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

CCM presentation The 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

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

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  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 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

  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 <13) • 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 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

  11. 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

  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. What’s 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 ICU……Fertility?Hyperammonemia 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; 132:1368–1378)

  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 > 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 > 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. 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 Clinical feature

  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 <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; 29:648–653 Am J Med 2003; 114:188–193 Gastroenterology 2001; 121:1109–1119 J Cereb Blood Flow Metab 2006; 26:21–27

  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

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