CCM presentationThe forgotten area in ICU…………..Fertility?Dr. HK Tsang
TMH ICU Resident
Case presentation
55/F Housewife Exsmoker and non drinker Lives with family, ADLI
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
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
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
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 residue+Previous 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
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
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
Past medical history
Xylose absorption test borderline normal 5 days stool x Alpha antitrypsin clearance
study in QMH 18 (NR <13) Suggestive of Protein losing enteropathy
Albumin scan and small bowel enema scheduled 04/08
History of present illness Admitted 4/4/08 for decreased GC x 1/52
Irrelevant speech+bizarre behaviour in recent 2-3 days Confused on admission Cough with sputum+SOB No fever all along Cachexic++
WCC 26 (Neutrophil predominent) CXR: RUZ pneumonic changes Mx as CAP with Rocephin & zithromax
Resp failure and intubated
History of present illness Tracheal aspirate
C/ST, TB PCR, AFB smear, Influenza/parainfluenza: neg Urine x Legionella Ag neg Mycoplasma <10 Blood x C/ST: neg
TPN 5/4/08 Clinomel NT 1000
Clinically improved with good ventilation & oxygenation Sedation off 07/4/08 Remained comatose>48hrs ?Reason
?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
What’s the next Ix?
CT brain: mild cerebral atrophy EEG: episodic frontal prominent sharp and slow waves,
non specific encephalopathy LP unremarkable
Reasons of coma
A blood test was performed
Reasons of coma
Reasons of coma
Coagulation profile normal USG abd: No evidence of cirrhosis
History Stopped and given patient some Px
Extubated 11/04/08 Sitting out, watching TV ?Happy ending
History Sudden ↑SOB 12/04/08 ECG
TnI 9 Cardiac arrest and failed CPR
The forgotten area in ICU……Fertility?Hyperammonemia in the ICU
Ammonia and fertility
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; 132:1368–1378)
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
The urea cycle
3 mechanisms of hyperammonemia1. Capacity of the normal liver to metabolize ammonia is overcome
Ammonia production > Metabolic capacity of the liver
2. Ammonia bypassing the liver Congenital AVM in liver, portal hypertension in cirrhosis
3. Liver is unable to metabolize ammonia Acute liver failure, cirrhosis
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)
Causes of hyperammonemia
Causes of hyperammonemia
Fulminant liver failure Drugs IEM Infection Idiopathic
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)
Causes of hyperammonemia
Fulminant liver failure Drugs IEM Infection Idiopathic
Causes of hyperammonemia
Hepatotoxic drugs
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
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
Causes of hyperammonemia
Fulminant liver failure Drugs IEM Infection Idiopathic
Causes of hyperammonemia
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
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
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
Causes of hyperammonemia
Fulminant liver failure Drugs IEM Infection Idiopathic
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
Causes of hyperammonemia
Fulminant liver failure Drugs IEM Infection Idiopathic
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 > 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
Pathophysiology of hyperammonemic encephalopathy
Astrocytes support adjacent neurons with ATP, glutamine, cholesterol
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
Pathophysiology of hyperammonemic encephalopathyWhen 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
↑
Pathophysiology of hyperammonemic encephalopathy
X
Decreased expression of glutamate receptors in astrocytes cause ↑ concentrations of glutamate & seizures
NH3
↑↑GLU
End result1. Cerebral blood flow ↑2. Cerebral autoregulation lost3. Cerebral edema4. ↑ICP5. Herniation6. Death
GLN: GlutamineGLU: Glutamate
Clinical feature
Acute hyperammonemia Cerebral edema, herniation &
seizures Usually occur only when
arterial NH3 are > 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
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 <1hr in 4°C) 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; 29:648–653Am J Med 2003; 114:188–193
Gastroenterology 2001; 121:1109–1119J Cereb Blood Flow Metab 2006; 26:21–27
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
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
Diagnosis of the cause of hyperammonemia
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 &
kidneyJ Clin Gastroenterol 2005; 39:S147–S157
Management of Hyperammonemia2. N-acetylcysteine
May reduce cerebral edema & cerebral metabolism Beneficial even in the absence of acetaminophen toxicity
Semin Liver Dis 2003; 23:271–282
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
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
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
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
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
Management of Hyperammonemia
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
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
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
Our case TPN feeding stopped Given some Px: Neomycin and lactulose
Extubated 11/04/08 Died of AMI 12/04/08
Our case
Our case
Our case
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)
Our case: Cause of coma
Zn deficiency
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
Take home message Comatose patient with normal LFT
Consider hyperammonaemic encephalopathy Common causes in ICU: TPN, drugs Ix and Novel management
The END