I can breath but not see

1. I can breath but not see Intensive Care Unit Tseung Kwan O Hospital 17 Oct 2009

2. M/55, NSND, travelled to China weekly for work • Atrial flutter > 10 years defaulted FU since 2003 • Admit for on and off fever for 10 days • SOB, cough and sputum • No GI or urinary symptoms • No significant contact history • Family members well • No improvement with zithromax by GP

3. Temp 36.9 BP 172/112 P 133/min • SpO2 90% on 6L/min O2 • RR 40/min • Chest: reduced AE and crepitations over RLZ • CVS: no murmur, abdomen soft, no ankle edmea • ECG: atrial flutter 130/min

4. CXR

5. Transferred to ICU for ventilatory support • Electively intubated for mechanical ventilation • Started empirical rocephin and levofloxacin • NPA for influenza A & B: negative • Urine pneumococal and legionella antigen negative • No positive growth from tracheal aspirate

8. High and fluctuating blood pressure • Agitation requiring different sedation and analgesics

9. Complicated by ARDS with high ventilatory support • IV hydrocortisone started • Slow weaning of mechanical ventilation • Tracheostomy performed on D7 after ICU admission • Noted weakness of 4 limbs after IV sedation and analgesics tailed down on D8 • Tones were flaccid and reflexes were absent

10. How do we approach a weak patient in ICU? • History • Physical examination • Investigations

12. History • Any systemic complications of the underlying disorder or ICU admission • hypoxic brain damage, sepsis, SIRS, metabolic or endocrine abnormalities • Medications used in ICU • Sedation, antibiotics, neuromuscular blockers or steroids • Adequacy of feeding and hydration • Pattern of weakness • Pattern of breathing on attempted weaning • Seizures • Intercurrent events may occur

13. Physical examination • Conscious level and responsiveness • Eyes • Pupils, ocular movement or ptosis • Bulbar function • Neck flexon and shoulder abduction • Coexisting weakness of respiratory muscles and diaphragm • Upper and lower motor types of lesion

14. Investigations • Imaging of brain (CT/MRI) • cerebrovascular accident • toxic encephalopahy • posterior reversible encephalopathy syndrome (PRES) • central pontine myelinolysis • EEG • CSF examination

15. Investigations • Neurophysiological testing of nerve and muscles • Nerve conduction test • Needle EMG • Neuromuscular junction testing • Repetitive nerve stimulation • Single-fiber EMG • Train-of-4 stimulation

16. Normal conduction velocity and compoundmuscle potential. Normal conduction velocity with reduced CMAP amplitude, suggesting axonal neuropathy or axonal loss. Markedly slow conduction with normal CMAP amplitude, consistent with demyelinating neuropathy. Slow conduction with reduced amplitude and temporal dispersion of CMAP on proximal stimulation, signifying conduction block and focal demylination. Resp Care 2009(Sep), Vol 51, 9

17. Neurogenic pattern shows the presence of spontaneously activity, large polyphasic motor-unit potentials and motor interference potentials. The myopathic pattern shows variable spontaneous activity, small polyphasic acitivty and a low amplitude, full interference pattern. Resp Care 2009(Sep), Vol 51, 9

18. Decrement response on low (2 Hz) rate of stimulation. Increment response on 50Hz stimulation. Resp Care 2009(Sep), Vol 51, 9

19. record a pair of muscle fibre action potentials belonging to the same motor unit. Variability in the interspike interval (jitter) and absence (blocking) of second potential is observed. These characterize neuromuscular junction dysfunction. Resp Care 2009(Sep), Vol 51, 9

20. Investigations • Repiratory EMG • Phrenic nerve conduction • Needle EMG of diaphragm • Special techniques • Blink techniques • Direct muscle stimulation • Muscle and nerve biopsy

21. Normal diaphragm compound muscle action potential (CMAP) and reduced amplitude of diaphragm CMAP. Electrode placement for stimulation, ground and recording. Needle EMG recording from diaphragm, showing normal EMG bursts during inspiration. Resp Care 2009(Sep), Vol 51, 9

22. Both the stimulating and recording electrodes are place in the muscle Direct muscle potentials is absent or reduced in myopathy. Direct muscle potentials is normal in neuropathy. Potentials on direct muscle and nerve stimulation are obtained. Resp Care 2009(Sep), Vol 51, 9

25. Clinically compatible with critical illness polyneuropathy • Warfarin and fraxiparine started on D9 in view of history of atrial flutter • Poor recovery of neurological state after IV sedation and analgesics stopped on D13

26. CT brain on D14

27. Warfarin was stopped • Ventilatory support gradually decreased and weaned off ventilator on D20 • Limb power slowly improved • Blood pressure stable around 140/80 • GCS E4VTM4 but did not follow commands • EEG: no epileptic activity

28. Repeat CT brain on D24

29. MRI and MRV brain 4 days later

30. MRI and MRV brain 4 days later

31. What is the cause of poor neurological recovery?

32. PRES • Posterior reversible encephalopathy syndrome (PRES) • Posterior reversible leukoencephalopathy syndrome • Reversible posterior cerebral edema syndrome • Posterior leukoencephalopathy syndrome • Hyperperfusion encephalopathy • Brain capillary leak syndrome • Potentially reversible encephalopathy syndrome

33. PRES • Clinical syndrome of headache, confusion or decreased consciousness, visual changes and seizures • Characteristic neuroimaging findings of posterior cerebral white matter edema • Increasingly recognised and reported since first described in 1996

34. Epidemiology • Reported in case reports and case series • Incidence not known • Ranged from 2-90 years old • More common in women, even when those with preclampsia excluded

35. Associated factors • Cyclosporine/FK-506 neurotoxicity in 46% • Isolated infection, sepsis or shock in 24% • Autoimmune disease in 10% • Eclampsia in 10% • Post-chemotherapy in 4% • Am J Neuroradiol 2006 Nov-Dec; 27(10): 2179

37. Mechanisms • Autoregulation failure • Cerebral ischaemia • Endothelial dysfunction • Other possible mechanisms

38. Autoregulation failure • Normal autoregulation maintains constant cerebral blood flow over a range of systemic pressure

39. Autoregulation failure • Arterioles dilate and cerebral blood flow increases with rise in SBP when upper limit of cerebral autoregulation is exceeded • Brain hyperperfusion in elevated blood pressure lead to breakdown of BBB allowing extravasation of fluid and blood products into brain parenchyma

40. Autoregulation failure • Rate of blood pressure elevation is important • Adapative vascular changes ‘reset’ autoregulation to higher SBP in chronic hypertension

41. Cerebral ischaemia • Disordered autoregulation lead to vasoconstriction leading to hypoperfusion and cerebral infarction • Infarctions can also result from compression of microcirculation from mass effect of vasogenic edema • Not believed to play the major pathophysiological role

42. Endothelial dysfunction • Cytotoxic drugs may have direct toxicity on endothelium • Capillary leakage, BBB disruption and axonal swelling result in vaosgenic edema • PRES can occur in normal BP and non-toxic levels of cytotoxic drugs

43. Endothelial dysfunction • Makers of endothelial dysfunction (LDH, abnormal RBC morphology) arise before clinical syndrome of preelampsia and correlates with extent of cerebral edema • More specific markers are found to be released (fibronectin, tissue plasminogen activator, thrombomodulin, endothelin-1 and vWF) • Also found in chronic renal failure, lupus nephritis, haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura

44. Other possible mechanisms • Fluid overload • Autonomic dysfunction • Vasogenic control affected by sepsis, uraemia and electrolyte disturbances

45. Anatomic distribution • White matter in posterior circulation more commonly involved • Cerebral cortex resists accumulation of vasogenic edema as it is structurally more packed than white matter • Regional heterogenicity of sympathetic innervation of intracranial arterioles • More adrenergic nerves around vessels in anterior circulation

46. Hypertensive encephalopathy • Results from acute elevation of blood pressure beyond autoregulation limits • Percent elevation of blood pressure over baseline are importmant • May occur in normotensive patients • More common in those with comorbidities such as SLE, cryoglobulinaemia, HUS or those with cyclosporine or cisplatin

47. Preelampsia • Similar mechanisms as hypertensive encephalopathy • Occurs during puerperium rather than pregnancy • Some suggest PRES as indicator of eclampsia • BP in those with preelampsia who develop PRES are generally lower

48. Systemic lupus erythematosus • Major preceding factors • Hypertension • Renal failure • High dose of immunosuppression • PRES may mimic • Neurological SLE flare • Infection related to immunosuppressive treatment like progressive multifocal leukoencephalopathy • Thrombotic event due to anti-phospholipid syndrome

49. Immunosuppression • May occur in therapeutic dose and after several months of exposure to drugs • Cyclosporine is a common association • Neurotoxicity (25-59%) is the second most serious side effects of cyclosporine • Cellular toxicity is mediated through mitochondrial dysfunction

50. Immunosuppression • Hypomagnesemia, hypocholesterolemia, vasoactive agent endothelin and hypertension facilitates cyclosporine neurotoxicity • Cyclosporine further exacerbate hypertension by inhibiting nitric oxide production • PRES also associated with tacrolimus, sirolimus, cisplastin, interferon and bevacizumab