CCM presentation The forgotten area in ICU …………..Fertility?

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


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)




Hepatotoxic drugs


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 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




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 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



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


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

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CCM presentation The forgotten area in ICU …………..Fertility?