CCM presentation The forgotten area in ICU

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CCM presentationThe forgotten area in
ICU..Fertility?

• Dr. HK Tsang
• TMH ICU Resident

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Case presentation

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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?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

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Whats the next Ix?

• CT brain mild cerebral atrophy
• EEG episodic frontal prominent sharp and slow
  waves, non specific encephalopathy
• LP unremarkable

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Reasons of coma

• A blood test was performed

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Reasons of coma
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Reasons of coma

• Coagulation profile normal
• USG abd No evidence of cirrhosis

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History

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

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History

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

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The forgotten area in ICUFertility?Hyperammonem
ia in the ICU
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Ammonia and fertility
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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)
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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

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The urea cycle
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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

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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)

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Causes of hyperammonemia
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Causes of hyperammonemia

• Fulminant liver failure
• Drugs
• IEM
• Infection
• Idiopathic

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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)

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Causes of hyperammonemia

• Fulminant liver failure
• Drugs
• IEM
• Infection
• Idiopathic

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Causes of hyperammonemia
Hepatotoxic drugs
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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

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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

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Causes of hyperammonemia

• Fulminant liver failure
• Drugs
• IEM
• Infection
• Idiopathic

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Causes of hyperammonemia
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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

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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

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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

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Causes of hyperammonemia

• Fulminant liver failure
• Drugs
• IEM
• Infection
• Idiopathic

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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

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Causes of hyperammonemia

• Fulminant liver failure
• Drugs
• IEM
• Infection
• Idiopathic

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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

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Pathophysiology of hyperammonemic encephalopathy
Astrocytes support adjacent neurons with ATP,
glutamine, cholesterol
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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
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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
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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
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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

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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

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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

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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

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Diagnosis of the cause of hyperammonemia
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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

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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

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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

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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

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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

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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

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Management of Hyperammonemia
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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

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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

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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

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Our case

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

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Our case
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Our case
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Our case
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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)

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Our case Cause of coma

• Zn deficiency

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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

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Take home message

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

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The END