present in adulthood when unmasked by
    precipitants

36
Causes of hyperammonemia
  • Inborn errors of metabolism (IEM)
  • Physiologic stressors that provoke hyperammonemia
  • Infection urease-splitting organisms, URI or
    pneumonia
  • Dietary changes
  • Fever
  • Pregnancy
  • GI bleeding
  • Insults to the liver, eg alcohol or acetaminophen
  • TPN
  • Provides more protein than consumes enterally
  • Provoked hyperammonemia in many patients with
    UCDs, most often OTC
  • The presence of hyperammonemia following TPN
    should prompt an investigation of a UCD

37
Causes of hyperammonemia
  • Inborn errors of metabolism
  • Other presentations
  • Seizure disorders, including complex partial
    seizures
  • A history of repetitive or cyclical vomiting
  • Intellectual limitations
  • Prolonged clinical course with a seemingly
    routine illness
  • Family history of early infant mortality
  • Voluntarily limit their protein intake (called
    auto-vegetarianism) to avoid postprandial
    headaches or somnolence
  • Patients with citrullinemia (ie, ASS deficiency)
    often have a history of preferring beans, provide
    arginine which is an essential amino acid in
    these patients

38
Causes of hyperammonemia
  • Fulminant liver failure
  • Drugs
  • IEM
  • Infection
  • Idiopathic

39
Causes of hyperammonemia
  • Urea splitting urinary tract infection
  • Urea splitting organism e.g. Proteus mirabilis,
    Pseudomonas aeruginosa, Klebsiella
  • Cause rise in urine ammonia conc
  • Prerequisite of hyperammonaemia
  • Distended bladder with large surface area for NH3
    diffusion e.g.bladder or pouch retention
  • Diffusion facilitated by alkaline urine

40
Causes of hyperammonemia
  • Fulminant liver failure
  • Drugs
  • IEM
  • Infection
  • Idiopathic

41
Causes of hyperammonemia
  • Idiopathic hyperammonemia (IHA)
  • Elevated ammonia levels are disproportionate to
    liver dysfunction in the absence of an inherited
    metabolic disorder
  • A complication of intensive chemotherapy in
    leukemia
  • Also found in patients
  • Undergoing bone marrow transplantation
  • Solid tumors treated with continuous infusions of
    5-fluorouracil
  • After lung transplantation
  • Mortality rate gt 75
  • The incidence is unknown ? 0.5 to 2.4
  • The etiology of IHA is not known
  • ?Transient abnormalities in urea synthesis
  • Increased production of ammonia from tissue
    breakdown, mucositis, and GI bleeding

42
Pathophysiology of hyperammonemic encephalopathy
Astrocytes support adjacent neurons with ATP,
glutamine, cholesterol
43
Pathophysiology of hyperammonemic encephalopathy
  • The neuron metabolizes glutamine to glutamate
  • a neurotransmitter that activate NMDA receptors
  • After release into the synapse, glutamate is
    recycled by the astrocyte to glutamine

NH3
GLN Glutamine GLU Glutamate
44
Pathophysiology of hyperammonemic encephalopathy
  • When ammonia levels?
  • acutely within the brain,
  • astrocytes rapidly metabolize
  • ammonia to glutamine
  • ??in intracellular osmolarity
  • ? astrocyte swelling loss
  • ? TNF, IL-1, IL-6 interferon are released

?
??NH3
45
Pathophysiology of hyperammonemic encephalopathy
Decreased expression of glutamate receptors in
astrocytes cause ? concentrations of glutamate
seizures
NH3
X
End result 1. Cerebral blood flow ? 2. Cerebral
autoregulation lost 3. Cerebral edema 4. ?ICP 5.
Herniation 6. Death
??GLU
GLN Glutamine GLU Glutamate
46
Clinical feature
  • Acute hyperammonemia
  • Cerebral edema, herniation seizures
  • Usually occur only when arterial NH3 are gt
    200umol/L
  • Elevations of glutamine osmolarity
  • Excitatory effect of glutamine
  • Chronic effect of hyperammonemia on the brain
  • Osmolarity does not rise acutely
  • Down-regulation of NMDA receptors results in less
    neuroexcitation from glutamate
  • NH3 has more of an effect on neuroinhibitory GABA
    receptors

47
Dx Ammonia level in blood
  • Experimentally, at least 85 of liver function
    must be impaired before ammonia starts to
    accumulate
  • Specimen
  • Heparin (Reduce RBC ammonia production)/EDTA
  • Placed on ice (stable lt1hr in 4C) and plasma
    separated within 15mins (NH3 concentrations
    increases spontaneously in standing blood and
    plasma)
  • Arterial NH3 do not correlate with venous NH3
    levels
  • Venous ammonia levels vary locally, e.g. muscle
    contraction
  • Liver is adept at the metabolism of ammonia
  • Acute hyperammonemia may be an exception
  • In fulminant hepatic failure, venous ammonia
    levels correlate with arterial ammonia levels
  • Arterial ammonia levels
  • More accurate assessment of the amount of ammonia
    at the blood brain barrier
  • Correlate with glutamine levels
  • Correlate with the development of Intracranial
    hypertension
  • Hepatology 1999 29648653

48
Diagnosis of the cause of hyperammonemia
  • Initially focus on fulminant hepatic failure
  • LFT coagulation tests, acetaminophen levels,
    alcohol/drug toxicology, viral serologies for the
    hepatitides
  • Medication social history to rule out
    drug-induced acute liver failure
  • Ultrasound to rule out portal vein thrombosis and
    fatty infiltration
  • Abdominal CT scanning may be helpful
  • The presence of infection, increased protein
    catabolism, or drug administration should be
    evaluated
  • For comatose patients
  • CT brain
  • EEG
  • continuous generalized slowing, predominance of
    theta delta activity
  • occasional bursts of frontal intermittent
    rhythmic delta activity
  • triphasic wave

49
Diagnosis of the cause of hyperammonemia
  • Workup for IEM if hyperammonemia cannot be
    explained
  • Elevations of transaminase levels indirect
    bilirubin levels, coagulopathy, respiratory
    alkalosis, metabolic acidosis (High AG)
  • Quantitative plasma and urine amino acids
    (citrulline, argininosuccinic acid, and
    glutamine)
  • Urine organic acid analysis, urine orotic acid,
    carnitine
  • Liver biopsy should be considered
  • Mutation analysis utilizing DNA derived from
    blood lymphocytes
  • High frequency of genetic polymorphisms in large
    genes, genetic confirmation of the disease may
    not be possible until the expression of the
    presumed mutations is undertaken

50
Diagnosis of the cause of hyperammonemia
51
Management of Hyperammonemia
  • Initial treatment must focus on the management of
    intracranial hypertension
  • Cerebral edema
  • Decreased cerebral metabolism
  • 1. Hypothermia
  • The least controversial of treatments
  • Decrease free radical production, astrocyte
    swelling, inflammation
  • Improve cerebral blood flow and autoregulation
  • Slows protein catabolism production of ammonia
    by bacteria kidney
  • J Clin Gastroenterol 2005 39S147S157

52
Management of Hyperammonemia
  • 2. N-acetylcysteine
  • May reduce cerebral edema cerebral metabolism
  • Beneficial even in the absence of acetaminophen
    toxicity
  • Semin Liver Dis 2003 23271282
  • 3. Mannitol
  • Reduce cerebral edema improve mortality
  • 4. Dilantin or phenobarbital should be considered
  • 40 of patients have subclinical seizures
  • 5. Indomethacin
  • Reduce inflammation decrease cerebral blood
    flow but may cause renal failure
  • 6. Propofol
  • Seation decrease CBF but harmful in those with
    inadequate CPP

53
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54
Management of Hyperammonemia
  • Other supportive managements
  • Lactulose
  • Osmotic cathartic action
  • Lower colonic pH (bacterial fermentation)
  • promote the growth of non-urease-producing
    lactobacilli
  • No mortality benefit in patients with acute
    hyperammonemia
  • Cochrane review 2004 found non absorbable
    disaccharides seem to reduce the risk of no
    improvement of hepatic encephalopathy but are
    inferior to antibiotics
  • Unlikely to be harmful

55
Management of Hyperammonemia
  • Antibiotics
  • Treat underlying infection prevent
    superinfection
  • Poorly absorbed antibiotics (neomycin)
  • Still absorbed with sufficient amount to cause
    serious adverse (deafness, renal toxicity,
    malabsorption)
  • May enhance clinical response if combined with
    lactulose
  • Alter gut flora, reduce the disaccharide
    metabolizing intestinal bacteria the effect of
    lactulose
  • Consider to stop antibiotics if stool pH
    increased

56
Management of Hyperammonemia
  • Other supportive managements
  • Nutritional support
  • Enough calorie by dextrose and lipids minimal
    daily protein (0.8-1.0g/kg) must be provided to
    prevent protein catabolism
  • May restrict protein temporarily and feed
    enterally
  • Long term protein restriction should be avoided

57
Management of Hyperammonemia
  • Ammonia reducing therapy
  • Renal replacement therapy
  • Peritoneal dialysis, hemodialysis, CVVH, CVVHDF
    CAVHDF
  • effective to remove ammonia
  • helpful in treating hyperammonemia associated
    with urea cycle disorders in children and adults
  • serve as a potential bridge for adults with
    fulminant hepatic failure who are awaiting
    transplantation
  • Sodium phenylacetate and sodium benzoate
  • Promote the degradation of ammonia through
    alternate metabolic pathways
  • Side effects nausea, vomiting, and hypokalemia
  • FDA for hyperammonemic crisis in patients with
    IEMs
  • May prevent the need for dialysis

58
Management of Hyperammonemia
59
Management of Hyperammonemia
  • IV or oral L-ornithine L-asparate (LOLA)
  • Decreased protein breakdown and stimulate protein
    synthesis in muscle
  • RCCT confirmed efficacy in patients with HE
  • S/E nausea, vomiting

60
Management of Hyperammonemia
  • Ammonia reducing therapy
  • L-carnitine
  • Facilitates lipid metabolism
  • Reduce cerebral lactate levels by indirectly
    stimulating pyruvate dehydrogenase
  • Facilitate transport of valporate into
    mitochondria maintaining the ratio of acyl-CoA
    to free CoA in the mitochondria
  • Use in Valproic acid induced hyperammonemic
    encephalopathy
  • Zinc
  • Cofactor for enzymes of urea cycle
  • Deficiency common esp in alcoholic cirrhosis due
    to poor dietary intake, impaired absorption,
    excessive urinary loss
  • Zinc supplement 600mg daily speeds up the
    kinetics of urea formation from amino acids
    ammonia
  • No study performed in ICU setting

61
Management of Hyperammonemia
  • Ammonia reducing therapy
  • Artificial liver support
  • Use extracorporeal blood purification to dialyse
    albumin bound hydrophobic substances
  • Clinical benefit unclear
  • Improve encephalopathy as bridge to transplant
  • Liver transplantation
  • Successful for cirrhosis fulminant hepatic
    failure

62
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63
Our case
  • TPN feeding stopped
  • Given some Px Neomycin and lactulose
  • Extubated 11/04/08
  • Died of AMI 12/04/08

64
Our case
65
Our case
66
Our case
67
Our case Cause of coma
  • Hyperammonaemic encephalopathy secondary to
  • TPN (High protein content)
  • Bacteria overgrowth
  • Hx of BII gastrectomy stagnant bowel loop
    syndrome
  • ?Aspirin intake for migraine (Drugs)
  • ?IEM/UCD (Underlying liver disease)

68
Our case Cause of coma
  • Zn deficiency

69
Take home message
  • C-CO2 narcosis
  • O-Overdose of medications/Sedations
  • M-Metabolic Hypoglycaemia, DKA, hypothyroidism,
    hypercalcaemia, adrenal failure, uraemia, hepatic
    coma
  • A-Apoplexy HI, CVA, ICH, CNS infection, epilepsy

70
Take home message
  • Comatose patient with normal LFT
  • Consider hyperammonaemic encephalopathy
  • Common causes in ICU TPN, drugs
  • Ix and Novel management

71
The END
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