1. Associate Professor Dr. Suat Biçer Yeditepe University Faculty of Medicine Department of Child Health and Pediatrics Subdivision of Pediatric Emergency

2. Definition  coma is a state of unresponsiveness without arousal caused by interruption of neuronal networks that regulate consciousness (2)2 Edlow JA, Rabinstein A, Traub SJ, Wijdicks EF. Diagnosis of reversible causes of coma. Lancet. 2014 Dec 6;384(9959):2064-76 Lancet. 2014 Dec 6;384(9959):2064-76

3.  arousal is based in ascending reticular activating system in the brainstem (2)2  neurons originate in dorsal pons and midbrain, connect in thalamus, and project to several areas in cortex  cortex processes, integrates, and contextualizes information to generate awareness Edlow JA, Rabinstein A, Traub SJ, Wijdicks EF. Diagnosis of reversible causes of coma. Lancet. 2014 Dec 6;384(9959):2064-76 Lancet. 2014 Dec 6;384(9959):2064-76

4. coma may be caused bycaused - structural brain lesions such as from trauma, mass effect, or stroke (either hemorrhagic or thrombotic) - diffuse neuronal dysfunction from various metabolic abnormalities  toxins or medications

5. history  history is often sparse and uncertain and must be obtained from indirect sources such as history is often sparse  bystanders  medical records  medication lists

6. goal of neurologic exam isneurologic exam  to identify lateralizing or focal findings  to recognize signs of brainstem dysfunction  to define the severity of the coma

7. Assesment: severity assessment can be done with a Glaskow Coma scale, which includes evaluation ofscale  Eye opening  Verbal responses  Motor responses

8. initial testinginitial testing should include  serum chemistries  complete blood count (CBC) including platelets  coagulation factors  thyroid function tests  serum ammonia  venous blood gas

9. brain imagingbrain imaging indicated immediately for patients with any of  unclear diagnoses  possible structural injury suggested by clinical assessment  preceding head trauma

10. acute managementacute management: initial stabilization includes  maintaining oxygenation > 96%  protecting airway (may need intubation)  establishing IV access  giving saline if hypotensive  giving glucose if hypoglycemic  routine use of a "coma cocktail" (thiamine, naloxone, glucose, flumazenil, and physostigmine) is not recommended  consider empiric treatment with IV antimicrobial therapy (after lumbar puncture if indicated) if sepsis suspected

11. chronic management chronic management considerations  enteral nutrition (EN) support preferable to parenteral nutrition support when feasible  tracheotomy should be considered after initial stabilization on ventilator when it becomes apparent patient will require prolonged mechanical ventilation  strategies to prevent pressure ulcers include repositioning, nutritional support, and special mattresses

12. patients may recover from coma or progress to(3)3  minimally conscious state (may progress through confusional state to increasing independence)  permanent unresponsive wakefulness syndrome (> 3 months if nontraumatic, > 1 year if traumatic)  locked-in syndrome  brain death 3. Monti MM, Laureys S, Owen AM. The vegetative state. BMJ. 2010 Aug 2;341:c3765 BMJ. 2010 Aug 2;341:c3765

13. Reversible causes of coma  trauma  structural brain lesions  diffuse neuronal dysfunction  toxins  medications

14. structural brain lesions  brain mass  anoxic-hypoxic brain disease with return of spontaneous circulation after cardiac arrest  stroke stroke  intracerebral hemorrhage intracerebral hemorrhage  status epilepticus status epilepticus  sepsis sepsis  hydrocephalus hydrocephalus  subdural hematoma subdural hematoma  cerebral venous thrombosis (CTV) cerebral venous thrombosis (CTV)

15. diffuse neuronal dysfunction  ketotic hypoglycemia ketotic hypoglycemia  hyperosmolar hyperglycemic state hyperosmolar hyperglycemic state  severe hypothyroidism (myxedema coma)hypothyroidismmyxedema coma  hyponatremia hyponatremia  hypercalcemia hypercalcemia  chronic kidney disease chronic kidney disease  hepatic encephalopathy hepatic encephalopathy  hyperthyroidism and thyrotoxicosis hyperthyroidism and thyrotoxicosis

16. toxins  alcohol intoxication  cyanide poisoning cyanide poisoning  carbon monoxide poisoning carbon monoxide poisoning

17. medications  sedative-hypnotics  opioids opioids  methemoglobinemia  antipsychotics antipsychotics  clonidine clonidine  isoniazid  salicylates salicylates  neuroleptics neuroleptics  serotonin serotonin Tricyclic antidepressants Opioids Hypoglycemics

18. Pathophysiology of coma  arousal based in ascending reticular activating system in brainstem  neurons originate in dorsal pons and midbrain, connect in thalamus, and project to several areas in cortex  cortex processes, integrates, and contextualizes information to generate awareness  injury to any of these areas or their connections can result in - impaired consciousness - increasing intracranial mass effect  smaller masses initially compensated for by translocation of cerebral spinal fluid or blood

19. effect on consciousness depends on  rate of progression of mass (for example, slowly growing posterior fossa tumor may not alter mental status, whereas acute hemorrhage of similar size may cause coma)  increased intracranial mass causes structures from one intracranial compartment to shift into another across different lines of force  lateral tissue displacement more closely related to level of consciousness than downward shift

20. History  history is often sparse and uncertain  if possible, obtain available information from:  bystanders, friends or family, prehospital personnel, or police officers  previous medical records  medical alert bracelets or cards  medication lists  patients' belongings

21. ask about onset  if acute, consider stroke, seizure, or poisoning  if gradual, consider expanding mass or inflammation

22. other factors include:  medication history (including anticoagulants)  psychiatric history  vascular risk factors  history of trauma

23. potential causes based on patient history if preceded by severe headache, consider  aneurysmal subarachnoid hemorrhage  parenchymal intracranial hemorrhage  cerebral venous sinus thrombosis  idiopathic intracranial hypotension

24. if history of seizures, consider  convulsive or nonconvulsive status epilepticus  toxin exposure  carbon monoxide poisoning  cyanide poisoning  hypoglycemic agents  organophosphates

25. medication effect/overdose  bupropion  gamma-hydroxybutyrate  baclofen  tricyclic antidepressants  carbamazepine  propoxyphene

26. if history of bleeding disorder, consider  intracerebral hemorrhage or subdural hematoma if history of hypercoagulable state, consider  cerebral venous sinus thrombosis

27. main objectives of neurologic exam:  identify lateralizing or focal findings  recognize signs of brainstem dysfunction  define severity Physical

28. severity assessment includes evaluation of  level of consciousness  brainstem assessment  motor examination  breathing patterns

29. Physical findings suggestive of underlying cause of coma  hyperpyrexia / fever  hypothermia  respiratory abnormalities  cardiovascular findings  specific breath odor  specific skin findings  specific neurological abnormalities  other physical findings

30. Patients with hyperpyrexia / fever  sepsis  focal infections (including central nervous system [CNS] infections)  phencyclidine or ketamine intoxication  neuroleptic malignant syndrome  serotonin syndrome  massive pontine hemorrhage  subarachnoid hemorrhage  heat stroke  hypothalamic injury  salicylates  cholinergic agents  methylenedioxymethamphetamine (MDMA)

31. Patients with hypothermia  hypothermia may be due to:  hypoglycemia  alcohol and sedative/hypnotic or opioid intoxication  sepsis  myxoedema  adrenal crisis

32. Patients with respiratory abnormalities if tachypneic, consider:  early sepsis or metabolic acidosis of any cause  diencephalic damage  salicylate intoxication if slow respiratory rate, consider  sedative-hypnotic or opioid overdose  organophosphate compounds  terminal event with medullary involvement

33. Patients with cardiovascular findings Tachycardic  antidepressants, antipsychotic or ketamine intoxication  adrenergic hyperactivity from acute structural brain injury Bradycardic  beta blockers with membrane-stabilizing activity  clonidine  organophosphate  sedative-hypnotic agents  gamma-hydroxybutyrate  opioids  raised intracerebral pressure (including hydrocephalus)

34. HypotensiveHypertensive  sepsis  tricyclic antidepressants  sedative-hypnotic agents  cyanide  phenothiazines  clonidine  hypertensive encephalopathy  posterior reversible encephalopathy syndrome  eclampsia  intoxication with phencyclidine, ketamine, clonidine (early)  nonspecific response to acute CNS disease (combination of hypertension and bradycardia can indicate raised intracranial pressure)  elevated systolic blood pressure associated with increased risk for brain condition as cause of impaired consciousness

35. Patients with specific breath odor potential causes based on specific breath odor dirty lavatory - consider uremia(2)2 fruity - consider ketoacidosis(2)2 musty or fishy - consider hepatic encephalopathy(2)2 garlic - consider organophosphates(2)2 bitter almond - consider cyanide poisoning

36. Patients with specific skin findings  bullae are nonspecific, but classically associated with barbiturates  if cool skin with yellow tinge and puffy face, consider myxedema  if dark pigmentation, consider adrenal crisis  if dry skin, consider anticholinergic agents such as tricyclic antidepressants or antipsychotics  if needle track marks, consider opioid overdose  if jaundice, caput medusa, palmar erythema, or spider angiomata, consider hepatic encephalopathy

37. if purpura or petechiae, considerif sweating, consider  thrombotic thrombocytopenic purpura (TTP) thrombotic thrombocytopenic purpura (TTP)  vasculitis  disseminated intravascular coagulopathy  sepsis with meningococcal, streptococcal, or staphylococcal species or rickettsia  organophosphates  hypoglycemia  thyroid storm  sympathetic hyperactivity  neuroleptic malignant syndrome  serotonin syndrome Patients with specific skin findings

38. Patients with specific neurological abnormalities  ocular findings  neurologic findings

39. potential causes based on ocular findings  if miosis, consider opioid or organophosphate intoxication, or clonidine  if mydriasis, consider tricyclic antidepressant intoxication  if horizontal nystagmus, consider ethanol, antiepileptic drugs, or dissociative agents  if vertical nystagmus, consider brainstem lesions or dissociative agents

40. neurologic findings that may help identify site of structural brain disease: signs of supratentorial (bilateral hemispheric) lesions  spontaneous eye movements (roving, dipping, ping-pong, nystagmoid jerks)  upward or downward eye deviation  oculovestibular reflexes intact  pupillary and corneal reflexes intact  variable motor responses  adventitious limb movements (subtle manifestations of seizures, myoclonus, asterixis)

41. signs of intrinsic brainstem disease:  vertical nystagmus or bobbing  miosis (with pontine lesions)  internuclear ophthalmoplegia  variable pupillary and corneal reflexes (can both be absent)  absent oculocephalic and oculovestibular responses  extensor or flexor posturing  ataxic breathing (pontomedullary damage)

42. signs of brainstem displacement from hemispheric mass  anisocoria or unilateral fixed and dilated pupil (predominant lateral displacement)  midposition fixed pupils (predominant downward displacement)  extensor or flexor posturing  central hyperventilation (diencephalic)

43. signs of brainstem displacement from cerebellar mass  direction-changing or vertical nystagmus from cerebellar lesion  ocular bobbing  absent corneal reflexes with intact pupillary reflexes  extensor or flexor posturing  facial or abducens nerve palsy  vertical misalignment of eyes  internuclear ophthalmoplegia

44. Patients with other physical findings other physical exam findings that may indicate a specific cause  if tongue laceration, consider seizure  if goiter, consider myxoedema coma  if meningismus, consider meningitis or subarachnoid hemorrhage  if ascites, jaundice, or caput medusa are present, consider hepatic failure  if peripheral edema, consider renal and hepatic failure or myxedema  if increased secretions, consider organophosphate or ketamine intoxication  if decreased bowel sound, consider opioid medications  if increased bowel sounds, consider organophosphates

45. Glasgow Coma Scale: best possible score 15 points eye opening best motor response  spontaneously - 4 points  to verbal commands – 3 p.  to pain - 2 points  none - 1 point  follows verbal command - 6 points  localizes painful stimuli - 5 points  normal flexion to painful stimuli - 4 points  abnormal flexion to painful stimuli - 3 points  decerebrate posturing to painful stimuli - 2 points  none - 1 point best verbal response oriented conversation - 5 points disoriented conversation - 4 points inappropriate words - 3 points incomprehensible words - 3 points incomprehensible sounds - 2 points none - 1 point

46. Laboratory and Electrocardiography (ECG) Findings İnitial tests:other tests:  serum glucose  complete blood count (CBC) including platelets  coagulation factors  electrolytes  renal function  liver function  thyroid function  serum ammonia  venous blood gas  co-oximetry if carbon monoxide poisoning or methemoglobinemia is suspected  blood culture if infection is suspected  specific toxins as suggested by clinical presentation

47. if hypoglycemic, considerif hyperglycemic, consider  insulin  sulfonylureas  diabetic ketoacidosis  nonketotic hyperosmolar coma

48. if hyponatremic, considerif hypernatremic, consider  methylenedioxymethamph etamine (MDMA)  carbamazepine  syndrome of inappropriate antidiuretic hormone secretion (SIADH) syndrome of inappropriate antidiuretic hormone secretion (SIADH)  inadequate free water intake in patients with hypovolemia  other states of disordered sodium homoeostasis

49. if hyperammonemic, consider  liver failure  valproic acid  urea cycle disorder

50. Blood gas findings if metabolic acidosis if respiratory acidosis, consider  methanol, ethylene glycol, paraldehyde, isoniazid, or salicylate poisoning  lactic acidosis of any cause (including cyanide and hydrogen sulfide poisoning )  ketoacidosis  central nervous system (CNS) depressant (opioid, benzodiazepine, barbiturate)  hypercarbic respiratory failure

51. if respiratory alkalosis, consider if anion gap metabolic acidosis, consider  central hyperventilation  salicylates  cyanide  hydrogen sulfide  toxic alcohols  salicylates  lactic acidosis of any cause

52. ECG findings if prolonged QTc interval, consider if prolonged QRS interval, consider  tricyclic antidepressant or antipsychotic intoxication  various forms of acute structural brain injury  tricyclic antidepressants  phenothiazines  carbamazepine  propoxyphene  various forms of acute structural brain injury

53. Brain Imaging brain imaging indicated immediately for patients with  unclear diagnoses  possible structural injury suggested by clinical assessment  preceding head trauma computed tomography (CT)computed tomography (CT) scan is usual imaging choice due to widespread availability and speed, magnetic resonance imaging (MRI)magnetic resonance imaging (MRI) preferred for diagnosis of treatable cerebrovascular causes of coma

54. brain CT not routinely indicated for patients with likely diagnosis associated with diffuse neuronal dysfunction, such as  hypoglycemic patients who respond to dextrose  patients with diabetic ketoacidosis  patients admitted from nursing homes with fever and infected urine

55. evaluate CT for  midline brain tissue shift  hydrocephalus  intracranial hemorrhage (including bilateral isodense hematomas)  obliteration of basal cisterns  thalamic abnormalities  hyperdense basilar artery  diffuse brain edema without mass lesion (consider insertion of device to monitor intracranial pressure)

56. if CT positive, consult neurologist or neurosurgeon to  distinguish true positive results from false ones  decide on next diagnostic and therapeutic steps  low incidence of pathologic findings on brain CT in patients clinically diagnosed with metabolic cause of coma

57. if CT negative or with unrelated findings, consider  magnetic resonance imaging (MRI) or vascular imaging (such as CT angiography)  can exclude cerebrovascular causes including basilar occlusion  MRI is imaging of choice for pituitary apoplexy

58. MRI may detect some treatable cerebrovascular causes of coma that can be missed on computed tomography (CT) scan, including  basilar artery occlusion  posterior reversible encephalopathy syndrome with or without reversible cerebral vasoconstriction syndrome  early thalamic and brainstem ischaemic stroke  cerebral venous sinus thrombosis  MRI generally identifies edema as bright signal on FLAIR and T2- weighted sequences  MRI may also give false-negative result within first 48 hours of brainstem strokes

59. functional MRI  functional MRI may demonstrate signs of consciousness, but negative studies do not necessarily reflect proof of absence of unconsciousness

60. emergency electroencephalogram (EEG)  may be used to exclude nonconvulsive status epilepticus (prolonged seizure activity with absence of major motor signs) in patients who remain comatose after several generalized seizuresstatus epilepticus  especially important in patients intubated for convulsive status epilepticus, since electrical seizures can persist even if outward manifestations obscured by paralytic or sedative drugs

61. brain death diagnostic features include  irreversible and unresponsive coma  absence of brainstem reflexes  apnea

62. Acute management initial stabilization includes  maintaining oxygenation > 96%  protecting airway (may need intubation)  establishing IV access  giving saline if hypotensive  giving glucose if hypoglycemic  routine administration of "coma cocktail" (thiamine, naloxone, glucose, flumazenil, physostigmine) not recommended(2)thiaminenaloxoneflumazenilphysostigmine2  hypoglycemia should be identified and treated

63.  naloxone can precipitate withdrawal symptoms in opioid-habituated patients with coma due to different cause  flumazenil can precipitate benzodiazepine withdrawal which may be life-threatening  supportive care is superior to routine use of possible antidotes for coma caused by toxins

64. empiric treatment considerations may include  IV antimicrobial therapy (after lumbar puncture if indicated)  consider meningitis, encephalitis, and brain abscess as causes of coma  contraindications to lumbar puncture

65. contraindications to lumbar puncture  brain abscess  coagulopathy  severe hemodynamic or respiratory instability

66. Empirical antibiotherapy  patients with sepsis may present with encephalopathy without hypotension, hypoxia, or central nervous system infection (due to increased vascular permeability and neuroinflammation)  performing computed tomography (CT) scan prior to lumbar puncture recommended, but therapy for suspected infections should not be delayed

67.  treatment for poisoning

68. Prognosis patients may recover from coma or progress to  minimally conscious state (may progress through confusional state to increasing independence)  permanent unresponsive wakefulness syndrome (> 3 months if nontraumatic, > 1 year if traumatic)  locked-in syndrome  brain death  extent and speed of improvement varies widely and depends on cause of coma (for example, patients may improve rapidly after treatment for hypoglycemic coma, but may have slow and limited recovery after severe structural brain injury)

69. prediction of mortality  abnormal tympanometry may predict increased mortality risk in children with nontraumatic coma

70. based on cohort study 72 children aged 6 months to 13 years presenting with acute nontraumatic coma had right ear tympanometry causes of coma included  cerebral malaria (53%)  acute bacterial meningitis (11%)  sepsis (6%)  encephalopathy of unknown etiology (30%)  47 children (65%) had abnormal tympanometry  20 children (28%) died  abnormal tympanometry associated with increased risk of death (adjusted odds ratio 17, 95% CI 1.9-152.4)  Reference - Pediatrics 2013 Sep;132(3):e713Pediatrics 2013 Sep;132(3):e713